FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lee, EM Hong, SH Lee, YJ Kang, YH Choi, KC Choi, SH Kim, IH Lim, SJ AF Lee, EM Hong, SH Lee, YJ Kang, YH Choi, KC Choi, SH Kim, IH Lim, SJ TI Liposome-complexed adenoviral gene transfer in cancer cells expressing various levels of coxsackievirus and adenovirus receptor SO JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY LA English DT Article DE adenovirus; gene therapy; liposome; polyethylene glycol; uptake; coxsackievirus and adenovirus receptor ID INTRACELLULAR DELIVERY; TRANSGENE EXPRESSION; POLYETHYLENE-GLYCOL; IN-VITRO; EFFICIENCY; VECTORS; PLASMID; ENHANCE; LIPOFECTION; THERAPY AB Purpose. Loss of coxsackievirus and adenovirus receptor (CAR) is frequently observed in malignant cancer, hampering adenoviral gene therapy approaches. Complexing adenovirus with cationic liposomes can increase adenoviral transgene expression, particularly in cells with CAR-deficiency. We investigated whether other factors such as lipid composition might be involved in determining the efficiency of liposome-complexed adenoviral gene transfer in cancer cells. Material and methods. Human cancer cell lines with different expression levels of CAR were infected with a GFP transgene. The efficiency of transgene expression was assessed by determining GFP expression using FACS analysis. Results. The efficiency of liposome-complexed adenoviral gene transfer was dependent on the lipid composition constituting liposomes. Polyethylene glycol (PEG)-containing liposomes were most effective in increasing liposome-complexed adenoviral gene transfer. In CAR-deficient cells, use of PEG-containing liposomes enhanced adenoviral gene transfer, whereas in CAR-expressing cells enhancement varied depending on cell type. In some CAR-expressing cells, the effect of liposome complexing was even comparable to that in CAR-deficient cells. Increased adenoviral transgene expression following complexing with PEG-containing liposomes correlated with liposome uptake in cancer cells. Conclusions. Liposome-complexed adenoviral gene transfer appears to depend on lipid composition and the level of liposome uptake by cancer cells, in addition to CAR levels. Our study suggest that these multiple factors should be considered in designing liposome-complexed adenoviral vectors to improve outcomes of current adenoviral cancer gene therapies. C1 Natl Canc Ctr, Res Inst, Goyang, Gyeonggi, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Lim, SJ (reprint author), Natl Canc Ctr, Res Inst, 809 Madu Dong, Goyang, Gyeonggi, South Korea. EM sjlim@ncc.re.kr NR 29 TC 18 Z9 21 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0171-5216 J9 J CANCER RES CLIN JI J. Cancer Res. Clin. Oncol. PD MAR PY 2004 VL 130 IS 3 BP 169 EP 177 DI 10.1007/s00432-003-0521-z PG 9 WC Oncology SC Oncology GA 779FR UT WOS:000189285100004 PM 14677059 ER PT J AU Alsheimer, M Liebe, B Sewell, L Stewart, CL Scherthan, H Benavente, R AF Alsheimer, M Liebe, B Sewell, L Stewart, CL Scherthan, H Benavente, R TI Disruption of spermatogenesis in mice lacking A-type lamins SO JOURNAL OF CELL SCIENCE LA English DT Article DE spermatogenesis; meiosis; nuclear lamins; LMNA ID FAMILIAL PARTIAL LIPODYSTROPHY; NUCLEAR-ENVELOPE PROTEINS; MUSCULAR-DYSTROPHY; HUMAN-DISEASE; A/C GENE; MUTATIONS; MOUSE; ARCHITECTURE; EXPRESSION; REDISTRIBUTION AB Nuclear lamins are structural protein components of the nuclear envelope. Mutations in LMNA, the gene coding for A-type lamins, result in several human hereditary diseases, the laminopathies, which include Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy and Hutchinson-Gilford progeria. Similar to the human conditions, it has been shown that Lmna(-/-) mice develop severe dystrophies of muscle and fat tissues. Here we report that Lmna(-/-) mice display impaired spermatogenesis, with a significant accumulation of spermatocytes I during early prophase I stages, while pachytene spermatocytes are severely defective in synaptic pairing of the sex chromosomes in particular, leading to massive apoptosis during the pachytene stage of meiosis I. In contrast, oogenesis remains largely unaffected in Lmna(-/-) mice. These results reveal A-type lamins as important determinants of male fertility. C1 Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. RP Benavente, R (reprint author), Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, Hubland, D-97074 Wurzburg, Germany. EM schertha@molgen.mpg.de; benavente@biozentrum.uni-wuerzburg.de NR 33 TC 37 Z9 39 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 MAR 1 PY 2004 VL 117 IS 7 BP 1173 EP 1178 DI 10.1242/jcs.00975 PG 6 WC Cell Biology SC Cell Biology GA 811HL UT WOS:000220762900020 PM 14996939 ER PT J AU Mohla, S AF Mohla, S TI Under-investigated area in prostate cancer: Cross talk between the bone microenvironment and prostate cancer bone metastasis SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article C1 NCI, Div Canc Biol, Tumor Biol & Metastasis Branch, NIH, Bethesda, MD 20892 USA. RP Mohla, S (reprint author), NCI, Div Canc Biol, Tumor Biol & Metastasis Branch, NIH, Bethesda, MD 20892 USA. EM mohlas@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAR 1 PY 2004 VL 91 IS 4 BP 684 EP 685 DI 10.1002/jcb.20055 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800LA UT WOS:000220028600005 PM 15952250 ER PT J AU Sagui, C Pomorski, P Darden, TA Roland, C AF Sagui, C Pomorski, P Darden, TA Roland, C TI Ab initio calculation of electrostatic multipoles with Wannier functions for large-scale biomolecular simulations SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; PARTICLE-MESH EWALD; INTERMOLECULAR INTERACTION ENERGIES; PARTITIONED ELECTRIC PROPERTIES; FORCE-FIELDS; CHARGE-DISTRIBUTION; LIQUID WATER; MECHANICS; POLARIZATION; POTENTIALS AB It has long been known that accurate electrostatics is a key issue for improving current force fields for large-scale biomolecular simulations. Typically, this calls for an improved and more accurate description of the molecular electrostatic potential, which eliminates the artifacts associated with current point charge-based descriptions. In turn, this involves the partitioning of the extended molecular charge distribution, so that charges and multipole moments can be assigned to different atoms. As an alternate to current approaches, we have investigated a charge partitioning scheme that is based on the maximally localized Wannier functions. This has the advantage of partitioning the charge, and placing it around the molecule in a chemically meaningful manner. Moreover, higher order multipoles may all be calculated without any undue numerical difficulties. Tests on isolated molecules and water dimers, show that the molecular electrostatic potentials generated by such a Wannier-function based approach are in excellent agreement with the density functional-based calculations. (C) 2004 American Institute of Physics. C1 N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Sagui, C (reprint author), N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. EM sagui@unity.ncsu.edu NR 60 TC 23 Z9 23 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 1 PY 2004 VL 120 IS 9 BP 4530 EP 4544 DI 10.1063/1.1644800 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 777XM UT WOS:000189209200051 PM 15268621 ER PT J AU Richards, MH Larson, R Miller, BV Luo, ZP Sims, B Parrella, DP McCauley, C AF Richards, MH Larson, R Miller, BV Luo, ZP Sims, B Parrella, DP McCauley, C TI Risky and protective contexts and exposure to violence in urban African American young adolescents SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID INNER-CITY YOUTH; COMMUNITY VIOLENCE; ANTISOCIAL-BEHAVIOR; LATE CHILDHOOD; TIME USE; CHILDREN; FAMILY; IMPACT; COMPANIONSHIP; NEIGHBORHOODS AB Contexts of risk for and protection from exposure to violence were identified and the relation of exposure to violence to delinquent behaviors and symptoms of trauma was examined. Using the Experience Sampling Method (ESM), the immediate daily experience of risky and protective contexts was examined. One hundred sixty-seven African American 6th-, 7th-, and 8th-grade children from urban neighborhoods carried watches and booklets for 1 week. Structural equation modeling supported the hypotheses that more time in risky contexts and less time in protective contexts was related to more exposure to violence. Exposure to violence partially mediated the relation of time in protective and risky contexts to delinquent behaviors, assessed with the Juvenile Delinquency Scale and the Child Behavior Checklist, and distress levels, assessed by a posttraumatic stress disorder (PTSD) score. C1 Loyola Univ, Dept Psychol, Chicago, IL 60626 USA. Univ Illinois, Dept Human & Community Dev, Urbana, IL 61801 USA. Univ Georgia, Ctr Family Res, Athens, GA 30602 USA. NIMH, Bethesda, MD 20892 USA. RP Richards, MH (reprint author), Loyola Univ, Dept Psychol, 6525 N Sheridan Rd, Chicago, IL 60626 USA. EM mrichar@luc.edu FU NIMH NIH HHS [R01 MH53486] NR 54 TC 35 Z9 35 U1 3 U2 6 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 1537-4416 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD MAR PY 2004 VL 33 IS 1 BP 138 EP 148 DI 10.1207/S15374424JCCP3301_13 PG 11 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 773EH UT WOS:000188884400013 PM 15028548 ER PT J AU Kashdan, TB Jacob, RG Pelham, WE Lang, AR Hoza, B Blumenthal, JD Gnagy, EM AF Kashdan, TB Jacob, RG Pelham, WE Lang, AR Hoza, B Blumenthal, JD Gnagy, EM TI Depression and anxiety in parents of children with ADHD and varying levels of oppositional defiant behaviors: Modeling relationships with family functioning SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SOCIAL-ADJUSTMENT; MATERNAL PSYCHOPATHOLOGY; INDIVIDUAL-DIFFERENCES; ALCOHOL-CONSUMPTION; EXPRESSED EMOTION; MOTHERS; METHYLPHENIDATE; BOYS AB This study investigated the relation between parental anxiety and family functioning. Parental anxiety and depression, child attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) symptoms were all included as predictors of 3 measures of family functioning to examine the independent contributions of each. Using a self-report battery completed by 45 mother-father pairs, 3 family functioning factors were derived: Parental Warmth and Positive Involvement, Intrusiveness and Negative Discipline, and Social Distress. Multilevel modeling simultaneously estimated the unique contributions of parental and child symptoms on family functioning. Results indicated that parental anxiety was negatively associated with Parental Warmth and Positive Involvement, Intrusiveness and Negative Discipline, and Social Distress; Parental depression was only negatively associated with Social Distress. Child ODD symptoms had independent associations with all outcomes; no relations were found with ADHD. Sex moderated the effects of parental anxiety on Parental Warmth and Positive Involvement such that only for mothers did greater anxiety lead to less Parental Warmth and Positive Involvement. C1 SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. Univ Pittsburgh, Sch Med, Dept Psychol & Otolaryngol, Pittsburgh, PA 15260 USA. Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. Purdue Univ, Dept Psychol, W Lafayette, IN 47907 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Jacob, RG (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM kashdan@buffalo.edu; jacobr@msx.upmc.edu FU NIAAA NIH HHS [AA06267, AA11873]; NIDA NIH HHS [DA05605]; NIMH NIH HHS [F31 MH 63565, MH 45576, MH 47390, MH 48157, MH 50467, MH 53554] NR 72 TC 44 Z9 46 U1 3 U2 12 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 1537-4416 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD MAR PY 2004 VL 33 IS 1 BP 169 EP 181 DI 10.1207/S15374424JCCP3301_16 PG 13 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 773EH UT WOS:000188884400016 PM 15028551 ER PT J AU Mantzoros, C Petridou, E Dessypris, N Chavelas, C Dalamaga, M Alexe, DM Papadiamantis, Y Markopoulos, C Spanos, E Chrousos, G Trichopoulos, D AF Mantzoros, C Petridou, E Dessypris, N Chavelas, C Dalamaga, M Alexe, DM Papadiamantis, Y Markopoulos, C Spanos, E Chrousos, G Trichopoulos, D TI Adiponectin and breast cancer risk SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-FACTOR-I; BODY-MASS INDEX; INSULIN-RESISTANCE; ENDOMETRIAL CANCER; PROSPECTIVE COHORT; FASTING INSULIN; IGF SYSTEM; PPAR-GAMMA; OBESITY; PLASMA AB Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance and was recently found to be inversely and independently associated with endometrial cancer. Because insulin resistance in the setting of obesity has also been associated with the development of breast cancer, we have hypothesized that decreased adiponectin levels might underlie the association between breast cancer and obesity/insulin resistance. We evaluated the association of adiponectin with the occurrence of breast cancer in a case-control study comprising 174 women with newly diagnosed, histologically confirmed breast cancer and 167 controls. We found an inverse, fairly strong, and statistically significant association of serum adiponectin with breast cancer ( odds ratio, 0.84; 95% confidence interval, 0.71 - 0.99). Importantly, despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women ( odds ratio, 0.82; 95% confidence interval, 0.67 - 1.00), no such significant association between adiponectin and breast cancer was found among premenopausal women. The observed associations were independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known risk factors for breast cancer. Future studies are needed to prove causality and provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in breast cancer. C1 Univ Athens, Sch Med, Dept Hyg & Epidemiol, GR-11527 Athens, Greece. Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Endocrinol & Metab, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Elena Venizelou Hosp, Athens 11521, Greece. Univ Athens, Sch Med, Dept Propedeut Surg 2, Breast Unit, GR-11527 Athens, Greece. BIOMED, Int Diagnost Ctr, Athens 11528, Greece. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1, GR-11527 Athens, Greece. RP Petridou, E (reprint author), Univ Athens, Sch Med, Dept Hyg & Epidemiol, 75 Mikras Asias, GR-11527 Athens, Greece. EM epetrid@med.uoa.gr OI Markopoulos, Christos/0000-0002-5072-6390; Dalamaga, Maria/0000-0002-7008-388X NR 41 TC 329 Z9 352 U1 0 U2 13 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 MAR PY 2004 VL 89 IS 3 BP 1102 EP 1107 DI 10.1210/jc.2003-031804 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800LV UT WOS:000220030700013 PM 15001594 ER PT J AU Parikh, SJ Edelman, M Uwaifo, GI Freedman, RJ Semega-Janneh, M Reynolds, J Yanovski, JA AF Parikh, SJ Edelman, M Uwaifo, GI Freedman, RJ Semega-Janneh, M Reynolds, J Yanovski, JA TI The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DIETARY CALCIUM; PERFORMANCE; ADIPOSITY; ASSAY AB Several previous reports of small cohorts have found significantly higher serum 1,25-dihydroxy vitamin D (1,25-vit D) in obese compared with nonobese whites. Based on these reports and on recent in vitro studies of adipocytes which suggest that administration of 1,25-vit D can stimulate lipogenesis and inhibit lipolysis, some investigators have proposed that high 1,25-vit D may play a role in promoting or maintaining adipocyte triglyceride stores in obese adults. To test the hypothesis that obesity is commonly associated with increased 1,25-vit D, we examined the relationships between calciotropic hormones and body adiposity in a large cohort of healthy adults. Serum intact PTH, 25-hydroxy vitamin D, and 1,25-vit D were measured in the postabsorptive state in 302 healthy adults who were Caucasian (n = 190; 71% female), African-American (n = 84; 89% female), and of other race/ethnicity ( n = 28; 61% female). Results from the 154 obese subjects [ body mass index (BMI) 37.3 +/- 5.8 kg/m(2); range, 30.1 - 58.2 kg/m(2)] were compared with those from 148 nonobese (BMI 25.6 +/- 2.9 kg/m(2); range, 18.0 - 29.9 kg/m(2)) age-, race-, and sex-matched participants. Body composition was measured by dual energy x-ray absorptiometry. Serum intact PTH was positively correlated with both BMI (r = 0.42; P< 0.0001) and body fat mass ( r = 0.37; P < 0.0001). Serum 25-hydroxy vitamin D was negatively correlated with BMI (r = - 0.4; P < 0.0001) and body fat mass (r = -0.41; P < 0.0001). Serum 1,25-vit D was also negatively correlated with BMI (r = -0.26; P < 0.0001) and body fat mass (r = -0.25; P = 0.0001). Serum 1,25-vit D was significantly lower in obese than nonobese subjects (105.7 +/- 41.1 vs. 124.8 +/- 36.7 pmol/liter; P < 0.0001) in both Caucasian and African-American adults. We conclude that, because 1,25-vit D concentrations fall with increasing adiposity, it appears unlikely that elevation in 1,25-vit D is an important hormonal mechanism causing or maintaining obesity in adults. C1 GlaxoSmithKline, King Of Prussia, PA 19406 USA. NICHHD, Unit Growth & Obes, NIH, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC 20003 USA. NIH, Dept Nucl Med, Ctr Clin, US Dept HHS, Bethesda, MD 20892 USA. RP Parikh, SJ (reprint author), GlaxoSmithKline, 2301 Renaissance Blvd,RN0410, King Of Prussia, PA 19406 USA. EM shamik.j.parikh@gsk.com RI Uwaifo, Gabriel/M-2361-2016; OI Uwaifo, Gabriel/0000-0002-6962-9304; Yanovski, Jack/0000-0001-8542-1637 FU NICHD NIH HHS [Z01 HD-00641]; NIH HHS [Y2-OD-2067] NR 22 TC 330 Z9 343 U1 1 U2 17 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 MAR PY 2004 VL 89 IS 3 BP 1196 EP 1199 DI 10.1210/jc.2003-031398 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800LV UT WOS:000220030700028 PM 15001609 ER PT J AU Ward, AMV Syddall, HE Wood, PJ Chrousos, GP Phillips, DIW AF Ward, AMV Syddall, HE Wood, PJ Chrousos, GP Phillips, DIW TI Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: Low birth weight and central HPA regulation SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; PLASMA-CORTISOL CONCENTRATIONS; CHRONIC-FATIGUE-SYNDROME; BLOOD-PRESSURE; DEXAMETHASONE; DEPRESSION; RAT; EXPRESSION; DISORDERS; PREGNANCY AB Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases. Previous studies have shown that small size at birth is associated with increased fasting plasma cortisol and adrenal responsiveness to ACTH stimulation. We have extended these studies by evaluating the salivary cortisol response to awakening and plasma ACTH and cortisol responses to CRH stimulation and a dexamethasone-suppressed CRH (DEX/CRH) test in a group of low birth weight [LBW; <3.18 kg (7 lb), n = 58] and high birth weight [>3.86 kg (8.5 lb), n = 65] men aged 60-69 yr. Despite no difference in basal pituitary-adrenal activity or in their ACTH and cortisol responses to CRH, LBW men had significantly lower pituitary-adrenal responses in the DEX/CRH test. Although these findings do not explain the HPA abnormalities associated with LBW in previous studies, they provide further evidence of dysregulation of the HPA axis in people who were small at birth. C1 Southampton Gen Hosp, MRC, Environm Epidemiol Unit, Southampton SO16 6YD, Hants, England. Southampton Gen Hosp, Reg Endocrine Lab, Southampton SO16 6YD, Hants, England. NICHHD, Pediat Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Phillips, DIW (reprint author), Southampton Gen Hosp, MRC, Environm Epidemiol Unit, Tremona Rd, Southampton SO16 6YD, Hants, England. FU NICHD NIH HHS [1 R01 HD41107-01] NR 29 TC 72 Z9 74 U1 1 U2 7 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 MAR PY 2004 VL 89 IS 3 BP 1227 EP 1233 DI 10.1210/jc.2003-030978 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800LV UT WOS:000220030700034 PM 15001615 ER PT J AU Wegienka, G Baird, DD Hertz-Picciotto, I Harlow, SD Hartmann, KE AF Wegienka, G Baird, DD Hertz-Picciotto, I Harlow, SD Hartmann, KE TI Uterine leiomyomata (fibroids): are bleeding symptoms more likely to be reported after diagnosis? SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article ID MENSTRUAL BLOOD-LOSS; PICTORIAL CHART; UNITED-STATES; HYSTERECTOMY C1 Henry Frod Hlth Syst, Dept Biostat & Res Epidemiol, Detroit, MI 48202 USA. NIEHS, Epidemiol Branch, Natl Inst Hlth, US Dept HHS, Res Triangle Pk, NC 27709 USA. Univ Calif Davis, Dept Epidemiol & Prevent Med, Davis, CA 95616 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. Univ N Carolina, N Carolina Program Womens Hlth Res, Chapel Hill, NC 27599 USA. RP Wegienka, G (reprint author), Henry Frod Hlth Syst, Dept Biostat & Res Epidemiol, 1 Ford Pl,3E, Detroit, MI 48202 USA. EM gwegien1@hfhs.org OI Baird, Donna/0000-0002-5544-2653 NR 11 TC 8 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD MAR PY 2004 VL 57 IS 3 BP 318 EP 320 DI 10.1016/j.jclinepi.2003.09.004 PG 3 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 814OH UT WOS:000220983500013 PM 15066693 ER PT J AU Hunger, RE Sieling, PA Ochoa, MT Sugaya, M Burdick, AE Rea, TH Brennan, PJ Belisle, JT Blauvelt, A Porcelli, SA Modlin, RL AF Hunger, RE Sieling, PA Ochoa, MT Sugaya, M Burdick, AE Rea, TH Brennan, PJ Belisle, JT Blauvelt, A Porcelli, SA Modlin, RL TI Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID C-TYPE LECTIN; DC-SIGN; MYCOBACTERIUM-TUBERCULOSIS; PROTEIN ANTIGENS; BIRBECK GRANULES; DENDRITIC CELLS; INTACT PROTEIN; LIPID ANTIGENS; LYMPHOCYTES-T; RECOGNITION AB Langerhans cells (LCs) constitute a subset of DCs that initiate immune responses in skin. Using leprosy as a model, we investigated whether expression of CD1a and langerin, an LC-specific C-type lectin, imparts a specific functional role to LCs. LC-like DCs and freshly isolated epidermal LCs presented nonpeptide antigens of Mycobacterium leprae to T cell clones derived from a leprosy patient in a CD1a-restricted and langerin-dependent manner. LC-like DCs were more efficient at CD1a-restricted antigen presentation than monocyte-derived DCs. LCs in leprosy lesions coexpress CD1a and langerin, placing LCs in position to efficiently present a subset of antigens to T cells as part of the host response to human infectious disease. C1 Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, Dept Med, Los Angeles, CA 90095 USA. NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Miami Univ, Dept Dermatol & Cutaneous Surg, Miami, FL USA. Univ So Calif, Keck Sch Med, Dermatol Sect, Los Angeles, CA USA. Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacterial Res Labs, Ft Collins, CO 80523 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Inst Mol Biol, Los Angeles, CA USA. RP Modlin, RL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, Dept Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM rmodlin@mednet.ucla.edu RI Belisle, John/B-8944-2017; OI Belisle, John/0000-0002-2539-2798; Modlin, Robert/0000-0003-4720-031X FU NIAID NIH HHS [AI22553, AI45889, AI48933, R01 AI022553, R01 AI045889, R01 AI048933]; NIAMS NIH HHS [AR40312, R01 AR040312] NR 45 TC 165 Z9 171 U1 0 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2004 VL 113 IS 5 BP 701 EP 708 DI 10.1172/JCI200419655 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 780KH UT WOS:000189379500012 PM 14991068 ER PT J AU Tang, XW Kim, AL Feith, DJ Pegg, AE Russo, J Zhang, H Aszterbaum, M Kopelovich, L Epstein, EH Bickers, DR Athar, M AF Tang, XW Kim, AL Feith, DJ Pegg, AE Russo, J Zhang, H Aszterbaum, M Kopelovich, L Epstein, EH Bickers, DR Athar, M TI Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch(1+/-) mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID XERODERMA-PIGMENTOSUM PATIENTS; HEDGEHOG SIGNALING PATHWAY; PHASE-I CHEMOPREVENTION; FOLLICULAR STEM-CELLS; TRANSGENIC MICE; ODONTOGENIC KERATOCYSTS; NUCLEAR ANTIGEN; ALPHA-DIFLUOROMETHYLORNITHINE; NEOPLASTIC GROWTH; GENE-MUTATIONS AB Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility we first overexpressed ODC in the skin of Ptch1(+/-) mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle. UVB irradiation of these mice accelerated induction of BCCs as compared with their Ptch1(+/-) litter-mates. To further verify the role of ODC in BCC tumorigenesis, we used an antizyme (AZ) approach to inhibit ODC activity in the Ptcb1(+/-) mice. Ptcb1(+/-) mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB. Furthermore, oral administration of the suicidal ODC inhibitor alpha-difluoromethylornithine reduced UVB-induced BCCs in Ptcb1(+/-) mice. These results demonstrate the crucial importance of ODC for the induction of BCCs and indicate that chemopreventive strategies directed at inhibiting this enzyme may be useful in reducing BCCs in human populations. C1 Columbia Univ Coll Phys & Surg, Dept Dermatol, New York, NY 10032 USA. Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Columbia Univ Coll Phys & Surg, Dept Dermatol, 630 W 168th St, New York, NY 10032 USA. EM ma493@columbia.edu FU NCI NIH HHS [U19 CA081888, U19 CA81888, N01 CN15109, R01 CA97249-01, R01 CA097249, R01 CA018138, CA-18138, R37 CA018138]; NIAMS NIH HHS [P30 AR44535, P30 AR044535] NR 66 TC 46 Z9 47 U1 0 U2 2 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 MAR PY 2004 VL 113 IS 6 BP 867 EP 875 DI 10.1172/JCI200420732 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 803ZO UT WOS:000220269200014 PM 15067319 ER PT J AU Fritz, CL Bronson, LR Smith, CR Schriefer, ME Tucker, JR Schwan, TG AF Fritz, CL Bronson, LR Smith, CR Schriefer, ME Tucker, JR Schwan, TG TI Isolation and characterization of Borrelia hermsii associated with two foci of tick-borne relapsing fever in California SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE GLPQ; LYME-DISEASE; SEROLOGICAL DISCRIMINATION; INTERSTATE OUTBREAK; UNITED-STATES; BURGDORFERI; ANTIBODY; PROTEINS AB Relapsing fever, caused by the spirochete Borrelia hermsii and transmitted by the soft tick Ornithodoros hermsi, is endemic in many rural mountainous areas of California. Between 1996 and 1998, 12 cases of relapsing fever associated with two exposure sites in northern California were investigated. Follow-up at exposure sites included collection of soft ticks and serum specimens from sylvatic rodents. Attempts to cultivate spirochetes were made through inoculation of patient blood into mice and by feeding Ornithodoros ticks on mice. Three isolates of B. hermsii were recovered from two blood specimens and one pool of ticks. The protein and plasmid profiles of the three isolates were comparable to those of previous B. hermsii isolates from the western United States. Western immunoblotting of patient sera demonstrated an expanding immunologic response to antigens within four distinct molecular weight regions by 3 to 4 weeks postonset. Antibody to B. hermsii was detected in sera from 4 of 11 yellow-pine chipmunks (Tamias amoenus); no other rodent species collected were seropositive. C1 Calif Dept Hlth Serv, Div Communicable Dis Control, Sacramento, CA 95899 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Vector Borne Infect Dis, Ft Collins, CO USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Fritz, CL (reprint author), Calif Dept Hlth Serv, Div Communicable Dis Control, MS 7307,POB 997413, Sacramento, CA 95899 USA. EM cfritz@dhs.ca.gov NR 24 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2004 VL 42 IS 3 BP 1123 EP 1128 DI 10.1128/JCM.42.3.1123-1128.2004 PG 6 WC Microbiology SC Microbiology GA 805OZ UT WOS:000220376900028 PM 15004063 ER PT J AU Cox, MC Figg, WD Thurman, PW AF Cox, MC Figg, WD Thurman, PW TI No rational theory for drug pricing SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, Canc Res Ctr, Med Oncol Res Unit, NIH, Bethesda, MD 20892 USA. Columbia Univ, Grad Sch Business, New York, NY 10027 USA. RP Cox, MC (reprint author), NCI, Canc Res Ctr, Med Oncol Res Unit, NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 5 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2004 VL 22 IS 5 BP 962 EP 963 DI 10.1200/JCO.2004.99.318 PG 2 WC Oncology SC Oncology GA 780KY UT WOS:000189380900031 PM 14990657 ER PT J AU Slattery, MJ Dubbert, BK Allen, AJ Leonard, HL Swedo, SE Gourley, ME AF Slattery, MJ Dubbert, BK Allen, AJ Leonard, HL Swedo, SE Gourley, ME TI Prevalence of obsessive-compulsive disorder in patients with systemic lupus erythematosus SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID QUALITY-OF-LIFE; HEALTH-STATUS; NEUROPSYCHIATRIC DISORDERS; ANTINEURONAL ANTIBODIES; CLINICAL-PRACTICE; SYDENHAMS CHOREA; BASAL GANGLIA; EPIDEMIOLOGY; SYMPTOMS; MANIFESTATIONS AB Background: The goal of this pilot study was to investigate the prevalence of obsessive-compulsive disorder (OCD) in a group of patients with systemic lupus erythematosus (SLE). Method: Fifty adult patients enrolled in outpatient SLE studies at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (February 1995-October 1996) completed a self-report questionnaire adapted from the Yale-Brown Obsessive Compulsive Scale and an in-person psychiatric clinical inter-view with a psychiatrist or psychiatric clinical nurse specialist. DSM-IV lifetime diagnosis of OCD was determined by clinical interview. Results: Sixteen subjects (32%) met DSM-IV lifetime diagnostic criteria for OCD and an additional 5 (10%) met criteria for subclinical OCD. Mean +/- SD number of symptoms reported on the self-report questionnaire was significantly higher among subjects diagnosed with OCD on clinical interview (40.7 +/- 23.2) compared with those without OCD (8.9 +/- 11.7; t = 5.8, df = 27, p < .001). Conclusion: Obsessive-compulsive disorder was 10 to 15 times more common in this cohort of patients with SLE compared with those in community-based studies of OCD. The use of an OCD self-report rating scale proved helpful in the identification of OCD symptoms among patients with SLE. Results suggest that further studies of OCD in patients with SLE are needed and may provide new insight into the pathophysiology of both disorders. C1 Univ Wisconsin, Sch Med, Dept Psychiat, Madison, WI 53719 USA. NIMH, Bethesda, MD 20892 USA. NIAMSD, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Slattery, MJ (reprint author), Univ Wisconsin, Sch Med, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM mslattery@wisc.edu NR 67 TC 3 Z9 3 U1 2 U2 4 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2004 VL 65 IS 3 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 831JJ UT WOS:000222190400003 ER PT J AU Tabak, LA AF Tabak, LA TI Dental, oral, and craniofacial research: the view from the NIDCR SO JOURNAL OF DENTAL RESEARCH LA English DT Editorial Material DE NIDCR; research; strategic plan C1 NIDCR, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), NIDCR, Bldg 31,Room 2C39,31 Ctr Dr,MSC 2290, Bethesda, MD 20892 USA. EM Lawrence.Tabak@nih.gov NR 0 TC 4 Z9 4 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2004 VL 83 IS 3 BP 196 EP 197 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 802BS UT WOS:000220139600001 PM 14981117 ER PT J AU Martin, SE Maxwell, CD White, HR Zhang, Y AF Martin, SE Maxwell, CD White, HR Zhang, Y TI Trends in alcohol use, cocaine use, and crime: 1989-1998 SO JOURNAL OF DRUG ISSUES LA English DT Article ID WHITE MALE ARRESTEES; VIOLENT CRIME; AGGRESSIVE CRIME; SPATIAL DYNAMICS; MEXICAN-AMERICAN; DRUG-USE; AVAILABILITY; EXPLANATIONS; VALIDITY; ABUSE AB The widespread belief that illicit drugs are closely associated with crime has contributed to America's "War on Drugs" and attendant increases in arrests, convictions, and prison populations. However, the links between alcohol and crime have received less attention from policy makers and the public despite consistent evidence that alcohol is more likely than other drugs to be associated with violence. This study explores the relationship between alcohol and cocaine use and crime from 1989-1998, based on findings from the Drug Use Forecasting/Arrestee Drug and Alcohol Monitoring Program and the Uniform Crime Reports Program. We examine correlations among cocaine use, alcohol use, property crime, and violent crime at the city level to determine if there is a consistent pattern across cities over time. The analyses show a wide variation across cities in the links between both alcohol and cocaine use and violent and property crime rates over the 10-year period. However, the association between the annual rates of alcohol use and violent crime is stronger than that of alcohol use and property crime. These associations for alcohol remain in multivariate analyses, including statistical controls for temporal autocorrelation, SES, and heroin use. Cocaine use, in contrast, is not closely associated with either property or violent crime rates in the multivariate analyses. The findings suggest that to reduce violent crime rates, policy makers need to focus on addressing the contribution of alcohol. Furthermore, given the variation found across sites, efforts to reduce the drug/alcohol-crime links need to be tailored to local patterns and problems. C1 NIDA, Prevent Res Branch, Bethesda, MD USA. Michigan State Univ, Sch Criminal Justice, E Lansing, MI 48824 USA. Rutgers State Univ, Ctr Alcohol Studies, Piscataway, NJ 08855 USA. Rutgers State Univ, Dept Sociol, Piscataway, NJ 08855 USA. RP Martin, SE (reprint author), NIDA, Prevent Res Branch, Bethesda, MD USA. NR 58 TC 18 Z9 18 U1 1 U2 8 PU J DRUG ISSUES INC PI TALLAHASSEE PA FLORIDA STATE UNIV, SCHOOL CRIMINOLOGY CRIMINAL JUSTICE, PO BOX 66696, TALLAHASSEE, FL 32313-6696 USA SN 0022-0426 J9 J DRUG ISSUES JI J. Drug Issues PD SPR PY 2004 VL 34 IS 2 BP 333 EP 359 PG 27 WC Substance Abuse SC Substance Abuse GA 833CX UT WOS:000222315100006 ER PT J AU LeRoith, D Levetan, CS Hirsch, IB Riddle, MC AF LeRoith, D Levetan, CS Hirsch, IB Riddle, MC TI Type 2 diabetes: The role of basal insulin therapy SO JOURNAL OF FAMILY PRACTICE LA English DT Article ID BLOOD-GLUCOSE CONTROL; NPH INSULIN; MULTIFACTORIAL INTERVENTION; MICROVASCULAR COMPLICATIONS; MYOCARDIAL-INFARCTION; CONTROLLED-TRIAL; MELLITUS; GLARGINE; QUALITY; HYPOGLYCEMIA C1 Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. Hahnemann & Med Coll Penn Hosp, Div Endocrinol, Philadelphia, PA USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Univ Washington, Med Ctr, Diabet Care Ctr, Seattle, WA 98195 USA. Oregon Hlth Sci Univ, Sch Med, Div Endocrinol Diabet Clin Nutr, Portland, OR 97201 USA. RP LeRoith, D (reprint author), NIH, Bldg 10,Room 8D12,MSC 1758, Bethesda, MD 20892 USA. EM leroith@comcast.net NR 40 TC 4 Z9 4 U1 0 U2 1 PU DOWDEN PUBLISHING CORP PI MONTVALE PA 110 SUMMIT AVE, MONTVALE, NJ 07645-1712 USA SN 0094-3509 J9 J FAM PRACTICE JI J. Fam. Pract. PD MAR PY 2004 VL 53 IS 3 BP 215 EP 222 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 807ZC UT WOS:000220538400014 PM 15000929 ER PT J AU Silk, JS Sessa, FM Morris, AS Steinberg, L Avenevoli, S AF Silk, JS Sessa, FM Morris, AS Steinberg, L Avenevoli, S TI Neighborhood cohesion as a buffer against hostile maternal parenting SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article ID PRESCHOOL-CHILDREN; LONGITUDINAL PERSPECTIVE; EXTERNALIZING BEHAVIOR; FAMILY; RISK; PSYCHOPATHOLOGY; COMPETENCE; NETWORK; CRIME AB This study explored the moderating effects of children's neighborhoods on the link between hostile parenting and externalizing behavior. Participants were 1st- or 2nd-grade children in an urban northeastern community. Children were administered the Parenting and Neighborhood scales of the Child Puppet Interview, and mothers completed questionnaires on neighborhood quality and parenting practices. Census tract measures of neighborhood quality and teachers' reports of children's externalizing behavior also were obtained. Results indicated that children's and mothers' perceptions of neighborhood involvement-cohesion buffered the link between hostile parenting and externalizing problems. Children's externalizing behavior was unrelated to census tract variables. Findings highlight the protective effect of neighborhood social cohesion and the utility of including young children's perspectives in research on neighborhoods and families. C1 Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Penn State Univ, Dept Psychol, Abington, PA USA. Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. NIMH, Mood & Anxiety Disorders Program, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. RP Silk, JS (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM jss4@pitt.edu OI Silk, Jennifer/0000-0002-8638-4337 NR 50 TC 44 Z9 44 U1 0 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD MAR PY 2004 VL 18 IS 1 BP 135 EP 146 DI 10.1037/0893-3200.18.1.135 PG 12 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 800PA UT WOS:000220039000012 PM 14992616 ER PT J AU Okada, T Caplen, NJ Ramsey, WJ Onodera, M Shimazaki, K Nomot, T Ajalli, R Wildner, O Morris, J Kume, A Hamada, H Blaese, RM Ozawa, K AF Okada, T Caplen, NJ Ramsey, WJ Onodera, M Shimazaki, K Nomot, T Ajalli, R Wildner, O Morris, J Kume, A Hamada, H Blaese, RM Ozawa, K TI In situ generation of pseudotyped retroviral progeny by adenovirus-mediated transduction of tumor cells enhances the killing effect of HSV-tk suicide gene therapy in vitro and in vivo SO JOURNAL OF GENE MEDICINE LA English DT Article DE suicide gene therapy; adeno-retroviral hybrid vector; in situ generation; glioma; HSV-tk ID STABLE TRANSDUCTION; CHIMERIC VECTORS; HYBRID VECTOR; EXPRESSION; LINES; DNA; MECHANISM; SYSTEM; TITER AB Background Hybrid adeno-retroviral vector systems utilize the high efficiency of adenovirus transduction to direct the in situ production of retroviral progeny. In this study, we show that a single-step transduction of glioma cells with traps-complementing hybrid adeno-retroviral vectors effectively turns these cells into retrovirus vector-producing cells, which in turn facilitates the transduction of adjacent cells. Methods We have adapted the adeno-retroviral hybrid viral vector system to enhance the ganciclovir (GCV) killing of glioma cells following transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene. To assess the effect of the in situ production of retroviral vectors on the transduction efficiency of glioma cells, 9L cells were transduced with adeno-retroviral hybrid vectors that separately express a retroviral genome (AVC2.GCEGFP or AVC2.GCTK) and retroviral packaging proteins (AxTetGP and AxTetVSVG). The generation of an integrated HSV-tk provirus by traps-complementation of the adeno-retroviral vectors was verified by analysis of the flanking retroviral LTR sequences. Tumors established on nu/nu mice were injected with the viruses followed by intraperitoneal injections of either PBS or GCV. We also estimated the copy numbers of the HSV-tk transgene present in the tumors of the treated mice. To determine the expression pattern of the HSV-tk transcripts within a tumor, in situ hybridization analysis was performed using an RNA probe specific for HSV-tk. Results The co-transduction of rat 9L glioma cells with AVC2.GCEGFP together with vectors expressing packaging proteins of retroviruses increased the transduction efficiency. Transduction with AVC2.GCTK together with packaging vectors increased the in vitro sensitivity of cells to the pro-drug GCV by one log compared with control cells that were incapable of generating retrovirus. In vivo, the injection of established subcutaneous 9L tumors on athymic mice with a combination of AVC2.GCTK and packaging vectors followed by GCV treatment resulted in complete tumor regression in 50% of tumors at day 22 while no tumor regression was observed in control animals. Retroviral sequences diagnostic of 3' LTR reduplication in vivo were detected in genomic DNA extracted from the transduced tumors, indicating pro-viral integration of the retroviral genome derived from the adeno-retroviral hybrid vector. Furthermore, the relative copy number of the HSV-tk gene in tumors treated with the adeno-retroviral vectors was up to similar to250-fold higher than in control tumors. In situ hybridization suggested dispersion of the HSV-tk product across a wider area of the tumor than in control tumors, which indicates the spread of the in situ generated retroviruses. Conclusions Although the efficacy of this system has to be evaluated in orthotopic models, our observations suggest that this hybrid adeno-retroviral vector system could improve the suicide gene therapy of tumors. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Jichi Med Sch, Ctr Mol Med, Div Genet Therapeut, Minamimaki, Tochigi 3290498, Japan. NHGRI, Med Genet Branch, NCI, NIH, Bethesda, MD 20892 USA. Link Pharmaceut, Ames, IA USA. Univ Tsukuba, Inst Basic Med Sci, Dept Hematol, Tsukuba, Ibaraki 305, Japan. Jichi Med Sch, Dept Physiol, Minamimaki, Tochigi 3290498, Japan. Ruhr Univ Bochum, Abt F Mol & Med Virol, D-4630 Bochum, Germany. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. Sapporo Med Univ, Biomed Res Ctr, Biomol Med Sect, Sapporo, Hokkaido, Japan. PreGentis, Newtown, PA USA. RP Okada, T (reprint author), Jichi Med Sch, Ctr Mol Med, Div Genet Therapeut, 3311-1 Yakushiji, Minamimaki, Tochigi 3290498, Japan. EM tokada@jichi.ac.jp RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 30 TC 14 Z9 19 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD MAR PY 2004 VL 6 IS 3 BP 288 EP 299 DI 10.1002/jgm.490 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 809YE UT WOS:000220671200005 PM 15026990 ER PT J AU DuVal, G Clarridge, B Gensler, G Danis, M AF DuVal, G Clarridge, B Gensler, G Danis, M TI A national survey of US Internists' experiences with ethical dilemmas and ethics consultation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE questionnaires; internal medicine; ethics, clinical; ethicists; referral and consultation ID TEACHING MEDICAL-ETHICS; CONTROLLED-TRIAL; RESPONSE RATES; SERVICE; RESIDENCY; STUDENTS AB OBJECTIVE: To identify the ethical dilemmas that internists encounter, the strategies they use to address them, and the usefulness of ethics consultation. DESIGN: National telephone survey. SETTING: Doctors' offices. PARTICIPANTS: General internists, oncologists, and critical care/pulmonologists (N = 344, 64% response rate). MEASUREMENTS: Types of ethical dilemmas recently encountered and likelihood of requesting ethics consultation; satisfaction with resolution of ethical dilemmas with and without ethics consultation. RESULTS: Internists most commonly reported dilemmas regarding end-of-life decision making, patient autonomy, justice, and conflict resolution. General internists, oncologists, and critical care specialists reported participating in an average of 1.4, 1.3, and 4.1 consultations in the preceding 2 years, respectively (P < .0001). Physicians with the least ethics training had the least access to and participated in the fewest ethics consultations; 19% reported consultation was unavailable at their predominant practice site. Dilemmas about end-of-life decisions and patient autonomy were often referred for consultation, while dilemmas about justice, such as lack of insurance or limited resources, were rarely referred. While most physicians thought consultations yielded information that would be useful in dealing with future ethical dilemmas (72%), some hesitated to seek ethics consultation because they believed it was too time consuming (29%), might make the situation worse (15%), or that consultants were unqualified (11%). CONCLUSIONS: While most internists recall recent ethical dilemmas in their practices, those with the least preparation and experience have the least access to ethics consultation. Health care organizations should emphasize ethics educational activities to prepare physicians for handling ethical dilemmas on their own and should improve the accessibility and responsiveness of ethics consultation when needed. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Toronto, Joint Ctr Bioeth, Toronto, ON, Canada. Univ Massachusetts, Boston, MA 02125 USA. EMMES Corp, Rockville, MD USA. RP Danis, M (reprint author), NIH, Dept Clin Bioeth, Bldg 10 Room 1C118, Bethesda, MD 20892 USA. EM mdanis@nih.gov NR 33 TC 75 Z9 76 U1 1 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2004 VL 19 IS 3 BP 251 EP 258 DI 10.1111/j.1525-1497.2004.21238.x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 800TM UT WOS:000220050600007 PM 15009780 ER PT J AU Yesavage, JA Friedman, L Kraemer, H Tinklenberg, JR Salehi, A Noda, A Taylor, JL O'Hara, R Murphy, G AF Yesavage, JA Friedman, L Kraemer, H Tinklenberg, JR Salehi, A Noda, A Taylor, JL O'Hara, R Murphy, G TI Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article DE Alzheimer's disease; dementia severity; longitudinal studies; sleep/wake disturbances; circadian rhythm; apolipoprotein epsilon ID NURSING-HOME PATIENTS; ACTIGRAPHIC MEASURES; APOLIPOPROTEIN-E; DEMENTIA; DISTURBANCES; WAKEFULNESS; ASSOCIATION; BEHAVIOR AB Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status 14 may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance 14 in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele. C1 Palo Alto VA Hlth Care Syst, Natl Inst Aging Alzheimers Dis Core Ctr, Palo Alto, CA 94304 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Yesavage, JA (reprint author), Palo Alto VA Hlth Care Syst, Natl Inst Aging Alzheimers Dis Core Ctr, 151Y,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM yesavage@stanford.edu OI Salehi, Ahmad/0000-0001-8257-3280 FU NIA NIH HHS [U19 AG010483, AG 17824] NR 30 TC 29 Z9 30 U1 6 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0891-9887 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD MAR PY 2004 VL 17 IS 1 BP 20 EP 24 DI 10.1117/0891988703261994 PG 5 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA 848NR UT WOS:000223474900004 PM 15018693 ER PT J AU Shaib, YH Davila, JA McGlynn, K El-Serag, HB AF Shaib, YH Davila, JA McGlynn, K El-Serag, HB TI Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? SO JOURNAL OF HEPATOLOGY LA English DT Article DE intrahepatic cholangiocarcinoma; SEER; incidence ID PRIMARY SCLEROSING CHOLANGITIS; HEPATITIS-C VIRUS; MORTALITY-RATES; LIVER; CANCER; CIRRHOSIS; BILIARY; TRENDS; RISK AB Background/Aims: The incidence of intrahepatic cholangiocarcinoma (ICC) has been reported to be increasing in the USA. The aim of this study is to examine whether this is a true increase or a reflection of improved detection or reclassification. Methods: Using data from the Surveillance Epidemiology and End Results (SEER) program, incidence rates for ICC between 1975 and 1999 were calculated. We also calculated the proportions of cases with each tumor stage, microscopically confirmed cases, and the survival rates. Results: A total of 2864 patients with ICC were identified. The incidence of ICC increased by 165% during the study period. Most of this increase occurred after 1985. There were no significant changes in the proportion of patients with unstaged cancer, localized cancer, microscopic confirmation, or with tumor size <5 cm during the period of the most significant increase. The 1-year survival rate increased significantly from 15.8% in 1975-1979 to 26.3% in 1995-1999, while 5-year survival rate remained essentially the same (2.6 vs. 3.5%). Conclusions: The incidence of ICC continues to rise in the USA. The stable proportions over time of patients with early stage disease, unstaged disease, tumor size <5 cm, and microscopic confirmation suggest a true increase of ICC. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. RP El-Serag, HB (reprint author), Vet Affairs Med Ctr, Sect Hlth Serv Res, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu NR 16 TC 265 Z9 280 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2004 VL 40 IS 3 BP 472 EP 477 DI 10.1016/j.jhep.2003.11.030 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 803ZZ UT WOS:000220270300016 PM 15123362 ER PT J AU Kelly-Welch, AE Wang, HY Wang, LM Pierce, JH Jay, G Finkelman, F Keegan, AD AF Kelly-Welch, AE Wang, HY Wang, LM Pierce, JH Jay, G Finkelman, F Keegan, AD TI Transgenic expression of insulin receptor substrate 2 in murine B cells alters the cell density-dependence of IgE production in vitro and enhances IgE production in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GERMLINE EPSILON-PROMOTER; IL-4 RECEPTOR; SIGNALING PATHWAY; GENE-EXPRESSION; PROLIFERATION; INTERLEUKIN-4; GROWTH; PHOSPHORYLATION; ACTIVATION; APOPTOSIS AB Previous studies have shown that insulin receptor substrate (IRS)1 and IRS2 mediate proliferative and antiapoptotic signaling through the IL-4R in 32D cells; however their role in regulating normal B cell responses is not clear. To investigate the role of IRS2 in normal B cell function, we developed IRS2 transgenic (Tg) mice on the C57BL/6 background. Western blot analysis revealed a 2-fold elevation in IRS2 protein levels in Tg(+) mice compared with littermate controls and a 3-fold increase in basal tyrosine phosphorylated IRS2 in the absence of IL-4 stimulation. IL-4-induced tyrosine phosphorylation of IRS2 was elevated in Tg(+) B cells, whereas IL-4-induced phosphorylation of STAT6 was similar between Tg(+) and Tg(-) B cells. Tg expression of IRS2 had little effect on IL-4-mediated proliferation and no effect on protection from apoptosis. However, production of IgE and IgG1 by Tg(+) B cells using standard in vitro conditions was diminished 50-60%. Because Ig production in vitro is known to be highly cell concentration-dependent, we performed experiments at different cell concentrations. Interestingly, at very low B cell concentrations (1000-5000 B cells/well), IgE and IgG1 production by Tg(+) B cells was greater than that of controls, whereas at higher cell concentrations (10,000-20,000 cells/well) Ig production by Tg(+) B cells was less than controls. Furthermore, in vivo immunization with OVA-alum or goat anti-IgD resulted in elevated serum IgE levels in the Tg(+) mice. These results indicate that overexpression of IRS2 alters the B cell intrinsic density-dependence of IgE and IgG1 production in vitro and enhances IgE responses in vivo. C1 Amer Red Cross, Jerome Holland Labs, Dept Immunol, Rockville, MD 20855 USA. NCI, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. Univ Cincinnati, Childrens Res Hosp, Cincinnati, OH 45267 USA. RP Keegan, AD (reprint author), Amer Red Cross, Jerome Holland Labs, Dept Immunol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM keegana@usa.redcross.org FU NCI NIH HHS [CA77415]; NHLBI NIH HHS [T32HL07698-09]; NIAID NIH HHS [AI45662] NR 44 TC 8 Z9 8 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2004 VL 172 IS 5 BP 2803 EP 2810 PG 8 WC Immunology SC Immunology GA 777PD UT WOS:000189186000015 PM 14978080 ER PT J AU Candon, S McHugh, RS Foucras, G Natarajan, K Shevach, EM Margulies, DH AF Candon, S McHugh, RS Foucras, G Natarajan, K Shevach, EM Margulies, DH TI Spontaneous organ-specific Th2-mediated autoimmunity in TCR transgenic mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; REACTIVE T-CELLS; DENDRITIC CELLS; TH2 CELLS; OXAZOLONE COLITIS; SELF-TOLERANCE; GASTRITIS; MODEL; INDUCTION; PEPTIDE AB CD4(+) T cells that lead to autoimmune gastritis (AIG) in BALB/c mice are either Th1 or Th2 cells. To test whether the phenotype of disease is related to the particular TCR expressed by the pathogenic cell, we have generated several lines of TCR transgenic mice using receptors cloned from pathogenic Th1 or Th2 cells. We previously described spontaneous inflammatory AIG in A23 mice, caused by the transgenic expression of the TCR from a Th1 clone, TXA23. In this study we describe the generation of A51 mouse-lines, transgenic for the TCR of a CD4(+) self-reactive Th2 clone, TXA51. A proportion of A51 mice spontaneously develop AIG by 10 wk of age, with a disease characterized by eosinophilic infiltration of the gastric mucosa and Th2 differentiation of transgenic T cells in the gastric lymph node. The Th2 phenotype of this autoimmune response seems to be related to a low availability of MHC class II-self peptide complexes. This in vivo model of spontaneous Th2-mediated, organ-specific autoimmunity provides a unique example in which the clonotypic TCR conveys the Th2 disease phenotype. C1 NIAID, Mol Biol Sect, Immunol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAID, Cellular Immunol Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAID, Immune Regulat Unit, Immunol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH,Dept Hlth & Human Serv, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM dhm@nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 46 TC 21 Z9 21 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 MAR 1 PY 2004 VL 172 IS 5 BP 2917 EP 2924 PG 8 WC Immunology SC Immunology GA 777PD UT WOS:000189186000029 PM 14978094 ER PT J AU Hesse, M Piccirillo, CA Belkaid, Y Prufer, J Mentink-Kane, M Leusink, M Cheever, AW Shevach, EM Wynn, TA AF Hesse, M Piccirillo, CA Belkaid, Y Prufer, J Mentink-Kane, M Leusink, M Cheever, AW Shevach, EM Wynn, TA TI The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INHIBITS CYTOKINE PRODUCTION; SYNTHASE ARGINASE BALANCE; MANSONI-INFECTED MICE; MOUSE BONE-MARROW; GRANULOMA-FORMATION; MURINE SCHISTOSOMIASIS; HELPER-CELL; IN-VIVO; DOWN-REGULATION; TH2 CYTOKINES AB IL-10 reduces immunopathology in many persistent infections, yet the contribution of IL-10 from distinct cellular sources remains poorly defined. We generated IL-10/recombination-activating gene (RAG)2-deficient mice and dissected the role of T cell- and non-T cell-derived IL-10 in schistosomiasis by performing adoptive transfers. In this study, we show that IL-10 is generated by both the innate and adaptive immune response following infection, with both sources regulating the development of type-2 immunity, immune-mediated pathology, and survival of the infected host. Importantly, most of the CD4(+) T cell-produced IL-10 was confined to a subset of T cells expressing CD25. These cells were isolated from egg-induced granulomas and exhibited potent suppressive activity in vitro. Nevertheless, when naive, naturally occurring CD4(+)CD25(+) cells were depleted in adoptive transfers, recipient IL-10/RAG2-deficient animals were more susceptible than RAG2-deficient mice, confirming an additional host-protective role for non-T cell-derived IL-10. Thus, innate effectors and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, NIH, 50 South Dr,Room 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 NR 60 TC 237 Z9 255 U1 2 U2 12 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2004 VL 172 IS 5 BP 3157 EP 3166 PG 10 WC Immunology SC Immunology GA 777PD UT WOS:000189186000057 PM 14978122 ER PT J AU Gillespie, SR DeMartino, RR Zhu, JF Chong, HJ Ramirez, C Shelburne, CP Bouton, LA Bailey, DP Gharse, A Mirmonsef, P Odom, S Gomez, G Rivera, J Fischer-Stenger, K Ryan, JJ AF Gillespie, SR DeMartino, RR Zhu, JF Chong, HJ Ramirez, C Shelburne, CP Bouton, LA Bailey, DP Gharse, A Mirmonsef, P Odom, S Gomez, G Rivera, J Fischer-Stenger, K Ryan, JJ TI IL-10 inhibits Fc epsilon RI expression in mouse mast cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AFFINITY IGE RECEPTOR; IMMUNOGLOBULIN-E RECEPTOR; BETA-SUBUNIT; STIMULATORY FACTOR; TRANSFECTED CELLS; GENE-EXPRESSION; POINT MUTATION; ATOPIC ASTHMA; IN-VITRO; C-KIT AB FcepsilonRI expression and function is a central aspect of allergic disease. Using bone marrow-derived mouse mast cell populations, we have previously shown that the Th2 cytokine IL-4 inhibits FcepsilonRI expression and function. In the current study we show that the Th2 cytokine IL-10 has similar regulatory properties, and that it augments the inhibitory effects of IL-4. FcepsilonRI down-regulation was functionally significant, as it diminished inflammatory cytokine production and IgE-mediated FcepsilonRI up-regulation. IL-10 and IL-4 reduced FcepsilonRI beta protein expression without altering the alpha or gamma subunits. The ability of IL-4 and IL-10 to alter FcepsilonRI expression by targeting the beta-chain, a critical receptor subunit known to modulate receptor expression and signaling, suggests the presence of a Th2 cytokine-mediated homeostatic network that could serve to both initiate and limit mast cell effector function. C1 Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. Univ Richmond, Dept Biol, Richmond, VA 23173 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Box 842012, Richmond, VA 23284 USA. EM jjryan@saturn.vcu.edu RI Zhu, Jinfang/B-7574-2012 FU NCI NIH HHS [1R01CA91839]; NIAID NIH HHS [1R01AI43433] NR 64 TC 42 Z9 44 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2004 VL 172 IS 5 BP 3181 EP 3188 PG 8 WC Immunology SC Immunology GA 777PD UT WOS:000189186000060 PM 14978125 ER PT J AU Gendelman, M Hecht, T Logan, B Vodanovic-Jankovic, S Komorowski, R Drobyski, WR AF Gendelman, M Hecht, T Logan, B Vodanovic-Jankovic, S Komorowski, R Drobyski, WR TI Host conditioning is a primary determinant in modulating the effect of IL-7 on murine graft-versus-host disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; DONOR LEUKOCYTE INFUSIONS; HEMATOPOIETIC-CELL TRANSPLANTATION; HUMAN DENDRITIC CELLS; HUMAN T-LYMPHOCYTES; IMMUNE RECONSTITUTION; THYMIC FUNCTION; POTENTIAL ROLE; IN-VITRO; INTERLEUKIN-7 AB Interleukin-7 has been shown to enhance T cell reconstitution after allogeneic bone marrow transplantation, in part, by expansion of mature donor T cells, but whether IL-7 also exacerbates graft-vs-host disease (GVRD) remains unresolved. To address this issue, we examined the effect of IL-7 on GVHD induction using a well-defined murine GVHD model (B6-->B6AF1/J). Administration of IL-7 to nonirradiated B6AF1/J recipients of B6 T cells resulted in expansion of splenic donor CD4(+) and CD8(+) T cells and increased GVHD mortality. In contrast, administration of IL-7 on the same schedule failed to increase GVHD mortality in either sublethally or lethally irradiated animals that received graded doses of T cells designed to induce varying degrees of GVHD severity. Moreover, IL-7 failed to increase the number of alloreactive T cells when examined in a murine model (B6-->BALB.B) that allowed for direct quantitation of graft-vs-host-reactive T cells. The combination of irradiation and transplantation of alloreactive donor T cells resulted in significantly increased levels of endogenous splenic IL-7 mRNA when compared with nonirradiated transplanted animals, providing a potential explanation for why exogenous IL-7 did not increase GVHD severity in these mice. We conclude that host conditioning modulates the ability of exogenous IL-7 to exacerbate GVHD and that this occurs through induction of endogenous IL-7 production. C1 Med Coll Wisconsin, Bone Marrow Transplant Program, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Biostat, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. NCI, Frederick, MD 21791 USA. RP Drobyski, WR (reprint author), Med Coll Wisconsin, Bone Marrow Transplant Program, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM bill@bmt.mcw.edu FU NHLBI NIH HHS [HL55388, HL64603] NR 46 TC 25 Z9 26 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 MAR 1 PY 2004 VL 172 IS 5 BP 3328 EP 3336 PG 9 WC Immunology SC Immunology GA 777PD UT WOS:000189186000076 PM 14978141 ER PT J AU Parkhurst, MR Riley, JP Robbins, PF Rosenberg, SA AF Parkhurst, MR Riley, JP Robbins, PF Rosenberg, SA TI Induction of CD4+ Th1 lymphocytes that recognize known and novel class 11 MHC restricted epitopes from the melanoma antigen gp100 by stimulation with recombinant protein SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE T lymphocytes; Th1/Th2 cells; MHC; tumor immunity ID CD4(+) T-CELLS; HUMAN DENDRITIC CELLS; HLA-DR MOLECULES; TUMOR-ANTIGEN; IN-VITRO; IDENTIFICATION; ASSOCIATION; SPECIFICITY; REPRESENTS; EXPRESSION AB CD4(+) T helper cells may play a critical role in the induct on and maintenance of a therapeutic immune response to cancer. To evaluate the efficacy with which a recombinant tumor-associated protein can induce antigen-reactive CD4(+) T cells, we stimulated peripheral blood lymphocytes from patients with melanoma in vitro with the purified melanoma antigen gp100 produced in Escherichia coli. In preliminary experiments, we observed that peripheral blood mononuclear cells could process and present known HLA-DRbeta1*0401 and HLA-DRbeta1*0701 restricted epitopes to gp100-reactive CD4(+) T cell I ties after being loaded exogenously with protein. Therefore, we used autologous protein-loaded peripheral blood mononuclear cells as antigen presenting cells. From four of nine patients who expressed both HLA-DRbeta1*0401 and HLA-DRbeta1*0701, we raised five gp100-reactive CD4(+) T cell populations that secreted T, I type cytokines in response to exogenously loaded protein as well as target cells that endogenously expressed gp100 and MHC class 11 molecules, including transfectants and melanoma cells. Four of the five cultures specifically recognized the known HLA-DRbeta1*0401 and HLA-DRbeta1*0701 restricted epitopes gp100:44-59 and gp100:170-190, respectively. The fifth culture, and 30 T cell clones derived from it, specifically recognized anew peptide, gp100:420-435, in the context of HLA-DRbeta1*0701. These results Suggest that recombinant tumor-associated proteins may be clinically applicable for the generation of CD4(+) T helper cells in active vaccination strategies or adoptive cellular immunotherapies. C1 NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Parkhurst, MR (reprint author), NCI, NIH, Surg Branch, Bldg 10 Rm 2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Maria_Parkhurst@nih.gov FU Intramural NIH HHS [Z01 SC003811-32] NR 41 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAR-APR PY 2004 VL 27 IS 2 BP 79 EP 91 DI 10.1097/00002371-200403000-00001 PG 13 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 779YT UT WOS:000189330800001 PM 14770079 ER PT J AU McDonald, DM Teicher, BA Stetler-Stevenson, W Ng, SSW Figg, WD Folkman, J Hanahan, D Auerbach, R O'Reilly, M Herbst, R Cheresh, D Gordon, M Eggermont, A Libutti, SK AF McDonald, DM Teicher, BA Stetler-Stevenson, W Ng, SSW Figg, WD Folkman, J Hanahan, D Auerbach, R O'Reilly, M Herbst, R Cheresh, D Gordon, M Eggermont, A Libutti, SK TI Report from the society for biological therapy and vascular biology faculty of the NO workshop on angiogenesis monitoring SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE tumor; models; angiogenesis; therapy ID ENDOTHELIAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; ISOLATED LIMB PERFUSION; LIPOSOMAL DOXORUBICIN DOXIL(R); SYNERGISTIC ANTITUMOR-ACTIVITY; RECOMBINANT HUMAN ENDOSTATIN; SARCOMA-BEARING RATS; TUMOR ANGIOGENESIS; PHASE-I; ADVANCED CANCER AB The field of tumor angiogenesis has seen explosive growth over the last 5 years. Preclinical as well as early clinical evaluation of novel compounds is progressing at a rapid pace. To gain a perspective on the field and to take stock of advances in the understanding of molecular mechanisms underlying the process of tumor angiogenesis as well as ways of monitoring, the activity of agents, the So piety for Biologic Therapy and the National Cancer Institute's Vascular Biology Faculty convened a Workshop on Angiogenesis Monitoring in November 2002. The Workshop was composed of invited speakers and participants from academia, industry, and government. It was divided into 3 sessions, each chaired by leaders in the field. The first focused on advances in the understanding of the cellular and molecular mechanisms of angiogenesis in tumors. The second examined preclinical assay systems that are useful in vascular biology. The third addressed the translation to the clinic and monitoring of antiangiogenic activity of agents in patients and novel trial designs. What follows is a Summary of the discussions and findings of each session. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Genzyme Corp, Framingham, MA 01701 USA. NCI, Vasc Biol Fac, Bethesda, MD 20892 USA. Boston Childrens Hosp, Boston, MA USA. Univ Wisconsin, Madison, WI USA. MD Anderson Canc Ctr, Houston, TX USA. Scripps Inst, La Jolla, CA USA. Univ Arizona, Phoenix, AZ USA. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. RP McDonald, DM (reprint author), Int Soc Biol Therapy Canc, 611 E Wells St, Milwaukee, WI 53202 USA. EM info@isbtc.org RI Stetler-Stevenson, William/H-6956-2012; Figg Sr, William/M-2411-2016 OI Stetler-Stevenson, William/0000-0002-5500-5808; NR 69 TC 17 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAR-APR PY 2004 VL 27 IS 2 BP 161 EP 175 DI 10.1097/00002371-200403000-00010 PG 15 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 779YT UT WOS:000189330800010 PM 14770088 ER PT J AU LaMonte, AC Paul, ME Read, JS Frederick, MM Erdman, DD Han, LL Anderson, LJ AF LaMonte, AC Paul, ME Read, JS Frederick, MM Erdman, DD Han, LL Anderson, LJ CA Women Infants Transmission Study TI Persistent parvovirus b19 infection without the development of chronic anemia in HIV-infected and -uninfected children: The women and infants transmission study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 26-30, 2002 CL SAN DIEGO, CA ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIBODIES; DNA AB We evaluated the prevalence of persistent parvovirus B19 (B19) infection and associated anemia in human immunodeficiency virus (HIV)-infected and HIV-uninfected children. B19 persistence was defined as B19 DNA detected in specimens collected 116 weeks apart. Of 182 children, 3 HIV-infected children and two HIV-uninfected children had evidence of persistent B19 infection. Of the 5 children, none had evidence of B19-associated anemia. Our data suggest that B19 infections can persist in children without the development of symptomatic anemia. C1 Ctr Dis Control & Prevent, Resp & Enter Virus Branch, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. Clin Trials & Surveys, Baltimore, MD USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP LaMonte, AC (reprint author), Ctr Dis Control & Prevent, Resp & Enter Virus Branch, Natl Ctr Infect Dis, 1600 Clifton Rd,NE MS-A34, Atlanta, GA 30333 USA. EM ahl4@cdc.gov FU NCRR NIH HHS [RR00188, RR00645]; NIAID NIH HHS [U01 AI 34858, N01 AI 85339, U01 AI 34842, 1 U01 AI 50274-01, U01 AI 34840, U01 AI 34856, U01 AI 34841]; NICHD NIH HHS [HD-8-2913]; PHS HHS [R0-1-IID-25714] NR 17 TC 20 Z9 21 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 MAR 1 PY 2004 VL 189 IS 5 BP 847 EP 851 DI 10.1086/381899 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 800AI UT WOS:000220000900013 PM 14976602 ER PT J AU Chien, PC Chen, D Chen, PD Tuen, M Cohen, S Migueles, SA Connors, M Rosenberg, E Malhotra, U Gonzalez, C Hioe, CE AF Chien, PC Chen, D Chen, PD Tuen, M Cohen, S Migueles, SA Connors, M Rosenberg, E Malhotra, U Gonzalez, C Hioe, CE TI HIV-1-Infected patients with envelope-specific lymphoproliferation or long-term nonprogression lack antibodies suppressing glycoprotein 120 antigen presentation SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Keystone Symposium on Twenty Years of HIV Research from Discovery to Understanding CY MAR 28-APR 03, 2003 CL BANFF, CANADA ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; CD4(+) T-CELLS; DISEASE PROGRESSION; HIV-1 INFECTION; HUMORAL RESPONSES; BINDING DOMAIN; GP120; NEUTRALIZATION; GLYCOSYLATION AB Background. Antibodies to the CD4-binding domain (CD4bd) of human immunodeficiency virus type 1 (HIV-1) glycoprotein 120 (gp120) inhibit gp120 antigen presentation to CD4 T cells. These findings imply that the presence of anti-CD4bd antibodies might contribute to the dearth of envelope-specific T helper responses observed in most HIV-1-positive patients. In the absence of these antibodies, however, anti-envelope T helper responses might be maintained. Methods. We used ELISA to evaluate the levels of anti-CD4bd antibodies in rare HIV-1-positive patients who exhibit envelope-specific lymphoproliferation. Subsequently, we examined the contribution of anti-CD4bd antibodies to disease progression by comparing anti-CD4bd antibody levels in 3 cohorts of HIV-1-positive patients with distinct rates of disease progression. Results. Although most HIV-1-positive individuals produce anti-CD4bd antibodies, 77% of patients with envelope-specific lymphoproliferation have undetectable anti-CD4bd antibody levels. Moreover, comparison of the 3 HIV-1-positive cohorts revealed that individuals with long-term nonprogression have significantly lower anti-CD4bd antibody titers than do those with rapid or slow progression. Unlike immunoglobulin G (IgG) from rapid progressors, IgG from nonprogressors had no suppressive effects on glycoprotein (gp) 120-specific T cell proliferation. Conclusions. Low anti-CD4bd antibody levels are associated with the absence of disease progression. A number of HIV-1-positive individuals without these antibodies also appear to sustain gp120-specific T helper responses needed to help control the infection. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Program Infect Dis, Seattle, WA 98104 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. NYU, Sch Med, Dept Med, New York, NY USA. NYU, Sch Med, Dept Pathol, New York, NY USA. RP Hioe, CE (reprint author), Vet Adm Med Ctr, 423 E 23rd St,Rm 18-24 N, New York, NY 10010 USA. EM catarina.hioe@med.nyu.edu FU NIAID NIH HHS [AI-01550, AI-48371, AI-27742, AI-27757] NR 35 TC 7 Z9 7 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 MAR 1 PY 2004 VL 189 IS 5 BP 852 EP 861 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 800AI UT WOS:000220000900014 PM 14976603 ER PT J AU Emanuel, EJ Wendler, D Killen, J Grady, C AF Emanuel, EJ Wendler, D Killen, J Grady, C TI What makes clinical research in developing countries ethical? The benchmarks of ethical research SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID INTERNATIONAL RESEARCH; INFORMED CONSENT; RANDOMIZED-TRIAL; DEVELOPING-WORLD; VACCINE; TRANSMISSION; IMPERIALISM; PREVENTION; BENEFITS; HELSINKI C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 60 TC 269 Z9 276 U1 5 U2 24 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 MAR 1 PY 2004 VL 189 IS 5 BP 930 EP 937 DI 10.1086/381709 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 800AI UT WOS:000220000900022 PM 14976611 ER PT J AU Hwang, ST AF Hwang, ST TI Chemokine receptors in melanoma: CCR9 has a potential role in metastasis to the small bowel SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID LYMPH-NODE METASTASIS; EXPRESSION; CELLS; CXCR4 C1 NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM hwangs@mail.nih.gov NR 13 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 BP XIV EP XV DI 10.1111/j.0022-202X.2004.22346.x PG 2 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500004 PM 15086589 ER PT J AU Andl, T Chu, EY Metzger, D Chambon, P Mishina, Y Seykora, JT Crenshaw, EB Millar, SE AF Andl, T Chu, EY Metzger, D Chambon, P Mishina, Y Seykora, JT Crenshaw, EB Millar, SE TI Loss of epithelial Bmpr1a results in continuous proliferation of hair follicle epithelium and the development of matricomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. Univ Strasbourg 1, Inst Genet & Biol Mol & Cellulaaire, Strasbourg, France. Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. Childrens Hosp Philadelphia, Abramson Res Ctr, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 661 BP A111 EP A111 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500711 ER PT J AU Blauvelt, A Lederman, M Veazey, R Mosier, D Hartley, O Offord, R AF Blauvelt, A Lederman, M Veazey, R Mosier, D Hartley, O Offord, R TI Targeted inhibition of CCR5 with PSC-RANTES is sufficient to block intravaginal transmission of SHIV in rhesus macaques SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Bethesda, MD USA. Case Western Reserve Univ, Dept Med, Cleveland, OH USA. Tulane Med Sch, Tulane Natl Primate Reg Ctr, Covington, LA USA. Scripps Res Inst, La Jolla, CA USA. Univ Geneva, Dept Biochim Med, Geneva, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 279 BP A47 EP A47 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500328 ER PT J AU Cardones, AR Leitner, WW Hwang, ST AF Cardones, AR Leitner, WW Hwang, ST TI Gene gun-mediated delivery of full-length cDNA encoding the human lymphatic endothelial cell selective marker, LYVE-1, to skin yields function-blocking mouse antibodies that recognize native structure for flow cytometry and immunohistochemistry SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIH, Dermatol Branch, Bethesda, MD 20892 USA. RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 019 BP A4 EP A4 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500072 ER PT J AU Cataisson, C Pearson, A Torgerson, S Nedospasov, S Yuspa, SH AF Cataisson, C Pearson, A Torgerson, S Nedospasov, S Yuspa, SH TI Dissecting the role of NF-kappa B and TNF alpha on cutaneous inflammation in K5-PKC alpha overexpressing mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 080 BP A14 EP A14 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500135 ER PT J AU Cha, J Shrayer, D Butmarc, J Carson, P Roberts, AB Kim, S Falanga, V AF Cha, J Shrayer, D Butmarc, J Carson, P Roberts, AB Kim, S Falanga, V TI Proliferation regulatory signal between SMAD 3 and MAPK p42/44 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Roger Williams Med Ctr, Providence, RI USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 569 BP A95 EP A95 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500617 ER PT J AU Chan, JL Ehrlich, A Moshell, AN Turner, ML Kimball, AB AF Chan, JL Ehrlich, A Moshell, AN Turner, ML Kimball, AB TI Validation study comparing spectrophotometric measurement of skin color to digital colorimetry SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. George Washington Univ, Washington, DC 20052 USA. NIAMSD, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 350 BP A59 EP A59 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500402 ER PT J AU Chu, E Andl, T Glick, A Millar, SE AF Chu, E Andl, T Glick, A Millar, SE TI WNT/beta-catenin signaling is required at early stages of tooth development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Penn, Philadelphia, PA 19104 USA. Natl Canc Inst, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 642 BP A107 EP A107 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500692 ER PT J AU Gerdes, MJ Frost, NA Levy, MR Moitra, J Glick, AB Vinson, C Yuspa, SH AF Gerdes, MJ Frost, NA Levy, MR Moitra, J Glick, AB Vinson, C Yuspa, SH TI AP-1 transcriptional activity determines keratinocyte lineage commitment during tumorigenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Lab Cell Canc Tum Promo, Bethesda, MD 20892 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 130 BP A22 EP A22 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500184 ER PT J AU Glick, AB Ryscavage, A Blazanin, N AF Glick, AB Ryscavage, A Blazanin, N TI Benign and malignant mouse epidermal tumors have distinct transcriptional responses to TGF beta 1 in vivo reflecting tumor suppressor to oncogene switch SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, LCCTP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 160 BP A27 EP A27 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500213 ER PT J AU Grachtchouk, M Wang, A Wei, L Liu, I Hutchin, M Lowe, L Glick, A Dlugosz, AA AF Grachtchouk, M Wang, A Wei, L Liu, I Hutchin, M Lowe, L Glick, A Dlugosz, AA TI Deregulated hedgehog signaling in extracutancous basaloid squamous cell carcinomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Michigan, Ann Arbor, MI 48109 USA. NCI, LCCTP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 165 BP A28 EP A28 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500216 ER PT J AU Hebert, J Khaimskiy, Y Athar, M Kopelovich, L Bickers, D Epstein, E AF Hebert, J Khaimskiy, Y Athar, M Kopelovich, L Bickers, D Epstein, E TI Phorbol 12-myristate 13-acetate (TPA) inhibits the induction of basal cell carcinomas in Ptch1+/- mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Columbia Univ, New York, NY USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 164 BP A28 EP A28 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500218 ER PT J AU Higashi, Y Fukushige, T Kanzaki, T Strott, CA AF Higashi, Y Fukushige, T Kanzaki, T Strott, CA TI Cholesterol sulfotransferase (SULT2B1b) is a late marker of human keratinocyte differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD USA. Kagoshima Univ, Sch Med, Kagoshima 890, Japan. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 429 BP A72 EP A72 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500478 ER PT J AU Hutchin, ME Kariapper, T Grachtehouk, M Wang, A Wei, L Cummings, D Liu, J Michael, LE Glick, A Dlugosz, AA AF Hutchin, ME Kariapper, T Grachtehouk, M Wang, A Wei, L Cummings, D Liu, J Michael, LE Glick, A Dlugosz, AA TI Conditional expression of Gli2 in skin reveals a requirement for sustained hedgehog signaling in basal cell carcinoma growth SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. Univ Michigan, CMB Grad Program, Ann Arbor, MI 48109 USA. NCI, LCCTP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 157 BP A27 EP A27 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500209 ER PT J AU Hwang, M Kalinin, O Morasso, MI AF Hwang, M Kalinin, O Morasso, MI TI Role of the Ca-binding protein Scarf, during epidermal differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 465 BP A78 EP A78 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500515 ER PT J AU Kakinuma, T Murakami, M Nadiminti, H Kobayashi, H Hwang, ST AF Kakinuma, T Murakami, M Nadiminti, H Kobayashi, H Hwang, ST TI Acquisition and evasion of host anti-tumor immune responses following rapid accumulation of immunogenic B16 murine melanoma cells in skin-draining lymph nodes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 128 BP A22 EP A22 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500183 ER PT J AU Kalinin, A Takahashi, K Jang, S AF Kalinin, A Takahashi, K Jang, S TI Characterization of epiplakin as an intermediate filament-associated cytolinker SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 207 BP A35 EP A35 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500257 ER PT J AU Kalinin, AE Kalinin, AE Aho, M Uitto, J Aho, S AF Kalinin, AE Kalinin, AE Aho, M Uitto, J Aho, S TI Breaking the connection: caspase 6 cleaves periplakin releasing the intermediate filament binding tail region from the actin binding N-terminal domain SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIAMS, NIH, Bethesda, MD USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NR 0 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 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 437 BP A73 EP A73 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500485 ER PT J AU Kawamura, T Iwamoto, T Koyanagi, Y Ito, M Blauvelt, A Shimada, S AF Kawamura, T Iwamoto, T Koyanagi, Y Ito, M Blauvelt, A Shimada, S TI Virus replication begins in Langerhans cells and not in dermal dendritic cells during transmission of HIV from skin emigrants to T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Yamanashi, Yamanashi, Japan. Tohoku Univ, Sendai, Miyagi 980, Japan. NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 796 BP A133 EP A133 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500846 ER PT J AU Khan, SG Oh, K Emmert, S Shahlavi, T Baker, CC Schmidt, DE DiGiovanna, JJ Kraemer, KH AF Khan, SG Oh, K Emmert, S Shahlavi, T Baker, CC Schmidt, DE DiGiovanna, JJ Kraemer, KH TI An identical mutation in the human XPC DNA repair gene in two patients with and without neurological symptoms SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, BRL, Bethesda, MD 20892 USA. Univ Gottingen, D-3400 Gottingen, Germany. NCI, LCO, Bethesda, MD 20892 USA. Brown Univ, Sch Med, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 505 BP A85 EP A85 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500555 ER PT J AU Kikuchi, K Kato, E Komine, M Tamaki, K Hoashi, T Hearing, VJ AF Kikuchi, K Kato, E Komine, M Tamaki, K Hoashi, T Hearing, VJ TI Cytokine and melanogenetic marker profiles in vitiligo vulgaris: therapeutic effects of narrow band UVB SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Tokyo, Grad Sch Med, Dept Dermatol, Bunkyo Ku, Tokyo, Japan. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 896 BP A150 EP A150 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500946 ER PT J AU Koch, T Ehrlich, A Turner, M Blauvelt, A AF Koch, T Ehrlich, A Turner, M Blauvelt, A TI Validation of an instrument to collect medically relevant information from psoriasis patients in a standardized manner SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 George Washington Univ, Dept Dermatol, Washington, DC USA. NCI, Dermatol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 386 BP A65 EP A65 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500438 ER PT J AU Li, S Takeuchi, F Wang, J Moss, J Darling, TN AF Li, S Takeuchi, F Wang, J Moss, J Darling, TN TI Tuberous sclerosis skin tumors overexpress MCP-1 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NHLBI, P CCMB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 BP A19 EP A19 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500163 ER PT J AU Liang, CA Schlucker, S Morris, A Imoto, K Levin, I Price, V Menefee, E Kraemer, KH DiGiovanna, JJ AF Liang, CA Schlucker, S Morris, A Imoto, K Levin, I Price, V Menefee, E Kraemer, KH DiGiovanna, JJ TI Structural and molecular hair abnormalities in trichothiodystrophy SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, BRL, Bethesda, MD USA. NIDDK, Phys Chem Lab, Bethesda, MD USA. UCSF, San Francisco, CA USA. Brown Med Sch, Providence, RI USA. RI Schlucker, Sebastian/D-1031-2010 OI Schlucker, Sebastian/0000-0003-4790-4616 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 644 BP A108 EP A108 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500696 ER PT J AU Liao, W Borris, D Blauvelt, A AF Liao, W Borris, D Blauvelt, A TI Kaposi's sarcoma-associated herpesvirus (KSHV) infection of human dermal microvascular endothelial cells (HDMEC) causes increased cellular proliferation, decreased cellular adhesion, and marked up-regulation of angiogenic growth factors SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 023 BP A4 EP A4 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500074 ER PT J AU Liu, X Llanso, A Salomon, D Glick, A AF Liu, X Llanso, A Salomon, D Glick, A TI Cripto-1 induces keratin 8 and 18 expression in primary mouse keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 158 BP A27 EP A27 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500212 ER PT J AU Miyagawa, F Sato, A Katz, SI AF Miyagawa, F Sato, A Katz, SI TI Identification of CD3+CD4-CD8-T cells as potential regulatory cells in tolerant double transgenic mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 741 BP A124 EP A124 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500789 ER PT J AU Morris, R Liu, Y Marles, L Yang, Z Trempus, C Li, S Lin, J Sawicki, J Cotsarelis, G AF Morris, R Liu, Y Marles, L Yang, Z Trempus, C Li, S Lin, J Sawicki, J Cotsarelis, G TI Isolation and characterization of adult hair follicle stem cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Penn, Philadelphia, PA 19104 USA. Columbia Univ, New York, NY USA. NIEHS, Res Triangle Pk, NC 27709 USA. Lankenau Med Inst, Wynewood, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 665 BP A111 EP A111 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500713 ER PT J AU Moslehi, R DiGiovanna, JJ Goldstein, AM Khan, SG Tucker, MA Schmidt, DE Kraemer, K AF Moslehi, R DiGiovanna, JJ Goldstein, AM Khan, SG Tucker, MA Schmidt, DE Kraemer, K TI Cancer risk and developmental abnormalities in xeroderma pigmentosum patients and heterozygotes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, DCEG, Bethesda, MD USA. NCI, BRL, Bethesda, MD USA. Brown Med Sch, Providence, RI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 371 BP A62 EP A62 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500419 ER PT J AU Niedermeier, A Sells, R Blauvelt, A AF Niedermeier, A Sells, R Blauvelt, A TI Small interfering RNA (siRNA) inhibition of Kaposi's sarcoma-associated herpes virus (KSHV) latency-associated nuclear antigen (LANA) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 803 BP A134 EP A134 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500850 ER PT J AU Oh, W Gerdes, M Orosz, A Yuspa, S Vinson, C AF Oh, W Gerdes, M Orosz, A Yuspa, S Vinson, C TI Inhibition of C/EBP family function in the mouse epidermis suppresses skin tumor formation and induces irreversibly hair loss SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Lab Cellular Carcinogenesis, NIH, Conshohocken, PA USA. NCI, Lab Tumor Promot, NIH, Conshohocken, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 113 BP A19 EP A19 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500164 ER PT J AU Ohyama, M Tock, C Terunuma, A Radonovich, M Brady, J Vogel, J AF Ohyama, M Tock, C Terunuma, A Radonovich, M Brady, J Vogel, J TI Microarray analysis of gene expression in the bulge of human anagen hair follicle following laser capture microdissection SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 678 BP A113 EP A113 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500728 ER PT J AU Owens, P Qiao, W Deng, C Wang, X AF Owens, P Qiao, W Deng, C Wang, X TI Smad4 is required in the maintenance of hair follicle integrity SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 OHSU, CDB, Portland, OR USA. NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 606 BP A101 EP A101 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500656 ER PT J AU Segre, J AF Segre, J TI Tetracycline-regulated transactivators driven by the involucrin promoter to achieve epidermal conditional gene expression SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NHGRI, GMBB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 534 BP A89 EP A89 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500584 ER PT J AU Stepp, M Pal-Ghosh, S Gerdes, MJ Larsen, M Yuspa, S AF Stepp, M Pal-Ghosh, S Gerdes, MJ Larsen, M Yuspa, S TI Genetic ablation of syndecan-1 increases proliferation and cell adhesion and delays senescence of mouse keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Univ Washington, Sch Med, Washington, DC USA. LCCTP, NCI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 210 BP A35 EP A35 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500261 ER PT J AU Sugaya, M Liao, W Blauvelt, A AF Sugaya, M Liao, W Blauvelt, A TI Oncostatin M-stimulated enclothelial cells, endothelial cells infected with Kaposi's sarcoma-associated herpesvirus, and KS tumor cells express CCL21 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 808 BP A135 EP A135 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500858 ER PT J AU Tada, Y Riedl, E Udey, MC AF Tada, Y Riedl, E Udey, MC TI Characterization of recombinant soluble mouse Langerin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 728 BP A122 EP A122 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500779 ER PT J AU Takeuchi, F Takeuchi, S Katz, SI AF Takeuchi, F Takeuchi, S Katz, SI TI Differential Langerhans cell gene expression profiling during the induction of contact hypersensitivity SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 744 BP A124 EP A124 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500793 ER PT J AU Takeuchi, S Kraemer, K Brash, DE AF Takeuchi, S Kraemer, K Brash, DE TI Contribution of pheomelanin and eumelanin to ultraviolet-induced apoptosis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Yale Univ, Sch Med, New Haven, CT USA. NCI, Basic Res Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 886 BP A148 EP A148 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500935 ER PT J AU Takeuchi, S Katz, SI AF Takeuchi, S Katz, SI TI Engraftment of Langerhans cells, as compared to plasmacytoid- or lymphoid-dendritic cells, occurs in an interleukin 7 receptor-independent manner SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 745 BP A125 EP A125 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500794 ER PT J AU Tang, X Kim, AL Kopelovich, L Bickers, DR Athar, M AF Tang, X Kim, AL Kopelovich, L Bickers, DR Athar, M TI Chemical inhibition of nuclear factor kappa B (NF kappa B) prevents UVB-induced squamous cell carcinomas (SCCs) in SKH-1 mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 Columbia Univ, New York, NY USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 150 BP A25 EP A25 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500202 ER PT J AU Terunuma, A Blonder, J Yee, C Conrads, TP Veenstra, TD Vogel, JC AF Terunuma, A Blonder, J Yee, C Conrads, TP Veenstra, TD Vogel, JC TI A proteomic characterization of the plasma membrane of human epidermis by high-throughput mass spectrometry SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Bethesda, MD 20892 USA. NCI, Mass Spec Ctr, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 464 BP A78 EP A78 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500517 ER PT J AU Trempus, C Morris, R Gerdes, M Fostel, J Bortner, C Humble, M Yuspa, S Tennant, R AF Trempus, C Morris, R Gerdes, M Fostel, J Bortner, C Humble, M Yuspa, S Tennant, R TI Gene expression by CD34-positive hair follicle bulge keratinocytes and expression patterns of bulge-specific genes following abrasion-induced epidermal regeneration SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIEHS, NCT Canc Biol Grp, Res Triangle Pk, NC USA. Columbia Univ, Dept Dermatol, New York, NY USA. NCI, LCCTP, Bethesda, MD USA. NIEHS, LST, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 440 BP A74 EP A74 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500492 ER PT J AU Ueda, T Gonzalez, V Khan, SG Oh, K Imoto, K Shahlavi, T Inui, H Busch, D DiGiovanna, JJ Kraemer, KH AF Ueda, T Gonzalez, V Khan, SG Oh, K Imoto, K Shahlavi, T Inui, H Busch, D DiGiovanna, JJ Kraemer, KH TI The R683W common mutation occurs in xeroderma pigmentosum group D patients with and without neurological symptoms SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NIH, Basic Res Lab, Bethesda, MD 20892 USA. AFIP, Washington, DC USA. Brown Univ, Sch Med, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 538 BP A90 EP A90 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500589 ER PT J AU Weinberg, WC Yamashita, T Tokino, T Young, M Ponnamperuma, R King, K AF Weinberg, WC Yamashita, T Tokino, T Young, M Ponnamperuma, R King, K TI Delta Np63 isotypes differentially regulate keratinocyte proliferation and differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 OBP FDA, Immunobiol Lab, Bethesda, MD USA. Sapporo Med Univ, Sapporo, Hokkaido, Japan. NIDCR, NIH, Bethesda, MD USA. RI Weinberg, Wendy/A-8920-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 134 BP A23 EP A23 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500189 ER PT J AU Yamaguchi, Y Itami, S Watabe, H Yasumoto, K Rouzaud, F Abdel-Malek, ZA Kubo, T Tanemura, A Yoshikawa, K Hearing, VJ AF Yamaguchi, Y Itami, S Watabe, H Yasumoto, K Rouzaud, F Abdel-Malek, ZA Kubo, T Tanemura, A Yoshikawa, K Hearing, VJ TI Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits mellanocyte growth and differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the Society-for-Investigative-Dermatology CY APR 28-MAY 01, 2004 CL Providence, RI SP Soc Investigat Dermatol C1 NCI, Cell Biol Lab, Bethesda, MD 20892 USA. Osaka Univ, Grad Sch Med, Suita, Osaka, Japan. Univ Cincinnati, Cincinnati, OH USA. RI Yamaguchi, Yuji/B-9312-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2004 VL 122 IS 3 MA 891 BP A149 EP A149 PG 1 WC Dermatology SC Dermatology GA 809UB UT WOS:000220660500938 ER PT J AU Segarra, M Vilardell, C Esparza, J Lozano, E Serra, C Campo, E Yamada, K Cid, MC AF Segarra, M Vilardell, C Esparza, J Lozano, E Serra, C Campo, E Yamada, K Cid, MC TI Dual role of focal adhesion kinase in regulating fibronectin-induced gelatinase (MMP-2 and MMP-9) production and release by human T lymphoid cell lines. SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Combined Annual Meeting of the Central-Society-for-Clinical-Research/Midwestern Section of the American-Federation-for-Medical-Research CY APR 15, 2004 CL Chicago, IL SP Cent Soc Clin Res, Amer Federat Med Res, Midwest Sect C1 Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain. NICDR, Craniofacial Dev & Regenerat Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2004 VL 52 IS 2 BP S402 EP S403 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 806EH UT WOS:000220416700195 ER PT J AU Emanuel, EJ AF Emanuel, EJ TI Ending concerns about undue inducement SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID RESEARCH SUBJECT; DEATH AB The charge of undue inducement is among the most serious ethical charges in clinical research. This is mistaken. Worries about undue inducement are really displacements of other ethical concerns. That undue inducements should not be an ethical concern related to human subjects research does not imply that there are no ethical concerns about payment for research, only that they are not related to high payments inducing poor judgment that lead to harm. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20814 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20814 USA. NR 22 TC 59 Z9 61 U1 0 U2 2 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SPR PY 2004 VL 32 IS 1 BP 100 EP + DI 10.1111/j.1748-720X.2004.tb00453.x PG 7 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 809SF UT WOS:000220655700011 PM 15152431 ER PT J AU Freund, CL Clayton, EW Wilfond, BS AF Freund, CL Clayton, EW Wilfond, BS TI Natural settings trials - Improving the introduction of clinical genetic tests SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID PRIMARY-CARE; SERVICES; CONSENT; TIME AB Clinical application of genetic tests is expanding from tests for single gene diseases of high penetrance to tests for single-gene disorders with low penetrance and genetic markers of susceptibility for common diseases. Testing is also moving from the research and subspecialty context to primary care settings. We propose that natural setting trials (NST), collecting rigorous research data while maintaining the natural practice environment be conducted to learn more about the translation of genetic tests from the research phase to actual clinical practice. Data from such studies could then be used to inform the development of realistic strategies for clinical use of genetic tests. C1 Vanderbilt Univ, Sch Med, Ctr Genet & Hlth Policy, Dept Pediat, Nashville, TN 37212 USA. NHGRI, Bioeth Res Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Freund, CL (reprint author), Vanderbilt Univ, Sch Med, Ctr Genet & Hlth Policy, Dept Pediat, 221 Kirkland Hall, Nashville, TN 37212 USA. NR 23 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SPR PY 2004 VL 32 IS 1 BP 106 EP + DI 10.1111/j.1748-720X.2004.tb00454.x PG 6 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 809SF UT WOS:000220655700012 PM 15152432 ER PT J AU Miller, FG AF Miller, FG TI Research ethics and misguided moral intuition SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID CLINICAL-RESEARCH; PLACEBO SURGERY AB Ethical evaluation of clinical research often appeals to moral judgments about the appropriate conduct of physicians in providing medical care. This article argues that this common ethical approach derives from misguided moral intuitions that conflate the ethics of clinical research with the ethics of medical care. Examples of this erroneous ethical approach are examined critically and objections to this critique are considered. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20814 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20814 USA. NR 18 TC 17 Z9 17 U1 0 U2 2 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SPR PY 2004 VL 32 IS 1 BP 111 EP + DI 10.1111/j.1748-720X.2004.tb00455.x PG 7 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 809SF UT WOS:000220655700013 PM 15152433 ER PT J AU Bafica, A Scanga, CA Equils, O Sher, A AF Bafica, A Scanga, CA Equils, O Sher, A TI The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE AIDS; bacterial; LPS; inflammation; TLR; HIV ID IMMUNODEFICIENCY-VIRUS TYPE-1; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; CHRONICALLY INFECTED-CELLS; LONG TERMINAL REPEAT; IMMUNE ACTIVATION; FACTOR-ALPHA; IN-VITRO; LIPOPOLYSACCHARIDE; MACROPHAGES AB Microbial-induced proinflammatory pathways are thought to play a key role in the activation of human immunodeficiency virus type 1 (HIV-1) gene expression. The induction of Toll-like receptor (TLR) tolerance leads to a complex reprogramming in the pattern of inflammatory gene expression and down-modulates tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, and IL-6 production. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome, including the long-terminal repeat, we have previously demonstrated that a number of different TLR ligands induce HIV-1 gene expression in cultured splenocytes as well as purified antigen-presenting cell populations. Here, we have used this model to determine the effect of TLR-mediated tolerance as an approach to inhibiting microbial-induced viral gene expression in vivo. Unexpectedly, Tg splenocytes and macrophages, rendered tolerant in vitro to TLR2, TLR4, and TLR9 ligands as assessed by proinflammatory cytokine secretion and nuclear factor-kappaB activation, showed enhanced HIV-1 p24 production. A similar enhancement was observed in splenocytes tolerized and then challenged with heterologous TLR ligands. Moreover, TLR2- and TLR4-homotolerized mice demonstrated significantly increased plasma p24 production in vivo despite lower levels of TNF-alpha. Together, these results demonstrate that HIV-1 expression is enhanced in TLR-reprogrammed host cells, possibly reflecting a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo. C1 NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20982 USA. Univ Calif Los Angeles, Sch Med, Div Pediat Infect Dis,Cedars Sinai Med Ctr, Steven Spielberg Pediat Res Ctr,Burns & Allen Res, Los Angeles, CA USA. RP Bafica, A (reprint author), NIAID, Immunol Sect, Parasit Dis Lab, NIH, 50 S Dr,MSC-8003,Bldg 50,Room 6146, Bethesda, MD 20982 USA. EM abafica@niaid.nih.gov NR 25 TC 23 Z9 24 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2004 VL 75 IS 3 BP 460 EP 466 DI 10.1189/jlb.0803388 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 801DL UT WOS:000220076500012 PM 14657211 ER PT J AU Megjugorac, NJ Young, HA Amrute, SB Olshalsky, SL Fitzgerald-Bocarsly, P AF Megjugorac, NJ Young, HA Amrute, SB Olshalsky, SL Fitzgerald-Bocarsly, P TI Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE cell trafficking; interferon; herpes simplex virus ID ALPHA-PRODUCING CELLS; INTERFERON-PRODUCING CELLS; NECROSIS-FACTOR-ALPHA; MANNOSE RECEPTOR; IFN-ALPHA; PERIPHERAL-BLOOD; ACCESSORY CELLS; CUTTING EDGE; HSV-1-INFECTED FIBROBLASTS; FUNCTIONAL DEFICIENCIES AB The natural interferon (IFN)-producing cell is now known to be identical to the plasmacytoid dendritic cell (PDC). These are Lin(-), CD123(+), CD11c(-), and human leukocyte antigen-DR+ cells that secrete large amounts of IFN-alpha (1-2 IU/cell) when stimulated by enveloped viruses such as herpes simplex virus. In the current study, we have evaluated chemokine expression by virally stimulated PDC. Up-regulation of mRNA for CCL4, CCL3, CCL5, CCL2, and CXC chemokine ligand (CXCL)10 in herpes simplex virus-stimulated PDC was detected by RNAse protection assays. In contrast, PDC-depleted peripheral blood mononuclear cells did not up-regulate these mRNA species upon viral stimulation. Enzyme-linked immunosorbent assay and/or intracellular flow cytometry confirmed production of these proteins, and studies indicated overlapping production of IFN-alpha and the other cytokines/chemokines by PDC. Endocytosis plays a critical role in chemokine induction, as disruption of the pathway inhibits the response. However, transcription of viral genes is not required for chemokine induction. Autocrine IFN-alpha signaling in the PDC could account for a portion of the CXCL10 and CCL2 production in virally stimulated PDC but was not responsible for the induction of the other chemokines. To evaluate the functional role of the chemokines, chemotaxis assays were performed using supernatants from virally stimulated PDC. Activated T cells and natural killer cells, but not naive T cells, were preferentially recruited by these PDC supernatants. Migration was subsequently inhibited by addition of neutralizing antibody to CCL4 and CXCL10. We hypothesize that virally induced chemokine production plays a pivotal role in the homing of leukocytes to PDC. C1 Univ Med & Dent New Jersey, Dept Pathol & Lab Med, Sch Med, Newark, NJ 07103 USA. Univ Med & Dent New Jersey Grad Sch Biomed Sci, Newark, NJ USA. NCI, Canc Res Ctr, Expt Immunol Lab, Frederick, MD USA. RP Fitzgerald-Bocarsly, P (reprint author), Univ Med & Dent New Jersey, Dept Pathol & Lab Med, Sch Med, 185 S Orange Ave, Newark, NJ 07103 USA. EM bocarsly@umdnj.edu RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 NR 70 TC 101 Z9 116 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2004 VL 75 IS 3 BP 504 EP 514 DI 10.1189/jlb.0603291 PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 801DL UT WOS:000220076500017 PM 14742635 ER PT J AU Vasko, V Saji, M Hardy, E Kruhlak, M Larin, A Savchenko, V Miyakawa, M Isozaki, O Murakami, H Tsushima, T Burman, KD De Micco, C Ringel, MD AF Vasko, V Saji, M Hardy, E Kruhlak, M Larin, A Savchenko, V Miyakawa, M Isozaki, O Murakami, H Tsushima, T Burman, KD De Micco, C Ringel, MD TI Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PROTEIN-KINASE B; PHOSPHATIDYLINOSITOL 3-KINASE; CELL-PROLIFERATION; BREAST-CANCER; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; TYROSINE KINASE; PLASMA-MEMBRANE; COWDEN-DISEASE; GROWTH-FACTORS AB Introduction: Akt activation is involved in the pathogenesis of inherited thyroid cancer in Cowden's syndrome and in sporadic thyroid cancers. In cell culture, Akt regulates thyroid cell growth and survival; but recent data suggest that Akt also regulates cell motility in non-thyroid cell lines. We therefore sought to evaluate the role of Akt in thyroid cancer progression. Methods: We evaluated 46 thyroid cancer, 20 thyroid follicular adenoma, and adjacent normal tissues samples by immunohistochemistry for activated Akt (pAkt), Akt 1, 2, and 3, and p27 expression. Immunoblots were performed in 14 samples. Results: Akt activation was identified in 10/10 follicular cancers, 26/26 papillary cancers, and 2/10 follicular variant of papillary cancers, but in only 4/66 normal tissue samples and 2/10 typical benign follicular adenomas. Immunoactive pAkt was greatest in regions of capsular invasion; and was localised to the nucleus in follicular cancers and the cytoplasm in papillary cancers, except for invasive regions of papillary cancers where it localised to both compartments. Immunoactive Akt 1, but not Akt 2 or Akt 3, correlated with pAkt localisation, and nuclear pAkt was associated with cytoplasmic expression of p27. In vitro studies using human thyroid cancer cells demonstrated that nuclear translocation of Akt 1 and pAkt were associated with cytoplasmic p27 and cell invasion and migration. Cell migration and the localisation of Akt 1, pAkt, and p27 were inhibited by PI3 kinase, but not MEK inhibition. Discussion: These data suggest an important role for nuclear activation of Akt 1 in thyroid cancer progression. C1 Ohio State Univ, Sch Med, Div Endocrinol, Columbus, OH 43210 USA. Ohio State Univ, Sch Med, Div Oncol, Columbus, OH 43210 USA. Arthur G James Canc Ctr, Columbus, OH USA. Washington Hosp Ctr, MedStar Res Inst, Washington, DC 20010 USA. Ctr Endocrine Surg, Kiev, Ukraine. Mediterranean Univ, INSERM, U555, Marseille, France. NCI, NIH, Bethesda, MD 20892 USA. Tokyo Womens Med Univ, Tokyo, Japan. RP Ringel, MD (reprint author), Ohio State Univ, Sch Med, Div Endocrinol, 455D McCambell Hall,1581 Dodd Dr, Columbus, OH 43210 USA. EM ringel-1@medctr.osu.edu RI Saji, Motoyasu/E-4007-2011; OI Larin, Oleksandr/0000-0002-5090-5110 FU NCI NIH HHS [CAN 8335479] NR 63 TC 149 Z9 155 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1468-6244 J9 J MED GENET JI J. Med. Genet. PD MAR 1 PY 2004 VL 41 IS 3 BP 161 EP 170 DI 10.1136/jmg.2003.015339 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 779ZR UT WOS:000189344300005 PM 14985374 ER PT J AU Villablanca, A Calender, A Forsberg, L Hoog, A Cheng, JD Petillo, D Bauters, C Kahnoski, K Ebeling, T Salmela, P Richardson, AL Delbridge, L Meyrier, A Proye, C Carpten, JD Teh, BT Robinson, BG Larsson, C AF Villablanca, A Calender, A Forsberg, L Hoog, A Cheng, JD Petillo, D Bauters, C Kahnoski, K Ebeling, T Salmela, P Richardson, AL Delbridge, L Meyrier, A Proye, C Carpten, JD Teh, BT Robinson, BG Larsson, C TI Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP) SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; MEN1 GENE; HEREDITARY HYPERPARATHYROIDISM; PARATHYROID TUMORS; RECEPTOR; LOCUS; MAPS; HYPERCALCEMIA; MOSAICISM; KINDREDS C1 Karolinska Hosp, Dept Mol Med, S-10401 Stockholm, Sweden. Karolinska Hosp, Dept Oncol Pathol, S-10401 Stockholm, Sweden. Canc Genet Lab, CNRS, UMR, Lyon, France. Van Andel Res Inst, Grand Rapids, MI USA. CHRU Lille, Serv Endocrinol, Lille, France. Oulu Univ Hosp, Dept Internal Med, Oulu, Finland. Royal N Shore Hosp, Kolling Inst Med Res, Canc Genet Unit, Sydney, NSW, Australia. Univ Sydney, Dept Mol Med, Sydney, NSW 2006, Australia. Hop Broussais, Serv Nephrol, F-75674 Paris, France. CHRU Lille, Serv Chirurg Endocrine, Lille, France. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Villablanca, A (reprint author), Karolinska Hosp, Dept Mol Med, S-10401 Stockholm, Sweden. EM andrea.villablanca@cmm.ki.se NR 34 TC 37 Z9 38 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1468-6244 J9 J MED GENET JI J. Med. Genet. PD MAR 1 PY 2004 VL 41 IS 3 AR e32 DI 10.1136/jmg.2003.012369 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 779ZR UT WOS:000189344300031 PM 14985403 ER PT J AU Milanowski, DJ Rashid, MA Gustafson, KR O'Keefe, BR Nawrocki, JP Pannell, LK Boyd, MR AF Milanowski, DJ Rashid, MA Gustafson, KR O'Keefe, BR Nawrocki, JP Pannell, LK Boyd, MR TI Cyclonellin, a new cyclic octapeptide from the marine sponge Axinella carteri SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ANTINEOPLASTIC AGENTS; AXINASTATIN-4 AB Cyclonellin (1), a new cyclic octapeptide, was isolated from an aqueous extract of the marine sponge Axinella carteri. Its structure was elucidated by interpretation of NMR spectral data of the intact compound and N-terminal Edman sequencing of linear peptide fragments obtained by partial hydrolysis of 1. The absolute configurations of the constituent amino acids were determined by acid hydrolysis, derivitization with FDAA, and LC-MS analyses. C1 Canc Res Ctr, Mol Targets Dev Program, NCI, Frederick, MD 21702 USA. SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ S Alabama, Coll Med, USA Canc Res Inst, Mobile, AL 36688 USA. RP Gustafson, KR (reprint author), Canc Res Ctr, Mol Targets Dev Program, NCI, Bldg 1052,Room 121, Frederick, MD 21702 USA. EM manuscripts@mail.ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 18 TC 9 Z9 10 U1 0 U2 4 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 MAR PY 2004 VL 67 IS 3 BP 441 EP 444 DI 10.1021/np030336x PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 807TJ UT WOS:000220523500026 PM 15043426 ER PT J AU Grant, P Pant, HC AF Grant, P Pant, HC TI Topographic regulation of phosphorylation in giant neurons of the squid, Loligo pealei: Role of phosphatases SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE axon; kinase; phosphorylation; squid; tyrosine phosphatase ID PROTEIN-TYROSINE PHOSPHATASES; NEUROFILAMENT PROTEIN; SCAFFOLD PROTEINS; CDC2-LIKE KINASE; OKADAIC ACID; AXOPLASM; COMPLEX; AXON; 2A; MICROTUBULES AB In previous studies of phosphorylation in squid stellate ganglion neurons, we demonstrated that a specific multimeric phosphorylation complex characterized each cellular compartment. Although the endogenous protein profile of cell body extracts (giant fiber lobe, GFL), as determined by Coomassie staining, was similar to that of axoplasm from the giant axon, in this study we show that the protein phospborylation profiles are qualitatively different. Whereas many axoplasm proteins were phosphorylated, including most cytoskeletal proteins, virtually all phosphorylation in perikarya was confined to low molecular weight compounds (<6 kDa). Because phosphorylation of exogenous substrates, histone and casein, was equally active in extracts from both compartments, failure to detect endogenous protein phosphorylation in cell bodies was attributed to the presence of more active phosphatases. To further explore the role of phosphatases in these neurons, we studied phosphorylation in the presence of serine/threonine and protein tyrosine phosphatase (PTP) inhibitors. We found that phosphorylation of axonal cytoskeletal proteins was modulated by okadaic acid-sensitive ser/thr phosphatases, whereas cell body phosphorylation was more sensitive to an inhibitor of protein tyrosine phosphatases, such as vanadate. Inhibition of PTPs by vanadate stimulated endogenous phosphorylation of GFL proteins, including cytoskeletal proteins. Protein tyrosine kinase activity was equally stimulated by vanadate in cell body and axonal whole homogenates and Triton X-100 free soluble extracts, but only the Triton X soluble fraction (membrane bound proteins) of the GFL exhibited significant activation in the presence of vanadate, suggesting higher PTP activities in this fraction than in the axon. The data are consistent with the hypothesis that neuronal protein phosphorylation in axons and cell bodies is modulated by different phosphatases associated with compartment-specific multimeric complexes. (C) 2004 Wiley Periodicals, Inc. C1 Natl Inst Neurol Disorders & Stroke, Neurochem Lab, LNC, NINDS,NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP Natl Inst Neurol Disorders & Stroke, Neurochem Lab, LNC, NINDS,NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov NR 42 TC 7 Z9 7 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD MAR PY 2004 VL 58 IS 4 BP 514 EP 528 DI 10.1002/neu.10305 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 779YB UT WOS:000189329000008 PM 14978728 ER PT J AU Hamelink, C Hahm, SH Huang, H Eiden, LE AF Hamelink, C Hahm, SH Huang, H Eiden, LE TI A restrictive element 1 (RE-1) in the VIP gene modulates transcription in neuronal and non-neuronal cells in collaboration with an upstream tissue specifier element SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE gene expression; neuroblastoma; repression; signal transduction ID VASOACTIVE-INTESTINAL-PEPTIDE; BETA-HYDROXYLASE GENE; SILENCER ELEMENT; TRANSGENIC MICE; BLASTOMA CELLS; RECEPTOR GENE; EXPRESSION; RAT; IDENTIFICATION; ACTIVATION AB The vasoactive intestinal peptide (VIP) gene has been studied extensively as a prototype neuronal gene containing multiple cis-active elements that confer responsiveness to cell lineage, neurotrophic, and activity-dependent intrinsic and extrinsic cues. However, reporter genes containing the presumptive complete regulatory region 5' to the start of transcription do not confer tissue-specific gene expression in vivo. We therefore sought cis-regulatory elements downstream of the transcriptional start that might confer additional tissue-specific and tissue-restrictive properties to the VIP transcriptional unit. We report here a repressor element, similar to the canonical restrictive element-1 (RE-1), located within the first non-coding exon of the human VIP gene. The ability of this element to regulate VIP reporter gene expression in neuroblastoma and fibroblastic cells was examined. Endogenous VIP expression is high in SH-EP neuroblastoma cells, low but inducible in SH-SY5Y cells, and absent in HeLa cells. Endogenous RE-1 silencer factor (REST) expression was highest in SH-EP and HeLa cells, and significantly lower in SH-SY5Y cells. Transient transfection of a VIP reporter gene containing a mutated RE-1 sequence revealed an RE-1-dependent regulation of VIP gene expression in all three cell types, with regulation greatest in cells (SH-EP, HeLa) with highest levels of REST expression. Serial truncation of the VIP reporter gene further revealed a specific interaction between the RE-1 and a tissue-specifier element located 5 kb upstream in the VIP gene. Thus, REST can regulate VIP gene expression in both neuroblastic and non-neuronal cells, but requires coupling to the upstream tissue specifier element. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Recognit, NIH, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), Bldg 36,Room 2 A-11,9000 Rockville Pike, Bethesda, MD 20814 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X NR 37 TC 7 Z9 8 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2004 VL 88 IS 5 BP 1091 EP 1101 DI 10.1046/j.1471-4159.2003.02241.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 775QA UT WOS:000189051800006 PM 15009665 ER PT J AU Quarta, D Ferre, S Solinas, M You, ZB Hockemeyer, J Popoli, P Goldberg, SR AF Quarta, D Ferre, S Solinas, M You, ZB Hockemeyer, J Popoli, P Goldberg, SR TI Opposite modulatory roles for adenosine A(1) and A(2A) receptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adenosine; caffeine; dopamine; glutamate; microdialysis; nucleus accumbens ID RAT STRIATUM; NEUROTRANSMITTER RELEASE; EXTRACELLULAR DOPAMINE; IN-VIVO; BRAIN; MICRODIALYSIS; FACILITATION; INHIBITION; PATHWAY; OUTFLOW AB Previous studies have demonstrated opposing roles for adenosine A(1) and A(2A) receptors in the modulation of extracellular levels of glutamate and dopamine in the striatum. In the present study, acute systemic administration of motor-activating doses of the A(2A) receptor antagonist MSX-3 significantly decreased extracellular levels of dopamine and glutamate in the shell of the rat nucleus accumbens (NAc) and counteracted both dopamine and glutamate release induced by systemic administration of motor-activating doses of either the A(1) receptor antagonist CPT or caffeine. Furthermore, exposure to caffeine in the drinking water (1 mg/mL, 14 days) resulted in tolerance to the effects of systemic injection of CPT or caffeine, but not MSX-3, on extracellular levels of dopamine and glutamate in the NAc shell. The present results show: first, the existence of opposite tonic effects of adenosine on extracellular levels of dopamine and glutamate in the shell of the NAc mediated by A(1) and A(2A) receptors; second, that complete tolerance to caffeine's dopamine- and glutamate-releasing effects which develops after chronic caffeine exposure is attributable to an A(1) receptor-mediated mechanism. Development of tolerance to the dopamine-releasing effects of caffeine in the shell of the NAc may explain its weak addictive properties and atypical psychostimulant profile. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch,IRP, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Behav Neurosci Sect, Behav Neurosci Branch,IRP, NIH,DHHS, Baltimore, MD 21224 USA. Univ Bonn, Ist Super Sanita, D-5300 Bonn, Germany. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch,IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov RI Popoli, Patrizia/B-5397-2008; Ferre, Sergi/K-6115-2014; Solinas, Marcello/M-3500-2016 OI Ferre, Sergi/0000-0002-1747-1779; Solinas, Marcello/0000-0002-0664-5964 NR 33 TC 85 Z9 87 U1 1 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2004 VL 88 IS 5 BP 1151 EP 1158 DI 10.1046/j.1471-4159.2003.02245.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 775QA UT WOS:000189051800011 PM 15009670 ER PT J AU Rosenberger, TA Villacreses, NE Hovda, JT Bosetti, F Weerasinghe, G Wine, RN Harry, GJ Rapoport, SI AF Rosenberger, TA Villacreses, NE Hovda, JT Bosetti, F Weerasinghe, G Wine, RN Harry, GJ Rapoport, SI TI Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; neuroinflammation; phospholipase A(2); phospholipid; plasmalogen; prostaglandin ID CYTOSOLIC PHOSPHOLIPASE A(2); PERFORMANCE LIQUID-CHROMATOGRAPHY; ALZHEIMERS-DISEASE BRAIN; NECROSIS-FACTOR-ALPHA; SIGNAL-TRANSDUCTION; CHRONIC NEUROINFLAMMATION; PLASMALOGEN DEFICIENCY; TNF-ALPHA; CELL-LINE; IN-VIVO AB In a rat model of acute neuroinflammation, produced by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide (LPS), we measured brain activities and protein levels of three phospholipases A(2) (PLA(2)) and of cyclo-oxygenase-1 and -2, and quantified other aspects of brain phospholipid and fatty acid metabolism. The 6-day intracerebral ventricular infusion increased lectin-reactive microglia in the cerebral ventricles, pia mater, and the glial membrane of the cortex and resulted in morphological changes of glial fibrillary acidic protein (GFAP)-positive astrocytes in the cortical mantel and areas surrounding the cerebral ventricles. LPS infusion increased brain cytosolic and secretory PLA(2) activities by 71% and 47%, respectively, as well as the brain concentrations of non-esterified linoleic and arachidonic acids, and of prostaglandins E-2 and D-2. LPS infusion also increased rates of incorporation and turnover of arachidonic acid in phosphatidylethanolamine, plasmenylethanolamine, phosphatidylcholine, and plasmenylcholine by 1.5- to 2.8-fold, without changing these rates in phosphatidylserine or phosphatidylinositol. These observations suggest that selective alterations in brain arachidonic acid metabolism involving cytosolic and secretory PLA(2) contribute to early pathology in neuroinflammation. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Rosenberger, TA (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Room 6 N202, Bethesda, MD 20892 USA. EM plsetn@mail.nih.gov NR 76 TC 85 Z9 85 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2004 VL 88 IS 5 BP 1168 EP 1178 DI 10.1046/j.1471-4159.2003.02246.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 775QA UT WOS:000189051800013 PM 15009672 ER PT J AU Takahashi, S Kulkarni, AB AF Takahashi, S Kulkarni, AB TI Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin-dependent kinase 5 activation by p35 or p25 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; amyotrophic lateral sclerosis; cyclin-dependent kinase 5; p35; neurodegeneration; superoxide dismutase 1 ID AMYOTROPHIC-LATERAL-SCLEROSIS; GLIAL GLUTAMATE TRANSPORTER; TRANSGENIC MICE; NEUROFIBRILLARY TANGLES; INTRACELLULAR CALCIUM; SOD1 MUTANTS; MOUSE MODEL; TAU-PROTEIN; DISEASE; ALS AB Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Neurotoxicity mediated by glutamate is thought to play a role in the neuronal death through intracellular calcium-dependent signaling cascades. Cyclin-dependent kinase 5 (Cdk5) has been proposed as one of the calcium-dependent mediators that may cause neuronal death observed in this disease. Cdk5 is activated in neurons by the association with its activators, p35 or p39. The calcium-activated protease calpain cleaves p35 to its truncated product, p25, which eventually causes the cellular mislocalization and prolonged activation of Cdk5. This deregulated Cdk5 induces cytoskeletal disruption and apoptosis. To examine whether inhibition of the calpain-mediated conversion of p35 to p25 can delay the disease progression of ALS, we generated double transgenic mice in which ALS-linked mutant copper/zinc superoxide dismutase 1 (SOD1(G93A)) was expressed in a p35-null background. The absence of p35 neither affected the onset and progression of motor neuron disease in the mutant SOD1 mice nor ameliorated the pathological lesions in these mice. Our results provide direct evidence that the pathogenesis of motor neuron disease in the mutant SOD1 mice is independent of the Cdk5 activation by p35 or p25. C1 Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bldg 30,Room 527,30 Convent Dr, Bethesda, MD 20892 USA. EM ak40m@nih.gov NR 43 TC 11 Z9 14 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2004 VL 88 IS 5 BP 1295 EP 1304 DI 10.1046/j.1471-4159.2003.02256.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 775QA UT WOS:000189051800026 PM 15009685 ER PT J AU Wu, Z Ji, H Hassan, A Aguilera, G Sandberg, K AF Wu, Z Ji, H Hassan, A Aguilera, G Sandberg, K TI Regulation of pituitary corticotropin releasing factor type-1 receptor mRNA binding proteins by modulation of the hypothalamic-pituitary-adrenal axis SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE corticotropin releasing factor type 1 receptor (CRF-R1); adrenalectomy; angiotensin type 1a receptor (AT(1a)); 5 ' leader sequence (5 ' LS); mRNA binding proteins; post-transcriptional regulation; hypothalamic-pituitary-adrenal (HPA) axis ID FACTOR CRF RECEPTORS; RIBONUCLEIC-ACID; GLUCOCORTICOID REGULATION; SECONDARY STRUCTURE; HORMONE CRH; RAT; PHARMACOLOGY; EXPRESSION; GLAND; BRAIN AB Long-term adrenalectomy (ADX) is associated with marked down-regulation of pituitary corticotropin releasing factor type-1 receptors (CRF-R1) but normal CRF-R1 mRNA levels, suggesting that regulation of receptor levels occurs at post-transcriptional sites. We have reported that adrenal cytosolic proteins, which bind to cis elements in the 5' leader sequence (5'LS) of the rat angiotensin II type 1a receptor (AT(1a)R) mRNA, participate in the regulation of AT(1a)R density by inhibiting AT(1a)R mRNA translation. In this study, we examined anterior pituitary cytosolic proteins that form RNA protein complexes (RPC) with the 5'LS of the CRF-R1 and the AT(1a)R. Competition studies and ultraviolet-crosslinking analysis suggest that formation of CRF-R1 and AT(1a)R 5'LS RPC require at least some proteins that are common to both receptor mRNAs. Pituitaries isolated from male Sprague-Dawley rats six days after ADX showed significant (P < 0.05) increases of 2.9-fold in CRF-R1 5'LS RNA binding protein (BP) activity compared to pituitaries from sham-operated rats; this effect of ADX was prevented by glucocorticoid replacement. By contrast, no differences in the number of pituitary AT(1a)R binding sites or pituitary AT(1a)R 5'LS BP activity were observed between sham and ADX rats, indicating that the effect of ADX on RPC formation was specific for CRF-R1 mRNA. Addition of pituitary cytosolic extracts inhibited in vitro translation of CRF-R1 mRNA by 79% under conditions that had no significant effects on the translation of a control mRNA. The data suggest that CRF-R1 translation is regulated by modulation of the HPA axis through pituitary cytosolic proteins binding to the CRF-R1 5'LS. C1 Georgetown Univ, Ctr Study Sex Differences, Washington, DC 20057 USA. NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Sandberg, K (reprint author), Georgetown Univ, Ctr Study Sex Differences, Suite 232,Bldg D,4000 Reservoir Rd NW, Washington, DC 20057 USA. EM sandberg@georgetown.edu FU NHLBI NIH HHS [HL 57502] NR 25 TC 4 Z9 5 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD MAR PY 2004 VL 16 IS 3 BP 214 EP 220 DI 10.1111/j.0953-8194.2004.01153.x PG 7 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 807EZ UT WOS:000220486100005 PM 15049852 ER PT J AU Read, JCA Cumming, BG AF Read, JCA Cumming, BG TI Ocular dominance predicts neither strength nor class of disparity selectivity with random-dot stimuli in primate V1 SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CATS VISUAL-CORTEX; SIMPLE CELLS; BINOCULAR DISPARITY; HORIZONTAL-DISPARITY; STRIATE CORTEX; COMPLEX CELLS; STEREOSCOPIC MECHANISMS; DEPTH DISCRIMINATION; NEURAL MECHANISMS; RECEPTIVE-FIELDS AB We address two unresolved issues concerning the coding of binocular disparity in primary visual cortex. Experimental studies and theoretical models have suggested a relationship between a cell's ocular dominance, assessed with monocular stimuli, and its tuning to binocular disparity. First, the disparity energy model of disparity selectivity suggests that there should be a correlation between ocular dominance and the strength of disparity tuning. Second, several studies have reported a relationship between ocular dominance and the shape of the disparity tuning curve, with cells dominated by one eye more likely to have disparity tuning of the tuned-inhibitory type. We investigated both of these relationships in single neurons recorded from the primary visual cortex of awake fixating macaques, using dynamic random-dot patterns as a stimulus. To classify disparity tuning curves quantitatively, we develop a new measure of symmetry, which can be applied to any function. We find no evidence for any correlation between ocular dominance and the nature of disparity tuning. This places constraints on the circuitry underlying disparity tuning. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Read, JCA (reprint author), NEI, Sensorimotor Res Lab, NIH, 49-2A50 Convent Dr, Bethesda, MD 20892 USA. EM jcr@lsr.nei.nih.gov RI Read, Jenny/A-7493-2013 OI Read, Jenny/0000-0002-9029-5185 FU NEI NIH HHS [Z01 EY000404-04] NR 36 TC 25 Z9 25 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR 1 PY 2004 VL 91 IS 3 BP 1271 EP 1281 DI 10.1152/jn.00588.2003 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 774VG UT WOS:000189005800016 PM 14523074 ER PT J AU Vinnikova, AK Alam, RI Malik, SA Ereso, GL Feldman, GM McCarty, JM Knepper, MA Heck, GL DeSimone, JA Lyall, V AF Vinnikova, AK Alam, RI Malik, SA Ereso, GL Feldman, GM McCarty, JM Knepper, MA Heck, GL DeSimone, JA Lyall, V TI Na+-H+ exchange activity in taste receptor cells SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID INTRACELLULAR PH; EXTRACELLULAR PH; CHORDA TYMPANI; CAROTID-BODY; NEONATAL RAT; NEURONS; TRANSDUCTION; INHIBITION; MECHANISMS; RESPONSES AB mRNA for two Na+-H+-exchanger isoforms 1 and 3 (NHE-1 and NHE-3) was detected by RT-PCR in fungiform and circumvallate taste receptor cells (TRCs). Anti-NHE-1 antibody binding was localized to the basolateral membranes, and the anti-NHE-3 antibody was localized in the apical membranes of fungiform and circumvallate TRCs. In a subset of TRCs, NHE-3 immunoreactivity was also detected in the intracellular compartment. For functional studies, an isolated lingual epithelium containing a single fungiform papilla was mounted with apical and basolateral sides isolated and perfused with nominally CO2/HCO3--free physiological media (pH 7.4). The TRCs were monitored for changes in intracellular pH (pH(i)) and Na+ ([Na+](i)) using fluorescence ratio imaging. At constant external pH, 1) removal of basolateral Na+ reversibly decreased pH(i) and [Na+](i); 2) HOE642, a specific blocker, and amiloride, a nonspecific blocker of basolateral NHE-1, attenuated the decrease in pH(i) and [Na+](i); 3) exposure of TRCs to basolateral NH4Cl or sodium acetate pulses induced transient decreases in pH i that recovered spontaneously to baseline; 4) pH(i) recovery was inhibited by basolateral amiloride, 5-(N-methyl-N-isobutyl)-amiloride (MIA), 5-(N-ethyl-N-isopropyl)amiloride (EIPA), HOE642, and by Na+ removal; 5) HOE642, MIA, EIPA, and amiloride inhibited pH(i) recovery with K-i values of 0.23, 0.46, 0.84, and 29 muM, respectively; and 6) a decrease in apical or basolateral pH acidified TRC pH(i) and inhibited spontaneous pH(i) recovery. The results indicate the presence of a functional NHE-1 in the basolateral membranes of TRCs. We hypothesize that NHE-1 is involved in sour taste transduction since its activity is modulated during acid stimulation. C1 Virginia Commonwealth Univ, Dept Physiol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA. McGuire Dept Vet Affairs Med Ctr, Richmond, VA 23249 USA. NIH, Bethesda, MD 20892 USA. RP Lyall, V (reprint author), Virginia Commonwealth Univ, Dept Physiol, Sanger Hall 3002,1101 E Marshall St, Richmond, VA 23298 USA. EM vlyall@hsc.vcu.edu FU NIDCD NIH HHS [DC-02422, DC-00122] NR 36 TC 23 Z9 23 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR 1 PY 2004 VL 91 IS 3 BP 1297 EP 1313 DI 10.1152/jn.00809.2003 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 774VG UT WOS:000189005800018 PM 14602837 ER PT J AU Sommer, MA Wurtz, RH AF Sommer, MA Wurtz, RH TI What the brain stem tells the frontal cortex. I. Oculomotor signals sent from superior colliculus to frontal eye field via mediodorsal thalamus SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID LATERAL GENICULATE-NUCLEUS; 3 MOTOR AREAS; RETROGRADE HORSERADISH-PEROXIDASE; POSTERIOR PARIETAL CORTEX; CAT STRIATE CORTEX; VISUAL-CORTEX; RHESUS-MONKEY; NEURAL REPRESENTATIONS; VISUOMOTOR FUNCTIONS; CEREBRAL-CORTEX AB Neuronal processing in cerebral cortex and signal transmission from cortex to brain stem have been studied extensively, but little is known about the numerous feedback pathways that ascend from brain stem to cortex. In this study, we characterized the signals conveyed through an ascending pathway coursing from the superior colliculus (SC) to the frontal eye field (FEF) via mediodorsal thalamus (MD). Using antidromic and orthodromic stimulation, we identified SC source neurons, MD relay neurons, and FEF recipient neurons of the pathway in Macaca mulatta. The monkeys performed oculomotor tasks, including delayed-saccade tasks, that permitted analysis of signals such as visual activity, delay activity, and presaccadic activity. We found that the SC sends all of these signals into the pathway with no output selectivity, i.e., the signals leaving the SC resembled those found generally within the SC. Visual activity arrived in FEF too late to contribute to short-latency visual responses there, and delay activity was largely filtered out in MD. Presaccadic activity, however, seemed critical because it traveled essentially unchanged from SC to FEF. Signal transmission in the pathway was fast (similar to2 ms from SC to FEF) and topographically organized (SC neurons drove MD and FEF neurons having similarly eccentric visual and movement fields). Our analysis of identified neurons in one pathway from brain stem to frontal cortex thus demonstrates that multiple signals are sent from SC to FEF with presaccadic activity being prominent. We hypothesize that a major signal conveyed by the pathway is corollary discharge information about the vector of impending saccades. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,MSC 4435,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mas@lsr.nei.nih.gov NR 105 TC 168 Z9 171 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 MAR 1 PY 2004 VL 91 IS 3 BP 1381 EP 1402 DI 10.1152/jn.00738.2003 PG 22 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 774VG UT WOS:000189005800024 PM 14573558 ER PT J AU Sommer, MA Wurtz, RH AF Sommer, MA Wurtz, RH TI What the brain stem tells the frontal cortex. II. Role of the SC-MD-FEF pathway in corollary discharge SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID MONKEY SUPERIOR COLLICULUS; SACCADIC EYE-MOVEMENTS; REVERSIBLE INACTIVATION; FUNCTIONAL-PROPERTIES; VISUAL RESPONSES; RHESUS-MONKEY; FIELD; NEURONS; LESIONS; SYSTEM AB One way we keep track of our movements is by monitoring corollary discharges or internal copies of movement commands. This study tested a hypothesis that the pathway from superior colliculus (SC) to mediodorsal thalamus (MD) to frontal eye field (FEF) carries a corollary discharge about saccades made into the contralateral visual field. We inactivated the MD relay node with muscimol in monkeys and measured corollary discharge deficits using a double-step task: two sequential saccades were made to the locations of briefly flashed targets. To make second saccades correctly, monkeys had to internally monitor their first saccades; therefore deficits in the corollary discharge representation of first saccades should disrupt second saccades. We found, first, that monkeys seemed to misjudge the amplitudes of their first saccades; this was revealed by systematic shifts in second saccade end points. Thus corollary discharge accuracy was impaired. Second, monkeys were less able to detect trial-by-trial variations in their first saccades; this was revealed by reduced compensatory changes in second saccade angles. Thus corollary discharge precision also was impaired. Both deficits occurred only when first saccades went into the contralateral visual field. Single-saccade generation was unaffected. Additional deficits occurred in reaction time and overall performance, but these were bilateral. We conclude that the SC-MD-FEF pathway conveys a corollary discharge used for coordinating sequential saccades and possibly for stabilizing vision across saccades. This pathway is the first elucidated in what may be a multilevel chain of corollary discharge circuits extending from the extraocular motoneurons up into cerebral cortex. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,MSC 4435,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mas@lsr.nei.nih.gov NR 90 TC 131 Z9 132 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR 1 PY 2004 VL 91 IS 3 BP 1403 EP 1423 DI 10.1152/jn.00740.2003 PG 21 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 774VG UT WOS:000189005800025 PM 14573557 ER PT J AU Choo, D Shotland, L Mastroianni, M Glenn, G Van Waes, C Linehan, WM Oldfield, EH AF Choo, D Shotland, L Mastroianni, M Glenn, G Van Waes, C Linehan, WM Oldfield, EH TI Endolymphatic sac tumors in von Hippel-Lindau disease SO JOURNAL OF NEUROSURGERY LA English DT Article DE von Hippel-Lindau disease; endolymphatic sac; Meniere disease; adenocarcinoma; inner ear ID MENIERES-DISEASE; SUPPRESSOR GENE; PATHOGENESIS; MUTATIONS; SYMPTOMS; FEATURES; HYDROPS AB Object. Von Hippel-Lindau (VHL) disease is a hereditary multiple-neoplasia syndrome mapping to chromosome 3p25-26. Endolymphatic sac (ELS) tumors have been identified as a neoplastic manifestation of VHL disease. The purpose of this study was to evaluate comprehensively the natural history of inner ear disease in a large population of patients with confirmed or suspected VHL disease and to correlate the clinical features with the VHL genotype. Methods. The authors collated and analyzed clinical and genotypic data obtained in patients enrolled in an Institutional Review Board-approved protocol in which families and individuals affected by VHL disease were studied. These data included results from multidisciplinary history workups and physical examinations, imaging studies, and a battery of audiological tests. One hundred seventy-five patients were enrolled in the study, 129 with confirmed VHL disease and 46 of their family members in whom test results for VHL disease were negative and who served as controls. Twenty-one patients had ELS tumors that were evident on magnetic resonance images; three of them had bilateral ELS lesions. Hearing loss, often sudden in onset and severe to profound in nature, vestibulopathy, aural fullness, and tinnitus represented the primary symptoms of ELS tumor. Distinct patterns of auditory and vestibular dysfunction occurred at different stages of the disease. Phenotypic data showed that 17 of 21 patients with ELS tumors did not have pheochromocytomas, whereas all had VHL disease affecting the kidney, all but two had VHL disease affecting the central nervous system, and all but one had disease affecting the pancreas. Genotyping revealed 10 rearrangements (partial deletions), eight single bp substitutions, and one 3-bp insertion. Although there was no difference in the incidence of hearing loss between populations, symptoms of imbalance and aural fullness were more common in patients with VHL disease but without imaging evidence of ELS tumor than they were in family members who did not have VHL disease (p < 0.01). Conclusions. Endolymphatic sac tumors are frequently associated with VHL disease. Symptoms of disequilibrium or aural fullness in patients with VHL disease may be an early indication of endolymphatic dysfunction. Patients with VHL disease provide a unique opportunity to examine the effects of specific gene mutations and a discrete neoplastic process on the human inner ear. The study of ELS tumors in this group also provides a pathological model of ELS function and supplies evidence for a role of the ELS in clinical Meniere-like disease(s). C1 Natl Inst Deafness & Other Commun Disorders, Neuro Otol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), Natl Inst Deafness & Other Commun Disorders, Neuro Otol Branch, NIH, Room 5D37,Bldg 10, Bethesda, MD 20892 USA. EM eo10d@nih.gov NR 23 TC 40 Z9 41 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD MAR PY 2004 VL 100 IS 3 BP 480 EP 487 DI 10.3171/jns.2004.100.3.0480 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 802TS UT WOS:000220186400019 PM 15035284 ER PT J AU Ross, SA Srinivas, PR Clifford, AJ Lee, SC Philbert, MA Hettich, RL AF Ross, SA Srinivas, PR Clifford, AJ Lee, SC Philbert, MA Hettich, RL TI New technologies for nutrition research SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Experimental Biology 2003 Meeting CY APR 11-15, 2003 CL SAN DIEGO, CA DE bioactive food components; food science; accelerator mass spectrometry; nanotechnology; proteomics ID ATOMIC-FORCE MICROSCOPY; SINGLE LIVING CELLS; OPTICAL NANOSENSORS; MASS-SPECTROMETRY; CHEMICAL-ANALYSIS; GENE-EXPRESSION; PEBBLE SENSORS; BETA-CAROTENE; NANOTECHNOLOGY; DESIGN AB The Experimental Biology 2003 symposium entitled "New Technologies for Nutrition Research" was organized to highlight new and emerging technologies, including nanotechnology and proteomics, and to suggest ways for their integration into nutrition research. Speakers focused on topics that included accelerator mass spectrometry for ultra-low level radiolabel tracing, nanodevices for real-time optical intracellular sensing, mass spectrometric techniques for examining protein expression, as well as potential applications for nanotechnology in the food sciences. These technologies may be particularly useful in obtaining accurate spatial information and low-level detection of essential and nonessential bioactive food components (nutrients) and their metabolites, and in enhancing the understanding of the impact of nutrient/metabolite and biomolecular interactions. Highlights from this symposium are presented briefly herein. C1 NCI, Nutrit Sci Res Grp, Div Canc Prevent, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Vasc Biol Res Program, Div Heart & Vasc Dis, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. Ohio State Univ, Coll Engn, Ctr Biomed Engn, Columbus, OH 43210 USA. Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. Oak Ridge Natl Lab, Div Chem Sci, Oak Ridge, TN 37831 USA. RP Ross, SA (reprint author), NCI, Nutrit Sci Res Grp, Div Canc Prevent, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM rosssha@mail.nih.gov RI Lee, Stephen/C-2394-2011; Hettich, Robert/N-1458-2016 OI Hettich, Robert/0000-0001-7708-786X NR 46 TC 24 Z9 27 U1 3 U2 8 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAR PY 2004 VL 134 IS 3 BP 681 EP 685 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 801EV UT WOS:000220080100033 PM 14988467 ER PT J AU Zhang, YW Cantor, KP Lynch, CF Zheng, TZ AF Zhang, YW Cantor, KP Lynch, CF Zheng, TZ TI A population-based case-control study of occupation and renal cell carcinoma risk in Iowa SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OIL REFINERY WORKERS; BLADDER-CANCER; ALCOHOL-CONSUMPTION; UNITED-STATES; KIDNEY CANCER; MORTALITY; EXPOSURE; SMOKING; COHORT; TRICHLOROETHYLENE AB A case-control study involving 406 incident cases and 2434 controls was conducted in Iowa to examine the association between occupational exposures and renal cell carcinoma risk. After adjusting for major an increased risk was observed for men among mechanics confounders, 95% confidence interval [CI] = and repairers (odds ratio [OR] 1.9, 1.2-2.9); assemblers (OR 2.5, 95% CI = 0.8-7.6); automotive dealership and service station employees (OR 1.9, 95% CI = 0.9-3.9); wholesale traders of durable goods (OR 1.5, 95 % CI = 0.7-3.2); farm product vendors (OR 4.4, 95 % CI = 1.3-15.5); service organization managers (OR 2.2, 95 % CI = 1.0-5.1); financial specialists (OR 2.7, 95 % CI = 1.0-7.6); sales occupation supervisors (OR 1. 8, 95 % CI = 1.0-3.3); guards (OR 5.4 95 % CI = 1.4-20.7); and general, farm workers (OR 1.9, 95% CI = 1.0-3.7). Among women, an increased risk was found for employees in depository institutions (OR 3.6, 95 % CI = 1.1-11.3); colleges and universities (OR 7.6-95 % CI = 2.3-25.6); and retail, including those in grocery stores (OR 2.2, 95 % CI = 1.0-4.7). Our results indicate that occupational exposures may increase the risk of renal cell carcinoma. C1 Yale Univ, Sch Publ Hlth, New Haven, CT USA. NIH, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NCI, Bethesda, MD USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700-703, New Haven, CT 06510 USA. EM tongzhang.zheng@yale.edu NR 49 TC 9 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD MAR PY 2004 VL 46 IS 3 BP 235 EP 240 DI 10.1097/01.jom.0000116805.62079.d6 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803ZS UT WOS:000220269600008 PM 15091286 ER PT J AU Wilson, RT Moore, LE Dosemeci, M AF Wilson, RT Moore, LE Dosemeci, M TI Occupational exposures and salivary gland cancer mortality among African American and white workers in the United States SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID EPSTEIN-BARR-VIRUS; ATOMIC-BOMB SURVIVORS; SQUAMOUS-CELL CARCINOMA; 24 US STATES; RISK-FACTORS; FORMALDEHYDE EXPOSURE; DEATH CERTIFICATES; PHYSICAL-ACTIVITY; MORTUARY SCIENCE; TUMORS AB We conducted a large death certificate-based case-control study to assess occupational risks for salivary gland cancer. African American (168 cases, 672 controls) and white (2237 cases, 8748 controls) cases from 24 states (1984-1989) were matched to controls by age, sex, race, and region. Race- and sex-stratified multiple logistic regression models calculated adjusted odds ratios. The proportion of young cases (<50 years) was greatest among African Americans (20.8% vs. 8.8%). Higher socioeconomic status, ionizing radiation, formaldehyde, solvents, outdoor work, and animal contact were associated with elevated risk among white men. Physical activity reduced mortality risks among men, although significantly only among whites. Odds ratios for formaldehyde, solvents, benzene, and animal contact were 2.0 or greater among African American women, although not statistically significant. These findings suggest occupational and demographic factors needing further investigation. C1 NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. DHHS, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NCI, Bethesda, MD USA. RP Wilson, RT (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, MSC 7240, Bethesda, MD 20892 USA. EM rw266w@nih.gov NR 79 TC 4 Z9 5 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD MAR PY 2004 VL 46 IS 3 BP 287 EP 297 DI 10.1097/01.jom.0000446802.01928.83 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803ZS UT WOS:000220269600014 PM 15091292 ER PT J AU McDuffie, JR Calis, KA Uwaifo, GI Sebring, NG Fallon, EM Frazer, TE Hubbard, VS Yanovski, JA AF McDuffie, JR Calis, KA Uwaifo, GI Sebring, NG Fallon, EM Frazer, TE Hubbard, VS Yanovski, JA TI Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE obesity; weight loss; adolescence; pharmacotherapy; orlistat; diabetes mellitus; lipids ID AIR-DISPLACEMENT PLETHYSMOGRAPHY; RESTING ENERGY-EXPENDITURE; PERFORMANCE LIQUID-CHROMATOGRAPHY; GASTROINTESTINAL LIPASE INHIBITOR; SENSITIVITY CHECK INDEX; HUMAN-BODY COMPOSITION; BETA-CELL FUNCTION; WEIGHT-LOSS; INSULIN SENSITIVITY; WHITE-CHILDREN AB This pilot study compared the efficacy of orlistat as an adjunctive treatment for obesity between African American and Caucasian adolescents. Twenty obese adolescents with obesity-related co-morbid conditions underwent measurements of body composition, glucose homeostasis by frequently sampled intravenous glucose tolerance test (FSIGT), and fasting lipids before and after 6 months treatment with orlistat 120 mg tid in conjunction with a comprehensive behavioral program. Weight (p <0.05), BMI (p <0.001), total cholesterol (p <0.001), LDL cholesterol (p <0.001), fasting insulin (p <0.02) and fasting glucose (p <0.003) were lower after treatment. Insulin sensitivity, measured during the FSIGT, improved significantly (p <0.02), as did fasting indices such as the homeostasis model assessment for insulin resistance (p <0.01). African American subjects exhibited significantly less improvement in weight (p <0.05), BMI (p <0.01), waist circumference (p = 0.03), and insulin sensitivity (p = 0.05). Improvements in cholesterol were not significantly different between African Americans and Caucasians. We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African Americans, but both exhibited improvements in plasma lipids. The true benefit of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials. C1 NICHD, DEB, Unit Growth & Obes, NIH, Bethesda, MD 20892 USA. Drug Informat Serv, Dept Pharm, Bethesda, MD USA. Warren G Magnuson Clin Ctr, Dept Nutr, Bethesda, MD USA. NIDDK, Div Nutr Res Coordinat, NIH, Bethesda, MD USA. Ponce Sch Med, Bethesda, MD USA. RP McDuffie, JR (reprint author), NICHD, DEB, Unit Growth & Obes, NIH, 10 Ctr Dr,Bldg 10,Room 10N262,MSC 1862, Bethesda, MD 20892 USA. EM Mcduffj@mail.nih.gov RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NICHD NIH HHS [Z01 HD000641] NR 70 TC 48 Z9 48 U1 0 U2 5 PU FREUND PUBLISHING HOUSE LTD PI LONDON PA STE 500, CHESHAM HOUSE, 150 REGENT ST, LONDON W1R 5FA, ENGLAND SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD MAR PY 2004 VL 17 IS 3 BP 307 EP 319 PG 13 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 809XV UT WOS:000220670300005 PM 15112907 ER PT J AU Fuss, IJ AF Fuss, IJ TI Treatment of ulcerative colitis with infliximab: Are we there yet? SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; MONOCLONAL-ANTIBODY CA2; NECROSIS-FACTOR-ALPHA; CROHNS-DISEASE; EFFICACY; CELLS C1 NIH, Mucosal Immun Sect, Bethesda, MD 20892 USA. RP Fuss, IJ (reprint author), NIH, Mucosal Immun Sect, 10 Ctr Dr,Bldg 10,Room 11N238, Bethesda, MD 20892 USA. EM ifuss@niaid.nih.gov NR 26 TC 3 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD MAR PY 2004 VL 38 IS 3 BP 247 EP 249 DI 10.1097/00005176-200403000-00005 PG 3 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 808SU UT WOS:000220589600005 PM 15076622 ER PT J AU Avaria, MD Mills, JL Kleinsteuber, K Aros, S Conley, MR Cox, C Klebanoff, M Cassorla, F AF Avaria, MD Mills, JL Kleinsteuber, K Aros, S Conley, MR Cox, C Klebanoff, M Cassorla, F TI Peripheral nerve conduction abnormalities in children exposed to alcohol in utero SO JOURNAL OF PEDIATRICS LA English DT Article ID NEUROPATHY AB Objective We performed a longitudinal study of nerve conduction velocity to determine the effect of prenatal alcohol exposure on the peripheral nervous system. Study design We studied 17 children exposed to >2 oz of absolute alcohol/day prenatally and 13 unexposed children, identified prospectively from a cohort of pregnant women screened during prenatal care. Nerve conduction assessment was done on the median, ulnar, peroneal and tibial nerves during the newborn period and between 12 and 14 months of age. Results At both assessments the alcohol-exposed subjects had significantly slower ulnar motor nerve velocity (P =.007), smaller proximal (P =.018) and distal amplitude (P =.051). They also showed reduced tibial nerve velocity (P =.06) and a decrease in distal amplitude. Conclusions This study demonstrates that prenatal alcohol exposure is associated with abnormalities in nerve electrical properties, and that the pattern is different from that. seen in adults. Electrophysiologic abnormalities in peripheral nerves should be added to the problems found in children of alcohol abusing mothers. C1 Univ Chile, Dept Pediat, Fac Sci, Santiago, Chile. Univ Chile, Inst Invest Materno Infantil, Fac Sci, Santiago, Chile. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Mills, JL (reprint author), NICHHD, NIH, Div Hlth & Human Serv, 6100 Bldg Room 7 B03, Bethesda, MD 20892 USA. EM jamesmills@anih.gov NR 14 TC 20 Z9 22 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2004 VL 144 IS 3 BP 338 EP 343 PG 6 WC Pediatrics SC Pediatrics GA 802HY UT WOS:000220155800010 ER PT J AU Witkin, JM Dijkstra, D Levant, B Akunne, HC Zapata, A Peters, S Shannon, HE Gasior, M AF Witkin, JM Dijkstra, D Levant, B Akunne, HC Zapata, A Peters, S Shannon, HE Gasior, M TI Protection against cocaine toxicity in mice by the dopamine D-3/D-2 agonist R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H[1]benzopyrano[4,3-b]-1,4- oxazin-9-ol[(+)-PD 128,907] SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID D-3 RECEPTOR LIGANDS; FUNCTIONAL-CHARACTERIZATION; MAXIMAL ELECTROSHOCK; ANTICONVULSANT DRUGS; INDUCED SEIZURES; RAT; D3; PHARMACOLOGY; ANTAGONIST; IDENTIFICATION AB Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D-3/D-2 receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D-3-preferring agonists R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) [(+)-PD 128,907], (+)-7-hydroxy-dipropylaminotetralin, and the mixed D-3/D-2 agonists quinpirole and quinelorane were all effective against cocaine toxicity in mice. The anticonvulsant effects of these compounds occurred at doses below those that produced motor impairment as assessed in the inverted screen test. Protection against the convulsant effects of the selective dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl- propyl] piperazine (GBR 12909) was also conferred by (+)-PD 128,907. The possible selectivity of the effects of (+)-PD 128,907 (3 mg/kg) for these dopaminergic compounds was demonstrated by its general lack of protective efficacy against a host of convulsants acting through other neural mechanisms [pentylenetetrazol, (+)-bicuculline, and picrotoxin, 4-aminopyridine, and t-butylbiclyclophosphoorothionate, N-methyl-D-aspartate, kainate, pilocarpine, nicotine, strychnine, aminophylline, threshold electric shock, and 6-Hz electrical stimulation]. Direct and correlational evidence suggests that these effects were mediated by D-3 receptors. Protection was stereospecific and reversible by an antagonist of D-3 receptors [3-{4[1-(4-{2[4-(3-diethyamino-propoxy)-phenyl]benzoimidazol-1-yl}-butyl)-1H-benzoimidazol-2-yl]-phenoxy}propyl)-diethyl-amine; PD 58491] but not D-2 receptors [3[[4-(4-chlorophenyl)-4hydroxypipeidin-1-yl]methyl-1H-indole; L-741,626]. Anticonvulsant potencies were positively associated with potencies in a functional assay of D-3 but not D-2 receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D-3 receptor-mediated events. C1 Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. NIDA, Behav Neurosci Branch, NIH, Baltimore, MD USA. Univ Groningen, Ctr Pharm, Dept Med Chem, NL-9713 AW Groningen, Netherlands. Univ Kansas, Med Ctr, Dept Pharmacol, Kansas City, KS 66103 USA. Pfizer Inc, Neurosci Pharmacol, Ann Arbor, MI USA. RP Witkin, JM (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. EM jwitkin@lilly.com NR 39 TC 14 Z9 14 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR 1 PY 2004 VL 308 IS 3 BP 957 EP 964 DI 10.1124/jpet.103.059980 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 777YU UT WOS:000189212300021 PM 14711932 ER PT J AU Wang, TG Liu, B Zhang, W Wilson, B Hong, JS AF Wang, TG Liu, B Zhang, W Wilson, B Hong, JS TI Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; ANTIINFLAMMATORY AGENTS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; EXPRESSION; LIPOPOLYSACCHARIDE; BRAIN; MECHANISMS AB Inflammation plays an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. Recent reports have indicated that andrographolide (ANDRO) has an anti-inflammatory effect by modulating macrophage and neutrophil activity. Whereas microglia, the counterpart of macrophages in the brain, are pivotal in the inflammatory process in the central nervous system, the effect of ANDRO on inflammation-mediated neurodegeneration has not been examined. In this study, we show that both pretreatment and post-treatment with ANDRO exhibited a significant protective effect against lipopolysaccharide (LPS)-induced neurotoxicity in mixed neuron-glia cultures, as determined by [H-3]dopamine uptake and immunocytochemical analysis. In contrast, ANDRO showed no protective effect on 1-methyl-4-phenyl-pyridine (0.5 muM)-induced neurotoxicity in neuron-enriched cultures. ANDRO significantly attenuated LPS-induced microglial activation and production of reactive oxygen species, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E-2. Furthermore, ANDRO dose-dependently attenuated LPS-induced inducible nitric-oxide synthase and cyclooxygenase-2 protein expression in BV-2 microglia, as determined by Western blot. These findings demonstrate that ANDRO reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. In addition, these results indicate that ANDRO may have clinical utility for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, TG (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wang16@niehs.nih.gov RI liu, Bin/A-7695-2009 NR 37 TC 51 Z9 52 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR 1 PY 2004 VL 308 IS 3 BP 975 EP 983 DI 10.1124/jpet.103.059683 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 777YU UT WOS:000189212300023 PM 14718612 ER PT J AU Schwarz, M Katagiri, Y Kotani, M Bassler, N Loeffler, C Bode, C Peter, K AF Schwarz, M Katagiri, Y Kotani, M Bassler, N Loeffler, C Bode, C Peter, K TI Reversibility versus persistence of GPIIb/IIIa blocker-induced conformational change of GPIIb/IIIa (alpha(IIb)beta(3), CD41/CD61) SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GLYCOPROTEIN IIB/IIIA ANTAGONISTS; INTEGRIN ALPHA(IIB)BETA(3); IIB-IIIA; PLATELET ACTIVATION; FIBRINOGEN BINDING; INTRINSIC PROPERTY; EXPRESSION; CORONARY; RECEPTOR; INHIBITORS AB Clinically used GPIIb/IIIa blockers are ligand mimetics, and thereby their binding can induce conformational changes of the platelet integrin GPIIb/IIIa. Since the reversibility of these conformational changes may be an important determinant of potential adverse effects of GPIIb/IIIa blockers, we produced a new monoclonal antibody (anti-LIBS-mAb), and by using its binding properties, we investigated the conformational changes of GPIIb/IIIa during the binding and especially the dissociation of GPIIb/IIIa blockers. Production of monoclonal antibody (mAb) clones was performed using purified GPIIb/IIIa in a high affinity conformation and using activated platelets. Clone anti-LIBS-145-mAb was chosen, since it allowed the sensitive probing of eptifibatide-induced conformational changes of GPIIb/IIIa. On resting and activated platelets and on GPIIb/IIIa-expressing Chinese hamster ovary cells, anti-LIBS-145-mAb binding returned to background binding after dissociation of eptifibatide, indicating a complete reversibility of the eptifibatide-induced conformational change. Furthermore, with the mixing of eptifibatide-preincubated and nonincubated cells, a fast reversibility could be demonstrated. However, when fibrinogen was present in a physiological concentration, the GPIIb/IIIa blocker-induced conformation was partially retained after the dissociation of eptifibatide and to the same extent binding of fibrinogen and the activation-specific mAb Pac-1 was induced. In conclusion, a fast reversibility of the conformational change of GPIIb/IIIa after dissociation of GPIIb/IIIa blockers could be demonstrated as an intrinsic property of the GPIIb/IIIa receptor. This mechanism prevents general platelet aggregation after dissociation of ligand mimetic GPIIb/IIIa blockers. Nevertheless, in the presence of fibrinogen this reversibility is not complete, which may explain some of the side effects of GPIIb/IIIa blockers, especially those of the oral GPIIb/IIIa blockers. C1 Univ N Carolina, Carolina Cardiovasc Biol Ctr, Chapel Hill, NC 27599 USA. Univ Freiburg, Dept Internal Med 3, Freiburg, Germany. NIH, Bethesda, MD 20892 USA. Tokyo Metropolitan Inst Med Sci, Dept Clin Genet, Tokyo 113, Japan. RP Peter, K (reprint author), Univ N Carolina, Carolina Cardiovasc Biol Ctr, CB 7126,8200 Med Biomol Res Bldg, Chapel Hill, NC 27599 USA. EM peterkh@email.unc.edu RI Peter, Karlheinz/E-8772-2010 OI Peter, Karlheinz/0000-0002-8040-2258 NR 41 TC 31 Z9 33 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR 1 PY 2004 VL 308 IS 3 BP 1002 EP 1011 DI 10.1124/jpet.103.058883 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 777YU UT WOS:000189212300026 PM 14617694 ER PT J AU Chavkin, C Sud, S Jin, WZ Stewart, J Zjawiony, JK Siebert, DJ Toth, BA Hufeisen, SJ Roth, BL AF Chavkin, C Sud, S Jin, WZ Stewart, J Zjawiony, JK Siebert, DJ Toth, BA Hufeisen, SJ Roth, BL TI Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious kappa-opioid receptor agonist: Structural and functional considerations SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; XENOPUS OOCYTES; MINT; AUGMENTATION; POTENT AB The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist ( Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2- heptanoate were found to be either full ( salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective kappa-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for kappa-opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K+ channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than ( trans)-3,4-dichloro-N-methyl-N[ 2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N[ 2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate (U69593) ( two standard kappa-opioid agonists) and similar in efficacy to dynorphin A ( the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors. C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Cleveland, OH 44106 USA. Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. Salvia Divinorum Res & Informat Ctr, Los Angeles, CA USA. Univ Mississippi, Dept Pharmacognosy, Oxford, MS USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, Room RT500-9,2109 Adelbert Rd, Cleveland, OH 44106 USA. EM roth@biocserver.cwru.edu RI Roth, Bryan/F-3928-2010; Chavkin, Charles/G-2797-2010 FU NIDA NIH HHS [R01 DA04123, R01DA017204]; NIMH NIH HHS [K02MH01366] NR 25 TC 124 Z9 127 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR 1 PY 2004 VL 308 IS 3 BP 1197 EP 1203 DI 10.1124/jpet.103.059394 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 777YU UT WOS:000189212300048 PM 14718611 ER PT J AU Petricoin, E Wulfkuhle, J Espina, V Liotta, LA AF Petricoin, E Wulfkuhle, J Espina, V Liotta, LA TI Clinical proteomics: Revolutionizing disease detection and patient tailoring therapy SO JOURNAL OF PROTEOME RESEARCH LA English DT Review DE proteomics; pharmacoproteomics; patterns; mass spectrometry; protein microarrays ID PROTEIN IDENTIFICATION TECHNOLOGY; TYROSINE KINASE INHIBITOR; IMMOBILIZED PH GRADIENTS; OVARIAN-CANCER; MASS-SPECTROMETRY; PROSTATE-CANCER; BREAST-CANCER; 2-DIMENSIONAL ELECTROPHORESIS; TRASTUZUMAB HERCEPTIN; MYELOID-LEUKEMIA AB The evolving discipline of Clinical Proteomics is more than simply describing and enumerating the systematic changes in the protein constituency of a cell, or just generating lists of proteins that increase or decrease in expression as a cause or consequence of disease. Clinical applications of proteomics involve the use of proteomic technologies at the bedside with the ultimate goal to characterize the information flow through the intra- and extracellular molecular protein networks that interconnect organ and circulatory systems together. These networks are both new targets for therapeutics themselves as well as underpin the dynamic changes that give rise to cascades of new diagnostic biomarkers. The analysis of human cancer can be used as a model for how clinical proteomics is having an impact at the bedside for early detection, rational therapeutic targeting, and patient-tailored therapy. C1 US FDA, NCI FDA Clin Proteom Program, Off Cell & Gene Therapy, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, NCI FDA Clin Proteom Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Petricoin, E (reprint author), US FDA, NCI FDA Clin Proteom Program, Off Cell & Gene Therapy, Ctr Biol Evaluat & Res, Bldg 29A-2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov; liottal@mail.nih.gov OI Espina, Virginia/0000-0001-5080-5972 NR 82 TC 68 Z9 76 U1 0 U2 3 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 MAR-APR PY 2004 VL 3 IS 2 BP 209 EP 217 DI 10.1021/pr049972m PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 812IK UT WOS:000220833000006 PM 15113096 ER PT J AU Richell, RA Anderson, M AF Richell, RA Anderson, M TI Reproducibility of negative mood induction: a self-referent plus musical mood induction procedure and a controllable/uncontrollable stress paradigm SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE controllable stress; mood induction; reproducibility; uncontrollable stress ID LEARNED HELPLESSNESS; DEPRESSION; VOLUNTEERS; STATES; VELTEN; HUMANS AB Mood induction procedures (MIPs) have been used extensively as a means of inducing a variety of mood states in laboratory settings. Recently, MIPs have been employed in a repeated measures design in combination with such techniques as functional imaging and psychopharmacological investigations. This study attempted to assess the repeatability of two paradigms designed to induce a depressed/ negative affect, a self-referent plus musical MIP and a controllable/ uncontrollable stress paradigm, to assess the viability of using such procedures in a repeated design. Healthy volunteers were enrolled in to one of two studies. Study I administered a self-referent plus musical MIP on three separate occasions: neutral and depressive mood induction (MI) in a balanced order, followed by a further depressive MI. In study 2, volunteers were subjected to sessions of controllable and uncontrollable noise stress in a balanced order on two different occasions. Subjective ratings of mood were obtained prior to and following the interventions. Depressive MI successfully increased ratings of negative affect, although this effect tended to be greater on the first occasion than on the second. Correlation between mood change on the first and second occasions were tow, both for the MIP and stress paradigm. As such, caution should be exercised in using these procedures in a repeated measures design. However, the results may vary depending on the type of MIP employed. C1 Univ Manchester, Neurosci & Psychiat Unit, Manchester M13 9PL, Lancs, England. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Anderson, M (reprint author), Univ Manchester, Neurosci & Psychiat Unit, Room G809,Stopford Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. EM ian.anderson@man.ac.uk NR 24 TC 10 Z9 10 U1 2 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD MAR PY 2004 VL 18 IS 1 BP 94 EP 101 DI 10.1177/02698811044040246 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 817DR UT WOS:000221158700016 PM 15107191 ER PT J AU Pillemer, SR Tilley, B AF Pillemer, SR Tilley, B TI Clinical trials, outcome measures, and response criteria SO JOURNAL OF RHEUMATOLOGY LA English DT Editorial Material ID COLLEGE-OF-RHEUMATOLOGY; MODIFYING ANTIRHEUMATIC DRUGS; WORLD-HEALTH-ORGANIZATION; PRIMARY SJOGRENS-SYNDROME; OMERACT CONFERENCE; MULTIPLE OUTCOMES; ARTHRITIS TRIALS; END-POINTS; CORE SET; IMPROVEMENT C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. RP Pillemer, SR (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, 10 Ctr Dr MCS 1190,Room 1N113, Bethesda, MD 20892 USA. EM Pillemer@nih.gov NR 29 TC 1 Z9 1 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD MAR PY 2004 VL 31 IS 3 BP 407 EP 410 PG 4 WC Rheumatology SC Rheumatology GA 802FF UT WOS:000220148700001 PM 14994378 ER PT J AU Szyk, A Lu, WY Xu, CQ Lubkowski, J AF Szyk, A Lu, WY Xu, CQ Lubkowski, J TI Structure of the scorpion toxin BmBKTtx1 solved from single wavelength anomalous scattering of sulfur SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE SIRAS from sulfur; scorpion toxin; BmBKTx1 ID PROTEIN CRYSTALLOGRAPHY; LYSINE RESIDUES; SODIUM-CHANNELS; REFINEMENT; RESOLUTION; MOLSCRIPT; INSIGHTS AB This report describes the crystal structure of the K+ channel-blocking toxin, BmBKTx1, isolated recently from the venom of the scorpion Buthus martensi Karsch. This is only the second structure of the short-chain K+ channel-blocking toxin from scorpion solved by means of X-ray crystallography. Additionally, reductive dimethylation of folded BmBKTx1 employed to induce its crystallization and solution of the structure based on the anomalous signal from the sulfur atoms make this example quite unique. The monomer of BmBKTx1 is formed by 31 amino acid residues, including 6 cysteines connected in 3 disulfide bridges. Crystals of this toxin belong to the space group P2(1) with two molecules present in the asymmetric unit. The unit cell parameters are a = 21.40 Angstrom, b = 39.70 Angstrom, c = 29.37 Angstrom, and beta = 94.13degrees. Based on the high-quality dataset (anomalous signal) collected to the resolution 1.72 Angstrom using the conventional X-radiation generator (lambda(Cu,Kalpha) = 1.5478 Angstrom), the positions of sulfur atoms contributed by 12 cysteine residues have been identified, and subsequent improvement of the experimental phases have allowed structure solution. The final model was refined to the crystallographic R-factor of 0.166. The methyl groups on several lysine residues could be easily modeled into the electron density. Published by Elsevier Inc. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov RI Lu, Wuyuan/B-2268-2010 NR 29 TC 9 Z9 11 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAR PY 2004 VL 145 IS 3 BP 289 EP 294 DI 10.1016/j.jsb.2003.11.012 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 775AM UT WOS:000189018600012 PM 14960379 ER PT J AU Saremi, A Hanson, RL Tulloch-Reid, M Williams, DE Knowler, WC AF Saremi, A Hanson, RL Tulloch-Reid, M Williams, DE Knowler, WC TI Alcohol consumption predicts hypertension but not diabetes SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID AMERICAN-INDIAN POPULATION; ATHEROSCLEROSIS RISK; BLOOD-PRESSURE; PIMA-INDIANS; MELLITUS; DEPENDENCE; DRINKING; COMMUNITIES; PATTERNS; WOMEN AB Objective: This study examines the associations between alcohol consumption, Type 2 diabetes and hypertension in a native American population. Method: Data were collected in a population-based cross-sectional and prospective study conducted on 3,789 individuals aged 20 years. Reported alcohol consumption was classified as never, occasional or <1 a day, 1-2 drinks a day, greater than or equal to3 drinks a day, and occasional heavy drinking. The prevalence and incidence of diabetes and hypertension by categories of alcohol intake were determined. Results: About 68% of men and 39% of women reported some degree of alcohol consumption. There was no association between alcohol consumption and prevalence or incidence of diabetes, but a positive, statistically significant association between blood pressure and alcohol consumption was found in both genders. After adjustment for age, body mass index (BMI) and diabetes in a proportional hazards model in men, moderate drinkers (occasional or <1 drink a day and 1-2 drinks a day combined) had 1.24 (95% confidence interval: 0.98-1.57) and occasional heavy drinkers had 1.49 (1.02-2.17) times the incidence of hypertension as nondrinkers. The corresponding estimates of hypertension incidence for women were 1.53 (1.29-1.83) for moderate drinking and 1.38 (0.81-2.36) for occasional heavy drinking. As only 1% of participants reported greater than or equal to3 drinks a day., this group was excluded from these analyses. Conclusions: Alcohol consumption did not affect the development of Type 2 diabetes, but it was associated with increased risk of hypertension, and this effect was independent of diabetes or BMI in both genders. C1 NIDDKD, Diabet & Arthritis Epidemiol Sect, Phoenix, AZ 85016 USA. RP Saremi, A (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM asaremi@mail.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 23 TC 25 Z9 25 U1 0 U2 4 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD MAR PY 2004 VL 65 IS 2 BP 184 EP 190 PG 7 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 815IV UT WOS:000221036900004 PM 15151348 ER PT J AU Breslow, RA Smothers, B AF Breslow, RA Smothers, B TI Drinking patterns of older Americans: National Health Interview Surveys, 1997-2001 SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID ALCOHOL-USE; ADULTS AB Objective: The objective of this study was to estimate the quantity and frequency of alcohol consumption among current drinking Americans age 60 years and older, by gender and age. Method: Five years (1997-2001) of cross-sectional National Health Interview Survey data were pooled. Quantity (number of drinks consumed on average, on drinking days), frequency (number of drinking days per year) and a composite quantity-frequency measure (average number of drinks per day) were defined. Age trends (between age 60 and 84 years) were tested using logistic regression. Analyses were weighted to produce national estimates. Results: Among 40,556 adults age 60 years and older, 52.8% (n = 8,136) of men and 37.2% (n = 8,710) of women were current drinkers. Over increasingly older age groups of current drinking men and women (I) proportions consuming higher quantities of alcohol (two drinks or more) decreased (p trend <.001), whereas proportions consuming lower quantities (one drink) increased (p trend <.001); and (2) proportions drinking least frequently (<12 days per year) and most frequently (260-365 days per year) increased (p trend <.05), whereas proportions drinking at intermediate frequencies remained stable or decreased. Differences in patterns for quantity alone and frequency alone were obscured by the composite quantity-frequency measure. Conclusions: In a nationally representative survey, quantity and frequency of alcohol consumption showed strikingly different patterns of cross-sectional age-related change. In epidemiologic studies, quantity and frequency have been differentially associated with medical conditions prevalent in older populations. Investigators studying alcohol consumption in older people should consider reporting results separately by quantity and frequency. C1 NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Breslow, RA (reprint author), NIAAA, Div Epidemiol & Prevent Res, NIH, 5635 Fishers Lane,Room 2086,MSC 9304, Bethesda, MD 20892 USA. EM rbreslow@mail.nih.gov NR 20 TC 36 Z9 36 U1 0 U2 2 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD MAR PY 2004 VL 65 IS 2 BP 232 EP 240 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 815IV UT WOS:000221036900011 PM 15151355 ER PT J AU Schrump, DS AF Schrump, DS TI Genomic surgery for lung cancer SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT Festschrift in Honor of David B Skinner held at the Meeting of the American-College-of-Surgeons CY OCT, 2003 CL Chicago, IL SP Amer Coll Surg DE 5-aza-2 '-deoxycytidine; Depsipeptide FX228; lung cancer; tumor suppressor gene; cancer-testis antigen ID ABERRANT PROMOTER METHYLATION; DNA METHYLATION; HISTONE ACETYLATION; MULTIPLE GENES; CHROMATIN STRUCTURE; CELL-PROLIFERATION; CIGARETTE SMOKERS; FREQUENT LOSS; EARLY EVENT; H19 GENE AB An emerging body of literature indicates that reversible alterations in chromatin structure modulate gene expression during malignant transformation. Chromatin structure is regulated in part by DNA methylation and histone acetylation; these independent yet highly interrelated epigenetic processes are influenced by a variety of signal transduction pathways. The present review highlights recent advances regarding cancer epigenetics, focusing on the potential utilization of chromatin remodeling agents to induce apoptosis and enhance the immunogenicity of thoracic malignancies. C1 NCI, Canc Res Ctr, Surg Branch, Thorac Oncol Sect, Bethesda, MD USA. RP Schrump, DS (reprint author), 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. EM david_Schrump@nih.gov NR 53 TC 5 Z9 5 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD MAR PY 2004 VL 117 IS 1 BP 107 EP 113 DI 10.1016/j.jss.2003.11.024 PG 7 WC Surgery SC Surgery GA 802SB UT WOS:000220182100014 PM 15013720 ER PT J AU Chan, JL Moshell, A Turner, M Kimball, A AF Chan, JL Moshell, A Turner, M Kimball, A TI Assessing the role of race in quantitative measures of skin pigmentation and clinical assessments of photosensitivity SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the American-Academy-of-Dermatology CY FEB 06-11, 2004 CL WASHINGTON, DC SP Amer Acad Dermatol C1 Stanford Univ, Sch Med, Dept Dermatol, Stanford, CA 94305 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2004 VL 50 IS 3 SU S MA P328 BP P86 EP P86 DI 10.1016/j.jaad.2003.10.270 PG 1 WC Dermatology SC Dermatology GA 802CC UT WOS:000220140600326 ER PT J AU Jorge, TR Zbar, B Turner, M Linehan, M AF Jorge, TR Zbar, B Turner, M Linehan, M TI Mutations in fumarate hydratase cause hereditary leiomyomatosis and renal cell carcinoma in families in North America SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the American-Academy-of-Dermatology CY FEB 06-11, 2004 CL WASHINGTON, DC SP Amer Acad Dermatol C1 NCI, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2004 VL 50 IS 3 SU S MA P36 BP P9 EP P9 DI 10.1016/j.jaad.2003.10.042 PG 1 WC Dermatology SC Dermatology GA 802CC UT WOS:000220140600037 ER PT J AU Liang, CA Kraemer, K Morris, A DiGiovanna, J AF Liang, CA Kraemer, K Morris, A DiGiovanna, J TI Characterization of tiger tail banding and hair shaft abnormalities in trichothiodystrophy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the American-Academy-of-Dermatology CY FEB 06-11, 2004 CL WASHINGTON, DC SP Amer Acad Dermatol C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2004 VL 50 IS 3 SU S MA P346 BP P91 EP P91 DI 10.1016/j.jaad.2003.10.288 PG 1 WC Dermatology SC Dermatology GA 802CC UT WOS:000220140600344 ER PT J AU Toro, JR Turner, M Linehan, M Zbar, B AF Toro, JR Turner, M Linehan, M Zbar, B TI Birt-Hogg-Dube syndrome: Identification of a novel gene and its clinical manifestations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the American-Academy-of-Dermatology CY FEB 06-11, 2004 CL WASHINGTON, DC SP Amer Acad Dermatol C1 NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2004 VL 50 IS 3 SU S MA P341 BP P89 EP P89 DI 10.1016/j.jaad.2003.10.283 PG 1 WC Dermatology SC Dermatology GA 802CC UT WOS:000220140600339 ER PT J AU Caan, B Ballard-Barbash, R Slattery, ML Pinsky, JL Iber, FL Mateski, DJ Marshall, JR Paskett, ERD Shike, M Weissfeld, JL Schatzkin, A Lanza, E AF Caan, B Ballard-Barbash, R Slattery, ML Pinsky, JL Iber, FL Mateski, DJ Marshall, JR Paskett, ERD Shike, M Weissfeld, JL Schatzkin, A Lanza, E TI Low energy reporting may increase in intervention participants enrolled in dietary intervention trials SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article; Proceedings Paper CT 4th International Conference on Dietary Assessment Methods CY SEP 17-20, 2000 CL TUCSON, ARIZONA ID DOUBLY-LABELED WATER; NUTRITION EXAMINATION SURVEY; HABITUAL FOOD-INTAKE; 3RD NATIONAL-HEALTH; BODY-MASS INDEX; PREVENTION TRIAL; FUNDAMENTAL PRINCIPLES; SOCIAL DESIRABILITY; GOLDBERG CUTOFF; MULTIPLE-PASS AB Objective To examine differences in low energy intake reporting between intervention and control groups during a dietary intervention trial. Design Retrospective data analysis from a subcohort of participants in the Polyp Prevention Trial (PPT), a 4-year, multisite, randomized, controlled dietary intervention trial. Intervention consisted of educational material and counseling sessions supporting a low-fat, high-fiber diet. Baseline and annual demographics, behavioral characteristics, energy intake (EI) based on self-reported 4-day food records, and height and weight of participants were collected at baseline and annually. Basal metabolic rate (BMR) was estimated (using the Schofield equation) to calculate EI/BMR. Subjects Of the 443 participants (302 male, 141 female) at baseline, 195 (43.3%) were younger than 60 years, and 394 (91%) were white. At Year 4, 383 participants remained: 186 (122 men, 64 women) in the intervention group, and 197 (133 men, 64 women) in the control group. Statistical Analyses Using either paired t tests or analysis of variance, the differences between the means for EI, weight, and EI/BMR were compared at baseline, Year 1, and Year 4 for the participants who remained at Year 4. The Goldberg EI/BMR cutoff value of 1.06 (for plausible EI) identified participants who reported low EI. Linear regression was used to quantify the association of various risk factors to EI/BMR and for multivariate analyses within groups. chi(2) contingency table analysis quantified differences of low energy reporting within groups. Results At baseline, 46.8% of women and 11.6% of men reported lower than plausible El. Only men had a significant increase in low energy reporting after randomization. At Year 1, 18.9% of intervention group men reported low EI compared with 9.8% of control group men (P<.05). At Year 4, 23.0% of intervention group men reported low EI compared with 12.8% of control group men (P<.05). Conclusions/Applications Difference in low EI reporting between intervention and control groups could distort results from dietary intervention trials; interpretation of findings from dietary trials must include this potential bias. Intervention study design should include dietary intake data collection methods that are not subject to such bias (ie, biomarkers and performance criteria) to measure intervention compliance. C1 Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94612 USA. NCI, Div Canc Prevent & Control, Appl Res Program, Bethesda, MD USA. Univ Utah, Sch Med, Dept Family & Prevent Med, Salt Lake City, UT USA. Westat Corp, Rockville, MD USA. Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. Edward Hines Jr Vet Adm Hosp, Gastroenterol Clin, Hines, IL USA. Walter Reed Army Med Ctr, Gastroenterol Serv, Washington, DC 20307 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Serv, Winston Salem, NC 27109 USA. Mem Hosp Canc & Allied Dis, MSK Canc Prevent & Wellness Program, Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. RP Caan, B (reprint author), Kaiser Permanente Med Care Program, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM bjc@dor.kaiser.org FU NCI NIH HHS [R01 CA048998-10, N01 SC 05316, R01 CA048998] NR 49 TC 14 Z9 14 U1 1 U2 1 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 MAR PY 2004 VL 104 IS 3 BP 357 EP 366 DI 10.1016/j.jada.2003.12.023 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 801DB UT WOS:000220075500007 PM 14993857 ER PT J AU McDermott, MM Guralnik, JM Albay, M Bandinelli, S Miniati, B Ferrucci, L AF McDermott, MM Guralnik, JM Albay, M Bandinelli, S Miniati, B Ferrucci, L TI Impairments of muscles and nerves associated with peripheral arterial disease and their relationship with lower extremity functioning: The InCHIANTI Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE ankle-brachial index; peripheral arterial disease; functional impairment ID ANKLE-ARM INDEX; SKELETAL-MUSCLE; HEALTH; ADULTS; DISABILITY; VALIDITY AB OBJECTIVES: To define the relationships between lower extremity peripheral arterial disease (PAD), pathophysiological findings in lower extremity muscles and nerves, and lower extremity performance. DESIGN: Cross-sectional. SETTING: Two communities in Italy. PARTICIPANTS: Nine-hundred seventy-nine community-dwelling men and women aged 60 and older (109 with PAD). MEASUREMENTS: Presence and degree of lower extremity arterial obstruction were determined using the ankle-brachial index (ABI). Lower extremity muscle cross-sectional area was measured using computed tomography. Peroneal nerve conduction velocity (NCV) and leg power were also determined. Measures of lower extremity functioning were fast walking speed over 4 meters, time required to walk 400 meters, and the summary performance score. RESULTS: Participants with PAD had significantly poorer performance on functional outcomes than participants without PAD. Adjusting for age and sex, presence of PAD was associated with reduced leg muscle power (83.69 vs 103.51 watts, P<.001), reduced muscle cross-sectional area (61.5 vs 63.5 cm(2), P=.14), and reduced NCV (43.0 vs 44.2 m/s, P=.003). Adjustment for leg power diminished the independent association between ABI and the functional outcomes measures. CONCLUSION: In community-dwelling individuals, PAD is associated with reduced NCV and reduced muscle power in the lower extremities. Muscle power may mediate the association between lower ABI levels and poorer functional performance. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Italian Natl Res Council Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Don Gnocchi Fdn, Florence, Italy. NIA, Longitudinal Studies Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu NR 29 TC 64 Z9 70 U1 0 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2004 VL 52 IS 3 BP 405 EP 410 DI 10.1111/j.1532-5415.2004.52113.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 774PA UT WOS:000188990600012 PM 14962156 ER PT J AU Parker, TF Blantz, R Hostetter, T Himmelfarb, J Kliger, A Lazarus, M Nissenson, AR Pereira, B Weiss, J AF Parker, TF Blantz, R Hostetter, T Himmelfarb, J Kliger, A Lazarus, M Nissenson, AR Pereira, B Weiss, J TI The chronic kidney disease initiative SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article AB The Chronic Kidney Disease Initiative was implemented at the request of the Council of American Kidney Societies to formulate a plan of action to solve many of the perceived problems associated with identifying, caring for, and attaining the best outcomes for patients with chronic kidney disease. With the assistance of a community of stakeholders and a formalized workshop and process, the Chronic Kidney Disease Initiative identified the barriers to solving this complicated problem. Barriers were given hierarchal significance, and solutions and action plans to the barriers were formulated. This article describes the process, the barriers encountered, and the solutions required to fully identify and manage this large and complicated population of patients. C1 Univ Texas, SW Med Ctr, Dallas Nephrol Associates, Dallas, TX USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. VA San Diego Healthcare Syst, San Diego, CA USA. NIDDK, NIH, Bethesda, MD USA. Maine Med Ctr, Div Nephrol & Transplantat, Portland, ME USA. Hosp St Raphael, Yale Med Sch, New Haven, CT USA. Fresenius Med Care, Lexington, MA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Renal Endocrine Associates, Pittsburgh, PA USA. RP Parker, TF (reprint author), 6010 Forest Pk, Dallas, TX 75235 USA. EM tfparker3@cs.com NR 1 TC 28 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2004 VL 15 IS 3 BP 708 EP 716 DI 10.1097/01.ASN.0000112129.20838.3F PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 778BG UT WOS:000189218800022 PM 14978173 ER PT J AU Chatterjee, N AF Chatterjee, N TI A two-stage regression model for epidemiological studies with multivariate disease classification data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE colorectal ademona; genetic marker; polytomous logistic regressions; protein expression; pseudo-conditional-likelihood; semiparametric inference ID LOGISTIC-REGRESSION; CANCER AB Polytomous logistic regression is commonly used to analyze epidemiological data with disease subtype information. In this approach effects of exposures on different disease subtypes are studied through separate exposure odds ratios comparing different case groups to the common control group. This article considers the situation where disease subtypes can be defined Using multiple characteristics of a disease. For efficient analysis of such data, a two-stage modeling approach is proposed. At the first stage, a standard polytomous logistic regression model is considered for all possible distinct disease subtypes that can be defined by the cross-classification of the different disease characteristics. At the second stage, the exposure odds ratio parameters for the first-stage disease subtypes are further modeled in terms of the defining characteristics of the Subtypes. When the total number of first-stage disease subtypes is small, standard maximum likelihood methods can be used for inference in the proposed model. For dealing with a large number of disease Subtypes. a novel semiparametric pseudo-conditional-likelihood approach is proposed that does not require any model assumption about the baseline probabilities for the different disease subtypes. This article develops the asymptotic theory for the estimator and studies its small-sample properties using simulation experiments. The proposed method is applied to study the effect of fiber on the risk of various forms of colorectal adenoma using data available from a large screening study, the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM chattern@mail.nih.gov NR 15 TC 23 Z9 23 U1 1 U2 5 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD MAR PY 2004 VL 99 IS 465 BP 127 EP 138 DI 10.1198/016214504000000124 PG 12 WC Statistics & Probability SC Mathematics GA 809LM UT WOS:000220638200013 ER PT J AU Kim, S Toivola, Y Cook, RF Char, K Chu, SH Lee, JK Yoon, DY Rhee, HW AF Kim, S Toivola, Y Cook, RF Char, K Chu, SH Lee, JK Yoon, DY Rhee, HW TI Organosilicate spin-on glasses - I. Effect of chemical modification on mechanical properties SO JOURNAL OF THE ELECTROCHEMICAL SOCIETY LA English DT Article ID K HYDROGEN SILSESQUIOXANE; NH3 PLASMA TREATMENT; METHYL SILSESQUIOXANE; SENSING INDENTATION; FILMS AB Methylsilsesquioxane (MSSQ) films were chemically modified by (i) the bulk incorporation of a short-chain polymer or (ii) surface treatment by an NH3 plasma, and the effects of these modifications on elastic, plastic, and fracture properties were investigated. In (i), a copolymer of 10 mol % 1,2-bis(trimethoxysilyl) ethane (BTMSE) and methyltrimethoxysilane was synthesized and cured to form an MSSQ: BTMSE copolymer film. In ( ii), an NH3 plasma treatment was applied to cured MSSQ films for 5, 15, 30, or 60 min. Films were characterized using scanning electron microscopy (SEM), IR spectroscopy, and ellipsometry. Depth-sensing indentation was used to determine plane strain modulus, E', and hardness, H. Indentation traces and SEM images of residual indentation damage were used to determine the threshold load for cracking, Pc. The addition of BTMSE to MSSQ doubled E', H, and P-c relative to MSSQ with a slight increase in relative dielectric constant, k, from 2.70 to 2.86. Apparent E' and H at the surface of plasma-treated films increased with plasma treatment time. IR spectroscopy indicated that improved properties resulted in (i) from increased organic and inorganic networking and in (ii) from the formation of a dense, largely inorganic, surface layer. Such chemical modifications may be used to improve the performance of organosilicates as low-k dielectrics in microelectronic interconnection structures. (C) 2004 The Electrochemical Society. C1 Seoul Natl Univ, Sch Chem Engn, Seoul, South Korea. Univ Minnesota, Dept Chem Engn & Mat Sci, Minneapolis, MN 55455 USA. NASA, Langley Res Ctr, NIA, Hampton, VA 23681 USA. Seoul Natl Univ, Sch Chem, Seoul, South Korea. Sogang Univ, Dept Chem Engn, Seoul, South Korea. RP Kim, S (reprint author), Seoul Natl Univ, Sch Chem Engn, Seoul, South Korea. EM rfc@cems.umn.edu NR 23 TC 24 Z9 25 U1 0 U2 2 PU ELECTROCHEMICAL SOC INC PI PENNINGTON PA 65 SOUTH MAIN STREET, PENNINGTON, NJ 08534 USA SN 0013-4651 J9 J ELECTROCHEM SOC JI J. Electrochem. Soc. PD MAR PY 2004 VL 151 IS 3 BP F37 EP F44 DI 10.1149/1.1643072 PG 8 WC Electrochemistry; Materials Science, Coatings & Films SC Electrochemistry; Materials Science GA 773VA UT WOS:000188943800051 ER PT J AU McDermott, MM Criqui, MH Greenland, P Guralnik, JM Liu, K Pearce, WH Taylor, L Chau, CL Celic, L Woolley, C O'Brien, MP Schneider, JR AF McDermott, MM Criqui, MH Greenland, P Guralnik, JM Liu, K Pearce, WH Taylor, L Chau, CL Celic, L Woolley, C O'Brien, MP Schneider, JR TI Leg strength in peripheral arterial disease: Associations with disease severity and lower-extremity performance SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; SKELETAL-MUSCLE; HEART-FAILURE; INTERMITTENT CLAUDICATION; EXERCISE; WALKING; MEN; CLASSIFICATION; OSTEOARTHRITIS; METABOLISM AB Objective: The purpose of this study was to determine relationships between lower-extremity arterial obstruction, leg strength, and lower-extremity functioning. Design: The study design was cross-sectional. A total of 514 outpatients (269 with ankle-brachial index [ABI] <0.90), aged 55 and older, were identified from three Chicago-area hospitals. Individuals with history of lower-extremity revascularization were excluded. Main outcome measures. Strength in each leg, 6-minute walk, 4-meter walking velocity, accelerometer-measured physical activity, and a summary performance score were measured. The summary performance score is a composite measure of lower-extremity functioning, ranging from 0 to 12 (12 = best). The leg with the lower ABI was defined as the "index" leg, and the leg with higher ABI was defined as the "contralateral" leg. Results: Index leg ABI levels were associated linearly and significantly with strength for hip extension (P <.001), hip flexion (P <.001), knee extension (P =.066), and knee flexion (P =.003), adjusting for known and potential confounders. In adjusted analyses, the index ABI was also associated linearly and significantly with strength in the contralateral leg. Adjusting for confounders, including ABI, knee extension strength, was associated independently with functional measures. Conclusion: Among patients without prior leg revascularization, strength in each leg is highly correlated with the lower-leg ABI. Leg strength is associated independently with functional performance. Further study is needed to determine whether lower-extremity resistance training improves functioning in patients with peripheral arterial disease. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Evanston Hosp Corp, Evanston, IL USA. RP McDermott, MM (reprint author), 675 N St Clair,Ste 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu NR 29 TC 53 Z9 59 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAR PY 2004 VL 39 IS 3 BP 523 EP 530 DI 10.1016/j.jvs.2003.08.038 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 902WJ UT WOS:000227387100006 PM 14981443 ER PT J AU Frahm, N Korber, BT Adams, CM Szinger, JJ Draenert, R Addo, MM Feeney, ME Yusim, K Sango, K Brown, NV SenGupta, D Piechocka-Trocha, A Simonis, T Marincola, FM Wurcel, AG Stone, DR Russell, CJ Adolf, P Cohen, D Roach, T StJohn, A Khatri, A Davis, K Mullins, J Goulder, PJR Walker, BD Brander, C AF Frahm, N Korber, BT Adams, CM Szinger, JJ Draenert, R Addo, MM Feeney, ME Yusim, K Sango, K Brown, NV SenGupta, D Piechocka-Trocha, A Simonis, T Marincola, FM Wurcel, AG Stone, DR Russell, CJ Adolf, P Cohen, D Roach, T StJohn, A Khatri, A Davis, K Mullins, J Goulder, PJR Walker, BD Brander, C TI Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; PLASMA VIRAL LOAD; TYPE-1 SUBTYPE-C; CELL RESPONSES; HIV-1 INFECTION; DISEASE PROGRESSION; CD8-T-CELL MEMORY; IMMUNE-RESPONSES; CD4-T-CELL HELP; HLA-A AB Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most Affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. Massachusetts Gen Hosp, Endocrine Unit, Charlestown, MA USA. Fenway Community Hlth Ctr, Boston, MA USA. Lemuel Shattuck Hosp, Boston, MA USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Queen Elizabeth Hosp, Bridgetown, Barbados. Los Alamos Natl Lab, Los Alamos, NM USA. Santa Fe Inst, Santa Fe, NM 87501 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. RP Brander, C (reprint author), Partners AIDS Res Ctr, 5th Floor MGH E,5239,149 13th St, Charlestown, MA 02129 USA. EM brander@helix.mgh.harvard.edu OI Brander, Christian/0000-0002-0548-5778; Korber, Bette/0000-0002-2026-5757 FU PHS HHS [N01-A1-15422] NR 55 TC 224 Z9 235 U1 3 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 MAR PY 2004 VL 78 IS 5 BP 2187 EP 2200 DI 10.1128/JVI.78.5.2187-2200.2004 PG 14 WC Virology SC Virology GA 775AV UT WOS:000189019300003 PM 14963115 ER PT J AU Patterson, LJ Malkevitch, N Venzon, D Pinczewski, J Gomez-Roman, VR Wang, LQ Kalyanaraman, VS Markham, PD Robey, FA Robert-Guroff, M AF Patterson, LJ Malkevitch, N Venzon, D Pinczewski, J Gomez-Roman, VR Wang, LQ Kalyanaraman, VS Markham, PD Robey, FA Robert-Guroff, M TI Protection against mucosal simian immunodeficiency virus SIVmac251 challenge by using replicating adenovirus-SIV multigene vaccine priming and subunit boosting SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; REGIMEN INDUCES BROAD; HOST-RANGE MUTANT; RHESUS MACAQUES; IMMUNE-RESPONSES; LYMPHOCYTE RESPONSES; DISEASE PROGRESSION; VAGINAL CHALLENGE; VIRAL REPLICATION; PATHOGENIC SIV AB Whereas several recent AIDS vaccine strategies have protected rhesus macaques against a pathogenic simian/human immunodeficiency virus (SHIV)(89.6P) challenge, similar approaches have provided only modest, transient reductions in viral burden after challenge with virulent, pathogenic SIV, which is more representative of HIV infection of people. We show here that priming with replicating adenovirus recombinants encoding SIV env/rev, gag, and/or nef genes, followed by boosting with SIV gp120 or an SIV polypeptide mimicking the CD4 binding region of the envelope, protects rhesus macaques from intrarectal infection with the highly pathogenic SIVmac251. Using trend analysis, significant reductions in acute-phase and set point viremia were correlated with anti-gp120 antibody and cellular immune responses, respectively. Within immunization groups exhibiting significant protection, a subset (39%) of macaques have exhibited either no viremia, cleared viremia, or controlled viremia at the threshold of detection, now more than 40 weeks postchallenge. This combination prime-boost strategy, utilizing replication competent adenovirus, is a promising alternative for HIV vaccine development. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Data Management Sect, NIH, Bethesda, MD 20892 USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Adv Biosci Labs Inc, Kensington, MD 20895 USA. RP Robert-Guroff, M (reprint author), NCI, Basic Res Lab, NIH, 41 Medlars Dr,MSC5065,Bldg 41,Rm D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Venzon, David/B-3078-2008 FU NIAID NIH HHS [N01-AI15430, N01AI15430] NR 46 TC 134 Z9 139 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 MAR PY 2004 VL 78 IS 5 BP 2212 EP 2221 DI 10.1128/JVI.78.5.2212-2221.2004 PG 10 WC Virology SC Virology GA 775AV UT WOS:000189019300005 PM 14963117 ER PT J AU Yung, E Sorin, M Wang, EJ Perumal, S Ott, D Kalpana, GV AF Yung, E Sorin, M Wang, EJ Perumal, S Ott, D Kalpana, GV TI Specificity of interaction of INI1/hSNF5 with retroviral integrases and its functional significance SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CENTRAL DNA FLAP; HIV-1 INTEGRASE; SWI/SNF COMPLEX; CYCLOPHILIN-A; VIRION PRODUCTION; PROTEIN; REPLICATION; TRANSCRIPTION; MUTATIONS AB Integrase interactor 1 (INI1)/hSNF5 is a host factor that directly interacts with human immunodeficiency virus type 1 (HIV-1) integrase and is incorporated into HIV-1 virions. Here, we show that while INI1/hSNF5 is completely absent from purified microvesicular fractions, it is specifically incorporated into HIV-1 virions with an integrase-to-INI1/hSNF5 stoichiometry of approximately 2:1 (molar ratio). In addition, we show that INI1/hSNF5 is not incorporated into related primate lentiviral and murine retroviral particles despite the abundance of the protein in producer cells. We have found that the specificity in incorporation of INI1/hSNF5 into HIV-1 virions is directly correlated with its ability to exclusively interact with HIV-1 integrase but not with other retroviral integrases. This specificity is also reflected in our finding that the transdominant mutant S6, harboring the minimal integrase interaction domain of INI1/hSNF5, blocks HIV-1 particle production but not that of the other retroviruses in 293T cells. Taken together, these results suggest that INI1/hNSF5 is a host factor restricted for HIV-1 and that S6 acts as a highly specific and potent inhibitor of HIV-1 replication. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Kalpana, GV (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, 1300 Morris Pk Ave,Ullman 821, Bronx, NY 10461 USA. EM kalpana@aecom.yu.edu OI Yung, Eric/0000-0002-7328-7204 FU NCI NIH HHS [N01CO12400, N01-CO-12400]; NIAID NIH HHS [N01AI30051, R01 AI30051-01, T32 AI007501, T32-AI07501] NR 51 TC 52 Z9 55 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 MAR PY 2004 VL 78 IS 5 BP 2222 EP 2231 DI 10.1128/JVI.78.5.2222-2231.2004 PG 10 WC Virology SC Virology GA 775AV UT WOS:000189019300006 PM 14963118 ER PT J AU Center, RJ Lebowitz, J Leapman, RD Moss, B AF Center, RJ Lebowitz, J Leapman, RD Moss, B TI Promoting trimerization of soluble human immunodeficiency virus type 1 (HIV-1) Env through the use of HIV-1/simian immunodeficiency virus chimeras SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN COMPLEX; BROADLY NEUTRALIZING ANTIBODIES; INTERMOLECULAR DISULFIDE BOND; 2ND HYPERVARIABLE REGION; OLIGOMERIC STRUCTURE; MONOCLONAL-ANTIBODY; PARTIAL DELETION; RHESUS MACAQUES; GP41 SUBUNITS; GP120 AB The envelope proteins (Env) of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) form homo-oligomers in the endoplasmic reticulum. The oligomeric structure of Env is maintained, but is less stable, after cleavage in a Golgi compartment and transport to the surface of infected cells. Functional, virion-associated HIV-1 and SIV Env have an almost exclusively trimeric structure. In addition, a soluble form of SIV Env (gp140) forms a nearly homogeneous population of trimers. Here, we describe the oligomeric structure of soluble, uncleaved HIV-1 gp140 and modifications that promote a stable trimeric structure. Biochemical and biophysical analyses, including sedimentation equilibrium and scanning transmission electron microscopy, revealed that unmodified HIV-1 gp140 purified as a heterogeneous range of oligomeric species, including dimers and aggregates. Deletion of the V2 domain alone or, especially, both the V1 and V2 domains reduced dimer formation but promoted aggregation rather than trimerization. Expressing gp140 with mannose-only oligosaccharides did not eliminate heterogeneity. Replacement of the entire gp41 segment of HIV-1 gp140 or just the N-terminal half (85 amino acids) of this segment with the corresponding region of SIV was sufficient to confer efficient trimerization for gp140 derived from clade B and C isolates. Importantly, the relatively small segment of the HIV Env replaced by SIV sequences contains no known targets of neutralizing antibody. The soluble trimeric form of HIV-1 Env should prove useful for assessment of antigenic structure and immunogenicity. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Center, RJ (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 229,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rcenter@unimelb.edu.au; bmoss@nih.gov NR 53 TC 35 Z9 35 U1 1 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 MAR PY 2004 VL 78 IS 5 BP 2265 EP 2276 DI 10.1128/JVI.78.5.2265-2276.2004 PG 12 WC Virology SC Virology GA 775AV UT WOS:000189019300011 PM 14963123 ER PT J AU Agrawal, L Lu, XH Qingwen, J VanHorn-Ali, Z Nicolescu, IV McDermott, DH Murphy, PM Alkhatib, G AF Agrawal, L Lu, XH Qingwen, J VanHorn-Ali, Z Nicolescu, IV McDermott, DH Murphy, PM Alkhatib, G TI Role for CCR5 Delta 32 protein in resistance to R5, R5X4, and X4 human immunodeficiency virus type 1 in primary CD4(+) cells SO JOURNAL OF VIROLOGY LA English DT Article ID MACROPHAGE-TROPIC HIV-1; M2 MUSCARINIC RECEPTORS; CHEMOKINE RECEPTOR; FUNCTIONAL CORECEPTOR; SURFACE EXPRESSION; ADENOVIRUS TYPE-5; T-LYMPHOCYTES; CCR5; INFECTION; CXCR4 AB CCR5Delta32 is a loss-of-function mutation that abolishes cell surface expression of the human immunodeficiency virus (HIV) coreceptor CCR5 and provides genetic resistance to HIV infection and disease progression. Since CXCR4 and other HIV coreceptors also exist, we hypothesized that CCR5Delta32-mediated resistance may be due not only to the loss of CCR5 function but also to a gain-of-function mechanism, specifically the active inhibition of alternative coreceptors by the mutant CCR5Delta32 protein. Here we demonstrate that efficient expression of the CCR5Delta32 protein in primary CD4(+) cells by use of a recombinant adenovirus (Ad5/Delta32) was able to down-regulate surface expression of both wild-type CCR5 and CXCR4 and to confer broad resistance to R5, R5X4, and X4 HIV type 1 (HIV-1). This may be important clinically, since we found that CD4(+) cells purified from peripheral blood mononuclear cells of individuals who were homozygous for CCR5Delta32, which expressed the mutant protein endogenously, consistently expressed lower levels of CXCR4 and showed less susceptibility to X4 HIV-1 isolates than cells from individuals lacking the mutation. Moreover, CD4(+) cells from individuals who were homozygous for CCR5Delta32 expressed the mutant protein in five of five HIV-exposed, uninfected donors tested but not in either of two HIV-infected donors tested. The mechanism of inhibition may involve direct scavenging, since we were able to observe a direct interaction of CCR5 and CXCR4 with CCR5Delta32, both by genetic criteria using the yeast two-hybrid system and by biochemical criteria using the coimmunoprecipitation of heterodimers. Thus, these results suggest that at least two distinct mechanisms may account for genetic resistance to HIV conferred by CCR5Delta32: the loss of wild-type CCR5 surface expression and the generation of CCR5Delta32 protein, which functions as a scavenger of both CCR5 and CXCR4. C1 Indiana Univ, Sch Med, Walther Oncol Ctr, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Alkhatib, G (reprint author), Indiana Univ, Sch Med, Walther Oncol Ctr, Dept Microbiol & Immunol, 635 Barnhill Dr,Rm 420, Indianapolis, IN 46202 USA. EM galkhati@iupui.edu FU NIAID NIH HHS [R01 AI052019]; PHS HHS [A152019-01A1] NR 51 TC 63 Z9 67 U1 1 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 MAR PY 2004 VL 78 IS 5 BP 2277 EP 2287 DI 10.1128/JVI.78.5.2277-2287.2004 PG 11 WC Virology SC Virology GA 775AV UT WOS:000189019300012 PM 14963124 ER PT J AU Senkevich, TG Ward, BM Moss, B AF Senkevich, TG Ward, BM Moss, B TI Vaccinia virus A28L gene encodes an essential protein component of the virion membrane with intramolecular disulfide bonds formed by the viral cytoplasmic redox pathway SO JOURNAL OF VIROLOGY LA English DT Article ID GOLGI INTERMEDIATE COMPARTMENT; INTRACELLULAR MATURE VIRIONS; ENDOPLASMIC-RETICULUM; EXPRESSION; MORPHOGENESIS; POXVIRUSES; GENOME AB We report the initial characterization of the product of the vaccinia virus A28L gene, which is highly conserved in all sequenced poxviruses. Our studies showed that the A28 protein is expressed at late times during the virus replication cycle and is a membrane component of the intracellular mature virion. An N-terminal hydrophobic sequence, present in all poxvirus A28 orthologs, anchors the protein in the virion surface membrane so that most of it is exposed to the cytoplasm. The cytoplasmic domain contains four conserved cysteines, which form two intramolecular disulfide bonds. Disulfide bond formation depended on the expression of three viral proteins, E10, A2.5, and G4, which together comprise a conserved cytoplasmic redox pathway. A28 is the third identified substrate of this pathway; the others are the L1 and F9 proteins. We constructed a conditional-lethal recombinant vaccinia virus with an inducible A28L gene. The recombinant virus was propagated in the presence of inducer but was unable to replicate and spread in its absence. During a single round of an abortive infection in the absence of inducer, the synthesis and processing of viral proteins, assembly of intra- and extracellular virions, and formation of actin tails occurred normally. In another paper (T. Senkevich, B. M. Ward, and B. Moss, I Virol. 78:2357-2366, 2004), we have demonstrated that virions assembled without A28 cannot carry out a second round of infection because they are defective in cell penetration. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 26 TC 45 Z9 47 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 MAR PY 2004 VL 78 IS 5 BP 2348 EP 2356 DI 10.1128/JVI.78.5.2348-2356.2004 PG 9 WC Virology SC Virology GA 775AV UT WOS:000189019300019 PM 14963131 ER PT J AU Senkevich, TG Ward, BM Moss, B AF Senkevich, TG Ward, BM Moss, B TI Vaccinia virus entry into cells is dependent on a virion surface protein encoded by the A28L gene SO JOURNAL OF VIROLOGY LA English DT Article ID INTRACELLULAR MATURE VIRIONS; OPEN READING FRAME; NEUTRALIZING MONOCLONAL-ANTIBODIES; 14-KILODALTON ENVELOPE PROTEIN; MEMBRANE-PROTEIN; FUSION PROTEIN; A27L PROTEIN; INTERMEDIATE COMPARTMENT; ENDOPLASMIC-RETICULUM; CONFOCAL MICROSCOPY AB The A28L gene of vaccinia virus is conserved in all poxviruses and encodes a protein that is anchored, to the surface of infectious intracellular mature virions (IMV) and consequently lies beneath the additional envelope of extracellular virions. A conditional lethal recombinant vaccinia virus, vA28-HAi, with an inducible A28L gene, undergoes a single round of replication in the absence of inducer, producing IMV, as well as extracellular virions with actin tails, but fails to infect neighboring cells. We show here that purified A28-deficient IMV appeared to be indistinguishable from wild-type IMV and were competent to synthesize RNA in vitro. Nevertheless, A28-deficient virions did not induce cytopathic effects, express early genes, or initiate a productive infection. Although A28-deficient IMV bound to the surface of cells, their cores did not penetrate into the cytoplasm. An associated defect in membrane fusion was demonstrated by the failure of low pH to trigger syncytium formation when cells were infected with vA28-HAi in the absence of inducer (fusion from within) or when cells were incubated with a high multiplicity of A28-deficient virions (fusion from without). The correlation between the entry block and the inability of A28-deficient virions to mediate fusion provided compelling evidence for a relationship between these events. Because repression of A28 inhibited cell-to-cell spread, which is mediated by extracellular virions, all forms of vaccinia virus regardless of their outer coat must use a common A28-dependent mechanism of cell penetration. Furthermore, since A28 is conserved, all poxviruses are likely to penetrate cells in a similar way. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 69 TC 73 Z9 76 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 MAR PY 2004 VL 78 IS 5 BP 2357 EP 2366 DI 10.1128/JVI.78.5.2357-2366.2004 PG 10 WC Virology SC Virology GA 775AV UT WOS:000189019300020 PM 14963132 ER PT J AU Gorny, MK Revesz, K Williams, C Volsky, B Louder, MK Anyangwe, CA Krachmarov, C Kayman, SC Pinter, A Nadas, A Nyambi, PN Mascola, JR Zolla-Pazner, S AF Gorny, MK Revesz, K Williams, C Volsky, B Louder, MK Anyangwe, CA Krachmarov, C Kayman, SC Pinter, A Nadas, A Nyambi, PN Mascola, JR Zolla-Pazner, S TI The V3 loop is accessible on the surface of most human immunodeficiency virus type 1 primary isolates and serves as a neutralization epitope SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN; HIV-1 GP120; SOLUBLE CD4; CLADE-B; BINDING; VIRIONS; CORECEPTOR; INTACT; DOMAIN AB Antibodies (Abs) against the V3 loop of the human immunodeficiency virus type 1 gp120 envelope glycoprotein were initially considered to mediate only type-specific neutralization of T-cell-line-adapted viruses. However, recent data show that cross-neutralizing V3 Abs also exist, and primary isolates can be efficiently neutralized with anti-V3 monoclonal Abs (MAbs). The neutralizing activities of anti-V3 polyclonal Abs and MAN may, however, be limited due to antigenic variations of the V3 region, a lack of V3 exposure on the surface of intact virions, or Ab specificity. For clarification of this issue, a panel of 32 human anti-V3 MAbs were screened for neutralization of an SF162-pseudotyped virus in a luciferase assay. MAbs selected with a V3 fusion protein whose V3 region mimics the conformation of the native virus were significantly more potent than MAbs selected with V3 peptides. Seven MAbs were further tested for neutralizing activity against 13 clade B viruses in a single-round peripheral blood mononuclear cell assay. While there was a spectrum of virus sensitivities to the anti-V3 MAbs observed, 12 of the 13 viruses were neutralized by one or more of the anti-V3 MAbs. MAb binding to intact virions correlated significantly with binding to solubilized gp120s and with the potency of neutralization. These results demonstrate that the V3 loop is accessible on the native virus envelope, that the strength of binding of anti-V3 Abs correlates with the potency of neutralization, that V3 epitopes may be shared rather than type specific, and that Abs against the V3 loop, particularly those targeting conformational epitopes, can mediate the neutralization of primary isolates. C1 Vet Affairs New York Harbor Healthcare Syst, Res Enhancement Award Program, New York, NY 10010 USA. NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. NYU, Sch Med, Inst Environm Med, New York, NY 10016 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Alpha Royal Clin, Bamenda, Cameroon. Publ Hlth Res Inst, Lab Retroviral Biol, Newark, NJ 07103 USA. RP Zolla-Pazner, S (reprint author), Vet Affairs Med Ctr, 423 E 23rd St,Room 18124N, New York, NY 10010 USA. EM zollas01@endeavor.med.nyu.edu FU NHLBI NIH HHS [HL59725, R01 HL059725]; NIAID NIH HHS [AI 47053, AI27742, AI36085, P30 AI027742, R01 AI036085, R01 AI047053] NR 57 TC 86 Z9 91 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 MAR PY 2004 VL 78 IS 5 BP 2394 EP 2404 DI 10.1128/JVI.78.5.2394-2404.2004 PG 11 WC Virology SC Virology GA 775AV UT WOS:000189019300023 PM 14963135 ER PT J AU Ward, BM Moss, B AF Ward, BM Moss, B TI Vaccinia virus A36R membrane protein provides a direct link between intracellular enveloped virions and the microtubule motor kinesin SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIN-BASED MOTILITY; EXTRACELLULAR VIRUS ENVELOPE; TO-CELL SPREAD; VACCINIA VIRUS; CONTAINING MICROVILLI; INTERMEDIATE COMPARTMENT; ENDOPLASMIC-RETICULUM; TAIL FORMATION; A36R PROTEIN; F12L PROTEIN AB Previous work demonstrated that intracellular enveloped vaccinia virus virions use microtubules to move from the site of membrane wrapping to the cell periphery. The mechanism and direction of intracellular virion movement predicted that viral proteins directly or indirectly interact with the microtubule motor protein kinesin. The yeast two-hybrid assay was used to test for interactions between the light chain of kinesin and the cytoplasmic tails from five viral envelope proteins. We found that the N-terminal tetratricopeptide repeat region of the kinesin light chain (KLC-TPR) interacted with the cytoplasmic tail of the viral A36R protein. A series of C- and N-terminal truncations of A36R further defined a region from residues 81 to 111 that was sufficient for interaction with KLC-TPR. Interactions were confirmed by using pull-down assays with purified glutathione S-transferase (GST)-A36R and S-35-labeled KLC-TPR. The defined region on A36R for interaction with kinesin overlaps the recently defined region (residues 91 to 111) for interaction with the A33R envelope protein. The yeast three-hybrid system was used to demonstrate that expression of A33R interrupted the interaction between A36R and KLC-TPR, indicating that the binding of A36R is mutually exclusive to either A33R or kinesin. Pull-down assays with purified GST-A36R and S-35-labeled KLC-TPR in. the presence of competing A33R corroborated these findings. Collectively, these results demonstrated that the viral A36R protein interacts directly with the microtubule motor protein kinesin and that the viral protein A33R may regulate this interaction. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 55 TC 51 Z9 54 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 MAR PY 2004 VL 78 IS 5 BP 2486 EP 2493 DI 10.1128/JVI.78.5.2486-2493.2004 PG 8 WC Virology SC Virology GA 775AV UT WOS:000189019300033 PM 14963148 ER PT J AU Tang, SA Yamanegi, K Zheng, ZM AF Tang, SA Yamanegi, K Zheng, ZM TI Requirement of a 12-base-pair TATT-containing sequence and viral lytic DNA replication in activation of the Kaposi's sarcoma-associated herpesvirus K8.1 late promoter SO JOURNAL OF VIROLOGY LA English DT Article ID SIMPLEX-VIRUS TYPE-1; LATE-GENE-EXPRESSION; EPSTEIN-BARR-VIRUS; HUMAN-HERPESVIRUS-8; PROTEIN; RNA; TRANSCRIPTION; PURIFICATION; DOWNSTREAM; ELEMENT AB Kaposi's sarcoma-associated herpesvirus (KSHV) K8.1 late promoter consists of a minimal 24-bp sequence, with a TATA-like, 12-bp promoter core, AATATTAAAGGG, and is active on a reporter only in butyrate-induced KSHV-infected cells. The activity of the K8.1 promoter can be enhanced (>15-fold) by the KSHV left-end lytic origin of DNA replication (oriLyt-L) sequence while providing inefficient replication of plasmid DNA and is inhibited by viral DNA replication inhibitors, suggesting that activation of the K8.1 promoter on the reporter is involved in KSHV lytic DNA replication largely by trans. C1 NCI, HIV & AIDS Malignancy Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, Canc Res Ctr, NIH, Bldg 10,Rm 10S255,MSC 1868,10 Center Dr, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov RI Tang, Shuang/F-9115-2014 OI Tang, Shuang/0000-0002-3084-0903 NR 32 TC 20 Z9 21 U1 1 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 MAR PY 2004 VL 78 IS 5 BP 2609 EP 2614 DI 10.1128/JVI.78.5.2609-2614.2004 PG 6 WC Virology SC Virology GA 775AV UT WOS:000189019300050 PM 14963167 ER PT J AU Rutigliano, JA Johnson, TR Hollinger, TN Fischer, JE Aung, S Graham, BS AF Rutigliano, JA Johnson, TR Hollinger, TN Fischer, JE Aung, S Graham, BS TI Treatment with anti-LFA-1 delays the CD8(+) cytotoxic-T-lymphocyte response and viral clearance in mice with primary respiratory syncytial virus infection SO JOURNAL OF VIROLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; EPITHELIAL-CELLS A549; TUMOR-NECROSIS-FACTOR; IMMUNOLOGICAL SYNAPSE; EXTRACELLULAR-MATRIX; RHINOVIRUS RECEPTOR; IMMUNE-SYSTEM; IN-VIVO; LFA-1; EXPRESSION AB Cytotoxic T lymphocytes (CTLs) play an important role in the immune response against respiratory syncytial virus (RSV) infection. The cell surface molecule lymphocyte function-associated antigen 1 (LFA-1) is an important contributor to CTL activation, CTL-mediated direct cell lysis, and lymphocyte migration. In an attempt to determine the role of LFA-1 during RSV infection, we treated BALB/c mice with monoclonal antibodies to LFA-1 at days -1, +1, and +4 relative to primary RSV infection. Anti-LFA-1 treatment during primary RSV infection led to reduced illness and delayed clearance of virus-infected cells. CTLs from RSV-infected mice that were treated with anti-LFA-1 exhibited diminished cytolytic activity and reduced gamma interferon production. In addition, studies with BrdU (5-bromo-2'-deoxyuridine)- and CFSE [5-(and 6)carboxyfluorescein diacetate succinimidyl ester]-labeled lymphocytes showed that anti-LFA-1 treatment led to delayed proliferation during RSV infection. These results indicate that LFA-1 plays a critical role in the initiation of the immune response to RSV infection by facilitating CTL activation. These results may prove useful in the development of new therapies to combat RSV infection or other inflammatory diseases. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 2502,40 Convent Dr,MSC 3017, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU NIAID NIH HHS [R01 AI033933, R01-AI-33933] NR 57 TC 19 Z9 20 U1 1 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 MAR PY 2004 VL 78 IS 6 BP 3014 EP 3023 DI 10.1128/JVI.78.6.3014-3023.2004 PG 10 WC Virology SC Virology GA 800QP UT WOS:000220043100036 PM 14990720 ER PT J AU Massad, LS Schneider, MF Watts, DH Strickler, HD Melnick, S Palefsky, J Anastos, K Levine, AM Minkoff, H AF Massad, LS Schneider, MF Watts, DH Strickler, HD Melnick, S Palefsky, J Anastos, K Levine, AM Minkoff, H TI HPV testing for triage of HIV-infected women with papanicolaou smears read as atypical squamous cells of uncertain significance SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; UNDETERMINED SIGNIFICANCE; INTERAGENCY HIV; RISK-FACTORS; PREVALENCE; CYTOLOGY; CANCER; ABNORMALITIES AB Purpose: To assess the utility of testing for high-risk human papillomavirus (HPV) DNA as a triage strategy for detecting cervical intraepithelial neoplasia (CIN) grade 2/3 in women with human immunodeficiency virus-1 (HIV-1) infection and cytology read as atypical cells of uncertain significance (ASCUS). Methods: Conventional cervical cytology and cervicovaginal lavage were obtained at 6-month intervals between October 1, 1994, and September 30, 2002, from women enrolled in the Women's Interagency HIV Study, a multicenter cohort studying the natural history of HIV in women. HPV typing was performed by PCR. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 were classified as carrying high oncogenic risk. Women with ASCUS smears were referred for colposcopy. Analyses of the sensitivity of HPV testing were cross-sectional, using colposcopy results within 90 days of first ASCUS result. Results: Of the 270 women evaluated, 7 (3%) had CIN 2, and 3 (1%) had CIN3 or adenocarcinoma in situ. High-risk HPV DNA was found in 81 (30%) of the 270 participants. The sensitivity of high-risk HPV DNA detection for CIN 2/3 was 50% (95% Cl 0.19, 0.81), the specificity was 71% (95% Cl 0.65, 0.76), the positive predictive value was 6% (95% Cl 0.01, 0.11), and the negative predictive value was 97% (95% Cl 0.95, 1.00). HPV of any risk type was found in 176 (65%) of the 270 women, including 9 of 10 women with CIN 2/3, for a sensitivity of 90% (95% CI 0.56, 1.00), a specificity of 36% (95% Cl 0.30, 0.42), a positive predictive value of 5% (95% Cl 0.02, 0.08), and a negative predictive value of 99% (95% Cl 0.94, 1.00). Conclusions: For women with HIV and Papanicolaou smears read as ASCUS, DNA testing for high risk HPV may not be sensitive enough for clinical use. C1 So Illinois Univ, Sch Med, Dept Obstet & Gynecol, Springfield, IL 62794 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NCI, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Montefiore Med Ctr, New York, NY USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Maimonides Hosp, Brooklyn, NY 11219 USA. RP Massad, LS (reprint author), So Illinois Univ, Sch Med, Dept Obstet & Gynecol, POB 19640, Springfield, IL 62794 USA. EM smassad@siumed.edu FU NCRR NIH HHS [M-01-RR-00083, M01-RR-00079]; NIAID NIH HHS [U01-AI-31834, U01-AI-34993, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 23 TC 12 Z9 13 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2004 VL 13 IS 2 BP 147 EP 153 DI 10.1089/154099904322966128 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 805PY UT WOS:000220379400003 PM 15072728 ER PT J AU Cesari, M Penninx, BWJH Pahor, M Lauretani, F Corsi, AM Williams, GR Guralnik, JM Ferrucci, L AF Cesari, M Penninx, BWJH Pahor, M Lauretani, F Corsi, AM Williams, GR Guralnik, JM Ferrucci, L TI Inflammatory markers and physical performance in older persons: The InCHIANTI study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; FACTOR-ALPHA; SKELETAL-MUSCLE; CYTOKINE RECEPTORS; BODY-COMPOSITION; HEART-FAILURE; RISK-FACTORS; SERUM-LEVELS AB Background. Some studies have proposed chronic inflammation as an underlying biological mechanism responsible for physical function decline in elderly people. The aim of this study is to evaluate the relationship between several inflammatory markers and physical performance in an older population. Methods. This study is part of the "Invecchiare in Chianti" (InCHIANTI) study, a prospective population-based study of older people, aimed at identifying risk factors for late-life disability. The study sample consisted of 1020 participants aged 65 years and older living in the Chianti area of Italy. Physical performance was assessed using walking speed, the chair-stand test, and the standing balance test. Hand-grip strength was assessed using a hand-held dynamometer. Serum levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), IL-10, IL-1beta, IL-6sR, and IL- RA were determined. Linear regression analyses were used to assess the multivariate relationship of inflammatory marker levels with physical performance, scored as a continuous variable from 0 to 3, and hand-grip strength after adjustment for demographics, chronic conditions, medication use, and other biological variables. Results. CRP, IL-6. and IL I RA were significantly correlated with physical performance (r = -0. 162, r = -0.251, and r = -0. 127, respectively). Significant correlations with hand-grip strength were found for CRP and IL-6 (r = -0.081 and r = -0.089, respectively). After adjustment for covariates, high levels of IL-6 and IL-IRA continued to be strongly associated with worse physical performance (p <.001 and p=0.004, respectively). High levels of CRP (p <.001) and IL-6 (p <.001) were associated with low hand-grip strength. Mean adjusted physical performance scores ranged from 2.21 in the CRP < 0.59 mg/dl group to 2.07 in the CRP > 0.60 mg/dl group (p for trend -.004), and from 2.25 in the lowest IL-6 quartile to 2.08 in the highest IL-6 quartile (p for trend <.001). This trend was also reflected in mean adjusted hand-grip strength, with a range from 28.8 kg for the CRP < 0.59 mg/dl group to 26.0 kg for the CRP > 0.60 mg/dl group (p for trend =.001), and from 27.4 kg for the lowest IL-6 quartile to 25.1 kg for the highest IL-6 quartile (p for trend =.001). Conclusions. Inflammation. measured as high levels of IL-6, CRP, and IL- IRA, is significantly associated with poor physical performance and muscle strength in older persons. These data also support the biological face validity of physical performance measures. The assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention. C1 Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Italian Natl Res Council Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RP Cesari, M (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mcesafi@wfubmc.edu RI Cesari, Matteo/A-4649-2008; Lauretani, Fulvio/K-5115-2016 OI Cesari, Matteo/0000-0002-0348-3664; Lauretani, Fulvio/0000-0002-5287-9972 FU NIA NIH HHS [P30-AG-021332-01]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13] NR 45 TC 359 Z9 375 U1 0 U2 11 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2004 VL 59 IS 3 BP 242 EP 248 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 805LP UT WOS:000220368100006 PM 15031308 ER PT J AU Cesari, M Penninx, BWJH Lauretani, F Russo, CR Carter, C Bandinelli, S Atkinson, H Onder, G Pahor, M Ferrucci, L AF Cesari, M Penninx, BWJH Lauretani, F Russo, CR Carter, C Bandinelli, S Atkinson, H Onder, G Pahor, M Ferrucci, L TI Hemoglobin levels and skeletal muscle: Results from the InCHIANTI study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID OLDER PERSONS; COMPUTED-TOMOGRAPHY; HEART-FAILURE; FAT MASS; ANEMIA; STRENGTH; PREVALENCE; HYPOXIA; HEALTHY; DECLINE AB Background. Anemia is associated with reduced physical performance and muscle strength. The aim of the study was to explore whether anemia and hemoglobin levels are associated with differences in quantitative and qualitative measures of muscle and fat. Methods. The study sample consisted of 909 participants 65 years and older enrolled in the "Invecchiare in Chianti" (InCHIANTI) study, a prospective population-based study of older people aimed at identifying risk factors for late-life disability. All the analyses were performed considering continuous hemoglobin levels as well as the dichotomous anemia variable (defined according to World Health Organization criteria as hemoglobin < 12 g/dL in women and < 13 g/dL in men). A peripheral quantitative computed tomography (pQCT) scan was performed in all participants to evaluate total, muscular. and fat cross-sectional areas of the calf and relative muscle density. Ankle extension strength was measured using a hand-held dynamometer. Linear regression analyses were used to assess the multivariate relationship of pQCT and skeletal muscle strength measures with hemoglobin levels and anemia after adjustment for demographics, chronic conditions. medication use, and other biological variables. Results. Participants were aged 74.8 +/- 6.8 years. In our sample, 94 participants (10.3%) were anemic. Hemoglobin levels were significantly associated with muscle density (P = 0.225 [SE, standard error 0.098], p =.02), muscle area/total area ratio (beta = 0.778 [SE 0.262] p =.003), fat area/total area ratio (beta = -0.869 [SE 0.225]; p <.001). Skeletal muscle strength and muscle density were highly associated with anemia (P = -3.266 [SE 1.173], p =.005 and P = -0.816 [SE 0.374] p =.03, respectively). Results did not change when analyses were rerun in a restricted sample of participants not affected by major medical conditions. Conclusion. The present study shows that hemoglobin levels are associated with the parameters of body composition obtained by pQCT, and that decreases in muscular strength measures occur in the presence of anemia. C1 Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Sacred Heart, Dept Geriatr, I-00168 Rome, Italy. Italian Natl Res Council Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RP Cesari, M (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mcesari@wfubmc.edu RI Cesari, Matteo/A-4649-2008; Carter, Christy/E-6630-2011; Lauretani, Fulvio/K-5115-2016 OI Cesari, Matteo/0000-0002-0348-3664; Lauretani, Fulvio/0000-0002-5287-9972 FU NIA NIH HHS [P30-AG-021332-01, P30 AG021332]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13] NR 43 TC 86 Z9 91 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2004 VL 59 IS 3 BP 249 EP 254 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 805LP UT WOS:000220368100007 PM 15031309 ER PT J AU Fried, LP Ferrucci, L Darer, J Williamson, JD Anderson, G AF Fried, LP Ferrucci, L Darer, J Williamson, JD Anderson, G TI Untangling the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review ID OLDER-ADULTS; ELDERLY-PEOPLE; CARDIOVASCULAR HEALTH; WOMENS-HEALTH; RISK-FACTORS; OSTEOARTHRITIS; INTERLEUKIN-6; ASSOCIATION; DIFFICULTY; PREVALENCE AB Three terms are commonly used interchangeably to identify vulnerable older adults: comorbidity, or multiple chronic conditions, frailty, and disability. However, in geriatric medicine, there is a growing consensus that these are distinct clinical entities that are causally related. Each, individually, occurs frequently and has high import clinically. This article provides a narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions, including their clinical relevance and distinct prevention and therapeutic issues, and how they are related. Review of the current state of published knowledge is supplemented by targeted analyses in selected areas where no current published data exists. Overall, the goal of this article is to provide a basis for distinguishing between these three important clinical conditions in older adults and showing how use of separate, distinct definitions of each can improve our understanding of the problems affecting older patients and lead to development of improved strategies for diagnosis, care, research, and medical education in this area. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Bloomberg Sch Publ Hlth, Baltimore, MD USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. Mid Atlantic Permanente Med Grp, Baltimore, MD USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Fried, LP (reprint author), Johns Hopkins Med Inst, Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM lfried@jhmi.edu NR 54 TC 1089 Z9 1131 U1 10 U2 88 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2004 VL 59 IS 3 BP 255 EP 263 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 805LP UT WOS:000220368100008 PM 15031310 ER PT J AU Klaunberg, BA Lizak, MJ AF Klaunberg, BA Lizak, MJ TI Considerations for setting up a small-animal imaging facility SO LAB ANIMAL LA English DT Article ID RAY COMPUTED-TOMOGRAPHY; GENE C1 NIH, Mouse Imaging Facil, Bethesda, MD 20892 USA. RP Klaunberg, BA (reprint author), NIH, Mouse Imaging Facil, 10 Ctr Dr,Room B1D-69, Bethesda, MD 20892 USA. EM klaunbeb@ninds.nih.gov NR 16 TC 11 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2004 VL 33 IS 3 BP 28 EP 34 DI 10.1038/laban0304-28 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 779NW UT WOS:000189307600008 PM 15235626 ER PT J AU Nelson, KB Lynch, JK AF Nelson, KB Lynch, JK TI Stroke in newborn infants SO LANCET NEUROLOGY LA English DT Review ID FACTOR-V-LEIDEN; NEONATAL CEREBRAL INFARCTION; MATERNAL ANTICARDIOLIPIN ANTIBODIES; TEMPORAL ARTERY CATHETERIZATION; ACTIVATED PROTEIN-C; BLOOD-FLOW VELOCITY; FULL-TERM INFANTS; RISK-FACTORS; ISCHEMIC-STROKE; METHYLENETETRAHYDROFOLATE REDUCTASE AB The few days before and after birth are a time of special risk for stroke in both mother and infant, probably related to activation of coagulation mechanisms in this critical period. Arterial ischaemic stroke around the time of birth is recognised in about one in 4000 full-term infants, and may present with neurological and systemic signs in the newborn. Neonatal seizures are most commonly the clinical finding that triggers assessment. In other children, perinatal stroke is recognised only retrospectively, with emerging hemiparesis or seizures after the early months of life. Risk factors for perinatal stroke include hereditary or acquired thrombophilias and environmental factors. Perinatal stroke underlies an important share of congenital hemiplegic cerebral palsy, and probably some spastic quadriplegic cerebral palsy and seizure disorders. There is much to be learned about the natural history of perinatal stroke, and there are as yet no evidence-based strategies for prevention or treatment. C1 NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), Bldg 10,Room 5S220,10 Ctr Dr,MSC 1447, Bethesda, MD 20892 USA. EM knelson@helix.nih.gov NR 110 TC 193 Z9 203 U1 1 U2 8 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2004 VL 3 IS 3 BP 150 EP 158 DI 10.1016/S1474-4422(04)00679-9 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 802MK UT WOS:000220167400017 PM 14980530 ER PT J AU Czarneski, J Lin, YC Chong, S McCarthy, B Fernandes, H Parker, G Mansour, A Huppi, K Marti, GE Raveche, E AF Czarneski, J Lin, YC Chong, S McCarthy, B Fernandes, H Parker, G Mansour, A Huppi, K Marti, GE Raveche, E TI Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma SO LEUKEMIA LA English DT Article DE B-lymphocytes; cytokines; knockout ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; IN-VIVO; B-1 CELLS; SPEED CONGENICS; INTERLEUKIN-10; APOPTOSIS; GROWTH; EXPRESSION; INHIBITION AB NZB mice develop an age-related malignant expansion of a subset of B cells, B-1 cells, with autocrine production of IL-10. IL-10, a pleiotropic cytokine with anti-inflammatory properties, is a potent growth and survival factor for malignant B cells. To further examine the in vivo requirement for IL-10 in the development and expansion of malignant B-1 clones in NZB mice, we developed a strain of homozygous IL-10 knockout (KO) mice on an NZB background. The NZB IL-10 KO mice develop peritoneal B-1 cells with approximately the same frequency as heterozygous and wild-type littermates. In contrast, the development of malignant B-1 cells in the peripheral blood and spleen, observed in wild-type NZB, rarely occurred in the NZB IL-10 KO. Phenotypic analysis of surface marker expression in splenic B cells indicated that, in contrast to the NZB with malignant B-1 splenic lymphoma, the surface marker expression of NZB IL-10 KO splenic B cells indicated that the majority of the B cells were typical B-2 cells. In the absence of IL-10, spontaneously activated B cells and antiapoptotic gene expression were reduced and lymphoma incidence was decreased. These results indicate that IL-10 is a critical factor for the progression of this B-cell malignant disease. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pathol, Newark, NJ 07103 USA. NCI, Canc Prevent Studies Branch, NIH, Rockville, MD USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Raveche, E (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pathol, 185 S Orange Ave, Newark, NJ 07103 USA. EM raveches@umdnj.edu FU NCI NIH HHS [R01 CA 71478-11] NR 40 TC 38 Z9 39 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2004 VL 18 IS 3 BP 597 EP 606 DI 10.1038/sj.leu.2403244 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 777UT UT WOS:000189197800029 PM 14712288 ER PT J AU Benitez-Hess, ML DiPaolo, JA Alvarez-Salas, LM AF Benitez-Hess, ML DiPaolo, JA Alvarez-Salas, LM TI Antisense activity detection by inhibition of fluorescence resonance energy transfer SO LUMINESCENCE LA English DT Article DE fluorescence; antisense; energy transfer; green fluorescent protein; oligodeoxynucleotides ID THEORETICAL APPROACH; SECONDARY STRUCTURE; MAMMALIAN-CELLS; GENE-EXPRESSION; IN-VIVO; PROTEIN; FRET; CALMODULIN; SELECTION; RNAS AB Use of antisense nucleic acids to modulate expression of particular genes is a promising approach to the therapy of human papillomavirus type 16 (HPV-16)-associated cervical cancer. Understandably, evaluation of the in vivo performance of synthetic antisense oligodeoxynucleotides (AS-ODNs) or ribozymes is of ultimate importance to development of effective antisense tools. Here we report the use of a bacterial reporter system based on the inhibition of fluorescence resonance energy transfer (FRET) to measure the interaction of AS-ODNs with HPV-16 target nt 410-445, using variants of the green fluorescent protein (GFP). An optimal FRET-producing pair was selected with GFP as the donor and yellow fluorescent protein (YFP) as the acceptor molecule. Hybridization of AS-ODNs with a chimaeric mRNA containing the antisense target site flanked by GFP variants resulted in the inhibition of the FRET effect. Use of different linkers suggested that the amino acid content of the linker has no significant effect on FRET effect. Antisense accessibility, tested by RNaseH assays with phosphorothioated target-specific and mutant AS-ODNs, suggested a specific effect on the chimaeric mRNA. FRET inhibition measurements correlated with the presence of truncated proteins confirming true antisense activity over the target. Therefore, FRET inhibition may be used for the direct measurement of AS-ODNs activity in vivo. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Ctr Invest & Estudios Avanzados, Dept Genet & Biol Mol, Lab Terapia Genica, Mexico City 07360, DF, Mexico. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Alvarez-Salas, LM (reprint author), Ctr Invest & Estudios Avanzados, Dept Genet & Biol Mol, Lab Terapia Genica, Av IPN 2508, Mexico City 07360, DF, Mexico. EM lalvarez@mail.cinvestav.mx NR 39 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1522-7235 J9 LUMINESCENCE JI Luminescence PD MAR-APR PY 2004 VL 19 IS 2 BP 85 EP 93 DI 10.1002/bio.763 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821PJ UT WOS:000221474000005 PM 15098208 ER PT J AU Duyn, J AF Duyn, J TI Specificity of high-resolution BOLD and CBF fMRI at 7 T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Letter ID HUMAN BRAIN; TESLA C1 NINDS, Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. RP Duyn, J (reprint author), Bldg 10,Rm B1D-118,MSC 1065,10 Ctr Dr, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov RI Duyn, Jozef/F-2483-2010 NR 5 TC 4 Z9 4 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2004 VL 51 IS 3 BP 644 EP 645 DI 10.1002/mrm.20040 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 800BF UT WOS:000220003200032 PM 15004812 ER PT J AU Hastings, IM Paget-McNicol, S Saul, A AF Hastings, IM Paget-McNicol, S Saul, A TI Can mutation and selection explain virulence in human P-falciparum infections? SO MALARIA JOURNAL LA English DT Article ID ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; ANTIGENIC VARIATION; MALARIA PARASITES; ADAPTATION; ERYTHROCYTES; EVOLUTION AB Background: Parasites incur periodic mutations which must ultimately be eliminated to maintain their genetic integrity. Methods: It is hypothesised that these mutations are eliminated not by the conventional mechanisms of competition between parasites in different hosts but primarily by competition between parasites within the same infection. Results: This process is enhanced by the production of a large number of parasites within individual infections, and this may significantly contribute to parasitic virulence. Conclusions: Several features of the most virulent human malaria parasite Plasmodium falciparum can usefully be re-interpreted in this light and lend support to this interpretation. More generally, it constitutes a novel explanation for the evolution of virulence in a wider range of microparasites. C1 Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. NIAID, Malaria Vaccine Dev Unit, LPD, NIH, Rockville, MD 20852 USA. RP Hastings, IM (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Pembroke Pl, Liverpool L3 5QA, Merseyside, England. EM hastings@liverpool.ac.uk; smcnicol@optusnet.com.au; ASAUL@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 20 TC 6 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAR PY 2004 VL 3 AR 2 DI 10.1186/1475-2875-3-2 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 820RO UT WOS:000221407200007 PM 14992697 ER PT J AU Matzavinos, A Chaplain, MAJ Kuznetsov, VA AF Matzavinos, A Chaplain, MAJ Kuznetsov, VA TI Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour SO MATHEMATICAL MEDICINE AND BIOLOGY-A JOURNAL OF THE IMA LA English DT Article DE solid tumour growth; immune response; T-lymphocytes; chemokines; spatiotemporal heterogeneity ID NECROSIS-FACTOR-ALPHA; SPHEROID MODEL; HUMAN-MELANOMA; ADHESION MOLECULES; MALIGNANT-MELANOMA; PATTERN-FORMATION; CELL RECOGNITION; KINETIC-ANALYSIS; IMMUNE-RESPONSE; DORMANT STATE AB In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium-cancer dormancy-a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries-multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals the existence of a stable limit cycle. This is verified further when a subsequent bifurcation analysis is undertaken using a numerical continuation package. These results then explain the complex heterogeneous spatio-temporal dynamics observed in the partial differential equation (PDE) system. Our approach may lead to a deeper understanding of the phenomenon of cancer dormancy and may be helpful in the future development of more effective anti-cancer vaccines. C1 Univ Dundee, Div Math, SIMBIOS Ctr, Dundee DD1 4HN, Scotland. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Chaplain, MAJ (reprint author), Univ Dundee, Div Math, SIMBIOS Ctr, Dundee DD1 4HN, Scotland. EM tasos@maths.dundee.ac.uk; chaplain@maths.dundee.ac.uk; vk28u@nih.gov RI Chaplain, Mark/A-5355-2010 OI Chaplain, Mark/0000-0001-5727-2160 NR 89 TC 77 Z9 79 U1 2 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0265-0746 J9 MATH MED BIOL JI Math. Med. Biol. PD MAR PY 2004 VL 21 IS 1 BP 1 EP 34 PG 34 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 809VO UT WOS:000220664400001 PM 15065736 ER PT J AU Kleta, R Blair, SC Bernardini, I Kaiser-Kupfer, MI Gahl, WA AF Kleta, R Blair, SC Bernardini, I Kaiser-Kupfer, MI Gahl, WA TI Keratopathy of multiple myeloma masquerading as corneal crystals of ocular cystinosis SO MAYO CLINIC PROCEEDINGS LA English DT Article ID MONOCLONAL GAMMOPATHY; NEPHROPATHIC CYSTINOSIS; DEPOSITS; DYSPROTEINEMIA; CYSTEAMINE AB We describe a 49-year-old woman in whom ocular cystinosis was diagnosed on the basis of a routine eye examination 12 years previously. Conjunctival biopsy was reported to support the diagnosis. The patient described photophobia for the past 5 years and reported a 2-fold increase in her serum IgG level for the past 12 years. On ophthalmic examination, corneal crystals were evident in the epithelium and superficial stromal layers, rather than throughout the corneal epithelium and the entire stroma as in ocular cystinosis: The patient's serum protein level was elevated at 8.7 g/dL; protein electrophoresis showed an elevated gamma-globulin peak, and the IgG level was twice that of normal at 2820 mg/dL. Bone marrow biopsy confirmed the diagnosis of multiple myeloma. This case illustrates that multiple myeloma can mimic corneal findings of cystinosis. C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet Branch, NIH, Bethesda, MD 20892 USA. Riverside Methodist Hosp, Hematol Oncol Sect, Columbus, OH 43214 USA. RP Kleta, R (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-107, Bethesda, MD 20892 USA. EM kletar@mail.nih.gov NR 26 TC 10 Z9 11 U1 0 U2 0 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD MAR PY 2004 VL 79 IS 3 BP 410 EP 412 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 778MC UT WOS:000189244500016 PM 15008615 ER PT J AU Ribeiro, JMC Zeidner, NS Ledin, K Dolan, MC Mather, TN AF Ribeiro, JMC Zeidner, NS Ledin, K Dolan, MC Mather, TN TI How much pilocarpine contaminates pilocarpine-induced tick saliva? SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Amblyomma americanum; Ixodes scapularis; haematophagy; pilocarpine; salivary glands; salivation; tick ID MUSCARINIC AGONIST PILOCARPINE; LYME-DISEASE VECTOR; IXODES-SCAPULARIS; BORRELIA-BURGDORFERI; HOST IMMUNITY; SECRETION; DAMMINI; EXPRESSION; ACTIVATION; RESISTANCE AB Pilocarpine is often applied or injected into ticks to induce salivation, and the resulting saliva used to test for various pharmacological, biochemical and immunological activities. To measure the amount of pilocarpine in pilocarpine-induced tick saliva, an HPLC-MS/MS method, based on capillary strong cation exchange chromatography online with an ion trap mass spectrometer, was used to measure pilocarpine in the pg to ng range. Results indicate large concentrations of pilocarpine in Ixodes scapularis Say and Amblyomma americanum (Linnaeus) (Acari: Ixodidae) saliva, ranging from 3 to 50 mM. Due to the known effects of pilocarpine on smooth muscle and immune cells, appropriate controls are proposed and discussed for proper interpretation of results using this saliva preparation. C1 NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20852 USA. Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Natl Ctr Infect Dis, Ft Collins, CO USA. Univ Rhode Isl, Ctr Vectorborne Dis, Kingston, RI 02881 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,Room 4-126,MSC 0425, Bethesda, MD 20852 USA. EM JRibeiro@NIH.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI 37230] NR 28 TC 16 Z9 16 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-283X J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD MAR PY 2004 VL 18 IS 1 BP 20 EP 24 DI 10.1111/j.0269-283X.2003.0469.x PG 5 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 801HU UT WOS:000220087800004 PM 15009442 ER PT J AU Shavers, VL Brown, M Klabunde, CN Potosky, AL Davis, W Moul, J Fahey, A AF Shavers, VL Brown, M Klabunde, CN Potosky, AL Davis, W Moul, J Fahey, A TI Race/ethnicity and the intensity of medical monitoring under 'watchful waiting' for prostate cancer SO MEDICAL CARE LA English DT Article DE race; ethnicity; treatment; disparities; prostate cancer ID UNITED-STATES; CARCINOMA; SURVIVAL; AGE; DIAGNOSIS; PATTERNS; TRENDS; STAGE; TIME; RACE AB Background: Previous studies have found that racial/ethnic minority patients with prostate cancer are more frequently managed with "watchful waiting." Little, however, is known about the medical care received among men managed with watchful waiting. We examine the type and intensity of medical monitoring received by African American, Hispanic, and white patients with prostate cancer managed with "watchful waiting" in fee-for-service systems. Methods: Surveillance Epidemiology and End Results-Medicare data for men diagnosed with prostate cancer 1994-1996 were used in this study. Men were determined to have initially received watchful waiting if they did not receive surgery, radiation, or hormone treatment within the first 7 months of diagnosis. Crosstabulations, multivariate logistic, and Cox regressions were used to examine the association between clinical and sociodemographic variables and the receipt of a primary care, urology visit, prostate-specific antigen test, or bone scan. Results: In general, Hispanic and African American men received less medical monitoring and had longer median times from diagnosis to receipt of a medical monitoring visit or procedure than white men. Furthermore, nearly 6% of African American, 5% of Hispanic, and 1% of white men did not have any medical monitoring visits or procedures during the 60-month follow-up period (P <0.001). Differences in observed clinical or sociodemographic characteristics did not explain variations in medical monitoring. Conclusion: Regular medical monitoring is considered by most medical authorities to be a necessary component of management with watchful waiting. The disproportionately low receipt of medical monitoring visits and procedures observed for African American and Hispanic men managed with watchful waiting in this study suggest that there are racial/ethnic disparities in the receipt of appropriate prostate cancer management. C1 NCI, Div Canc Control & Populat Sci, Appl Res program, HSEB, Bethesda, MD 20892 USA. NCI, Surveillance Res Program, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Surg, DoD Ctr Prostate Dis Res, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Bethesda, MD 20814 USA. Informat Management Syst, Silver Spring, MD USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res program, HSEB, 6130 Execut Blvd EPN 4005 MSC 7344, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 40 TC 47 Z9 48 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2004 VL 42 IS 3 BP 239 EP 250 DI 10.1097/01.mlr.0000117361.61444.71 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 779KC UT WOS:000189293000006 PM 15076823 ER PT J AU Shen, J Andersen, R Brook, R Kominski, G Albert, PS Wenger, N AF Shen, J Andersen, R Brook, R Kominski, G Albert, PS Wenger, N TI The effects of payment method on clinical decision-making - Physician responses to clinical scenarios SO MEDICAL CARE LA English DT Article DE payment incentives; capitated healthcare; physician payment; clinical decision-making ID PRIMARY-CARE PHYSICIANS; FINANCIAL INCENTIVES; MANAGED-CARE; ORGANIZATIONS; BEHAVIOR; REIMBURSEMENT; EXPERIENCE; SERVICE; QUALITY; VALUES AB Background: The influence of payment mechanisms on physician decisions is not well understood. Objectives: The objective of this study was to test 2 null hypotheses: 1) physicians' clinical decisions would not be influenced by payment incentives; and 2) physicians would have equal concern about medical decisions made under capitation or fee-for-service (FFS) arrangements. Research Design: We conducted a physician survey in which patient insurance status (capitated or FFS) was randomly incorporated into 4 clinical scenarios using a Latin square design. Subjects: We used a nationally representative random sample of family physicians in direct patient care. Measures: We used treatment decisions and physician "bother" scores (a measure of discomfort about decisions) in response to the clinical scenarios and adjusted for physician gender, age, board certification, income, practice location, practice mix, practice setting, geographic region, local area managed care penetration, and capitation or risk pool contracts in practice. Results: Seventy-two percent of sampled physicians responded. Comparing decisions made under capitation to FFS, physicians were less likely to indicate they would perform discretionary care (relative risks [RR] range, .64-.82; P <0.001), but payment had no effect on selection of life-saving care (RR, 1.02, not significant). Physicians felt significantly more "bothered" when they made clinical decisions under capitatedpayment (P <0.001 in all scenarios), regardless of whether a treatment was discretionary or life-saving, and whether the decision was made for or against the treatment (P <0.001). Conclusions: Payment mechanism has significant effects on clinical decision-making. Reduction of resources spent for discretionary care might be achieved under capitated arrangements; however, physicians respond with greater levels of discomfort under capitation than FFS. C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20814 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA 90407 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Geriatr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Publ Hlth, Ctr Hlth Policy Res, Los Angeles, CA 90024 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Healthcare Eth Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90024 USA. RP Shen, J (reprint author), NIAA, Clin Studies Lab, Sect Brain Electrophysiol & Imaging, NIH, Bldg 10,Room 6S-240,10 Ctr Dr,MSC 1610, Bethesda, MD 20814 USA. EM jshen@nih.gov OI Kominski, Gerald/0000-0001-5214-7133 FU BHP HRSA HHS [PE19001-09] NR 25 TC 47 Z9 48 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2004 VL 42 IS 3 BP 297 EP 302 DI 10.1097/01.mlr.0000114918.50088.1c PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 779KC UT WOS:000189293000013 PM 15076830 ER PT J AU Bergmann-Leitner, ES Leitner, WW AF Bergmann-Leitner, ES Leitner, WW TI Danger, death and DNA vaccines SO MICROBES AND INFECTION LA English DT Review DE DNA vaccine; apoptosis; innate immunity ID DOUBLE-STRANDED-RNA; DENDRITIC CELLS; IMMUNE-RESPONSES; CIRCUMSPOROZOITE PROTEIN; CROSS-PRESENTATION; APOPTOTIC CELLS/; MOLECULAR-BASIS; GENE GUN; IN-VIVO; T-CELLS AB DNA vaccines, although successful in many animal models of various diseases, remain insufficiently immunogenic in humans. Among the countless approaches to improve them is the stimulation of the innate immune system by promoting the apoptotic death of the transfected host cells, which is the focus of this review. (C) 2003 Elsevier SAS. All rights reserved. C1 Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD 20910 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Bergmann-Leitner, ES (reprint author), Walter Reed Army Inst Res, Dept Immunol, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM Elke.Bergmann-Leitner@na.amedd.army.mil RI Bergmann-Leitner, Elke/B-3548-2011; Leitner, Wolfgang/F-5741-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Leitner, Wolfgang/0000-0003-3125-5922 NR 42 TC 17 Z9 18 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD MAR PY 2004 VL 6 IS 3 BP 319 EP 327 DI 10.1016/j.micinf.2003.11.015 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 805UV UT WOS:000220392100010 PM 15065568 ER PT J AU Nath, KA Katusic, ZS Gladwin, MT AF Nath, KA Katusic, ZS Gladwin, MT TI The perfusion paradox and vascular instability in sickle cell disease SO MICROCIRCULATION LA English DT Review DE heme oxygenase; kidney; nitric oxide; prostaglandins; renal injury; sickle cell disease; systemic perfusion; vasoconstriction; vasorelaxation ID ACUTE CHEST SYNDROME; NITRIC-OXIDE BIOAVAILABILITY; PROTEIN-KINASE PATHWAY; HEME OXYGENASE-1; BLOOD-PRESSURE; OXIDATIVE STRESS; RENAL INFARCTION; CARBON-MONOXIDE; GENE-EXPRESSION; GLOMERULAR DYSFUNCTION AB Sickle cell disease (SCD) exhibits a curious coexistence of contrasting perfusion profiles in the circulatory system: hypoperfusion is endemic in microcirculatory beds occluded by hemoglobin S-containing erythrocytes while hyperperfusion characterizes the systemic ( macro) circulation and a number of regional vascular circuits. This review highlights this perfusion paradox of SCD, focusing on forearm blood flow and the renal circulation, and exploring the extent to which alterations in vasoactive systems ( such as nitric oxide and prostanoids) are involved. Also reviewed are the mechanisms and pathways that contribute to altered vascular reactivity and vascular instability observed in SCD. Finally, the possibility that the induction of heme oxygenase-1, recently described in SCD, may confer a protective response in the vasculature and other tissues is discussed. C1 Mayo Clin & Mayo Fdn, Div Nephrol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Anesthesiol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Mol Pharmacol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Expt Therapeut, Rochester, MN 55905 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. RP Nath, KA (reprint author), Mayo Clin & Mayo Fdn, Div Nephrol, 200 1st St SW, Rochester, MN 55905 USA. EM nath.karl@mayo.edu FU NHLBI NIH HHS [P01 HL55552, P01 HL66958]; NIDDK NIH HHS [R01 DK47060] NR 118 TC 39 Z9 40 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1073-9688 J9 MICROCIRCULATION JI Microcirculation PD MAR-APR PY 2004 VL 11 IS 2 BP 179 EP 193 DI 10.1080/10739680490278592 PG 15 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 829XN UT WOS:000222085100007 PM 15280091 ER PT J AU Oki, M Valenzuela, L Chiba, T Ito, T Kamakaka, RT AF Oki, M Valenzuela, L Chiba, T Ito, T Kamakaka, RT TI Barrier proteins remodel and modify chromatin to restrict silenced domains SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RESOLUTION STRUCTURAL-ANALYSIS; SACCHAROMYCES-CEREVISIAE; HISTONE ACETYLATION; GENE-EXPRESSION; BUDDING YEAST; IN-VIVO; HETEROCHROMATIN; LOCI; TRANSCRIPTION; METHYLATION AB Transcriptionally active and inactive domains are frequently found adjacent to one another in the eukaryotic nucleus. To better understand the underlying mechanisms by which domains maintain opposing transcription patterns, we performed a systematic genomewide screen for proteins that may block the spread of silencing in yeast. This analysis identified numerous proteins with efficient silencing blocking activities, and some of these have previously been shown to be involved in chromatin dynamics. We isolated subunits of Swi/Snf, mediator, and TFIID, as well as subunits of the Sas-I, SAGA, NuA3, NuA4, Spt10p, Rad6p, and Dot1p complexes, as barrier proteins. We demonstrate that histone acetylation and chromatin remodeling occurred at the barrier and correlated with a block to the spread of silencing. Our data suggest that multiple overlapping mechanisms were involved in delimiting silenced and active domains in vivo. C1 NICHHD, NIH, UCT, Bethesda, MD 20892 USA. Kanazawa Univ, Canc Res Inst, Div Genome Biol, Kanazawa, Ishikawa 9200934, Japan. RP Kamakaka, RT (reprint author), NICHHD, NIH, UCT, Bldg 18T,Rm 106,18 Library Dr, Bethesda, MD 20892 USA. EM rohinton@helix.nih.gov FU NICHD NIH HHS [Z01 HD01904] NR 74 TC 75 Z9 80 U1 0 U2 4 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 MAR PY 2004 VL 24 IS 5 BP 1956 EP 1967 DI 10.1128/MCB.24.5.1956-1967.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 779PP UT WOS:000189309500012 PM 14966276 ER PT J AU Kaneko, KJ Rein, T Guo, ZS Latham, K DePamphilis, ML AF Kaneko, KJ Rein, T Guo, ZS Latham, K DePamphilis, ML TI DNA methylation may restrict but does not determine differential gene expression at the Sgy/Tead2 locus during mouse development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; ENHANCER FACTOR-I; TRANSCRIPTION FACTORS; MAMMALIAN DEVELOPMENT; HISTONE DEACETYLASE; PREIMPLANTATION EMBRYOS; HUMAN GENOME; UPSTREAM; CANCER; FAMILY AB Soggy (Sgy) and Tead2, two closely linked genes with CpG islands, were coordinately expressed in mouse preimplantation embryos and embryonic stem (ES) cells but were differentially expressed in differentiated cells. Analysis of established cell lines revealed that Sgy gene expression could be fully repressed by methylation of the Sgy promoter and that DNA methylation acted synergistically with chromatin deacetylation. Differential gene expression correlated with differential DNA methylation, resulting in sharp transitions from methylated to unmethylated DNA at the open promoter in both normal cells and tissues, as well as in established cell lines. However, neither promoter was methylated in normal cells and tissues even when its transcripts were undetectable. Moreover, the Sgy promoter remained unmethylated as Sgy expression was repressed during ES cell differentiation. Therefore, DNA methylation was not the primary determinant of Sgy/Tead2 expression. Nevertheless, Sgy expression was consistently restricted to basal levels whenever downstream regulatory sequences were methylated, suggesting that DNA methylation restricts but does not regulate differential gene expression during mouse development. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Max Planck Inst Psychiat, D-80804 Munich, Germany. Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov OI Rein, Theo/0000-0003-2850-4289 FU NCRR NIH HHS [R24 RR015253, RR15253] NR 55 TC 34 Z9 37 U1 0 U2 0 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 MAR PY 2004 VL 24 IS 5 BP 1968 EP 1982 DI 10.1128/MCB.24.5.1968-1982.2004 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 779PP UT WOS:000189309500013 PM 14966277 ER PT J AU Kim, BC Lee, HJ Park, SH Lee, SR Karpova, TS McNally, JG Felici, A Lee, DK Kim, SJ AF Kim, BC Lee, HJ Park, SH Lee, SR Karpova, TS McNally, JG Felici, A Lee, DK Kim, SJ TI Jab1/CSN5, a component of the COP9 signalosome, egulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MODULATE AP-1 ACTIVITY; MAD-RELATED PROTEIN; NEGATIVE REGULATION; UBIQUITIN LIGASE; NUCLEAR EXPORT; JAB1 INTERACTS; XENOPUS SMAD7; RECEPTOR; COMPLEX; APOPTOSIS AB Smad7 inhibits responses mediated by transforming growth factor beta (TGF-beta) and acts in a negative-feedback loop to regulate the intensity or duration of the TGF-beta signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-beta resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-beta-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-beta signaling. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Inha Univ, Coll Med, Inchon, South Korea. Kangweon Natl Univ, Coll Nat Sci, Div Life Sci, Chunchon, Kangwon Do, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, NIH Bldg 41,Room B1106, Bethesda, MD 20892 USA. EM kims@mail.nih.gov NR 59 TC 70 Z9 80 U1 0 U2 0 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 MAR PY 2004 VL 24 IS 6 BP 2251 EP 2262 DI 10.1128/MCB.24.6.2251-2262.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 801MM UT WOS:000220100000005 PM 14993265 ER PT J AU Desper, R Gascuel, O AF Desper, R Gascuel, O TI Theoretical foundation of the balanced minimum evolution method of phylogenetic inference and its relationship to weighted least-squares tree fitting SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE minimum evolution; least-squares; distance-based phylogenetic inference; consistency; method comparison using simulations ID SEQUENCE DATA; PRINCIPLE; MODEL; RECONSTRUCTION; ALGORITHMS; DISTANCES; RATES AB Due to its speed, the distance approach remains the best hope for building phylogenies on very large sets of taxa. Recently (R. Desper and O. Gascuel, J. Comp. Biol. 9:687-705, 2002), we introduced a new "balanced" minimum evolution (BME) principle, based on a branch length estimation scheme of Y. Pauplin (J. Mol. Evol. 51:41-47, 2000). Initial simulations suggested that FASTME, our program implementing the BME principle, was more accurate than or equivalent to all other distance methods we tested, with running time significantly faster than Neighbor-Joining (NJ). This article further explores the properties of the BME principle, and it explains and illustrates its impressive topological accuracy. We prove that the BME principle is a special case of the weighted least-squares approach, with biologically meaningful variances of the distance estimates. We show that the BME principle is statistically consistent. We demonstrate that FASTME only produces trees with positive branch lengths, a feature that separates this approach from NJ (and related methods) that may produce trees with branches with biologically meaningless negative lengths. Finally, we consider a large simulated data set, with 5,000 100-taxon trees generated by the Aldoas beta-splitting distribution encompassing a range of distributions from Yule-Harding to uniform, and using a covarion-like model of sequence evolution. FASTME produces trees faster than NJ, and much faster than WEIGHBOR and the weighted least-squares implementation of PAUP*. Moreover, FASTME trees are consistently more accurate at all settings, ranging from Yule-Harding to uniform distributions, and all ranges of maximum pairwise divergence and departure from molecular clock. Interestingly, the covarion parameter has little effect on the tree quality for any of the algorithms. FASTME is freely available on the web. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. LIRMM, Equipes Methods & Algorithmes Bioinformat, Montpellier, France. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM gascuel@lirmm.fr NR 36 TC 95 Z9 96 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD MAR PY 2004 VL 21 IS 3 BP 587 EP 598 DI 10.1093/molbev.msh049 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 804BG UT WOS:000220273600016 PM 14694080 ER PT J AU Lo, CM Buxton, DB Chua, GCH Dembo, M Adelstein, RS Wang, YL AF Lo, CM Buxton, DB Chua, GCH Dembo, M Adelstein, RS Wang, YL TI Nonmuscle myosin IIB is involved in the guidance of fibroblast migration SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ACTIN MESSENGER-RNA; CULTURED-CELLS; FOCAL ADHESIONS; HEAVY-CHAIN; DIFFERENTIAL LOCALIZATION; NEURITE OUTGROWTH; 3T3 FIBROBLASTS; RHO-KINASE; MOTILITY; SUBSTRATE AB Although myosin II is known to play an important role in cell migration, little is known about its specific functions. We have addressed the function of one of the isoforms of myosin II, myosin IIB, by analyzing the movement and mechanical characteristics of fibroblasts where this protein has been ablated by gene disruption. Myosin IIB null cells displayed multiple unstable and disorganized protrusions, although they were still able to generate a large fraction of traction forces when cultured on flexible polyacrylamide substrates. However, the traction forces were highly disorganized relative to the direction of cell migration. Analysis of cell migration patterns indicated an increase in speed and decrease in persistence, which were likely responsible for the defects in directional movements as demonstrated with Boyden chambers. In addition, unlike control cells, mutant cells failed to respond to mechanical signals such as compressing forces and changes in substrate rigidity. Immunofluorescence staining indicated that myosin IIB was localized preferentially along stress fibers in the interior region of the cell. Our results suggest that myosin IIB is involved not in propelling but in directing the cell movement, by coordinating protrusive activities and stabilizing the cell polarity. C1 Univ Massachusetts, Sch Med, Dept Physiol, Worcester, MA 01605 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Wang, YL (reprint author), Univ Massachusetts, Sch Med, Dept Physiol, Worcester, MA 01605 USA. EM yuli.wang@umassmed.edu RI Dembo, Micah/C-2755-2013 FU NIGMS NIH HHS [GM-32476, GM-61806, R01 GM032476, R01 GM061806, R37 GM032476] NR 43 TC 153 Z9 154 U1 0 U2 12 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 MAR PY 2004 VL 15 IS 3 BP 982 EP 989 DI 10.1091/mbc.E03-06-0359 PG 8 WC Cell Biology SC Cell Biology GA 800TZ UT WOS:000220051900005 PM 14699073 ER PT J AU Hara, T Ishida, H Raziuddin, R Dorkhom, S Kamijo, K Miki, T AF Hara, T Ishida, H Raziuddin, R Dorkhom, S Kamijo, K Miki, T TI Novel kelch-like protein, KLEIP, is involved in actin assembly at cell-cell contact sites of Madin-Darby canine kidney cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CULTURED-MAMMALIAN-CELLS; RAC1 SMALL GTPASES; ADHERENS JUNCTIONS; BINDING PROTEINS; DROSOPHILA KELCH; RHO-FAMILY; CADHERIN; ADHESION; DYNAMICS; IDENTIFICATION AB Dynamic rearrangements of cell-cell adhesion underlie a diverse range of physiological processes, but their precise molecular mechanisms are still obscure. Thus, identification of novel players that are involved in cell-cell adhesion would be important. We isolated a human kelch-related protein, Kelch-like ECT2 interacting protein (KLEIP), which contains the broad-complex, tramtrack, bric-a-brac (BTB)/poxvirus, zinc finger (POZ) motif and six-tandem kelch repeats. KLEIP interacted with F-actin and was concentrated at cell-cell contact sites of Madin-Darby canine kidney cells, where it colocalized with F-actin. Interestingly, this localization took place transiently during the induction of cell-cell contact and was not seen at mature junctions. KLEIP recruitment and actin assembly were induced around E-cadherin-coated beads placed on cell surfaces. The actin depolymerizing agent cytochalasin B inhibited this KLEIP recruitment around E-cadherin-coated beads. Moreover, constitutively active Rac1 enhanced the recruitment of KLEIP as well as F-actin to the adhesion sites. These observations strongly suggest that KLEIP is localized on actin filaments at the contact sites. We also found that N-terminal half of KLEIP, which lacks the actin-binding site and contains the sufficient sequence for the localization at the cell-cell contact sites, inhibited constitutively active Rac1-induced actin assembly at the contact sites. We propose that KLEIP is involved in Rac1-induced actin organization during cell-cell contact in Madin-Darby canine kidney cells. C1 NCI, Mol Tumor Biol Sect, Basic Res Lab, Bethesda, MD 20892 USA. RP Miki, T (reprint author), NCI, Mol Tumor Biol Sect, Basic Res Lab, Bethesda, MD 20892 USA. EM toru@helix.nih.gov NR 39 TC 24 Z9 26 U1 0 U2 2 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 MAR PY 2004 VL 15 IS 3 BP 1172 EP 1184 DI 10.1091/mbc.E03-07-0531 PG 13 WC Cell Biology SC Cell Biology GA 800TZ UT WOS:000220051900022 PM 14668487 ER PT J AU Shakoury-Elizeh, M Tiedeman, J Rashford, J Ferea, T Demeter, J Garcia, E Rolfes, R Brown, PO Botstein, D Philpott, CC AF Shakoury-Elizeh, M Tiedeman, J Rashford, J Ferea, T Demeter, J Garcia, E Rolfes, R Brown, PO Botstein, D Philpott, CC TI Transcriptional remodeling in response to iron deprivation in Saccharomyces cerevisiae SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; GLUTAMATE SYNTHASE; ESCHERICHIA-COLI; SIDEROPHORE-IRON; GENE-EXPRESSION; DNA-BINDING; YEAST; TRANSPORTERS; IDENTIFICATION; OXIDASE AB The budding yeast Saccharomyces cerevisiae responds to depletion of iron in the environment by activating Aft1p, the major iron-dependent transcription factor, and by transcribing systems involved in the uptake of iron. Here, we have studied the transcriptional response to iron deprivation and have identified new Aft1p target genes. We find that other metabolic pathways are regulated by iron: biotin uptake and biosynthesis, nitrogen assimilation, and purine biosynthesis. Two enzymes active in these pathways, biotin synthase and glutamate synthase, require an iron-sulfur cluster for activity. Iron deprivation activates transcription of the biotin importer and simultaneously represses transcription of the entire biotin biosynthetic pathway. Multiple genes involved in nitrogen assimilation and amino acid metabolism are induced by iron deprivation, whereas glutamate synthase, a key enzyme in nitrogen assimilation, is repressed. A CGG palindrome within the promoter of glutamate synthase confers iron-regulated expression, suggesting control by a transcription factor of the binuclear zinc cluster family. We provide evidence that yeast subjected to iron deprivation undergo a transcriptional remodeling, resulting in a shift from iron-dependent to parallel, but iron-independent, metabolic pathways. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Genet, Stanford, CA 94305 USA. RP Philpott, CC (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA. EM carolinep@intra.niddk.nih.gov OI Demeter, Janos/0000-0002-7301-8055 NR 59 TC 123 Z9 125 U1 0 U2 3 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 MAR PY 2004 VL 15 IS 3 BP 1233 EP 1243 DI 10.1091/mbc.E03-09-0642 PG 11 WC Cell Biology SC Cell Biology GA 800TZ UT WOS:000220051900027 PM 14668481 ER PT J AU Yun, C Cho, H Kim, SJ Lee, JH Park, SY Chan, GK Cho, H AF Yun, C Cho, H Kim, SJ Lee, JH Park, SY Chan, GK Cho, H TI Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway SO MOLECULAR CANCER RESEARCH LA English DT Article ID PAPILLOMAVIRUS TYPE-16 E6; CELL-CYCLE PROGRESSION; HBX PROTEIN; TRANSGENIC MICE; GENETIC ALTERATIONS; HEPATOCELLULAR-CARCINOMA; CHROMOSOME INSTABILITY; GENOMIC INSTABILITY; MEDIATED APOPTOSIS; DEPENDENT MANNER AB Multinucleated cells have been noted in pathophysiological states of the liver including infection with hepatitis B virus (HBV), the status of which is also closely associated with genomic instability in liver cancer. Here, we showed that hepatitis B virus X oncoprotein (HBx) expression in Chang cells results in a multinuclear phenotype and an abnormal number of centrosomes (n greater than or equal to 3). Regulation of centrosome duplication in HBx-expressing ChangX-34 cells was defective and uncoupled from the cell cycle. HBx induced amplification of centrosomes, multipolar spindle formation, and chromosomal missegregation during mitosis and subsequently increased the generation of multinucleated cells and micronuclei formation. Treatment with PD98059, a mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2 inhibitor, significantly reduced the number of cells with hyperamplified centrosomes and decreased the multinucleated cells and micronuclei formation. Consistently, the phospho-ERK level during cell progression was substantially higher in ChangX-34 cells than that of Chang cells. In contrast, neither wortmannin, an inhibitor of phosphoinositide-3 kinase, nor SB203589, an inhibitor of p38 mitogen-activated protein kinase (MAPK), showed any effects. Introduction of Ras dominant-negative (D/N) and MEK2 D/N genes. C1 Ajou Univ, Sch Med, Dept Biochem & Mol Biol, Chron Inflammatory Dis Res Ctr, Suwon 442741, South Korea. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Cross Canc Inst, Dept Expt Oncol, Edmonton, AB T6G 1Z2, Canada. RP Cho, H (reprint author), Ajou Univ, Sch Med, Dept Biochem & Mol Biol, Chron Inflammatory Dis Res Ctr, 5 Wonchon Dong, Suwon 442741, South Korea. EM hscho@ajou.ac.kr OI Chan, Gordon/0000-0003-0497-9407 NR 57 TC 72 Z9 80 U1 0 U2 1 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 MAR PY 2004 VL 2 IS 3 BP 159 EP 169 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 804IC UT WOS:000220291400003 PM 15037655 ER PT J AU Sidransky, E AF Sidransky, E TI Gaucher disease. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NIMH, NSB, Bethesda, MD 20892 USA. 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 MAR PY 2004 VL 81 IS 3 BP 156 EP 156 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400004 ER PT J AU Correa-Cerro, LS Wassif, CA Kratz, L Kelly, RI Porter, FD AF Correa-Cerro, LS Wassif, CA Kratz, L Kelly, RI Porter, FD TI Development, characterization, and treatment of a hypomorphic SLOS mouse model SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NICHD, NIH, Bethesda, MD USA. Kennedy Krieger Inst, Baltimore, 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 MAR PY 2004 VL 81 IS 3 BP 160 EP 160 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400013 ER PT J AU Goker-Alpan, O Orvisky, E Stubblefield, B Sidransky, E AF Goker-Alpan, O Orvisky, E Stubblefield, B Sidransky, E TI Altered lysosomal targeting in fibroblasts from patients with acute neuronopathic Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, 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 MAR PY 2004 VL 81 IS 3 BP 161 EP 161 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400016 ER PT J AU Nguyen, JM Walker, JM Lwin, A Goker-Alpan, O Orvisky, E Hardy, J Singleton, A Sidransky, E AF Nguyen, JM Walker, JM Lwin, A Goker-Alpan, O Orvisky, E Hardy, J Singleton, A Sidransky, E TI Glucocerebrosidase mutations in two cohorts with Parkinson disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009 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 MAR PY 2004 VL 81 IS 3 BP 163 EP 163 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400022 ER PT J AU Walker, JM Orvisky, E Martin, BM Sidransky, E AF Walker, JM Orvisky, E Martin, BM Sidransky, E TI Glucocerebrosidase isoforms in brains of patients with Gaucher disease. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIMH, Lab Neurotoxicol, 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 MAR PY 2004 VL 81 IS 3 BP 163 EP 163 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400023 ER PT J AU Bernardini, I Kleta, R Morse, RP Orvisky, E Krasnewich, D Alroy, J Ucci, AA Wenger, DA Gahl, WA AF Bernardini, I Kleta, R Morse, RP Orvisky, E Krasnewich, D Alroy, J Ucci, AA Wenger, DA Gahl, WA TI Clinical, biochemical, and molecular findings in a free sialic acid storage disease patient of moderate severity SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Intramural Program, Off Director, Bethesda, MD 20892 USA. Dartmouth Hitchcock Med Ctr, Dept Pediat, Lebanon, NH 03766 USA. NIMH, NSB, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. Tufts New England Med Ctr, Boston, MA USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol, Philadelphia, PA 19107 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 MAR PY 2004 VL 81 IS 3 BP 167 EP 167 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400028 ER PT J AU Griffin, A Anderson, P Claassen, D Gahl, WA Huizing, M AF Griffin, A Anderson, P Claassen, D Gahl, WA Huizing, M TI Hemizygosity at 10q23 in a family with Hermansky-Pudlak syndrome type 1. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, MGB, 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 MAR PY 2004 VL 81 IS 3 BP 171 EP 171 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400042 ER PT J AU Helip-Wooley, A Huizing, M Dorward, H Claassen, D Hess, R Gahl, WA AF Helip-Wooley, A Huizing, M Dorward, H Claassen, D Hess, R Gahl, WA TI Abnormal vesicle formation and trafficking in Hermansky-Pudlak syndrome cells SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NIH, Med Genet Branch, 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 MAR PY 2004 VL 81 IS 3 BP 172 EP 172 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400045 ER PT J AU Bendavid, A Kleta, R Long, R Ouspenskaia, M Haddad, BR Muenke, M Gahl, WA AF Bendavid, A Kleta, R Long, R Ouspenskaia, M Haddad, BR Muenke, M Gahl, WA TI FISH analysis of the common 57-kb deletion in cystinosis. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 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 MAR PY 2004 VL 81 IS 3 BP 174 EP 175 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400052 ER PT J AU Merideth, M Freundlich, M Stuart, C Gahl, WA Kleta, R AF Merideth, M Freundlich, M Stuart, C Gahl, WA Kleta, R TI Clinical and molecular findings in a discordant twin with Bartter syndrome type II. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, MGB, NIH,DHHS, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Intramural Program, Off Director,DHHS, Bethesda, MD USA. Univ Miami, Dept Pediat, Miami, FL 33152 USA. Joe DiMaggio Childrens Hosp, Hollywood, FL 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 MAR PY 2004 VL 81 IS 3 BP 176 EP 176 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400057 ER PT J AU Sparks, SE Lalor, M Orvisky, E Huizing, M Krasnewich, D Sun, MS Dalakas, M Gahl, WA AF Sparks, SE Lalor, M Orvisky, E Huizing, M Krasnewich, D Sun, MS Dalakas, M Gahl, WA TI Hereditary inclusion body myopathy due to mutations in GNE: epimerase activity and treatment strategies SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, MGB, NIH, US Dept HHS, Bethesda, MD 20892 USA. NIMH, NSB, NIH, US Dept HHS, Bethesda, MD 20892 USA. NINDS, NIH, US Dept HHS, 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 MAR PY 2004 VL 81 IS 3 BP 179 EP 180 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400069 ER PT J AU Stuart, C Kleta, R Gahl, WA AF Stuart, C Kleta, R Gahl, WA TI Renal glucosuria due to SGLT2 mutations. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Intramural Program, Off Director, 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 MAR PY 2004 VL 81 IS 3 BP 180 EP 180 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400071 ER PT J AU Sun, MS Huizing, M Sparks, S Krasnewich, D Schwartzberg, PL Settara, C Gahl, WA AF Sun, MS Huizing, M Sparks, S Krasnewich, D Schwartzberg, PL Settara, C Gahl, WA TI Generation of a conditional knock-in mouse model with deficiency of UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase to mimic hereditary inclusion body myopathy SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH,DHHS, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, US Dept HHS, 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 MAR PY 2004 VL 81 IS 3 BP 180 EP 181 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400072 ER PT J AU Suwannarat, P Bernardini, I Tsilou, E Rubin, BI Perry, MB Gerber, L O'Brien, K Gahl, WA AF Suwannarat, P Bernardini, I Tsilou, E Rubin, BI Perry, MB Gerber, L O'Brien, K Gahl, WA TI Therapeutic use of nitisinone in alkaptonuria SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 NHGRI, Sect Human Biochem Genet, MGB, NIH,DHHS, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Visual Funct Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Rehabil Med, US Dept HHS, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2004 VL 81 IS 3 BP 181 EP 181 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400073 ER PT J AU Tifft, CJ Kurtzberg, J Proia, RL AF Tifft, CJ Kurtzberg, J Proia, RL TI Elevated chitotriosidase activity in CSF in patients with GM1 and GM2 gangliosidosis: a surrogate marker of disease progression? SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. RI Proia, Richard/A-7908-2012 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2004 VL 81 IS 3 BP 181 EP 182 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400075 ER PT J AU Tifft, CJ Kurtzberg, J Proia, RL AF Tifft, CJ Kurtzberg, J Proia, RL TI Elevated chitotriosidase activity in CSF in patients with tay-Sachs disease: a surrogate marker of disease progression? SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2004) CY MAR 07-10, 2004 CL Orlando, FL SP Soc Inherited Metabolic Disorders C1 Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. RI Proia, Richard/A-7908-2012 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 MAR PY 2004 VL 81 IS 3 BP 182 EP 182 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400076 ER PT J AU Huizing, M Rakocevic, G Sparks, SE Mamali, L Shatunov, A Goldfarb, L Krasnewich, D Gahl, WA Dalakas, MC AF Huizing, M Rakocevic, G Sparks, SE Mamali, L Shatunov, A Goldfarb, L Krasnewich, D Gahl, WA Dalakas, MC TI Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE hereditary inclusion body myopathy; O-mannosylation; dystroglycan; sialic acid; GNE; muscular dystrophy; dystrophin-glycoprotein complex ID CONGENITAL MUSCULAR-DYSTROPHY; ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; ABNORMAL GLYCOSYLATION; DISTAL MYOPATHY; RIMMED VACUOLES; GENE; SIALYLATION; DEFICIENCY; FORM AB Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein of the skeletal muscle dystrophin-glycoprotein complex, results in disturbed interactions with extracellular matrix proteins. This has recently been identified as the pathomechanism involved in several congenital muscular dystrophies. We examined the glycosylation status of alpha-dystroglycan in muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one American, two Indians, and one Greek). Two of these patients carry novel compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle biopsies showed absent or markedly reduced immunolabeling with two different antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan. Normal labeling was found using antibodies to the core alpha-dystroglycan protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. Univ Athens, Dept Neurol, GR-10679 Athens, Greece. RP Dalakas, MC (reprint author), Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov RI Shatunov, Aleksey/E-6946-2011 NR 24 TC 56 Z9 56 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2004 VL 81 IS 3 BP 196 EP 202 DI 10.1016/j.ymgme.2003.11.012 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 778MB UT WOS:000189244400088 PM 14972325 ER PT J AU Wang, ZR Neville, DM AF Wang, ZR Neville, DM TI Expression and characterization of recombinant soluble monkey CD3 molecules: mapping the FN18 polymorphic epitope SO MOLECULAR IMMUNOLOGY LA English DT Article DE CD3; FN18; monkey; heterodimer; immunotoxin; T cell ID CELL-RECEPTOR COMPLEX; ANTI-CD3 IMMUNOTOXIN; MACACA-FASCICULARIS; RHESUS MACAQUES; DEPLETION; TOLERANCE; LYMPHOCYTES; INDUCTION; CD3-GAMMA; ANTIGEN AB The monoclonal antibody FN18 has been used as a marker for monkey T cells and as a T cell depleting reagent when conjugated to binding site mutants of diphtheria toxin. This anti-CD3 antibody shares certain properties with its anti-human counterparts UCHT1, OKT3 and Leu-4 in that it precipitates two different CD3 chains from membrane detergent extracts. However, in contrast to human CD3, rhesus and cynomolgus monkeys display CD3 polymorphisms producing FN18 negative phenotypes. Using recently published sequence data, we have expressed the ectodomains of cynomolgus CD3-epsilon CD3-gamma and CD-delta chains in E. coli, and have refolded these chains separately and in pairs to produce CD3 homo- and heterodimeric proteins. These proteins were fractionated by anion exchange according to their differing isoelectric points and further identified by size differences on SDS gels. On the basis of ELISA, the FN18 epitope is restricted to the C133-epsilongamma ectodomain heterodimer, CD-epsilongamma and CD-epsilonepsilon being non-reactive. Either of the two amino acid polymorphisms reported in the CD3-e chain were sufficient to degrade the bioactivity of the CD3-epsilongamma towards FN18. Published by Elsevier Ltd. C1 NIMH, Mol Biol Lab, Sect Biophys Chem, Bethesda, MD 20892 USA. RP Neville, DM (reprint author), NIMH, Mol Biol Lab, Sect Biophys Chem, Bldg 36,Room 1B08,36 Convent Dr, Bethesda, MD 20892 USA. EM davidn@helix.nih.gov NR 23 TC 5 Z9 5 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 MAR PY 2004 VL 40 IS 16 BP 1179 EP 1188 DI 10.1016/j.molimm.2003.11.025 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 800DD UT WOS:000220008200004 PM 15104123 ER PT J AU Christensen, SK Maenhaut-Michel, G Mine, N Gottesman, S Gerdes, K Van Melderen, L AF Christensen, SK Maenhaut-Michel, G Mine, N Gottesman, S Gerdes, K Van Melderen, L TI Overproduction of the Lon protease triggers inhibition of translation in Escherichia coli: involvement of the yefM-yoeB toxin-antitoxin system SO MOLECULAR MICROBIOLOGY LA English DT Article ID PROGRAMMED CELL-DEATH; SALMONELLA-TYPHIMURIUM; NUTRITIONAL STRESS; STABLE MAINTENANCE; PLASMID R100; HEMA PROTEIN; PROTEOLYSIS; DEGRADATION; GENE; RNA AB In Escherichia coli, the Lon ATP-dependent protease is responsible for degradation of several regulatory proteins and for the elimination of abnormal proteins. Previous studies have shown that the overproduction of Lon is lethal. Here, we showed that Lon overproduction specifically inhibits translation through at least two different pathways. We have identified one of the pathways as being the chromosomal yefM-yoeB toxin-antitoxin system. The existence of a second pathway is demonstrated by the observation that the deletion of the yefM-yoeB system did not completely suppress lethality and translation inhibition. We also showed that the YoeB toxin induces cleavage of translated mRNAs and that Lon overproduction specifically activates YoeB-dependent mRNAs cleavage. Indeed, none of the other identified chromosomal toxin-antitoxin systems (relBE, mazEF, chpB and dinJ-yafQ) was involved in Lon-dependent lethality, translation inhibition and mRNA cleavage even though the RelB and MazE antitoxins are known to be Lon substrates. Based on our results and other studies, translation inhibition appears to be the key element that triggers chromosomal toxin-antitoxin systems. We propose that under Lon overproduction conditions, translation inhibition is mediated by Lon degradation of a component of the YoeB-independent pathway, in turn activating the YoeB toxin by preventing synthesis of its unstable YefM antidote. C1 Univ Brussels, Inst Biol & Med Mol, Lab Genet Procaryotes, B-6041 Gosselies, Belgium. Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. NIH, Mol Biol Lab, Bethesda, MD 20814 USA. RP Van Melderen, L (reprint author), Univ Brussels, Inst Biol & Med Mol, Lab Genet Procaryotes, B-6041 Gosselies, Belgium. EM lvmelder@ulb.ac.be RI Gerdes, Kenn/M-2420-2014 OI Gerdes, Kenn/0000-0002-7462-4612 NR 42 TC 128 Z9 132 U1 1 U2 16 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2004 VL 51 IS 6 BP 1705 EP 1717 DI 10.1046/j.1365-2958.2003.03941.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 801AB UT WOS:000220067700015 PM 15009896 ER PT J AU Guo, J Ikeda, SR AF Guo, J Ikeda, SR TI Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons SO MOLECULAR PHARMACOLOGY LA English DT Article ID DEPOLARIZATION-INDUCED SUPPRESSION; RAT SYMPATHETIC NEURONS; BETA-GAMMA-SUBUNITS; K+ CHANNELS; ENDOGENOUS CANNABINOIDS; HIPPOCAMPAL SYNAPSES; NEUROBLASTOMA-CELLS; PURKINJE-CELLS; CA2+ CHANNELS; AGONIST AB Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca2+ channels by activating G(i/o)-protein-coupled CB1 cannabinoid receptors (CB1R)-a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca2+ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca2+ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC50 = 2 nM) > 2-AGE (350 nM) similar to 2-AG ( 480 nM) > AEA (similar to3 muM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 muM) also inhibited Ca2+ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function. C1 NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Ikeda, SR (reprint author), NIAAA, Lab Mol Physiol, NIH, Pk Bldg,Room 150,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM sikeda@mail.nih.gov OI Ikeda, Stephen/0000-0002-4088-9508 NR 37 TC 79 Z9 82 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR 1 PY 2004 VL 65 IS 3 BP 665 EP 674 DI 10.1124/mol.65.3.665 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 775TX UT WOS:000189077700022 PM 14978245 ER PT J AU Sauna, ZE Peng, XH Nandigama, K Tekle, S Ambudkar, SV AF Sauna, ZE Peng, XH Nandigama, K Tekle, S Ambudkar, SV TI The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1) SO MOLECULAR PHARMACOLOGY LA English DT Article ID HUMAN P-GLYCOPROTEIN; DRUG-RESISTANCE; IN-VITRO; MONOCLONAL-ANTIBODIES; TRANSITION-STATE; CATALYTIC CYCLE; CROSS-LINKING; NIH3T3 CELLS; HYDROLYSIS; CANCER AB The overexpression of multidrug resistance protein 1 (MDR1) and multidrug resistance protein 1 (MRP1) gene products is a major cause of multidrug resistance in cancer cells. A recent study suggested that disulfiram, a drug used to treat alcoholism, might act as a modulator of P-glycoprotein. In this study, we investigated the molecular and chemical basis of disulfiram as a multidrug resistance modulator. We demonstrate that in intact cells, disulfiram reverses either MDR1- or MRP1-mediated efflux of fluorescent drug substrates. Disulfiram inhibits ATP hydrolysis and the binding of [alpha-P-32] 8-azidoATP to P-glycoprotein and MRP1, with inhibition curves comparable with those of N-ethylmaleimide, a cysteine-modifying agent. However, if the ATP sites are protected with excess ATP, disulfiram stimulates ATP hydrolysis by both transporters in a concentration-dependent manner. Thus, in addition to modifying cysteines at the ATP sites, disulfiram may interact with the drug-substrate binding site. We demonstrate that disulfiram, but not N-ethylmaleimide, inhibits in a concentration-dependent manner the photoaffinity labeling of the multidrug transporter with I-125-iodoarylazidoprazosin and [H-3] azidopine. This suggests that the interaction of disulfiram with the drug-binding site is independent of its role as a cysteine-modifying agent. Finally, we have exploited MRP4 (ABCC4) to demonstrate that disulfiram can inhibit ATP binding by forming disulfide bonds between cysteines located in the vicinity of, although not in, the active site. Taken together, our results suggest that disulfiram has unique molecular interactions with both the ATP and/or drug-substrate binding sites of multiple ATP binding cassette transporters, which are associated with drug resistance, and it is potentially an attractive agent to combat multidrug resistance. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 1B-22,37 Convent Dr, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI Ambudkar, Suresh/B-5964-2008 NR 34 TC 52 Z9 53 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR 1 PY 2004 VL 65 IS 3 BP 675 EP 684 DI 10.1124/mol.65.3.675 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 775TX UT WOS:000189077700023 PM 14978246 ER PT J AU Ma, J Graves, J Bradbury, JA Zhao, Y Swope, DL King, L Qu, W Clark, J Myers, P Walker, V Lindzey, J Korach, KS Zeldin, DC AF Ma, J Graves, J Bradbury, JA Zhao, Y Swope, DL King, L Qu, W Clark, J Myers, P Walker, V Lindzey, J Korach, KS Zeldin, DC TI Regulation of mouse renal CYP2J5 expression by sex hormones SO MOLECULAR PHARMACOLOGY LA English DT Article ID ARACHIDONIC-ACID EPOXYGENASE; ESTROGEN-RECEPTOR GENE; GROWTH-HORMONE; MOLECULAR-CLONING; EPOXIDE HYDROLASE; ENANTIOFACIAL SELECTIVITY; DEPENDENT EXPRESSION; TARGETED DISRUPTION; RAT; TESTOSTERONE AB Mouse CYP2J5 is abundant in kidney and active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids. Western blots of microsomes prepared from mouse kidneys demonstrate that after puberty, CYP2J5 protein is present at higher levels in male mice than in female mice. Northern analysis reveals that CYP2J5 transcripts are more abundant in adult male versus female kidneys, indicating that gender differences in renal CYP2J5 expression are regulated at a pretranslational level. Castration of male mice results in decreased renal CYP2J5 expression, and treatment of castrated male mice or female mice with 5alpha-dihydrotestosterone increases expression to levels that approximate those in intact male mice. In contrast, treatment of ovariectomized female mice or castrated male mice with 17beta-estradiol causes a further reduction in CYP2J5 expression. Growth hormone-deficient (lit/lit) mice respond similarly to castration and 5alpha-dihydrotestosterone treatment, indicating that the androgen effects are not mediated by alterations in the growth hormone secretory pattern. Mice that lack a functional androgen receptor (Tfm hemizygous) have reduced levels of renal CYP2J5 and do not respond to 5alpha-dihydrotestosterone treatment. Similarly, wild-type male mice treated with flutamide, an androgen antagonist, exhibit reduced renal CYP2J5 levels. Female estrogen receptor-alpha knockout (alphaERKO) mice, which are known to have elevated circulating testosterone levels, have significantly increased renal CYP2J5 expression compared with wild-type female mice, and these differences are abrogated by ovariectomy or treatment with flutamide. Based on these data, we conclude that the renal expression of CYP2J5 is up-regulated by androgen and downregulated by estrogen. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ S Florida, Dept Biol, Tampa, FL 33620 USA. RP NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101,Room D236, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 50 TC 21 Z9 23 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR 1 PY 2004 VL 65 IS 3 BP 730 EP 743 DI 10.1124/mol.65.3.730 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 775TX UT WOS:000189077700029 PM 14978252 ER PT J AU Byfield, SD Major, C Laping, NJ Roberts, AB AF Byfield, SD Major, C Laping, NJ Roberts, AB TI SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7 SO MOLECULAR PHARMACOLOGY LA English DT Article ID MICE LACKING SMAD3; TGF-BETA; ALK7 SIGNALS; CELL-LINE; RADIATION; APOPTOSIS; PROTEINS; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION AB Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. GlaxoSmithKline, Dept Renal Res, King Of Prussia, PA USA. GlaxoSmithKline, Dept Urol Res, King Of Prussia, PA USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Rm C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. EM robertsa@dce41.nci.nih.gov NR 36 TC 138 Z9 148 U1 3 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR 1 PY 2004 VL 65 IS 3 BP 744 EP 752 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 775TX UT WOS:000189077700030 ER PT J AU Sporn, A Addington, A Reiss, AL Dean, M Gogtay, N Potocnik, U Greenstein, D Hallmayer, J Gochman, P Lenane, M Baker, N Tossell, J Rapoport, JL AF Sporn, A Addington, A Reiss, AL Dean, M Gogtay, N Potocnik, U Greenstein, D Hallmayer, J Gochman, P Lenane, M Baker, N Tossell, J Rapoport, JL TI 22q11 deletion syndrome in childhood onset schizophrenia: an update SO MOLECULAR PSYCHIATRY LA English DT Letter ID ABNORMALITIES C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Sporn, A (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM sporna@intra.nimh.nih.gov RI Gogtay, Nitin/A-3035-2008; Addington, Anjene/C-3460-2008; Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Potocnik, Uros/0000-0003-1624-9428 NR 9 TC 50 Z9 51 U1 1 U2 1 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 MAR PY 2004 VL 9 IS 3 BP 225 EP 226 DI 10.1038/sj.mp.4001477 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 801XS UT WOS:000220129200001 PM 14699434 ER PT J AU Arcos-Burgos, M Castellanos, FX Konecki, D Lopera, F Pineda, D Palacio, JD Rapoport, JL Berg, K Bailey-Wilson, J Muenke, M AF Arcos-Burgos, M Castellanos, FX Konecki, D Lopera, F Pineda, D Palacio, JD Rapoport, JL Berg, K Bailey-Wilson, J Muenke, M TI Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate SO MOLECULAR PSYCHIATRY LA English DT Article DE ADHD; complex trait; genetics; genetic isolate; linkage analysis; association FBAT; PDT; DRD4; Colombia; paisa ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DOPAMINE-D4 RECEPTOR GENE; FAMILY-BASED ASSOCIATION; INTERNATIONAL DIAGNOSTIC INTERVIEW; DUPLICATION POLYMORPHISM UPSTREAM; CONTINUOUS PERFORMANCE-TEST; III REPEAT POLYMORPHISM; SUBSTANCE USE DISORDERS; CIGARETTE-SMOKING AB Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms ( a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Antioquia, Populat Genet Mutacarcinogenesis & Genet Epidemio, Medellin, Colombia. NIMH, NIH, Bethesda, MD 20892 USA. NYU, Ctr Child Study, New York, NY USA. Univ Antioquia, Neurosci Grp, Medellin, Colombia. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. EM muenke@nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920; Castellanos, Francisco/0000-0001-9192-9437 NR 98 TC 47 Z9 48 U1 1 U2 2 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 MAR PY 2004 VL 9 IS 3 BP 252 EP 259 DI 10.1038/sj.mp.4001396 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 801XS UT WOS:000220129200004 PM 15094785 ER PT J AU Hashimoto, R Straub, RE Weickert, CS Hyde, TM Kleinman, JE Weinberger, DR AF Hashimoto, R Straub, RE Weickert, CS Hyde, TM Kleinman, JE Weinberger, DR TI Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE neuregulin-1; schizophrenia; expression; postmortem brain; isoform; dorsolateral prefrontal cortex ID RECEPTOR SUBUNIT GENE; SUSCEPTIBILITY GENES; BIPOLAR DISORDER; GABAERGIC INTERNEURONS; LINKAGE ANALYSIS; CEREBRAL-CORTEX; NERVOUS-SYSTEM; RADIAL GLIA; IN-VITRO; NEURONS AB Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and beta-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia. C1 NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, IRP, NIH, Room 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM weinberd@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011; Hashimoto, Ryota/P-8572-2014 OI Hashimoto, Ryota/0000-0002-5941-4238 NR 52 TC 175 Z9 187 U1 1 U2 8 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 MAR PY 2004 VL 9 IS 3 BP 299 EP 307 DI 10.1038/sj.mp.4001434 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 801XS UT WOS:000220129200011 PM 14569272 ER PT J AU Kiem, HP Sellers, S Thomasson, B Morris, JC Tisdale, JF Horn, PA Hematti, P Adler, R Kuramoto, K Calmels, B Bonifacino, A Hu, J von Kalle, C Schmidt, M Sorrentino, B Nienhuis, A Blau, CA Andrews, RG Donahue, RE Dunbar, CE AF Kiem, HP Sellers, S Thomasson, B Morris, JC Tisdale, JF Horn, PA Hematti, P Adler, R Kuramoto, K Calmels, B Bonifacino, A Hu, J von Kalle, C Schmidt, M Sorrentino, B Nienhuis, A Blau, CA Andrews, RG Donahue, RE Dunbar, CE TI Long-term clinical and molecular follow-up of large animals receiving retrovirally transduced stem and progenitor cells: No progression to clonal hematopoiesis or leukemia SO MOLECULAR THERAPY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; FIBRONECTIN FRAGMENT CH-296; MARROW REPOPULATING CELLS; MEDIATED GENE-TRANSFER; EX-VIVO; IN-VIVO; NONHUMAN-PRIMATES; MEGAKARYOCYTE GROWTH; FLT-3 LIGAND; THERAPY AB There has been significant progress toward clinically relevant levels of retroviral gene transfer into hematopoietic stem cells (HSC), and the therapeutic potential of HSC-based gene transfer has been convincingly demonstrated in children with severe combined immunodeficiency syndrome (SCID). However, the subsequent development of leukemia in two children with X-linked SCID who were apparently cured after transplantation of retrovirally corrected CD34(+) cells has raised concerns regarding the safety of gene therapy approaches utilizing integrating vectors. Nonhuman primates and dogs represent the best available models for gene transfer safety and efficacy and are particularly valuable for evaluation of long-term effects. We have followed 42 rhesus macaques, 23 baboons, and 17 dogs with significant levels of gene transfer for a median of 3.5 years (range 1-7) after infusion of CD34(+) cells transduced with retroviral vectors expressing marker or drug-resistance genes. None developed abnormal hematopoiesis or leukemia. Integration site analysis confirmed stable, polyclonal retrovirally marked hematopoiesis, without progression toward mono- or oligoclonality over time. These results suggest that retroviral integrations using replication-incompetent vectors, at copy numbers achieved using standard protocols, are unlikely to result in leukemogenesis and that patient- or transgene-specific factors most likely contributed to the occurrence of leukemia in the X-SCID gene therapy trial. C1 NHBLI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98195 USA. Univ Washington, Div Orcol, Seattle, WA 98195 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Univ Freiburg, Dept Internal Med, D-7800 Freiburg, Germany. St Jude Childrens Res Hosp, Div Expt Hematol, Memphis, TN 38105 USA. Univ Washington, Div Hematol, Seattle, WA 98195 USA. RP Dunbar, CE (reprint author), NHBLI, Hematol Branch, NIH, Bldg 10,Room 7C103,900 Rockville Pike, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI calmels, boris/R-2538-2016 FU NCRR NIH HHS [RR00166]; NHLBI NIH HHS [HL36444, HL53750, HL54881, HL74162]; NIDDK NIH HHS [DK56465] NR 35 TC 64 Z9 69 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 MAR PY 2004 VL 9 IS 3 BP 389 EP 395 DI 10.1016/j.ymthe.2003.12.006 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 802NL UT WOS:000220170100014 PM 15006605 ER PT J AU Karp, BI AF Karp, BI TI Botulinurn toxin treatment of occupational and focal hand dystonia SO MOVEMENT DISORDERS LA English DT Article; Proceedings Paper CT Toxins 2002 Conference CY 2002 CL Hannover, GERMANY DE Botulinum toxin writer's cramp dystonias injection; focal hand dystonia ID CERVICAL DYSTONIA; WRITERS CRAMP; INTRACORTICAL INHIBITION; LIMB DYSTONIA; GAG DELETION; MUSICIANS; PATHOPHYSIOLOGY; INFREQUENT; INJURIES AB Botulinum toxin is now the first-line therapy for writer's cramp and other occupational dystonias, with well-established efficacy and safety. Future studies will allow us to understand better the physiological effects of injection and to refine and enhance our treatment of focal hand dystonia. (C) 2004 Movement Disorder Society. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Karp, BI (reprint author), NINDS, NIH, Bldg 10,Room 5S-209,9000 Rockville Pike, Bethesda, MD 20892 USA. EM karpb@ninds.nih.gov NR 30 TC 23 Z9 24 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2004 VL 19 SU 8 BP S116 EP S119 DI 10.1002/mds.20025 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 803KX UT WOS:000220231100017 PM 15027063 ER PT J AU Lehky, RJ Leonard, GD Wilson, RH Grem, JL Floeter, MK AF Lehky, RJ Leonard, GD Wilson, RH Grem, JL Floeter, MK TI Oxaliplatin-induced neurotoxicity: Acute hyperexcitability and chronic neuropathy SO MUSCLE & NERVE LA English DT Article DE drug-induced neuropathy neuromyotonia; neurotoxicity; oxatolatin; SNAPs ID PERIPHERAL-NERVE HYPEREXCITABILITY; ACQUIRED NEUROMYOTONIA; CISPLATIN; PHARMACOKINETICS; CHANNEL; BIOTRANSFORMATION; ORMAPLATIN; AUTOIMMUNE; MANAGEMENT; MECHANISMS AB Oxaliplatin, a platinum-based chemotherapeutic agent, is effective in the treatment of solid tumors, particularly colorectal cancer. During and immediately following oxaliplatin infusion, patients may experience cold-induced paresthesias, throat and jaw tightness, and occasionally focal weakness. We assessed nerve conduction studies and findings on needle electromyography of patients with metastatic colorectal cancer before and during treatment with oxaliplatin. Twenty-two patients had follow-up studies within 48 h following oxaliplatin infusions, and 14 patients had follow-up studies after 3-9 treatment cycles. Repetitive compound muscle action potentials and neuromyotonic discharges were observed in the first 24-48 h following oxaliplatin infusion, but resolved by 3 weeks. After 8-9 treatment cycles, sensory nerve action potential amplitudes declined, without conduction velocity changes or neuromyotonic discharges. The acute neurological symptoms reflect a state of peripheral nerve hyperexcitability that likely represents a transient oxaliplatin-induced channelopathy. Chronic treatment causes an axonal neuropathy similar to other platinum-based chemotherapeutic agents. C1 Natl Naval Med Res Inst, Dept Neurol, Bethesda, MD 20889 USA. NINDS, Electromyog Sect, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Queens Univ Belfast, Belfast, Antrim, North Ireland. RP Lehky, RJ (reprint author), Natl Naval Med Res Inst, Dept Neurol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM TJLehky@Bethesda.med.navy.mil NR 37 TC 16 Z9 16 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD MAR PY 2004 VL 29 IS 3 BP 387 EP 392 DI 10.1002/mus.10559 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 779WD UT WOS:000189324000007 ER PT J AU Pierce, SK AF Pierce, SK TI To cluster or not to cluster: FRETting over rafts SO NATURE CELL BIOLOGY LA English DT Editorial Material ID T-CELL-RECEPTOR; LIPID RAFTS; IMMUNOLOGICAL SYNAPSE; SIGNALING ASSEMBLIES; MEMBRANE DOMAINS; ACCUMULATION AB Lipid rafts are thought to be important for signalling cascades by compartmentalizing signalling components in the membrane. This view has recently come under fire because the common method used for isolation of rafts detergent extraction - is fraught with artefacts. A variety of techniques, including FRET, have been used recently to investigate rafts in their native environment in intact cells. Now, FRET analysis provides evidence that rafts may not have a role in T-cell activation after all. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov NR 12 TC 22 Z9 22 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD MAR PY 2004 VL 6 IS 3 BP 180 EP 181 DI 10.1038/ncb0304-180 PG 2 WC Cell Biology SC Cell Biology GA 780GB UT WOS:000189363000004 PM 15039785 ER PT J AU Puertollano, R Bonifacino, JS AF Puertollano, R Bonifacino, JS TI Interactions of GGA3 with the ubiquitin sorting machinery SO NATURE CELL BIOLOGY LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTORS; TRANS-GOLGI NETWORK; GAMMA-ADAPTIN; VHS DOMAINS; ENDOSOMAL TRAFFICKING; DOWN-REGULATION; EGF RECEPTOR; BINDING; PROTEINS; COMPLEX AB The Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins constitute a family of clathrin adaptors that are mainly associated with the trans-Golgi network (TGN)(1-3) and mediate the sorting of mannose 6-phosphate receptors(4-6). This sorting is dependent on the interaction of the VHS domain of the GGAs with acidic-cluster-dileucine signals in the cytosolic tails of the receptors(4,5). Here we demonstrate the existence of another population of GGAs that are associated with early endosomes. RNA interference (RNAi) of GGA3 expression results in accumulation of the cation-independent mannose 6-phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes. This perturbation impairs the degradation of internalized EGF, a process that is normally dependent on the sorting of ubiquitinated EGF receptors (EGFRs) to late endosomes. Protein interaction analyses show that the GGAs bind ubiquitin. The VHS and GAT domains of GGA3 are responsible for this binding, as well as for interactions with TSG101, a component of the ubiquitin-dependent sorting machinery. Thus, GGAs may have additional roles in sorting of ubiquitinated cargo. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 34 TC 155 Z9 163 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD MAR PY 2004 VL 6 IS 3 BP 244 EP 251 DI 10.1038/ncb1106 PG 8 WC Cell Biology SC Cell Biology GA 780GB UT WOS:000189363000016 PM 15039775 ER PT J AU Burton, DR Desrosiers, RC Doms, RW Koff, WC Kwong, PD Moore, JP Nabel, GJ Sodroski, J Wilson, IA Wyatt, RT AF Burton, DR Desrosiers, RC Doms, RW Koff, WC Kwong, PD Moore, JP Nabel, GJ Sodroski, J Wilson, IA Wyatt, RT TI HIV vaccine design and the neutralizing antibody problem SO NATURE IMMUNOLOGY LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN; TYPE-1; BINDING; GP120; SELECTIVITY; RECOGNITION; ANTIGENS; REGION; GP41 AB Eliciting broadly neutralizing antibodies to human immunodeficiency virus could bring closer the goal of a successful AIDS vaccine. Here the International AIDS Vaccine Initiative Neutralizing Antibody Consortium discusses current approaches to overcome the problems faced. C1 Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Microbiol, Southborough, MA 01772 USA. Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. Int AIDS Vaccine Initiat, New York, NY USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Ctr, Dept Microbiol & Immunol, New York, NY USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM burton@scripps.edu NR 21 TC 569 Z9 591 U1 5 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2004 VL 5 IS 3 BP 233 EP 236 DI 10.1038/ni0304-233 PG 4 WC Immunology SC Immunology GA 779ZV UT WOS:000189344600002 PM 14985706 ER PT J AU Faure, S Salazar-Fontana, LI Semichon, M Tybulewicz, VLJ Bismuth, G Trautmann, A Germain, RN Delon, J AF Faure, S Salazar-Fontana, LI Semichon, M Tybulewicz, VLJ Bismuth, G Trautmann, A Germain, RN Delon, J TI ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation SO NATURE IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; EXCHANGE FACTOR VAV; IMMUNOLOGICAL SYNAPSE; INTRACELLULAR CALCIUM; ACTIN POLYMERIZATION; RECEPTOR SIGNALS; RHO-GTPASES; IN-VIVO; RECOGNITION; ACTIVATION AB During activation, T cells associate with antigen-presenting cells, a dynamic process that involves the formation of a broad area of intimate membrane contact known as the immunological synapse. The molecular intermediates that link initial antigen recognition to the cytoskeletal changes involved in this phenomenon have not yet been defined. Here we demonstrate that ezrin-radixin-moesin proteins are rapidly inactivated after antigen recognition through a Vav1-Rac1 pathway. The resulting disanchoring of the cortical actin cytoskeleton from the plasma membrane decreased cellular rigidity, leading to more efficient T cell-antigen-presenting cell conjugate formation. These findings identify an antigen-dependent molecular pathway that favors immunological synapse formation and the subsequent development of an effective immune response. C1 Univ Paris 05, Inst Cochin, Dept Biol Cellulaire, INSERM,U567,CNRS,UMR 8104, F-75014 Paris, France. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Med Res, Div Immune Cell Biol, London NW7 1AA, England. RP Delon, J (reprint author), Univ Paris 05, Inst Cochin, Dept Biol Cellulaire, INSERM,U567,CNRS,UMR 8104, 22 Rue Mechain, F-75014 Paris, France. EM delon@cochin.inserm.fr OI Tybulewicz, Victor/0000-0003-2439-0798 NR 50 TC 173 Z9 180 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2004 VL 5 IS 3 BP 272 EP 279 DI 10.1038/ni1039 PG 8 WC Immunology SC Immunology GA 779ZV UT WOS:000189344600010 PM 14758359 ER PT J AU Liu, XL Bosselut, R AF Liu, XL Bosselut, R TI Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; POSITIVE SELECTION; ANTIGEN RECEPTOR; CD4 LINEAGE; NEGATIVE SELECTION; THYMIC SELECTION; THYMOCYTE DIFFERENTIATION; CD4(+)CD8(+) THYMOCYTES; STOCHASTIC MECHANISM; TYROSINE KINASE AB The duration of T cell receptor (TCR) signaling is thought to be important for thymocyte differentiation into the CD4 or CD8 lineage. However, the in vivo relevance of this hypothesis is unclear. Here we divided T cell positive selection into genetically separable developmental steps by confining TCR signal transduction to discrete thymocyte developmental windows. TCR signals confined to the double-positive thymocyte stage promoted CD8, but not CD4, lineage differentiation. Major histocompatibility complex (MHC) class II-restricted thymocytes were, instead, redirected into the CD8 lineage. These findings support the hypothesis that distinct kinetics of MHC class I- and MHC class II-induced TCR signals direct intrathymic developmental decisions. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM remy@helix.nih.gov NR 66 TC 72 Z9 72 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2004 VL 5 IS 3 BP 280 EP 288 DI 10.1038/ni1040 PG 9 WC Immunology SC Immunology GA 779ZV UT WOS:000189344600011 PM 14770180 ER PT J AU Sausville, EA AF Sausville, EA TI Aurora kinases dawn as cancer drug targets SO NATURE MEDICINE LA English DT Editorial Material C1 NCI, Dev Therapeut Program, Rockville, MD 20852 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, Rockville, MD 20852 USA. EM sausville@nih.gov NR 10 TC 22 Z9 23 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2004 VL 10 IS 3 BP 234 EP 235 DI 10.1038/nm0304-234 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 779LH UT WOS:000189297700023 PM 14991042 ER PT J AU Braz, JC Gregory, K Pathak, A Zhao, W Sahin, B Klevitsky, R Kimball, TF Lorenz, JN Nairn, AC Liggett, SB Bodi, I Wang, S Schwartz, A Lakatta, EG DePaoli-Roach, AA Robbins, J Hewett, TE Bibb, JA Westfall, MV Kranias, EG Molkentin, JD AF Braz, JC Gregory, K Pathak, A Zhao, W Sahin, B Klevitsky, R Kimball, TF Lorenz, JN Nairn, AC Liggett, SB Bodi, I Wang, S Schwartz, A Lakatta, EG DePaoli-Roach, AA Robbins, J Hewett, TE Bibb, JA Westfall, MV Kranias, EG Molkentin, JD TI PKC-alpha regulates cardiac contractility and propensity toward heart failure SO NATURE MEDICINE LA English DT Article ID PROTEIN-KINASE-C; SARCOPLASMIC-RETICULUM; DILATED CARDIOMYOPATHY; CROSS-TALK; PHOSPHOLAMBAN; PHOSPHATASE; HYPERTROPHY; EXPRESSION; PHOSPHORYLATION; TRANSLOCATION AB The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane- associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca2+ handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-activity affects dephosphorylation of the sarcoplasmic reticulum Ca2+ ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca2+ loading and the Ca2+ transient. PKC-directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca2+ and signal transduction events, which can profoundly affect propensity toward heart failure. C1 Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. Univ Cincinnati, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. Univ Texas SW, Dept Psychiat, Dallas, TX 75390 USA. Univ Cincinnati, Dept Cellular & Mol Physiol, Cincinnati, OH 45267 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06508 USA. Univ Cincinnati, Inst Mol Pharmacol & Biophys, Cincinnati, OH 45267 USA. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Univ Michigan, Sect Cardiac Surg, Ann Arbor, MI 48109 USA. RP Molkentin, JD (reprint author), Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. EM jeff.molkentin@cchmc.org RI Hewett, Timothy/G-1023-2011; Hewett, Timothy/E-3241-2011; liggett, stephen/E-7453-2012; OI Nairn, Angus/0000-0002-7075-0195 FU NHLBI NIH HHS [5T32 HL07382] NR 30 TC 342 Z9 359 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2004 VL 10 IS 3 BP 248 EP 254 DI 10.1038/nm1000 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 779LH UT WOS:000189297700035 PM 14966518 ER PT J AU Friedrich, TC Dodds, EJ Yant, LJ Vojnov, L Rudersdorf, R Cullen, C Evans, DT Desrosiers, RC Mothe, BR Sidney, J Sette, A Kunstman, K Wolinsky, S Piatak, M Lifson, J Hughes, AL Wilson, N O'Connor, DH Watkins, DI AF Friedrich, TC Dodds, EJ Yant, LJ Vojnov, L Rudersdorf, R Cullen, C Evans, DT Desrosiers, RC Mothe, BR Sidney, J Sette, A Kunstman, K Wolinsky, S Piatak, M Lifson, J Hughes, AL Wilson, N O'Connor, DH Watkins, DI TI Reversion of CTL escape-variant immunodeficiency viruses in vivo SO NATURE MEDICINE LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; PEPTIDE-BINDING-SPECIFICITY; CELLULAR IMMUNE-RESPONSES; ACUTE-PHASE; DISEASE PROGRESSION; PRIMARY INFECTION; TYPE-1 INFECTION; VIRAL ESCAPE; HIV; VIREMIA AB Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations. C1 Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI 53706 USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. Calif State Univ San Marcos, San Marcos, CA 92096 USA. La Jolla Inst Allergy & Immunol, San Diego, CA 92121 USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. NCI, AIDS Vaccine Program, Frederick, MD 21702 USA. Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. RP Watkins, DI (reprint author), Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM watkins@primate.wisc.edu RI Wolinsky, Steven/B-2893-2012; OI Wolinsky, Steven/0000-0002-9625-6697; o'connor, david/0000-0003-2139-470X; Yant, Levi/0000-0003-3442-0217; Friedrich, Thomas/0000-0001-9831-6895 FU NCRR NIH HHS [P51 RR001676-43]; NIAID NIH HHS [R01-AI-46366, N01-AI-95362, R01-AI-49120, R01-AI-52056] NR 38 TC 289 Z9 294 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2004 VL 10 IS 3 BP 275 EP 281 DI 10.1038/nm998 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 779LH UT WOS:000189297700039 PM 14966520 ER PT J AU Boknik, P Grote, S Hanske, G Jiang, M Bimbaumer, L Schmitz, W Neumann, J AF Boknik, P Grote, S Hanske, G Jiang, M Bimbaumer, L Schmitz, W Neumann, J TI Genetic disruption of Gia2 and Goa does not abolish inotropic and chronotropic effects of M-cholinoceptor stimulation in atria. SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Univ Klinikum Munster, Inst Pharmakol & Toxikol, D-48129 Munster, Germany. Univ Calif Los Angeles, Dept Anesthesiol, Los Angeles, CA 90024 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 368 BP R92 EP R92 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800369 ER PT J AU Dietrich, A Schnitzler, MMY Storch, U Lauterbach, B Essin, K Obst, M Gross, V Gollasch, M Birnbaumer, L Gudermann, T AF Dietrich, A Schnitzler, MMY Storch, U Lauterbach, B Essin, K Obst, M Gross, V Gollasch, M Birnbaumer, L Gudermann, T TI TRPC6 deficient mice develop an elevated blood-pressure and an early onset of the myogenic tone in cerebral arteries SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Max Delbruck Ctr Mol Med, Franz Volhard Klin, Berlin, Germany. Univ Marburg, Inst Pharmakol & Toxikol, D-35032 Marburg, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. RI Dietrich, Alexander/G-8619-2013 NR 0 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 242 BP R61 EP R61 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800243 ER PT J AU Groner, F Foerster, K Matthes, J Birnbaumer, L Koch, WJ Herzig, S AF Groner, F Foerster, K Matthes, J Birnbaumer, L Koch, WJ Herzig, S TI G(i)-protein G alpha(i3) is responsible for cardiac Ca2+ channel regulation via the beta(2)-adrenergic cascade SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Univ Cologne, Dept Pharmacol, D-50931 Cologne, Germany. NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. Thomas Jefferson Univ, Jefferson Med Coll, Ctr Translat Med, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 357 BP R90 EP R90 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800358 ER PT J AU Hartz, AMS Bauer, B Miller, DS Fricker, G AF Hartz, AMS Bauer, B Miller, DS Fricker, G TI Short-term regulation of P-glycoprotein at the blood-brain barrier: The role of endothelin-1 SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Univ Heidelberg, Inst Pharm & Mol Biotechnol, Div Pharmaceut Technol & Pharmacol, D-69120 Heidelberg, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 2 BP R1 EP R1 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800003 ER PT J AU Notenboom, S Kuik, LH Miller, DS Russel, FGM Masereeuw, R AF Notenboom, S Kuik, LH Miller, DS Russel, FGM Masereeuw, R TI Short-term gentamicin exposure to renal proximal tubule has long-term intracellular signaling consequences SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 2nd Joint Meeting of the Italian-and-Dutch-Pharmacological-Societies CY FEB 12-14, 2003 CL Lunteren, NETHERLANDS SP Italian Pharmacol Soc, Dutch Pharmacol Soc C1 NCMLS, Dept Pharmacol & Toxicol, Nijmegen, Netherlands. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Mt Desert Isl Biol Lab, Salsbury Cove, ME USA. RI Russel, Frans/B-3184-2014; Masereeuw, Roos/N-3582-2014 OI Russel, Frans/0000-0002-7959-2314; NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 32 BP R172 EP R172 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800673 ER PT J AU Schirmer, M Belyantseva, IA Al-Falah, M Propsting, M Gernert, M Fedrowitz, M Naim, HY Friedman, TB Loscher, W AF Schirmer, M Belyantseva, IA Al-Falah, M Propsting, M Gernert, M Fedrowitz, M Naim, HY Friedman, TB Loscher, W TI The role of myosin XVa in the phenotype of the circling (ci2) rat mutant SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Sch Vet Med, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany. Sch Vet Med, Dept Physiol Chem, D-30559 Hannover, Germany. Natl Inst Deafness & Other Commun Disorders, Genet Mol Lab, NIH, Rockville, MD 20850 USA. RI Al Falah, Dr. Marwan /C-6281-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 344 BP R86 EP R86 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800345 ER PT J AU Schraut, C Hammer, S Sauer, B Schafer-Korting, M Kleuser, B AF Schraut, C Hammer, S Sauer, B Schafer-Korting, M Kleuser, B TI Cytoprotective actions of glucocorticoids in epidermal and dermal cells are mediated via sphingosine 1-phosphate SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Free Univ Berlin, Inst Pharm Pharmakol & Toxikol, D-14195 Berlin, Germany. NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 56 BP R14 EP R14 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800057 ER PT J AU Schroeder, C Birkenfeld, A Tank, J Goldstein, DS Luft, FC Jordan, J AF Schroeder, C Birkenfeld, A Tank, J Goldstein, DS Luft, FC Jordan, J TI Influence of St. John's wort on norepinephrine turnover and cardiovascular regulation in humans SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 45th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology CY MAR 09-11, 2004 CL Mainz, GERMANY SP German Soc Exptl & Clin Pharmacol & Toxicol C1 Humboldt Univ, Franz Volhard Clin Res Ctr, Fac Med, Charite, Berlin, Germany. Humboldt Univ, Helios Klinikum, Berlin, Germany. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2004 VL 369 SU 1 MA 634 BP R159 EP R159 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 808UA UT WOS:000220592800635 ER PT J AU Bondolfi, L Ermini, F Long, JM Ingram, DK Jucker, M AF Bondolfi, L Ermini, F Long, JM Ingram, DK Jucker, M TI Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice SO NEUROBIOLOGY OF AGING LA English DT Article DE mouse brain; aging; neurogenesis; glia; caloric restriction; hippocampus; progenitor cells; proliferation; gliogenesis ID ADULT-RAT; HIPPOCAMPAL NEUROGENESIS; TRANSGENIC MICE; GRANULE CELLS; NEURONS; NUMBER; BRAIN; PROLIFERATION; EXPRESSION; SUBEPENDYMA AB Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to I I months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Univ Basel, Inst Pathol, Dept Neuropathol, CH-4003 Basel, Switzerland. NIA, Lab Expt Gerontol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, D-72076 Tubingen, Germany. RP Jucker, M (reprint author), Univ Basel, Inst Pathol, Dept Neuropathol, Schonbeinstr 40, CH-4003 Basel, Switzerland. EM mjucker@uhbs.ch NR 44 TC 129 Z9 133 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2004 VL 25 IS 3 BP 333 EP 340 DI 10.1016/S0197-4580(03)00083-6 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 778FV UT WOS:000189229600009 PM 15123339 ER PT J AU Lerner, A Shill, H Hanakawa, T Bushara, K Goldfine, A Hallett, M AF Lerner, A Shill, H Hanakawa, T Bushara, K Goldfine, A Hallett, M TI Regional cerebral blood flow correlates of the severity of writer's cramp symptoms SO NEUROIMAGE LA English DT Article DE PET; writer's cramp; dystonia; sensory cortex ID PRIMARY SOMATOSENSORY CORTEX; REPETITIVE STRAIN INJURY; MOTOR CORTICAL AREAS; FOCAL HAND DYSTONIA; BOTULINUM TOXIN; SUPPLEMENTARY MOTOR; RECIPROCAL INHIBITION; IDIOPATHIC DYSTONIA; CERVICAL DYSTONIA; HUMAN BRAIN AB Writer's cramp is a type of idiopathic focal dystonia with incompletely understood pathophysiology. Recent studies provide evidence that one element might be a sensory processing defect. We performed a PET study with O-15 H2O to find out in which brain areas activity correlates with the severity of writer's cramp symptoms. Methods: We studied 10 patients with writer's cramp and 10 age- and gender-matched control subjects. There were seven conditions, each repeated twice: rest, writing, tapping with index finger for 2, 3, 4, and 5 min. For each scan, we obtained EMG recordings from the flexor digitorum superficialis (FDS), extensor indicis proprius (EIP) muscles, and a subjective score of severity of dystonia. Scans were realigned, normalized, smoothed, and analyzed using SPM99. Analysis included both intra- and intergroup comparisons and a correlation analysis where we used EMG recordings and subjective dystonia score as covariates. Results: Random effect analysis of the writing task showed overactivity of the primary sensory cortex and no significant underactivity. Correlation analysis of dystonia patients showed activation of SI when we used the subjective dystonia score as a covariate, and activation of both the SI and primary motor cortex when the normalized EMG score of FDS was used. Conclusion: While some overactivity of MI is not surprising, overactivity of SI is more dramatic and suggests a primary deficit in processing sensory feedback. Writer's cramp may arise in part as a dysfunction of sensory circuits, which causes defective sensorimotor integration resulting in co-contractions of muscles and overflow phenomena. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, Human Motor Control Sci, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sci, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Goldfine, Andrew/0000-0003-1962-5564 NR 50 TC 71 Z9 74 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2004 VL 21 IS 3 BP 904 EP 913 DI 10.1016/j.neuroimage.2003.10.019 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 802FH UT WOS:000220148900011 PM 15006657 ER PT J AU Momenan, R Rawlings, R Fong, G Knutson, B Hommer, D AF Momenan, R Rawlings, R Fong, G Knutson, B Hommer, D TI Voxel-based homogeneity probability maps of grapy matter in groups: assessing the reliability of functional effects SO NEUROIMAGE LA English DT Article DE voxel-based; group analysis; gray matter; structural; functional; segmentation; registration; homogeneity probability map; confidence interval ID ALZHEIMERS-DISEASE; BRAIN; ATROPHY; FMRI; MRI AB A subject of increasing importance in magnetic resonance imaging (MRI) is the analysis of intersubject structural differences, particularly when comparing groups of subjects with different conditions or diagnoses. On the other hand, determining structural homogeneity across subjects using voxel-based morphological (VBM) methods has become even more important to investigators who test for group brain activation using functional magnetic resonance images (fMRI) or positron emission tomography (PET). In the absence of methods that evaluate structural differences, one does not know how much reliability to assign to the functional differences. Here, we describe a voxel-based method for quantitatively assessing the homogeneity of tissues from structural magnetic resonance images of groups. Specifically, this method determines the homogeneity of gray matter for a group of,subjects. Homogeneity probability maps (HPMs) of a given tissue type (e.g., gray matter) are generated by using a confidence interval based on binomial distribution. These maps indicate for each voxel the probability that,, the tissue type is gray for the population being studied. Therefore, HPMs can accompany functional analyses to indicate the confidence one can assign to functional difference at any given voxel. In this paper, examples of HPMs generated for a group of control subjects are shown and discussed. The application of this method to functional analysis is demonstrated. (C) 2004 Elsevier Inc. All rights reserved. C1 NIAAA, Sect Brain Electrophysiol & Imaging, LCS, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RP Momenan, R (reprint author), NIAAA, Sect Brain Electrophysiol & Imaging, LCS, NIH, Room 3C114,Bldg 10,10 Ctr Dr,MSC 1256, Bethesda, MD 20892 USA. EM rezam@nih.gov NR 15 TC 10 Z9 10 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2004 VL 21 IS 3 BP 965 EP 972 DI 10.1016/j.neuroimage.2003.10.038 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 802FH UT WOS:000220148900017 PM 15006663 ER PT J AU Morgen, K Kadom, N Sawaki, L Tessitore, A Ohayon, J Frank, J McFarland, H Martin, R Cohen, LG AF Morgen, K Kadom, N Sawaki, L Tessitore, A Ohayon, J Frank, J McFarland, H Martin, R Cohen, LG TI Kinematic specificity of cortical reorganization associated with motor training SO NEUROIMAGE LA English DT Article DE kinematic specificity; cortical reorganization; motor training ID USE-DEPENDENT PLASTICITY; POSITRON-EMISSION-TOMOGRAPHY; BRAIN ACTIVATION; PARIETAL CORTEX; D-AMPHETAMINE; ATTENTION; TASK; MEMORY; PET; REPRODUCIBILITY AB Motor training consisting of repetition of directionally specific voluntary thumb movements elicits a short-term memory trace that encodes the kinematic details of the practiced motions in the primary motor cortex. Here, we studied activation patterns associated with this form of training using functional magnetic resonance imaging under careful monitoring of motor training kinematics and electromyography. We identified task-specific reductions in activation in contralaterat motor cortex, a region that controls executive motor output, as well as somatosensory cortex and inferior parietal lobule, regions in charge of monitoring motor training kinematics. Our findings are consistent with the hypothesis that a short training period consisting of repetition of finger motions leads to cortical reorganization characterized by a smaller and more efficient network that is specific for the trained movement direction. Published by Elsevier Inc. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Giessen, Dept Neurol, Giessen, Germany. Bender Inst Neuroimaging, Giessen, Germany. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Radiol Res, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N234,10 Ctr Dr,MSC-1430, Bethesda, MD 20892 USA. EM CohenL@ninds.nih.gov OI Kadom, Nadja/0000-0002-7073-956X NR 35 TC 41 Z9 42 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2004 VL 21 IS 3 BP 1182 EP 1187 DI 10.1016/j.neuroimage.2003.11.006 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 802FH UT WOS:000220148900039 PM 15006685 ER PT J AU Bielsky, IF Hu, SB Szegda, KL Westphal, H Young, LJ AF Bielsky, IF Hu, SB Szegda, KL Westphal, H Young, LJ TI Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE vasopressin; V1a receptor; social recognition; anxiety; neuropeptide; knockout ID LATERAL SEPTAL VASOPRESSIN; SPECIES-DIFFERENCES; MONOGAMOUS VOLE; GENE-EXPRESSION; ANIMAL-MODELS; PLUS-MAZE; RATS; OXYTOCIN; MEMORY; BRAIN AB Considerable evidence suggests that arginine vasopressin (AVP) is critically involved in the regulation of many social and nonsocial behaviors, including emotionality. The existence of two AVP receptors in the brain, namely the VIa and VIb subtypes, and the lack of clear pharmacological data using selective agonists or antagonists, make it difficult to determine which receptor is responsible for the AVP-mediated effects on behavior. Here we report the behavioral effects of a null mutation in the VIa receptor (VIoR) in male mice. Male mice lacking functional VIaR (V I aRKO) exhibit markedly reduced anxiety-like behavior and a profound impairment in social recognition. V IaRKC) performed normally on spatial and nonsocial olfactory learning and memory tasks. Acute central administration of AVP robustly stimulated stereotypical scratching and autogrooming in wild-type (VVT), but not V I aRKO males. AVP and oxytocin (OT) mRNA and OT receptor-binding levels were similar in VVT and V I aRKO mice. Given the current findings, the V I aR may provide a novel potential pharmacological target for social and affective disorders including autism, and anxiety disorders. C1 Emory Univ, Dept Psychiat, Ctr Behav Neurosci, Atlanta, GA 30322 USA. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Bielsky, IF (reprint author), Yerkes Natl Primate Res Ctr, 954 Gatewood Dr, Atlanta, GA 30329 USA. EM irapopo@emory.edu RI chen, xuanlan/H-4158-2011 FU NCRR NIH HHS [RR00165]; NIMH NIH HHS [K02 MH64692, R01 MH56897] NR 51 TC 271 Z9 279 U1 2 U2 34 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2004 VL 29 IS 3 BP 483 EP 493 DI 10.1038/sj.npp.1300360 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 800FE UT WOS:000220013500005 PM 14647484 ER PT J AU Morgan, MA Schulkin, J Pfaff, DW AF Morgan, MA Schulkin, J Pfaff, DW TI Estrogens and non-reproductive behaviors related to activity and fear SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE estrogens; arousal; open field; elevated plus; running wheel; locomotion; fear; fear conditioning; corticotropin releasing hormone; mice; rats; activity; environment ID CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED AVOIDANCE RESPONSES; ELEVATED PLUS-MAZE; CENTRAL-NERVOUS-SYSTEM; FACTOR MESSENGER-RNA; ESTROUS-CYCLE; SEX-DIFFERENCES; GENE-EXPRESSION; FEMALE MICE; OVARIECTOMIZED RATS AB Estrogens affect a variety of behaviors in addition to sexual responses, some of them related to motor activity and emotional reactivity. This is true in experimental animals and in humans. The literatures on these subjects are confusing because not all of the experimental results point in the same direction. Here we propose the following theoretical suggestion, hoping to account for the variety of reports extant: following the generally arousing effects of estrogens, their hormonal actions on motor activity and fear depend on context. In a safe environment. estrogen treatment causes increased activity. But in a novel environment or in contexts otherwise perceived as threatening, activity is reduced by estrogen, due to the hormone's arousing action, which heightens fear. Many hormone-dependent neural circuits involving several neuropeptides could provide mechanisms for this dynamic. We suggest a causal route could involve the activation of corticotropin releasing hormone gene expression in the brain. In sum, estrogenic effects on arousal states, as manifest differently according to details of the environmental context during behavioral test, could account for some of the discrepancies in the literature. (C) 2003 Elsevier Ltd. All rights reserved. C1 Amer Coll Obstetricians & Gynecologists, Dept Res, Washington, DC 20024 USA. Rockefeller Univ, Dept Neurobiol & Behav, New York, NY 10021 USA. Georgetown Univ, Dept Physiol & Biophys, Washington, DC USA. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD USA. RP Morgan, MA (reprint author), Amer Coll Obstetricians & Gynecologists, Dept Res, 409 12th St SW, Washington, DC 20024 USA. EM mmorgan@acog.org NR 96 TC 89 Z9 92 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD MAR PY 2004 VL 28 IS 1 BP 55 EP 63 DI 10.1016/j.neubiorev.003.11.017 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 800FO UT WOS:000220014500005 PM 15036933 ER PT J AU Bonne, O Grillon, C Vythilingam, M Neumeister, A Charney, DS AF Bonne, O Grillon, C Vythilingam, M Neumeister, A Charney, DS TI Adaptive and maladaptive psychobiological responses to severe psychological stress: implications for the discovery of novel pharmacotherapy SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE post-traumatic stress disorder; adaptive and maladaptive; fear and anxiety; fear conditioning; extinction; learned helplessness; neural circuitry; neurochemistry; psychophysiology; pharmacotherapy ID CORTICOTROPIN-RELEASING HORMONE; DORSAL RAPHE NUCLEUS; FEAR-POTENTIATED STARTLE; PITUITARY-ADRENAL AXIS; CHILDHOOD SEXUAL-ABUSE; MEDIAL PREFRONTAL CORTEX; MINERALOCORTICOID RECEPTOR FUNCTION; INTERNATIONAL CONSENSUS GROUP; BASOLATERAL AMYGDALA NEURONS; POSITRON-EMISSION-TOMOGRAPHY AB Post-traumatic stress disorder (PTSD) is one of the few DSM-IV diagnoses contingent upon a psychosocial stressor. In this context, there is an urgent need to acquire a better understanding of both the adaptive and maladaptive psychobiological responses to traumatic stress. Preclinical investigators have utilized a variety of animal models to identify the behavioral and neurobiological features of the organism's response to stress. However, given the complexity of the healthy and pathological human response to physiological and psychological stress, the extent to which the animal data is immediately transferable to human remains to be fully determined. This review draws upon preclinical and clinical literature to examine the transformation of an adaptive human stress response into a maladaptive and debilitating mental disorder. An integrative psychobiological model for PTSD is presented, linking psychological processes and behavioral patterns with current findings in neurocircuitry, neurochemistry and psychophysiology. The implications of this model for the discovery of novel pharmacological approaches to the treatment of severe psychological distress are discussed. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Hadassah Hebrew Univ Hosp, Dept Psychiat, IL-91120 Jerusalem, Israel. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K N Dr,Rm 200, Bethesda, MD 20892 USA. EM bonneo@intra.nimh.nih.gov NR 362 TC 65 Z9 66 U1 13 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD MAR PY 2004 VL 28 IS 1 BP 65 EP 94 DI 10.1016/j.neubiorev.2003.12.001 PG 30 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 800FO UT WOS:000220014500006 PM 15036934 ER PT J AU Reszka, KJ Bilski, P Chignell, CF AF Reszka, KJ Bilski, P Chignell, CF TI Spin trapping of nitric oxide by aci anions of nitroalkanes SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE EPR; nitric oxide; nitroalkanes; nitromethane; nitroethane; nitropropane; nitrobutane; aci anion; spin trapping ID GLUCAMINE DITHIOCARBAMATE COMPLEX; AQUEOUS-SOLUTIONS; NITROSO-COMPOUNDS; FORMING REACTIONS; GEM-DINITRO; RESONANCE; EPR; NITROMETHANE; RADICALS; TRAPS AB In alkaline solutions, nitroalkanes (RCH2NO2) undergo deprotonation and rearrange to an aci anion (RHG=NO2-), which may function as a spin trap. Using electron paramagnetic resonance (EPR) spectroscopy, we have investigated suitability of aci anions of a series of nitroalkanes (CH3NO2, CH3CH2NO2, CH3(CH2)(2)NO2, and CH3(CH2)(3)NO2) to spin trap nitric oxide ((NO)-N-.). Based on the observed EPR spectra, the general structure of the adducts, formed by addition of (NO)-N-. to RHC=NO2-, was identified as nitronitroso dianion radicals of general formula [RC(NO)NO2](.2-) in strong base (0.5 M NaOH), and as a mono-anion radical [RCH(NO)NO2](.-) in alkaline buffers, pH 10-13. The hyperfine splitting on N-14 in the -NO2 moiety (11.2-12.48 G) is distinctly different from the splitting on N-14 in the -NO moiety of the adducts (5.23-6.5 G). The structure of the adducts was verified using N-15-labeled (NO)-N-., which produced radicals, in which triplet due to splitting on N-14 (I = 1) in (NO)-N-14/aci nitro adducts was replaced by a doublet due to N-15 (I = 1/2) in (NO)-N-15/aci nitro adducts. EPR spectra of aci nitromethane/NO adduct recorded in NaOH and NaOD (0.5 M) showed that the hydrogen at a-carbon can be exchanged for deuterium, consistent with structures of the adducts being [CH(NO)NO2](.2-) and [CD(NO)NO2](.2-), respectively. These results indicate that nitroalkanes could potentially be used as prototypes for development of (NO)-N-.-specific spin traps suitable for EPR analysis. Published by Elsevier Inc. C1 NIEHS, Mol Biophys Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Reszka, KJ (reprint author), VA Med Ctr, Res 151,601 Highway 6 W, Iowa City, IA 52246 USA. EM reszka@icva.gov NR 27 TC 8 Z9 8 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD MAR PY 2004 VL 10 IS 2 BP 53 EP 59 DI 10.1016/j.niox.2004.03.001 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 825KG UT WOS:000221755100001 PM 15135358 ER PT J AU Kondrashov, FA Ogurtsov, AY Kondrashov, AS AF Kondrashov, FA Ogurtsov, AY Kondrashov, AS TI Bioinformatical assay of human gene morbidity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-DISEASE GENES; CAENORHABDITIS-ELEGANS; NONESSENTIAL GENES; LETHAL MUTATIONS; MOUSE GENOME; EVOLUTION; DISPENSABILITY; SEQUENCE; DATABASE; SCREEN AB Only a fraction of eukaryotic genes affect the phenotype drastically. We compared 18 parameters in 1273 human morbid genes, known to cause diseases, and in the remaining 16 580 unambiguous human genes. Morbid genes evolve more slowly, have wider phylogenetic distributions, are more similar to essential genes of Drosophila melanogaster, code for longer proteins containing more alanine and glycine and less histidine, lysine and methionine, possess larger numbers of longer introns with more accurate splicing signals and have higher and broader expressions. These differences make it possible to classify as non-morbid 34% of human genes with unknown morbidity, when only 5% of known morbid genes are incorrectly classified as non-morbid. This classification can help to identify disease-causing genes among multiple candidates. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Kondrashov, AS (reprint author), NIH, Natl Ctr Biotechnol Informat, 38A Ctr Dr,6S602, Bethesda, MD 20892 USA. EM kondrashov@ncbi.nlm.nih.gov RI Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 44 TC 46 Z9 48 U1 0 U2 0 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 MAR PY 2004 VL 32 IS 5 BP 1731 EP 1737 DI 10.1093/nar/gkh330 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807FK UT WOS:000220487200018 PM 15020709 ER PT J AU Shabalina, SA Ogurtsov, AY Rogozin, IB Koonin, EV Lipman, DJ AF Shabalina, SA Ogurtsov, AY Rogozin, IB Koonin, EV Lipman, DJ TI Comparative analysis of orthologous eukaryotic mRNAs: potential hidden functional signals SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSLATION TERMINATION; UNTRANSLATED REGIONS; REGULATORY ELEMENTS; NONCODING SEQUENCES; INITIATION-FACTORS; STOP CODON; GENES; POLYADENYLATION; EFFICIENCY; EVOLUTION AB Sequencing of multiple, nearly complete eukaryotic genomes creates opportunities for detecting previously unnoticed, subtle functional signals in non-coding regions. A genome-wide comparative analysis of orthologous sets of mammalian and yeast mRNAs revealed distinct patterns of evolutionary conservation at the boundaries of the untranslated regions (UTRs) and the coding region (CDS). Elevated sequence conservation was detected in similar to30 nt regions around the start codon. There seems to be a complementary relationship between sequence conservation in the similar to30 nt regions of the 5'-UTR immediately upstream of the start codon and that in the synonymous positions of the 5'-terminal 30 nt of the CDS: in mammalian mRNAs, the 5'-UTR shows a greater conservation than the CDS, whereas the opposite trend holds for yeast mRNAs. Unexpectedly, a similar to30 nt region downstream of the stop codon shows a substantially lower level of sequence conservation than the downstream portions of the 3'-UTRs. However, the sequence in this poorly conserved 30 nt portion of the 3'-UTR is non-random in that it has a higher GC content than the rest of the UTR. It is hypothesized that the elevated sequence conservation in the region immediately upstream of the start codon is related to the requirement for initiation factor binding during pre-initiation ribosomal scanning. In contrast, the poorly conserved region downstream of the stop codon could be involved in the post- termination scanning and dissociation of the ribosomes from the mRNA, which requires only the mRNA-ribosome interaction. Additionally, it was found that the choice of the stop codon in mammals, but not in yeasts, and the context in the immediate vicinity of the stop codons in both mammals and yeasts are subject to strong selection. Thus, genome-wide analysis of orthologous gene sets allows detection of previously unrecognized patterns of sequence conservation, which are likely to reflect hidden functional signals, such as ribosomal filters that could regulate translation by modulating the interaction between the mRNA and ribosomes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Lipman, DJ (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM lipman@ncbi.nlm.nih.gov RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 NR 60 TC 56 Z9 59 U1 1 U2 4 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 MAR PY 2004 VL 32 IS 5 BP 1774 EP 1782 DI 10.1093/nar/gkh313 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807FK UT WOS:000220487200023 PM 15031317 ER PT J AU Cusack, G Jones-Wells, A Chisholm, L AF Cusack, G Jones-Wells, A Chisholm, L TI Patient intensity in an ambulatory oncology research center: A step forward for the field of ambulatory care SO NURSING ECONOMICS LA English DT Article ID CLASSIFICATION AB In part one of this three-part series the authors discuss the current thinking in acuity/intensity tools and outline the process that one organization pursued to develop their own Ambulatory Intensity System (AIS). Based upon a review of the literature and current industry practices, the group pursued the development of a patient intensity system that reflected both the severity of patient illness/need and the complexity of service required in the, clinic setting. Direct and indirect care measures, patient outcomes, performance improvement opportunities, and staff satisfaction were also addressed in the process. The staff satisfaction data revealed the value that the staff derived through the tool. Specifically, the staff gained the ability to articulate patient needs and distinguish between system and staffing issues while the charge nurse gained the ability to make dynamic staffing assignments. C1 NIH, Warren G Magnuson Clin Ctr, Crit & Acute Care Serv, Bethesda, MD 20892 USA. RP Cusack, G (reprint author), NIH, Warren G Magnuson Clin Ctr, Crit & Acute Care Serv, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 10 Z9 11 U1 0 U2 1 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD MAR-APR PY 2004 VL 22 IS 2 BP 58 EP 63 PG 6 WC Nursing SC Nursing GA 046GT UT WOS:000237800200002 PM 15108473 ER PT J AU Ulrich, CM Grady, C AF Ulrich, CM Grady, C TI Financial incentives and response rates in nursing research SO NURSING RESEARCH LA English DT Editorial Material C1 Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Ulrich, CM (reprint author), Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. EM culrich@nursing.upenn.edu NR 6 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2004 VL 53 IS 2 BP 73 EP 74 DI 10.1097/00006199-200403000-00001 PG 2 WC Nursing SC Nursing GA 814ZG UT WOS:000221012000001 PM 15084990 ER PT J AU Raymond, EG Chen, PL Luoto, J AF Raymond, EG Chen, PL Luoto, J CA Spermicide Trial Grp TI Contraceptive effectiveness and safety of five nonoxynol-9 spermicides: A randomized trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BACTERIAL VAGINOSIS; INFECTION; RATES AB OBJECTIVES: To estimate and compare the effectiveness and safety of 5 spermicides over 6 and 7 months of use, respectively. The spermicides included 3 gels containing 52.5 mg, 100 mg, and 150 mg of nonoxynol-9 per dose and a film and a suppository, each containing 100 mg of nonoxynol-9 per dose. METHODS: Women wishing to use only spermicide for contraception for 7 months were randomly assigned to use I of the 5 spermicides with emergency contraception backup. Participants were followed up for up to 30 weeks after admission. RESULTS: Of 1,536 women enrolled, 868 (57%) either relied on the spermicide for 6 months or became pregnant. The probability of pregnancy during 6 months of typical use of the spermicide was 22% (95% confidence limits 16%, 28%) in the 52.5-mg gel group, 16% (10%,21%) in the 100-mg gel group, 14% (9%, 19%) in the 150-mg gel group, 12% (7%, 17%) in the film group, and 10% (6%,15%) in the suppository group. The pregnancy risk in the 52.5-mg gel group was significantly different (P < .05) from that in either of the other gel groups. The pregnancy risks in the three 100-mg product groups were not significantly different (P = .35). No significant differences among groups were found in the 7-month probability of specified urogenital conditions. CONCLUSION: The gel with the lowest amount of nonoxynol-9 was less effective than the 2 higher-dose gels. Among 3 products containing 100 mg of nonoxynol-9, formulation did not significantly affect pregnancy risk. All products were safe. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Family Hlth Int, Div Clin Res, Res Triangle Pk, NC 27709 USA. NICHHD, Rockville, MD USA. RP Raymond, EG (reprint author), Family Hlth Int, Div Clin Res, POB 13950, Res Triangle Pk, NC 27709 USA. EM eraymond@fhi.org FU NICHD NIH HHS [N01 HD 73271] NR 15 TC 32 Z9 32 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2004 VL 103 IS 3 BP 430 EP 439 DI 10.1097/01.AOG.0000113620.18395.0b PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 809OO UT WOS:000220646200005 PM 14990402 ER PT J AU Raghunathan, A Price, ND Galperin, MY Makarova, KS Purvine, S Picone, AF Cherny, T Xie, T Reilly, TJ Munson, R Tyler, RE Akerley, BJ Smith, AL Palsson, BO Kolker, E AF Raghunathan, A Price, ND Galperin, MY Makarova, KS Purvine, S Picone, AF Cherny, T Xie, T Reilly, TJ Munson, R Tyler, RE Akerley, BJ Smith, AL Palsson, BO Kolker, E TI In silico metabolic model and protein expression of Haemophilus influenzae strain Rd KW20 in rich medium SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; ESCHERICHIA-COLI; SIGNAL-TRANSDUCTION; STATISTICAL-MODEL; GENOME; PURIFICATION; KINASE; GENES; IDENTIFICATION; DEHYDROGENASE AB The intermediary metabolism of Haemophilus influenzae strain Rd KW20 was studied by a combination of protein expression analysis using a recently developed direct proteomics approach, mutational analysis, and mathematical modeling. Special emphasis was placed on carbon utilization, sugar fermentation, TCA cycle, and electron transport of H. influenzae cells grown microaerobically and anaerobically in a rich medium. The data indicate that several H. influenzae metabolic proteins similar to Escherichia coli proteins, known to be regulated by low concentrations of oxygen, were well expressed in both growth conditions in H. influenzae. An in silico model of the H. influenzae metabolic network was used to study the effects of selective deletion of certain enzymatic steps. This allowed us to define proteins predicted to be essential or non-essential for cell growth and to address numerous unresolved questions about intermediary metabolism of H. influenzae. Comparison of data from in vivo protein expression with the protein list associated with a genome-scale metabolic model showed significant coverage of the known metabolic proteome. This study demonstrates the significance of an integrated approach to the characterization of H. influenzae metabolism. C1 BIATECH, Bothell, WA 98011 USA. Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO USA. Childrens Res Inst, Columbus, OH 43210 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01605 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. RP Kolker, E (reprint author), BIATECH, 19310 N Creek Pkwy,Ste 115, Bothell, WA 98011 USA. EM ekolker@biatech.org RI Akerley, Brian/B-7343-2008; Kolker, Eugene/C-6711-2008; Munson, Jr, Robert/E-3710-2011; Galperin, Michael/B-5859-2013 OI Akerley, Brian/0000-0002-8142-7035; Munson, Jr, Robert/0000-0002-3204-3019; Galperin, Michael/0000-0002-2265-5572 FU NIAID NIH HHS [AI44002]; NIDCD NIH HHS [DC005980, DC03915] NR 59 TC 27 Z9 29 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD SPR PY 2004 VL 8 IS 1 BP 25 EP 41 DI 10.1089/153623104773547471 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 832CO UT WOS:000222245000004 PM 15107235 ER PT J AU Kaplan, RS Schoenfeldt, M AF Kaplan, RS Schoenfeldt, M TI Current Clinical Trials in CNS tumors SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID CHEMOTHERAPY; SURVIVAL C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Kaplan, RS (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2004 VL 18 IS 3 BP 322 EP + PG 4 WC Oncology SC Oncology GA 052DF UT WOS:000238210600014 PM 15065702 ER PT J AU Cusack, G Bevans, M Mayberry, H Scott, K AF Cusack, G Bevans, M Mayberry, H Scott, K TI A collaborative practice model for hematology/oncology and transplant care. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 56 BP 395 EP 395 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400076 ER PT J AU Lee, C AF Lee, C TI Adverse reactions in CAM cancer care: Support for widespread evidence-based practice (EBP) interventions. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NCI, Off Canc COmplementary & Alternat Med, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 80 BP 402 EP 402 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400100 ER PT J AU Cogswell, J Morales, E Duque, L Davis, C AF Cogswell, J Morales, E Duque, L Davis, C TI Interpretation of PSA lab values in sexually active men with prostate cancer: The role of nursing assessment. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 96 BP 407 EP 408 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400118 ER PT J AU deCarvalho, M Herringa, C AF deCarvalho, M Herringa, C TI The cancer nurse internship: A model for professional development. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 191 BP 434 EP 434 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400211 ER PT J AU Rivera, P Hawks, G AF Rivera, P Hawks, G TI Effective strategies to ensure quality care for Spanish speaking patients. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 227 BP 445 EP 445 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400247 ER PT J AU Carroll, E Antill, MW AF Carroll, E Antill, MW TI When things get stuck: Getting a research study moving. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 230 BP 446 EP 446 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400250 ER PT J AU O'Mara, A Padberg, RM Westendorp, J AF O'Mara, A Padberg, RM Westendorp, J TI Ensuring the success of symptom management trials in the community setting: The critical roles that oncology nurses SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Kalamazoo CCOP, Kalamazoo, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2004 VL 31 IS 2 MA 238 BP 448 EP 448 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 875RC UT WOS:000225438400258 ER PT J AU Sen, HN Chan, CC Caruso, RC Fariss, RN Nussenblatt, RB Buggage, RR AF Sen, HN Chan, CC Caruso, RC Fariss, RN Nussenblatt, RB Buggage, RR TI Waldenstrom's macroglobulinemia - Associated retinopathy SO OPHTHALMOLOGY LA English DT Article ID RECOVERIN-ASSOCIATED RETINOPATHY; OCULAR MANIFESTATIONS; MULTIPLE-MYELOMA; OCCLUSION; PATIENT; DISEASE; EYE AB Objective: To report the clinical, electrophysiologic, and immunopathologic findings in a patient with progressive retinal degeneration associated with Waldenstrom's macroglobulinemia. Design: Case report with immunohistochemical studies. Methods: A 46-year-old female with elevated serum immunoglobulin M (IgM) levels complained of photophobia and photopsias. Complete ophthalmic examinations including electrophysiologic testing and hematologic evaluations were performed over a 3-year period. Immunohistochemical studies to determine the presence of serum antiretinal antibodies were evaluated using confocal microscopy. Results: Examination of the patient's fundus remained normal, although there was deterioration in her visual acuity, visual field, and electroretinogram over the follow-up period. Waldenstrom's macroglobulinemia was diagnosed by bone marrow biopsy. Indirect immunohistochemistry revealed reactivity of the patient's serum against the photoreceptor-connecting cilium. Conclusion: The paraneoplastic retinopathy associated with Waldenstrom's macroglobulinemia in this patient is presumed to result from antibodies of the IgM subtype reacting to proteins in the retinal photoreceptors. (C) 2004 by the American Academy of Ophthalmology. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Lab Mechanisms Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 17 TC 14 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2004 VL 111 IS 3 BP 535 EP 539 DI 10.1016/j.ophtha.2003.05.036 PG 5 WC Ophthalmology SC Ophthalmology GA 780BR UT WOS:000189351800021 PM 15019332 ER PT J AU Gannot, G Buchner, A Keisari, Y AF Gannot, G Buchner, A Keisari, Y TI Interaction between the immune system and tongue squamous cell carcinoma induced by 4-nitroquinoline N-oxide in mice SO ORAL ONCOLOGY LA English DT Article DE carcinoma; cytokines; immune infiltrate; 4NQO; mice ID ORAL-CAVITY TUMORS; NECK-CANCER; GROWTH-FACTOR; TNF-ALPHA; HEAD; EXPRESSION; CARCINOGENESIS; MECHANISMS; INDUCTION; CYTOKINES AB Squamous cell carcinoma of the oral cavity (SCC) accounts for 3% of cancers in the western world and 40% of cancers in India. The overall 5-year survival rate is only 50%. Most of the lesions appear intra-orally on the tongue. Results from a previous study demonstrated a significant increase in T and B-lymphocytes under the transformed epithelium when examining human lesions of hyperkeratosis, dysplasia and carcinoma of the tongue. In order to investigate the interaction between the host immunity and SCC, carcinogen induced SCC of the tongue was studied in mice. The water-soluble carcinogen, 4 nitroquinoline N-oxide (4NQO), was applied to BALB/c mice tongues and produced tongue SCC after a long incubation period of several months. Immunologic properties were examined systemically in the spleens and locally, at the tumor site. Examination of spleen lymphocytes from 4NQO induced mice revealed enlargement of the spleens and a significant decrease in the CD3, CD4, CD8 and CD19 cells. In the tongues, expression of TGF-beta, TNF-alpha, GM-CSF, and IL-1beta mRNA were detected. TNF-alpha protein was detected in the affected tongues using immunoassays. mRNA expression of TNF-alpha was detected in the cancerous epithelium when extracted from the connective tissue. CD11b and CD3 cells were detected in the connective tissue under the developing carcinoma. CD11b positive cells were more prominent. The infiltrate was very scattered and not prominent as the infiltrate in the human tongue tissues. These results indicate that the growing tumor affected the immune response around the tumor and systemically. Most of the cytokines, which appeared in the affected tongues, originated from the tumor surroundings, but TNF-a was found also in the tumor. The interaction between the tumor and immune response components is important for diagnosis and treatment purposes. (C) 2003 Elsevier Ltd. All rights reserved. C1 Tel Aviv Univ, Maurice & Gabriela Goldschleger Sch Dent Med, Dept Oral Pathol & Oral Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Dept Human Microbiol, Tel Aviv, Israel. RP Gannot, G (reprint author), NCI, NIH, 10 Ctr Dr,Room 2C500, Bethesda, MD 20892 USA. EM gannotg@pop.nci.nih.gov NR 32 TC 10 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD MAR PY 2004 VL 40 IS 3 BP 287 EP 297 DI 10.1016/j.oraloncology.2003.08.008 PG 11 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 772LJ UT WOS:000188843100007 PM 14747060 ER PT J AU Seitzman, RL Glover, DA Meadows, AT Mills, JL Nicholson, HS Robison, LL Byrne, J Zeltzer, LK AF Seitzman, RL Glover, DA Meadows, AT Mills, JL Nicholson, HS Robison, LL Byrne, J Zeltzer, LK TI Self-concept in adult survivors of childhood acute lymphoblastic leukemia: A cooperative children's cancer group and national institutes of health study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia; cancer survivor; childhood cancer; self-concept ID LONG-TERM SURVIVORS; INTRATHECAL METHOTREXATE; CRANIAL IRRADIATION; SOCIAL COMPETENCE; ADJUSTMENT AB Background. Self-concept was compared between adult survivors of childhood acute lymphoblastic leukemia (ALL) and sibling controls. Adult survivor subgroups at greatest risk for negative self-concept were identified. Procedure. Survivors (n = 578) aged greater than or equal to 18 years, treated before age 20 years on Children's Cancer Group (CCG) ALL protocols, and 396 sibling controls completed a telephone interview and the Harter Adult Self-Perception Profile (ASPP). Results. Survivors global self-worth scores were significantly lower than sibling controls (mean 3.09 vs. 3.18; P=0.022). Unemployed survivors reported lower global self-worth scores than employed (mean 2.77 vs. 3.12; P = 0.0001), whereas employment status was not associated with self-worth in controls. Among survivors, predictors of negative self-concept included unemployment (odds ratio (OR) = 2.87; 95% CI: 1.50-5.50), and believing that cancer treatment limited employability (OR=3.17; 95% CI: 1.79-5.62). Unemployment increased the odds for negative self-concept among survivors who received combinations of central nervous system (CNS) irradiation (CRT) and intrathecal methotrexate (IT-MTX), except high CRT with no or low dose IT-MTX. Employed survivors who perceived that treatment limited their employability showed increased odds of negative self-concept for all treatment groups compared to those who did not. Minority ethnic group membership was a borderline significant predictor of negative self-concept (OR=1.79; 95% CI: 0.94-3.33). Conclusions. Global self-worth was significantly lower in ALL survivors than sibling controls, however, 81% Of Survivors had positive self-concept. Survivor subgroups most vulnerable to negative self-concept were the unemployed survivors, believing that cancer treatment affected employability, and ethnic minority group members. Targeted intervention may have greater clinical relevance for these subgroups. (C) 2003 Wiley-Liss, Inc. C1 Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. NICHHD, Epidemiol Branch, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Doernbecher Mem Hosp Children, Div Pediat Hematol Oncol, Portland, OR 97201 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. RP Seitzman, RL (reprint author), Care of Mason S, Childrens Oncocol Grp, POB 60012, Arcadia, CA 91066 USA. EM seitzman@ucla.edu OI Zeltzer, Lonnie/0000-0001-9306-9450 FU NCI NIH HHS [CA 02971, CA 07306, CA 14560, CA 28882, CA 79753, CA 42764, CA 26270, CA 20549, CA 02649, CA 11796, CA 13809, CA 17829, CA 27678, CA 29013, CA 55362] NR 26 TC 20 Z9 22 U1 2 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2004 VL 42 IS 3 BP 230 EP 240 DI 10.1002/pbc.10434 PG 11 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 812WE UT WOS:000220868800006 PM 14752860 ER PT J AU Bauer, TR Gu, YC Creevy, KE Tuschong, LM Embree, L Holland, SM Sokolic, RA Hickstein, DD AF Bauer, TR Gu, YC Creevy, KE Tuschong, LM Embree, L Holland, SM Sokolic, RA Hickstein, DD TI Leukocyte adhesion deficiency in children and Irish setter dogs SO PEDIATRIC RESEARCH LA English DT Review ID BONE-MARROW-TRANSPLANTATION; CELL TRANSPLANTATION; BETA-SUBUNIT; INFECTIONS; DISEASE; FAMILY; MODEL; LFA-1; CORD AB Children with the genetic immunodeficiency disease leukocyte adhesion deficiency, or LAD, develop life-threatening bacterial infections as a result of the inability of their leukocytes to adhere to the vessel wall and migrate to the sites of infection. Recently. the canine counterpart to LAD, known as canine leukocyte adhesion deficiency, or CLAD, has been described in Irish setter dogs. This review describes how the clinical phenotype of dogs with CLAD closely parallels that of children with the severe deficiency phenotype of LAD, thus enabling the CLAD dog to provide a disease-specific, large-animal model for testing novel hematopoietic stem cell and gene therapy strategies before their translation to children with LAD. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC1907,Bldg 10,Room 12C116, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov RI Sokolic, Robert/I-6072-2012 NR 30 TC 14 Z9 14 U1 3 U2 3 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2004 VL 55 IS 3 BP 363 EP 367 DI 10.1203/01.PDR.0000111287.74989.1B PG 5 WC Pediatrics SC Pediatrics GA 776HR UT WOS:000189111000002 PM 14711903 ER PT J AU Harada, H Bharwani, S Pavlick, KP Korach, KS Grisham, MB AF Harada, H Bharwani, S Pavlick, KP Korach, KS Grisham, MB TI Estrogen receptor-alpha sexual dimorphism and reduced-size liver ischemia and reperfusion injury in mice SO PEDIATRIC RESEARCH LA English DT Article ID NITRIC-OXIDE SYNTHASE; COA-REDUCTASE INHIBITORS; LOW-DENSITY-LIPOPROTEIN; ENDOTHELIAL-CELLS; ISCHEMIA/REPERFUSION INJURY; GENDER DIFFERENCES; NO SYNTHASE; TRANSPLANTATION; GENE; EXPRESSION AB Estrogen (E-2) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-alpha or ER-beta. The role that these E-2 receptors play in mediating the protective effects observed in RSL+I/R induced injury remains to be defined. To study the role of ER-alpha, we anesthetized female and male wild type (wt; C57131/6) and ER-alpha-deficient (alphaERKO) mice and subjected them to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of the ischernic tissue. For some experiments, wt and alphaERKO male mice were injected with E-2. Survival was monitored on a daily basis while liver injury was assessed by quantifying serum alanine aminotransferase (ALT) levels and histopathology. Hepatic eNOS mRNA levels were evaluated using semi-quantitative RT-PCR. Our data showed that untreated females or males treated with E-2 survived RSL+I/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in alphaERKO female mice such that only 40% of alphaERKO females survived 7 d following RSL+I/R. Furthermore, liver injury was significantly higher in alphaERKO females compared with their wt counterparts and similar to those seen in wild type males and alphaERKO males. The protective effect observed in wild type females or E-2 treated males correlated well with increases in hepatic eNOS message whereas both male and female alphaERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E-2/ER-alpha-mediated activation of eNOS. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, Shreveport, LA 71130 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. NIH, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. RP Bharwani, S (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, 1501 Kings Hwy,Med Sch Bldg 4-315, Shreveport, LA 71130 USA. EM sbharw@lsuhsc.edu OI Bharwani, Sulaiman/0000-0002-2651-2640; Korach, Kenneth/0000-0002-7765-418X FU NIDDK NIH HHS [DK43875, DK47663] NR 47 TC 20 Z9 20 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2004 VL 55 IS 3 BP 450 EP 456 DI 10.1203/01.PDR.0000110524.88784.DD PG 7 WC Pediatrics SC Pediatrics GA 776HR UT WOS:000189111000017 PM 14711905 ER PT J AU Llanos, AR Mena, P Lin, Y Salem, N Uauy, R AF Llanos, AR Mena, P Lin, Y Salem, N Uauy, R TI Essential fatty acids metabolism (EFA) in the full term newborn: Equivalence of precursors and intermediaries in the synthesis of N-6 and N-3 long chain polyunsaturated fatty acids (LCP) SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT 41st Annual Meeting of the Latin-American-Society-for-Paediatric-Research (LASPR) CY OCT, 2003 CL MARBELLA, CHILE C1 Univ Chile, INTA, Santiago, Chile. NIAAA, Rockville, MD 20852 USA. NEORED Neonatal Network, Santiago, Chile. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2004 VL 55 IS 3 MA 22 BP 531 EP 531 PG 1 WC Pediatrics SC Pediatrics GA 776HR UT WOS:000189111000050 ER PT J AU Oh, W Vohr, BR Tyson, JE Fanaroff, AA Stoll, BJ Ehrenkranz, RA Carlo, W Shankaran, S Poole, K Wright, L AF Oh, W Vohr, BR Tyson, JE Fanaroff, AA Stoll, BJ Ehrenkranz, RA Carlo, W Shankaran, S Poole, K Wright, L TI Importance of bilirubin effect questioned - Reply SO PEDIATRICS LA English DT Letter C1 Brown Univ, Providence, RI 02912 USA. Univ Texas, Houston Med Sch, Houston, TX 77030 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Emory Univ, Atlanta, GA 30322 USA. Yale Univ, New Haven, CT 06520 USA. Univ Alabama, Tuscaloosa, AL 35487 USA. Wayne State Univ, Detroit, MI 48202 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NICHD, Rockville, MD 20847 USA. RP Oh, W (reprint author), Brown Univ, Providence, RI 02912 USA. NR 1 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 MAR 1 PY 2004 VL 113 IS 3 BP 627 EP 628 PG 3 WC Pediatrics SC Pediatrics GA 779ZT UT WOS:000189344400040 ER PT J AU Lester, BM Tronick, EZ LaGasse, L Seifer, R Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Lu, J AF Lester, BM Tronick, EZ LaGasse, L Seifer, R Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Lu, J TI Summary statistics of Neonatal Intensive Care Unit Network Neurobehavioral Scale scores from the maternal lifestyle study: A quasinormative sample SO PEDIATRICS LA English DT Article DE MLS; multisite; NNNS; neurobehavioral; norms; prenatal dry exposure; summary scores ID PRENATAL COCAINE EXPOSURE; SUBSTANCE EXPOSURE; PREGNANCY; MECONIUM; OUTCOMES AB Descriptive statistics for the Neonatal Intensive Care Unit Network Neurobehavioral Scale summary scores are provided based on data from 1388 1-month-old infants in the Maternal Lifestyle Study (MLS) of prenatal drug exposure and child outcome. The multisite MLS is described, followed by tables with descriptive statistics and percentile for the Neonatal Intensive Care Unit Network Neurobehavioral Scale summary scores. The tables include data for the entire MLS sample as well as tables by drug exposure status, gestational age, poverty status, sex, race and ethnicity, and MLS study site. These tables can be used as quasinorms for comparison with other infants of this age. C1 Brown Univ, Women & Infants Hosp, Sch Med, Infant Dev Ctr, Providence, RI 02903 USA. Bradley Hosp, Providence, RI USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat,Child Dev Unit, Boston, MA 02115 USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Univ Miami, Sch Med, Miami, FL USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Tennessee, Sch Med, Memphis, TN 38163 USA. NICHHD, Bethesda, MD 20892 USA. NIDA, Bethesda, MD 20892 USA. RP Lester, BM (reprint author), Brown Univ, Women & Infants Hosp, Sch Med, Infant Dev Ctr, 79 Plain St,2nd Fl, Providence, RI 02903 USA. EM barry_lester@brown.edu OI Seifer, Ronald/0000-0003-4879-2839 FU NICHD NIH HHS [U10 HD 27856, N01-HD-2-3159, U10 HD 21385, U10 HD 21397, U10 HD 27904]; NIDA NIH HHS [U10 DA024119] NR 11 TC 20 Z9 20 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR 1 PY 2004 VL 113 IS 3 SU S BP 668 EP 675 PG 8 WC Pediatrics SC Pediatrics GA 779ZU UT WOS:000189344500005 PM 14993525 ER PT J AU Veasy, LG Tani, LY Daly, JA Korgenski, K Miner, L Bale, J Kaplan, EL Musser, JM Hill, HR AF Veasy, LG Tani, LY Daly, JA Korgenski, K Miner, L Bale, J Kaplan, EL Musser, JM Hill, HR TI Temporal association of the appearance of mucoid strains of Streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah SO PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY MAY 04, 2003 CL Seattle, WA SP Pediat Acad Soc DE rheumatic fever; mucoid strains; Streptococcus pyogenes ID RESURGENCE; DISEASE; OUTBREAK; CITY; AREA AB Objective. Our objective was to confirm an observed temporal association of increased numbers of rheumatic fever cases concomitant with the appearance of an increased prevalence of mucoid strains of Streptococcus pyogenes. During the resurgence of rheumatic fever (RF) that has occurred in the Intermountain area surrounding Salt Lake City, Utah, since 1985, the largest number of cases occurred in 1985 and 1986 and 12 years later in 1997 and 1998. During the initial outbreak and the later exacerbation of the resurgence, an increased number of mucoid strains of S pyogenes were present in the community. Methods. The referred cases of RF that fulfilled Jones criteria have been systematically reviewed by the medical staff at Primary Children's Medical Center yearly since 1985. Before the resurgence of RF, a program was initiated by the microbiology laboratory at Primary Children's Medical Center to store frozen isolates of S pyogenes. All frozen specimens were randomly selected and entered into a log; the coded entry allowed for comments regarding the origin of the isolate and whether the isolate had a mucoid appearance on the blood agar culture plate. This log was reviewed in October 2002 to determine whether the percentage of frozen mucoid isolates stored during the resurgence of RF would support the clinical and epidemiologic suspicion that mucoid isolates seemed to be present with a higher frequency during the 2 periods of high incidence of RF. The percentage of mucoid isolates was compared with the yearly number of cases of RF. A Pearson r correlation analysis was completed to determine whether there was a significant association between the percentage of mucoid isolates and the number of cases of RF. Results. The highest number of cases of RF was temporally associated with the highest percentage of mucoid isolates. There was statistically significant correlation between percentage of mucoid strains and the number of RF cases. Conclusions. The Utah experience with the resurgence of RF in a civilian population during the last decade and a half of the 20th century confirmed the temporal association of mucoid strains of S pyogenes, primarily M-type 18, with a high incidence of RF. C1 Univ Utah, Sch Med, Dept Pediat, Primary Childrens Med Ctr, Salt Lake City, UT 84113 USA. Univ Utah, Sch Med, Dept Med, Salt Lake City, UT USA. Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Veasy, LG (reprint author), Univ Utah, Sch Med, Dept Pediat, Primary Childrens Med Ctr, 100 N Med Dr, Salt Lake City, UT 84113 USA. EM george.veasy@hsc.utah.edu FU PHS HHS [A022749] NR 28 TC 47 Z9 48 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR 1 PY 2004 VL 113 IS 3 BP E168 EP E172 DI 10.1542/peds.113.3.e168 PG 5 WC Pediatrics SC Pediatrics GA 779ZT UT WOS:000189344400047 PM 14993572 ER PT J AU Aguilera, G Nikodemova, M Wynn, PC Catt, KJ AF Aguilera, G Nikodemova, M Wynn, PC Catt, KJ TI Corticotropin releasing hormone receptors: two decades later SO PEPTIDES LA English DT Review DE pituitary corticotroph; corticotropin releasing hormone (CRH); type 1 CRH receptor (CRHR1); CRHR1 mRNA; CRHR1 regulation; translation ID MESSENGER-RIBONUCLEIC-ACID; IMPAIRED STRESS-RESPONSE; FACTOR CRF RECEPTORS; CENTRAL-NERVOUS-SYSTEM; ANXIETY-LIKE BEHAVIOR; BINDING-PROTEIN; RAT PITUITARY; HOMOLOGOUS DESENSITIZATION; GLUCOCORTICOID REGULATION; DIFFERENTIAL REGULATION AB Hypothalamic corticotropin releasing hormone (CRH) regulates pituitary ACTH secretion and mediates behavioral and autonomic responses to stress, through interaction with type I plasma membrane receptors (CRHR1) located in pituitary corticotrophs and the brain. Although CRHR1 are essential for ACTH responses to stress, their number in the pituitary gland does not con-elate with corticotroph responsiveness, suggesting that activation of a small number of receptors is sufficient for maximum ACTH production. CRH binding and hybridization studies in adrenalectomized, glucocorticoid-treated or stressed rats revealed divergent changes in CRH receptors and CRHR1 mRNA in the pituitary, with a reduction in receptor binding but normal or elevated expression of CRHR1 mRNA levels. Western blot analysis of CRHR1 protein in pituitary membranes from adrenalectomized rats showed unchanged receptor mRNA levels and increased CRHR1 protein, despite the binding down-regulation, suggesting that decreased binding is due to homologous desensitization, rather than reduced receptor synthesis. In contrast, decreased CRH binding following glucocorticoid administration is associated with a reduction in CRHR1 protein. suggesting inhibition of CRHR1 mRNA translation. The regulation of CRHR1 translation may involve binding of cytosolic proteins, and a minicistron in the 5'-UTR of the CRHR1 mRNA. It is likely that post-transcriptional regulatory mechanisms that permit rapid changes in CRH receptor activity are important for adaptation of corticotroph responsiveness to continuous changes in physiological demands. (C) 2004 Elsevier Inc. All rights reserved. C1 NICHHD, Sect Endrocrine Physiol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Univ Sydney, Fac Vet Sci, Camden, NSW 2570, Australia. NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD USA. RP Aguilera, G (reprint author), NICHHD, Sect Endrocrine Physiol, Dev Endocrinol Branch, 10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. EM Greti_Aguilera@nih.gov NR 89 TC 84 Z9 90 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD MAR PY 2004 VL 25 IS 3 BP 319 EP 329 DI 10.1016/j.peptides.2004.02.002 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 823RK UT WOS:000221630500002 PM 15134857 ER PT J AU Jacobowitz, DM Kresse, A Skofitsch, G AF Jacobowitz, DM Kresse, A Skofitsch, G TI Galanin in the brain: chemoarchitectonics and brain cartography - a historical review SO PEPTIDES LA English DT Review DE galanin; brain; histochemistry; brain cartography; chemoarchitectonics; brain maps; Neuropeptides; in situ hybridization histochemistry; brain atlas; colocalization; gene expression ID CENTRAL-NERVOUS-SYSTEM; GENE-RELATED PEPTIDE; ATRIAL-NATRIURETIC-FACTOR; ACETYLCHOLINESTERASE-CONTAINING NEURONS; VASOACTIVE INTESTINAL POLYPEPTIDE; MELANOCYTE STIMULATING HORMONE; FACTOR-LIKE IMMUNOREACTIVITY; CAPSAICIN SENSITIVE NEURONS; BASAL FOREBRAIN COMPLEX; DORSAL-ROOT GANGLIA AB We present a review of galanin in the brain from a historical perspective of the development of "chemoarchitectonics" and "brain cartography" accomplished in the Histopharmacology Section at the National Institutes of Health. It was the mapping of potential brain neuroregulators that served as a springboard of ideas from which behavioral studies emanate. The integration of the known localization of neurotransmitter/neuromodulatory nerves ("chemoarchitectonic maps") and receptor binding sites with biochemical data derived from brain micropunches Coupled with behavioral analysis at the level of discrete brain allows one to define the anatomical circuits which support behavioral changes and which ultimately will improve our understanding of mental disorders. (C) 2004 Elsevier Inc. All rights reserved. C1 NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Graz Univ, Dept Zool, Sect Wildlife Res & Parasitol, A-1080 Graz, Austria. RP Jacobowitz, DM (reprint author), NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. EM dwj@helix.nih.gov NR 101 TC 40 Z9 45 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD MAR PY 2004 VL 25 IS 3 BP 433 EP 464 DI 10.1016/j.peptides.2004.02.015 PG 32 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 823RK UT WOS:000221630500011 PM 15134866 ER PT J AU Moody, TW Merali, Z AF Moody, TW Merali, Z TI Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications SO PEPTIDES LA English DT Review DE bombesin; gastrin-releasing peptide; neuromedin B; rat CNS; behavior ID GASTRIN-RELEASING-PEPTIDE; CELL LUNG-CANCER; NEUROMEDIN-B RECEPTOR; CENTRAL-NERVOUS-SYSTEM; DECREASES FOOD-INTAKE; RAT-BRAIN; HIGH-AFFINITY; MESSENGER-RNAS; MICE LACKING; BIOCHEMICAL-CHARACTERIZATION AB As we commemorate the 25th anniversary of the journal Peptides, it is timely to review the functional significance of the bombesin (BB)-like peptides and receptors in the CNS. Over two decades ago we published an article in the journal Peptides demonstrating that BB-like peptides are present in high densities in certain rat brain regions (such as the paraventricular nucleus of the hypothalamus). Subsequently, one of the mammalian forms of BB, gastrin-releasing peptide (GRP) containing cell bodies were found in the suprachiasmatic nucleus of the hypothalamus and nucleus of the solitary tract of the hindbrain. Another related peptide, namely neuromedin (NM)B, was detected in the olfactory bulb and dentate gyrus. BB and GRP bind with high affinity to BB2 receptors, whereas NMB binds with high affinity to BB1 receptors. The actions of BB or GRP are blocked by BB2 receptor antagonists such as (pSi(13.14)-Leu(14))BB whereas PD 168368 is a BB1 receptor antagonist. Exogenous administration of BB into the rat brain causes hypothermia, hyperglycemia, grooming and satiety. BB-like peptides activate the sympathetic nervous system and appear to modulate stress, fear and anxiety responses. GRP and NMB modulate distinct biological processes through discrete brain regions or circuits, and globally these peptidergic systems may serve in an integrative or homeostatic function. Crown Copyright (C) 2004 Published by Elsevier Inc. All rights reserved. C1 NCI, DHHS, NIH, Off Director,CCR, Bethesda, MD 20892 USA. Univ Ottawa, Mental Hlth Res Inst, Ottawa, ON K1N 6N5, Canada. RP Moody, TW (reprint author), NCI, DHHS, NIH, Off Director,CCR, Room 3A34,Bldg 31,31 Ctr Dr, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov NR 111 TC 71 Z9 76 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD MAR PY 2004 VL 25 IS 3 BP 511 EP 520 DI 10.1016/j.peptides.2004.02.012 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 823RK UT WOS:000221630500015 PM 15134870 ER PT J AU Kaftarian, S Robinson, E Compton, W Davis, BW Volkow, N AF Kaftarian, S Robinson, E Compton, W Davis, BW Volkow, N TI Blending prevention research and practice in schools: Critical issues and suggestions SO PREVENTION SCIENCE LA English DT Editorial Material C1 NIDA, NIH, Bethesda, MD 20892 USA. Subst Abuse & Mental Hlth Serv Adm, Ctr Subst Abuse Prevent, Kensington, MD USA. RP Kaftarian, S (reprint author), NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM jkaftari@nida.nih.gov NR 1 TC 20 Z9 20 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD MAR PY 2004 VL 5 IS 1 BP 1 EP 3 DI 10.1023/B:PREV.0000013975.74774.bc PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 832BJ UT WOS:000222241900001 PM 15058906 ER PT J AU Rutten, LJF Nelson, DE Meissner, HI AF Rutten, LJF Nelson, DE Meissner, HI TI Examination of population-wide trends in barriers to cancer screening from a diffusion of innovation perspective (1987-2000) SO PREVENTIVE MEDICINE LA English DT Article DE mammography; mammography screening; pap screening; colorectal screening ID HEALTH INTERVIEW SURVEY; COLORECTAL-CANCER; BREAST-CANCER; CERVICAL-CANCER; UNITED-STATES; MAMMOGRAPHY; WOMEN; SIGMOIDOSCOPY; MORTALITY; PROGRESS AB Background. Barriers to cancer screening may change over time as screening becomes more widespread. Methods. Using 1987, 1992, and 2000 National Health Interview Survey data, we examined population-wide trends in barriers to Pap, mammography, and colorectal screening (n =66,452). Results. Lack of awareness was the most common barrier for all screening tests; it decreased by 13.5 percentage points for mammography and by 4.6 percentage points for colorectal screening, but increased by 3.0 percentage points for Pap test from 1987 to 2000. Decreases in not recommended by a doctor were observed for mammography (from 20.5% to 3.7%) and colorectal screening (from 22.3% to 14.2%). Examination of trends in barriers among sociodemographic and health care access subgroups revealed disparities for each screening test. Conclusions. Although population-wide progress has been made in reducing barriers to screening, lack of awareness, and not recommended by a doctor remain important barriers, especially among traditionally underserved populations. (C) 2003 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA 30341 USA. NCI, Appl Canc Screening Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Rutten, LJF (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Prevent, 6130 Execut Blvd,4051A MSC 7365, Bethesda, MD 20892 USA. EM finneyl@mail.nih.gov NR 44 TC 56 Z9 56 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD MAR PY 2004 VL 38 IS 3 BP 258 EP 268 DI 10.1016/j.ypmed.2003.10.011 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 773JV UT WOS:000188921400002 ER PT J AU Tuo, JS Bojanowski, CM Chan, CC AF Tuo, JS Bojanowski, CM Chan, CC TI Genetic factors of age-related macular degeneration SO PROGRESS IN RETINAL AND EYE RESEARCH LA English DT Review ID SORSBY FUNDUS DYSTROPHY; RETINAL-PIGMENT EPITHELIUM; LOW-DENSITY-LIPOPROTEIN; STARGARDT-DISEASE GENE; APOLIPOPROTEIN-E GENE; PERIPHERIN-RDS GENE; TISSUE INHIBITOR; ALLELIC VARIATION; BEST-DISEASE; MOUSE MODEL AB Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies. Published by Elsevier Ltd. C1 NEI, Immunol Lab, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunol Lab, Immunopathol Sect, NIH, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000418-04] NR 174 TC 56 Z9 59 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-9462 J9 PROG RETIN EYE RES JI Prog. Retin. Eye Res. PD MAR PY 2004 VL 23 IS 2 BP 229 EP 249 DI 10.1016/j.preteyers.2004.02.001 PG 21 WC Ophthalmology SC Ophthalmology GA 819AU UT WOS:000221286400004 PM 15094132 ER PT J AU Veech, RL AF Veech, RL TI The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Review ID NICOTINAMIDE-ADENINE DINUCLEOTIDE; AMYLOID PRECURSOR PROTEIN; BETA-HYDROXYBUTYRATE; ALZHEIMERS-DISEASE; RAT-BRAIN; PEDIATRIC-PATIENTS; ENERGY-METABOLISM; GLUCOSE; HEART; MICE AB The effects of ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present in D-beta-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the DeltaG' of ATP hydrolysis. The large categories of disease for which ketones may have therapeutic effects are: (1) diseases of substrate insufficiency or insulin resistance, (2) diseases resulting from free radical damage, (3) disease resulting from hypoxia. Current ketogenic diets are all characterized by elevations of free fatty acids, which may lead to metabolic inefficiency by activation of the PPAR system and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of ketone bodies themselves or their esters may obviate this present difficulty. Published by Elsevier Ltd. C1 NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20850 USA. RP Veech, RL (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 12501 Washington Ave, Rockville, MD 20850 USA. EM rveech@mail.nih.gov NR 75 TC 220 Z9 225 U1 7 U2 50 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD MAR PY 2004 VL 70 IS 3 BP 309 EP 319 DI 10.1016/j.plefa.2003.09.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 776AE UT WOS:000189092200009 PM 14769489 ER PT J AU Hou, EW Prasad, R Beard, WA Wilson, SH AF Hou, EW Prasad, R Beard, WA Wilson, SH TI High-level expression and purification of untagged and histidine-tagged HIV-1 reverse transcriptase SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE HIV-1; heterodimer; DNA polymerase; expression; subunit-specific mutagenesis ID IMMUNODEFICIENCY-VIRUS TYPE-1; ALANINE-SCANNING MUTAGENESIS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; DNA; HETERODIMER; SUBUNITS; BINDING; DIMERIZATION; RESISTANCE AB We have devised simplified protocols to purify large quantities of histidine-tagged (His-tagged) and untagged heterodimeric forms of human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT). Here, we report the optimization of overexpressim and purification of heterodimeric RT expressed in Escherichia coli. The coding sequences of p66 and p51 subunits of RT were amplified using PCR from HXB2 HIV-1 and cloned into a bacterial expression system. The resulting expression plasmids for the RGamma subunits, pET-RT66 and pET-RT51, were under a strong T7/lac promoter that is induced by isopropyl-beta-D-thiogalactopyranoside. Purification of heterodimeric forms of RT was facilitated by high-level expression of these subunits that represented approximately 30-40% of total cell protein. For purification of the His-tagged heterodimeric RT, cell pellet from cells expressing the untagged p66 subunit was mixed in excess with a cell pellet expressing tagged p51. For untagged heterodimeric RT, the pellet from cells expressing p51 was mixed in excess with pellet expressing p66. Subunit dimerization occurred during cell lysis. During the subsequent chromatography steps, stable p66/p51 heterodimer was purified to homogeneity. The heterodimeric nature of the final preparations of RT was confirmed by analytical gel filtration, mass spectrometry, and denaturing gel electrophoresis. Further, the sensitivity of these enzyme preparations to AZTTP indicated that the histidine tag had no effect on nucleoside inhibitor binding, nucleotide binding or insertion, or DNA binding, The application of these expression/purification methodologies represents a useful method to purify large quantities of heterodimeric RT for structural investigations and provides an efficient protocol to produce subunit-specific amino acid alterations necessary for unambiguous structure/function investigations. (C) 2003 Elsevier Inc. All rights reserved. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 28 TC 22 Z9 23 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2004 VL 34 IS 1 BP 75 EP 86 DI 10.1016/j.pep.2003.10.018 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 777ZL UT WOS:000189214300008 PM 14766302 ER PT J AU Banerjee-Basu, S Baxevanis, AD AF Banerjee-Basu, S Baxevanis, AD TI Structural analysis of disease-causing mutations in the P-subfamily of forkhead transcription factors SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE FOXP3; FOXP2; IPEX; speech disorders; molecular modeling; surface electrostatic potential ID DNA-BINDING DOMAIN; LYMPHEDEMA-DISTICHIASIS; IMMUNE DYSREGULATION; GENE-MUTATIONS; SEQUENCE; FOXP3; MOTIF; HEAD; POLYENDOCRINOPATHY; ENTEROPATHY AB Mutations in a number of forkhead transcription factors are associated with the development of inherited diseases in humans. Two closely related genes, FOXP2 and FOXP3, are implicated in two completely different human disorders. A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. Homology model building techniques were used to generate atomic structures of FOXP2 and FOXP3, using the solution structures of the forkhead domain of the adipocyte-transcription factor FREAC-11 and AFX as templates. The impact of these disease-causing missense mutations on the three-dimensional structure, stability, and surface electrostatic charge distribution of the forkhead domains is examined here. The missense mutations R553H in FOYCP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains. (C) 2004 Wiley-Liss, Inc. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM andy@nhgri.nih.gov NR 34 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAR 1 PY 2004 VL 54 IS 4 BP 639 EP 647 DI 10.1002/prot.10621 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 814MX UT WOS:000220979900005 PM 14997560 ER PT J AU Leak, LV Liotta, LA Krutzsch, H Jones, M Fusaroa, VA Ross, SJ Zhaos, YM Petricoin, EF AF Leak, LV Liotta, LA Krutzsch, H Jones, M Fusaroa, VA Ross, SJ Zhaos, YM Petricoin, EF TI Proteomic analysis of lymph SO PROTEOMICS LA English DT Article DE biomarkers; cancer; lymph; surface-enhanced laser desorption/ionization-time of flight-mass spectrometry ID HUMAN PROSTATE-CANCER; HUMAN-PLASMA PROTEINS; MASS-SPECTROMETRY; 2-DIMENSIONAL ELECTROPHORESIS; ANCHORING FILAMENTS; HEMOSTATIC FACTORS; DENDRITIC CELLS; FLUID; IMMUNODETECTION; GLYCOPROTEIN AB This report provides the first proteomic analysis of normal ovine lymph. By establishing the fact that lymph is more than an ultrafiltrate of blood plasma, it documents that the lymph proteome contains an array of proteins that differentiates it from plasma. The protein chip technology, surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS), two-dimensional gel electrophoresis (2-D PAGE) and MS, were employed to examine the protein expression profiles of ovine lymph. Using a weak cation exchange chip surface to assay lymph and plasma samples by SELDI-TOF-MS showed that the analysis of peak maps from lymph contained three protein peaks that were found only in lymph, while analysis of peak maps from plasma samples showed that five protein peaks were found only in plasma. Lymph and plasma samples showed eight peaks that were common to both. There were also more ions present in plasma than in lymph, which is consistent with the 2-D PAGE analysis. MS analysis of a large number of protein spots from 2-D PAGE gels of lymph produced MS/MS sequences for 18 proteins that were identified by searching against a comprehensive protein sequence database. As in plasma, large protein spots of albumin dominated the protein pattern in lymph. Other major proteins identified in 2-D PAGE gels of lymph included, fibrinogen alpha- and beta-chains, immunoglobulin G (IgG) heavy chain, serotransferrin precursor, lactoferrin, and apolipoprotein A-1. Two Proteins that were identified and were differentially expressed in lymph were glial fibrillary astrocyte acidic protein and neutrophil cytosol factor-1. By bringing the technologies of proteomics to bear on the analysis of lymph, it is possible to detect proteins in lymph that are quantitatively and qualitatively differentially expressed from those of plasma. C1 US FDA, Ctr Biol Evaluat & Res, Clin Proteom Program Therapeut Prot, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Ernest E Just Lab Cellular Med, Washington, DC 20059 USA. NHLBI, Lab Anim Surg, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75230 USA. RP Petricoin, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, Clin Proteom Program Therapeut Prot, 800 Rockville Pike,Bldg 29A,Room 2A17, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov NR 50 TC 48 Z9 51 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD MAR PY 2004 VL 4 IS 3 BP 753 EP 765 DI 10.1002/pmic.200300573 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 802QX UT WOS:000220179100019 PM 14997497 ER PT J AU Alexe, G Alexe, S Liotta, LA Petricoin, E Reiss, M Hammer, PL AF Alexe, G Alexe, S Liotta, LA Petricoin, E Reiss, M Hammer, PL TI Ovarian cancer detection by logical analysis of proteomic data SO PROTEOMICS LA English DT Article DE logical analysis of data; ovarian cancer ID PROSTATE-CANCER; BREAST-CANCER; SERUM; PATTERNS; IDENTIFICATION; PREDICTION; CARCINOMA; MARKERS; RISK AB A new type of efficient and accurate proteomic ovarian cancer diagnosis systems is proposed. The system is developed using the combinatorics and optimization-based methodology of logical analysis of data (LAD) to the Ovarian Dataset 8-7-02 (http://clinicalproteomics.steem.com), which updates the one used by Petricoin et al, in The Lancet 2002, 359, 572-577. This mass spectroscopy-generated dataset contains expression profiles of 15154 peptides defined by their mass/charge ratios (m/z) in serum of 162 ovarian cancer and 91 control cases. Several fully reproducible models using only 7-9 of the 15 154 peptides were constructed, and shown in multiple cross-validation tests (k-folding and leave-one-out) to provide sensitivities and specificities of up to 100%. A special diagnostic system for stage I ovarian cancer patients is shown to have similarly high accuracy. Other results: (i) expressions of peptides with relatively low m/z values in the dataset are shown to be better at distinguishing ovarian cancer cases from controls than those with higher m/z values; (ii) two large groups of patients with a high degree of similarities among their formal (mathematical) profiles are detected; (iii) several peptides with a blocking or promoting effect on ovarian cancer are identified. C1 Rutgers State Univ, Rutgers Ctr Operat Res, RUTCOR, Piscataway, NJ 08854 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, NIH, Clin Proteom Program,Dept Therapeut, Bethesda, MD 20014 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Inst Canc, Dept Med, New Brunswick, NJ USA. RP Hammer, PL (reprint author), Rutgers State Univ, Rutgers Ctr Operat Res, RUTCOR, 640 Bartholomew Rd, Piscataway, NJ 08854 USA. EM hammer@rutcor.rutgers.edu RI Reiss, Michael/A-8314-2009 NR 38 TC 54 Z9 56 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD MAR PY 2004 VL 4 IS 3 BP 766 EP 783 DI 10.1002/pmic.200300574 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 802QX UT WOS:000220179100020 PM 14997498 ER PT J AU Berman, DM Shih, LM Burke, LA Veenstra, TD Zhao, YM Conrads, TP Kwon, SW Hoang, V Yu, LR Zhou, M Kurman, RJ Petricoin, EF Liotta, LA AF Berman, DM Shih, LM Burke, LA Veenstra, TD Zhao, YM Conrads, TP Kwon, SW Hoang, V Yu, LR Zhou, M Kurman, RJ Petricoin, EF Liotta, LA TI Profiling the activity of G proteins in patient-derived tissues by rapid affinity-capture of signal transduction proteins (GRASP) SO PROTEOMICS LA English DT Article DE affinity capture; G protein signal transduction; mass spectrometry; ovarian carcinoma; protein-protein interactions ID GUANINE-NUCLEOTIDE EXCHANGE; GTP-BINDING PROTEIN; RHO-GTPASES; PROTEOMIC ANALYSIS; CANCER; SPECIFICITY; PATHWAYS; BIOLOGY AB The next phase in molecular medicine will require the ability to identify signal transduction events inside a cell, in the biologic context of the disease-host interface and at a given point in time. New technologies are needed to profile the activity of these signaling pathways in patient tissue rather than cultured cell lines since the tumor-host microenvironment influences the cellular proteome. We introduce such a technology, rapid affinity capture of signaling proteins (GRASP), to investigate the activity of signaling pathways from patient-derived carcinomas and benign epithelial surfaces and apply it to studying important signaling events in ovarian carcinoma. During the progression from benign ovarian epithelium to invasive carcinoma, there is loss of repression of Rho A as evidenced by its dissociation from its inhibitor, Rho Guanine Nucleotide Dissociation Inhibitor (RhoGDI). GRASP is more informative than simply profiling transcript or protein levels. Furthermore, GRASP coupled with mass spectrometry allowed us to identify a protein-binding partner of RhoGDI, demonstrating the power of this technology in the discovery of potentially novel protein-protein interactions. GRASP represents an advance in the field of proteomics as it detects protein interactions present in cells as they exist in their native tissue microenvironment. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21218 USA. NCI, SAIC Frederick, Frederick, MD 21701 USA. Univ Texas, SW Med Sch, Dept Biochem, Dallas, TX USA. US FDA, Ctr Biol Evaluat & Res, NCI, Clin Proteom Program, Bethesda, MD 20014 USA. RP Berman, DM (reprint author), NCI, Pathol Lab, NIH, 10-2N212,Ctr Dr, Bethesda, MD 20892 USA. EM bermand@mail.nih.gov RI Burke, Luke/C-7655-2011 NR 27 TC 11 Z9 11 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD MAR PY 2004 VL 4 IS 3 BP 812 EP 818 DI 10.1002/pmic.200300579 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 802QX UT WOS:000220179100023 PM 14997501 ER PT J AU Yan, J Feng, JN Goldman, D Cook, EH Craddock, N Jones, IR Heston, LL Sommer, SS AF Yan, J Feng, JN Goldman, D Cook, EH Craddock, N Jones, IR Heston, LL Sommer, SS TI Mutation scanning of the androgen receptor gene in patients with psychiatric disorders reveals highly conserved variants in alcoholic and phobia patients SO PSYCHIATRIC GENETICS LA English DT Article DE androgen receptor; schizophrenia; DOVAM-S; mutation detection ID MISSENSE MUTATIONS; DOVAM-S; SCHIZOPHRENIA; ASSOCIATION; SEQUENCE AB Sex steroids exert potent effects on mood and mental state in humans. They may contribute to the risk of psychiatric disorders. To investigate this hypothesis, coding and splice junction sequences of the androgen receptor gene were scanned in genomic DNA samples to search for variants affecting protein structure and expression (VAPSEs). Ninety-six schizophrenics, along with pilot samples of patients with bipolar disorder, attention-deficit hyperactivity disorder, alcoholism and autism were analyzed with DOVAM-S, a robotically enhanced, optimized form of single-strand conformation polymorphism analysis. A total of 669 kb of genomic sequence was analyzed. Two VAPSEs were identified: R726L was found in one of 17 scanned alcoholics, and P516S, a novel VAPSE, was identified in one of three phobia patients. There were no length trends of the CAG triplets associated with schizophrenia. R726L and P516S occur at highly conserved amino acids. Further study is required to assess whether these VAPSEs contribute to the risk of alcoholism or phobia or other diseases. Psychiatr Genet 14:57-60 (C) 2004 Lippincott Williams Wilkins. C1 City Hope Natl Med Ctr, Dept Mol Genet, Duarte, CA 91010 USA. City Hope Natl Med Ctr, Dept Mol Diagnosis, Duarte, CA 91010 USA. NIAAA, Dept Psychiat, NIH, Bethesda, MD USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Birmingham, Queen Elizabeth Psychiat Hosp, Div Neurosci, Birmingham B15 2QZ, W Midlands, England. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. RP Sommer, SS (reprint author), City Hope Natl Med Ctr, Dept Mol Genet, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sommerlab@coh.org RI Jones, Ian/B-4925-2009; turton, miranda/F-4682-2011; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Medical Research Council [G9810900] NR 18 TC 7 Z9 7 U1 0 U2 4 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 MAR PY 2004 VL 14 IS 1 BP 57 EP 60 DI 10.1097/01.ypg.0000084949.07075.d3 PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 809YA UT WOS:000220670800010 PM 15091318 ER PT J AU Ikemoto, S AF Ikemoto, S TI Unconditional hyperactivity and transient reinforcing effects of NMDA administration into the ventral tegmental area in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE reward; intracranial self-administration; locomotion; rearing; glycine binding site agonist; -serine; supramammillary nucleus ID METHYL-D-ASPARTATE; BRAIN-STIMULATION REWARD; IN-VIVO MICRODIALYSIS; NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; SELF-STIMULATION; DOPAMINE NEURONS; D-AMPHETAMINE; BEHAVIORAL SENSITIZATION; RECEPTOR AGONISTS AB Rationale. The dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens plays an important role in positive reinforcement and locomotion. Intra-VTA administration of many drugs capable of activating these neurons has been shown to be reinforcing and induce locomotion. Administration of the excitatory amino acid NMDA (N-methyl-D-aspartate) into the VTA may likewise be positively reinforcing, because it stimulates the meso-accumbens dopamine system and locomotion. Objectives and methods. Locomotor-rearing experiments were conducted to pinpoint the range of NMDA concentrations that induce significant locomotion and rearing, and to determine whether co-administration of the glycine binding site agonist d-serine would enhance the effects of NMDA administration into the VTA. Reinforcing effects of NMDA were assessed by intracranial self-administration procedures: a lever-press delivered a 75-nl infusion containing NMDA (0.1, 0.3 or 1.0 mM) plus serine into the VTA or an adjacent region, the supramammillary nucleus. Results. Co-administration of serine slightly enhanced rearing induced by NMDA administration. Administration of NMDA at concentrations of 0.3 or 1.0 mM (500 nl) induced vigorous locomotion and rearing. NMDA (0.3 mM) was self-administered into the VTA slightly more than vehicle in the first or second sessions, yet this small reinforcing effect became irregular in subsequent sessions. The rats did not learn to self-administer NMDA into the supramammillary nucleus. Conclusions. Ventral tegmental NMDA injections, in the concentration range that induced marked unconditional hyperactivity, supported only marginal and transient self-administration. C1 NIDA, Behav Neurosci Branch, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, Dept Hlth & Human Serv, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sikemoto@intra.nida.nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 55 TC 9 Z9 9 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2004 VL 172 IS 2 BP 202 EP 210 DI 10.1007/s00213-003-1651-3 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 779AB UT WOS:000189272500011 PM 14634715 ER PT J AU Jun, JH Thorndike, EB Schindler, CW AF Jun, JH Thorndike, EB Schindler, CW TI Abuse liability and stimulant properties of dextromethorphan and diphenhydramine combinations in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE abuse liability; dextromethorphan; diphenhydramine; rat ID METHYL-D-ASPARTATE; RECEPTOR ANTAGONISTS; LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; RHESUS-MONKEYS; METHAMPHETAMINE; DOPAMINE; COCAINE; CHLORPHENIRAMINE; INHIBITION AB Rationale. The abuse of over-the-counter (OTC) medications has been widely reported. However, there are few preclinical studies examining the behavioral effects of OTC medications at higher, abused doses. Objectives. The objectives of the current study were to determine whether the anti-histamine diphenhydramine (DIP) and the antitussive dextromethorphan (DEX), either alone or in combination, would have stimulant properties and be self-administered in animals. Methods. For drug self-administration, naive rats with no history of exposure to other drugs were trained to self-administer IV DEX+DIP (0.5+0.5, 1+1 or 2+2 mg/kg per injection), DEX alone (1 mg/kg) or DIP (1 mg/kg) alone under five-response fixed-ratio (FR) schedule with a 30-s time-out after each injection in 2-h sessions 3-5 days a week. Separate groups of rats were tested on locomotor activity. After 8 consecutive days of habituation, naive rats were injected with 3, 10, or 30 mg/kg DEX or DIP alone IP, or in combination of 3+3 mg/kg, 10+10 mg/kg, or 30+30 mg/kg DEX+DIP IP. Saline was injected IP during the intervening days. Locomotor activity was measured for each session. Results. DEX+DIP combinations were self-administered, but the drugs alone were not. The acquisition of DEX+DIP self-administration was rapid with a majority of rats reaching the final FR5 schedule in 22-23 sessions. The total IV combination dose for each final scheduled session ranged from 40 mg/kg to 160 mg/kg DEX+DIP. Significant increases in locomotor activity were observed for DIP, an effect that was significantly enhanced when DIP was given in combination with DEX. Significant mortality was also observed for the drug combination at each dose tested when given IV, with the highest mortality following the highest dose (2+2 mg/kg). When given IP, no mortality was observed. Conclusions. These results show that combinations of DEX and DIP have stimulant properties and are self-administered by animals. Abuse of this combination in humans would be expected. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM cschindl@helix.nih.gov NR 45 TC 7 Z9 7 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2004 VL 172 IS 3 BP 277 EP 282 DI 10.1007/s00213-003-1650-4 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 802UR UT WOS:000220188900006 PM 14634714 ER PT J AU Lubin, JH Schafer, DW Ron, E Stovall, M Carroll, RJ AF Lubin, JH Schafer, DW Ron, E Stovall, M Carroll, RJ TI A reanalysis of thyroid neoplasms in the Israeli tinea capitis study accounting for dose uncertainties SO RADIATION RESEARCH LA English DT Article ID X-RAY TREATMENT; RESIDENTIAL RADON; LUNG-CANCER; EXPOSURE ASSESSMENT; EXTERNAL RADIATION; SCALP IRRADIATION; MEASUREMENT ERROR; RISK; CHILDHOOD; COHORT AB In the 1940s and 1950s, children in Israel were treated for tinea capitis by irradiation to the scalp to induce epilation. Follow-up studies of these patients and of other radiation-exposed populations show an increased risk of malignant and benign thyroid tumors. Those analyses, however, assume that thyroid dose for individuals is estimated precisely without error. Failure to account for uncertainties in dosimetry may affect standard errors and bias dose-response estimates. For the Israeli tinea capitis study, we discuss sources of uncertainties and adjust dosimetry for uncertainties in the prediction or true dose from X-ray treatment parameters. We also account for missing ages at exposure for patients with multiple X-ray treatments, since only ages at first treatment are known, and for missing data on treatment center, which investigators use to define exposure. Our reanalysis of the dose response for thyroid cancer and benign thyroid tumors indicates that uncertainties in dosimetry have minimal effects on dose-response estimation and for inference on the modifying effects of age at first exposure, time since exposure, and other factors. Since the components of the dose uncertainties we describe are likely to be present in other epidemiological studies of patients treated with radiation, our analysis may provide a model for considering the potential role of these uncertainties. (C) 2004 by Radiation Research Society. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Oregon State Univ, Dept Stat, Corvallis, OR 97331 USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7244, Bethesda, MD 20892 USA. EM lubinj@mail.nih.gov FU NCI NIH HHS [CA57030]; NIEHS NIH HHS [P30-ES09106] NR 32 TC 22 Z9 22 U1 1 U2 2 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2004 VL 161 IS 3 BP 359 EP 368 DI 10.1667/RR3135 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 779NZ UT WOS:000189307900014 PM 14982478 ER PT J AU Heesch, KC Masse, LC AF Heesch, KC Masse, LC TI Do women have enough time for leisure-time physical activity? SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Meeting Abstract C1 Univ Oklahoma, Norman, OK 73019 USA. NCI, Bethesda, MD 20892 USA. EM kheesch@ou.edu; massel@mail.nih.gov RI Heesch, Kristi/B-7863-2009; Heesch, Kristiann/J-1288-2012 OI Heesch, Kristiann/0000-0003-1931-3683 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD MAR PY 2004 VL 75 IS 1 SU S BP A101 EP A101 PG 1 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 806IT UT WOS:000220428300257 ER PT J AU Stratakis, CA Bossis, I AF Stratakis, CA Bossis, I TI Genetics of the adrenal gland SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE adrenal; cortex; medulla; congenital adrenocortical hyperplasia; pheochromocytoma; adrenocortical cancer; Cushing syndrome; adrenocortical insufficiency; molecular genetics ID ACUTE REGULATORY PROTEIN; STAR GENE; 17,20-LYASE DEFICIENCY; GONADAL DEVELOPMENT; MOLECULAR-GENETICS; SEX REVERSAL; HYPERPLASIA; MUTATIONS; INSIGHTS; STEROIDOGENESIS C1 NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 52 TC 9 Z9 10 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD MAR PY 2004 VL 5 IS 1 BP 53 EP 68 DI 10.1023/B:REMD.0000016124.44064.8f PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 807OM UT WOS:000220510800005 PM 14966389 ER PT J AU Olsson, N Taub, DD Nilsson, G AF Olsson, N Taub, DD Nilsson, G TI Regulation of mast cell migration by T-H1 and T-H2 cytokines: Identification of tumour necrosis factor-alpha and interleukin-4 as mast cell chemotaxins SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOTACTIC ACTIVITY; EXPRESSION; TRYPTASE; IL-4; DIFFERENTIATION; RECEPTORS; RELEASE; FLUID; CCR3; C3A AB Mast cells act as central effector and regulatory cells in many inflammatory disorders, including T helper 1 (T-H1)-mediated inflammations such as autoimmunity and T-H2-mediated inflammations such as allergy and parasite infections. One characteristic for mast cell-mediated inflammations is the accumulation of mast cells in the inflamed tissue. The factors regulating mast cell recruitment in these inflammations are still not fully characterized. We have investigated the potency of T-H1- and T-H2-secreted cytokines to mediate mast cell migration. Supernatants from six different T-H1 and T-H2 clones were tested for mast cell-chemotactic activity using the human mast cell line (HMC-1) as a responder cell. All six clones produced factors that induced mast cell migration. Using blocking antibodies to a broad range of cytokines, we found that anti-tumour necrosis factor-alpha (anti-TNF-alpha) reduced the migration of mast cells to supernatants from T-H1 clones. In contrast, the main mast cell chemoattractants secreted by T-H2 clones were found to be interleukin-4 (IL-4) and IL-8. The potency of these cytokines to act as mast cell chemoattractants was confirmed by using recombinant IL-4, IL-8 and TNF-alpha. Our results suggest that TNF-alpha can be involved in the recruitment of mast cells in T-H1-mediated inflammations, whereas IL-4 and IL-8 might play a similar role in T-H2-mediated inflammations. C1 Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, SE-75185 Uppsala, Sweden. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Nilsson, G (reprint author), Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, SE-75185 Uppsala, Sweden. EM gunnar.nilsson@genpat.uu.se NR 28 TC 23 Z9 27 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD MAR PY 2004 VL 59 IS 3 BP 267 EP 272 DI 10.1111/j.0300-9475.2004.01397.x PG 6 WC Immunology SC Immunology GA 805HB UT WOS:000220356300005 PM 15030577 ER PT J AU Black, S AF Black, S TI Enzymatic origins SO SCIENTIST LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Black, S (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM SimonB@BDG8.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAR 1 PY 2004 VL 18 IS 4 BP 10 EP 10 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 779BH UT WOS:000189275400003 ER PT J AU Briggs, JP AF Briggs, JP TI Evidence-based medicine in the dialysis unit: A few lessons from the USRDS and the NCDS and HEMO trials SO SEMINARS IN DIALYSIS LA English DT Article ID NATIONAL COOPERATIVE DIALYSIS; HEMODIALYSIS-PATIENTS; MAINTENANCE HEMODIALYSIS; NOCTURNAL HEMODIALYSIS; MEMBRANE FLUX; BODY-SIZE; MORTALITY; MORBIDITY; PRESCRIPTION; PATIENT AB This short review argues for the importance of evidence-based medicine in the evolution of improved dialysis care. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has supported two major randomized clinical trials in dialysis, the National Cooperative Dialysis Study (NCDS), completed in 1981, and the Hemodialysis (HEMO) study, completed in 2002, and supports a major body of ongoing observational research through the U.S. Renal Data System (USRDS). The main results from the two randomized clinical trials and their implications for clinical practice and subsequent research are discussed here. The importance of observational research in the formulation of hypotheses and improvement of quality of care is examined. A brief historical perspective is provided on the critical examination of dialysis care in the late 1980s that occurred following completion of the NCDS. Finally, the rationale for continued investment in dialysis research and the plans of NIDDK to launch studies of more intensive dialysis regimens are discussed. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), NIDDK, NIH, Bldg 31C,Rm 9A17,31 Ctr Dr, Bethesda, MD 20892 USA. EM Jbriggs@nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 38 TC 6 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD MAR-APR PY 2004 VL 17 IS 2 BP 136 EP 141 DI 10.1111/j.0894-0959.2004.17211.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 806XC UT WOS:000220465600012 PM 15043616 ER PT J AU Bulayeva, NN Gametchu, B Watson, CS AF Bulayeva, NN Gametchu, B Watson, CS TI Quantitative measurement of estrogen-induced ERK 1 and 2 activation via multiple membrane-initiated signaling pathways SO STEROIDS LA English DT Article DE non-genomic; membrane estrogen receptor; signaling pathway inhibitors; Ca(2+); Src kinase; PI3K; EGF receptor ID PITUITARY-TUMOR CELLS; GROWTH-FACTOR RECEPTOR; PROTEIN-COUPLED RECEPTORS; ELEMENT-BINDING PROTEIN; PLASMA-MEMBRANE; MAP KINASE; GENE-TRANSCRIPTION; ALPHA; ESTRADIOL; PROLACTIN AB Estradiol (E(2)) and other steroids have recently been shown to initiate various intracellular signaling cascades from the plasma membrane, including those stimulating mitogen-activated protein kinases (MAPKs), and particularly extracellular-regulated kinases (ERKs). In this study we demonstrated the ability of E(2) to activate ERKs in the GH3/B6/F 10 pituitary tumor cell line, originally selected for its enhanced expression of membrane estrogen receptor-alpha (mERalpha). We compared E2 to its cell-impermeable analog (E(2) conjugated to peroxidase, E(2)-P), and to the synthetic estrogen diethylstilbestrol (DES). Time-dependent ERK activation was quantified with a novel fixed cell-based immunoassay developed to efficiently determine activation by multiple compounds over multiple parameters. Both E(2) and DES produced bimodal responses, but with distinctly different time courses of enzyme phosphorylation (activation) and inactivation; E(2)-P induced a monophasic ERK activation. E(2) also phosphorylated ERKs in concentration-dependent manner with two concentration optima (10(-14) and 10(-8) M). Inhibitors were employed to determine pathway (ER, EGFR, membrane organization, PI3 kinase, Src kinase, Ca(2+)) involvement and timing of pathway activations; all affected ERK activation as early as 3-6 min, suggesting simultaneous, not sequential, activation. Therefore, E(2) and other estrogenic compounds can produce rapid ERK phosphorylations via nongenomic pathways, using more than one pathway for signal generation. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. NIH, Bethesda, MD 20892 USA. RP Watson, CS (reprint author), Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. EM cswatson@utmb.edu FU NIEHS NIH HHS [R01 ES010987]; PHS HHS [010987] NR 52 TC 78 Z9 79 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD MAR PY 2004 VL 69 IS 3 BP 181 EP 192 DI 10.1016/j.steroids.2003.12.003 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 810CR UT WOS:000220682900004 PM 15072920 ER PT J AU Janardhan, V Wolf, PA Kase, CS Massaro, JM D'Agostino, RB Franzblau, C Wilson, PWF AF Janardhan, V Wolf, PA Kase, CS Massaro, JM D'Agostino, RB Franzblau, C Wilson, PWF TI Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack - The Framingham cohort and offspring study SO STROKE LA English DT Article; Proceedings Paper CT 28th International Stroke Conference CY FEB 13-15, 2003 CL PHOENIX, ARIZONA DE antibodies, anticardiolipin; antibodies, antiphospholipid; cerebral ischemia, transient; risk factors; stroke, ischemic ID THROMBO-OCCLUSIVE EVENTS; ANTIPHOSPHOLIPID ANTIBODIES; MYOCARDIAL-INFARCTION; WORKSHOP; TITER; DEATH AB Background and Purpose-The role of anticardiolipin antibodies (aCLs) as novel risk factors for ischemic stroke and transient ischemic attacks (TIAs) has been a matter of debate. Prior cohort studies included only selected subjects, mostly men. We related serum concentrations of aCLs to incident first ischemic stroke/TIA among men and women in the Framingham Heart Study cohort and offspring. Methods-There were a total of 2712 women (mean age, 59.3 years) and 2262 men (mean age, 58.3 years) free of stroke/TIA at the time of their baseline examinations. An enzyme immunoassay was used to measure aCLs. Optical density of the sample serum compared with the reference serum was defined as the aCL screening ratio (aCL SR). Analyses were based on sex-specific aCL SR quartiles and individual ratios. Results-During the 11-year follow-up, 222 ischemic strokes/TIAs occurred. In multivariate analysis, after adjustment for age, prior cardiovascular disease, systolic blood pressure, diabetes, smoking, C-reactive protein, and total and high-density lipoprotein cholesterol levels, an aCL SR of >0.4 (78% of sample) was significantly associated with an increased risk of ischemic stroke/TIA for women (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.3 to 5.4; absolute risk, 3.2%, 95% CI, 2.2 to 4.3) but not in men (HR, 1.3; 95% CI, 0.7 to 2.4; absolute risk, 4.5%; 95% CI, 3.0 to 6.0). Similar results were obtained when the higher 3 aCL SR quartiles were compared with the lowest. Conclusions-Elevated serum concentrations of aCLs, independently of other cardiovascular risk factors, significantly predict the risk of future ischemic stroke and TIA in women but not in men. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Dis Epidemiol Study, Bethesda, MD 20892 USA. RP Wolf, PA (reprint author), 715 Albany St,B-608, Boston, MA 02118 USA. EM pawolf@bu.edu OI Franzblau, Carl/0000-0001-9248-6324; Massaro, Joseph/0000-0002-2682-4812 FU NHLBI NIH HHS [N01-HC-25195]; NINDS NIH HHS [5-R01-NS-17950-21] NR 20 TC 62 Z9 64 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2004 VL 35 IS 3 BP 736 EP 741 DI 10.1161/01.STR.0000117575.48205.2D PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 778LQ UT WOS:000189243400024 PM 14764933 ER PT J AU Fox, CS Larson, MG Corey, D Feng, DL Lindpaintner, K Polak, JF Wolf, PA D'Agostino, RB Tofler, GH O'Donnell, CJ AF Fox, CS Larson, MG Corey, D Feng, DL Lindpaintner, K Polak, JF Wolf, PA D'Agostino, RB Tofler, GH O'Donnell, CJ TI Absence of association between polymorphisms in the hemostatic factor pathway genes and carotid intimal medial thickness - The Framingham Heart Study SO STROKE LA English DT Article DE coagulation; epidemiology; genetics; risk factors ID DISEASE AB Background and Purpose-Fibrinogen, plasminogen activator inhibitor-1, and other key proteins in the coagulation cascade have been implicated in the origin of cardiovascular disease. Polymorphisms in genes encoding these proteins have been associated with variability in plasma levels of these proteins. Carotid intimal medial thickness (IMT) is a heritable, quantitative measure of atherosclerosis that is predictive of subsequent myocardial infarction and stroke. We sought to test whether carotid IMT is associated with polymorphisms in several well-characterized genes in the hemostatic factor pathways. Methods-Here, 867 men and 911 women (mean age, 57 years) in the Framingham offspring cohort underwent B-mode carotid ultrasonography to determine the mean internal (ICA) and common carotid artery (CCA) IMT. Age-, sex-, and multivariable-adjusted linear regression was used to estimate the association of the following variants with log-transformed CCA and ICA IMT: factor V Leiden, factor VII Arg/Gln, fibrinogen HindIII beta-148, plasminogen activator inhibitor-1 4G/5G, and the glycoprotein IIIa Pl(A2) polymorphism. Results-Mean ICA IMT was 0.58 mm; mean CCA IMT was 0.60 mm. There were no differences in ICA or CCA IMT by genotype for any of the candidate genes in unadjusted, age- or sex-adjusted, and multivariable-adjusted models. Conclusions-There is no evidence for an association between well-studied polymorphisms in the hemostatic factor genes and carotid IMT. Whether other common genetic variants in hemostatic factor genes are associated with subclinical atherosclerosis remains to be determined. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Med Sch, Dept Internal Med, Boston, MA USA. Roche Genet, Basel, Switzerland. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM chris@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254 NR 15 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2004 VL 35 IS 3 DI 10.1161/01.STR.0000117095.96234.A6 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 778LQ UT WOS:000189243400044 ER PT J AU Rudresh Ramakumar, S Ramagopal, UA Inai, Y Goel, S Sahal, D Chauhan, VS AF Rudresh Ramakumar, S Ramagopal, UA Inai, Y Goel, S Sahal, D Chauhan, VS TI De novo design and characterization of a helical hairpin eicosapeptide: Emergence of an anion receptor in the linker region SO STRUCTURE LA English DT Article ID O HYDROGEN-BOND; SUCCESSIVE RESIDUES; WEAK-INTERACTIONS; BETA-HAIRPINS; PROTEINS; PEPTIDE; CRYSTAL; CONFORMATION; EVOLUTION; ZIPPERS AB De novo design of supersecondary structures is expected to provide useful molecular frameworks for the incorporation of functional sites as in proteins. A 21 residue long, dehydrophenylalanine-containing peptide has been de novo designed and its crystal structure determined. The apolar peptide folds into a helical hairpin supersecondary structure with two right-handed helices, connected by a tetraglycine linker. The helices of the hairpin interact with each other through a combination of C-(HO)-O-... and N-(HO)-O-... hydrogen bonds. The folding of the apolar peptide has been realized without the help of either metal ions or disulphide bonds. A remarkable feature of the peptide is the unanticipated occurrence of an anion binding motif in the linker region, strikingly similar in conformation and function to the "nest" motif seen in several proteins. The observation supports the view for the possible emergence of rudimentary functions over short sequence stretches in the early peptides under prebiotic conditions. C1 Int Ctr Genet Engn & Biotechnol, New Delhi, India. Indian Inst Sci, Bioinformat Ctr, Dept Phys, Bangalore 560012, Karnataka, India. NCI Frederick, Upton, NY 11973 USA. Brookhaven Natl Lab, NSLS, Upton, NY 11973 USA. Nagoya Inst Technol, Grad Sch Engn, Dept Environm Technol & Urban Planning, Showa Ku, Nagoya, Aichi 4668555, Japan. RP Chauhan, VS (reprint author), Int Ctr Genet Engn & Biotechnol, New Delhi, India. EM virander@icgeb.res.in NR 32 TC 9 Z9 9 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR PY 2004 VL 12 IS 3 BP 389 EP 396 DI 10.1016/j.str.2004.02.014 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 821AB UT WOS:000221430300007 PM 15016355 ER PT J AU Zanuy, D Porat, Y Gazit, E Nussinov, R AF Zanuy, D Porat, Y Gazit, E Nussinov, R TI Peptide sequence and amyloid formation: Molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs SO STRUCTURE LA English DT Article ID YEAST PRION SUP35; BETA-SHEET; DYNAMICS SIMULATIONS; FIBRIL FORMATION; FORMING PEPTIDE; FIBRILLOGENESIS; IDENTIFICATION; RESIDUES; STATE; A-BETA(16-22) AB We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues. C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, George S Wise Fac Life Sci, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Sackler Inst Mol Med, I-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. EM ruthn@ncifcrf.gov RI Gazit, Ehud/C-3715-2011; Zanuy, David/G-3930-2014 OI Gazit, Ehud/0000-0001-5764-1720; Zanuy, David/0000-0001-7704-2178 FU NCI NIH HHS [N01-CO-12400] NR 34 TC 69 Z9 69 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR PY 2004 VL 12 IS 3 BP 439 EP 455 DI 10.1016/j.str.2004.02.002 PG 17 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 821AB UT WOS:000221430300012 PM 15016360 ER PT J AU Blaszczyk, J Gan, JH Tropea, JE Court, DL Waugh, DS Ji, XH AF Blaszczyk, J Gan, JH Tropea, JE Court, DL Waugh, DS Ji, XH TI Noncatalytic assembly of ribonuclease III with double-stranded RNA SO STRUCTURE LA English DT Article ID DSRNA-BINDING DOMAIN; ESCHERICHIA-COLI; PROCESSING ACTIVITY; MOLECULAR-BASIS; PROTEIN; CLEAVAGE; GENE; INTERFERENCE; RECOGNITION; REFINEMENT AB Ribonuclease III (RNase III) represents a family of double-stranded RNA (dsRNA) endonucleases. The simplest bacterial enzyme contains an endonuclease domain (endoND) and a dsRNA binding domain (dsRBD). RNase III can affect RNA structure and gene expression in either of two ways: as a dsRNA-processing enzyme that cleaves dsRNA, or as a dsRNA binding protein that binds but does not cleave dsRNA. We previously determined the endoND structure of Aquifex aeolicus RNase III (Aa-RNase III) and modeled a catalytic complex of full-length Aa-RNase III with dsRNA. Here, we present the crystal structure of Aa-RNase III in complex with dsRNA, revealing a noncatalytic assembly. The major differences between the two functional forms of RNase III(.)dsRNA are the conformation of the protein and the orientation and location of dsRNA. The flexibility of a 7 residue linker between the endoND and dsRBD enables the transition between these two forms. C1 NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 45 TC 89 Z9 93 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR PY 2004 VL 12 IS 3 BP 457 EP 466 DI 10.1016/j.str.2004.02.004 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 821AB UT WOS:000221430300013 PM 15016361 ER PT J AU Blaszczyk, J Shi, GB Li, Y Yan, HG Ji, XH AF Blaszczyk, J Shi, GB Li, Y Yan, HG Ji, XH TI Reaction trajectory of pyrophosphoryl transfer catalyzed by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase SO STRUCTURE LA English DT Article ID ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; THIAMIN PYROPHOSPHOKINASE; ARGININE RESIDUE-82; TERNARY COMPLEX; REFINEMENT; RESOLUTION; ANALOG; ROLES AB 6-hydroxymethyl-7,8-dihydropterin pyrophospholkinase (HPPK) catalyzes the Mg2+-dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). The reaction follows a bi-bi mechanism with ATP as the first substrate and AMP and HIP pyrophosphate (HPPP) as the two products. HPPK is a key enzyme in the folate biosynthetic pathway and is essential for microorganisms but absent from mammals. For the HPPK-catalyzed pyrophosphoryl transfer, a reaction coordinate is constructed on the basis of the thermodynamic and transient kinetic data we reported previously, and the reaction trajectory is mapped out with five three-dimensional structures of the enzyme at various liganded states. The five structures are apo-HPPK (ligand-free enzyme), HPPK(.)MgATP(analog) (binary complex of HPPK with its first substrate) and HPPK-MgATP(analog) HP (ternary complex of HPPK with both substrates), which we reported previously, and HPPK-AMP-HPPP (ternary complex of HPPK with both product molecules) and HPPK-HPPP (binary complex of HPPK with one product), which we present in this study. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. Vanderbilt Univ, Sch Med, Div Nephrol, MCN, Nashville, TN 37232 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 25 TC 26 Z9 27 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR PY 2004 VL 12 IS 3 BP 467 EP 475 DI 10.1016/j.str.2004.02.003 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 821AB UT WOS:000221430300014 PM 15016362 ER PT J AU Feldman, AL Espina, V Petricoin, EF Liotta, LA Rosenblatt, KP AF Feldman, AL Espina, V Petricoin, EF Liotta, LA Rosenblatt, KP TI Use of proteomic patterns to screen for gastrointestinal malignancies SO SURGERY LA English DT Review ID COLORECTAL-CANCER; PROTEIN MICROARRAYS; MARKERS; SERUM C1 NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Feldman, AL (reprint author), NCI, Pathol Lab, Canc Res Ctr, NIH, Bldg 10,Rm 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012; OI Espina, Virginia/0000-0001-5080-5972 NR 15 TC 22 Z9 22 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAR PY 2004 VL 135 IS 3 BP 243 EP 247 DI 10.1016/j.surg.2003.08.019 PG 5 WC Surgery SC Surgery GA 779QE UT WOS:000189310900001 PM 14976472 ER PT J AU Mikaelian, I Nanney, LB Parman, KS Kusewitt, DF Ward, JM Naf, D Krupke, DM Eppig, JT Bult, CJ Seymour, R Ichiki, T Sundberg, JP AF Mikaelian, I Nanney, LB Parman, KS Kusewitt, DF Ward, JM Naf, D Krupke, DM Eppig, JT Bult, CJ Seymour, R Ichiki, T Sundberg, JP TI Antibodies that label paraffin-embedded mouse tissues: A collaborative endeavor SO TOXICOLOGIC PATHOLOGY LA English DT Article DE antigen retrieval; immunohistochemistry; monoclonal antibodies; polyclonal antibodies; mouse; epitope retrieval; paraffin; fixation; whole-mount immunohistochemistry ID POLYMERASE CHAIN-REACTION; IMMUNOHISTOCHEMICAL DETECTION; FORMALIN-FIXATION; FORMALDEHYDE FIXATION; ANTIGEN RETRIEVAL; CANCER; AMPLIFICATION; MICROWAVE; PATHOLOGY; DATABASE AB Histology and immunohistochemistry are important tools in the study of human diseases and their respective animal models. The study of mouse models has been hampered by the absence of a large set of mouse-specific antibodies adapted to paraffin-embedded tissues. A total of 196 antibodies were tested on paraffin-embedded mouse tissues preserved in five different fixatives (Fekete's acid-alcohol-formalin, 10% neutral buffered formalin, 4% paraformaldehyde, IHC Zinc Fixative, and Bouin's fixative). The antibodies were targeted to proteins of the cytoplasm (n=100), plasma membrane (n= 48), nucleus (n= 36), extracellular compartment (n= 5), cytoplasm/cell membrane ( n = 4), and viral proteins ( n = 3). A total of 83 antibodies provided an adequate signal to noise ratio. Of these, adequate labeling required heat-mediated epitope retrieval or enzymatic digestion for 32 and 8 antibodies, respectively. Epitope recognition was best for tissues fixed with Fekete's acid-alcohol-formalin. However, some proteins could be detected only in IHC Zinc Fixative, confirming that there is no single fixative suitable for the preservation of all epitopes. Four of 13 antibodies that failed to label their cellular targets on tissue sections successfully labeled whole-mount tissues, indicating that tissue processing plays an important role in epitope degradation. Regularly updated information on immunohistochemistry of normal and neoplastic mouse tissues is accessible online at (http://tumor.informatics.jax.org); links to antibody suppliers' web sites are provided. C1 Jackson Lab, Bar Harbor, ME 04609 USA. Vanderbilt Univ Sch Med, Dept Surg, Nashville, TN 37212 USA. Vanderbilt Univ Sch Med, Dept Cell & Dev Biol, Nashville, TN 37212 USA. Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA. NIAID, Bethesda, MD 20892 USA. Transgen Inc, Kumamoto 8600802, Japan. RP Mikaelian, I (reprint author), Jackson Lab, 98,600 Main St, Bar Harbor, ME 04609 USA. EM imikaeli@jax.org OI Krupke, Debra/0000-0002-3165-2891 FU NCI NIH HHS [CA89713, CA34196]; NCRR NIH HHS [RR173]; NIAMS NIH HHS [P30 AR41943]; NIDDK NIH HHS [U24 DK59637] NR 57 TC 22 Z9 23 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR-APR PY 2004 VL 32 IS 2 BP 181 EP 191 DI 10.1080/01926230490274335 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA 804WJ UT WOS:000220328500002 PM 15200156 ER PT J AU Nyska, A Haseman, JK Kohen, R Maronpot, RR AF Nyska, A Haseman, JK Kohen, R Maronpot, RR TI Association of liver hemangiosarcoma and secondary iron overload in B6C3F1 mice - The National Toxicology Program Experience SO TOXICOLOGIC PATHOLOGY LA English DT Article DE hemangiosarcoma; liver; mouse; hemosiderin; hemolysis ID DIAMOND-BLACKFAN-ANEMIA; ANILINE HYDROCHLORIDE; OXIDATIVE STRESS; DEXTRAN COMPLEX; RATS; 2-BUTOXYETHANOL; CANCER; RISK; CARCINOGENICITY; SARCOMA AB The literature evidencing the role of iron in promoting a range of neoplasms in humans and animals prompted us to search for a possible association between chemically induced hemosiderosis and hemangiosarcomas in the liver of mice in selected studies conducted by the National Toxicology Program (NTP). Its historical control database was examined for studies in which treatment-related liver hemangiosarcoma was noted; 130 consecutive NTP studies in B6C3F1 mice from Technical Report (TR)-340 to TR-493 were evaluated. Three compounds (2-butoxyethanol, p-nitroaniline, and para-chloroaniline) were associated with a relatively high incidence of Kupffer cell pigmentation consisting of hemosiderin in both sexes; only the male mice developed a relatively low incidence of treatment-related hemangiosarcoma. With a fourth compound (o-nitroanisole), a relatively low incidence (16/50, high-dose males) of chemical-related hemosiderosis was noted, with no associated increase of hemangiosarcoma. Two chemicals ( pentachlorophenol and tetrafluoroethylene) increased the incidence of liver hemangiosarcoma in male and female mice, with no increase in Kupffer cell pigmentation. The overall association between liver hemangiosarcoma and Kupffer cell pigmentation was highly significant ( p < 0.001). The cause for hemosiderosis in all cases was the erythrocytic hemolytic effect of the compounds. The reason for the sex-increased susceptibility for development of hemangiosarcoma is unknown but may be due to a hormone-related, reduced antioxidative defensive capacity through modulation of the activities of antioxidative enzymes. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Hebrew Univ Jerusalem, Sch Pharm, Dept Pharmaceut, IL-91120 Jerusalem, Israel. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, MD B3-06,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov NR 54 TC 9 Z9 10 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR-APR PY 2004 VL 32 IS 2 BP 222 EP 228 DI 10.1080/01926230490274371 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 804WJ UT WOS:000220328500006 PM 15200160 ER PT J AU Germolec, DR Nyska, A Kashon, M Kuper, CF Portier, C Kommineni, C Johnson, KA Luster, MI AF Germolec, DR Nyska, A Kashon, M Kuper, CF Portier, C Kommineni, C Johnson, KA Luster, MI TI Extended histopathology in immunotoxicity testing: Interlaboratory validation studies SO TOXICOLOGICAL SCIENCES LA English DT Article DE immunology; pathology; spleen; thymus; lymph node; histopathology; immunopathology; risk assessment ID FEMALE B6C3F1 MICE; RISK-ASSESSMENT; IMMUNOLOGICAL PARAMETERS; EXOGENOUS CORTICOSTERONE; RESTRAINT STRESS; HOST-RESISTANCE; IMMUNE; THYMUS; RAT; TOXICOLOGY AB There has been considerable interest in the use of expanded histopathology as a primary screen for immunotoxicity assessment. To determine the utility of a semiquantitative histopathology approach for examining specific structural and architectural changes in lymphoid tissues, a validation effort was initiated. This study addresses the interlaboratory reproducibility of extended histopathology, using tissues from studies of ten test chemicals and both negative and positive controls from the National Toxicology Program's immunotoxicology testing program. We examined the consistency between experienced toxicologic pathologists, who had varied expertise in immunohistopathology in identifying lesions in immune tissues, and in the sensitivity of the individual and combined histopathological endpoints to detect chemical effects and dose response. Factor analysis was used to estimate the association of each pathologist with a so-called "common factor" and analysis-of-variance methods were used to evaluate biases. Agreement between pathologists was highest in the thymus, in particular, when evaluating cortical cellularity of the thymus; good in spleen follicular cellularity and in spleen and lymph node-germinal center development; and poorest in spleen red-pulp changes. In addition, the ability to identify histopathological change in lymphoid tissues was dependent upon the experience/training that the individual pathologist possessed in examining lymphoid tissue and the apparent severity of the specific lesion. C1 NIEHS, Mol Toxicol Lab, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIOSH, Biostat Branch, Morgantown, WV USA. TNO, Nutr & Food Res, NL-3700 AJ Zeist, Netherlands. NIEHS, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. NIOSH, Pathol & Physiol Res Branch, Morgantown, WV USA. Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. NIOSH, Toxicol & Mol Biol Branch, Morgantown, WV USA. RP Germolec, DR (reprint author), NIEHS, Mol Toxicol Lab, Natl Toxicol Program, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM germolec@niehs.nih.gov RI Portier, Christopher/A-3160-2010; OI Portier, Christopher/0000-0002-0954-0279; Kuper, Frieke/0000-0001-8273-2915 NR 46 TC 27 Z9 27 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 MAR PY 2004 VL 78 IS 1 BP 107 EP 115 DI 10.1093/toxsci/kfh049 PG 9 WC Toxicology SC Toxicology GA 801DG UT WOS:000220076000013 PM 14691208 ER PT J AU Sakurai, T Kojima, C Ochiai, M Ohta, T Sakurai, MH Waalkes, MP Fujiwara, K AF Sakurai, T Kojima, C Ochiai, M Ohta, T Sakurai, MH Waalkes, MP Fujiwara, K TI Cellular glutathione prevents cytolethality of monomethylarsonic acid SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE monomethylarsenic; monomethylarsonic acid; arsenic; glutathione; apoptosis ID HAMSTER OVARY CELLS; MALE F344 RATS; DIMETHYLARSINIC ACID; SODIUM ARSENITE; IN-VITRO; PENTAVALENT ARSENICALS; REDUCED GLUTATHIONE; MALIGNANT NEOPLASMS; INORGANIC ARSENICS; URINARY-EXCRETION AB Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenic often undergoes methylation, forming compounds such as monomethylarsonic acid (MMAsv) and dimethylarsinic acid (DMAsv). However, much less information is available on the in vitro toxic potential or mechanisms of these methylated arsenicals, especially MMAsv. We studied the molecular mechanisms of in vitro cytolethality of MMAsv using a rat liver epithelial cell line (TRL 1215). MMAsv was not cytotoxic in TRL 1215 cells even at concentrations exceeding 10 mM, but it became weakly cytotoxic and induced both necrotic and apoptotic cell death when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO), or the glutathione reductase inhibitor, carmustine. Similar results were observed in the other mammalian cells, such as human skin TIG-112 cells, chimpanzee skin CRT-1609 cells, and mouse metallothionein (NIT) positive and NIT negative embryonic cells. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase (GST) that catalyses GSH-substrate conjugation, also enhanced the cytolethality of MMAsv but aminooxyacetic acid (AOAA), an inhibitor of beta-lyase that catalyses the final breakdown of GSH-substrate conjugates, had no effect. Both the cellular GSH levels and the cellular GST activity were increased by the exposure to MMAsv in TRL 1215 cells. On the other hand, the addition of exogenous extracellular GSH enhanced the cytolethality of MMAsv although cellular GSH levels actually prevented the cytolethality of combined MMAsv and exogenous GSH. These findings indicate that human arsenic metabolite MMAsv is not a highly toxic compound in mammalian cells, and the level of cellular GSH is critical to its eventual toxic effects. (C) 2004 Elsevier Inc. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, Tokyo 1920392, Japan. Azabu Univ, Dept Environm Hlth, Lab Environm Hyg, Kanagawa 2298501, Japan. NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Sakurai, T (reprint author), Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, Horinouchi 1432-1, Tokyo 1920392, Japan. EM salcurai@ls.toyaku.ac.jp NR 61 TC 24 Z9 29 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 1 PY 2004 VL 195 IS 2 BP 129 EP 141 DI 10.1016/j.taap.2003.11.022 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 801KJ UT WOS:000220094500001 PM 14998680 ER PT J AU Studitsky, VM Walter, W Kireeva, M Kashlev, M Felsenfeld, G AF Studitsky, VM Walter, W Kireeva, M Kashlev, M Felsenfeld, G TI Chromatin remodeling by RNA polymerases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID II ELONGATION COMPLEX; TWIST-DIFFUSION MECHANISM; HUMAN SWI-SNF; HISTONE OCTAMER; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION ELONGATION; IN-VIVO; INTERGENIC TRANSCRIPTION; TRANSCRIBING POLYMERASE; NUCLEOSOMAL TEMPLATES AB Chromatin packages DNA tightly into the eukaryotic nucleus and maintains its proper functioning. Recent studies suggest the existence of two distinct mechanisms of progression of RNA polymerases through chromatin. The first is characteristic of eukaryotic RNA polymerase III, bacteriophage RNA polymerases, and probably ATP-dependent chromatin remodeling complexes. In this mechanism, nucleosomes are translocated without release of the octamer into solution. By contrast, transcription by RNA polymerase II (Pol II) involves displacement of one H2A-H2B dimer. Nucleosomes can present a barrier for transcribing Pol II that can be regulated in vivo. Analysis of the mechanisms of transcription through chromatin should provide important information about mechanisms of chromatin remodeling and gene regulation at the level of transcript elongation. C1 Univ Med & Dent New Jersey, Dept Pharmacol, Piscataway, NJ 08854 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. NCI, Ctr Canc Res, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Studitsky, VM (reprint author), Univ Med & Dent New Jersey, Dept Pharmacol, 675 Hoes Lane,Room 405, Piscataway, NJ 08854 USA. EM studitvm@umdnj.edu RI Studitsky, Vasily/A-9382-2014 FU NIGMS NIH HHS [GM58650] NR 70 TC 68 Z9 72 U1 1 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2004 VL 29 IS 3 BP 127 EP 135 DI 10.1016/j.tibs.2004.01.003 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 806VN UT WOS:000220461500005 PM 15003270 ER PT J AU Byfield, SD Roberts, AB AF Byfield, SD Roberts, AB TI Lateral signaling enhances TGF-beta response complexity SO TRENDS IN CELL BIOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; EARLY XENOPUS DEVELOPMENT; I RECEPTORS; L3 LOOP; ACTIVIN; ACTIVATION; SPECIFICITY; ENDOTHELIUM; EXPRESSION; PATHWAYS AB TGF-beta elicits context-dependent and cell-specific effects that often appear conflicting, such as stimulation or inhibition of growth, apoptosis or differentiation. It is puzzling how such a diverse array of responses can result from binding of TGF-beta to a single receptor complex that activates a seemingly straightforward signal-transduction scheme dependent on shuttling of Smad transducer proteins from the receptor to the nucleus. Here, we discuss a novel paradigm for TGF-beta signaling in endothelial cells in which the same ligand can induce opposing effects mediated by activation of two different classes of Smads through a chimeric receptor complex. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. EM Robertsa@dce41.nci.nih.gov NR 26 TC 40 Z9 44 U1 0 U2 0 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 MAR PY 2004 VL 14 IS 3 BP 107 EP 111 PG 5 WC Cell Biology SC Cell Biology GA 806VG UT WOS:000220460800002 PM 15055198 ER PT J AU Shah, BH Catt, KJ AF Shah, BH Catt, KJ TI Matrix metalloproteinases in reproductive endocrinology SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID GONADOTROPIN-RELEASING-HORMONE; EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR TRANSACTIVATION; PROTEIN-COUPLED RECEPTORS; EGF RECEPTOR; CARDIAC-HYPERTROPHY; SECRETION; EXPRESSION; ACTIVATION; CELLS AB One of the most common mechanisms for transactivation of epidermal growth factor receptor (EGF-R) by G protein-coupled receptors (GPCRs) is through the release of local EGF-like ligands from transmembrane precursors by the proteolytic action of matrix metalloproteinases (MMPs). These enzymes are crucial factors in the normal physiology of the reproductive system and also participate in neuroendocrine regulation through mediation of gonadotropin-releasing hormone (GnRH) action. Recent studies by Roelle et al. showed that GnRH-induced activation of the EGF-R and extracellular signal-regulated kinases 1 and 2 (ERK1/2) in pituitary gonadotrophs occurs through ectodomain shedding of heparin binding-EGF (HB-EGF) by MMP2 and MMP9, indicating a crucial role for MMPs in GnRH signaling. C1 NICHHD, Sect Hormonal Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Shah, BH (reprint author), NICHHD, Sect Hormonal Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM shahb@mail.nih.gov NR 17 TC 23 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2004 VL 15 IS 2 BP 47 EP 49 DI 10.1016/j.tem.2004.01.004 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 804VN UT WOS:000220326300001 PM 15080147 ER PT J AU Paolini, M Sapone, A Gonzalez, FJ AF Paolini, M Sapone, A Gonzalez, FJ TI Parkinson's disease, pesticides and individual vulnerability SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID ENVIRONMENTAL RISK-FACTORS; S-TRANSFERASE M1; DOPAMINERGIC-NEURONS; POLYMORPHISMS; EXPOSURE; GENE; SUSCEPTIBILITY; PARAQUAT; DEGENERATION; INSECTICIDES AB Current theories suggesting that degeneration of the nigrostriatal pathway following pesticide exposure could be a cause of Parkinson's disease (PD) are supported by epidemiological data linking environmental factors to an increased risk of parkinsonism. PD in humans is therefore thought to be a function of genetic predisposition, potentially associated with how efficiently an individual is able to metabolize dopamine-related neurotoxins. However, meta-analyses of susceptibility studies have failed to demonstrate clear-cut links between polymorphisms of xenobiotic-metabolizing enzymes (XMEs) and PD. We hypothesize that PD-related vulnerability to pesticides is linked to a strictly personal 'chemico-genetic XME blend' involving many variables. Innate XME genetic fingerprints undergo acquired 'modulations', which in turn are influenced by a myriad of individual exposures to chemical mixtures of environmental pollutants. We make a series of suggestions for the design of susceptibility studies focusing on persistent exposure to a specific pesticide in genetically defined population subsets of workers and gardeners within a geographically defined area. C1 Univ Bologna, Alma Mater Studiorum, Dept Pharmacol, I-40126 Bologna, Italy. NCI, NIH, Bethesda, MD 20892 USA. RP Paolini, M (reprint author), Univ Bologna, Alma Mater Studiorum, Dept Pharmacol, Via Irnerio 48, I-40126 Bologna, Italy. EM paolini@biocfarm.unibo.it RI Sapone, Andrea/E-6704-2013; OI Sapone, Andrea/0000-0001-8496-6977; paolini, moreno/0000-0002-2338-8859 NR 45 TC 36 Z9 36 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2004 VL 25 IS 3 BP 124 EP 129 DI 10.1016/j.tips.2004.01.007 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 806VT UT WOS:000220462100004 PM 15019266 ER PT J AU Hasko, G Sitkovsky, MV Szabo, C AF Hasko, G Sitkovsky, MV Szabo, C TI Immunomodulatory and neuroprotective effects of inosine SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; ISCHEMIA-REPERFUSION INJURY; ADENOSINE RECEPTOR AGONISTS; MAST-CELL DEGRANULATION; RETINAL GANGLION-CELLS; TUMOR-NECROSIS-FACTOR; MULTIPLE-SCLEROSIS; A(3) RECEPTORS; IMPROVES SURVIVAL; ANIMAL-MODELS AB Adenosine has been considered as a potential immunomodulatory and neuroprotective agent for 30 years. Inosine, a major degradation product of adenosine, was thought originally to have no biological effects. However, recent studies demonstrate that inosine has potent immunomodulatory and neuroprotective effects. Inosine enhances mast-cell degranulation, attenuates the production of pro-inflammatory mediators by macrophages, lymphocytes and neutrophils, and is protective in animal models of sepsis, ischemia-reperfusion and autoimmunity. Inosine preserves the viability of glial cells and neuronal cells during hypoxia, and stimulates axonal regrowth after injury. The biological actions of inosine might involve effects on adenosine receptors, poly(ADP-ribose) polymerase and cellular energy levels. In this article, we review recent observations indicating that it might be possible to exploit inosine therapeutically for the treatment of tissue damage caused by inflammation and ischemia. C1 Inotek Pharmaceut Corp, Beverly, MA 01915 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1450 Budapest, Hungary. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Sch Med, Inst Human Physiol & Clin Expt Res, H-1082 Budapest, Hungary. RP Szabo, C (reprint author), Inotek Pharmaceut Corp, Beverly, MA 01915 USA. EM szabocsaba@aol.com FU NIGMS NIH HHS [R43 GM 59676, R01 GM 66189] NR 65 TC 117 Z9 123 U1 3 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2004 VL 25 IS 3 BP 152 EP 157 DI 10.1016/j.tips.2004.01.006 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 806VT UT WOS:000220462100009 PM 15019271 ER PT J AU Starost, MF Hill, LR Nehete, PN Sastry, KJ AF Starost, MF Hill, LR Nehete, PN Sastry, KJ TI Extramedullary hematopoiesis in the mandibular lymph node of simian-human immunodeficiency virus-infected rhesus monkeys (Macaca mulatta): A report of three cases SO VETERINARY PATHOLOGY LA English DT Article DE extramedullary hematopoiesis; lymph node; Macaca mulatta; rhesus monkeys ID MARMOSETS CALLITHRIX-JACCHUS; HEREDITARY SPHEROCYTOSIS; MYELOID METAPLASIA; HEMOLYTIC-ANEMIA; EXPRESSION; PATHOLOGY; PATIENT; BLOOD AB Three cases of extramedullary hematopoiesis (EMH) in the mandibular lymph nodes of rhesus monkeys, experimentally infected intravenously with a chimeric simian human immunodeficiency virus, are described. On histopathologic evaluation, multiple sections of mandibular lymph node from all animals showed evidence of EMH, which included erythroid, myeloid, or megakaryocytic precursor cells (or all) within the medullary sinuses. Immunohistochemistry was used for positive identification of multiple cell types. Evidence of EMH was not observed in numerous sections of axillary, inguinal, cervical, hilar, or mesenteric lymph nodes or in any other tissues examined. To our knowledge, this is the first report on EMH within the lymph nodes of rhesus monkeys without an obvious underlying disease process or stringent blood-sampling schedule warranting the need for increased hematopoiesis outside the confines of the bone marrow. C1 NIH, Natl Ctr Res Resources, Vet Resources Program, Bethesda, MD 20892 USA. RP Starost, MF (reprint author), NIH, Natl Ctr Res Resources, Vet Resources Program, Bldg 28A,Room 115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM starostm@mail.nih.gov FU NIAID NIH HHS [AI 42694] NR 30 TC 2 Z9 2 U1 0 U2 0 PU AMER COLL VET PATHOLOGIST PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2004 VL 41 IS 2 BP 186 EP 190 DI 10.1354/vp.41-2-186 PG 5 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 803QX UT WOS:000220246700015 PM 15017035 ER PT J AU Chomel, BB Kikuchi, Y Martenson, JS Roelke-Parker, ME Chang, CC Kasten, RW Foley, JE Laudre, J Murphy, K Swift, PK Kramer, VL O'Brien, SJ AF Chomel, BB Kikuchi, Y Martenson, JS Roelke-Parker, ME Chang, CC Kasten, RW Foley, JE Laudre, J Murphy, K Swift, PK Kramer, VL O'Brien, SJ TI Seroprevalence of Bartonella infection in American free-ranging and captive pumas (Felis concolor) and bobcats (Lynx rufus) SO VETERINARY RESEARCH LA English DT Article DE Bartonella henselae; bobcat; Felis concolor; Lynx rufus; puma ID CAT-SCRATCH DISEASE; ROCHALIMAEA-HENSELAE INFECTION; DOMESTIC CATS; PREVALENCE; ANTIBODY; CLARRIDGEIAE; SIPHONAPTERA; INOCULATION; CALIFORNIA; BACTEREMIA AB Bartonella henselae is the main agent of cat scratch disease in humans and domestic cats are the main reservoir of this bacterium. We conducted a serosurvey to investigate the role of American wild felids as a potential reservoir of Bartonella species. A total of 479 samples (439 serum samples and 40 Nobuto strips) collected between 1984 and 1999 from pumas (Felis concolor) and 91 samples (58 serum samples and 33 Nobuto strips) collected from bobcats (Lynx rufus) in North America, Central America and South America were screened for B. henselae antibodies. The overall prevalence of B. henselae antibodies was respectively 19.4% in pumas and 23.1% in bobcats, with regional variations. In the USA, pumas from the southwestern states were more likely to be seropositive for B. henselae (prevalence ratio (PR) = 2.82,95% confidence interval (CI)= 1.55, 5.11) than pumas from the Northwest and Mountain states. Similarly, adults were more likely to be B. henselae seropositive than juveniles and kittens (PR = 1.77, 95% CI = 1.07, 2.93). Adult pumas were more likely to have higher B. henselae antibody titers than juveniles and kittens (p = 0.026). B. henselae antibody prevalence was 22.4% (19/85) in bobcats from the USA and 33.3% (2/6) in the Mexican bobcats. In the USA, antibody prevalence varied depending on the geographical origin of the bobcats. In California, the highest prevalence was in bobcats from the coastal range (37.5%). These results suggest a potential role of wild felids in the epidemiological cycle of Bartonella henselae or closely related Bartonella species. C1 Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Univ Calif Davis, Sch Vet Med, Dept Med & Epidemiol, Davis, CA 95616 USA. Idaho State Univ, Dept Biol Sci, Pocatello, ID USA. Hornocker Wildlife Res Inst, Moscow, ID 83843 USA. Calif Dept Fish & Game, Wildlife Invest Lab, Rancho Cordova, CA 95670 USA. Calif Dept Hlth Serv, Div Vector Borne Dis, Sacramento, CA 94234 USA. RP Chomel, BB (reprint author), Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM bbchomel@ucdavis.edu OI Chang, Chao-chin/0000-0002-6299-9214 NR 25 TC 13 Z9 13 U1 2 U2 7 PU E D P SCIENCES PI LES ULIS CEDEXA PA 7, AVE DU HOGGAR, PARC D ACTIVITES COURTABOEUF, BP 112, F-91944 LES ULIS CEDEXA, FRANCE SN 0928-4249 J9 VET RES JI Vet. Res. PD MAR-APR PY 2004 VL 35 IS 2 BP 233 EP 241 DI 10.1051/vetres:2004001 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA 825MB UT WOS:000221761500007 PM 15099499 ER PT J AU Kaesler, S Bugnon, P Gao, JL Murphy, PM Goppelt, A Werner, S AF Kaesler, S Bugnon, P Gao, JL Murphy, PM Goppelt, A Werner, S TI The chemokine receptor CCR1 is strongly up-regulated after skin injury but dispensable for wound healing SO WOUND REPAIR AND REGENERATION LA English DT Article ID MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; GENETICALLY DIABETIC MOUSE; TRANSGENIC MICE REVEALS; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; GROWTH-FACTORS; HOST-DEFENSE; REPAIR; INFECTION; TISSUE AB To identify key regulators of cutaneous wound repair, we analyzed a subtractive cDNA library of normal and wounded mouse skin. One of the identified genes encodes the chemokine receptor CCR1, which binds several chemokines present at the wound site. Expression of CCR1 was barely detectable in nonwounded skin, but strong up-regulation was observed after injury to wild-type mice. Most important, the healing abnormalities observed in glucocorticoid-treated mice and activin-overexpressing transgenic mice correlated with an altered expression of CCR1. CCR1-positive cells were identified as macrophages and neutrophils within the wounded area. To determine the importance of CCR1 for wound repair, we analyzed this process in CCR1 knockout mice. Surprisingly, no alterations in either wound closure, wound appearance, wound bursting strength, granulation tissue formation, or re-epithelialization were observed. In addition, the inflammatory response was unaltered in CCR1-deficient mice and the expression of several chemokines, chemokine receptors, and other important regulators of wound repair were normal in these animals. These results show that CCR1 is dispensable for wound healing, most likely due to redundancy in chemokine/chemokine receptor signaling. C1 ETH, Inst Cell Biol, CH-8093 Zurich, Switzerland. ETH, Dept Biol, CH-8093 Zurich, Switzerland. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Switch Biotech AG, Neuried, Germany. RP Werner, S (reprint author), ETH, Inst Cell Biol, CH-8093 Zurich, Switzerland. EM Sabine.werner@cell.biol.ethz.ch OI Goppelt, Andreas/0000-0002-0780-1332 NR 54 TC 17 Z9 17 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2004 VL 12 IS 2 BP 193 EP 204 DI 10.1111/j.1067-1927.2004.012112.x PG 12 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 812QA UT WOS:000220852800010 PM 15086771 ER PT J AU Wan, J Bae, MA Song, BJ AF Wan, J Bae, MA Song, BJ TI Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE acetaminophen; cytochrome p450 CYP2E1; DNA repair enzymes ID ACETAMINOPHEN HEPATOTOXICITY; COVALENT BINDING; EXCISION-REPAIR; RAT; DAMAGE; PARACETAMOL; PROTEIN; MICE; GENE; 8-HYDROXYGUANINE AB Large doses of acetaminophen (APAP) could cause oxidative stress and tissue damage through production of reactive oxygen/nitrogen (ROS/RNS) species and quinone metabolites of APAP. Although ROS/RNS are known to modify DNA, the effect of APAP on DNA modifications has not been studied systematically. In this study, we investigate whether large doses of APAP can modify the nuclear DNA in C6 glioma cells used as a model system, because these cells contain cytochrome P450-related enzymes responsible for APAP metabolism and subsequent toxicity (Geng and Strobel, 1995). Our results revealed that APAP produced ROS and significantly elevated the 8-oxodeoxyguanosine (8-oxodG) levels in the nucleus of C6 glioma cells in a time and concentration dependent manner. APAP significantly reduced the 8-oxodG incision activity in the nucleus by decreasing the activity and content of a DNA repair enzyme, Ogg1. These results indicate that APAP in large doses can increase the 8-oxodG level partly through significant reduction of Ogg1 DNA repair enzyme. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Univ Utah, Sch Med, Dept Pharmacol & Toxicol, Salt Lake City, UT USA. Korea Res Inst Chem Technol, Ctr Biol Modulator, Taejon, South Korea. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. EM bjs@mail.nih.gov NR 38 TC 17 Z9 19 U1 0 U2 0 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD FEB 29 PY 2004 VL 36 IS 1 BP 71 EP 77 PG 7 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 805VF UT WOS:000220393100010 PM 15031674 ER PT J AU Shea, TB Yabe, JT Ortiz, D Pimenta, A Loomis, P Goldman, RD Amin, N Pant, HC AF Shea, TB Yabe, JT Ortiz, D Pimenta, A Loomis, P Goldman, RD Amin, N Pant, HC TI Cdk5 regulates axonal transport and phosphorylation of neurofilaments in cultured neurons SO JOURNAL OF CELL SCIENCE LA English DT Article DE cdk5; p35; neurofilaments; axonal transport; phosphorylation; neurofibrillary pathology ID AMYOTROPHIC-LATERAL-SCLEROSIS; DEPENDENT KINASE-5 ACTIVITY; C-TERMINAL PHOSPHORYLATION; SUBUNIT NF-H; TRANSGENIC MICE; NEURITE OUTGROWTH; CELL NEURONS; IN-VIVO; P35; CALIBER AB Phosphorylation has long been considered to regulate neurofilament (NF) interaction and axonal transport, and, in turn, to influence axonal stability and their maturation to large-caliber axons. Cdk5, a serine/threonine kinase homologous to the mitotic cyclin-dependent kinases, phosphorylates NF subunits in intact cells. In this study, we used two different haptenized NF subunits and manipulated cdk5 activity by microinjection, transfection and pharmacological inhibition to monitor the effect of Cdk5-p35 on NF dynamics and transport. We demonstrate that overexpression of cdk5 increases NF phosphorylation and inhibits NF axonal transport, whereas inhibition both reduces NF phosphorylation and enhances NF axonal transport in cultured chicken dorsal-root-ganglion neurons. Large phosphorylated-NF 'bundles' were prominent in perikarya following cdk5 overexpression. These findings suggest that Cdk5-p35 activity regulates normal NF distribution and that overexpression of Cdk5-p35 induces perikaryal accumulation of phosphorylated-NFs similar to those observed under pathological conditions. C1 Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Biol Sci, Lowell, MA 01854 USA. Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Biochem, Lowell, MA 01854 USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Shea, TB (reprint author), Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Biol Sci, 1 Univ Ave, Lowell, MA 01854 USA. EM thomas_shea@uml.edu NR 56 TC 55 Z9 58 U1 1 U2 4 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 29 PY 2004 VL 117 IS 6 BP 933 EP 941 DI 10.1242/jcs.00785 PG 9 WC Cell Biology SC Cell Biology GA 804JI UT WOS:000220294600014 PM 14762105 ER PT J AU Cha, SW Hwang, YS Chae, JP Lee, SY Lee, HS Daar, I Park, MJ Kim, J AF Cha, SW Hwang, YS Chae, JP Lee, SY Lee, HS Daar, I Park, MJ Kim, J TI Inhibition of FGF signaling causes expansion of the endoderm in Xenopus SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Xenopus; FGF; mesendoderm specification; embryogenesis ID MESODERM INDUCTION; MATERNAL VEGT; EMBRYOS; SPECIFICATION; RECEPTOR; EXPRESSION; MUTANT; LAEVIS; VG1 AB Fibroblast growth factor (FGF) is established as an initiator of signaling events critical for neurogenesis and mesoderm formation during early Xenopus embryogenesis. However, less is known about the role FGF signaling plays in endoderm specification. Here, we show for the first time that endoderm-specific genes are induced when FGF signaling is blocked in animal cap explants. This block of FGF signaling is also responsible for a significant enhancement of endodermal gene expression in animal cap explants that are injected with a dominant-negative BMP-4 receptor (DNBR) RNA or treated with activin, however, neural and mesoderm gene expression is diminished. Consistent with these results, the injection of dominant-negative FGF receptor (DNFR) RNA expands endodermal cell fate boundaries while FGF treatment dramatically reduces endoderm in whole embryos. Taken together, these results indicate that inhibition of FGF signaling promotes endoderm formation, whereas the presence of active FGF signaling is necessary for neurogenesis/mesoderm formation. (C) 2004 Elsevier Inc. All rights reserved. C1 Kyungpook Natl Univ, Dept Anat, Sch Med, Taegu 700422, South Korea. Hallym Univ, Dept Biochem, Coll Med, Chunchon 200702, South Korea. Natl Canc Inst, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Park, MJ (reprint author), Kyungpook Natl Univ, Dept Anat, Sch Med, Taegu 700422, South Korea. EM mjpark@knu.ac.kr; jbkim@hallym.ac.kr RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X NR 29 TC 12 Z9 12 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 FEB 27 PY 2004 VL 315 IS 1 BP 100 EP 106 DI 10.1016/j.bbrc.2004.01.019 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 774EH UT WOS:000188966400015 PM 15013431 ER PT J AU Jonassen, AK Mjos, OD Sack, MN AF Jonassen, AK Mjos, OD Sack, MN TI P70s6 kinase is a functional target of insulin-activated Akt cell-survival signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE insulin; p70s6 kinase; cytoprotection; apoptosis ID ACUTE MYOCARDIAL-INFARCTION; S6 KINASE; ISCHEMIA-REPERFUSION; GENE-TRANSFER; GROWTH-FACTOR; IN-VIVO; PATHWAYS; INJURY; SIZE; APOPTOSIS AB Insulin administration attenuates cardiac ischemia-reperfusion apoptosis via activation of Akt-mediated cell-survival signaling. As p70s6 kinase is a cognate Akt-mediated phosphorylation target we evaluated whether p70s6 kinase activation is a functional requirement in insulin-mediated cell survival program during post-ischemic reoxygenation. Human cardiac-derived girardi cells were subjected to 6 h of simulated ischemia and 2 h of reoxygenation +/- insulin treatment [0.3 mU/ml]. Concurrently, cells were pre-treated with anti-sense oligodeoxynucleotides (ODNs) corresponding to the initiation start-site of human p70s6 kinase mRNA. Sense ODN and scrambled ODN were used as controls. Cell viability was measured using lactate dehydrogenase (LDH) release and propidium iodide (PI) exclusion. Insulin at reoxygenation enhanced cell viability with attenuated LDH release ( greater than or equal to 50%, p < 0.001 vs. ischemic controls) and reduced PI uptake by greater than or equal to 30% vs. ischemic controls. The protection afforded by insulin was abolished by anti-sense ODN targeting p70s6 kinase, but not by the sense or scrambled ODNs. In parallel, insulin administration at reoxygenation significantly increased p70s6 kinase levels and activity compared with controls. P70s6 kinase activity was abolished by pre-treatment with anti-sense ODNs. Collectively, these data demonstrate that p70s6 kinase activation is a functional target of Akt following insulin-activated cytoprotection during ischemia-reoxygenation-induced injury. Published by Elsevier Inc. C1 Univ Cape Town, Sch Med, Hatter Inst Cardiol Res, Cape Town, South Africa. Univ Tromso, Inst Med Biol, Dept Med Physiol, Tromso, Norway. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD USA. RP Sack, MN (reprint author), Univ Cape Town, Sch Med, Hatter Inst Cardiol Res, Cape Town, South Africa. EM Sackm@nih.gov NR 26 TC 32 Z9 34 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 27 PY 2004 VL 315 IS 1 BP 160 EP 165 DI 10.1016/j.bbrc.2004.01.029 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 774EH UT WOS:000188966400024 PM 15013440 ER PT J AU Berman, JJ Datta, M Kajdacsy-Balla, A Melamed, J Orenstein, J Dobbin, K Patel, A Dhir, R Becich, MJ AF Berman, JJ Datta, M Kajdacsy-Balla, A Melamed, J Orenstein, J Dobbin, K Patel, A Dhir, R Becich, MJ TI The tissue microarray data exchange specification: implementation by the Cooperative Prostate Cancer Tissue Resource SO BMC BIOINFORMATICS LA English DT Article ID PROLIFERATION AB Background: Tissue Microarrays (TMAs) have emerged as a powerful tool for examining the distribution of marker molecules in hundreds of different tissues displayed on a single slide. TMAs have been used successfully to validate candidate molecules discovered in gene array experiments. Like gene expression studies, TMA experiments are data intensive, requiring substantial information to interpret, replicate or validate. Recently, an open access Tissue Microarray Data Exchange Specification has been released that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. While this specification provides sufficient information for the reproduction of the experiment by outside research groups, its initial description did not contain instructions or examples of actual implementations, and no implementation studies have been published. The purpose of this paper is to demonstrate how the TMA Data Exchange Specification is implemented in a prostate cancer TMA. Results: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is funded by the National Cancer Institute to provide researchers with samples of prostate cancer annotated with demographic and clinical data. The CPCTR now offers prostate cancer TMAs and has implemented a TMA database conforming to the new open access Tissue Microarray Data Exchange Specification. The bulk of the TMA database consists of clinical and demographic data elements for 299 patient samples. These data elements were extracted from an Excel database using a transformative Perl script. The Perl script and the TMA database are open access documents distributed with this manuscript. Conclusions: TMA databases conforming to the Tissue Microarray Data Exchange Specification can be merged with other TMA files, expanded through the addition of data elements, or linked to data contained in external biological databases. This article describes an open access implementation of the TMA Data Exchange Specification and provides detailed guidance to researchers who wish to use the Specification. C1 NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Pathol, Milwaukee, WI 53201 USA. Univ Illinois, Med Ctr, Dept Pathol, Chicago, IL USA. New York Med Ctr, Dept Pathol, New York, NY USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. Univ Pittsburgh, Med Ctr, Ctr Pathol Informat, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Benedum Oncol Informat Ctr, Pittsburgh, PA USA. RP Berman, JJ (reprint author), NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. EM bermanj@mail.nih.gov; mdatta@mcw.edu; aballa@uic.edu; Jonathan.melamed@med.nyu.edu; jorenstein@mfa.gwu.edu; dobbinke@mail.nih.gov; patelaa@MSX.UPMC.EDU; dhirr@MSX.UPMC.EDU; becich@msx.upmc.edu FU NCI NIH HHS [U01 CA86772, U01 CA086735, U01 CA086739, U01 CA086743, U01 CA086772, U01 CA86735, U01 CA86739, U01 CA86743] NR 9 TC 24 Z9 26 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 27 PY 2004 VL 5 AR 19 DI 10.1186/1471-2105-5-19 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 814OR UT WOS:000220984500001 PM 15040818 ER PT J AU Zhang, RX Lao, LX Qiao, HT Ruda, MA AF Zhang, RX Lao, LX Qiao, HT Ruda, MA TI Effects of aging on hyperalgesia and spinal dynorphin expression in rats with peripheral inflammation SO BRAIN RESEARCH LA English DT Article DE Freund's adjuvant; serotonin; substance P; inflammation; persistent pain; spinal cord ID NEUROPATHIC PAIN; AGED RATS; INDUCED ANALGESIA; MONOAMINE LEVELS; ADVANCING AGE; DORSAL HORN; BRAIN; CORD; NOCICEPTION; RESPONSES AB The aging process is associated with various morphological and biochemical changes in the nervous system that may affect the processing of noxious inputs. This study showed greater hyperalgesia and up-regulation of spinal dynorphin (DYN) expression in aging than in young adult rats during CFA-induced peripheral inflammation. These data indicate that nociception is regulated differently in aging individuals, a fact that should be considered when selecting treatment strategies for aging populations with persistent pain. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Maryland, Sch Med, James Kernan Hosp Mans, Ctr Integrat Med, Baltimore, MD 21207 USA. Shanxi Med Univ, Dept Neurobiol, Shanxi 030001, Peoples R China. NIDCR, Pain & Neurosensory Mechan Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, RX (reprint author), Univ Maryland, Sch Med, James Kernan Hosp Mans, Ctr Integrat Med, 2200 Kernan Dr, Baltimore, MD 21207 USA. EM Rzhan001@umaryland.edu RI Lao, Lixing/I-7979-2013; OI Lao, Lixing/0000-0003-0198-9714 NR 46 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 27 PY 2004 VL 999 IS 1 BP 135 EP 141 DI 10.1016/j.brainres.2003.11.042 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 775ZU UT WOS:000189091200016 PM 14746931 ER PT J AU Hakli, M Lorick, KL Weissman, AM Janne, OA Palvimo, JJ AF Hakli, M Lorick, KL Weissman, AM Janne, OA Palvimo, JJ TI Transcriptional coregulator SNURF (RNF4) possesses ubiquitin E3 ligase activity SO FEBS LETTERS LA English DT Article DE SNURF/RNF4; transcriptional coregulator; E3 ubiquitin ligase; RING finger ID RING FINGER PROTEIN; CONJUGATING ENZYME; ENDOPLASMIC-RETICULUM; RECEPTOR; DEGRADATION; IDENTIFICATION; P53; BRCA1-BARD1; ACTIVATION; MECHANISMS AB SNURF/RNF4 has been implicated in transcriptional regulation and growth inhibition in a RING finger-dependent fashion. In this work, we show that SNURF mediates its own ubiquitination in vitro in a ubiquitin-conjugating enzyme (E2)-selective manner: SNURF acts as an E3 ligase with UbcH5A and B, HHR6B (RAD6B), E2-25K, MmUbc7 and UbcH13, but not with UbcH3, UbcM4, MmUbc6 or E2-20K. In contrast, the well-characterized RING E3, AO7, functions only with members of the UbcH5 family. Furthermore, depending on the E2 used, the ubiquitin modification manifests as mono- or multi-ubiquitination. Mutation of conserved cysteine residues within the RING finger motif of SNURF abolishes the ubiquitination in vitro and in intact cells. Size fractionation of murine embryonal carcinoma F9 cell proteins shows that the majority of endogenous SNURF resides in salt-resistant greater than or equal to500-kDa complexes, suggesting that SNURF functions as a RING component in a multiprotein complex. Taken together, SNURF/RNF4 functions as an E3 ligase and this activity is closely linked to its transcription regulatory functions. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Univ Helsinki, Inst Biomed, Biomedicum Helsinki, FIN-00014 Helsinki, Finland. NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Univ Helsinki, Dept Clin Chem, FIN-00014 Helsinki, Finland. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. RP Palvimo, JJ (reprint author), Univ Helsinki, Inst Biomed, Biomedicum Helsinki, FIN-00014 Helsinki, Finland. EM jorma.palvimo@helsinki.fi NR 43 TC 35 Z9 36 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 27 PY 2004 VL 560 IS 1-3 BP 56 EP 62 DI 10.1016/S0014-5793(04)00070-5 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 779YA UT WOS:000189328900012 PM 14987998 ER PT J AU Krieg, RC Liotta, LA Petricoin, EF Herrmann, PC AF Krieg, RC Liotta, LA Petricoin, EF Herrmann, PC TI Trapping radioactive carbon dioxide during cellular metabolic assays under standard culture conditions: description of a unique gas-capturing device SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE metabolism; physiological; carbon dioxide; radioactivity ID DECARBOXYLATION; GLUCOSE; CELLS AB Measurement of carbon dioxide levels has been employed to follow cellular metabolic reactions for quite some time. By radio-labeling substrate molecules and evaluating the radioactivity levels of the carbon dioxide released, insight into metabolic pathways can be gleaned. Currently, no carbon dioxide capturing device is available that can be used with large volume cell monolayers growing under standard conditions within a regular commercially available culture flask. In this note we describe a simple device for collecting radio-labeled carbon dioxide from a standard culture flask. The device is independent of the culture flask, but can be attached for metabolic measurements allowing cells to be grown under standard conditions prior to study. The presented design permits convenient transfer of the device between flasks without contaminating or disturbing cells growing within the flasks. Data are presented demonstrating the reproducibility of measurements made with multiple devices with different substrate concentrations and varying periods of time, ranging up to 3 h. Published by Elsevier B.V. C1 NCI, FDA, Clin Proteom Program, Pathol Lab,NIH, Bethesda, MD 20892 USA. US FDA, CBER, Off Director, Clin Proteom Program, Bethesda, MD 20892 USA. RP Herrmann, PC (reprint author), NCI, FDA, Clin Proteom Program, Pathol Lab,NIH, 10 Ctr Dr,Bldg 10 Room 2n212, Bethesda, MD 20892 USA. EM herrmanp@mail.nih.gov NR 8 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD FEB 27 PY 2004 VL 58 IS 2 BP 119 EP 124 DI 10.1016/j.jbbm.2003.10.002 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 801SF UT WOS:000220114900003 PM 14980785 ER PT J AU Johnson, AA Sayer, JM Yagi, H Kalena, GP Amin, R Jerina, DM Pommier, Y AF Johnson, AA Sayer, JM Yagi, H Kalena, GP Amin, R Jerina, DM Pommier, Y TI Position-specific suppression and enhancement of HIV-1 integrase reactions by minor groove benzo[a]pyrene diol epoxide deoxyguanine adducts - Implications for molecular interactions between integrase and DNA substrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VIRUS TYPE-1 INTEGRASE; TOPOISOMERASE-I; CLEAVAGE SITE; PROTEIN; SEQUENCE; COMPLEXES; BINDING; POLYAMIDES; DOMAINS; VITRO AB The viral protein HIV-1 integrase is required for insertion of the viral genome into human chromosomes and for viral replication. Integration proceeds in two consecutive integrase-mediated reactions: 3'-processing and strand transfer. To investigate the DNA minor groove interactions of integrase relative to known sites of integrase action, we synthesized oligodeoxynucleotides containing single covalent adducts of known absolute configuration derived from trans-opening of benzo[ a] pyrene 7,8-diol9,10-epoxide by the exocyclic 2-amino group of deoxyguanosine at specific positions in a duplex sequence corresponding to the terminus of the viral U5 DNA. Because the orientations of the hydrocarbon in the minor groove are known from NMR solution structures of duplex oligonucleotides containing these deoxyguanosine adducts, a detailed analysis of the relationship between the position of minor groove ligands and integrase interactions is possible. Adducts placed in the DNA minor groove two or three nucleotides from the 3'-processing site inhibited both 3'-processing and strand transfer. Inosine substitution showed that the guanine 2-amino group is required for efficient 3'-processing at one of these positions and for efficient strand transfer at the other. Mapping of the integration sites on both strands of the DNA substrates indicated that the adducts both inhibit strand transfer specifically at the minor groove bound sites and enhance integration at sites up to six nucleotides away from the adducts. These experiments demonstrate the importance of position-specific minor groove contacts for both the integrase-mediated 3'-processing and strand transfer reactions. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 31 TC 7 Z9 7 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 FEB 27 PY 2004 VL 279 IS 9 BP 7947 EP 7955 DI 10.1074/jbc.M311263200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300072 PM 14627697 ER PT J AU Watabe, H Valencia, JC Yasumoto, K Kushimoto, T Ando, H Muller, J Vieira, WD Mizoguchi, M Appella, E Hearing, VJ AF Watabe, H Valencia, JC Yasumoto, K Kushimoto, T Ando, H Muller, J Vieira, WD Mizoguchi, M Appella, E Hearing, VJ TI Regulation of tyrosinase processing and trafficking by organellar pH and by proteasome activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; MOUSE MELANOMA-CELLS; B-16 MURINE MELANOMA; VACUOLAR H+-ATPASE; ENDOPLASMIC-RETICULUM; OCULOCUTANEOUS ALBINISM; MAMMALIAN TYROSINASE; GENE-PRODUCT; HUMAN-SKIN; INTRACELLULAR TRAFFICKING AB Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum ( ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYR-positive amelanotic melanoma cells. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Div Viral Prod, Rockville, MD 20852 USA. St Marianna Univ, Sch Med, Dept Dermatol, Kawasaki, Kanagawa 2168511, Japan. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 1B25, Bethesda, MD 20892 USA. EM hearingv@nih.gov NR 81 TC 74 Z9 75 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2004 VL 279 IS 9 BP 7971 EP 7981 DI 10.1074/jbc.M309714200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300075 PM 14634018 ER PT J AU Kim, OJ Gardner, BR Williams, DB Marinec, PS Cabrera, DM Peters, JD Mak, CC Kim, KM AF Kim, OJ Gardner, BR Williams, DB Marinec, PS Cabrera, DM Peters, JD Mak, CC Kim, KM TI The role of phosphorylation in D-1 dopamine receptor desensitization - Evidence for a novel mechanism of arrestin association SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AGONIST-INDUCED DESENSITIZATION; PROTEIN-COUPLED RECEPTORS; CYTOPLASMIC TAIL; DEPENDENT PHOSPHORYLATION; DIFFERENTIAL REGULATION; BETA-ARRESTINS; ACTIVATION; BINDING; KINASE; IDENTIFICATION AB Homologous desensitization of D-1 dopamine receptors is thought to occur through their phosphorylation leading to arrestin association which interdicts G protein coupling. In order to identify the relevant domains of receptor phosphorylation, and to determine how this leads to arrestin association, we created a series of mutated D-1 receptor constructs. In one mutant, all of the serine/threonine residues within the 3rd cytoplasmic domain were altered (3rdTOT). A second construct was created in which only three of these serines (serines 256, 258, and 259) were mutated (3rd234). We also created four truncation mutants of the carboxyl terminus (T347, T369, T394, and T404). All of these constructs were comparable with the wild-type receptor with respect to expression and adenylyl cyclase activation. In contrast, both of the 3rd loop mutants exhibited attenuated agonist-induced receptor phosphorylation that was correlated with an impaired desensitization response. Sequential truncation of the carboxyl terminus of the receptor resulted in a sequential loss of agonist-induced phosphorylation. No phosphorylation was observed with the most severely truncated T347 mutant. Surprisingly, all of the truncated receptors exhibited normal desensitization. The ability of the receptor constructs to promote arrestin association was evaluated using arrestin-green fluorescent protein translocation assays and confocal fluorescence microscopy. The 3rd234 mutant receptor was impaired in its ability to induce arrrestin translocation, whereas the T347 mutant was comparable with wild type. Our data suggest a model in which arrestin directly associates with the activated 3rd cytoplasmic domain in an agonist-dependent fashion; however, under basal conditions, this is sterically prevented by the carboxyl terminus of the receptor. Receptor activation promotes the sequential phosphorylation of residues, first within the carboxyl terminus and then the 3rd cytoplasmic loop, thereby dissociating these domains and allowing arrestin to bind to the activated 3rd loop. Thus, the role of receptor phosphorylation is to allow access of arrestin to its receptor binding domain rather than to create an arrestin binding site per se. C1 NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. Chonnam Natl Univ, Coll Pharm, Kwangju 500757, South Korea. RP Kim, KM (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, Bldg 10,Rm 5C108,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov RI Cabrera, David/I-1013-2014 FU Intramural NIH HHS [Z01 NS002263-31] NR 38 TC 64 Z9 67 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2004 VL 279 IS 9 BP 7999 EP 8010 DI 10.1074/jbc.M308281200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300078 PM 14660631 ER PT J AU Carlson, BA Novoselov, SV Kumaraswamy, E Lee, BJ Anver, MR Gladyshev, VN Hatfield, DL AF Carlson, BA Novoselov, SV Kumaraswamy, E Lee, BJ Anver, MR Gladyshev, VN Hatfield, DL TI Specific excision of the selenocysteine tRNA([Ser]Sec) (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLUTATHIONE-PEROXIDASE; TRANSFER-RNA; SELENIUM; CELLS; MICE; TRANSLATION; DISRUPTION; INSERTION; PATTERNS; PROTEIN AB Selenium is essential in mammalian embryonic development. However, in adults, selenoprotein levels in several organs including liver can be substantially reduced by selenium deficiency without any apparent change in phenotype. To address the role of selenoproteins in liver function, mice homozygous for a floxed allele encoding the selenocysteine (Sec) tRNA([Ser]Sec) gene were crossed with transgenic mice carrying the Cre recombinase under the control of the albumin promoter that expresses the recombinase specifically in liver. Recombination was nearly complete in mice 3 weeks of age, whereas liver selenoprotein synthesis was virtually absent, which correlated with the loss of Sec tRNA([Ser] Sec) and activities of major selenoproteins. Total liver selenium was dramatically decreased, whereas levels of low molecular weight selenocompounds were little affected. Plasma selenoprotein P levels were reduced by about 75%, suggesting that selenoprotein P is primarily exported from the liver. Glutathione S-transferase levels were elevated in the selenoprotein-deficient liver, suggesting a compensatory activation of this detoxification program. Mice appeared normal until about 24 h before death. Most animals died between 1 and 3 months of age. Death appeared to be due to severe hepatocellular degeneration and necrosis with concomitant necrosis of peritoneal and retroperitoneal fat. These studies revealed an essential role of selenoproteins in liver function. C1 NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. Seoul Natl Univ, Sch Biol Sci, Mol Genet Lab, Seoul 151742, South Korea. NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Hatfield, DL (reprint author), NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bldg 37,Rm 6016,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hatfield@dc37a.nci.nih.gov RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU NCI NIH HHS [N01-CO-12400]; NIGMS NIH HHS [GM061603, GM065204] NR 30 TC 104 Z9 105 U1 1 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 FEB 27 PY 2004 VL 279 IS 9 BP 8011 EP 8017 DI 10.1074/jbc.M310470200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300079 PM 14660662 ER PT J AU Mattera, R Ritter, B Sidhu, SS McPherson, PS Bonifacino, JS AF Mattera, R Ritter, B Sidhu, SS McPherson, PS Bonifacino, JS TI Definition of the consensus motif recognized by gamma-adaptin ear domains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACCESSORY PROTEIN RECRUITMENT; APPENDAGE DOMAIN; STRUCTURAL EXPLANATION; PHAGE DISPLAY; BINDING MOTIF; CLATHRIN; GOLGI; INTERACTS; SYNERGIN; COMPLEX AB The heterotetrameric adaptor complex 1 (AP-1) and the monomeric Golgi-localized, gamma ear-containing, Arf-binding (GGA) proteins are components of clathrin coats associated with the trans-Golgi network and endosomes. The carboxyl-terminal ear domains (or gamma-adaptin ear (GAE) domains) of two gamma-adaptin subunit isoforms of AP-1 and of the GGAs are structurally similar and bind to a common set of accessory proteins. In this study, we have systematically defined a core tetrapeptide motif PsiG(P/D/E)(Psi/L/M) (where Psi is an aromatic residue), which is responsible for the interactions of accessory proteins with GAE domains. The definition of this motif has allowed us to identify novel GAE-binding partners named NECAP and aftiphilin, which also contain clathrin-binding motifs. These findings shed light on the mechanism of accessory protein recruitment to trans-Golgi network and endosomal clathrin coats. C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA. RP Bonifacino, JS (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Ritter, Brigitte/0000-0002-0094-0460 NR 36 TC 43 Z9 51 U1 1 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 FEB 27 PY 2004 VL 279 IS 9 BP 8018 EP 8028 DI 10.1074/jbc.M311873200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300080 PM 14665628 ER PT J AU Botos, I Melnikov, EE Cherry, S Tropea, JE Khalatova, AG Rasulova, F Dauter, Z Maurizi, MR Rotanova, TV Wlodawer, A Gustchina, A AF Botos, I Melnikov, EE Cherry, S Tropea, JE Khalatova, AG Rasulova, F Dauter, Z Maurizi, MR Rotanova, TV Wlodawer, A Gustchina, A TI The catalytic domain of Escherichia coli Lon protease has a unique fold and a Ser-Lys dyad in the active site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ATP-DEPENDENT PROTEASE; BACTERIAL SIGNAL PEPTIDASE; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; PROTEOLYTIC DOMAIN; MITOCHONDRIAL LON; QUALITY-CONTROL; EGLIN-C; COMPLEX; LA AB ATP-dependent Lon protease degrades specific short-lived regulatory proteins as well as defective and abnormal proteins in the cell. The crystal structure of the proteolytic domain (P domain) of the Escherichia coli Lon has been solved by single-wavelength anomalous dispersion and refined at 1.75-Angstrom resolution. The P domain was obtained by chymotrypsin digestion of the full-length, proteolytically inactive Lon mutant (S679A) or by expression of a recombinant construct encoding only this domain. The P domain has a unique fold and assembles into hexameric rings that likely mimic the oligomerization state of the holoenzyme. The hexamer is dome-shaped, with the six N termini oriented toward the narrower ring surface, which is thus identified as the interface with the ATPase domain in full-length Lon. The catalytic sites lie in a shallow concavity on the wider distal surface of the hexameric ring and are connected to the proximal surface by a narrow axial channel with a diameter of similar to18 Angstrom. Within the active site, the proximity of Lys(722) to the side chain of the mutated Ala(679) and the absence of other potential catalytic side chains establish that Lon employs a Ser(679)-Lys(722) dyad for catalysis. Alignment of the P domain catalytic pocket with those of several Ser-Lys dyad peptide hydrolases provides a model of substrate binding, suggesting that polypeptides are oriented in the Lon active site to allow nucleophilic attack by the serine hydroxyl on the si-face of the peptide bond. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Gustchina, A (reprint author), NCI, Macromol Crystallog Lab, Bldg 539,Rm 143, Frederick, MD 21702 USA. EM alla@ncifcrf.gov NR 70 TC 105 Z9 109 U1 0 U2 6 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 FEB 27 PY 2004 VL 279 IS 9 BP 8140 EP 8148 DI 10.1074/jbc.M312243200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300095 PM 14665623 ER PT J AU Gao, GH Prutzman, KC King, ML Scheswohl, DM DeRose, EF London, RE Schaller, MD Campbell, SL AF Gao, GH Prutzman, KC King, ML Scheswohl, DM DeRose, EF London, RE Schaller, MD Campbell, SL TI NMR solution structure of the focal adhesion targeting domain of focal adhesion kinase in complex with a paxillin LD peptide - Evidence for a two-site binding model SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; CHEMICAL-SHIFT INDEX; TYROSINE PHOSPHORYLATION; CELL-MIGRATION; DIFFERENTIAL REGULATION; BIOLOGICAL RESPONSES; DIPOLAR COUPLINGS; HIGH-SENSITIVITY; TERMINAL DOMAIN; C-13 AB Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is regulated by integrins. Upon activation, FAK generates signals that modulate crucial cell functions, including cell proliferation, migration, and survival. The C-terminal focal adhesion targeting ( FAT) sequence mediates localization of FAK to discrete regions in the cell called focal adhesions. Several binding partners for the FAT domain of FAK have been identified, including paxillin. We have determined the solution structure of the avian FAT domain in complex with a peptide mimicking the LD2 motif of paxillin by NMR spectroscopy. The FAT domain retains a similar fold to that found in the unliganded form when complexed to the paxillin-derived LD2 peptide, an antiparallel four-helix bundle. However, noticeable conformational changes were observed upon the LD2 peptide binding, especially the position of helix 4. Multiple lines of evidence, including the results obtained from isothermal titration calorimetry, intermolecular nuclear Overhauser effects, mutagenesis, and protection from paramagnetic line broadening, support the existence of two distinct paxillin-binding sites on the opposite faces of the FAT domain. The structure of the FAT domain-LD2 complex was modeled using the program HADDOCK based on our solution structure of the LD2-bound FAT domain and mutagenesis data. Our model of the FAT domain-LD2 complex provides insight into the molecular basis of FAK-paxillin binding interactions, which will aid in understanding the role of paxillin in FAK targeting and signaling. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. Univ N Carolina, Carolina Cardiovasc Biol Ctr, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Campbell, SL (reprint author), Univ N Carolina, Dept Biochem & Biophys, CB 7260, Chapel Hill, NC 27599 USA. EM campbesl@med.unc.edu FU NCI NIH HHS [CA90901]; NHLBI NIH HHS [HL45100]; NIDCR NIH HHS [DE13079] NR 77 TC 48 Z9 51 U1 1 U2 6 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 FEB 27 PY 2004 VL 279 IS 9 BP 8441 EP 8451 DI 10.1074/jbc.M309808200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300127 PM 14662767 ER PT J AU Machhor, N Balaji, T Raju, TNK AF Machhor, N Balaji, T Raju, TNK TI Postnatal dexamethasone and long term learning and memory functions in developing rats: Effect of postnatal age and gender SO LIFE SCIENCES LA English DT Article DE dexamethasone; postnatal; Morris water maze; rat pups ID CHRONIC LUNG-DISEASE; MORRIS WATER MAZE; PRENATAL EXPOSURE; PRETERM INFANTS; HIPPOCAMPUS; CORTICOSTEROIDS; SYSTEM AB In this study, we investigated the effect of dexamethasone on the long-term learning and memory functions in developing rats. In Sprague-Dawley rat pups, we administered a daily dose of dexamethasone (0.5 mg/kg/day) for three consecutive days in three groups of animals: the "ultra-early" group received steroids on postnatal days (PND) 1-3; the "early" group received the drug on PNDs 8-10, and the "late" group received the drug on PNDs 28-30. The control group was not given any medication. All animals underwent structured CNS examinations beginning on PND 15, and continued through PND 20. The pups were tested for spatial learning and memory functions using the Morris Water Maze (MWM) on PNDs 31 through 35, 45 through 49, and 59 through 63. They were also tested for reward-based learning and memory functions using Radial Arm Maze (RAM) on PNDs 70 through 72. We analyzed the effect of dexamethasone, postnatal age, and sex on neurological milestones, and learning and memory functions. We found that neurological examination findings were similar in all groups, as were the results of the reward-based learning using RAM. However, in the MWM, the total distance of swimming and the total time to find the hidden platform showed considerable difference among the groups. Although these functions improved with postnatal age, the female pups in all three steroid groups, and the male pups in the late-steroid group lagged significantly in learning and memory functions compared to the controls, and such lags were transient. However, the interaction terms between dexamethasone, age, and sex were also significant in MWM test results. Steroids administered postnatally may have transient, retarding effect on learning and memory functions, and that animal age and sex may modify such effects. Such lags are not global, but specific to the types of memory tests used, implicating different neural circuitries in the pathogenesis of such abnormalities. Although transient, if such adverse effects occur at critical phases during brain maturation, the implications for poor, long-term outcomes may be more significant. The mechanisms underlying such changes need to be explored. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Illinois, Dept Pediat, Div Neonatol, Chicago, IL 60612 USA. RP Raju, TNK (reprint author), NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,4B03, Bethesda, MD 20892 USA. EM Rajut@mail.nih.gov NR 27 TC 6 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD FEB 27 PY 2004 VL 74 IS 15 BP 1925 EP 1935 DI 10.1016/j.lfs.2003.09.044 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 773XD UT WOS:000188950100010 PM 14761673 ER PT J AU Garcia-Diaz, M Bebenek, K Krahn, JM Blanco, L Kunkel, TA Pedersen, LC AF Garcia-Diaz, M Bebenek, K Krahn, JM Blanco, L Kunkel, TA Pedersen, LC TI A structural solution for the DNA polymerase lambda-dependent repair of DNA gaps with minimal homology SO MOLECULAR CELL LA English DT Article ID INDUCED-FIT MECHANISM; CRYSTAL-STRUCTURES; NUCLEOTIDE INCORPORATION; ANGSTROM RESOLUTION; TERNARY COMPLEXES; RNA-POLYMERASE; LARGE FRAGMENT; MINOR-GROOVE; ACTIVE-SITE; BETA AB Human DNA polymerase lambda (Pol lambda) is a family X member with low frameshift fidelity that has been suggested to perform gap-filling DNA synthesis during base excision repair and during repair of broken ends with limited homology. Here, we present a 2.1 Angstrom crystal structure of the catalytic core of Pol lambda in complex with DNA containing a two nucleotide gap. Pol lambda makes limited contacts with the template strand at the polymerase active site, and superimposition with Pol beta in a ternary complex suggests a shift in the position of the DNA at the active site that is reminiscent of a deletion intermediate. Surprisingly, Pol lambda can adopt a closed conformation, even in the absence of dNTP binding. These observations have implications for the catalytic mechanism and putative DNA repair functions of Pol lambda. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Blanco, Luis/I-1848-2015 NR 53 TC 93 Z9 95 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 27 PY 2004 VL 13 IS 4 BP 561 EP 572 DI 10.1016/S1097-2765(04)00061-9 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800AG UT WOS:000220000700013 PM 14992725 ER PT J AU Hughes, CM Rozenblatt-Rosen, O Milne, TA Copeland, TD Levine, SS Lee, JC Hayes, DN Shanmugam, KS Bhattacharjee, A Biondi, CA Kay, GF Hayward, NK Hess, JL Meyerson, M AF Hughes, CM Rozenblatt-Rosen, O Milne, TA Copeland, TD Levine, SS Lee, JC Hayes, DN Shanmugam, KS Bhattacharjee, A Biondi, CA Kay, GF Hayward, NK Hess, JL Meyerson, M TI Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus SO MOLECULAR CELL LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; JUND-ACTIVATED TRANSCRIPTION; ELEGANS DOSAGE COMPENSATION; H3 LYSINE-4 METHYLATION; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-TRITHORAX; NUCLEAR-PROTEIN; ACUTE LEUKEMIAS; GENE AB The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. NCI, Basic Res Labs, Frederick, MD 21702 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. Queensland Inst Med Res, Herston, Qld 4006, Australia. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu RI Kay, Graham/A-4130-2011; Meyerson, Matthew/E-7123-2012; hayward, nicholas/C-1367-2015; Milne, Tom/E-1872-2016; OI hayward, nicholas/0000-0003-4760-1033; Milne, Tom/0000-0002-0413-4271; Hayes, D. Neil/0000-0001-6203-7771 FU NCI NIH HHS [CA92251, CA78815] NR 62 TC 371 Z9 387 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 27 PY 2004 VL 13 IS 4 BP 587 EP 597 DI 10.1016/S1097-2765(04)00081-4 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800AG UT WOS:000220000700015 PM 14992727 ER PT J AU Klausner, RD Fauci, AS Corey, L Nabel, GJ Gayle, H Berkley, S Haynes, BF Baltimore, D Collins, C Douglas, RG Esparza, J Francis, DP Ganguly, NK Gerberding, JL Johnson, MI Kazatchkine, MD McMichael, AJ Makgoba, MW Pantaleo, G Piot, P Shao, YM Tramont, E Varmus, H Wasserheit, JN AF Klausner, RD Fauci, AS Corey, L Nabel, GJ Gayle, H Berkley, S Haynes, BF Baltimore, D Collins, C Douglas, RG Esparza, J Francis, DP Ganguly, NK Gerberding, JL Johnson, MI Kazatchkine, MD McMichael, AJ Makgoba, MW Pantaleo, G Piot, P Shao, YM Tramont, E Varmus, H Wasserheit, JN TI The challenges of an HIV vaccine enterprise - Response SO SCIENCE LA English DT Letter C1 Bill & Melinda Gates Fdn, Seattle, WA 98102 USA. NIAID, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Program Infect Dis, HIV Vaccine Trials Network, Seattle, WA 98109 USA. Univ Washington, Seattle, WA 98109 USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. Int AIDS Vaccine Initiat, New York, NY 10038 USA. Duke Univ, Sch Med, Durham, NC 27710 USA. CALTECH, Pasadena, CA 91125 USA. AIDS Vaccine Advocacy Coalit, New York, NY 10011 USA. Sequella Global TB Fdn, Rockville, MD 20850 USA. World Hlth Org Joint United Nations Programme HIV, HIV Vaccine Initiat, Geneva 27, Switzerland. VaxGen Inc, Brisbane, CA 94005 USA. Indian Council Med Res, New Delhi 110029, India. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Agence Natl Rech Side, F-75013 Paris, France. Univ Oxford, Weatherall Inst Mol Med, MRC, Human Immunol Unit, Oxford OX3 9DS, England. Univ Natal, ZA-4041 Durban, South Africa. Univ Lausanne, CHU Vaudois, Div Immunol & Allergy, CH-1011 Lausanne, Switzerland. UNAIDS, Geneva 27, Switzerland. Natl Ctr AIDS STD Control & Prevent, Beijing 100050, Peoples R China. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Klausner, RD (reprint author), Bill & Melinda Gates Fdn, Seattle, WA 98102 USA. RI Pantaleo, Giuseppe/K-6163-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 27 PY 2004 VL 303 IS 5662 BP 1296 EP 1297 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778JN UT WOS:000189238600019 ER PT J AU Hettiaratchy, S Melendy, E Randolph, MA Coburn, RC Neville, DM Sachs, DH Huang, CA Lee, WPA AF Hettiaratchy, S Melendy, E Randolph, MA Coburn, RC Neville, DM Sachs, DH Huang, CA Lee, WPA TI Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine SO TRANSPLANTATION LA English DT Article ID LARGE-ANIMAL-MODEL; TRANSPLANTATION TOLERANCE; MIXED CHIMERISM; INDUCTION; SKIN; REGIMEN AB Background. Tolerance to composite tissue allografts might allow the widespread clinical use of reconstructive allotransplantation if protocols to achieve this could be rendered sufficiently nontoxic. The authors investigated whether tolerance could be generated in miniature swine to composite tissue allografts across a major histocompatibility (MHC) barrier. A clinically relevant tolerance protocol involving hematopoietic cell transplantation without the need for irradiation or myelosuppressive drugs was tested. Methods. Seven recipient animals were transiently T-cell depleted and a short course of cyclosporine was initiated. Twenty-four hours later, a donor hematopoietic cell transplant consisting of cytokine-mobilized peripheral blood mononuclear cells or bone marrow cells and a heterotopic limb transplant were performed. In vitro anti-donor responsiveness was assessed by mixed-lymphocyte reaction and cell-mediated lympholysis assays. Acceptance of the limb allografts was determined by gross and histologic appearance. Chimerism in the peripheral blood and lymphohematopoietic organs was assessed by flow cytometry. Results. All seven experimental animals accepted the musculoskeletal elements but rejected the skin of the allografts. All but one of the animals displayed donor-specific unresponsiveness in vitro. The animals that received cytokine mobilized-peripheral blood mononuclear cells showed chimerism but had clinical evidence of graft-versus-host disease (GVHD). None of the animals that received bone marrow cells showed stable chimerism and none developed GVHD. Conclusions. This protocol can achieve tolerance to the musculoskeletal elements of composite tissue allografts across an MHC barrier in miniature swine. Stable chimerism does not appear to be necessary for tolerance and may not be desirable because of the risk of GVHD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hettiaratchy, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, WACC-453,Fruit St, Boston, MA 02114 USA. EM shehan_h@hotmail.com NR 21 TC 75 Z9 79 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 27 PY 2004 VL 77 IS 4 BP 514 EP 521 DI 10.1097/01.TP.0000113806.52063.42 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 779QL UT WOS:000189311600008 PM 15084927 ER PT J AU Baccarelli, A Calista, D Minghetti, P Marinelli, B Albetti, B Tseng, T Hedayati, M Grossman, L Landi, G Struewing, JP Landi, MT AF Baccarelli, A Calista, D Minghetti, P Marinelli, B Albetti, B Tseng, T Hedayati, M Grossman, L Landi, G Struewing, JP Landi, MT TI XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE cutaneous malignant melanoma; XPD; ERCC2; DNA repair; age ID DNA-REPAIR GENES; CELL REACTIVATION ASSAY; LUNG-CANCER; ENVIRONMENT INTERACTION; HUMAN-LYMPHOCYTES; DYSPLASTIC NEVI; MODULATION; CARCINOMA; SMOKING; SAMPLE AB We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 0.9-2.5 for 312Asn; OR = 1.3, 95% CI = 0.8-2.1 for 751 Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics), However, XPD variants were associated with increased risk in older (> 50 years) subjects (OR = 3.4, 95% CI = 1.6-7.3 for 312Asn; OR = 2.3, 95% Cl = 1.1 -4.9 for 751 Gln). The 751 Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR = 2.6, 95% Cl = 1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR = 2.3, 95% Cl = 0.7-7.0 for 312Asn; OR = 3.0, 95% Cl = 1.0-8.8 for 751 Gln). DNA repair capacity was slightly decreased in subjects carrying 751 Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Bufalini Hosp, Dermatol Unit, I-47023 Cesena, Italy. Univ Milan, Epidemiol Res Ctr, EPOCA, I-20122 Milan, Italy. NCI, Lab Populat Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem, Baltimore, MD 21205 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Executive Blvd, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; Baccarelli, Andrea/0000-0002-3436-0640 FU NCI NIH HHS [CA/5558-01A2]; NIGMS NIH HHS [GM/22846] NR 29 TC 47 Z9 54 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 26 PY 2004 VL 90 IS 2 BP 497 EP 502 DI 10.1038/sj.bjc.6601385 PG 6 WC Oncology SC Oncology GA 774XA UT WOS:000189010600037 PM 14735199 ER PT J AU Ye, S Rezende, MA Deng, WP Herbert, B Daly, JW Johnson, RA Kirk, KL AF Ye, S Rezende, MA Deng, WP Herbert, B Daly, JW Johnson, RA Kirk, KL TI Synthesis of 2 ',5-dideoxy-2-fluoroadenosine and 2 ',5 '-dideoxy-2,5 '-difluoroadenosine: Potent P-site inhibitors of adenylyl cyclase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CONVENIENT SYNTHESIS; MEDIATED INHIBITION; NUCLEOSIDES; 2'-DEOXY-2-FLUOROADENOSINE; 2-FLUOROADENINE; GLYCOSYLATION; REQUIREMENTS; ADENOSINE AB Glycosylation of 2-fluoroadenine with the appropriate protected thioglycoside derivatives, followed by deprotection and anomer separation, produced the alpha- and beta-anomers of 2',5'-dideoxy-2-fluoroadenosine (1), 2',5'-dideoxy-2,5'-difluoroadenosine (2), and 2'-deoxy-2-fluoroadenosine (3). These were examined as P-site inhibitors of adenylyl cyclase. The presence of fluorine on the purine ring increased potency of inhibition, and the most potent compound, beta-2',5'-dideoxy-2-fluoroadenosine (1b), was 3 times more potent than beta-2',5'-dideoxyadenosine. C1 NIDDKD, Bioorgan Chem Lab, DDHS, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, DDHS, NIH, 8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov NR 26 TC 12 Z9 12 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 26 PY 2004 VL 47 IS 5 BP 1207 EP 1213 DI 10.1021/jm0303599 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 777AJ UT WOS:000189151500015 PM 14971900 ER PT J AU Abashkin, YG Burt, SK AF Abashkin, YG Burt, SK TI (Salen)Mn(III) compound as a nonpeptidyl mimic of catalase: DFT study of the metal oxidation by a peroxide molecule SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SUPEROXIDE-DISMUTASE; LIFE-SPAN; EPOXIDATION; COMPLEXES; MIMETICS; STRESS; APPROXIMATION; GEOMETRIES; ENERGIES; MODEL AB Catalase mimics can be used as therapeutic agents against oxidative stress in treatment of many diseases, including Alzheimer's disease, stroke, heart disease, aging, and cancer. (Salen)Mn(III) compounds have been proven to be promising as synthetic antioxidants that, in particular, dismutate H2O2, resulting in two water molecules and oxygen. An understanding of the mechanism of the dismutation process is an important basis for rational design and tuning these analogues to yield better therapeutic properties. In addition, the study of the catalytic mechanism of the functional biomimetics of enzymes might contribute to a better understanding of the complex enzymatic activities for the corresponding biological compounds. For the first time, using the density functional theory method, we have performed a quantum chemical investigation of the catalase activity of the (salen)Mn(III) compound. The real compound reacting with a peroxide molecule has been utilized in the calculations to avoid uncertainties connected with using incomplete models. The reaction has been studied on three different spin potential energy surfaces: the singlet, the triplet, and the quintet. The same H2O2 dismutation process has been also calculated with participation of an additional water molecule to check the possible explicit involvement of the solvent molecules in the proton-transfer process in the course of the reaction. Our findings suggest that the first part of the dismutation reaction-the metal oxidation by a peroxide molecule-is a one-step process. The concerted breaking of the O-O peroxide bond, oxidation of the Mn, and a water molecule formation occur on the triplet state potential energy surface. This process can be done effectively at the Mn catalytic center with only 3.6 kcal/mol of activation energy needed. No energetic advantages were found for the assisted proton-transfer mechanism with participation of an ancillary water molecule. Although the singlet state is not accessible on the reactant and TS parts of the reaction potential surface, it becomes the ground state in the vicinity of the final geometry and can play an important role in the second part of the dismutation process. C1 SAIC Frederick Inc, Adv Biomed Comp Ctr, Natl Canc Inst Frederick, Frederick, MD 21702 USA. RP Abashkin, YG (reprint author), SAIC Frederick Inc, Adv Biomed Comp Ctr, Natl Canc Inst Frederick, POB B, Frederick, MD 21702 USA. NR 34 TC 29 Z9 29 U1 1 U2 13 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 FEB 26 PY 2004 VL 108 IS 8 BP 2708 EP 2711 DI 10.1021/jp036905r PG 4 WC Chemistry, Physical SC Chemistry GA 777AP UT WOS:000189152000032 ER PT J AU Gladwin, MT Sachdev, V Jison, ML Shizukuda, Y Plehn, JF Minter, K Brown, B Coles, WA Nichols, JS Ernst, I Hunter, LA Blackwelder, WC Schechter, AN Rodgers, GP Castro, O Ognibene, FP AF Gladwin, MT Sachdev, V Jison, ML Shizukuda, Y Plehn, JF Minter, K Brown, B Coles, WA Nichols, JS Ernst, I Hunter, LA Blackwelder, WC Schechter, AN Rodgers, GP Castro, O Ognibene, FP TI Pulmonary hypertension as a risk factor for death in patients with sickle cell disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NITRIC-OXIDE BIOAVAILABILITY; BETA-THALASSEMIA MAJOR; CHRONIC LUNG-DISEASE; ACUTE CHEST SYNDROME; RELATIVE HYPERTENSION; FETAL-HEMOGLOBIN; ANEMIA; ENDOTHELIN-1; STROKE; ECHOCARDIOGRAPHY AB BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. C1 NHLBI, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Chem Biol, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Dept Med, Div Cardiol, Washington, DC USA. Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC USA. RP Gladwin, MT (reprint author), NHLBI, Dept Crit Care Med, Ctr Clin, NIH, Bldg 10,Rm 7D-43,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 43 TC 638 Z9 654 U1 4 U2 21 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 26 PY 2004 VL 350 IS 9 BP 886 EP 895 DI 10.1056/NEJMoa035477 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 777UM UT WOS:000189197300007 PM 14985486 ER PT J AU Woo, CW Lucarelli, E Thiele, CJ AF Woo, CW Lucarelli, E Thiele, CJ TI NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number SO ONCOGENE LA English DT Article DE NGF; TrkA; N-myc; MAPK; neuroblastoma; cell cycle; p27; E2F ID NERVE GROWTH-FACTOR; HUMAN NEURO-BLASTOMA; RETINOIC ACID; PROTEIN-KINASE; PC12 CELLS; FACTOR RECEPTOR; CYCLE ARREST; IN-VIVO; DIFFERENTIATION; INDUCTION AB In neuroblastoma (NB), expression of the TrkA receptor is correlated with good prognosis while N-myc amplification is correlated with poor prognosis. Decreased N-myc levels are key to controlling growth and inducing differentiation in NB cells. In this report, we detail mechanisms by which nerve growth factor (NGF) decreases N-myc levels in TrkA-transfected NB cells and its effect on NB cell proliferation. NGF induced a decrease in N-myc mRNA within 1 h of treatment that occurred in the presence of cycloheximide. The stability of N-myc mRNA was not affected by NGF, indicating a transcriptional control of N-myc mRNA by NGF. NGF but not brain-derived neurotrophic factor (BDNF) decreased N-myc levels demonstrating that p75 alone was not involved. The NGF-induced decrease in N-myc expression was blocked by the Trk tyrosine kinase (TK) antagonist K252a indicating that signals transduced by Trk TK downstream targets were involved. Pharmacologic inhibitors implicated the mitogen-activated protein kinase (MAPK) path. This was supported by the finding that expression of a constitutively activated component of the MAPK path, MAPK kinase (MEK), decreased N-myc levels. Alterations in the level of N-myc are known to alter NB cell cycle progression by affecting the levels of E2Fs and p27(kip1). Consistent with these findings, NGF decreased NB cell number and decreased cyclin E-dependent kinase activity via an increase in p27(kip1). Thus, our results indicate that the MAP kinase is selectively involved in the NGF-induced N-myc downregulation through a transcriptional mechanism. Furthermore, NGF affects the time required for 15N TrkA cells to complete a replication cycle by decreasing N-myc, E2Fs, cyclin E kinase activity and increasing p27(kip1) binding to cyclin E kinase. C1 NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bldg 10 Rm 13N240,10 Ctr MSC-1928, Bethesda, MD 20892 USA. EM thielec@mail.nih.gov RI Lucarelli, Enrico/G-3588-2015 OI Lucarelli, Enrico/0000-0002-6681-6374 NR 59 TC 24 Z9 28 U1 0 U2 6 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 26 PY 2004 VL 23 IS 8 BP 1522 EP 1530 DI 10.1038/sj.onc.1207267 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 778BP UT WOS:000189219500005 PM 14691455 ER PT J AU Huang, AM Montagna, C Sharan, S Ni, YJ Ried, T Sterneck, E AF Huang, AM Montagna, C Sharan, S Ni, YJ Ried, T Sterneck, E TI Loss of CCAAT/enhancer binding protein delta promotes chromosomal instability SO ONCOGENE LA English DT Article DE C/EBP; tumor suppressor; mouse embryo fibroblast; chromosomal rearrangements; genomic instability ID MOUSE MAMMARY-GLAND; GROWTH-FACTOR-BETA; EPITHELIAL-CELL PROLIFERATION; I GENE-TRANSCRIPTION; ARREST-SPECIFIC GENE; ALPHA C/EBP-ALPHA; ADIPOCYTE DIFFERENTIATION; MICE LACKING; CENTROSOME AMPLIFICATION; PLASMACYTOMA SUSCEPTIBILITY AB The transcription factor CCAAT/enhancer binding protein delta (Cebpd, also known as C/EBPdelta, CRP3, CELF, NF-IL6beta) is implicated in diverse cellular functions such as the acute phase response, adipocyte differentiation, learning and memory, and mammary epithelial cell growth control. Here, we report that lack of Cebpd causes genomic instability and centrosome amplifications in primary embryonic fibroblasts derived from 129S1 mice. Upon spontaneous immortalization, Cebpd-deficient fibroblasts acquire transformed features such as impaired contact inhibition and reduced serum dependence. These data identify a novel role for Cebpd in the maintenance of chromosomal stability and suggest a potential tumor suppressor function in vivo. C1 Regulat Cell Growth Lab, Frederick, MD 21702 USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sterneck, E (reprint author), Regulat Cell Growth Lab, POB B, Frederick, MD 21702 USA. EM sterneck@ncifcrf.gov NR 62 TC 55 Z9 55 U1 0 U2 2 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 26 PY 2004 VL 23 IS 8 BP 1549 EP 1557 DI 10.1038/sj.onc.1207285 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 778BP UT WOS:000189219500008 PM 14716301 ER PT J AU Bourdeau, I Antonini, SR Lacroix, A Kirschner, LS Matyakhina, L Lorang, D Libutti, SK Stratakis, CA AF Bourdeau, I Antonini, SR Lacroix, A Kirschner, LS Matyakhina, L Lorang, D Libutti, SK Stratakis, CA TI Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators SO ONCOGENE LA English DT Article; Proceedings Paper CT 84th Annual Meeting of the Endocrine-Society CY JUN 19-22, 2002 CL SAN FRANCISCO, CA SP Endocrine Soc DE adrenal cortex; Cushing syndrome; macronodular hyperplasia; genetics ID GASTRIC-INHIBITORY POLYPEPTIDE; DEPENDENT CUSHINGS-SYNDROME; SPORADIC ADRENOCORTICAL TUMORS; FAMILIAL ADENOMATOUS POLYPOSIS; GENOMIC HYBRIDIZATION ANALYSIS; ENDOCRINE NEOPLASIA TYPE-1; MEMBRANE HORMONE-RECEPTORS; ALPHA-CATENIN; CARNEY COMPLEX; HUMAN-DISEASE AB Corticotropin (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) is a heterogeneous condition in which cortisol secretion may be mediated by gastrointestinal peptide (GIP), vasopressin, catecholamines and other hormones. We studied the expression pro. le of AIMAH by genomic cDNA microarray analysis. Total RNA was extracted from eight tissues (three GIP-dependent) and compared to total RNA obtained from adrenal glands from 62 normal subjects. Genes had to be altered in 75% of the patients, and be up- or downregulated at a cutoff ratio of at least 2.0; 82 and 31 genes were found to be consistently up- and downregulated, respectively. Among the former were regulators of transcription, chromatin remodeling, and cell cycle and adhesion. Downregulated sequences included genes involved in immune responses and insulin signaling. Hierarchical clustering correlated with the two main AIMAH diagnostic groups: GIP-dependent and non-GIP-dependent. The genes encoding the 7B2 protein (SGNE1) and WNT1-inducible signaling pathway protein 2 (WISP2) were specifically overexpressed in the GIP-dependent AIMAH. For these, and six more genes, the data were validated by semiquantitative amplification in samples from a total of 32 patients (the original eight, six more cases of AIMAH, and 18 other adrenocortical hyperplasias and tumors) and the H295R adrenocortical cancer cell line. In conclusion, our data confirmed AIMAH's clinical heterogeneity by identifying molecularly distinct diagnostic subgroups. Several candidate genes that may be responsible for AIMAH formation and/or progression were also identified, suggesting pathways that affect the cell cycle, adhesion and transcription as possible mediators of adrenocortical hyperplasia. C1 NICHHD, Sect Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. CHUM, Hotel Dieu, Div Endocrinol, Montreal, PQ, Canada. NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Levesque, Isabelle/A-1899-2012; Antonini, Sonir /J-5264-2015 NR 64 TC 78 Z9 81 U1 1 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 26 PY 2004 VL 23 IS 8 BP 1575 EP 1585 DI 10.1038/sj.onc.1207277 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 778BP UT WOS:000189219500011 PM 14767469 ER PT J AU Kikuchi, Y Chomel, BB Kasten, RW Martenson, JS Swift, PK O'Brien, SJ AF Kikuchi, Y Chomel, BB Kasten, RW Martenson, JS Swift, PK O'Brien, SJ TI Seroprevalence of Toxoplasma gondii in American free-ranging or captive pumas (Felis concolor) and bobcats (Lynx rufus) SO VETERINARY PARASITOLOGY LA English DT Article DE bobcat; Felis concolor; Lynx rufus; puma; serologic survey; Toxoplasma gondii ID VANCOUVER-ISLAND; SEROLOGIC SURVEY; ANTIBODIES; CALIFORNIA; PREVALENCE; WILD; INFECTIONS; DIAGNOSIS; COUGARS; MAMMALS AB Toxoplasma gondii is a major zoonotic agent infecting a wide range of mammals, including wild felids. Like domestic cats, wild felids are involved in the complete infective cycle of T gondii, as they can host in. their gastrointestinal tract sexually mature parasites and shed infective oocysts in their feces. In order to evaluate the importance of this wildlife reservoir, 438 serum samples collected between 1984 and 1999 from 438 pumas (Felis concolor) and from 58 bobcats (Lynx rufus) from North America, Central America and South America were screened for antibodies to T gondii. The overall prevalence of T gondii antibodies was 22.4% in pumas and 51.7% in bobcats, with regional variations. Adults were more likely to be seropositive than juveniles and kittens (prevalence ratio (PR) = 2.15; 95% confidence interval (CI) = 1.15, 4.04). In the US, pumas from the southwestern states (Arizona, California and New Mexico) were more likely to be seropositive for T gondii (PR = 2.61; 95% CI = 1.32-5.18) than pumas from the northwestern and mountain states (Colorado, Idaho, Oregon, Utah and Wyoming). Male pumas from the US were more likely to be seropositive than females (PR = 2.08; 95 % Cl = 1.11-3.92), whereas female pumas from Mexico, Central America and South America were more likely to be seropositive than female pumas from Canada and the US (PR = 2.49; 95% CI = 1.09-5.69). Captive pumas were also more likely to be seropositive (21.7%, 29/92) for T gondii than free-ranging animals (19.9%, 69/346) (PR = 1.85; 95% CI = 1.06, 3.17). (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Calif Dept Fish & Game, Wildlife Invest Lab, Rancho Cordova, CA 95670 USA. RP Chomel, BB (reprint author), Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM bbchomel@ucdavis.edu NR 24 TC 24 Z9 26 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD FEB 26 PY 2004 VL 120 IS 1-2 BP 1 EP 9 DI 10.1016/j.vetpar.2004.01.002 PG 9 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 801XI UT WOS:000220128200001 PM 15019138 ER PT J AU Roy, S Lim, HM Liu, MF Adhya, S AF Roy, S Lim, HM Liu, MF Adhya, S TI Asynchronous basepair openings in transcription initiation: CRP enhances the rate-limiting step SO EMBO JOURNAL LA English DT Article DE activation; 2,aminopurine; fluorescence; intermediate; kinetics; transcription ID COLI GALACTOSE OPERON; OPEN COMPLEX-FORMATION; RNA-POLYMERASE HOLOENZYME; AMP RECEPTOR PROTEIN; ESCHERICHIA-COLI; STRUCTURAL BASIS; PROMOTER; DNA; 2-AMINOPURINE; FLUORESCENCE AB The mechanism of isomerization (basepair openings) during transcription initiation by RNA polymerase at the galP1 promoter of Escherichia coli was investigated by 2-aminopurine (2,AP) fluorescence. The fluorescence of 2,AP is quenched in DNA duplex and enhanced when the basepair is distorted or deformed. The increase of 2,AP fluorescence was used to monitor basepair distortion at several individual positions in the promoter. We observed that basepair distortions during isomerization are a multi-step process. Three distinct hitherto unresolved steps in kinetic terms were observed, where significant fluorescence change occurs: a fast step with a half-life of around 1 s, which is followed by two slower steps occurring with a half-life in the range of minutes at 25degreesC. Contrary to commonly held expectations, basepairs at different positions opened by 2,AP assays without any obvious pattern, suggesting that basepair opening is an asynchronous multi-step process. cAMP.CRP, which activates transcription at galP1, enhanced the rate-limiting step. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Bose Inst, Dept Biophys, Kolkata 700009, W Bengal, India. Chungnam Natl Univ, Dept Biol, Taejon, South Korea. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 5138, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov NR 42 TC 19 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD FEB 25 PY 2004 VL 23 IS 4 BP 869 EP 875 DI 10.1038/sj.emboj.7600098 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 810GZ UT WOS:000220694100019 PM 14963488 ER PT J AU Ding, JH Xu, XD Yang, DM Chu, PH Dalton, ND Ye, Z Yeakley, JM Cheng, HP Xiao, RP Ross, J Chen, J Fu, XD AF Ding, JH Xu, XD Yang, DM Chu, PH Dalton, ND Ye, Z Yeakley, JM Cheng, HP Xiao, RP Ross, J Chen, J Fu, XD TI Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart SO EMBO JOURNAL LA English DT Article DE heart disease; splicing regulation; SR proteins ID PRE-MESSENGER-RNA; TROPONIN-T ISOFORMS; SPLICING FACTORS; SR PROTEINS; CARDIAC-HYPERTROPHY; CELL-CYCLE; GENE; EXPRESSION; ORGANIZATION; INHIBITION AB Many genetic diseases are caused by mutations in cis-acting splicing signals, but few are triggered by defective transacting splicing factors. Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM). Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span. This nonlethal phenotype allowed the identification of downregulated genes by microarray, one of which was the cardiac-specific ryanodine receptor 2. We showed that downregulation of this critical Ca2+ release channel preceded disease symptoms and that the mutant cardiomyocytes exhibited frequency-dependent excitation-contraction coupling defects. The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses. These studies raise a new paradigm for the etiology of certain human heart diseases of genetic or environmental origin that may be triggered by dysfunction in RNA processing. C1 Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Inst Mol Med, La Jolla, CA 92093 USA. RP Fu, XD (reprint author), Univ Calif San Diego, Dept Cellular & Mol Med, CMM W 231A,9500 Gilman Dr, La Jolla, CA 92093 USA. EM xdfu@ucsd.edu RI Chen, Ju/E-5579-2011; Chu, Pao-Hsien/G-3685-2010; OI Xu, Xiangdong/0000-0003-2220-0890 FU NHLBI NIH HHS [R01 HL066100] NR 60 TC 83 Z9 84 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 25 PY 2004 VL 23 IS 4 BP 885 EP 896 DI 10.1038/sj.emboj.7600054 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 810GZ UT WOS:000220694100021 PM 14963485 ER PT J AU Bjork, JM Knutson, B Fong, GW Caggiano, DM Bennett, SM Hommer, DW AF Bjork, JM Knutson, B Fong, GW Caggiano, DM Bennett, SM Hommer, DW TI Incentive-elicited brain activation in adolescents: Similarities and differences from young adults SO JOURNAL OF NEUROSCIENCE LA English DT Article DE accumbens; activation; aging [ageing]; development; imaging; motivation; reward; adolescence ID AGE-RELATED-CHANGES; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; DECISION-MAKING; HUMAN STRIATUM; FMRI; ATTENTION; CORTEX; VISUALIZATION; ANTICIPATION AB Brain motivational circuitry in human adolescence is poorly characterized. One theory holds that risky behavior in adolescence results in part from a relatively overactive ventral striatal ( VS) motivational circuit that readily energizes approach toward salient appetitive cues. However, other evidence fosters a theory that this circuit is developmentally underactive, in which adolescents approach more robust incentives ( such as risk taking or drug experimentation) to recruit this circuitry. To help resolve this, we compared brain activation in 12 adolescents (12 - 17 years of age) and 12 young adults (22 - 28 years of age) while they anticipated the opportunity to respond to obtain monetary gains as well as to avoid monetary losses. In both age groups, anticipation of potential gain activated portions of the VS, right insula, dorsal thalamus, and dorsal midbrain, where the magnitude of VS activation was sensitive to gain amount. Notification of gain outcomes ( in contrast with missed gains) activated the mesial frontal cortex (mFC). Across all subjects, signal increase in the right nucleus accumbens during anticipation of responding for large gains independently correlated with both age and self-rated excitement about the high gain cue. In direct comparison, adolescents evidenced less recruitment of the right VS and right-extended amygdala while anticipating responding for gains ( in contrast with anticipation of nongains) compared with young adults. However, brain activation after gain outcomes did not appreciably differ between age groups. These results suggest that adolescents selectively show reduced recruitment of motivational but not consummatory components of reward-directed behavior. C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. RP Bjork, JM (reprint author), NIAAA, Clin Studies Lab, NIH, 10 Ctr Dr,Room 3C-103, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291; Knutson, Brian/0000-0002-7669-426X FU NIMH NIH HHS [MH066923] NR 48 TC 305 Z9 309 U1 6 U2 31 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 FEB 25 PY 2004 VL 24 IS 8 BP 1793 EP 1802 DI 10.1523/JNEUROSCI.4862-03.2004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 777XZ UT WOS:000189210300001 PM 14985419 ER PT J AU Walsh, JD Cabello-Villegas, J Wang, YX AF Walsh, JD Cabello-Villegas, J Wang, YX TI Periodicity in residual dipolar couplings and nucleic acid structures SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEIN-STRUCTURE; NMR MAPS; WAVES; DYNAMICS; TOPOLOGY; HELICES C1 NCI, Prot Nucleic Acid Interact Sect, Struct Biophys Lab, NIH, Ft Detrick, MD 21702 USA. RP Wang, YX (reprint author), NCI, Prot Nucleic Acid Interact Sect, Struct Biophys Lab, NIH, Ft Detrick, MD 21702 USA. EM wangyu@ncifcrf.gov NR 10 TC 17 Z9 17 U1 0 U2 0 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 FEB 25 PY 2004 VL 126 IS 7 BP 1938 EP 1939 DI 10.1021/ja039446g PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 776BY UT WOS:000189096200008 PM 14971918 ER PT J AU Lee, YS Krauss, M AF Lee, YS Krauss, M TI Dynamics of proton transfer in bacteriorhodopsin SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SCHIFF-BASE; VIBRATIONAL SPECTROSCOPY; MOLECULAR-MECHANICS; COMBINED POTENTIALS; QUANTUM-MECHANICS; INFRARED-SPECTRA; WATER-MOLECULES; N-INTERMEDIATE; PHOTOCYCLE; PROTEIN AB Proton transfer in bacteriorhodopsin from the cytoplasm to the extracellular side is initiated from protonated asp96 in the cytoplasmic region toward the deprotonated Schiff base. This occurs in the transition from the photocycle late M state to the N state. To investigate this proton-transfer process, a quantum mechanics/molecular mechanics (QM/MM) model is constructed from the bacteriorhodopsin E204Q mutant crystal structure. Three residues, asp96, asp85, and thr89, as well as most of the retinal chromophore and the Schiff base link of lys216 are treated quantum mechanically and connected to the remaining classical protein through linker atom hydrogens. Structural transformation in the M state results in the formation of a water channel between the Schiff base and asp96. Since a part of this channel is lined with hydrophobic residues, there has been a question on the mechanism of proton transfer in a hydrophobic channel. Ab initio dynamics using the CHARMM/GAMESS methodology is used to simulate the transfer of the proton through a partially hydrophobic channel. Once sufficient water molecules are added to the channel to allow the formation of a single chain of waters from asp96 to the Schiff base, the transfer occurs as a fast (less than a picosecond) concerted event irrespective of the protonation state of asp85. Dynamic transfer of the proton from asp96 to the nearest water initiates the organization of a strongly bonded water chain conducive to the transfer of the proton to the Schiff base nitrogen. C1 NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Lee, YS (reprint author), NIH, Ctr Mol Modeling, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM leeys@mail.nih.gov NR 35 TC 48 Z9 49 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 25 PY 2004 VL 126 IS 7 BP 2225 EP 2230 DI 10.1021/ja036115v PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 776BY UT WOS:000189096200048 PM 14971958 ER PT J AU Boudinot, E Yamada, M Wess, J Champagnat, J Foutz, AS AF Boudinot, E Yamada, M Wess, J Champagnat, J Foutz, AS TI Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE control of breathing, chemosensory afferents; muscarinic receptors; hypoxia, ventilatory response; mammals, mouse; mediators acetylcholine; pattern of breathing, acetylcholine; receptors, muscarinic; techniques, muscarinic receptor knockout mouse ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; CAROTID-BODY CHEMOTRANSDUCTION; BULBAR RESPIRATORY NEURONS; BRAIN-STEM; PREBOTZINGER COMPLEX; NEUROTRANSMITTERS; SUBTYPES; RELEASE; LACKING; MEDULLA AB Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O-2) and hypercapnia (3 and 5% CO2) in mice lacking either the M-1 or the M-3 muscarinic receptor, and in wild-type matched controls. M-1 knockout mice showed normal minute ventilation (<(V)over dot>(E)) but elevated tidal volume (V-T) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M-3 knockout mice had elevated <(V)over dot>(E) and V-T at rest, a reduced V-T response slope to hypercapnia, and blunted <(V)over dot>(E) and frequency responses to hypoxia. The results suggest that M-1 and M-3 muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M-3 receptors. (C) 2003 Elsevier B.V. All rights reserved. C1 CNRS, Inst Neurobiol Alfred FEssard, F-91198 Gif Sur Yvette, France. NIDDKD, Lab Bioinorgan Chem, Bethesda, MD 20892 USA. RP Foutz, AS (reprint author), CNRS, Inst Neurobiol Alfred FEssard, F-91198 Gif Sur Yvette, France. EM foutz@iaf.cnfs-gif.fr NR 47 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD FEB 25 PY 2004 VL 139 IS 3 BP 237 EP 245 DI 10.1016/j.resp.2003.10.006 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 808FC UT WOS:000220554000002 PM 15122990 ER PT J AU de Waal, L Wyatt, LS Yuksel, S van Amerongen, G Moss, B Niesters, HGM Osterhaus, ADME de Swart, RL AF de Waal, L Wyatt, LS Yuksel, S van Amerongen, G Moss, B Niesters, HGM Osterhaus, ADME de Swart, RL TI Vaccination of infant macaques with a recombinant modified vaccinia virus Ankara expressing the respiratory syncytial virus F and G genes does not predispose for immunopathology SO VACCINE LA English DT Article DE MVA; RSV; immunopathology ID PROTECTIVE IMMUNITY; IMMUNOGENICITY; MVA; IMMUNIZATION; SAFETY; EFFICACY; STRAIN; MICE; RSV AB We have evaluated the safety and immunogenicity of a recombinant modified vaccinia virus Ankara (MVA) vector expressing the respiratory syncytial virus (RSV) fusion (F) and attachment (G) proteins in infant macaques. Animals were vaccinated twice and 4 months later challenged with RSV. Although vaccination did not predispose for immunopathology upon challenge, we were also unable to demonstrate protection. Since vaccination had resulted in priming for secondary immune responses upon challenge, we suggest that vaccination efficacy will have to be improved by using MVA in a prime-boost strategy. (C) 2003 Elsevier Ltd. All rights reserved. C1 Erasmus MC, Dept Virol, NL-3000 DR Rotterdam, Netherlands. NIAID, Viral Dis Lab, NIH, Bethesda, MD USA. RP Osterhaus, ADME (reprint author), Erasmus MC, Dept Virol, POB 1738, NL-3000 DR Rotterdam, Netherlands. EM a.osterhaus@erasmusmc.nl OI Niesters, Hubert/0000-0002-1758-0430; Osterhaus, Albert/0000-0002-6074-1172; De Swart, Rik/0000-0003-3599-8969 NR 19 TC 25 Z9 25 U1 0 U2 0 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 FEB 25 PY 2004 VL 22 IS 8 BP 923 EP 926 DI 10.1016/j.vaccine.2003.10.010 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 778XN UT WOS:000189266800003 PM 15161069 ER PT J AU Cao, JJ Heart, HF Peterson, D Psaty, BM Kuller, L Barzilay, J Manolio, TA Wexler, J Bleyer, AJ Cushman, M AF Cao, JJ Heart, HF Peterson, D Psaty, BM Kuller, L Barzilay, J Manolio, TA Wexler, J Bleyer, AJ Cushman, M TI The association of microalbuminuria with prevalent cardiovascular disease in the elderly with and without obesity, the Cardiovascular Health Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Henry Ford Hosp, Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. Univ Washington, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Emory Univ, Kaiser Permanente Georgia, Atlanta, GA 30322 USA. NHLBI, Bethesda, MD 20892 USA. Univ Calif David, Davis, CA USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Vermont, Burlington, VT USA. RI rivera, miguel/D-5026-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P106 BP E102 EP E102 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800161 ER PT J AU Daviglus, ML Liu, K Greenland, P Colangelo, L Yan, LJL Van Horn, L Pirzada, A Schreiner, PJ Lewis, CE Loria, C AF Daviglus, ML Liu, K Greenland, P Colangelo, L Yan, LJL Van Horn, L Pirzada, A Schreiner, PJ Lewis, CE Loria, C TI Healthy lifestyle in young adulthood predicts lower risk of developing coronary atherosclerosis: The CARDIA study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Northwestern Univ, Chicago, IL 60611 USA. Univ Minnesota, Minneapolis, MN USA. Univ Alabama, Birmingham, AL USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA 13 BP E77 EP E77 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800049 ER PT J AU Diego, VP Cole, SA Goring, H Almasy, L North, K Howard, BV Lee, ET Best, LG Devereux, RB Fabsitz, RR Laston, S Wenger, C Bridges, J Cantu, T Dyke, B MacCluer, JW AF Diego, VP Cole, SA Goring, H Almasy, L North, K Howard, BV Lee, ET Best, LG Devereux, RB Fabsitz, RR Laston, S Wenger, C Bridges, J Cantu, T Dyke, B MacCluer, JW TI Linkage analyses in the strong heart family study reveal a region on chromosome 2 affecting traits potentially related to muscle tissue metabolism. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 SW Fdn Biomed Res, San Antonio, TX 78284 USA. Univ N Carolina, Chapel Hill, NC USA. MedStar Res Inst, Hyattsville, MD USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Strong Heart Study Dakota Ctr, Rolette, ND USA. NY Hosp Cornell Med Ctr, New York, NY USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P30 BP E86 EP E87 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800089 ER PT J AU Elmer, PJ Stevens, V Vollmer, B Svetkey, L Lin, PH Obarzanek, E Simons-Morton, D Proschan, M Harsha, D Champagne, C Appel, L Erlinger, T Young, D AF Elmer, PJ Stevens, V Vollmer, B Svetkey, L Lin, PH Obarzanek, E Simons-Morton, D Proschan, M Harsha, D Champagne, C Appel, L Erlinger, T Young, D TI 18-month results of PREMIER, a clinical trial of two comprehensive lifestyle modification programs. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. Duke Univ, Durham, NC USA. NHLBI, Bethesda, MD 20892 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA 22 BP E79 EP E79 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800058 ER PT J AU Fox, CS Heard-Costa, NL Wilson, PW Levy, D D'Agostino, RB Atwood, LD AF Fox, CS Heard-Costa, NL Wilson, PW Levy, D D'Agostino, RB Atwood, LD TI Genomewide linkage analysis of waist circumference in the Framingham Heart Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P220 BP E125 EP E125 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800273 ER PT J AU Fox, CS Larson, MG Leip, EP Meigs, JB Wilson, PW Levy, D AF Fox, CS Larson, MG Leip, EP Meigs, JB Wilson, PW Levy, D TI Glycemic status and development of kidney disease over 8-years: the Framingham Heart Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P199 BP E120 EP E120 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800252 ER PT J AU Gidding, SS Barton, BA Simons-Morton, DG Dorgan, J Kimm, SY Kwiterovich, P Lasser, N Robson, A Stevens, V Van Horn, L AF Gidding, SS Barton, BA Simons-Morton, DG Dorgan, J Kimm, SY Kwiterovich, P Lasser, N Robson, A Stevens, V Van Horn, L TI Higher self reported physical activity aver a three year interval is asociated with lower blood pressure and LDL-C in childhood. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 AI Dupont Hosp Children, Wilmington, DE USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Pittsburg, Pittsburgh, PA USA. Johns Hopkins Univ, Baltimore, MD USA. UMDNJ Newark, Newark, NJ USA. New Orleans Childrens Hosp, New Orleans, LA USA. Kaiser Permanente, Res Ctr, Portland, OR USA. Northwestern Univ, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P142 BP E109 EP E109 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800196 ER PT J AU Heckbert, SR Post, W Arnett, DK Gomes, AS Jerosch-Herold, M Olson, J Hundley, G Pearson, G Bluemke, D AF Heckbert, SR Post, W Arnett, DK Gomes, AS Jerosch-Herold, M Olson, J Hundley, G Pearson, G Bluemke, D TI Traditional cardiovascular risk factors in relation to left ventricular mass and function by magnetic resonance imaging: The Multi-Ethnic Study of Atherosclerosis. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Washington, Seattle, WA 98195 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Minnesota, Minneapolis, MN USA. Univ Calif Los Angeles, Los Angeles, CA USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Columbia Univ, New York, NY USA. RI Jerosch-Herold, Michael/F-2496-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P215 BP E124 EP E124 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800268 ER PT J AU Iribarren, C Gross, MD Darbinian, JA Jacobs, DR Sidney, S Loria, C AF Iribarren, C Gross, MD Darbinian, JA Jacobs, DR Sidney, S Loria, C TI Relation of lipoprotein-associated phospholipase A(2) mass and activity with coronary artery calcification in young adults: The CARDIA study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Kaiser Permanente, Oakland, CA USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P164 BP E113 EP E113 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800218 ER PT J AU Kathiresan, S Larson, MG Kupka, MJ Mitchell, GF Vasan, RS Keaney, JF Lehman, BT Fan, SX Osypiuk, E Vita, JA Benjamin, EJ AF Kathiresan, S Larson, MG Kupka, MJ Mitchell, GF Vasan, RS Keaney, JF Lehman, BT Fan, SX Osypiuk, E Vita, JA Benjamin, EJ TI Flow-mediated vasodilation is not impaired in individuals with a parental history of premature coronary heart disease: The Framingham Heart Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Cardiovasc Engn Inc, Holliston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, NHLBI, Framingham Heart Study, Sch Med, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P211 BP E123 EP E123 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800264 ER PT J AU Kathiresan, S Larson, MG Corey, D Benjamin, EJ Fox, CS Wilson, P AF Kathiresan, S Larson, MG Corey, D Benjamin, EJ Fox, CS Wilson, P TI Clinical correlates of serum aldosterone in the community. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Univ, Sch Med, NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P180 BP E116 EP E116 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800233 ER PT J AU Kathiresan, S Yang, Q Lochner, A Larson, MG Tofler, GH Gabriel, S O'Donnell, CJ AF Kathiresan, S Yang, Q Lochner, A Larson, MG Tofler, GH Gabriel, S O'Donnell, CJ TI Gene-based Haplotypes at the plasminogen activator inhibitor-1 locus are associated with circulating plasminogen activator inhibitor-1 levels. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. MIT, Whitehead Inst, Ctr Genome Res, Cambridge, MA 02139 USA. Royal N Shore Hosp, Sydney, NSW, Australia. RI Yang, Qiong/G-5438-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA 12 BP E77 EP E77 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800048 ER PT J AU Kreger, BE Evans, JC Splansky, GL AF Kreger, BE Evans, JC Splansky, GL TI Cancer provokes coronary events in Framingham Heart Study subjects. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Boston Univ, Sch Med, NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P109 BP E102 EP E102 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800164 ER PT J AU Li, RL Nicklas, B Pahor, M Newman, A Sutton-Tyrrell, K Bauer, D Ding, JZ Harris, T Lakatta, E Satterfield, S Kritchevsky, SB AF Li, RL Nicklas, B Pahor, M Newman, A Sutton-Tyrrell, K Bauer, D Ding, JZ Harris, T Lakatta, E Satterfield, S Kritchevsky, SB TI Association between renin angiotensin system haplotypes and measures of vascular health in the health, aging and body composition study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Tennessee, Memphis, TN USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P28 BP E86 EP E86 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800087 ER PT J AU Liu, YM Berthier-Schaad, Y Plantinga, L Fink, NE Tracy, RP Klag, MJ Smith, MW Coresh, J AF Liu, YM Berthier-Schaad, Y Plantinga, L Fink, NE Tracy, RP Klag, MJ Smith, MW Coresh, J TI Functional variants in the lymphotoxin alpha gene predict cardiovascular disease in dialysis patients. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 JHU, Baltimore, MD USA. Univ Vermont, Burlington, VT USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. RI Smith, Michael/B-5341-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P16 BP E84 EP E84 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800076 ER PT J AU Lloyd, K Cooper, L Mitchell, P Bittner, V Goldberg, R Zapka, J Labarthe, D Luepker, R Mann, NC Murray, DM Pandey, D AF Lloyd, K Cooper, L Mitchell, P Bittner, V Goldberg, R Zapka, J Labarthe, D Luepker, R Mann, NC Murray, DM Pandey, D TI Factors associated with myocardial infarction education in acute CVD patients: The Rapid Early Action for Coronary Treatment (REACT) Trial. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, NIH, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Alabama, Birmingham, AL USA. Univ Massachusetts, Sch Med, Worcester, MA USA. Ctr Dis Control, Atlanta, GA 30333 USA. Univ Minnesota, Minneapolis, MN USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Univ Memphis, Memphis, TN 38152 USA. Childrens Hosp, Boston, MA 02115 USA. Rush Med Coll, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P102 BP E101 EP E101 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800157 ER PT J AU Loria, CM Liu, K Carnethon, M Lewis, CE Sidney, S Savage, P AF Loria, CM Liu, K Carnethon, M Lewis, CE Sidney, S Savage, P TI Race-gender differences in prevalence of metabolic syndrome components: The CARDIA Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Northwestern Univ, Sch Med, Chicago, IL USA. Univ Alabama, Birmingham, AL USA. Kaiser Permanente, Oakland, CA USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P258 BP E132 EP E133 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800311 ER PT J AU Manolio, TA Chen, JS Sorlie, PD Stamler, J AF Manolio, TA Chen, JS Sorlie, PD Stamler, J TI U. s. trends in prevalence of low coronary risk, National Health and Nutrition Examination Surveys. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Bethesda, MD 20892 USA. Northwestern Univ, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P108 BP E102 EP E102 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800163 ER PT J AU Murabito, JM Evans, JC Larson, MG Wilson, PW Kannel, WB AF Murabito, JM Evans, JC Larson, MG Wilson, PW Kannel, WB TI Changes in cardiovascular risk factors with menopause: The Framingham Offspring Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Boston Med Ctr, NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P81 BP E97 EP E97 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800137 ER PT J AU Myerson, M Coady, S Goff, DC Taylor, H Rosamond, WD Sorlie, P AF Myerson, M Coady, S Goff, DC Taylor, H Rosamond, WD Sorlie, P TI Reduced severity of myocardial infarction: The Atherosclerosis Risk in Communities (ARIC) Study 1987-2000. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P62 BP E93 EP E93 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800120 ER PT J AU O'Donnell, CJ AF O'Donnell, CJ CA Cardiogenomics Program TI A systematic search for genetic variants associated with left ventricular structure and function phenotypes in the NHLBI CardioGenomics Program for Genomics Applications. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Program Genom Applicat, Cardiogenom Program, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA 9 BP E76 EP E77 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800045 ER PT J AU Patel, AS Sutton-Tyrrell, K Talbott, E Pratt, S Harris, T Ding, JZ Kenyon, E Satterfield, S Newman, A AF Patel, AS Sutton-Tyrrell, K Talbott, E Pratt, S Harris, T Ding, JZ Kenyon, E Satterfield, S Newman, A TI Hearing loss: Associations with cardiovascular risk factors and arterial pulse wave velocity within the health, aging, and body composition study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Pittsburgh, Pittsburgh, PA USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Tennessee, Memphis, TN USA. RI Pratt, Sheila/H-7139-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P167 BP E114 EP E114 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800221 ER PT J AU Powell, LH Bang, HJ Williams, R Saab, PG Schneiderman, N Thoresen, CE Kaufmann, P Blumenthal, JA AF Powell, LH Bang, HJ Williams, R Saab, PG Schneiderman, N Thoresen, CE Kaufmann, P Blumenthal, JA TI The impact of clinically significant psychosocial treatment on prognosis after myocardial infarction. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ N Carolina, Chapel Hill, NC USA. Duke Univ, Durham, NC USA. Univ Miami, Coral Gables, FL 33124 USA. Stanford Univ, Stanford, CA 94305 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P46 BP E90 EP E90 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800104 ER PT J AU Rasmussen-Torvik, LJ Pankow, JS Miller, MB Evans, GW Heiss, G Sholinsky, P AF Rasmussen-Torvik, LJ Pankow, JS Miller, MB Evans, GW Heiss, G Sholinsky, P TI Familial aggregation analysis and genome scan of carotid artery plaque in the NHLBI Family Heart Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Minnesota, Minneapolis, MN USA. Wake Forest Sch Med, Winston Salem, NC USA. Univ N Carolina, Chapel Hill, NC USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P33 BP E87 EP E87 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800092 ER PT J AU Resnick, HE Lindsay, RS McDermott, MM Devereux, RB Jones, KL Fabsitz, RR Howard, BV AF Resnick, HE Lindsay, RS McDermott, MM Devereux, RB Jones, KL Fabsitz, RR Howard, BV TI Relationship of high and low ankle-brachial index to all-cause and CVD mortality. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Medstar Res Inst, Hyattsville, MD USA. Northwestern Univ, Chicago, IL 60611 USA. Cornell Univ, New York, NY USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P312 BP E143 EP E143 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800365 ER PT J AU Scuteri, A Najjar, SS Muller, D Andres, R Morrell, CH Zonderman, AB Lakatta, EG AF Scuteri, A Najjar, SS Muller, D Andres, R Morrell, CH Zonderman, AB Lakatta, EG TI Apoe4 allele and the natural history of cardiovascular risk factors. Gender specific effects on longitudinal changes. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P8 BP E82 EP E82 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800069 ER PT J AU Truesdale, KP Stevens, J Loria, CM Schreiner, PJ Lewis, CE Cai, JW AF Truesdale, KP Stevens, J Loria, CM Schreiner, PJ Lewis, CE Cai, JW TI Impact of weight maintenance on blood pressure over 15-year follow-up: The CARDIA Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ N Carolina, Chapel Hill, NC USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. Univ Alabama, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P221 BP E125 EP E125 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800274 ER PT J AU Hague, S Peuralinna, T Eerola, J Hellstrom, O Tienari, PJ Singleton, AB AF Hague, S Peuralinna, T Eerola, J Hellstrom, O Tienari, PJ Singleton, AB TI Confirmation of the protective effect of iNOS in an independent cohort of Parkinson disease SO NEUROLOGY LA English DT Article AB Nitric oxide is a biologic messenger molecule involved in a diverse range of physiologic processes. An exon 22 inducible nitric oxide synthase genotype has recently been reported to be protective against Parkinson disease in a European cohort. The authors confirm the protective effect of this genotype (OR=0.5, 95% CI 0.27 to 0.93) in an independent Finnish case-control series. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. Univ Helsinki, Biomedicum Helsinki, Neurosci Programme, Helsinki, Finland. Seinajoki Cent Hosp, Seinajoki, Finland. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012 NR 5 TC 13 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 24 PY 2004 VL 62 IS 4 BP 635 EP 636 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 778JR UT WOS:000189238900022 PM 14981185 ER PT J AU Ling, H Sayer, JM Plosky, BS Yagi, H Boudsocq, F Woodgate, R Jerina, DM Yang, W AF Ling, H Sayer, JM Plosky, BS Yagi, H Boudsocq, F Woodgate, R Jerina, DM Yang, W TI Crystal structure of a benzo[a]pyrene diol epoxide adduct in a ternary complex with a DNA polymerase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; DEOXYGUANOSINE ADDUCTS; ESCHERICHIA-COLI; ERROR-PRONE; DUPLEX; OPPOSITE; CONFORMATION; CARCINOGEN; PRINCIPLES; MECHANISM AB The first occupation-associated cancers to be recognized were the sooty warts (cancers of the scrotum) suffered by chimney sweeps in 18th century England. In the 19th century, high incidences of skin cancers were noted among fuel industry workers. By the early 20th century, malignant skin tumors were produced in laboratory animals by repeatedly painting them with coal tar. The culprit in coal tar that induces cancer was finally isolated in 1933 and determined to be benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon. A residue of fuel and tobacco combustion and frequently ingested by humans, BP is metabolized in mammals to benzo[a]pyrene diol epoxide (BPDE), which forms covalent DNA adducts and induces tumor growth. In the 70 yr since its isolation, BP has been the most studied carcinogen. Yet, there has been no crystal structure of a BPDE DNA adduct. We report here the crystal structure of a BPDE-adenine adduct base-paired with thymine at a template-primer junction and complexed with the lesion-bypass DNA polymerase Dpo4 and an incoming nucleotide. Two conformations of the BPDE, one intercalated between base pairs and another solvent-exposed in the major groove, are observed. The latter conformation, which can be stabilized by organic solvents that reduce the dielectric constant, seems more favorable for DNA replication by Dpo4. These structures also suggest a mechanism by which mutations are generated during replication of DNA containing BPDE adducts. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Ling, Hong/E-3729-2010; Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 36 TC 129 Z9 130 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2265 EP 2269 DI 10.1073/pnas.0308332100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400009 PM 14982998 ER PT J AU Dmitrieva, NI Cai, Q Burg, MB AF Dmitrieva, NI Cai, Q Burg, MB TI Cells adapted to high NaCl have many DNA breaks and impaired DNA repair both in cell culture and in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MURINE KIDNEY-CELLS; HISTONE H2AX; GENOMIC INSTABILITY; IONIZING-RADIATION; DAMAGE CHECKPOINT; TRANSGENIC MOUSE; HYPEROSMOLALITY; PROLIFERATION; KINASE; MRE11 AB Acute exposure of cells in culture to high NaCl damages DNA and impairs its repair. However, after several hours of cell cycle arrest, cells multiply in the hypertonic medium. Here, we show that, although adapted cells proliferate rapidly and do not become apoptotic, they nevertheless contain numerous DNA breaks, which do not elicit a DNA damage response. Thus, in adapted cells, Mre11 exonuclease is mainly present in the cytoplasm, rather than nucleus, and histone H2AX and chk1 are not phosphorylated, as they normally would be in response to DNA damage. Also, the adapted cells are deficient in repair of luciferase reporter plasmids damaged by UV irradiation. On the other hand, the DNA damage response activates rapidly when the level of NaCl is reduced. Then, Mre11 moves into the nucleus, and H2AX and chk1 become phosphorylated. Renal inner medullary cells in vivo are normally exposed to a variable, but always high, level of NaCl. As with adapted cells in culture, inner medullary cells in normal mice exhibit numerous DNA breaks. These DNA breaks are rapidly repaired when the NaCl level is decreased by injection of the diuretic furosemide. Moreover, repair of DNA breaks induced by ionizing radiation is inhibited in the inner medulla. Histone H2AX does not become phosphorylated, and repair synthesis is not detectable in response to total body irradiation unless NaCl is lowered by furosemide. Thus, both in cell culture and in vivo, although cells adapt to high NaCl, their DNA is damaged and its repair is inhibited. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), 9000 Rockville Pike,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 35 TC 68 Z9 70 U1 1 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 FEB 24 PY 2004 VL 101 IS 8 BP 2317 EP 2322 DI 10.1073/pnas.0308463100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400018 PM 14983007 ER PT J AU Chun, TW Justement, JS Sanford, C Hallahan, CW Planta, MA Loutfy, M Kottilil, S Moir, S Kovacs, C Fauci, AS AF Chun, TW Justement, JS Sanford, C Hallahan, CW Planta, MA Loutfy, M Kottilil, S Moir, S Kovacs, C Fauci, AS TI Relationship between the frequency of HIV-specific CD8(+) T cells and the level of CD38(+)CD8(+) T cells in untreated HIV-infected individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VIRUS TYPE-1 INFECTION; LYMPH-NODES; APOPTOSIS; ACTIVATION; RESPONSES; LYMPHOCYTES; VIREMIA; DISEASE; CD4(+); PROGRESSORS AB CD8(+) T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8(+) T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8(+) T cells, HIV is not contained in many untreated patients. Active HIV replication is associated with numerous immunologic changes, the most notable and consistent of which is an increase in CD8(+) T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8(+) T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8(+) T cells is unclear. We demonstrate a correlation between levels of HIV-specific CD8(+) T cells and levels of CD8(+) T cells expressing CD38 in untreated patients. The distribution of HIV-specific CD8(+) T cells was heavily skewed toward CD38(+)CD8(+) T cells in patients with a high percentage of CD38(+)CD8(+) T cells. Spontaneous/Fas-mediated apoptosis in CD38(+)CD8(+) T cells was significantly higher in patients with high percentages of CD38(+)CD8(+) T cells. Our data suggest that a substantial proportion of the HIV-specific CD8(+) T cells present in CD38(+)CD8(+) T cells in patients with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activity against infected targets due to a high degree of susceptibility to apoptosis, thus providing an explanation of why HIV is not successfully contained by CD8(+) T cells in such individuals. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Toronto, Dept Med, Toronto, ON M5B 1L6, Canada. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A32, Bethesda, MD 20892 USA. EM twchun@nih.gov NR 26 TC 42 Z9 44 U1 0 U2 0 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 FEB 24 PY 2004 VL 101 IS 8 BP 2464 EP 2469 DI 10.1073/pnas.0307328101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400043 PM 14983032 ER PT J AU Mayer, DCG Mu, JB Kaneko, O Duan, JH Su, XZ Miller, LH AF Mayer, DCG Mu, JB Kaneko, O Duan, JH Su, XZ Miller, LH TI Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE parasite polymorphism ID CELL ENZYME POLYMORPHISMS; DUFFY-BLOOD-GROUP; GLYCOPHORIN-C; NEW-GUINEA; MALARIAL PARASITES; SERUM-PROTEIN; INVASION; ANTIGEN; VIVAX; MEROZOITES AB The malaria parasite lives within erythrocytes and depends on the binding of parasite ligands to host cell surface receptors for invasion. The most virulent human malaria parasite, Plasmodium, falciparum, uses multiple ligands, including EBA-175, BAEBL, and JESEBL of the Duffy-binding-like (DBL) family of erythrocyte-binding proteins, for invasion of human erythrocytes. Region II of these parasite ligands is the erythrocyte-binding domain. Previously, we had shown that polymorphism in region II of BAEBL leads to different erythrocyte-binding specificities. We have now identified and characterized the binding specificity of six JESEBL variants. We sequenced region II of JESEBL from 20 P. falciparum clones collected from various parts of the world where malaria is endemic. We observed eight JESEBL variants that contained amino acid polymorphisms at five positions among all clones. Seven of the eight variants could be connected by a single base change that led to an amino acid change. We investigated the functional significance of these polymorphisms by transiently expressing region II from six of JESEBL variants on the surface of Chinese hamster ovary cells. We observed four erythrocyte-binding patterns to enzyme-treated erythrocytes. Thus, A falciparum DBL ligands JESEBL and BAEBL can recognize multiple receptors on the erythrocyte surface. In contrast to Plasmodium vivax, which has disappeared from West Africa because of the Duffy-negative blood group, A falciparum may have been successful in endemic areas because it has mutated the ligands of the DBL family to create multiple pathways of invasion, thus making selection of refractory erythrocytes unlikely. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Ehime Univ, Sch Med, Dept Mol Parasitol, Shigenobu, Ehime 7910295, Japan. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,Room 4126, Bethesda, MD 20892 USA. EM lmiller@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 NR 44 TC 71 Z9 74 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 FEB 24 PY 2004 VL 101 IS 8 BP 2518 EP 2523 DI 10.1073/pnas.0307318101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400052 PM 14983041 ER PT J AU Erichsen, HC Chanock, SJ AF Erichsen, HC Chanock, SJ TI SNPs in cancer research and treatment SO BRITISH JOURNAL OF CANCER LA English DT Review DE cancer; genomics; haplotype; single-nucleotide polymorphism ID HUMAN GENOME; CLINICAL PRESENTATION; GENETIC-POLYMORPHISM; HAPLOTYPE STRUCTURE; COMMON DISEASE; ASSOCIATION; RISK; MYELOPEROXIDASE; METHYLTRANSFERASE; SUSCEPTIBILITY AB Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10-15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools (i.e., the single-nucleotide polymorphism, SNP) to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care. C1 NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Canc Res,Adv Technol Ctr,NIH, Bethesda, MD 20892 USA. NCI, Core Genotyping Facil, NIH, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Canc Res,Adv Technol Ctr,NIH, 8718 Grovemont Circle, Bethesda, MD 20892 USA. EM sc83a@nih.gov NR 35 TC 94 Z9 101 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 23 PY 2004 VL 90 IS 4 BP 747 EP 751 DI 10.1038/sj.bjc.6601574 PG 5 WC Oncology SC Oncology GA 802DN UT WOS:000220144300001 PM 14970847 ER PT J AU Hunter, KW AF Hunter, KW TI Host genetics and tumour metastasis SO BRITISH JOURNAL OF CANCER LA English DT Review DE metastasis; cancer; progression; genetics; microarray; gene expression; inefficiency; mouse models; modifiers; quantitative traits; genetic background ID BREAST-CANCER METASTASIS; SIGNAL-TRANSDUCTION; INBRED STRAINS; SECONDARY SITE; CELLS; PROGRESSION; EXPRESSION; DORMANCY; MODEL; INEFFICIENCY AB Metastasis, the spread and growth of tumours at secondary sites, is an extremely important clinical event, since a majority of cancer mortality is associated with the metastatic tumours, rather than the primary tumour. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumour cells can be shed into the vasculature daily; yet, few secondary tumours are formed. The classical hypothesis explaining the inefficiency was a series of secondary events occurring in the tumour, resulting in a small subpopulation of cells capable of completing all of the steps required to successfully colonise a distant site. However, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumour tissue are not consistent with only a small subpopulation of cells in the primary tumour acquiring metastatic ability, suggesting that metastatic ability might be pre-programmed in tumours by the initiating oncogenic mutations. Data supporting both of these seemingly incompatible theories exist. Therefore, to reconcile the observed results, additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background on which a tumour arises on can have significant affects on the ability of the tumour to metastasise and on gene expression profiles. Thus, the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which, subsequently, metastasis-promoting mutational and epigenetic events occur, If the genetic background is an important determinant of metastatic efficiency, it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Populat Genet, NIH, Bldg 41,Room D702,41 Lib Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov NR 35 TC 61 Z9 63 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 23 PY 2004 VL 90 IS 4 BP 752 EP 755 DI 10.1038/sj.bjc.6601590 PG 4 WC Oncology SC Oncology GA 802DN UT WOS:000220144300002 PM 14970848 ER PT J AU Lotem, M Shiloni, E Pappo, I Drize, O Hamburger, T Weitzen, R Isacson, R Kaduri, L Merims, S Frankenburg, S Peretz, T AF Lotem, M Shiloni, E Pappo, I Drize, O Hamburger, T Weitzen, R Isacson, R Kaduri, L Merims, S Frankenburg, S Peretz, T TI Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE autologous melanoma vaccine; interleukin-2; metastatic melanoma ID DOSE RECOMBINANT INTERLEUKIN-2; ACTIVE-SPECIFIC IMMUNOTHERAPY; CELL VACCINE; CONTINUOUS-INFUSION; RANDOMIZED TRIAL; PEPTIDE VACCINE; STAGE-III; SURVIVAL; CANCER; LYMPHOCYTES AB This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients star-Led the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, I I attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies. C1 Hadassah Univ Hosp, Sharett Inst Oncol, IL-91120 Jerusalem, Israel. Carmel Hosp, Dept Surg B, IL-34362 Haifa, Israel. Assaf Harofeh Med Ctr, Dept Surg A, IL-70300 Zerifin, Israel. Chaim Sheba Med Ctr, Dept Oncol, IL-52662 Ramat Gan, Israel. Shaare Zedek Med Ctr, Dept Oncol, IL-91031 Jerusalem, Israel. Hadassah Univ Hosp, Dept Dermatol, IL-91120 Jerusalem, Israel. RP Lotem, M (reprint author), NCI, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. EM lotemm@mail.nih.gov NR 30 TC 25 Z9 26 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 23 PY 2004 VL 90 IS 4 BP 773 EP 780 DI 10.1038/sj.bjc.6601563 PG 8 WC Oncology SC Oncology GA 802DN UT WOS:000220144300006 PM 14970852 ER PT J AU Honda, T Tamura, G Waki, T Kawata, S Terashima, M Nishizuka, S Motoyama, T AF Honda, T Tamura, G Waki, T Kawata, S Terashima, M Nishizuka, S Motoyama, T TI Demethylation of MAGE promoters during gastric cancer progression SO BRITISH JOURNAL OF CANCER LA English DT Article DE gastric cancer; MAGE; demethylation ID TUMOR-REJECTION ANTIGEN; HUMAN GENE MAGE-1; DNA HYPOMETHYLATION; EXPRESSION; METHYLATION; CARCINOMA; CELLS; MELANOMA; PEPTIDE; CARCINOGENESIS AB Melanoma antigen (MAGE)-encoding genes are expressed in various tumour types via demethylation of their promoter CpG islands, which are silent in all non-neoplastic tissues except for the testis and placenta. The clinicopathological significance of demethylation of MAGE genes in gastric carcinoma is not known. We investigated the promoter methylation status of MAGE-A1 and -A3 in 10 gastric cancer cell lines and in surgical specimens from 84 gastric cancer patients by methylation-specific PCR (MSP). Expression of MAGE-A1 and -A3 in the 10 gastric cancer cell lines was also investigated by RT-PCR. Any correlation between the methylation status of the MAGE promoters and clinicopathological characteristics of the gastric cancer patients was then assessed. Eight of the 10 gastric cancer cell lines showed demethylation of both MAGE-A1 and -A3, and the remaining two cell lines did either of MAGE-A1 or -A3. Expression of MAGE-A1 and -A3 was confirmed in seven and nine of the 10 gastric cancer cell lines, respectively. The MAGE-A1 and -A3 promoters were demethylated in 29% (25 out of 84) and 66% (56 out of 84) of the gastric tumour specimens, respectively. Demethylation of both MAGE-A1 and -A3 promoters (n = 22) was found more frequently in gastric cancer patients in advanced clinical stages (P = 0.0035), and these patients also exhibited a higher incidence of lymph node metastasis (P = 0.0007) compared to those patients without demethylation (n = 25). Furthermore, demethylation patients tended to have a worse prognosis, although this difference was not statistically significant (P = 0.183). Demethylation of MAGE-A1 and -A3 occurs during progressive stages of gastric cancer, and may be associated with aggressive biological behaviour of gastric cancer. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 99023, Japan. Yamagata Univ, Sch Med, Dept Internal Med, Yamagata 99023, Japan. Fukushima Med Univ, Dept Surg, Fukushima, Japan. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), Yamagata Univ, Sch Med, Dept Pathol, Yamagata 99023, Japan. EM gtamura@med.id.yamagata-u.ac.jp NR 39 TC 48 Z9 54 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 23 PY 2004 VL 90 IS 4 BP 838 EP 843 DI 10.1038/sj.bjc.6601600 PG 6 WC Oncology SC Oncology GA 802DN UT WOS:000220144300016 PM 14970862 ER PT J AU O'Sullivan, GJ Roth, BL Kinsella, A Waddington, JL AF O'Sullivan, GJ Roth, BL Kinsella, A Waddington, JL TI SK & F 83822 distinguishes adenylyl cyclase from phospholipase C-coupled dopamine D1-like receptors: behavioural topography SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE dopamine D1-like receptor; adenylyl cyclase-coupled; non-adenylyl cyclase-coupled; SK & F 83822; behavioural topography; dopamine D1-like; S2-like receptor interaction; (mouse) ID ETHOLOGICALLY BASED RESOLUTION; TARGETED GENE DELETION; JAW MOVEMENTS; RAT-BRAIN; PHOSPHOINOSITIDE HYDROLYSIS; D-1-LIKE RECEPTORS; VARYING EFFICACIES; ACCUMBAL SHELL; MICE LACKING; SKF 83959 AB Effects of SK&F 83822 [3-allyl-6-chloro-7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine], an agonist at dopamine D1-like receptors which stimulate adenylyl cyclase but not phosphoinositide hydrolysis, were studied topographically so as to clarify differences between these receptors in the regulation of behaviour. Using cloned receptors, SK&F 83822 showed high, selective affinity for dopamine D1 and D5 over D2, D3, D4 and several non-dopamine receptors. SK&F 83822 induced little intense grooming, but readily induced sniffing, locomotion and rearing; seizures were evident at higher doses, characterised by tonic convulsions, forepaw myoclonus and explosive hyperlocomotion. The dopamine D1-like receptor antagonist SCH 23390 [R(+)-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] readily antagonised these responses to SK&F 83822, particularly seizure activity. The dopamine D2-like receptor antagonist YM 09151-2 [cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide] did not alleviate seizures induced by SKF 83822; YM 09151-02 did, however, attenuate SK&F 83822-induced sniffing, locomotion and rearing, and released vacuous chewing. These findings indicate that dopamine D1-like receptors linked to adenylyl cyclase can be differentiated from those not linked to adenylyl cyclase in terms of their roles in the topographical regulation of behaviour. For example, the seizure and vacuous chewing responses appear to involve dopamine D1-like receptors that stimulate adenylyl cyclase, while intense grooming involves those which do not. (C) 2004 Elsevier B.V. All rights reserved. C1 Royal Coll Surgeons Ireland, Dept Clin Pharmacol, Dublin 2, Ireland. Royal Coll Surgeons Ireland, Inst Biopharmacuet Sci, Dublin 2, Ireland. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Dublin Inst Technol, Sch Math, Dublin 8, Ireland. RP Waddington, JL (reprint author), Royal Coll Surgeons Ireland, Dept Clin Pharmacol, St Stephens Green, Dublin 2, Ireland. EM jwadding@rcsi.ic RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [N01MH30003, N02MH80004] NR 42 TC 32 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 23 PY 2004 VL 486 IS 3 BP 273 EP 280 DI 10.1016/j.ejphar.2004.01.004 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 800HB UT WOS:000220018400005 PM 14985049 ER PT J AU Sklar, PA Agyemang, AF Monastra, R Kress, DR Metcalf, JA Robinson, MR Masur, H Polis, MA AF Sklar, PA Agyemang, AF Monastra, R Kress, DR Metcalf, JA Robinson, MR Masur, H Polis, MA TI Five-year follow-up of a cohort of profoundly immunosuppressed patients discontinuing therapy for cytomegalovirus retinitis SO AIDS LA English DT Article; Proceedings Paper CT 1st IAS Conference on HIV Pathogenesis and Treatment CY JUL 08-11, 2001 CL BUENOS AIRES, ARGENTINA SP Brazilian Minist Hlth STD/AIDS Program, PAPES, FIOCRUZ, PRONEX ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNE-DEFICIENCY-SYNDROME; VIRUS-INFECTED PATIENTS; MAINTENANCE THERAPY; ANTICYTOMEGALOVIRUS THERAPY; CELL COUNTS; IMMUNODEFICIENCY; GANCICLOVIR; INCREASE AB Potent antiretroviral therapy stimulates robust and durable immune reconstitution among profoundly immunosuppressed patients that is clinically important. Fifteen patients with cytomegalovirus retinitis (CMVR) were followed after discontinuing anti-cytomegalovirus therapy. No patient had progression or relapse for a median of 51 months. Survival from the diagnosis of CMVR was universal for up to 95 months, with an observation period averaging more than 6 years. The CD4 cell count continued to rise through the fourth year of follow-up. C1 NIAID, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD USA. RP Sklar, PA (reprint author), NIAID, Ctr Clin, Dept Crit Care Med, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 13 TC 4 Z9 4 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 FEB 20 PY 2004 VL 18 IS 3 BP 567 EP 569 DI 10.1097/01.aids.0000111426.91384.5a PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 803LQ UT WOS:000220233000027 PM 15090813 ER PT J AU Schairer, C Hill, D Sturgeon, SR Fears, T Pollak, M Mies, C Ziegler, RG Hoover, RN Sherman, ME AF Schairer, C Hill, D Sturgeon, SR Fears, T Pollak, M Mies, C Ziegler, RG Hoover, RN Sherman, ME TI Serum concentrations of IGF-I, IGFBP-3 and C-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IGF-I; IGFBP-3; c-peptide; breast cancer; hyperplasia ID GROWTH-FACTOR-I; FACTOR-BINDING PROTEIN-3; INSULIN; DISEASE; BENIGN; PLASMA; PROLIFERATION; SECRETION; CELLS AB Experimental evidence suggests that insulin and insulin-related growth factors may play a role in breast pathology through their mitogenic and anti-apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin-like growth factor-1 (IGF-1), its major binding protein (IGFBP-3), the ratio IGF-I:IGFBP-3, c-pepticle (a marker of insulin secretion) and the ratio c-peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, M1 between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF-1, IGFBP-3 and the ratio IGF-1:IGFBP-3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c-peptide or of c-peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [Cl] 1.4-63) and 3.3 (95% Cl 1.5-7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% Cl 0.7-3.0) and 1.6 (95% Cl 0.8-3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women. (C) 2003 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ Massachusetts, Amherst, MA 01003 USA. Jewish Gen Hosp, Montreal, PQ, Canada. McGill Univ, Montreal, PQ, Canada. Univ Penn, Dept Pathol, Philadelphia, PA USA. RP Schairer, C (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS,Room 8020 MSC 7234, Rockville, MD 20852 USA. EM schairec@exchange.nih.gov RI Pollak, Michael/G-9094-2011 OI Pollak, Michael/0000-0003-3047-0604 NR 34 TC 54 Z9 58 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 20 PY 2004 VL 108 IS 5 BP 773 EP 779 DI 10.1002/ijc.11624 PG 7 WC Oncology SC Oncology GA 763PB UT WOS:000188093800017 PM 14696106 ER PT J AU Arakawa, R Hayashi, M Remaley, AT Brewer, BH Yamauchi, Y Yokoyama, S AF Arakawa, R Hayashi, M Remaley, AT Brewer, BH Yamauchi, Y Yokoyama, S TI Phosphorylation and stabilization of ATP binding cassette transporter a1 by synthetic Amphiphilic helical peptides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CELLULAR CHOLESTEROL; TANGIER-DISEASE; APOLIPOPROTEINS; EFFLUX; MECHANISM; RELEASE; MICE; DEGRADATION; DEFICIENCY AB To investigate structural requirement of helical apolipoprotein to phosphorylate and stabilize ATP-binding cassette transporter A1 (ABCA1), synthetic peptides (Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J. Lipid Res. 44, 828 836) were examined for these activities. L37pA, an L amino acid peptide that contains two class-A amphiphilic helices, and D37pA, the same peptide with all D amino acids, both removed cholesterol and phospholipid from differentiated THP-1 cells more than apolipoproteins (apos) A-I, A-II, and E. Both peptides also mediated lipid release from human fibroblasts WI-38 similar to apoA-I. L2D37pA, an L-peptide whose valine and tyrosine were replaced with D amino acids also promoted lipid release from WI-38 but less so with THP-1, whereas L3D37pA, in which alanine, lysine, and asparatic acid were replaced with D amino acids was ineffective in lipid release for both cell lines. ABCA1 protein in THP-1 and WT-38 was stabilized against proteolytic degradation by apoA-I, apoA-II, and apoE and by all the peptides tested except for L3D37pA, and ABCA1 phosphorylation closely correlated with its stabilization. The analysis of the relationship among these parameters indicated that removal of phospholipid triggers signals for phosphorylation and stabilization of AECA1. We thus concluded that an amphiphilic helical motif is the minimum structural requirement for a protein to stabilize AECA1 against proteolytic degradation. C1 Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi 4678601, Japan. Grelan Pharmaceut Co Ltd, Div Res & Dev, Tokyo 2050002, Japan. NHLBI, NIH, Mol Dis Branch, Bethesda, MD 20892 USA. RP Yokoyama, S (reprint author), Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi 4678601, Japan. EM syokoyam@med.nagoya-cu.ac.jp RI Yamauchi, Yoshio/I-7539-2014 OI Yamauchi, Yoshio/0000-0001-5559-4596 NR 20 TC 55 Z9 55 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 FEB 20 PY 2004 VL 279 IS 8 BP 6217 EP 6220 DI 10.1074/jbc.C300553200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200004 PM 14701850 ER PT J AU Lannon, CL Martin, MJ Tognon, CE Jin, W Kim, SJ Sorensen, PHB AF Lannon, CL Martin, MJ Tognon, CE Jin, W Kim, SJ Sorensen, PHB TI A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1 - An essential interaction for transformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; PROTEIN-TYROSINE KINASE; SIGNAL-TRANSDUCTION; GENE FUSION; CONGENITAL FIBROSARCOMA; PROSTATE-CANCER; NEUROTROPHIN RECEPTORS; IRS-1 PHOSPHORYLATION; MESOBLASTIC NEPHROMA; MYELOGENOUS LEUKEMIA AB Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN-IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation. C1 British Columbia Res Inst Childrens & Womens Hlth, Dept Pathol, Vancouver, BC V5Z 4H4, Canada. British Columbia Res Inst Childrens & Womens Hlth, Dept Pediat, Vancouver, BC V5Z 4H4, Canada. Univ British Columbia, Vancouver, BC V5Z 4H4, Canada. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Sorensen, PHB (reprint author), British Columbia Res Inst Childrens & Womens Hlth, Dept Pathol, Rm 3082,950 W 28th Ave, Vancouver, BC V5Z 4H4, Canada. EM psor@interchange.ubc.ca NR 52 TC 41 Z9 42 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 FEB 20 PY 2004 VL 279 IS 8 BP 6225 EP 6234 DI 10.1074/jbc.M307388200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200006 PM 14668342 ER PT J AU Lee, G Tanaka, M Park, K Lee, SS Kim, YM Junn, E Lee, SH Mouradian, MM AF Lee, G Tanaka, M Park, K Lee, SS Kim, YM Junn, E Lee, SH Mouradian, MM TI Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PAIRED HELICAL FILAMENTS; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; NEURODEGENERATIVE DISORDERS; LEWY BODIES; ABNORMAL PHOSPHORYLATION; TRANSGENIC MICE; PROTEIN; SYNPHILIN-1; TAU AB alpha-Synuclein is a phosphoprotein that accumulates as a major component of Lewy bodies in the brains of patients with Parkinson disease. Synphilin-1, which is also present in Lewy bodies, binds with alpha-synuclein and forms cytoplasmic inclusions in transfected cells. Yet the molecular determinants of this protein-protein interaction are unknown. Here we report that casein kinase II (CKII) phosphorylates synphilin-1 and that the beta subunit of this enzyme complex binds to synphilin-1. Additionally, both CKII alpha and beta subunits are present within cytoplasmic inclusions in cells that overexpress synphilin-1. Notably, the interaction between synphilin-1 and alpha-synuclein is markedly dependent on phosphorylation. Inhibition of CKII activity by 5,6-dichlorol-beta-D-ribofuranosylbenzimidazole blocks the binding between these two proteins and significantly reduces the percentage of cells that contain eosinophilic cytoplasmic inclusions. Mutation of the major CKII phosphorylation site in alpha-synuclein (S129A) has no significant impact on the binding between alpha-synuclein and synphilin-1 or on the formation of synphilin-1/alpha-synuclein-positive inclusions. These data suggest that the CKII-mediated phosphorylation of synphilin-1 rather than that of alpha-synuclein is critical in modulating their tendency to aggregate into inclusions. These observations collectively indicate that a ubiquitous post-translational modification such as phosphorylation can regulate inclusion body formation in the context of alpha-synuclein and synphilin-1 interaction. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, Piscataway, NJ 08854 USA. NINDS, Genet Pharmacol Unit, NIH, Bethesda, MD 20824 USA. Ajou Univ, Sch Med, Med Genet Lab, Suwon 442721, South Korea. RP Mouradian, MM (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, 683 Hoes Lane,Rm 180, Piscataway, NJ 08854 USA. EM mouradian@umdnj.edu OI Mouradian, M. Maral/0000-0002-9937-412X NR 41 TC 55 Z9 58 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 FEB 20 PY 2004 VL 279 IS 8 BP 6834 EP 6839 DI 10.1074/jbc.M312760200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200077 PM 14645218 ER PT J AU Baek, SJ Kim, JS Nixon, JB DiAugustine, RP Eling, TE AF Baek, SJ Kim, JS Nixon, JB DiAugustine, RP Eling, TE TI Expression of NAG-1, a transforming growth factor-beta superfamily member, by troglitazone requires the early growth response gene EGR-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; SMOOTH-MUSCLE-CELLS; VASCULAR ENDOTHELIAL-CELLS; BREAST-CANCER CELLS; PPAR-GAMMA; TRANSCRIPTION FACTOR; INDUCE APOPTOSIS; CYCLE ARREST; SIGNALING PATHWAY; CARCINOMA CELLS AB Troglitazone (TGZ) and 15-deoxy-Delta(12,14) -prostaglandin J(2) (PGJ(2)) are peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands that have been shown to possess pro-apoptotic activity in human colon cancer. Although these compounds bind to PPARgamma transcription factors as agonists, emerging evidence suggests that TGZ acts independently of PPARgamma in many functions, including apoptosis. We previously reported that TGZ induces an early growth response transcription factor (EGR-1) by the ERK phosphorylation pathway rather than by the PPARgamma pathway (Baek, S. J., Wilson, L. C., Hsi, L. C., and Eling, T. E. (2003) J. Biol. Chem. 278, 5845-5853). In this report, we show that the expression of the antitumorigenic and/or pro-apoptotic gene NAG-1 (nonsteroidal anti-inflammatory drug-Activated gene-1) is induced by TGZ and correlates with EGR-1 induction. In cotransfection and gel shift assays, we show that EGR-1-binding sites are located within region -73 to -51 of the NAG-1 promoter and have an important role in the transactivation of TGZ-induced NAG-1 expression. In contrast, PGJ(2) induced NAG-1 protein expression, but PJG(2) may not affect the same region that TGZ does in the NAG-1 promoter. The effect of PGJ(2) is probably PPARgamma-dependent because a PPARgamma antagonist inhibited the PGJ(2)-induced expression of NAG-1. TGZ-induced NAG-1 expression was not inhibited by the PPARgamma antagonist. The fact that TGZ-induced NAG-1 expression was accompanied by the biosynthesis of EGR-1 also suggests that EGR-1 plays a pivotal role in TGZ-induced NAG-1 expression. Our results suggest that EGR-1 induction is a unique property of TGZ, but is independent of PPARgamma activation. The up-regulation of NAG-1 may provide a novel explanation for the antitumorigenic property of TGZ. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Coll Vet Med, Dept Pathobiol, Knoxville, TN 37996 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Eling@niehs.nih.gov OI Baek, Seung/0000-0001-7866-7778 NR 61 TC 102 Z9 106 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 FEB 20 PY 2004 VL 279 IS 8 BP 6883 EP 6892 DI 10.1074/jbc.M305295200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200083 PM 14662774 ER PT J AU Nakayama, M Kimura, M Wada, A Yahiro, K Ogushi, K Niidome, T Fujikawa, A Shirasaka, D Aoyama, N Kurazono, H Noda, M Moss, J Hirayama, T AF Nakayama, M Kimura, M Wada, A Yahiro, K Ogushi, K Niidome, T Fujikawa, A Shirasaka, D Aoyama, N Kurazono, H Noda, M Moss, J Hirayama, T TI Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; GASTRIC EPITHELIAL-CELLS; VACUOLATING CYTOTOXIN; MELANOMA-CELLS; CELLULAR VACUOLATION; HUMAN NEUTROPHILS; BINDING PROTEIN; AMINO-ACIDS; CYCLIN D1; P38 MAPK AB Persistent Helicobacter pylori colonization in the stomach induces gastritis and peptic ulcer and interferes with ulcer healing. Most strains of H. pylori produce a cytotoxin, VacA, that induces cytoplasmic vacuolation in epithelial cells with structural and functional changes, leading to gastric injury. VacA is known to cause cell death by mitochondrial damage. We hypothesized that VacA might disrupt other signaling pathways; to that end, we examined the effects of VacA on MAPKs to elucidate their role in the abnormalities seen in VacA-treated cells. VacA stimulated phosphorylation of p38 and Erk1/2, but not JNK, in AZ-521 cells. Both phosphorylation and kinase activation of p38 were maximal 10-30 min after addition of VacA and declined thereafter. Treatment with anti-VacA antibody or the p38 inhibitor SB203580 blocked p38 phosphorylation caused by VacA and inhibited VacA-induced phosphorylation of activating transcription factor 2 (ATF-2), which is implicated in transcriptional control of stress-responsive genes. These data indicate that VacA stimulates a p38/ ATF-2-mediated signal pathway. However, 10 muM SB203580, which is sufficient to decrease p38 phosphorylation, did not inhibit VacA-induced cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria. These results suggest that VacA-induced activation of p38/ATF-2-mediated signal pathway is independent of cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria caused by VacA. The cytotoxin may thus act independently on several cellular targets, leading to disruption of signaling, regulatory, and metabolic pathways. C1 Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. Okayama Univ, Sch Hlth Sci, Dept Med Technol, Okayama 7008558, Japan. Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. Nagasaki Univ, Fac Engn, Dept Appl Chem, Nagasaki 8528521, Japan. Natl Inst Basic Biol, Div Mol Neurobiol, Okazaki, Aichi 4448585, Japan. Kobe Univ, Sch Med, Dept Endoscopy, Kobe, Hyogo 6578501, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. EM hirayama@net.nagasaki-u.ac.jp RI Niidome, Takuro/F-1508-2010; Fujikawa, Akihiro/K-9805-2015; Noda, Masaharu/D-7146-2016 OI Niidome, Takuro/0000-0002-8070-8708; Fujikawa, Akihiro/0000-0002-3950-0550; Noda, Masaharu/0000-0002-3796-524X NR 60 TC 57 Z9 61 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 FEB 20 PY 2004 VL 279 IS 8 BP 7024 EP 7028 DI 10.1074/jbc.M308898200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200099 PM 14630932 ER PT J AU Saito, S Liu, XF Kamijo, K Raziuddin, R Tatsumoto, T Okamoto, I Chen, XY Lee, CC Lorenzi, MV Ohara, N Miki, T AF Saito, S Liu, XF Kamijo, K Raziuddin, R Tatsumoto, T Okamoto, I Chen, XY Lee, CC Lorenzi, MV Ohara, N Miki, T TI Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXPRESSION CDNA CLONING; GTP-BINDING PROTEINS; REPLICATION CHECKPOINT CONTROL; EXCHANGE FACTOR ECT2; FISSION YEAST; RAS TRANSFORMATION; DBL FAMILY; C-JUN; GTPASES; ONCOGENE AB The human ECT2 protooncogene encodes a guanine nucleotide exchange factor for the Rho GTPases and regulates cytokinesis. Although the oncogenic form of ECT2 contains an N-terminal truncation, it is not clear how the structural abnormality of ECT2 causes malignant transformation. Here we show that both the removal of the negative regulatory domain and alteration of subcellular localization are required to induce the oncogenic activity of ECT2. The transforming activity of oncogenic ECT2 was strongly inhibited by dominant negative Rho GTPases, suggesting the involvement of Rho GTPases in ECT2 transformation. Although deletion of the N-terminal cell cycle regulator-related domain (N) of ECT2 did not activate its transforming activity, removal of the small central domain (S), which contains two nuclear localization signals (NLSs), significantly induced the activity. The ECT2 N domain interacted with the catalytic domain and significantly inhibited the focus formation by oncogenic ECT2. Interestingly, the introduction of the NLS mutations in the S domain of N-terminally truncated ECT2 dramatically induced the transforming activity of this otherwise nononcogenic derivative. Among the known Rho GTPases expressed in NIH 3T3 cells, RhoA was predominantly activated by oncogenic ECT2 in vivo. Therefore, the mislocalization of structurally altered ECT2 might cause the untimely activation of cytoplasmic Rho GTPases leading to the malignant transformation. C1 NCI, Mol Tumor Biol Sect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Miki, T (reprint author), NCI, Mol Tumor Biol Sect, Basic Res Lab, NIH, 37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM toru@helix.nih.gov NR 31 TC 65 Z9 66 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 FEB 20 PY 2004 VL 279 IS 8 BP 7169 EP 7179 DI 10.1074/jbc.M306725200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200116 PM 14645260 ER PT J AU Ahvazi, B Boeshans, KM Idler, W Baxa, U Steinert, PM Rastinejad, F AF Ahvazi, B Boeshans, KM Idler, W Baxa, U Steinert, PM Rastinejad, F TI Structural basis for the coordinated regulation of transglutaminase 3 by guanine nucleotides and calcium/magnesium SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PIG LIVER TRANSGLUTAMINASE; CORNIFIED CELL-ENVELOPE; EPIDERMAL-KERATINOCYTES; TISSUE TRANSGLUTAMINASE; PROTRANSGLUTAMINASE-E; BINDING PROTEIN; PHOSPHOLIPASE-C; CALCIUM-IONS; GTP-BINDING; ACTIVATION AB Transglutaminase 3 (TGase 3) is a member of a family of Ca2+-dependent enzymes that catalyze covalent cross-linking reactions between proteins or peptides. TGase 3 isoform is widely expressed and is important for effective epithelial barrier formation in the assembly of the cell envelope. Among the nine TGase enzyme isoforms known in the human genome, only TGase 2 is known to bind and hydrolyze GTP to GDP; binding GTP inhibits its transamidation activity but allows it to function in signal transduction. Here we present biochemical and crystallographic evidence for the direct binding of GTP/GDP to the active TGase 3 enzyme, and we show that the TGase 3 enzyme undergoes a GTPase cycle. The crystal structures of active TGase 3 with guanosine 5% O-(thiotriphosphate) (GTPgammaS) and GDP were determined to 2.1 and 1.9 Angstrom resolution, respectively. These studies reveal for the first time the reciprocal actions of Ca2+ and GTP with respect to TGase 3 activity. GTPgammaS binding is coordinated with the replacement of a bound Ca2+ with Mg2+ and conformational rearrangements that together close a central channel to the active site. Hydrolysis of GTP to GDP results in two stable conformations, resembling both the GTP state and the nonnucleotide bound state, the latter of which allows substrate access to the active site. C1 NIAMS, Xray Crystallog Facil, NIH, Bethesda, MD 20892 USA. NIAMS, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Dept Pharmacol & Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Ahvazi, B (reprint author), NIAMS, Xray Crystallog Facil, NIH, Bldg 50,Rm 1345,50 South Dr, Bethesda, MD 20892 USA. EM ahvazib@mail.nih.gov NR 47 TC 27 Z9 27 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 20 PY 2004 VL 279 IS 8 BP 7180 EP 7192 DI 10.1074/jbc.M312310200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200117 PM 14645372 ER PT J AU Mamede, M Saga, T Ishimori, T Higashi, T Sato, N Kobayashi, H Brechbiel, MW Konishi, J AF Mamede, M Saga, T Ishimori, T Higashi, T Sato, N Kobayashi, H Brechbiel, MW Konishi, J TI Hepatocyte targeting of In-111-labeled oligo-DNA with avidin or avidin-dendrimer complex SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE hepatocyte; avidin; biotin; dendrimer; biodistribution ID MEDIATED GENE DELIVERY; EGG WHITE AVIDIN; ANTISENSE OLIGONUCLEOTIDES; POLYAMIDOAMINE DENDRIMERS; PERSISTENT EXPRESSION; STARBURST DENDRIMERS; NONVIRAL VECTOR; RAT HEPATOCYTES; LIVER-CELLS; IN-VIVO AB To establish an effective nonviral gene transfer vector to hepatocytes, various oligo-carrier complexes were developed employing dendrimer (G4) and avidin-biotin systems (Av-bt), and their biodistribution were evaluated. In-111-labeled-oligo, without any carriers, showed low uptake in normal organs other than the kidney (21.48% ID/g at 15 min, 18.48% ID/g at 60 min). In contrast, In-111-oligo coupled with avidin through biotin (In-111-oligo-bt-Av) showed very high accumulation in the liver (50.95% at 15 min, 47.88% at 60 min). In-111-oligo complexed with G4 showed high uptake in the kidney and spleen, but its hepatic uptake was relatively low (13.12% at 15 min, 10.67% at 60 min). When both G4 and Av-bt systems were employed, In-111-oligo/G4-bt-Av showed extremely high uptake in the lung (182.33% at 15 min, 125.54% at 60 min), probably due to the formation of large molecular weight complex and aggregates which are trapped in the lung, and its hepatic uptake was lower than In-111-oligo-bt-Av. In-111-oligo-bt-Av, which exhibited the highest hepatic uptake in vivo, also showed high and rapid internalization into hepatocytes. The avidin-biotin system seems to have potential as a carrier of oligo-DNA to the liver. (C) 2004 Elsevier B.V All rights reserved. C1 Kyoto Univ, Grad Sch Med, Dept Nucl Med & Diagnost Imaging, Sakyo Ku, Kyoto 6068507, Japan. Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Saga, T (reprint author), Kyoto Univ, Grad Sch Med, Dept Nucl Med & Diagnost Imaging, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. EM saga@kuhp.kyoto-u.ac.jp RI Mamede, Marcelo/A-1751-2014 OI Mamede, Marcelo/0000-0001-5818-0954 NR 57 TC 22 Z9 25 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD FEB 20 PY 2004 VL 95 IS 1 BP 133 EP 141 DI 10.1016/j.jconrel.2003.11.015 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 773YY UT WOS:000188954000012 PM 15013240 ER PT J AU Ghirlando, R Litt, MD Prioleau, MN Recillas-Targa, F Felsenfeld, G AF Ghirlando, R Litt, MD Prioleau, MN Recillas-Targa, F Felsenfeld, G TI Physical properties of a genomic condensed chromatin fragment SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chromatin structure; condensed chromatin; heterochromatin; hydrodynamics; physical genomics ID HIGHER-ORDER STRUCTURE; BETA-GLOBIN GENE; HYDRODYNAMIC PROPERTIES; HETEROCHROMATIN; REGION; MACROMOLECULES; COEFFICIENTS; SCATTERING; LENGTH AB We have studied the physical properties of a segment of condensed chromatin that lies upstream of the chicken beta-globin locus. This segment can be excised from an avian erythroleukemia cell line by restriction enzyme digestion and released from the nucleus as an essentially homogeneous fragment about 15.5 kbp long. Because of this homogeneity we could measure its sedimentation coefficient quite accurately by a combination of sucrose gradient and analytical ultracentrifugation. By measuring additionally the buoyant density of the cross-linked particle in CsCl we could deduce the total mass of the particle, hence its frictional coefficient, f, directly related to its shape. The measured value of f is consistent with a rod-like particle of the approximate length and diameter proposed earlier for the 30 nm chromatin fiber. The method is generally applicable to homogeneous particles of unique sequence at genomic abundance. Published by Elsevier Ltd. C1 NIDDK, Dept Hlth & Human Serv, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Dept Hlth & Human Serv, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Prioleau, Marie-Noelle/G-9824-2014 NR 31 TC 30 Z9 30 U1 0 U2 3 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 FEB 20 PY 2004 VL 336 IS 3 BP 597 EP 605 DI 10.1016/j.jmb.2003.12.049 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 773WU UT WOS:000188948500004 PM 15095975 ER PT J AU Hall, D Edskes, H AF Hall, D Edskes, H TI Silent prions lying in wait: A two-hit model of prion/amyloid formation and infection SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE two-hit model; amyloid; prion; chaperone ID TRANSMISSIBLE MINK ENCEPHALOPATHY; APOLIPOPROTEIN C-II; IN-VITRO; AMYLOID PROTOFILAMENTS; PROTEIN AGGREGATION; SCRAPIE; YEAST; FIBRILS; DISEASE; STRAINS AB Diseases such as type 2 diabetes, Alzheimer's and Parkinson's are associated with the formation of amyloid. The transmissible spongiform encephalopathies, such as variant Creutzfeldt-Jakob disease, are believed to result from infectious forms of amyloid proteins termed prions. The ability of amyloid to initiate spontaneously and in the case of prions, to transfer successfully from one host to another, has been hard to fully rationalize. In this paper we use a mathematical model to explore the idea that it might be a combination of the presence of the prion/amyloid form and a change in the state of the host that allows the amyloid/prion to successfully initiate and propagate itself. We raise the intriguing possibility that potentially infectious amyloid may lie dormant in an apparently healthy individual awaiting a change in the state of the host or transmittal to a new more susceptible host. On this basis we make an analogy between prion/amyloid disease development and the two-hit model of cancer progression. We additionally raise the possibility that infectious amyloid strains may be characterized by a size distribution of length or radius. Crown Copyright (C) 2003 Published by Elsevier Ltd. All rights reserved. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM drh32@cam.ac.uk RI Hall, Damien/D-9927-2012 OI Hall, Damien/0000-0003-1538-7618 NR 42 TC 58 Z9 58 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 20 PY 2004 VL 336 IS 3 BP 775 EP 786 DI 10.1016/j.jmb.2003.12.004 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 773WU UT WOS:000188948500016 PM 15095987 ER PT J AU Nguyen, KL Llano, M Akari, H Miyagi, E Poeschla, EM Strebel, K Bour, S AF Nguyen, KL Llano, M Akari, H Miyagi, E Poeschla, EM Strebel, K Bour, S TI Codon optimization of the HIV-1 vpu and vif genes stabilizes their mRNA and allows for highly efficient Rev-independent expression SO VIROLOGY LA English DT Review DE HIV-1; vpu; codon optimization; mRNA ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL PARTICLE RELEASE; ENVELOPE GLYCOPROTEIN; TYPE-1 VPU; MAMMALIAN-CELLS; PROTEIN VPU; GAG GENE; KAPPA-B; SEQUENCES; REGION AB Two HIV-1 accessory proteins, Vpu and Vif, are notoriously difficult to express autonomously in the absence of the viral Tat and Rev proteins. We examined whether the codon bias observed in the vpu and vif genes relative to highly expressed human genes contributes to the Rev dependence and low expression level outside the context of the viral genome. The entire vpu gene as well as the 5' half of the vif gene were codon optimized and the resulting open reading frames (ORFs) (vphu and hvif, respectively) were cloned in autonomous expression vectors under the transcriptional control of the CMV promoter. Codon optimization efficiently removed the expression block observed in the native genes and allowed high levels of Rev- and Tat-independent expression of Vpu and Vif Most of the higher protein levels detected are accounted for by enhanced steady-state levels of the mRNA encoding the optimized species. Nuclear run-on experiments show for the first time that codon optimization has no effect on the rate of transcriptional initiation or elongation of the vphu mRNA. Instead, optimization of the vpu gene was found to stabilize the vphu mRNA in the nucleus and enhance its export to the cytoplasm. This was achieved by allowing the optimized mRNA to use a new CRM1-independent nuclear export pathway. This work provides a better understanding of the molecular mechanisms underlying the process of codon optimization and introduces novel tools to study the biological functions of the Vpu and Vif proteins independently of other viral proteins. Published by Elsevier Inc. C1 NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. Mayo Clin, Program Mol Med, Rochester, MN 55905 USA. NIAID, Bioinformat Core, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Bour, S (reprint author), NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, 4 Ctr Dr,Room 337, Bethesda, MD 20892 USA. EM sbour@niaid.nih.gov OI Nguyen, Kim-Lien/0000-0002-8854-2976 FU NIAID NIH HHS [AI47356] NR 41 TC 123 Z9 128 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2004 VL 319 IS 2 BP 163 EP 175 DI 10.1016/j.virol.2003.11.021 PG 13 WC Virology SC Virology GA 800FN UT WOS:000220014400001 PM 15015498 ER PT J AU Oppenheim, AB Rattray, AJ Bubunenko, M Thomason, LC Court, DL AF Oppenheim, AB Rattray, AJ Bubunenko, M Thomason, LC Court, DL TI In vivo recombineering of bacteriophage lambda by PCR fragments and single-strand oligonucleotides SO VIROLOGY LA English DT Article DE bacteriophage; homologous recombination; lambda red; oligonucleotide; recombineering ID ESCHERICHIA-COLI; RECOMBINATION; DNA; VIRUSES; GENE AB We demonstrate that the bacteriophage lambda Red functions efficiently recombine linear DNA or single-strand oligonucleotides (ss-oligos) into bacteriophage lambda to create specific changes in the viral genome. Point mutations, deletions, and gene replacements have been created. While recombineering with oligonucleotides, we encountered other mutations accompanying the desired point mutational change. DNA sequence analysis suggests that these unwanted mutations are mainly frameshift deletions introduced during oligonucleotide synthesis. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Gene Regulat & Chromosome Biol Lab, Canc Res Ctr, Frederick, MD 21702 USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Genet & Biotechnol, Jerusalem, Israel. RP Court, DL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Gene Regulat & Chromosome Biol Lab, Canc Res Ctr, Room 243,Bldg 539,POB B, Frederick, MD 21702 USA. EM court@ncifcrf.gov RI Rattray, Alison/A-4847-2008 NR 23 TC 38 Z9 43 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2004 VL 319 IS 2 BP 185 EP 189 DI 10.1016/j.virol.2003.11.007 PG 5 WC Virology SC Virology GA 800FN UT WOS:000220014400003 PM 14980479 ER PT J AU Stevceva, L Moniuszko, M Alvarez, X Lackner, AA Franchini, G AF Stevceva, L Moniuszko, M Alvarez, X Lackner, AA Franchini, G TI Functional simian immunodeficiency virus Gag-specific CD8+ intraepithelial lymphocytes in the mucosae of SlVmac251- or simian-human immunodeficiency virus KU2-infected macaques SO VIROLOGY LA English DT Article DE CD8+IELs; SfVmac infection; mucosal compartments ID CYTOTOXIC T-LYMPHOCYTES; RHESUS MACAQUES; GAMMA-INTERFERON; IMMUNE-RESPONSES; INTRAVAGINAL INOCULATION; ROTAVIRUS INFECTION; VAGINAL CHALLENGE; TOXOPLASMA-GONDII; ADOPTIVE TRANSFER; CELL RESPONSES AB The vaginal and rectal mucosae are the first line of cellular immune defense to sexually transmitted human immunodeficiency virus type 1 (HIV-1) entry. Thus, intraepithelial lymphocytes (IELs) may be important in the immune response to HIV infection. Here we investigated whether functional IELs in mucosal compartments could be visualized by direct staining with a tetrameric complex specific for the simian immunodeficiency virus (SIV) immunodominant Gag epitope in either separated IEL cells or tissues of macaques infected with SIVmac251. Of the 15 Mamu-A*01-positive macaques studied here, eight were chronically infected with either SIVmac251 or simian-human immunodeficiency virus (SHIV) KU2 and the remaining seven were exposed mucosally to SIVmac251 and sacrificed within 48 h to assess the local immune response. Gag-specific CD8+ T-cells were found in separated IELs from the rectum, colon, jejunum, and vagina of most infected animals. Direct staining of tetramers also revealed their presence in intact tissue. These Gag-specific IELs expressed the activation marker CD69 and produced IFN-gamma, suggesting an active immune response in this locale. Published by Elsevier Inc. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, 41-D804, Bethesda, MD 20892 USA. EM lstevceva@yahoo.com; Marcin_Moniuszko@nih.gov; xavier@tpc.tulane.edu; alackner@tpc.tulane.edu; franchig@mail.nih.gov FU NCRR NIH HHS [RR00164]; NIDDK NIH HHS [DK50550] NR 49 TC 8 Z9 11 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2004 VL 319 IS 2 BP 190 EP 200 DI 10.1016/j.virol.2003.08.046 PG 11 WC Virology SC Virology GA 800FN UT WOS:000220014400004 PM 14980480 ER PT J AU Bandyopadhyay, S Cookson, MR AF Bandyopadhyay, S Cookson, MR TI Evolutionary and functional relationships within the DJ1 superfamily SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID ONSET PARKINSONS-DISEASE; ESCHERICHIA-COLI HSP31; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; INTRACELLULAR PROTEASE; PYROCOCCUS-FURIOSUS; HUMAN DJ-1; GENE; HYDROXYMETHYLPYRIMIDINE; RESOLUTION AB Background: Inferences about protein function are often made based on sequence homology to other gene products of known activities. This approach is valuable for small families of conserved proteins but can be difficult to apply to large superfamilies of proteins with diverse function. In this study we looked at sequence homology between members of the DJ-1/ThiJ/PfpI superfamily, which includes a human protein of unclear function, DJ-1, associated with inherited Parkinson's disease. Results: DJ-1 orthologs in a variety of eukaryotic species cluster together in a single group. The most closely related group is the bacterial ThiJ genes. These are kinases involved in the biosynthesis of thiamine, a function that has been dispensed with evolutionarily in most eukaryotes where thiamine is an essential nutrient. The similarity with other characterized members of the superfamily, including proteases, is more remote. This is congruent with the recently solved crystal structures that fail to demonstrate the presence of a catalytic triad required for protease activity. Conclusion: DJ-1 may have evolved from the bacterial gene encoding ThiJ kinase. However, as this function has been dispensed with in eukaryotes it appears that the gene has been co-opted for another function. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bandys@mail.nih.gov; cookson@mail.nih.gov NR 32 TC 84 Z9 85 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD FEB 19 PY 2004 VL 4 AR 6 DI 10.1186/1471-2148-4-6 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 808XD UT WOS:000220600900001 PM 15070401 ER PT J AU Rao, PV Maddala, R John, F Zigler, JS AF Rao, PV Maddala, R John, F Zigler, JS TI Expression of nonphagocytic NADPH oxidase system in the ocular lens SO MOLECULAR VISION LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; EPIDERMAL-GROWTH-FACTOR; HYDROGEN-PEROXIDE; EPITHELIAL-CELLS; C-JUN; ENDOTHELIAL-CELLS; REDOX-REGULATION; OXYGEN RADICALS; RAC-GTPASE; IN-VIVO AB purpose: The primary goal of this study was to characterize the Rac GTPase associated, NADPH oxidase-mediated Reactive Oxygen Species (ROS)-generating system in the lens tissue. Methods: NADPH oxidase activity in lens tissue was determined by quantifying superoxide-induced lucigenin photoemission. Immunological and PCR/RT-PCR techniques were utilized to determine expression of different components of the NADPH oxidase system in lens tissue. Growth factor stimulated ROS production was determined quantitatively in human lens epithelial cells using dichlorofluorescein diacetate. Results: Lens homogenates from different species showed generation of superoxide in a lucigenin-enhanced chemiluminescence assay in the presence of NADPH. This activity was found to be lens protein concentration dependent, heat sensitive, and inhibitable by superoxide dismutase and the flavoprotein inhibitor, diphenyleneiodonium (DPI). The distribution of superoxide generating activity in lens was confined predominantly to the lens epithelium, with very low levels in cortex and none in the nucleus. Immunological assays have demonstrated the presence of p67phox and p47phox in lens tissue, while PCR and RT-PCR reactions amplified DNA products corresponding to the p67phox, p40phox, p22phox, gp91phox, and Rac1 components of the NADPH oxidase complex from human and mouse lens cDNA libraries. Serum starved human lens epithelial cells stimulated with different growth factors including EGF, b-FGF, PDGF, TGF-beta, and LPA demonstrated increased production of ROS, a response which was blocked by inhibitors of NADPH oxidase, such as DPI and the antioxidant-N-acetyl cysteine (NAC). RT-PCR analysis of human lens RNA confirmed readily detectable levels of expression of low molecular weight protein tyrosine phosphatase (LMW-PTP), which is a well-characterized target of redox signaling pathway(s). Conclusions: These data demonstrate the presence of a functional nonphagocytic NADPH oxidase system in lens that is predominantly localized to the lens epithelium. Several growth factors appear to stimulate the activity of lens NADPH oxidase, resulting in increased production of ROS in lens epithelial cells, indicating that redox signaling may have an important role in growth factor effects on lens growth and development. C1 Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Rao, PV (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, Box 3802, Durham, NC 27710 USA. EM rao00011@mc.duke.edu FU NEI NIH HHS [EY 12201, EY 13573] NR 49 TC 39 Z9 40 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD FEB 19 PY 2004 VL 10 IS 15-16 BP 112 EP 121 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 778XH UT WOS:000189266300001 PM 14978478 ER PT J AU Ebong, S Chepelinsky, AB Robinson, ML Zhao, HT Yu, CR Egwuagu, CE AF Ebong, S Chepelinsky, AB Robinson, ML Zhao, HT Yu, CR Egwuagu, CE TI Characterization of the roles of STAT1 and STAT3 signal transduction pathways in mammalian lens development SO MOLECULAR VISION LA English DT Article ID GROWTH-FACTOR; GAMMA-INTERFERON; TRANSCRIPTIONAL CONTROL; CELL-PROLIFERATION; TRANSGENIC MICE; GENE-EXPRESSION; MOUSE LENS; DIFFERENTIATION; ACTIVATION; PROTEINS AB Purpose: IGF-1 and PDGF are implicated in regulating lens proliferation and/or providing spatial cues that restrict lens proliferation to germinative and transition zones of the lens. However, very little is known about how IGF-1- or PDGF-induced signals are transduced and coupled to gene transcription in lens cells. Therefore, we examined whether these growth factors mediate their effects in the lens through the evolutionarily conserved JAK/STAT signal transduction pathway and if STAT signaling is essential for mammalian lens development. Methods: Expression of STAT1 and STAT3 was analyzed in mouse lens and lens epithelial cells by RT-PCR and western blot analysis. Activation of the STAT signaling pathway was examined by a combination of gel-shift, super-shift, and western blotting assays. Regulation of lens proliferation and gene transcription by STAT pathways was assessed by H-3-Thymidine incorporation or RT-PCR assays with lens explants treated or untreated with Genistein or the JAK2 and STAT3 inhibitor, AG-490. Mice with targeted deletion of STAT3 in the lens were generated by Cre/lox recombination and STAT1(-/-), STAT3(-/-) deficient as well as normal lenses were characterized by histology. Results: We show that PDGF and IGF1 induce proliferation in 1AMLE6 lens cells and couple their extracellular signals to gene transcription, in part through activation of STAT3 and to a lesser extent STAT1 signal transduction pathways. We further show that targeted deletion of STAT3 in E10.5 lens does not produce overt developmental lens defects. STAT1 knockout mice also exhibit a normal lens phenotype. Conclusions: Our results showing that deletion of either STAT1 or STAT3 does not affect the normal development of the lens is surprising in view of the fact that STAT pathways are activated in developing chick or mouse lens and inappropriate activation of STAT1 pathway in the lens by ectopic lens expression of IFNg inhibits lens differentiation and induces cataract in transgenic mice. Our data thus suggest that although STAT-signaling pathways may contribute to activation of gene transcription in the lens, it may not be essential for normal lens development or STAT proteins may be functionally redundant during lens development. However, because several growth factors and cytokines present in the lens activate STATs in mouse lens explants and 1AMLE6 lens epithelial cells, it may well be that this evolutionarily conserved signaling pathway is under stringent control in the mammalian lens. Whereas deficiency in any particular STAT pathway can be compensated for by any of the functionally redundant STAT proteins induced by a wide array of growth factors in the lens, chronic or prolonged activation of a particular STAT protein may perturb homeostatic balance in STAT-dependent growth factor signaling, culminating in pathologic lens changes. C1 NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Childrens Res Inst, Columbus, OH USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM emeka@helix.nih.gov NR 42 TC 14 Z9 14 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD FEB 19 PY 2004 VL 10 IS 15-16 BP 122 EP 131 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 778XH UT WOS:000189266300002 PM 14978477 ER PT J AU Kruman, II Wersto, RP Cardozo-Pelaez, F Smilenov, L Chan, SL Chrest, FJ Emokpae, R Gorospe, M Mattson, MP AF Kruman, II Wersto, RP Cardozo-Pelaez, F Smilenov, L Chan, SL Chrest, FJ Emokpae, R Gorospe, M Mattson, MP TI Cell cycle activation linked to neuronal cell death initiated by DNA damage SO NEURON LA English DT Article ID BASE-EXCISION-REPAIR; DEPENDENT KINASE INHIBITORS; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; INDUCED APOPTOSIS; ATAXIA-TELANGIECTASIA; POSTMITOTIC NEURONS; G(1)/S TRANSITION; CEREBRAL-ISCHEMIA; STRAND BREAKS AB Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical component of the DNA damage response in postmitotic neurons. Different genotoxic compounds (etoposide, methotrexate, and homocysteine) induced apoptosis accompanied by cell cycle reentry of terminally differentiated cortical neurons. In contrast, apoptosis initiated by stimuli that do not target DNA (staurosporine and colchicine) did not initiate cell cycle activation. Suppression of the function of ataxia telangiectasia mutated (ATM), a proximal component of DNA damage-induced cell cycle checkpoint pathways, attenuated both apoptosis and cell cycle reentry triggered by DNA damage but did not change the fate of neurons exposed to staurosporine and colchicine. Our data suggest that cell cycle activation is a critical element of the DNA damage response of postmitotic neurons leading to apoptosis. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Cellular & Mol Biol Lab, Intramural Res Program, Baltimore, MD 21224 USA. Univ Montana, Environm Hlth Sci Ctr, Dept Pharmaceut Sci, Missoula, MT 59812 USA. Columbia Univ, Sch Med, Ctr Radiol Res, New York, NY 10032 USA. Sun Hlth Res Inst, Thomas H Christopher Ctr Parkinsons Dis Res, Sun City, AZ 85351 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Kruman, II (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM inna.kruman@sunhealth.org RI Mattson, Mark/F-6038-2012 NR 80 TC 186 Z9 199 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 19 PY 2004 VL 41 IS 4 BP 549 EP 561 DI 10.1016/S0896-6273(04)00017-0 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 821KC UT WOS:000221458100008 PM 14980204 ER PT J AU Makar, TK Trisler, D Eglitis, MA Mouradian, MM Dhib-Jalbut, S AF Makar, TK Trisler, D Eglitis, MA Mouradian, MM Dhib-Jalbut, S TI Brain-derived neurotrophic factor (BDNF) gene delivery into the CNS using bone marrow cells as vehicles in mice SO NEUROSCIENCE LETTERS LA English DT Article DE gene therapy; bone marrow cell transplantation; brain-derived neurotrophic factor; neurodegeneration ID NERVOUS-SYSTEM; RAT MODEL; NEURONS; DISEASE; FIBROBLASTS; PROTECTION AB Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is protective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the CNS when delivered peripherally is limited due to the blood-brain barrier. In the present study, bone marrow cells were used as vehicles to deliver the BDNF gene into the CNS. Marrow cells obtained from 6 to 8 week-old SJL/J mice were transduced with BDNF expressing pro-virus. RT-PCR analysis revealed that BDNF mRNA was expressed in transduced but not in non-transduced mar-row cells. Additionally, virus transduced marrow cells expressed the BDNF protein (296 +/- 1.2 unit/ml). BDNF-transduced marrow cells were then transplanted into irradiated mice through the tail vein. Three months post-transplantation, significant increases in BDNF as well as glutamic acid decarboxylase (GAD(67)) mRNA were detected in the brains of BDNF transplanted mice compared to untransplanted animals, indicating biological activity of the BDNF transgene. Thus, bone marrow cells can be used as vehicles to deliver the BDNF gene into the brain with implications for the treatment of neurological diseases. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. Dept Vet Affairs Med Ctr, Res Serv, Baltimore, MD 21201 USA. NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Dhib-Jalbut, S (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, 97 Paterson St,Room 205, New Brunswick, NJ 08901 USA. EM jalbutsu@umdnj.edu OI Mouradian, M. Maral/0000-0002-9937-412X NR 20 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 19 PY 2004 VL 356 IS 3 BP 215 EP 219 DI 10.1016/j.neulet.2003.11.045 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 774DX UT WOS:000188965400016 PM 15036633 ER PT J AU Zhang, J Klebanoff, MA AF Zhang, J Klebanoff, MA TI Small-for-gestational-age infants and risk of fetal death in subsequent pregnancies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. NR 0 TC 9 Z9 10 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 19 PY 2004 VL 350 IS 8 BP 754 EP 756 DI 10.1056/NEJMp038245 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 774VM UT WOS:000189006400003 PM 14973218 ER PT J AU Han, SU Kim, HT Seong, DH Kim, YS Park, YS Bang, YJ Yang, HK Kim, SJ AF Han, SU Kim, HT Seong, DH Kim, YS Park, YS Bang, YJ Yang, HK Kim, SJ TI Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer SO ONCOGENE LA English DT Article DE TGF-b; Smad3; gastric cancer; tumorigenicity; gene expression ID GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR GENE; II RECEPTOR GENE; TGF-BETA; E-CADHERIN; CARCINOMA-CELLS; MICROSATELLITE INSTABILITY; SIGNAL-TRANSDUCTION; TARGETED DISRUPTION; COLON AB Loss of the tumor suppressive effect of transforming growth factor-beta (TGF-beta) has been commonly found at later stages in carcinogenic progression. Although the genes encoding TGF-beta receptors and Smads have been found genetically altered in certain human cancers, no mutation in Smad3 has been observed. Therefore, suppression of Smad3 expression may mediate key oncogenic properties of TGF-beta. First, we observed that 37.5% of human gastric cancer tissues showed low to undetectable levels of Smad3 and that in nine human gastric cancer cell lines examined, two showed deficient Smad3 expression. Introduction of Smad3 into human gastric cancer cells that did not express Smad3, restored TGF-beta responsiveness: induction of p21 and p15 gene expression, and growth inhibition in response to TGF-beta. Furthermore, these Smad3-expressing cells showed markedly decreased and delayed tumorigenicity in vivo. These findings suggest that Smad3 expression may have a critical role in tumor suppression in the early stages of gastric carcinogenesis. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Hanyang Univ, Coll Med, Dept Biochem, Seoul 133791, South Korea. Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Dept Gen Surg, Seoul 110744, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room B1106, Bethesda, MD 20892 USA. EM kims@mail.nih.gov RI Yang, Han-Kwang/J-2767-2012; Bang, Yung Jue/J-2759-2012 NR 64 TC 90 Z9 97 U1 0 U2 2 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 19 PY 2004 VL 23 IS 7 BP 1333 EP 1341 DI 10.1038/sj.onc.1207259 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 775HZ UT WOS:000189035800001 PM 14647420 ER PT J AU Yu, CR Rahmani, M Almenara, J Sausville, EA Dent, P Grant, S AF Yu, CR Rahmani, M Almenara, J Sausville, EA Dent, P Grant, S TI Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process SO ONCOGENE LA English DT Article DE leukemia; apoptosis; adaphostin; ROS; ERK; Akt ID ACTIVATED PROTEIN-KINASE; CHRONIC MYELOGENOUS LEUKEMIA; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; IN-VIVO; GROWTH-FACTOR; MAP KINASES; PATHWAY; JNK; PHOSPHORYLATION AB Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells ( Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations greater than or equal to0.75 muM for intervals greater than or equal to6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D-1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated ( myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/ MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/ MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process. C1 Virginia Commonwealth Univ, Med Coll Virginia, Div Hematol Oncol, Dept Med, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Grant, S (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Div Hematol Oncol, Dept Med, MCV Stn Box 230, Richmond, VA 23298 USA. EM stgrant@hsc.vcu.edu FU NCI NIH HHS [CA 93738, CA63753] NR 45 TC 57 Z9 58 U1 0 U2 1 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 19 PY 2004 VL 23 IS 7 BP 1364 EP 1376 DI 10.1038/sj.onc.1207248 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 775HZ UT WOS:000189035800004 PM 14647418 ER PT J AU Yuan, BZ Jefferson, AM Baldwin, KT Thorgeirsson, SS Popescu, NC Reynolds, SH AF Yuan, BZ Jefferson, AM Baldwin, KT Thorgeirsson, SS Popescu, NC Reynolds, SH TI DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas SO ONCOGENE LA English DT Article DE DLC-1; tumor suppressor gene; non-small cell lung carcinoma; aberrant DNA methylation; tumorigenicity ID ABERRANT PROMOTER METHYLATION; HUMAN BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; CLINICAL IMPLICATIONS; RAS TRANSFORMATION; UNITED-STATES; RHOGAP; PATHOGENESIS; IMBALANCES; EXPRESSION AB The deleted in liver cancer (DLC-1) gene at chromosome 8p21-22 is altered mainly by genomic deletion or aberrant promoter methylation in a large number of human cancers such as breast, liver, colon and prostate and is known to have an inhibitory effect on breast and liver tumor cell growth. Given the high frequency of deletion involving region 8p21-22 in human non-small cell lung carcinoma (NSCLC), we examined alterations of DLC-1 in a series of primary tumors and tumor cell lines and tested effects of DLC-1 on tumor cell growth. A significant decrease or absence of the DLC-1 mRNA expression was found in 95% of primary NSCLC (20/21) and 58% of NSCLC cell lines (11/19). Transcriptional silencing of DLC-1 was primarily associated with aberrant DNA methylation, rather than genomic deletion as 5-aza-2'-deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1. It was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene. The transfer of DLC-1 into three DLC-1 negative cell lines caused a significant inhibition in cell proliferation and/or a decrease in colony formation. Furthermore, stable transfer of DLC-1 abolished tumorigenicity in nude mice of two cell lines, suggesting that DLC-1 plays a role in NSCLC by acting as a bona. de new tumor suppressor gene. C1 NIOSH, Lab Genet Susceptibil, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Yuan, BZ (reprint author), 1095 Willowdale Rd,Mailstop L-3014, Morgantown, WV 26505 USA. EM bby1@cdc.gov NR 34 TC 104 Z9 111 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 19 PY 2004 VL 23 IS 7 BP 1405 EP 1411 DI 10.1038/sj.onc.1207291 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 775HZ UT WOS:000189035800007 PM 14661059 ER PT J AU Mubiru, JN Shen-Ong, GL Valente, AJ Troyer, DA AF Mubiru, JN Shen-Ong, GL Valente, AJ Troyer, DA TI Alternative spliced variants of the alpha-methylacyl-CoA racemase gene and their expression in prostate cancer SO GENE LA English DT Article DE prostate cancer; alternative splicing; racemase; fumarate hydratase; peroxisome; mitochondria ID MOLECULAR-CLONING; MITOCHONDRIAL; HYPERPLASIA; MARKER; LIVER; P504S AB Alpha-methyacyl-CoA racemase (AMACR), a mitochondrial and peroxisomal enzyme essential in lipid metabolism, is overexpressed in prostate cancer. Two different AMACR transcripts (designated IA and IIA), each derived from five exons, have been reported. AMACR IA, the most abundant form, encodes a 382-amino acid protein (M-w 42 kDa, pI 6.07). AMACR IIA contains an alternative fifth exon that has extensive homology to the human fumarate hydratase (FH) and encodes a 288-amino acid protein (M-w 32 kDa, pI 9.6). Here we report additional variants of IA and IIA whereby the transcripts lack exon 3 and are designated as IB (M-w 22 kDa, pI 10.31) and IIB (M-w 31 kDa, pI 9.44). Due to a frameshift, the alternative fifth exon in the IIA transcript encodes a polypeptide that differs from FH. In contrast, the 1113 transcript, generated as a result of the dual alternative splicing events, encodes a polypeptide homologous with a highly conserved region of FH. We also identified a shorter variant form of IIA (IIAs, M-w 28 kDa, pI 9.65), which lacks the 5' half of the alternative fifth exon. The carboxy termini of all five gene products differ as a result of the alternative splicing events. In prostate tumor tissues that overexpressed AMACR, both the A and B forms were overexpressed, suggesting coregulation. Only the predominant AMACR IA has an acidic pI and contains the previously identified peroxisomal targeting signal (PTS1) peptide, while the other four variants are basic proteins that lack the peroxisomal targeting signal peptide. These observations have implications for the cellular localization and function of these AMACR variants. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. RP Troyer, DA (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, Mail Code 7750,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM Troyer@uthscsa.edu RI Shen-Ong, Grace/C-8327-2014 FU NCI NIH HHS [5U01-CA-86402-02] NR 23 TC 21 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 18 PY 2004 VL 327 IS 1 BP 89 EP 98 DI 10.1016/j.gene.2003.11.009 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 801GQ UT WOS:000220084800008 PM 14960364 ER PT J AU Smith-Bindman, R Kerlikowske, K Ballard-Barbash, R AF Smith-Bindman, R Kerlikowske, K Ballard-Barbash, R TI Optimal recall rates following mammography - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 18 PY 2004 VL 291 IS 7 BP 822 EP 822 DI 10.1001/jama.291.7.822 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 774TF UT WOS:000189000400017 ER PT J AU Velicer, CM Heckbert, SR Lampe, JW Potter, JD Robertson, CA Taplin, SH AF Velicer, CM Heckbert, SR Lampe, JW Potter, JD Robertson, CA Taplin, SH TI Antibiotic use in relation to the risk of breast cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID METABOLISM; VEGETABLES; ESTROGENS; INFECTIONS; EXPRESSION AB Context Use of antibiotics may be associated with risk of breast cancer through effects on immune function, inflammation, and. metabolism of estrogen and phytochemicals; however, clinical data on the association between antibiotic use and risk of. breast cancer are sparse. Objective To examine the association between use of antibiotics and risk of breast cancer. Design, Setting, and Participants Case-control Study among 2266,women older than 19 years with primary, invasive breast cancer (cases) enrolled in a large, non-profit health plan for at least 1 year between January 1, 1993, and June 30, 2001, and 7953 randomly selected female health plan members (controls), frequency-matched to cases on age and length of enrollment. Cases were ascertained from the Surveillance, Epidemiology, and End Results cancer registry. Antibiotic use was ascertained from computerized pharmacy records. Main Outcome Measure Association between extent of antibiotic use and risk of breast cancer. Results Increasing cumulative-days of antibiotic. use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment. For categories of increasing use (0, 1-50, 51-100, 101-500, 501-1000, and greater than or equal to1001 days), odds ratios (95% confidence intervals) for breast cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88),and 2.07 (1.48-2.89) (P<.001 for trend). Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length. of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87). Conclusions Use of antibiotics is associated with increased risk of incident and fatal breast cancer. It cannot be determined from this study whether antibiotic use is causally related to breast cancer, or whether indication for used overall weakened immune function, or other factors are pertinent underlying exposures. Although further studies are needed, these findings reinforce the need for prudent long-term use of antibiotics. C1 Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. Univ Washington, Dept Family Med, Seattle, WA 98195 USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. Grp Hlth Cooperat Puget Sound, Dept Pharm, Seattle, WA 98121 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. NCI, Appl Res Program, Bethesda, MD 20892 USA. RP Heckbert, SR (reprint author), Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. EM heckbert@u.washington.edu OI Potter, John/0000-0001-5439-1500 FU NCI NIH HHS [T32CA09168, UO1CA63731] NR 24 TC 123 Z9 124 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 18 PY 2004 VL 291 IS 7 BP 827 EP 835 DI 10.1001/jama.291.7.827 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 774TF UT WOS:000189000400020 PM 14970061 ER PT J AU Kotchen, TA Lindquist, T Malik, K Ehrenfeld, E AF Kotchen, TA Lindquist, T Malik, K Ehrenfeld, E TI NIH peer review of grant applications for clinical research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID INSTITUTES-OF-HEALTH; PHYSICIAN-SCIENTISTS; CHALLENGES; INVESTIGATORS; CRISIS AB Context Support of research to facilitate translation of scientific discoveries to the prevention and treatment of human disease is a high priority for the US National Institutes of Health (NIH). Nevertheless, a perception exists among clinical investigators that the NIH peer review process may discriminate against clinical research. Objective To describe recent trends and outcomes of peer review of grant applications to NIH requesting support for clinical research. Design and Setting Peer review outcomes of grant applications submitted to NIH by MDs were compared with those of non-MDs, and outcomes of applications involving inclusion of human subjects were compared with those not involving human subjects. Analyses were carried out using an inclusive definition of clinical research and after stratifying clinical research into specific categories. Main Outcome Measures Median priority scores and funding rates. Results Between 1997 and 2002, on average, 25.2% of total grant applications (ranging from 27 607 to 34 422 per year) were submitted by MDs, and 27.5% of awards (ranging from 8495 to 10769 awards per year) were made to MDs. Median priority scores (239.0 vs 250.0) and funding rates (31.4% vs 29.1%) reviewed in 2 grant cycles in 2002 were more favorable for MDs than for non-MDs (P<.001). However, median priority scores (254.0 vs 244.0) and funding rates (23.9% vs 28.1%) were less favorable (P<.001) for R01 applications for clinical research (n=7227 applications) than for nonclinical research (n=10209). This trend was most convincingly observed for clinical research categorized as mechanisms of disease (P=.006) or clinical trials and interventions (P=.001). Similar trends were observed for grant mechanisms other than R01. Concerns about safety and privacy of human subjects may have contributed to the less favorable outcomes of clinical research applications. Conclusion Although physicians compete favorably in the peer review process, review outcomes are modestly less favorable for grant applications for clinical research than for laboratory research. C1 NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Kotchen, TA (reprint author), Med Coll Wisconsin, Dept Med, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM tkotchen@mcw.edu NR 28 TC 71 Z9 72 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 18 PY 2004 VL 291 IS 7 BP 836 EP 843 DI 10.1001/jama.291.7.836 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 774TF UT WOS:000189000400021 PM 14970062 ER PT J AU Fox, CS Larson, MG Leip, EP Culleton, B Wilson, PWF Levy, D AF Fox, CS Larson, MG Leip, EP Culleton, B Wilson, PWF Levy, D TI Predictors of new-onset kidney disease in a community-based population SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID STAGE RENAL-DISEASE; BLOOD-PRESSURE CONTROL; NUTRITION EXAMINATION SURVEY; GLOMERULAR-FILTRATION-RATE; CORONARY HEART-DISEASE; OPTIMAL TREATMENT HOT; 3RD NATIONAL-HEALTH; SERUM CREATININE; CARDIOVASCULAR OUTCOMES; CLINICAL EPIDEMIOLOGY AB Context Kidney disease is associated with an increased risk for the development of cardiovascular disease and end-stage renal disease; however, risk factors for kidney disease have not been well studied. Objective To identify predictors of the development of new-onset kidney disease. Design, Setting, and Participants A community-based, longitudinal cohort study of 2585 participants who attended both a baseline examination in 1978-1982 and a follow-up examination in 1998-2001, and who were free of kidney disease at baseline. Main Outcome Measures Kidney disease was assessed by the Modification of Diet in Renal Disease Study equation and defined by a glomerular filtration rate (GFR) in the fifth or lower percentile (less than or equal to59.25 mL/min per 1.73 m(2) in women, less than or equal to64.25 mL/min per 1.73 m(2) in men). Stepwise logistic regression was used to determine the impact of risk factors on the occurrence of new-onset kidney disease. Baseline and long-term, 12-year, averaged risk factor models were explored. Results At baseline, there were 1223 men and 1362 women, with a mean age of 43 years, who were free of preexisting kidney disease. After a mean follow-up of 18.5 years, 244 participants (9.4%) had developed kidney disease. In multivariable models, baseline age (odds ratio [OR], 2.36 per 10-year increment; 95% confidence interval [CI], 2.00-2.78), GFR (<90 mL/min per 1.73 m(2): OR, 3.01; 95% CI, 1.98-4.58; 90-119 mL/min per 1.73 m(2): OR, 1.84; 95% CI, 1.16-2.93), body mass index (OR, 1.23 per 1 SD; 95% CI, 1.08-1.41), diabetes (OR, 2.60; 95% CI, 1.44-4.70), and smoking (OR, 1.42; 95% CI, 1.06-1.91) were related to the development of kidney disease. In addition to baseline age and GFR, the long-term, averaged risk factors that were predictive of kidney disease included hypertension (OR, 1.57; 95% CI, 1.17-2.12), high-density lipoprotein cholesterol level (OR, 0.80 per 1 SD; 95% CI, 0.69-0.92), and diabetes (OR, 2.38; 95% CI, 1.45-3.92). Compared with a normal GFR (&GE;120 mL/min per 1.73 m(2)), a mildly reduced GFR (<90 mL/min per 1.73 m(2)) predicted a 3-fold odds of progression to kidney disease (OR, 2.95; 95% CI, 1.94-4.49). Conclusions Established cardiovascular disease risk factors are associated with the development of new-onset kidney disease. Patients with a mildly reduced GFR should be monitored for progression to kidney disease. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Calgary, Foothills Hosp, Calgary, AB, Canada. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM caroline@fram.nhlbi.nih.gov FU NHLBI NIH HHS [N01-HC-25195] NR 45 TC 605 Z9 632 U1 2 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 18 PY 2004 VL 291 IS 7 BP 844 EP 850 DI 10.1001/jama.291.7.844 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 774TF UT WOS:000189000400022 PM 14970063 ER PT J AU Lu, L Dempsey, J Liu, SY Bossert, JM Shaham, Y AF Lu, L Dempsey, J Liu, SY Bossert, JM Shaham, Y TI A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting Potentiation of cocaine seeking after withdrawal SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain-derived nerve growth factor; drug self-administration; extinction; growth factors; MAP kinase; reinstatement; relapse; substantia nigra ID MESOLIMBIC DOPAMINE SYSTEM; TIME-DEPENDENT CHANGES; INDUCED REINSTATEMENT; EXTINCTION BEHAVIOR; SUBSTANTIA-NIGRA; PROTEIN-LEVELS; ADDICTION; RELAPSE; RATS; NEUROADAPTATIONS AB Cocaine addiction in humans is associated with long-term propensity to relapse. Using a rat relapse model, we found that cocaine seeking induced by exposure to cocaine-associated cues progressively increases after withdrawal. This progressive increase is associated with increases in brain-derived nerve growth factor (BDNF) levels within the mesolimbic dopamine system. Based on these findings, we studied whether BDNF infusions into the ventral tegmental area (VTA), the cell body region of mesolimbic dopamine neurons, would potentiate cocaine seeking after withdrawal. Rats were trained to self-administer cocaine for 10 d, and cocaine seeking was measured in extinction tests 3, 10, or 30 d after withdrawal. During testing, rats were exposed to contextual cues that had predicted cocaine availability during training, and lever presses resulted in contingent presentations of a discrete tone-light cue that was previously temporally paired with cocaine infusions. BDNF(0-0.75 mug/site) or nerve growth factor (NGF; 0-0.75 mug/site) was infused into the VTA 1-2 hr after the last self-administration session. To examine the role of the mitogen-activated protein kinase ( MAPK) pathway in BDNF effects, U0126 (1 mug/site), an MEK inhibitor, was used. A single intra-VTA infusion of BDNF, but not NGF, induced long-lasting enhancement of cocaine seeking for up to 30 d, an effect reversed by U0126. In contrast, neither BDNF infusions into the substantia nigra, nor acute intra-VTA BDNF infusions 2 hr before testing on day 3 of withdrawal, were effective. These data suggest that BDNF-mediated neuroadaptations in mesolimbic areas are involved in the persistent cocaine seeking induced by exposure to drug cues after withdrawal. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014 NR 40 TC 200 Z9 204 U1 0 U2 4 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 FEB 18 PY 2004 VL 24 IS 7 BP 1604 EP 1611 DI 10.1523/JNEUROSCI.5124-03.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 775HU UT WOS:000189035300009 PM 14973246 ER PT J AU Ronesi, J Gerdeman, GL Lovinger, DM AF Ronesi, J Gerdeman, GL Lovinger, DM TI Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal ganglia; cannabinoids; presynaptic; retrograde; transporter; glutamate ID SYNAPTIC PLASTICITY; ENDOGENOUS CANNABINOIDS; ANANDAMIDE TRANSPORTER; DORSAL STRIATUM; BASAL GANGLIA; SYNAPSES; INHIBITION; ACTIVATION; RECEPTORS; CELLS AB Activation of the CB1 cannabinoid receptor inhibits neurotransmission at numerous synapses in the brain. Indeed, CB1 is essential for certain types of both short- and long-term synaptic depression. It was demonstrated recently that CB1 is critical for activity-dependent long-term depression (LTD) at glutamatergic corticostriatal synapses in acute brain slice preparations. Here, we show that CB1 activation is necessary, but not solely sufficient, for induction of LTD and that the requisite signaling by endocannabinoids (eCBs) occurs during a time window limited to the first few minutes after high-frequency stimulation delivery. In addition, we have applied intracellularly anandamide membrane transporter inhibitors to provide novel evidence that postsynaptic transport mechanisms are responsible for the release of eCBs from striatal medium spiny neurons. These findings shed new light on the mechanisms by which transient eCB formation participates in the induction of long-lasting changes in synaptic efficacy that could contribute to brain information storage. C1 NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, 158H Pk 5 Bldg,12420 Parklawn Dr, Rockville, MD 20852 USA. EM lovindav@mail.nih.gov RI yu, yan/C-2322-2012 NR 37 TC 144 Z9 151 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 18 PY 2004 VL 24 IS 7 BP 1673 EP 1679 DI 10.1523/JNEUROSCI.5214-03.2004 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 775HU UT WOS:000189035300018 PM 14973237 ER PT J AU Solomon, D Schiffman, M AF Solomon, D Schiffman, M TI Have we resolved how to triage equivocal cervical cytology? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ATYPICAL SQUAMOUS-CELLS; UNDETERMINED SIGNIFICANCE; HIGH-RISK; RANDOMIZED-TRIAL; WOMEN; MANAGEMENT; CANCER C1 NCI, Breast & Gynecol CAnc Res GRp, Div Canc Prevent, NIH, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Solomon, D (reprint author), NCI, Breast & Gynecol CAnc Res GRp, Div Canc Prevent, NIH, 6130 Execut Blvd,Rm 2130, Rockville, MD 20852 USA. EM ds87v@nih.gov NR 13 TC 16 Z9 17 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 FEB 18 PY 2004 VL 96 IS 4 BP 250 EP 251 DI 10.1093/jnci/djh063 PG 2 WC Oncology SC Oncology GA 773YW UT WOS:000188953800002 PM 14970266 ER PT J AU Umar, A Boland, CR Terdiman, JP Syngal, S de la Chapelle, A Ruschoff, J Fishel, R Lindor, NM Burgart, LJ Hamelin, R Hamilton, SR Hiatt, RA Jass, J Lindblom, A Lynch, HT Peltomaki, P Ramsey, SD Rodriguez-Bigas, MA Vasen, HFA Hawk, ET Barrett, JC Freedman, AN Srivastava, S AF Umar, A Boland, CR Terdiman, JP Syngal, S de la Chapelle, A Ruschoff, J Fishel, R Lindor, NM Burgart, LJ Hamelin, R Hamilton, SR Hiatt, RA Jass, J Lindblom, A Lynch, HT Peltomaki, P Ramsey, SD Rodriguez-Bigas, MA Vasen, HFA Hawk, ET Barrett, JC Freedman, AN Srivastava, S TI Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MISMATCH REPAIR; COLON-CANCER; CELL-LINES; POPULATION; HNPCC; MUTATIONS; TUMORS; CARCINOMAS; EXPRESSION; FAMILIES AB Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with NISI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for NISI testing. C1 NCI, Div Canc Prevent, NIH, US Dept HHS, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, US Dept HHS, Bethesda, MD 20892 USA. Baylor Univ, Med Ctr, Div Gastroenterol, Dallas, TX USA. Univ Calif San Francisco, Dept Med, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Klinikum Kassel, Inst Pathol, Kassel, Germany. Thomas Jefferson Univ, Genet & Mol Biol Program, Dept Microbiol & Immunol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Ctr Etud Polymorphisme Humain, INSERM, U434, F-75010 Paris, France. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. McGill Univ, Dept Pathol, Montreal, PQ, Canada. Karolinska Inst, Dept Mol Med, Clin Genet Unit, Stockholm, Sweden. Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA. Univ Helsinki, Dept Med Genet, Helsinki, Finland. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Fdn Detect Hereditary Tumours, Leiden, Netherlands. RP Umar, A (reprint author), NCI, Div Canc Prevent, NIH, US Dept HHS, 6130 Execut Blvd,EPN 2141, Bethesda, MD 20892 USA. EM asad.umar@nih.gov OI Peltomaki, Paivi/0000-0001-8819-2980 FU NCI NIH HHS [R01 CA067007, U01 CA074800, U01 CA074800-05] NR 60 TC 1380 Z9 1421 U1 5 U2 60 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 FEB 18 PY 2004 VL 96 IS 4 BP 261 EP 268 DI 10.1093/jnci/djh034 PG 8 WC Oncology SC Oncology GA 773YW UT WOS:000188953800008 PM 14970275 ER PT J AU Huff, J AF Huff, J TI Re: Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 6 TC 0 Z9 0 U1 1 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 FEB 18 PY 2004 VL 96 IS 4 BP 333 EP 334 DI 10.1093/jnci/djh050 PG 2 WC Oncology SC Oncology GA 773YW UT WOS:000188953800016 PM 14970283 ER PT J AU Wang, XZ Burke, TR AF Wang, XZ Burke, TR TI Enantioselective synthesis of metathesis-derived ureapeptoid macrocycles SO SYNLETT LA English DT Article DE asymmetric synthesis; macrocycles; metathesis; ring closure; stereoselective ID RING-CLOSING METATHESIS; SOLID-PHASE SYNTHESES; SH2 DOMAIN INHIBITOR; OLEFIN METATHESIS; CYCLIC-PEPTIDES; AMINO-ACIDS; RUTHENIUM; CATALYSTS; DESIGN; PRODUCTS AB Ring-closing metathesis (RCM) was used for the preparation of the first member of a new class of ureapeptoid-containing macrocycles. Key to the approach was the enantioselective synthesis of functionalized carbamoyl alkenylglycine equivalents using (-)-B-allyldiisopinocampheylborane [(-)-d-Ipc(2)Ball]-mediated asymmetric allylation. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 NR 35 TC 7 Z9 7 U1 0 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 J9 SYNLETT JI Synlett PD FEB 18 PY 2004 IS 3 BP 469 EP 472 DI 10.1055/s-2004-815425 PG 4 WC Chemistry, Organic SC Chemistry GA 778GK UT WOS:000189231000010 ER PT J AU Johnston, SC O'Meara, ES Manolio, TA Lefkowitz, D O'Leary, DH Goldstein, S Carlson, MC Fried, LP Longstreth, WT AF Johnston, SC O'Meara, ES Manolio, TA Lefkowitz, D O'Leary, DH Goldstein, S Carlson, MC Fried, LP Longstreth, WT TI Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MINI-MENTAL-STATE; MIDDLE-AGED ADULTS; CARDIOVASCULAR HEALTH; ALZHEIMERS-DISEASE; OLDER-ADULTS; NEUROPSYCHOLOGICAL IMPROVEMENT; CEREBRAL INFARCTION; DIABETES-MELLITUS; BRAIN INFARCTION; ELDERLY PEOPLE AB Background: Whether carotid artery disease is a cause of cognitive impairment in persons who have not had stroke is unknown. If this is the case, diminished performance on the Modified Mini-Mental State Examination should be more common in persons with left carotid artery disease than in those with right carotid artery disease. Objective: To determine whether left carotid artery disease is associated with cognitive impairment. Design: Cross-sectional and cohort study. Setting: Four U.S. communities participating in the Cardiovascular Health Study. Patients: 4006 right-handed men and women 65 years of age or older without history of stroke, transient ischemic attack, or carotid endarterectomy. Measurements: internal carotid artery stenosis and intimamedia thickness of the common carotid artery were assessed by using duplex ultrasonography. Cognitive impairment was defined as a score less than 80 on the Modified Mini-Mental State Examination, and cognitive decline was defined as an average decrease of more than 1 point annually in Modified Mini-Mental State Examination score during up to 5 years of follow-up. Multivariate logistic regression models were used to estimate the risk for cognitive impairment and decline associated with left internal carotid artery stenosis and intima-media thickness, after adjustment for measures of right-sided disease and risk factors for vascular disease. Results: After adjustment for right-sided stenosis, high-grade (greater than or equal to75% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio, 6.7 [95% CI, 2.4 to 18.1] compared with no stenosis) and cognitive decline (odds ratio, 2.6 [CI, 1.1 to 6.3]). Intimamedia thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment. Conclusions: Cognitive impairment and decline are associated with asymptomatic high-grade stenosis of the left internal carotid artery. The persistence of the association after adjustment for right-sided stenosis indicates that the association is not due to underlying vascular risk factors or atherosclerosis in general. C1 Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Washington, Seattle, WA 98195 USA. NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Johnston, SC (reprint author), Univ Calif San Francisco, Dept Neurol, Box 0114,505 Parnassus Ave,M-798, San Francisco, CA 94143 USA. FU NHLBI NIH HHS [N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086]; NINDS NIH HHS [NS02254] NR 57 TC 153 Z9 168 U1 0 U2 2 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 FEB 17 PY 2004 VL 140 IS 4 BP 237 EP 247 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 774GA UT WOS:000188970400001 PM 14970146 ER PT J AU Darbha, R Phogat, S Labrijn, AF Shu, Y Gu, YJ Andrykovitch, M Zhang, MY Pantophlet, R Martin, L Vita, C Burton, DR Dimitrov, DS Ji, XH AF Darbha, R Phogat, S Labrijn, AF Shu, Y Gu, YJ Andrykovitch, M Zhang, MY Pantophlet, R Martin, L Vita, C Burton, DR Dimitrov, DS Ji, XH TI Crystal structure of the broadly cross-reactive HIV-1-neutralizing Fab X5 and fine mapping of its epitope SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BINDING-SITE; HIV-1; GP120; GLYCOPROTEIN; ANTIBODY; NEUTRALIZATION; RECEPTOR; DESIGN; ENTRY AB The human monoclonal antibody Fab X5 neutralizes a broad range of HIV-1 primary isolates. The crystal structure of X5 has been determined at 1.9 Angstrom resolution. There are two crystallographically independent Fab fragments in the asymmetric unit. The crystallographic R value for the final model is 0.22. The antibody-combining site features a long (22 amino acid residues) CDR H3 with a protruding hook-shaped motif. The X5 structure and site-directed mutagenesis data suggest that X5 amino acid residues W 100 and Y100F in the CDR H3 motif may be critical for the binding of Fab X5 to gp120. X5 bound to a complex of a CD4 mimetic and gp120 with approximately the same kinetics and affinity as to a CD4-gp120 complex, suggesting that specific interactions between CD4 and X5 are unlikely to contribute to the binding of X5 to gp120-CD4 complexes. Binding of X5 to alanine scanning mutants of gp120JR-CSF complexed with CD4 suggested a critical role of the highly conserved amino acid residues at positions 423 and 432. The X5 structure and fine mapping of its epitope may assist in the elucidation of the mechanisms of viral entry and neutralization, and the development of HIV-1 inhibitors and vaccines. C1 NCI Frederick, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. NCI Frederick, Lab Expt & Computat Biol, Ft Detrick, MD 21702 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. CEA Saclay, Protein Engn & Res Dept, F-91191 Gif Sur Yvette, France. RP Dimitrov, DS (reprint author), NCI Frederick, Macromol Crystallog Lab, POB B, Ft Detrick, MD 21702 USA. EM dimitrov@ncifcrf.gov; jix@ncifcrf.gov RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012; MARTIN, loic/E-1627-2011 OI Ji, Xinhua/0000-0001-6942-1514; MARTIN, loic/0000-0002-7940-2955 FU NIAID NIH HHS [AI33292] NR 26 TC 39 Z9 41 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 17 PY 2004 VL 43 IS 6 BP 1410 EP 1417 DI 10.1021/bi035323x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 773MX UT WOS:000188928500002 PM 14769016 ER PT J AU Blaszczyk, J Li, Y Wu, Y Shi, GB Ji, XH Yan, HG AF Blaszczyk, J Li, Y Wu, Y Shi, GB Ji, XH Yan, HG TI Essential roles of a dynamic loop in the catalysis of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; THIAMIN PYROPHOSPHOKINASE; ARGININE RESIDUE-82; TERNARY COMPLEX; SUBSTRATE; CRYSTALLOGRAPHY; RESOLUTION; BINDING; NMR AB 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the transfer of pyrophosphoryl group from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP) following an ordered bi-bi mechanism with ATP as the first substrate. The rate-limiting step of the reaction is product release, and the complete active center is assembled and sealed only upon the binding of both ATP and HP. The assembly of the active center involves large conformational changes in three catalytic loops, among which loop 3 undergoes the most dramatic and unusual changes. To investigate the roles of loop 3 in catalysis, we have made it deletion mutant, which has been investigated by biochemical and X-ray crystallographic analysis. The biochemical data showed that the deletion mutation does not have significant effects on the dissociation constants or the rate constants for the binding of the first substrate MgATP or its analogues. The dissociation constant of HP for the mutant increases by a factor of similar to100, which is due to a large increase in the dissociation rate constant. The deletion mutation causes a shift of the rate-limiting step in the reaction and a decrease in the rate constant for the chemical step by a factor of similar to1.1 x 10(5). The crystal structures revealed that the deletion mutation does not affect protein folding, but the catalytic center of the mutant is not fully assembled even upon the formation of the ternary complex and is not properly sealed. The results together suggest that loop 3 is dispensable for the folding of the protein and the binding of the first substrate MgATP, but is required for the assembling and sealing of the active center. The loop plays an important role in the stabilization of the ternary complex and is critical for catalysis. C1 Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Ji, XH (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM jix@ncifcrf.gov; yanh@msu.edu RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NIGMS NIH HHS [GM58221] NR 30 TC 22 Z9 24 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 17 PY 2004 VL 43 IS 6 BP 1469 EP 1477 DI 10.1021/bi0360531 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 773MX UT WOS:000188928500009 PM 14769023 ER PT J AU Marroquin, OC Kip, KE Kelley, DE Johnson, BD Shaw, LJ Merz, CNB Sharaf, BL Pepine, CJ Sopko, G Reis, SE AF Marroquin, OC Kip, KE Kelley, DE Johnson, BD Shaw, LJ Merz, CNB Sharaf, BL Pepine, CJ Sopko, G Reis, SE CA WISE Investigators TI Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women - A report from the Women's Ischemia Syndrome Evaluation SO CIRCULATION LA English DT Article DE metabolic syndrome; coronary disease; inflammation; obesity; women ID HOMEOSTASIS MODEL ASSESSMENT; INSULIN-RESISTANCE SYNDROME; SYNDROME EVALUATION WISE; HEART-DISEASE; ATHEROSCLEROSIS; CHOLESTEROL; MORTALITY; PART; MEN AB Background - The metabolic syndrome, which is characterized by a constellation of fasting hyperglycemia, hypertriglyceridemia, low HDL cholesterol, hypertension, and/or abdominal obesity, is a risk factor for the development of coronary artery disease ( CAD) and cardiovascular events. The interrelationship between metabolic status and CAD on cardiovascular risk in women is not known. Methods and Results - We evaluated interrelationships between angiographic CAD, the metabolic syndrome, and incident cardiovascular events among 755 women from the Women's Ischemia Syndrome Evaluation ( WISE) study who were referred for coronary angiography to evaluate suspected myocardial ischemia; 25% of the cohort had the metabolic syndrome at study entry. Compared with women with normal metabolic status, women with the metabolic syndrome had a significantly lower 4-year survival rate (94.3% versus 97.8%, P = 0.03) and event-free survival from major adverse cardiovascular events ( death, nonfatal myocardial infarction, stroke, or congestive heart failure; 87.8% versus 93.5%, P = 0.003). When the subjects were stratified by the presence or absence of angiographically significant CAD at study entry, in women with angiographically significant CAD, the metabolic syndrome resulted in significantly higher risk of cardiovascular events than in women with normal metabolic status ( hazard ratio 4.93, 95% CI 1.02 to 23.76; P = 0.05), whereas it did not result in increased 4-year cardiovascular risk in women without angiographically significant CAD ( hazard ratio 1.41, 95% CI 0.32 to 6.32; P = 0.65). Conclusions - These data suggest that in women with suspected myocardial ischemia, the metabolic syndrome modifies the cardiovascular risk associated with angiographic CAD. Specifically, the metabolic syndrome was found to be a predictor of 4-year cardiovascular risk only when associated with significant angiographic CAD. C1 Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Div Endocrinol, Pittsburgh, PA 15261 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Univ Florida, Div Cardiol, Gainesville, FL USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Reis, SE (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM reisse@msx.upmc.edu RI Reis, Steven/J-3957-2014; Marroquin, Oscar/F-2214-2015 OI Marroquin, Oscar/0000-0002-0909-0319 FU NHLBI NIH HHS [N01-HV-68162, N01-HV-68161, N01-HV-68163, N01-HV-68164] NR 19 TC 147 Z9 151 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 17 PY 2004 VL 109 IS 6 BP 714 EP 721 DI 10.1161/01.CIR.0000115517.26897.A7 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 774VE UT WOS:000189005500005 PM 14970105 ER PT J AU von Mering, GO Arant, CB Wessel, TR McGorray, SP Merz, CNB Sharaf, BL Smith, KM Olson, MB Johnson, BD Sopko, G Handberg, E Pepine, CJ Kerensky, RA AF von Mering, GO Arant, CB Wessel, TR McGorray, SP Merz, CNB Sharaf, BL Smith, KM Olson, MB Johnson, BD Sopko, G Handberg, E Pepine, CJ Kerensky, RA TI Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women - Results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) SO CIRCULATION LA English DT Article DE coronary disease; endothelium; acetylcholine; prognosis; women ID ENDOTHELIAL DYSFUNCTION; ARTERY-DISEASE; CHEST-PAIN; FLOW VELOCITY; PILOT PHASE; HUMANS AB Background - Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women. Methods and Results - As part of the Women's Ischemia Syndrome Evaluation ( WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease ( CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (DeltaCSA) in response to acetylcholine ( P = 0.0006) and nitroglycerin ( P = 0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events ( P = 0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, % DeltaCSA with acetylcholine ( P = 0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, % DeltaCSA with acetylcholine remained a significant predictor ( P = 0.006). Conclusions - In women in this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of CAD severity. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. Cedars Sinai Med Ctr, Dept Med, Cedars Sinai Res Inst, Div Cardiol, Los Angeles, CA 90048 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Epidemiol, Pittsburgh, PA USA. NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. RP Pepine, CJ (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. EM pepincj@medicine.ufl.edu FU NHLBI NIH HHS [UO1-HL64829-01, N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, UO1-HL64914-01, UO1-HL65924-01] NR 15 TC 167 Z9 171 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 17 PY 2004 VL 109 IS 6 BP 722 EP 725 DI 10.1161/01.CIR.0000115525.92645.16 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 774VE UT WOS:000189005500006 PM 14970106 ER PT J AU Johnson, BD Kip, KE Marroquin, OC Ridker, PM Kelsey, SF Shaw, LJ Pepine, CJ Sharaf, B Merz, CNB Sopko, G Olson, MB Reis, SE AF Johnson, BD Kip, KE Marroquin, OC Ridker, PM Kelsey, SF Shaw, LJ Pepine, CJ Sharaf, B Merz, CNB Sopko, G Olson, MB Reis, SE TI Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women - The National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) SO CIRCULATION LA English DT Article DE inflammation; amyloid; proteins; coronary disease; women ID C-REACTIVE PROTEIN; ACUTE-PHASE PROTEINS; APPARENTLY HEALTHY-MEN; MYOCARDIAL-INFARCTION; UNSTABLE ANGINA; ACUTE-PANCREATITIS; CHOLESTEROL LEVELS; PROGNOSTIC VALUE; RISK-FACTORS; CHEST-PAIN AB Background - Serum amyloid-alpha (SAA) is a sensitive marker of an acute inflammatory state. Like high-sensitivity C-reactive protein (hs-CRP), SAA has been linked to atherosclerosis. However, prior studies have yielded inconsistent results, and the independent predictive value of SAA for coronary artery disease ( CAD) severity and cardiovascular events remains unclear. Methods and Results - A total of 705 women referred for coronary angiography for suspected myocardial ischemia underwent plasma assays for SAA and hs-CRP, quantitative angiographic assessment, and follow-up evaluation. Cardiovascular events were death, myocardial infarction, congestive heart failure, stroke, and other vascular events. The women's mean age was 58 years ( range 21 to 86 years), and 18% were nonwhite. SAA and hs-CRP were associated with a broad range of CAD risk factors. After adjustment for these risk factors, SAA levels were independently but moderately associated with angiographic CAD ( P = 0.004 to 0.04) and highly predictive of 3-year cardiovascular events ( P < 0.0001). By comparison, hs-CRP was not associated with angiographic CAD ( P = 0.08 to 0.35) but, like SAA, was strongly and independently predictive of adverse cardiovascular outcome ( P < 0.0001). Conclusions - Our results show a strong independent relationship between SAA and future cardiovascular events, similar to that found for hs-CRP. Although SAA was independently but moderately associated with angiographic CAD, this association was not found for hs-CRP. These results are consistent with the hypothesis that systemic inflammation, manifested by high SAA or hs-CRP levels, may promote atherosclerotic plaque destabilization, in addition to exerting a possible direct effect on atherogenesis. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Atlanta Cardiovasc Res Inst, Atlanta, GA USA. Univ Florida, Gainesville, FL USA. Rhode Isl Hosp, Providence, RI USA. Cedars Sinai Med Ctr, Womens Hlth Program, Los Angeles, CA USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Johnson, BD (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Parran 127,130 DeSoto St, Pittsburgh, PA 15261 USA. EM djohnson@edc.pitt.edu RI Reis, Steven/J-3957-2014; Marroquin, Oscar/F-2214-2015 OI Marroquin, Oscar/0000-0002-0909-0319 FU NHLBI NIH HHS [N01-HV-68161, N01-HV-68163, N01-HV-68164, N01-HV68162, R01-HL-073412-01, U01 HL649141, U01 HL649241]; PHS HHS [U0164829] NR 55 TC 219 Z9 236 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 17 PY 2004 VL 109 IS 6 BP 726 EP 732 DI 10.1161/01.CIR.0000115516.54550.B1 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 774VE UT WOS:000189005500007 PM 14970107 ER PT J AU Resnick, HE Lindsay, RS McDermott, MM Devereux, RB Jones, KL Fabsitz, RR Howard, BV AF Resnick, HE Lindsay, RS McDermott, MM Devereux, RB Jones, KL Fabsitz, RR Howard, BV TI Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality - The Strong Heart Study SO CIRCULATION LA English DT Article DE epidemiology; mortality; peripheral vascular disease ID PERIPHERAL ARTERIAL-DISEASE; AMERICAN-INDIAN POPULATIONS; AGED 45-74 YEARS; RISK-FACTORS; ARM INDEX; PREVALENCE; PRESSURE; PREDICTOR; EVENTS; ASSOCIATION AB Background - The associations of low ( < 0.90) and high ( > 1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting. Methods and Results - We examined all- cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3 +/- 2.2 years ( 36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI ( 0.90 less than or equal to ABI less than or equal to 1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 ( 26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI ( 44.4%, 26.9%, and 36.5%), respectively ( P < 0.0001). Adjusted risk estimates for all- cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI. Conclusions - The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40. C1 MedStar Res Inst, Dept Epidemiol, Hyattsville, MD 20873 USA. Northwestern Univ, Feinberg Sch Med, Dept Med & Prevent Med, Chicago, IL 60611 USA. Cornell Univ, Med Ctr, New York, NY 10021 USA. NHLBI, Bethesda, MD 20892 USA. RP Resnick, HE (reprint author), MedStar Res Inst, Dept Epidemiol, 6495 New Hampshire Ave,Suite 201, Hyattsville, MD 20873 USA. EM helaine.e.resnick@medstar.net FU NHLBI NIH HHS [U01 HL-41654, U01-HL-41642, U01 HL-41652] NR 34 TC 477 Z9 532 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 17 PY 2004 VL 109 IS 6 BP 733 EP 739 DI 10.1161/01.CIR.0000112642.63927.54 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 774VE UT WOS:000189005500008 PM 14970108 ER PT J AU Scacheri, PC Rozenblatt-Rosen, O Caplen, NJ Wolfsberg, TG Umayam, L Lee, JC Hughes, CM Shanmugam, KS Bhattacharjee, A Meyerson, M Collins, FS AF Scacheri, PC Rozenblatt-Rosen, O Caplen, NJ Wolfsberg, TG Umayam, L Lee, JC Hughes, CM Shanmugam, KS Bhattacharjee, A Meyerson, M Collins, FS TI Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR; MENIN INTERACTS; CAENORHABDITIS-ELEGANS/; GENE-EXPRESSION; MICRORNAS; PRODUCT; IDENTIFICATION; MECHANISMS; SIRNAS; MOUSE AB RNA interference (RNAi) mediated by short interfering RNAs (siRNAs) is a widely used method to analyze gene function. To use RNAi knockdown accurately to infer gene function, it is essential to determine the specificity of siRNA-mediated RNAi. We have assessed the specificity of 10 different siRNAs corresponding to the MEN1 gene by examining the expression of two additional genes, TP53 (p53) and CDKN1A (p21), which are considered functionally unrelated to menin but are sensitive markers of cell state. MEN1 RNA and corresponding protein levels were all reduced after siRNA transfection of HeLa cells, although the degree of inhibition mediated by individual siRNAs varied. Unexpectedly, we observed dramatic and significant changes in protein levels of p53 and p21 that were unrelated to silencing of the target gene. The modulations in p53 and p21 levels were not abolished on titration of the siRNAs, and similar results were obtained in three other cell lines; in none of the cell lines tested did we see an effect on the protein levels of actin. These data suggest that siRNAs can induce nonspecific effects on protein levels that are siRNA sequence dependent but that these effects may be difficult to detect until genes central to a pivotal cellular response, such as p53 and p21, are studied. We find no evidence that activation of the double-stranded RNA- triggered IFN-associated antiviral pathways accounts for these effects, but we speculate that partial complementary sequence matches to off-target genes may result in a micro-RNA-like inhibition of translation. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Agilent Technol, Andover, MA 01810 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bldg 31,Room 4809,31 Ctr Dr, Bethesda, MD 20892 USA. EM fc23a@nih.gov RI Meyerson, Matthew/E-7123-2012; Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 29 TC 392 Z9 415 U1 2 U2 12 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 FEB 17 PY 2004 VL 101 IS 7 BP 1892 EP 1897 DI 10.1073/pnas.0308698100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600020 PM 14769924 ER PT J AU Acharya, U Mowen, MB Nagashima, K Acharya, JK AF Acharya, U Mowen, MB Nagashima, K Acharya, JK TI Ceramidase expression facilitates membrane turnover a and endocytosis of rhodopsin in photoreceptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DROSOPHILA-MELANOGASTER; G-PROTEIN; IN-VIVO; RETINAL DEGENERATION; VISUAL TRANSDUCTION; MOLECULAR-BASIS; MUTANTS; PHOTOTRANSDUCTION; METABOLISM; ARRESTIN AB Transgenic expression of ceramidase suppresses retinal degeneration in Drosophila arrestin and phospholipase C mutants. Here, we show that expression of ceramidase facilitates the dissolution of incompletely formed and inappropriately located elements of rhabdomeric membranes in ninaE(I17) mutants lacking the G protein receptor Rh1 in R1-R6 photoreceptor cells. Ceramidase expression facilitates the endocytic turnover of Rh1. Although ceramidase expression aids the removal of internalized rhodopsin, it does not affect the turnover of Rh1 in photoreceptors maintained in dark, where Rh1 is not activated and thus has a slower turnover and a long half-life. Therefore, the phenotypic consequence of ceramidase expression in photoreceptors is caused by facilitation of endocytosis. This study provides mechanistic insight into the sphingolipid biosynthetic pathway-mediated modulation of endocytosis and suppression of retinal degeneration. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp, Image Anal Lab, Electron Microscopy Facil, Frederick, MD 21702 USA. RP Acharya, U (reprint author), NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. EM acharyau@mail.ncifcrf.gov; acharyaj@mail.ncifcrf.gov NR 38 TC 34 Z9 35 U1 0 U2 0 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 FEB 17 PY 2004 VL 101 IS 7 BP 1922 EP 1926 DI 10.1073/pnas.0308693100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600025 PM 14769922 ER PT J AU Friedrichsen, DM Stanford, JL Isaacs, SD Janer, M Chang, BL Deutsch, K Gillanders, E Kolb, S Wiley, KE Badzioch, MD Zheng, SL Walsh, PC Jarvik, GP Hood, L Trent, JM Isaacs, WB Ostrander, EA Xu, JF AF Friedrichsen, DM Stanford, JL Isaacs, SD Janer, M Chang, BL Deutsch, K Gillanders, E Kolb, S Wiley, KE Badzioch, MD Zheng, SL Walsh, PC Jarvik, GP Hood, L Trent, JM Isaacs, WB Ostrander, EA Xu, JF TI Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SCAVENGER RECEPTOR-1 GENE; LINKAGE ANALYSIS; HIGH-RISK; RNASEL GENE; AGGRESSIVENESS LOCUS; DOMINANT INHERITANCE; GERMLINE MUTATIONS; PHENOTYPE ANALYSIS; SEQUENCE VARIANTS; ALLELIC IMBALANCE AB Results from over a dozen prostate cancer susceptibility genome-wide scans, encompassing some 1,500 hereditary prostate cancer families, indicate that prostate cancer is an extremely heterogeneous disease with multiple loci contributing to overall susceptibility. In an attempt to reduce locus heterogeneity, we performed a genomewide linkage scan for prostate cancer susceptibility genes with 36 Jewish families, which represent a stratification of hereditary prostate cancer families with potentially increased locus homogeneity. The 36 Jewish families represent a combined dataset of 17 Jewish families from the Fred Hutchinson Cancer Research Center-based Prostate Cancer Genetic Research Study dataset and 19 Ashkenazi Jewish families collected at Johns Hopkins University. All available family members, including 94 affected men, were genotyped at markers distributed across the genome with an average interval of <10 centimorgans. Nonparametric multipoint linkage analyses were the primary approach, although parametric analyses were performed as well. Our strongest signal was a significant linkage peak at 7q11-21, with a nonparametric linkage (NPL) score of 3.01 (P = 0.0013). Simulations indicated that this corresponds to a genomewide empirical P = 0.006. All other regions had NPL P values greater than or equal to0.02. After genotyping additional markers within the 7q11-21 peak, the NPL score increased to 3.35 (P = 0.0004) at D7S634 with an allele-sharing logarithm of odds of 3.12 (P = 0.00007). These studies highlight the utility of analyzing defined sets of families with a common origin for reducing locus heterogeneity problems associated with studying complex traits. C1 Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Univ Washington, Dept Epidemiol, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Brady Urol Inst, Res Labs, Baltimore, MD 21287 USA. Inst Syst Biol, Seattle, WA 98103 USA. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM eostrand@fhcrc.org RI Jarvik, Gail/N-6476-2014; OI Jarvik, Gail/0000-0002-6710-8708; Ostrander, Elaine/0000-0001-6075-9738 FU NCI NIH HHS [R01 CA58236, K05 CA090754, K05CA90754, P50 CA058236, R01 CA078836, R01 CA080122, R01 CA089600, R01 CA78836, R01 CA80122, T32 CA080416, U01 CA089600] NR 71 TC 19 Z9 20 U1 0 U2 0 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 FEB 17 PY 2004 VL 101 IS 7 BP 1939 EP 1944 DI 10.1073/pnas.0308336100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600028 PM 14769943 ER PT J AU Klebanoff, CA Finkelstein, SE Surman, DR Lichtman, MK Gattinoni, L Theoret, MR Grewal, N Spiess, PJ Antony, PA Palmer, DC Tagaya, Y Rosenberg, SA Waldmann, TA Restifo, NP AF Klebanoff, CA Finkelstein, SE Surman, DR Lichtman, MK Gattinoni, L Theoret, MR Grewal, N Spiess, PJ Antony, PA Palmer, DC Tagaya, Y Rosenberg, SA Waldmann, TA Restifo, NP TI IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8(+) T Cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR; LYMPHOCYTES; INTERLEUKIN-15; DEATH; PROLIFERATION; FAS; IMMUNOTHERAPY; AUTOIMMUNITY; MAINTENANCE; REGRESSION AB IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8(+) memory T cell survival and proliferation, IL-15 helps maintain a memory CD8(+) T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor/self-reactive CD8(+) T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8(+) T cells recognize an epitope derived from the self/melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8(+) T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients. C1 NCI, Surg Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Sch Program, Bethesda, MD 20814 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, Canc Res Ctr, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. EM restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Restifo, Nicholas/A-5713-2008; Klebanoff, Christopher/B-8088-2008; Palmer, Douglas/B-9454-2008; Klebanoff, Christopher/D-9581-2011; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 28 TC 304 Z9 315 U1 1 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 FEB 17 PY 2004 VL 101 IS 7 BP 1969 EP 1974 DI 10.1073/pnas.0307298101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600033 PM 14762166 ER PT J AU Fulkerson, PC Zimmermann, N Brandt, EB Muntel, EE Doepker, MP Kavanaugh, JL Mishra, A Witte, DP Zhang, HW Farber, JM Yang, M Foster, PS Rothenberg, ME AF Fulkerson, PC Zimmermann, N Brandt, EB Muntel, EE Doepker, MP Kavanaugh, JL Mishra, A Witte, DP Zhang, HW Farber, JM Yang, M Foster, PS Rothenberg, ME TI Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allergy; asthma; cytokine; eotaxin ID AIRWAY INFLAMMATION; INDUCIBLE PROTEIN-10; NATURAL ANTAGONIST; MUCUS PRODUCTION; MURINE MODEL; TH2 CELLS; MICE; RESPONSES; EOTAXIN; HYPERRESPONSIVENESS AB Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated with coordinate gene induction. Using DNA microarray analysis, we have identified a large panel of AAI signature genes. Unexpectedly, the allergen-challenged lung (a T helper 2 microenvironment) was found to be associated with the expression of T helper 1-associated CXCR3 ligands, monokine induced by lFN-gamma(Mig),and IFN-gamma-inducible protein of 10 kDa(IP-10). Here we report that Mig functions as a negative regulator of murine eosinophils. Whereas Mig was not able to induce chemotaxis of eosinophils, pretreatment with Mig induced a dose-dependent inhibition of chemoattractant-induced eosinophil transmigration in vitro. Moreover, i.v. administration of low doses of Mig (approximate to10-30 mug/kg) induced strong and specific dose-dependent inhibition of chemokine-, IL-13-, and allergen-induced eosinophil recruitment and, conversely, neutralization of Mig before allergen challenge increased airway eosinophilia. Importantly, Mig also inhibited a CCR3-mediated functional response in eosinophils. These results indicate that the ultimate distribution and function of inflammatory cells within the allergic lung is dictated by a balance between positively and negatively regulatory chemokines. The identification of a naturally occurring eosinophil inhibitory chemokine pathway in vivo provides a strategic basis for future therapeutic consideration. C1 Childrens Hosp, Med Ctr, Div Allergy & Immunol, Dept Pediat, Cincinnati, OH 45229 USA. Childrens Hosp, Med Ctr, Div Pathol, Dept Pediat, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45257 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Australian Natl Univ, John Curtin Sch Med Res, Div Mol Biosci, Canberra, ACT 0200, Australia. RP Rothenberg, ME (reprint author), Childrens Hosp, Med Ctr, Div Allergy & Immunol, Dept Pediat, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM rothenberg@cchmc.org RI Foster, Paul/G-5057-2013; OI Brandt, Eric/0000-0003-0617-4100 FU NIAID NIH HHS [AI45898, R01 AI045898, R01 AI42242, R37 AI045898]; NIAMS NIH HHS [R01 AR042242] NR 41 TC 71 Z9 74 U1 0 U2 0 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 FEB 17 PY 2004 VL 101 IS 7 BP 1987 EP 1992 DI 10.1073/pnas.0308544100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600036 PM 14769916 ER PT J AU Phillips, K Kedersha, N Shen, L Blackshear, PJ Anderson, P AF Phillips, K Kedersha, N Shen, L Blackshear, PJ Anderson, P TI Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein translation; mRNA stability; coordinate expression ID MESSENGER-RNA TURNOVER; COLONY-STIMULATING FACTOR; ZINC-FINGER PROTEINS; TNF-ALPHA; RHEUMATOID-ARTHRITIS; TRANSLATIONAL SILENCER; BONE-MARROW; TRISTETRAPROLIN; NEUTROPHILS; DEFICIENCY AB TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor alpha (TNF-alpha). TIA-1 inhibits the translation of TNF-alpha transcripts, whereas TTP promotes the degradation of TNF-alpha transcripts. Here we show that TIA-1 and TTP function as arthritis suppressor genes: TIA-1(-/-) mice develop mild arthritis, TTP-/- mice develop severe arthritis, and TIA-1(-/-)TTP(-/-) mice develop very severe arthritis. Peritoneal macrophages derived from all three genotypes overexpress cyclooxygenase 2 and TNF-a. Surprisingly, lipopolysaccharide-activated TIA-1(-/-)TTP(-/-) macrophages secrete less TNF-alpha protein than either TIA-1(-/-) or TTP-/- macrophages. In these mice, arthritogenic cytokine may be produced by neutrophils that accumulate in the bone marrow and peripheral blood. our results suggest that TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritogenic cytokines. C1 Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Smith 652,1 Jimmy Fund Way, Boston, MA 02115 USA. EM panderson@rics.bwh.harvard.edu FU NIAID NIH HHS [AI33600, AI50167, R01 AI033600, R01 AI050167, R56 AI033600] NR 27 TC 116 Z9 121 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 FEB 17 PY 2004 VL 101 IS 7 BP 2011 EP 2016 DI 10.1073/pnas.0400148101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600040 PM 14769925 ER PT J AU Okimoto, K Sakurai, J Kobayashi, T Mitani, H Hirayama, Y Nickerson, ML Warren, MB Zbar, B Schmidt, LS Hino, O AF Okimoto, K Sakurai, J Kobayashi, T Mitani, H Hirayama, Y Nickerson, ML Warren, MB Zbar, B Schmidt, LS Hino, O TI A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EKER RAT; TSC2 GENE; MUTATIONS; CARCINOMA; NEOPLASIA; TUMORS; MAPS AB A rat model of hereditary renal carcinoma (RC) was found in a rat colony of the Sprague-Dawley strain in Japan and named the "Nihon" rat. In heterozygotes, RCs, predominantly the clear cell type, develop from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The Nihon rat is an example of a Mendelian dominantly inherited predisposition for development of RCs like the Eker (Tsc2 gene mutant) rat. We have previously shown that the Nihon mutation was tightly linked to genes that are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2 gene (human 16p13.3)-Il3 gene-Nihon gene-Llg/1 locus-Myhse gene. We now describe a germ-line mutation in the Birt-Hogg-Dube gene (Bhd) (human 17p11.2) caused by the insertion of a single nucleotide in the Nihon rat, resulting in a frameshift and producing a stop codon 26 aa downstream. We found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. We detected a high frequency of loss of heterozygosity (LOH) in primary RCs (10/11) at the Bhd locus and found a point mutation (nonsense) in one LOH-negative case, fitting Knudson's "two-hit" model. The Nihon rat may therefore provide insights into a tumor-suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome. C1 Japanese Fdn Canc Res, Dept Expt Pathol, Inst Canc, Toshima Ku, Tokyo 1708455, Japan. Dainippon Pharmaceut Co Ltd, Dept Toxicol & Teratol, Dev Res Labs, Suita, Osaka 5640053, Japan. SAIC Frederick Inc, Immunobiol Lab, Canc Res Ctr, NCI, Frederick, MD 21702 USA. SAIC Frederick Inc, NCI, Basic Res Program, Frederick, MD 21702 USA. RP Hino, O (reprint author), Japanese Fdn Canc Res, Dept Expt Pathol, Inst Canc, Toshima Ku, 1-37-1 Kami Ikebukuro, Tokyo 1708455, Japan. EM ohino@ims.u-tokyo.ac.jp FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 15 TC 58 Z9 59 U1 0 U2 0 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 FEB 17 PY 2004 VL 101 IS 7 BP 2023 EP 2027 DI 10.1073/pnas.0308071100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600042 PM 14769940 ER PT J AU Cutler, RG Kelly, J Storie, K Pedersen, WA Tammara, A Hatanpaa, K Troncoso, JC Mattson, MP AF Cutler, RG Kelly, J Storie, K Pedersen, WA Tammara, A Hatanpaa, K Troncoso, JC Mattson, MP TI Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amyloid; apoptosis; hippocampus; lipid peroxidation; sphingomyelin ID AMYLOID PRECURSOR PROTEIN; LIPID-PEROXIDATION; CELL-DEATH; INDUCED APOPTOSIS; SERINE PALMITOYLTRANSFERASE; NEURONAL APOPTOSIS; CORTICAL-NEURONS; PLASMA-MEMBRANE; SPHINGOMYELINASE; ACCUMULATION AB Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid beta-peptide (Abeta) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Abeta deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Abeta induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Abeta. Our findings suggest a sequence of events in the pathogenesis of AD in which Abeta induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease. C1 NIA, Neurosci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. Rush Presbyterian St Lukes Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Ctr Gerontol Res, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [1RO3 AG19493-0, AG05146, P30 AG010161, P30 AG10161, P50 AG005146] NR 52 TC 474 Z9 492 U1 2 U2 29 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 FEB 17 PY 2004 VL 101 IS 7 BP 2070 EP 2075 DI 10.1073/pnas.0305799101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600050 PM 14970312 ER PT J AU Wieland, SF Spangenberg, HC Thimme, R Purcell, RH Chisari, FV AF Wieland, SF Spangenberg, HC Thimme, R Purcell, RH Chisari, FV TI Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; ACUTE VIRAL-HEPATITIS; TRANSGENIC MICE; HEPATOCYTE CULTURES; AVIAN HEPADNAVIRUS; ANTIVIRAL THERAPY; GENE-EXPRESSION; REPLICATION; CELLS; DNA AB We have previously shown that hepatitis B virus (HBV) replication is controlled by noncytolytic mechanisms that depend primarily on the effector functions of the CD8(+) T cell response, especially the production of IFN-gamma in the liver. The mechanisms that control the nuclear pool of viral covalently closed circular DNA (cccDNA) transcriptional template of HBV, which must be eliminated to eradicate infection, have been difficult to resolve. To examine those mechanisms, we quantitated intrahepatic HBV cccDNA levels in acutely infected chimpanzees whose virological, immunological, and pathological features were previously described. Our results demonstrate that the elimination kinetics of the cccDNA are more rapid than the elimination of HBV antigen-positive hepatocytes during the early phase of viral clearance, and they coincide with the influx of small numbers of IFN-gamma producing CD8+ T cells into the liver. In contrast, terminal clearance of the cccDNA is associated with the peak of liver disease and hepatocellular turnover and with a surge of IFN-gamma producing CD8+ T cells in the liver. Collectively, these results suggest that cccDNA clearance is a two-step process mediated by the cellular immune response. The first step reduces the pool of cccDNA molecules noncytolytically, probably by eliminating their relaxed circular DNA precursors and perhaps by destabilizing them. The second step enhances this process by destroying infected hepatocytes and triggering their turnover. Surprisingly, despite this multipronged response, traces of cccDNA persist indefinitely in the liver, likely providing a continuous antigenic stimulus that confers lifelong immunity. C1 Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. NIH, Infect Dis Lab, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. RP Chisari, FV (reprint author), Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM fchisari@scripps.edu RI Chisari, Francis/A-3086-2008; OI Chisari, Francis/0000-0002-4832-1044 FU NCI NIH HHS [N01-CO-56000, R01 CA076403, CA76403]; NIAID NIH HHS [AI20001, N01-AI-45180, N01-AI-52705, R01 AI020001, R21 AI052705] NR 29 TC 115 Z9 124 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2004 VL 101 IS 7 BP 2129 EP 2134 DI 10.1073/pnas.0308478100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600060 PM 14764900 ER PT J AU Hong, SJ Li, HW Becker, KG Dawson, VL Dawson, TM AF Hong, SJ Li, HW Becker, KG Dawson, VL Dawson, TM TI Identification and analysis of plasticity-induced late-response genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG-TERM POTENTIATION; IMMEDIATE EARLY GENE; EXPRESSION PATTERNS; GLUTAMATE RECEPTORS; CELL-DEATH; PROTEIN; TRANSCRIPTION; MECHANISMS; NEURONS; HIPPOCAMPUS AB The excitatory neurotransmitter, glutamate, activates N-methyl-D-aspartate (NMDA) receptors to induce long-lasting synaptic changes through alterations in gene expression. It is believed that these long-lasting changes contribute to learning and memory, drug tolerance, and ischemic preconditioning. To identify NMDA-induced late-response genes, we used a powerful gene-identification method, differential analysis of primary cDNA library expression (DAzLE), and cDNA microarray from primary cortical neurons. We report here that a variety of genes, which we have named plasticity-induced genes (PLINGs), are up-regulated with differential expression patterns after NMDA receptor activation, indicating that there is a broad and dynamic range of long-lasting neuronal responses that occur through NMDA receptor activation. Our results provide a molecular dissection of the activity-dependent long-lasting neuronal responses induced by NMDA receptor activation. C1 Johns Hopkins Univ, Sch Med, Inst Cell Engn, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Dept Physiol, Baltimore, MD 21205 USA. NIA, DNA Array Unit, NIH, Baltimore, MD 21224 USA. RP Dawson, VL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Dept Neurol, 733 N Broadway,Suite 731, Baltimore, MD 21205 USA. EM vdawson@jhmi.edu; tdawson@jhmi.edu OI Dawson, Valina/0000-0002-2915-3970; Becker, Kevin/0000-0002-6794-6656 FU NIDA NIH HHS [P50 DA000266, DA 00266]; NINDS NIH HHS [NS 37090, NS 40809, R01 NS040809] NR 41 TC 45 Z9 50 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2004 VL 101 IS 7 BP 2145 EP 2150 DI 10.1073/pnas.0305170101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600063 PM 14766980 ER PT J AU Karbowski, M Arnoult, D Chen, HC Chan, DC Smith, CL Youle, RJ AF Karbowski, M Arnoult, D Chen, HC Chan, DC Smith, CL Youle, RJ TI Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis SO JOURNAL OF CELL BIOLOGY LA English DT Article DE dynamin; fission; Opal; PAGFP; photoactivation ID ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; FISSION; ASSOCIATION; MORPHOLOGY; RELEASE; PROTEIN; DEATH; MFN2 AB A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix-targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis. C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. CALTECH, Beckman Inst, Div Biol, Pasadena, CA 91125 USA. RP Youle, RJ (reprint author), Bldg 10,Rm 5D-37,MSC 1414,10 Ctr Dr, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov NR 21 TC 256 Z9 258 U1 1 U2 20 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 FEB 16 PY 2004 VL 164 IS 4 BP 493 EP 499 DI 10.1083/jcb.200309082 PG 7 WC Cell Biology SC Cell Biology GA 775TR UT WOS:000189077200015 PM 14769861 ER PT J AU Malathi, K Higaki, K Tinkelenberg, AH Balderes, DA Almanzar-Paramio, D Wilcox, LJ Erdeniz, N Redican, F Padamsee, M Liu, Y Khan, S Alcantara, F Carstea, ED Morris, JA Sturley, SL AF Malathi, K Higaki, K Tinkelenberg, AH Balderes, DA Almanzar-Paramio, D Wilcox, LJ Erdeniz, N Redican, F Padamsee, M Liu, Y Khan, S Alcantara, F Carstea, ED Morris, JA Sturley, SL TI Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution SO JOURNAL OF CELL BIOLOGY LA English DT Article DE transport; vacuole; lysosome; ceramide; neurodegeneration ID DISEASE TYPE-C; CLEAVAGE-ACTIVATING PROTEIN; SACCHAROMYCES-CEREVISIAE; CHOLESTEROL HOMEOSTASIS; LATE ENDOSOMES; BUDDING YEAST; LIPID RAFTS; GENE; TRAFFICKING; MUTATIONS AB Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C-related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation. C1 Columbia Univ, Med Ctr, Inst Human Nutr, New York, NY 10032 USA. Columbia Univ, Med Ctr, Dept Pharmacol, New York, NY 10032 USA. Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Sturley, SL (reprint author), Columbia Univ, Med Ctr, Inst Human Nutr, 630 W 168 St, New York, NY 10032 USA. EM sts37@columbia.edu OI Padamsee, Mahajabeen/0000-0002-0741-3014 FU NIAID NIH HHS [R15 AI089518, R15 AI089518-01]; NIDDK NIH HHS [DK07715, DK54320, R01 DK054320, T32 DK007715] NR 53 TC 81 Z9 83 U1 0 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 FEB 16 PY 2004 VL 164 IS 4 BP 547 EP 556 DI 10.1083/jcb.200310046 PG 10 WC Cell Biology SC Cell Biology GA 775TR UT WOS:000189077200021 PM 14970192 ER PT J AU Takeda, K Yamaguchi, N Akiba, H Kojima, Y Hayakawa, Y Tanner, JE Sayers, TJ Seki, N Okumura, K Yagita, H Smyth, MJ AF Takeda, K Yamaguchi, N Akiba, H Kojima, Y Hayakawa, Y Tanner, JE Sayers, TJ Seki, N Okumura, K Yagita, H Smyth, MJ TI Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE apoptosis; macrophage; NK cells; CTL; TRAIL ID APOPTOSIS-INDUCING LIGAND; DENDRITIC CELLS; MONOCLONAL-ANTIBODIES; IN-VIVO; CROSS-PRESENTATION; FC-RECEPTORS; TUMORICIDAL ACTIVITY; DEATH; GROWTH; CANCER AB Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DFG is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence. C1 Juntendo Univ, Sch Med, Dept Immunol, Bukyou Ku, Tokyo 1138421, Japan. Juntendo Univ, Sch Med, Div Pathol, Cent Lab Med Sci,Bukyou Ku, Tokyo 1138421, Japan. Peter MacCallum Canc Ctr, Canc Immunol Program, Melbourne, Vic 8006, Australia. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Takeda, K (reprint author), Juntendo Univ, Sch Med, Dept Immunol, Bukyou Ku, 2-1-1 Hongo, Tokyo 1138421, Japan. EM ktakeda@med.juntendo.ac.jp RI Sayers, Thomas/G-4859-2015; Smyth, Mark/H-8709-2014 OI Smyth, Mark/0000-0001-7098-7240 FU PHS HHS [N01-C0-12400] NR 59 TC 144 Z9 161 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 16 PY 2004 VL 199 IS 4 BP 437 EP 448 DI 10.1084/jem.20031457 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 777NZ UT WOS:000189185600001 PM 14769851 ER PT J AU Iijima, H Neurath, MF Nagaishi, T Glickman, JN Nieuwenhuis, EE Nakajima, A Chen, DH Fuss, IJ Utku, N Lewicki, DN Becker, C Gallagher, TM Holmes, KV Blumberg, RS AF Iijima, H Neurath, MF Nagaishi, T Glickman, JN Nieuwenhuis, EE Nakajima, A Chen, DH Fuss, IJ Utku, N Lewicki, DN Becker, C Gallagher, TM Holmes, KV Blumberg, RS TI Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CEACAM1; inflammatory bowel disease; hapten-induced colitis; T cell immunity; Th1 cytokine ID BILIARY GLYCOPROTEIN CD66A; HAPTEN-INDUCED MODEL; HEPATITIS-VIRUS MHV; ADHESION MOLECULE-1; DENDRITIC CELLS; IN-VIVO; TRANSCRIPTION FACTOR; MONOCLONAL-ANTIBODY; CYTOPLASMIC DOMAIN; CEA FAMILY AB Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Gastroenterol Div, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Mainz, Med Clin 1, Immunol Lab, D-55128 Mainz, Germany. Yokohama City Univ, Sch Med, Dept Internal Med 3, Yokohama, Kanagawa 2360004, Japan. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Charite Humboldt Univ, Dept Immunol, D-10115 Berlin, Germany. Loyola Univ, Med Ctr, Dept Microbiol & Immunol, Maywood, IL 60153 USA. Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA. RP Blumberg, RS (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Gastroenterol Div, 75 Francis St, Boston, MA 02115 USA. EM rblumberg@partners.org RI Becker, Christoph/A-6694-2008; Becker, Christoph/L-2996-2016 OI Becker, Christoph/0000-0002-1388-1041; FU NIDDK NIH HHS [R01 DK051362, DK44319, DK51362, DK53056, R01 DK044319, R01 DK053056, R37 DK044319] NR 48 TC 63 Z9 64 U1 1 U2 3 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 FEB 16 PY 2004 VL 199 IS 4 BP 471 EP 482 DI 10.1084/jem.20030437 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 777NZ UT WOS:000189185600004 PM 14970176 ER PT J AU Bannenberg, GL Aliberti, J Hong, S Sher, A Serhan, C AF Bannenberg, GL Aliberti, J Hong, S Sher, A Serhan, C TI Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE antiinflammation; transcellular biosynthesis; lipid mediators; Toxoplasma gondii; leukocytes ID TOXOPLASMA-GONDII; IL-12 PRODUCTION; PLATELET 12-LIPOXYGENASE; DENDRITIC CELLS; IN-VITRO; A(4); IDENTIFICATION; EICOSANOIDS; SIGNAL; IMMUNOPATHOLOGY AB Lipoxin A(4), (LYA(4)) is a potent endogenous lipoxygenase-derived eicosanoid with antiinflammatory and proresolving properties. Supraphysiological levels of LXA(4) are generated during infection by Toxoplasma gondii, which in turn reduces interleukin (IL) 12 production by dendritic cells, thus dampening Th1-type cell-mediated immune responses and host immunopathology. In the present work, we sought evidence for the structural basis of T. gondii's ability to activate LXA(4) biosynthesis. Proteomic analysis of T. gondii extract (soluble tachyzoite antigen [STAg]), which preserves the immunosuppressive and antiinflammatory activity of the parasite, yielded several peptide matches to known plant lipoxygenases. Hence, we incubated STAg itself with arachidonic acid and found using LC-UV-MS-MS-based lipidomics that STAg produced both 15-HETE and 5,15-diHETE, indicating that T. gondii carries 15-lipoxygenase activity. In addition, T. gondii tachyzoites (the rapidly multiplying and invasive stage of the parasite) generated LXA(4) when provided with arachidonic acid. Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties. Administration of plant 15-lipoxygenase generated endogenous LXA(4) and mimicked the suppression of IL-12 production by splenic dendritic cells observed after T. gondii infection or STAg administration. Together, these results indicate that 15-lipoxygenase expressed by a pathogen as well as exogenously administered 15-lipoxygenase can interact with host biosynthetic circuits for endogenous "stop signals" that divert the host immune response and limit acute inflammation. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med,Ctr Expt T, Boston, MA 02115 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Serhan, C (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med,Ctr Expt T, Thorn Med Res Bldg,7th Fl, Boston, MA 02115 USA. EM cnserhan@zeus.bwh.harvard.edu RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013; OI Aliberti, Julio/0000-0003-3420-8478; Bannenberg, Gerard/0000-0001-7763-6224 FU NIDCR NIH HHS [P01 DE013499, P01-DE13499]; NIDDK NIH HHS [P01 DK050305, P01-DK50305]; NIGMS NIH HHS [GM-38765, R01 GM038765, R37 GM038765] NR 36 TC 57 Z9 67 U1 0 U2 2 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 FEB 16 PY 2004 VL 199 IS 4 BP 515 EP 523 DI 10.1084/jem.20031325 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 777NZ UT WOS:000189185600008 PM 14970178 ER PT J AU Walsh, CR Larson, MG Kupka, MJ Levy, D Vasan, RS Benjamin, EJ Manning, WJ Clouse, ME O'Donnell, CJ AF Walsh, CR Larson, MG Kupka, MJ Levy, D Vasan, RS Benjamin, EJ Manning, WJ Clouse, ME O'Donnell, CJ TI Association of aortic valve calcium detected by electron beam computed tomography with echocardiographic aortic valve disease and with calcium deposits in the coronary arteries and thoracic aorta SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CALCIFICATION; STENOSIS; PREVALENCE; ATHEROSCLEROSIS; QUANTIFICATION; SPECIFICITY; SENSITIVITY; PROGRESSION; WOMEN; MEN AB We conducted electron beam computed tomographic (EBCT) testing in a representative sample of 327 Framingham Heart Study subjects without clinical cardiovascular disease. EBCT was compared with 2-dimensional echocardiography for the detection of degenerative aortic valve (AV) disease. We determined the association between EBCT measures of AV calcium and calcium deposits in the coronary arteries and thoracic aorta. Of 327 subjects (mean age 60 9 years; 51% men), 14% had EBCT AV calcium (median Agatston score 0, range 0 to 1,592). The prevalence of AV calcium increased predictably across decades of age. Compared with echocardiography, the sensitivity and specificity of EBCT for the detection of degenerative AV disease were 24% and 94%, respectively. In unadjusted logistic regression models, the prevalence of EBCT AV calcium increased across tertiles of coronary artery calcium (for trend across tertiles, odds ratio [OR] 2.2, 95% confidence interval [CI] 1.4 to 3.5) and thoracic aorta calcium (for trend OR 2.8, 95% CI 1.7 to 4.4). After adjustment for age and gender, the associations of AV calcium with coronary calcium and thoracic aorta calcium were attenuated and no longer statistically significant. Thus, compared with echocardiography, EBCT was specific but insensitive for the detection of degenerative AV disease. EBCT AV calcium was associated with calcium deposits in the coronary arteries and the thoracic aorta, but these associations were confounded by age and risk factors. (C) 2004 by Excerpta Medica, Inc. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Cardiovasc Div, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM chris@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL 04334-01A1, N01-HC-38038]; NINDS NIH HHS [R01-NS-17950] NR 30 TC 18 Z9 18 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2004 VL 93 IS 4 BP 421 EP 425 DI 10.1016/j.amjcard.2003.10.035 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 774FJ UT WOS:000188968800007 PM 14969614 ER PT J AU Harik-Khan, RI Muller, DC Wise, RA AF Harik-Khan, RI Muller, DC Wise, RA TI Serum vitamin levels and the risk of asthma in children SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adolescent; antioxidants; ascorbic acid; asthma; child ID NUTRITION-EXAMINATION-SURVEY; NATIONAL-HEALTH; ASCORBIC-ACID; PULMONARY-FUNCTION; BRONCHIAL-ASTHMA; ALPHA-TOCOPHEROL; RESPONSIVENESS; ANTIOXIDANTS; CONSUMPTION; HISTAMINE AB Dietary intake, especially of antioxidant vitamins A, C, E, and the carotenoids, has been linked with the presence and severity of asthma. From the Third National Health and Nutrition Examination Survey (NHANES III), conducted in the United States between 1988 and 1994, the authors selected 4,093 children (aged 6-17 years) for whom relevant medical, socioeconomic, and anthropometric data were complete. The children were 50.6% female, and 9.7% reported a diagnosis of asthma. Bivariate analyses showed that asthma diagnosis was associated with lower levels of serum vitamin C, alpha-carotene, beta-carotene, and beta-cryptoxanthin. However, antioxidant levels may be surrogate markers for socioeconomic variables such as race, poverty, tobacco exposure, or general nutritional status. In logistic models that included age, body mass index, socioeconomic variables, antioxidant levels, parental asthma, and household smoking, the only antioxidants significantly associated with asthma were vitamin C (odds ratio = 0.72 per mg/dl, 95% confidence interval = 0.55, 0.95) and alpha-carotene (odds ratio = 0.95 per mug/dl, 95% confidence interval = 0.90, 0.99). The odds ratio for asthma in the highest quintile of serum vitamin C relative to the lowest was 0.65 (p < 0.05), whereas it was 0.74 for α-carotene (p = 0.066). The authors concluded that low vitamin C and α-carotene intakes are associated with asthma risk in children. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. NIA, Clin Res Branch, NIH, Baltimore, MD USA. RP Wise, RA (reprint author), Johns Hopkins Univ, Sch Med, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM rwise@jhmi.edu OI Wise, Robert/0000-0002-8353-2349 NR 32 TC 79 Z9 82 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 FEB 15 PY 2004 VL 159 IS 4 BP 351 EP 357 DI 10.1093/aje/kwh053 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 774GQ UT WOS:000188971800004 PM 14769638 ER PT J AU Lee, WJ Hoppin, JA Blair, A Lubin, JH Dosemeci, M Sandler, DP Alavanja, MCR AF Lee, WJ Hoppin, JA Blair, A Lubin, JH Dosemeci, M Sandler, DP Alavanja, MCR TI Cancer incidence among pesticide applicators exposed to alachlor in the Agricultural Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE agriculture; cohort studies; herbicides; leukemia; multiple myeloma; neoplasms; occupational exposure; pesticides ID LONG-EVANS RAT; PROSTATE-CANCER; RISK-FACTORS; MANUFACTURING WORKERS; IOWA; FARMERS; MEN; MINNESOTA; EXPOSURES; MORTALITY AB The authors evaluated the incidence of cancer among pesticide applicators with exposure to alachlor in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. A total of 49,980 pesticide applicators are included in this analysis; 26,510 applicators (53%) reported use of alachlor on the enrollment questionnaire. Detailed pesticide exposure and other information were obtained from a self-administered questionnaire completed at the time of enrollment (1993-1997). Poisson regression analysis was used to evaluate the exposure-response relations between alachlor and cancer incidence controlled for the effects of potential confounding factors. A total of 1,466 incident malignant neoplasms were diagnosed during the study period, 1993-2000. Among alachlor-exposed applicators, the authors found a significant increasing trend for incidence of all lymphohematopoietic cancers associated with lifetime exposure-days (p for trend = 0.02) and intensity-weighted exposure-days (p for trend = 0.03) to alachlor. The risks of leukemia (rate ratio = 2.83, 95% confidence interval: 0.74,10.9) and multiple myeloma (rate ratio = 5.66, 95% confidence interval: 0.70, 45.7) were increased among applicators in the highest alachlor exposure category. Our findings suggest a possible association between alachlor application and incidence of lymphohematopoietic cancers among applicators in the Agricultural Health Study. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Alavanja, MCR (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8000, Rockville, MD 20852 USA. EM alavanjm@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 NR 34 TC 77 Z9 84 U1 0 U2 6 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 FEB 15 PY 2004 VL 159 IS 4 BP 373 EP 380 DI 10.1093/aje/kwh040 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 774GQ UT WOS:000188971800007 PM 14769641 ER PT J AU Bates, MN Rey, OA Biggs, ML Hopenhayn, C Moore, LE Kalman, D Steinmaus, C Smith, AH AF Bates, MN Rey, OA Biggs, ML Hopenhayn, C Moore, LE Kalman, D Steinmaus, C Smith, AH TI Case-control study of bladder cancer and exposure to arsenic in Argentina SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arsenic; bladder neoplasms; case-control studies; water pollutants ID DRINKING-WATER; KIDNEY CANCER; ENDEMIC AREA; MORTALITY; LUNG; TAIWAN AB Studies have found increased bladder cancer risks associated with high levels of arsenic in drinking water, but little information exists about risks at lower concentrations. Ecologic studies in Argentina have found increased bladder cancer mortality in Cordoba Province, where some wells are contaminated with moderate arsenic concentrations. This population-based bladder cancer case-control study in two Cordoba counties recruited 114 case-control pairs, matched on age, sex, and county, during 1996-2000. Water samples, particularly from wells, were obtained from subjects' current residences and residences in the last 40 years. Statistical analyses showed no evidence of associations with exposure estimates based on arsenic concentrations in drinking water. However, when well-water consumption per se was used as the exposure measure, time-window analyses suggested that use of well water more than 50 years before interview was associated with increased bladder cancer risk. This association was limited to ever smokers (odds ratio = 2.5, 95% confidence interval: 1.1, 5.5 for 51-70 years before interview), and the possibility that this association is due to chance cannot be excluded. This study suggests lower bladder cancer risks for arsenic than predicted from other studies but adds to evidence that the latency for arsenic-induced bladder cancers may be longer than previously thought. C1 Univ Calif Berkeley, Sch Publ Hlth, Arsen Hlth Effects Res Grp, Berkeley, CA 94720 USA. Univ Catolica Cordoba, Fac Med, Cordoba, Argentina. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. Univ Kentucky, Canc Control Program, Lexington, KY USA. Univ Kentucky, Sch Publ Hlth, Lexington, KY USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Smith, AH (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Arsen Hlth Effects Res Grp, Berkeley, CA 94720 USA. EM ahsmith@uclink.berkeley.edu RI Smith, Allan/F-9249-2011 FU NIEHS NIH HHS [P42 ES04705, P30 ES01896-22] NR 24 TC 117 Z9 121 U1 1 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 FEB 15 PY 2004 VL 159 IS 4 BP 381 EP 389 DI 10.1093/aje/kwh054 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 774GQ UT WOS:000188971800008 PM 14769642 ER PT J AU Luo, XG Kranzler, H Lappalainen, J Rosenheck, R Charney, D Zuo, LJ Erdos, J van Kammen, DP Gelernter, J AF Luo, XG Kranzler, H Lappalainen, J Rosenheck, R Charney, D Zuo, LJ Erdos, J van Kammen, DP Gelernter, J TI CALCYON gene variation, schizophrenia, and cocaine dependence SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; cocaine dependence; CALCYON gene; haplotype; allele ID DOPAMINE D1 RECEPTOR; IN-SITU HYBRIDIZATION; WORKING-MEMORY; INTERACTING PROTEIN; PREFRONTAL CORTEX; SEEKING BEHAVIOR; CHROMOSOME 10Q26; RHESUS-MONKEYS; GENOME SCAN; D-1 AB Calcyon is a brain-specific D1 dopamine receptor-interacting protein, with a potential role in D1-mediated physiological processes, including motor control, reward mechanisms, and cognitive processes. Our objective was to investigate the relationship between polymorphism of the CALCYON gene and (1) schizophrenia and (2) cocaine dependence in African-American (AA) and European-American (EA) subjects. Two single nucleotide polymorphisms (SNPs) at the CALCYON locus were genotyped in 70 AA and 206 EA individuals with schizophrenia and 90 AA and 118 EA individuals with cocaine dependence. The control group was comprised of 46 AA and 207 EA subjects screened to exclude those with psychiatric or substance use disorders. The specific polymorphisms studied were markers +295214G/A and +297151T/G. Comparisons of allele and haplotype frequencies between cases and controls were performed with the Fisher's Exact Test. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. No alleles or haplotypes were found to be associated with schizophrenia or cocaine dependence either in AA or EA subjects. The markers +295214G/A and +297151T/G are in the same haplotype block in all subgroups. Allele and haplotype frequencies differed significantly between EA and AA subjects. These results suggest that these two genetic variants in the CALCYON gene do not play a major role in predisposition to either schizophrenia or cocaine dependence in AA or EA subjects. Furthermore, these findings begin to establish a haplotype map for this gene in the AA and EA populations. (C) 2003 Wiley-Liss, Inc. C1 Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare Syst, New Haven, CT 06516 USA. Univ Connecticut, Sch Med, Alcohol Res Ctr, Dept Psychiat, Farmington, CT USA. NIMH, Bethesda, MD 20892 USA. Aventis Pharmaceut, Bridgewater, MA USA. Univ Penn, Philadelphia, PA 19104 USA. RP Gelernter, J (reprint author), Yale Univ, Sch Med, Dept Psychiat, 950 Campbell AVe, West Haven, CT 06516 USA. EM joel.gelernter@yale.edu FU NCRR NIH HHS [M01-RR06192]; NIAAA NIH HHS [K24-AA13736]; NIDA NIH HHS [R01-DA12849, R01-DA12690]; NIMH NIH HHS [K02-MH01387] NR 47 TC 5 Z9 5 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 15 PY 2004 VL 125B IS 1 BP 25 EP 30 DI 10.1002/ajmg.b.20092 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 777PF UT WOS:000189186200004 PM 14755439 ER PT J AU Fanous, AH Neale, MC Straub, RE Webb, BT O'Neill, AF Walsh, D Kendler, KS AF Fanous, AH Neale, MC Straub, RE Webb, BT O'Neill, AF Walsh, D Kendler, KS TI Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: A family based association study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE schizophrenia; symptoms; association study; genetic; Irish ID DEFICIT HYPERACTIVITY DISORDER; 5-HT2A RECEPTOR GENE; DOPAMINE TRANSPORTER POLYMORPHISM; DINUCLEOTIDE REPEAT POLYMORPHISM; DENSITY SCHIZOPHRENIA FAMILIES; FETAL VENTRAL MESENCEPHALON; BIPOLAR AFFECTIVE-DISORDER; NEUROTROPHIC FACTOR GENE; SIB-PAIR ANALYSIS; NEGATIVE-SYMPTOMS AB Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia. (C) 2003 Wiley-Liss, Inc. C1 Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Mater Hosp, Belfast, Antrim, North Ireland. St Lomans Hosp, Dublin, Ireland. RP Fanous, AH (reprint author), VA Med Ctr, Mental Hlth Serv Line,50 Irving St NW, Washington, DC 20422 USA. EM ahfanous@hsc.vcu.edu RI Neale, Michael/B-1418-2008; Webb, Bradley/B-1459-2009; OI Webb, Bradley/0000-0002-0576-5366; O'Neill, Francis Anthony/0000-0002-7531-7657 FU NIMH NIH HHS [MH20030, MH41953, MH45390, MH52537] NR 103 TC 48 Z9 48 U1 3 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 15 PY 2004 VL 125B IS 1 BP 69 EP 78 DI 10.1002/ajmg.b.20103 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 777PF UT WOS:000189186200013 PM 14755448 ER PT J AU Pickering-Brown, S Baker, M Bird, T Trojanowski, J Lee, V Morris, H Rossor, M Janssen, JC Neary, D Craufurd, D Richardson, A Snowden, J Hardy, J Mann, D Hutton, M AF Pickering-Brown, S Baker, M Bird, T Trojanowski, J Lee, V Morris, H Rossor, M Janssen, JC Neary, D Craufurd, D Richardson, A Snowden, J Hardy, J Mann, D Hutton, M TI Evidence of a founder effect in families with frontotemporal dementia that Harbor the tau+16 splice mutation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE frontotemporal dementia; tau; MAPT; haplotype; founder effect ID PROGRESSIVE SUPRANUCLEAR PALSY; INTRONIC TAU-10(+16) MUTATION; PRESENILE-DEMENTIA; GENE MUTATION; FTDP-17; CHROMOSOME-17; ASSOCIATION; CONSENSUS AB The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we geno-typed 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD. (C) 2003 Wiley-Liss, Inc. C1 Inst Psychiat, Old Age Psychiat Sect, London SE5 8AF, England. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. VA Med Ctr, Geriatr Res Educ Clin Ctr 182B, Seattle, WA USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. UCL Natl Hosp Neurol, London, England. Univ London, Dept Clin Neurol, Inst Neurol, London, England. Hope Hosp, Greater Manchester Neurosci Ctr, Salford M6 8HD, Lancs, England. St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England. St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Pickering-Brown, S (reprint author), Inst Psychiat, Old Age Psychiat Sect, Denmark Hill, London SE5 8AF, England. EM s.pickering-brown@iop.kcl.ac.uk RI Morris, Huw/B-8527-2008; Pickering-Brown, Stuart/D-4008-2009; turton, miranda/F-4682-2011; Hardy, John/C-2451-2009; Craufurd, David/G-5277-2013; OI Morris, Huw/0000-0002-5473-3774; Pickering-Brown, Stuart/0000-0003-1561-6054; Snowden, Julie/0000-0002-3976-4310 NR 18 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 15 PY 2004 VL 125B IS 1 BP 79 EP 82 DI 10.1002/ajmg.b.20083 PG 4 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 777PF UT WOS:000189186200014 PM 14755449 ER PT J AU Lenfant, C AF Lenfant, C TI Pro: Greater funding of cell and molecular biology has delivered what was promised to respiratory medicine SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 NHLBI, Gaithersburg, MD USA. RP Lenfant, C (reprint author), NHLBI, Gaithersburg, MD USA. NR 4 TC 5 Z9 6 U1 0 U2 0 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 FEB 15 PY 2004 VL 169 IS 4 BP 437 EP 438 DI 10.1164/rccm.2312004 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 771JK UT WOS:000188781700004 PM 14766659 ER PT J AU D'Angelo, MA Sanguineti, S Reece, JM Birnbaumer, L Torres, HN Flawia, MM AF D'Angelo, MA Sanguineti, S Reece, JM Birnbaumer, L Torres, HN Flawia, MM TI Identification, characterization and subcellular localization of TcPDE1, a novel cAMP-specific phosphodiesterase from Trypanosoma cruzi SO BIOCHEMICAL JOURNAL LA English DT Article DE cAMP; flagellum; membrane; phosphodiesterase; Trypanosoma cruzi ID CYCLIC-AMP PHOSPHODIESTERASE; ADENYLYL-CYCLASE; 3'-5'-CYCLIC-AMP PHOSPHODIESTERASE; DELTA-SUBUNIT; BRUCEI; GENE; ROD; DIFFERENTIATION; PROTEINS; DOMAINS AB Compartmentalization of cAMP phosphodiesterases plays a key role in the regulation of cAMP signalling in mammals. In the present paper, we report the characterization and subcellular localization of TcPDE1, the first cAMP-specific phosphodiesterase to be identified from Trypanosoma cruzi. TcPDE1 is part of a small gene family and encodes a 929-amino-acid protein that can complement a heat-shock-sensitive yeast mutant deficient in phosphodiesterase genes. Recombinant TcPDE1 strongly associates with membranes and cannot be released with NaCl or sodium cholate, suggesting that it is an integral membrane protein. This enzyme is specific for cAMP and its activity is not affected by cGMP. Ca2+, calmodulin or fenotiazinic inhibitors. TcPDE1 is sensitive to the phosphodiesterase inhibitor dipyridamole but is resistant to 3-isobutyl-1-methylxanthine, theophylline, rolipram and zaprinast. Papaverine, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride, and vinpocetine are poor inhibitors of this enzyme. Confocal laser scanning of T. cruzi epimastigotes showed that TcPDE1 is associated with the plasma membrane and concentrated in the flagellum of the parasite. The association of TcPDE1 with this organelle was confirmed by subcellular fractionation and cell-disruption treatments. The localization of this enzyme is a unique feature that distinguishes it from all the trypanosomatid phosphodiesterases described so far and indicates that compartmentalization of cAMP phosphodiesterases could also be important in these parasites. C1 Univ Buenos Aires, Inst Invest & Ingn Genet & Biol Mol, Consejo Nacl Invest Cient & Tecn, RA-1428 Buenos Aires, DF, Argentina. Univ Buenos Aires, Fac Ciencias Exactas & Nat, RA-1428 Buenos Aires, DF, Argentina. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Flawia, MM (reprint author), Univ Buenos Aires, Inst Invest & Ingn Genet & Biol Mol, Consejo Nacl Invest Cient & Tecn, Vuelta Obligado 2490, RA-1428 Buenos Aires, DF, Argentina. EM mflawia@dna.uba.ar NR 47 TC 24 Z9 24 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2004 VL 378 BP 63 EP 72 DI 10.1042/BJ20031147 PN 1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779JB UT WOS:000189290600008 PM 14556647 ER PT J AU Berezhkovskii, AM Batsilas, L Slvartsman, SY AF Berezhkovskii, AM Batsilas, L Slvartsman, SY TI Ligand trapping in epithelial layers and cell cultures SO BIOPHYSICAL CHEMISTRY LA English DT Article DE ligand; receptor; diffusion; cell culture; epithelial layer ID SPATIAL RANGE; DROSOPHILA AB We analyze a stochastic model that describes receptor-mediated ligand trapping in epithelial layers and cell culture assays. In both cases, the problem is reduced to diffusion of a Brownian particle between the partially absorbing and reflective surfaces. We derive an analytical expression for the spatial distribution of the trapping points and identify the domains of applicability of the two limiting regimes. We conclude that a thin layer approximation is applicable for ligand trapping in epithelial layers while a typical cell culture experiment is appropriately described within an infinite layer approximation. (C) 2003 Elsevier B.V. All rights reserved. C1 Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Slvartsman, SY (reprint author), Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. EM stas@princeton.edu NR 21 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD FEB 15 PY 2004 VL 107 IS 3 BP 221 EP 227 DI 10.1016/j.bpc.2003.09.006 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 778CV UT WOS:000189222300002 PM 14967237 ER PT J AU Hall, D Minton, AP AF Hall, D Minton, AP TI Effects of inert volume-excluding macromolecules on protein fiber formation. II. Kinetic models for nucleated fiber growth SO BIOPHYSICAL CHEMISTRY LA English DT Article DE macromolecular crowding; thermodynamic nonideality; rate equations ID MICROSCOPIC PARTICLE LENGTH; POLYMERIZED IN-VITRO; SELF-ASSOCIATION; ACTIN-FILAMENTS; POROUS NETWORKS; HUMAN SPECTRIN; MECHANISM; DISTRIBUTIONS; FRAGMENTATION; MICROTUBULES AB A sequential model for nucleated protein fiber formation is proposed that is similar in broad outline to models proposed previously (Thermodynamics of the Polymerization of Protein, Academic Press, New York, (1975); Biophys. J. 50 (1986) 583) but generalized to allow for thermodynamic nonideality resulting from a high degree of volume occupancy by inert macromolecular cosolutes (macromolecular crowding). The effect of volume occupancy on the rate of fiber formation is studied in the transition-state rate-limited regime through systematic variation of rate-limiting step (prenuclear oligomer formation, nucleus formation or fiber growth), shape of prenuclear oligomer, size of nucleus, extent of reversibility, nature of inert cosolute (hard globular particle or random coil polymer) and size of inert cosolute relative to that of fiber-forming protein. It is found that crowding can accelerate the rate of fiber formation by as much as several orders of magnitude. The extent of acceleration for a given degree of volume occupancy depends upon several factors, the most conspicuous of which is the stoichiometry of the nucleus. In contrast, the rate of redistribution of fiber length, which occurs on a much slower time scale than polymer formation, is found to be insensitive to the extent of crowding. (C) 2003 Elsevier B.V All rights reserved. C1 NIDDKD, Lab Biochem & Genet, Sect Phys Biochem, NIH, Bethesda, MD USA. RP Hall, D (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1NE, England. EM drh32@cam.ac.uk RI Hall, Damien/D-9927-2012; OI Hall, Damien/0000-0003-1538-7618; Minton, Allen/0000-0001-8459-1247 NR 44 TC 15 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD FEB 15 PY 2004 VL 107 IS 3 BP 299 EP 316 DI 10.1016/j.bpc.2003.09.016 PG 18 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 778CV UT WOS:000189222300010 PM 14967245 ER PT J AU Agrawal, L VanHorn-Ali, Z Berger, EA Alkhatib, G AF Agrawal, L VanHorn-Ali, Z Berger, EA Alkhatib, G TI Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5 SO BLOOD LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT VACCINIA VIRUS; PROTEIN-COUPLED RECEPTOR; CHEMOKINE RECEPTOR; ENVELOPE GLYCOPROTEIN; FUNCTIONAL EXPRESSION; PRIMARY MACROPHAGES; MOLECULAR-CLONING; FUSION COFACTORS; AMINO-TERMINUS AB We used synthetic peptides to the extracellular loops (ECLs) of CCR5 to examine inhibitory effects on HIV infection/fusion with primary leukocytes and cells expressing recombinant CCR5. We show for the first time that peptides derived from the first, second, or third ECL caused dose-dependent inhibition of fusion and infection, although with varying potencies and specificities for envelope glycoproteins (Envs) from different strains. The first and third ECL peptides inhibited Envs from the R5 Ba-L strain and the R5X4 89.6 strain, whereas the second ECL peptide inhibited Ba-L but not 89.6 Env. None of the peptides affected fusion mediated by Env from the X4 LAV strain. Fusion mediated by Envs from several primary HIV-1 isolates was also inhibited by the peptides. These findings suggest that various HIV-1 strains use CCR5 domains in different ways. Experiments involving peptide pretreatment and washing, modulation of the expression levels of Env and CCR5, analysis of CCR5 peptide effects against different coreceptors, and inhibition of radiolabeled glycoprotein (gp) 120 binding to CCR5 suggested that the peptide-blocking activities reflect their interactions with gp120. The CCR5-derived ECL peptides thus provide a useful approach to analyze structure-f unction relationships involved in HIV-1 Env-coreceptor interactions and may have implications for the design of drugs that inhibit HIV infection. C1 Indiana Univ, Dept Microbiol & Immunol, Sch Med, Indianapolis, IN 46202 USA. Indiana Univ, Walther Canc Inst, Sch Med, Indianapolis, IN 46202 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Alkhatib, G (reprint author), Indiana Univ, Dept Microbiol & Immunol, Sch Med, Med Sci Bldg,Rm 420,635 Barnhill Dr, Indianapolis, IN 46202 USA. EM galkhati@iupui.edu FU NIAID NIH HHS [R01 AI052019] NR 43 TC 29 Z9 32 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 FEB 15 PY 2004 VL 103 IS 4 BP 1211 EP 1217 DI 10.1182/blood-2003-08-2669 PG 7 WC Hematology SC Hematology GA 772EL UT WOS:000188828200014 PM 14576050 ER PT J AU Katano, H Ali, MA Patera, AC Catalfamo, M Jaffe, ES Kimura, H Dale, JK Straus, SE Cohen, JI AF Katano, H Ali, MA Patera, AC Catalfamo, M Jaffe, ES Kimura, H Dale, JK Straus, SE Cohen, JI TI Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation SO BLOOD LA English DT Article ID FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; EBV INFECTION; T-CELLS; CYTOTOXIC LYMPHOCYTES; GRANULE EXOCYTOSIS; GENE-EXPRESSION; ENCODING GENE; KILLER-CELLS; DISEASE; MICE AB Chronic active Epstein-Barr virus infection (CAEBV) is a rare disease in which previously healthy persons develop severe, life-threatening illness. Mutations in the perforin gene have been found in familial hemophagocytic lymphohistiocytosis, which shares some features with CAEBV. We studied a patient who died at age 18, 10 years after the onset of CAEBV. The patient had high titers of antibodies to EBV, EBV RNA in lymph nodes, T-cell lymphoproliferative disease, and hemophagocytic lymphohistiocytosis. DNA sequencing showed novel mutations in both alleles of the perforin gene that resulted in amino acid changes in the protein. The quantity of the native form of perforin from the patient's stimulated peripheral blood mononuclear cells (PBMCs) was extremely low and immunoblotting showed accumulation of an uncleaved precursor form of perforin. Stimulated PBMCs from the patient were defective for Fas-independent cytotoxicity. These data imply that mutations in this patient resulted in reduced perforin-mediated cytotoxicity by his lymphocytes. This is the first case in which perforin mutations have been shown to result in accumulation of the uncleaved, immature form of perforin. Mutations in the perforin gene are associated with some cases of CAEBV with hemophagocytic lymphohistiocytosis. (C) 2004 by The American Society of Hematology. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Grad Sch Med, Dept Pediat, Aichi, Japan. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Rm 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov RI Kimura, Hiroshi/I-2246-2012 NR 55 TC 65 Z9 80 U1 0 U2 5 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 FEB 15 PY 2004 VL 103 IS 4 BP 1244 EP 1252 DI 10.1182/blood-2003-06-2171 PG 9 WC Hematology SC Hematology GA 772EL UT WOS:000188828200019 PM 14576041 ER PT J AU Takahashi, Y McCoy, JP Carvallo, C Rivera, C Igarashi, T Srinivasan, R Young, NS Childs, RW AF Takahashi, Y McCoy, JP Carvallo, C Rivera, C Igarashi, T Srinivasan, R Young, NS Childs, RW TI In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation SO BLOOD LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; BONE-MARROW TRANSPLANTATION; ANTIGEN-PRESENTING CELLS; ACQUIRED APLASTIC-ANEMIA; VERSUS-HOST-DISEASE; PIG-A; PERIPHERAL-BLOOD; ANCHORED PROTEINS; MEDIATED LYSIS; T-LYMPHOCYTES AB It has bee n proposed that paroxysmal nocturnal hemoglobinuria (PNH) cells may proliferate through their intrinsic resistance to immune attack. To evaluate this hypothesis, we examined the impact of alloimmune pressure on PNH and normal cells in the clinical setting of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Five patients with severe PNH underwent HCT from an HLA-matched family donor after conditioning with cyclophosphamide and fludarabine. PNH neutrophils (CD15(+)/CD66b(-)/CD16(-)) were detected in all patients at engraft-ment, but they subsequently declined to undetectable levels in all cases by 4 months after transplantation. To test for differences in susceptibility to immune pressure, minor histocompatibility antigen (mHa)-specific T-cell lines or clones were targeted against glycosylphosphatidylinositol (GPI)-negative and GPI-positive monocyte and B-cell fractions purified by flow cytometry sorting. Equivalent amounts of interferon-gamma (IFN-gamma) were secreted following coculture with GPI-negative and GPI-positive targets. Furthermore, mHa-specific T-cell lines and CD8(+) T-cell clones showed similar cytotoxicity against both GPI-positive and GPI-negative B cells. Presently, all 5 patients survive without evidence of PNH 5 to 39 months after transplantation. These in vitro and in vivo studies show PNH cells can be immunologically eradicated following nonmyeloablatlve HCT. Relative to normal cells, no evidence for a decreased sensitivity of PNH cells to T-cell-mediated immunity was observed. C1 NIH, Hematol Branch, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NIH, Hematol Branch, Dept Lab Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 7C103,MSC1652,9000 Rockville Pike, Bethesda, MD 20892 USA. EM childsr@nih.gov RI Takahashi, Yoshiyuki/I-1929-2012 NR 33 TC 33 Z9 36 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 FEB 15 PY 2004 VL 103 IS 4 BP 1383 EP 1390 DI 10.1182/blood-2003-04-1281 PG 8 WC Hematology SC Hematology GA 772EL UT WOS:000188828200038 PM 14525787 ER PT J AU Carvallo, C Geller, N Kurlander, R Srinivasan, R Mena, O Igarashi, T Griffith, LM Linehan, WM Childs, RW AF Carvallo, C Geller, N Kurlander, R Srinivasan, R Mena, O Igarashi, T Griffith, LM Linehan, WM Childs, RW TI Prior chemotherapy and allograft CD34(+) dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; HEMATOLOGIC MALIGNANCIES; CHIMERISM; LEUKEMIA; THERAPY AB Significant engraftment variability occurs among patients following nonmyeloablative hematopoietic cell transplantation. We analyzed the impact of multiple factors on donor myeloid and T-cell engraftment in 36 patients with metastatic tumors undergoing cyclophosphamide/fludarabine-based conditioning. Higher CD34(+) doses facilitated donor myeloid engraftment, while prior chemotherapy exposure facilitated both donor myeloid and T-cell engraftment. At day 30, median donor T-cell and myeloid chimerism was 98% and 76%, respectively, in those patients with prior chemotherapy versus 88% (P = .008) and 26% (P < .0001) in chemotherapy-naive patients. Donor myeloid chimerism at day 45 was predicted by prior chemotherapy exposure and the log, 0 of the CD34+ dose (adjusted coefficient of determination [R-2] = .47; P < .0001), while chemotherapy alone impacted donor T-cell engraftment. Patients with prior chemotherapy were more likely to develop acute grades II to IV graft-versus-host disease (GVHD; 8/18) compared with chemotherapy-naive patients (2/18; P = .031). Thus, tailoring the intensity of nonmyeloablative conditioning based on prior chemotherapy exposure is an important consideration in trial design. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, NCI, Urol Oncol Branch, Off Biostat Res,NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C103,MSC1652,9000 Rockville Pike, Bethesda, MD 20892 USA. EM childsr@nih.gov NR 15 TC 36 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 FEB 15 PY 2004 VL 103 IS 4 BP 1560 EP 1563 PG 4 WC Hematology SC Hematology GA 772EL UT WOS:000188828200064 PM 14551148 ER PT J AU Bhowmick, DA Zhuang, ZP Wait, SD Weil, RJ AF Bhowmick, DA Zhuang, ZP Wait, SD Weil, RJ TI A functional polymorphism in the EGF gene is found with increased frequency in glioblastoma multiforme patients and is associated with more aggressive disease SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; EXPRESSION; OVEREXPRESSION; AMPLIFICATION; SURVIVAL; TUMORS; MICE AB Glioblastoma multiforme, the most aggressive form of primary brain tumor in adults, is nearly universally fatal, with 5-year survivals of <5% (P. Kleihues and W. K. Cavenee, eds., pp. 1-314, Lyon: IARC, 2000). Alterations in the epidermal growth factor receptor (EGFR) are common events in many glioblastoma. We hypothesized that a polymorphism in the 5'-untranslated region of the epidermal growth factor (EGF) gene, a natural ligand of the EGFR, may play a role in the genesis of these malignant gliomas. We find that patients with the GA or GG genotype have higher tumoral levels of EGF, irrespective of EGFR status, that they are more likely to recur after surgery, and that they have a statistically significant shorter overall progression-free survival than patients with the AA genotype. These findings suggest that a single nucleotide polymorphism in EGF may play a role in the formation of glioblastomas, is a useful and powerful prognostic marker for these patients, and may be a target for tumor therapy. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,5D37,9000 Rockville Pike, Bethesda, MD 20892 USA. EM weilr@ninds.nih.gov NR 19 TC 96 Z9 97 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2004 VL 64 IS 4 BP 1220 EP 1223 DI 10.1158/0008-5472.CAN-03-3137 PG 4 WC Oncology SC Oncology GA 778MK UT WOS:000189245200003 PM 14973082 ER PT J AU Robey, RW Steadman, K Polgar, O Morisaki, K Blayney, M Mistry, P Bates, SE AF Robey, RW Steadman, K Polgar, O Morisaki, K Blayney, M Mistry, P Bates, SE TI Pheophorbide a is a specific probe for ABCG2 function and inhibition SO CANCER RESEARCH LA English DT Article ID CANCER RESISTANCE PROTEIN; MULTIDRUG-RESISTANCE; HALF-TRANSPORTER; LUNG-CANCER; IN-VITRO; CELLS; EXPRESSION; SUBSTRATE; MUTATIONS; GF120918 AB Pheophorbide a (PhA), a chlorophyll catabolite, was shown to be an ABCG2 substrate based on Abcg2(-/-) knockout mouse studies (J. W. Jonker et al., Proc. Natl. Acad. Sci. USA, 99: 15649-15654, 2002). We developed a functional assay for ABCG2 using PhA and the ABCG2 inhibitor fumitremorgin C. In selected cell lines expressing high levels of P-glycoprotein, multidrug resistance-associated protein 1, or ABCG2, PhA transport was observed only in cells expressing ABCG2. Fumitremorgin C-inhibitable PhA transport was found to correlate with cell surface ABCG2 expression as measured by the anti-ABCG2 antibody 5D3. We found that 100 mum of the cyclin-dependent kinase inhibitor UCN-01 or 1 mum of the P-glycoprotein inhibitor tariquidar inhibited ABCG2-mediated PhA transport. In 4-day cytotoxicity assays, ABCG2-mediated resistance to SN-38 and topotecan was abrogated in ABCG2-transfected HEK-293 cells treated with 1 lam tariquidar, and ABCG2-transfected cells were 6-7-fold resistant to UCN-01. PhA is an ABCG2-specific substrate with potential value in measuring ABCG2 function and expression in clinical samples. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Xenova Res, Slough, Berks, England. RP Robey, RW (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI Steadman, Kenneth/J-3883-2013 NR 22 TC 207 Z9 212 U1 0 U2 8 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 FEB 15 PY 2004 VL 64 IS 4 BP 1242 EP 1246 DI 10.1158/0008-5472.CAN-03-3298 PG 5 WC Oncology SC Oncology GA 778MK UT WOS:000189245200008 PM 14973080 ER PT J AU Rorie, CJ Thomas, VD Chen, PC Pierce, HH O'Bryan, JP Weissman, BE AF Rorie, CJ Thomas, VD Chen, PC Pierce, HH O'Bryan, JP Weissman, BE TI The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to ewing sarcoma/peripheral primitive neuroectodermal tumors SO CANCER RESEARCH LA English DT Article ID HEPATOMA CELL HYBRIDS; NERVE GROWTH-FACTOR; FRINGE GENES; DNA-BINDING; TGF-BETA; TRANSCRIPTIONAL ACTIVATION; TYROSINE AMINOTRANSFERASE; CHIMERIC TRANSCRIPTS; FIBROBLAST HYBRIDS; ADAPTER PROTEIN AB Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Curriculum Genet & Mol Biol, Chapel Hill, NC USA. Dept Pathol & Lab Med, Chapel Hill, NC USA. Curriculum Toxicol, Chapel Hill, NC USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Weissman, BE (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295, Chapel Hill, NC 27599 USA. EM bemard_weissman@med.unc.edu FU NCI NIH HHS [CA 91048, 5F31 CA 096576, CA 63176]; NIEHS NIH HHS [5T32 ES 07126] NR 91 TC 47 Z9 48 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 FEB 15 PY 2004 VL 64 IS 4 BP 1266 EP 1277 DI 10.1158/0008-5472.CAN-03-3274 PG 12 WC Oncology SC Oncology GA 778MK UT WOS:000189245200012 PM 14973077 ER PT J AU Deane, NG Lee, H Hamaamen, J Ruley, A Washington, MK LaFleur, B Thorgeirsson, SS Price, R Beauchamp, RD AF Deane, NG Lee, H Hamaamen, J Ruley, A Washington, MK LaFleur, B Thorgeirsson, SS Price, R Beauchamp, RD TI Enhanced tumor formation in cyclin D1 x transforming growth factor beta 1 double transgenic mice with characterization by magnetic resonance imaging SO CANCER RESEARCH LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; GROWTH-FACTOR-BETA-1 TRANSGENE; (TGF-BETA)-INDUCED APOPTOSIS; DEPENDENT KINASES; EPITHELIAL-CELLS; REGRESSING LIVER; ELEVATED LEVELS; UNITED-STATES; CANCER-CELLS; RAT-LIVER AB Transgenic mice that overexpress cyclin D1 protein in the liver develop liver carcinomas with high penetrance. Transforming growth factor beta (TGF-beta) serves as either an epithelial cell growth inhibitor or a tumor promoter, depending on the cellular context. We interbred LFABP-cyclin D1 and Alb-TGF-beta1 transgenic mice to produce cyclin D1/TGF-beta1 double transgenic mice and followed the development of liver tumors over time, characterizing cellular and molecular changes, tumor incidence, tumor burden, and tumor physiology noninvasively by magnetic resonance imaging. Compared with age-matched LFABP-cyclin D1 single transgenic littermates, cyclin D1/TGF-beta1 mice exhibited a significant increase in tumor incidence. Tumor multiplicity, tumor burden, and tumor heterogeneity were higher in cyclin D1/TGF-beta1 mice compared with single transgenic littermates. Characteristics of cyclin D1/TGF-beta1 livers correlated with a marked induction of the peripheral periductal oval cell/stem cell compartment of the liver. A number of cancerous lesions from cyclin D1/TGF-beta1 mice exhibited unique features such as ductal plate malformations and hemorrhagic nodules. Some lesions were contiguous with the severely diseased background liver and, in some cases, replaced the normal architecture of the entire organ. Cyclin D1/TGF-beta1 lesions, in particular, were associated with malignant features such as areas of vascular invasion by hepatocytes and heterogeneous hyperintensity of signal on T2-weighted magnetic resonance imaging. These findings demonstrate that TGF-beta1 promotes stem cell activation and tumor progression in the context of cyclin D1 overexpression in the liver. C1 Vanderbilt Univ, Med Ctr, Dept Surg, Div Surg Oncol, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Radiol, Div Radiol Sci, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. Natl Canc Inst, Expt Carcinogenesis Lab, Div Canc Etiol, Bethesda, MD USA. Natl Canc Inst, Chemoprevent Lab, Div Canc Etiol, Bethesda, MD USA. Vanderbilt Univ, Med Ctr, Dept Prevent Med & Biostat, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Deane, NG (reprint author), Vanderbilt Univ, Med Ctr, Dept Surg, Div Surg Oncol, 1161 21st Ave S,D2300, Nashville, TN 37232 USA. FU NCI NIH HHS [5P30 CA 68485, CA 69457, CA 92043]; NIDDK NIH HHS [DK 52334] NR 53 TC 19 Z9 20 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 FEB 15 PY 2004 VL 64 IS 4 BP 1315 EP 1322 DI 10.1158/0008-5472.CAN-03-1772 PG 8 WC Oncology SC Oncology GA 778MK UT WOS:000189245200018 PM 14973059 ER PT J AU Onda, M Wang, QC Guo, HF Cheung, NKV Pastan, I AF Onda, M Wang, QC Guo, HF Cheung, NKV Pastan, I TI In vitro and in vivo cytotoxic activities of recombinant immunotoxin 8H9(Fv)PE38 against breast cancer, osteosarcoma, and neuroblastoma SO CANCER RESEARCH LA English DT Article ID NONSPECIFIC ANIMAL TOXICITY; STABILIZED FV FRAGMENTS; ANTIBODY PHAGE DISPLAY; PSEUDOMONAS EXOTOXIN; COMPLETE REGRESSION; ISOELECTRIC POINT; FRAMEWORK REGIONS; FUSION PROTEINS; HUMAN CARCINOMA; SOLID TUMORS AB The 8H9 monoclonal antibody (MAb) is highly reactive with a cell surface glycoprotein expressed on human breast cancers, childhood sarcomas, and neuroblastomas but is not reactive with the cell surface of normal human tissues. This specific reactivity suggests that MAb 8H9 may be useful for targeted cancer therapy. To explore this possibility, we generated two recombinant immunotoxins (ITs) using the single-chain Fv (scFv) of MAb 8H9. Initially the 8H9(scFv) cDNA was fused to a DNA encoding a 38-kDa truncated form of Pseudomonas exotoxin (PE38) to generate the IT 8H9(scFv)-PE38. The fusion gene was expressed in Escherichia coli, and the IT was purified to near homogeneity from inclusion bodies. The purified IT showed specific cytotoxicity on nine different cancer cell lines derived from breast cancer, osteosarcoma, and neuroblastomas, known to react with MAb 8H9. The cytotoxic activity was inhibited by MAb 8H9, showing the cytotoxic activity is specific. The antitumor activity of 8H9(scFv)-PE38 was evaluated in severe combined immunodeficient mice bearing MCF-7 breast cancers or OHS-M1 osteosarcomas. The IT showed a specific dose-dependent antitumor activity at 0.075 and 0.15 mg/kg. Next, a more stable disulfide-linked IT, 8H9(dsFv)PE38, was constructed. It was produced in high yield (16%) and showed cytotoxic and antitumor activities similar to those of 8H9(scFv)-PE38. 8H9(dsFv)-PE38 was given to two cynomolgus monkeys at doses of 0.1 and 0.2 mg/kg i.v. QOD x 3 and was well tolerated. This shows that a dose that causes significant tumor regressions in mice is well tolerated by monkeys. These results make 8H9(dsFv)-PE38 a candidate for further development as a therapeutic agent for breast cancers, osteosarcomas, and neuroblastomas. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM panstani@mail.nih.gov NR 25 TC 39 Z9 44 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 FEB 15 PY 2004 VL 64 IS 4 BP 1419 EP 1424 DI 10.1158/0008-5472.CAN-03-0570 PG 6 WC Oncology SC Oncology GA 778MK UT WOS:000189245200030 PM 14973056 ER PT J AU Mandler, R Kobayashi, H Hinson, ER Brechbiel, MW Waldmann, TA AF Mandler, R Kobayashi, H Hinson, ER Brechbiel, MW Waldmann, TA TI Herceptin-geldanamycin immunoconjugates: Pharmacokinetics, biodistribution, and enhanced antitumor activity SO CANCER RESEARCH LA English DT Article ID METASTATIC BREAST-CANCER; IN-VIVO BIODISTRIBUTION; MONOCLONAL-ANTIBODY; SIGNALING NETWORK; CELL-LINES; EFFICACY; PROTEIN; IN-111; LEUKEMIA; THERAPY AB The efficacy of monoclonal antibodies (mAbs) as single agents in targeted cancer therapy has proven to be limited. Arming mAbs with a potent toxic drug could enhance their activity. Here we report that conjugating geldanamycin (GA) to the anti-HER2 mAb Herceptin improved the activity of Herceptin. The IC(50)s of the immunoconjugate H-GA were 10-200-fold lower than that of Herceptin in antiproliferative assays, depending on the cell line. The H-GA mode of action involved HER2 degradation, which was partially lactacystin sensitive and thus proteasome dependent. The linkage between GA and Herceptin remained stable in the circulation, as suggested by the pharmacokinetics of Herceptin and conjugated GA, which were almost identical and significantly different from that of free GA. Tumor uptake of Herceptin and H-GA were similar (52 +/- 7 and 43 +/- 7% of the initial injected dose per gram tissue, respectively; P = 0.077), indicating no apparent damage attributable to conjugation. Therapy experiments in xenograft-bearing mice consisted of weekly i.p. doses, 4 mg/kg for 4 months. H-GA showed a greater antitumor effect than Herceptin because it induced tumor regression in 69% of the recipients compared with 7% by Herceptin alone. Median survival time was 145 days as opposed to 78 days, and 31% of the recipients remained tumor free 2 months after therapy was terminated versus 0% in the Herceptin group. Enhancement of Herceptin activity could be of significant clinical value. In addition, the chemical linkage and the considerations in therapeutic regimen described here could be applied to other immunoconjugates for targeted therapy of a broad spectrum of cancers. C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, NIH, Bethesda, MD 20892 USA. RP Mandler, R (reprint author), 6701 Rockledge Dr,Room 5217,MSC 7840, Bethesda, MD 20892 USA. EM rayam@mail.nih.gov NR 35 TC 51 Z9 57 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2004 VL 64 IS 4 BP 1460 EP 1467 DI 10.1158/0008-5472.CAN-03-2485 PG 8 WC Oncology SC Oncology GA 778MK UT WOS:000189245200036 PM 14973048 ER PT J AU Rapisarda, A Uranchimeg, B Sordet, O Pommier, Y Shoemaker, RH Melillo, G AF Rapisarda, A Uranchimeg, B Sordet, O Pommier, Y Shoemaker, RH Melillo, G TI Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications SO CANCER RESEARCH LA English DT Article ID RNA-POLYMERASE-II; GROWTH-FACTOR EXPRESSION; OXIDE SYNTHASE PROMOTER; FACTOR 1-ALPHA; TRANSCRIPTIONAL ACTIVATION; PROLINE HYDROXYLATION; PROLYL HYDROXYLATION/; RESPONSIVE ELEMENT; DNA-REPLICATION; GENE-EXPRESSION AB We have shown previously that the camptothecin analogue topotecan (TPT), a topoisomerase I (Top 1) poison, inhibits hypoxia-inducible factor 1 (HIF-1) transcriptional activity and HIF-1alpha protein accumulation in hypoxia-treated U251 human glioma cells. In this article, we demonstrate that TPT does not affect HIF-1alpha protein half-life or mRNA accumulation but inhibits its translation. In addition, we demonstrate that Top 1 is required for the inhibition of HIF-1alpha protein accumulation by TPT as shown by experiments performed using camptothecin-resistant cell lines with known Top 1 alterations. Experiments performed with aphidicolin indicated that TPT inhibited HIF-1 protein accumulation in the absence of DNA replication. DNA-damaging agents, such as ionizing radiation and doxorubicin, did not affect HIF-1alpha protein accumulation. Ongoing transcription was essential for the inhibition of HIF-1alpha protein accumulation by TPT. Our results demonstrate the existence of a novel pathway connecting Top 1-dependent signaling events and the regulation of HIF-1alpha protein expression and function. In addition, our findings dissociate the cytotoxic activity of TPT from the inhibition of the HIF-1 pathway and raise the possibility of novel clinical applications of TPT aimed at targeting HIF-1-dependent responses. C1 Sci Applicat Int Corp, NCI, DPA Tumor Hypoxia Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp, NCI, Dev Therapeut Program, Frederick, MD 21702 USA. NCI, Canc Res Ctr, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Melillo, G (reprint author), Sci Applicat Int Corp, NCI, DPA Tumor Hypoxia Lab, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillog@ncifcrf.gov RI Sordet, Olivier/M-3271-2014 FU NCI NIH HHS [N01 CO 12400] NR 47 TC 194 Z9 204 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 FEB 15 PY 2004 VL 64 IS 4 BP 1475 EP 1482 DI 10.1158/0008-5472.CAN-03-3139 PG 8 WC Oncology SC Oncology GA 778MK UT WOS:000189245200038 PM 14983893 ER PT J AU Perlman, DC Segal, Y Rosenkranz, S Rainey, PM Peloquin, CA Remmel, RP Chirgwin, K Salomon, N Hafner, R AF Perlman, DC Segal, Y Rosenkranz, S Rainey, PM Peloquin, CA Remmel, RP Chirgwin, K Salomon, N Hafner, R CA ACTG 309 Team TI The clinical pharmacokinetics of pyrazinamide in HIV-infected persons with tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RIFAMPIN-MONORESISTANT TUBERCULOSIS; AIDS; MALABSORPTION; MEDICATIONS; COMBINATION; RIFAPENTINE; AGENTS AB The pharmacokinetics of pyrazinamide (PZA) in patients with human immunodeficiency virus (HIV)-related tuberculosis are incompletely characterized. Serum PZA concentrations were determined at 2, 6, and 10 h after dosing in 48 subjects with HIV-related tuberculosis. Estimates of drug exposure using 2-h concentrations and 2- and 3-time point estimates of area under time-concentration curves (AUCs) were compared. For daily dosing, 2- h concentrations less than low and very low literature-defined cut points (i.e., 20 and 10 mg/L) were noted for 2 subjects (4%) and 1 subject (2%), respectively. For intermittent PZA dosing, 1 subject (4%) had a 2-h concentration that was less than the low cut point (25 mg/L). Correlations between 2-h concentration and AUC estimates based on 2- or 3-time point concentration determinations were strong. In HIV-infected persons receiving antituberculosis regimens containing PZA, lower-than-expected 2-h concentrations are uncommon. For therapeutic monitoring of PZA drug exposure, determination of a 2-h postdose concentration appears as reliable as 2- or 3-time point estimates of the AUC for PZA. C1 Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. SUNY Downstate, Brooklyn, NY USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Washington, Seattle, WA 98195 USA. Natl Jewish Med & Res Ctr, Denver, CO USA. Univ Minnesota, Minneapolis, MN USA. NIAID, Bethesda, MD 20892 USA. RP Perlman, DC (reprint author), Beth Israel Deaconess Med Ctr, 1st Ave & 16th St, New York, NY 10003 USA. EM dperlman@bethisraelny.org RI Remmel, Rory/N-2453-2015 FU NCRR NIH HHS [M01 RR05096]; NIAID NIH HHS [AO603, 1U01AI46370, AI 38855, U01 AI046370]; PHS HHS [A12015802, A1701, A1802, A2205, A2503, A5802, A5901, A6201, UO1A127673, UO1A13844] NR 36 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2004 VL 38 IS 4 BP 556 EP 564 DI 10.1086/381096 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 770RY UT WOS:000188745700014 PM 14765350 ER PT J AU Leach, RE Kilburn, B Wang, J Liu, ZT Romero, R Armant, DR AF Leach, RE Kilburn, B Wang, J Liu, ZT Romero, R Armant, DR TI Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype SO DEVELOPMENTAL BIOLOGY LA English DT Article DE cytotrophoblast; placentation; HER/ErbB receptors; growth factors; proliferation; invasion; motility; integrins; extracellular matrix; preeclampsia ID TROPHOBLAST CELL INVASION; EXTRACELLULAR-MATRIX; BLASTOCYST IMPLANTATION; HUMAN ENDOMETRIUM; EPITHELIAL-CELLS; HUMAN-PLACENTA; SMOOTH-MUSCLE; IMMUNOHISTOCHEMICAL LOCALIZATION; EMBRYO IMPLANTATION; MOUSE BLASTOCYSTS AB Cytotrophoblasts of the anchoring villi convert during human placentation from a transporting epithelium to an invasive, extravillous phenotype that expresses a distinct repertoire of adhesion molecules. Developing extravillous trophoblasts accumulate heparin-binding EGF-like growth factor (HB-EGF), a multifunctional cytokine, which binds HER1 and HER4 of the human EGF receptor (HER/ErbB) family. HB-EGF is downregulated in placentae of women with preeclampsia, a disorder associated with deficient trophoblast invasion, raising important questions about its physiological impact on cytotrophoblasts. Addition of HB-EGF during explant culture of first-trimester chorionic villi enhanced extravillous trophoblast differentiation and invasive activity. Using a first-trimester human cytotrophoblast line, the potential for autocrine and paracrine regulation of the developing trophoblast was established based on the expression of all four HER isoforms, as well as HB-EGF and related growth factors. HB-EGF did not alter proliferation, but initiated extravillous differentiation, with decreased alpha6 integrin expression, increased alpha1, and elevated cell migration. Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching. We conclude that HER-mediated autocrine and paracrine signaling by HB-EGF or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype. (C) 2003 Elsevier Inc. All rights reserved. C1 Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Anat & Cell Biol, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, Intramural Div, NIH, Bethesda, MD USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, 275 E Hancock Ave, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU NIAAA NIH HHS [AA12057]; NICHD NIH HHS [HD36764, HD37500, HD98004] NR 59 TC 69 Z9 73 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2004 VL 266 IS 2 BP 223 EP 237 DI 10.1016/j.ydbio.2003.09.026 PG 15 WC Developmental Biology SC Developmental Biology GA 776RA UT WOS:000189129300001 PM 14738873 ER PT J AU Kolotuev, I Podbilewicz, B AF Kolotuev, I Podbilewicz, B TI Pristionchus pacificus vulva formation: polarized division, cell migration, cell fusion, and evolution of invagination SO DEVELOPMENTAL BIOLOGY LA English DT Article DE cell fusion; body patterning; organogenesis; Pristionchus pacificus; Caenorhabditis elegans; epithelial cells; vulva development; morphogenesis ID CAENORHABDITIS-ELEGANS VULVA; C-ELEGANS; HETEROCHRONIC GENES; EQUIVALENCE GROUP; PATTERN-FORMATION; PRECURSOR CELLS; NEMATODE; INDUCTION; PROTEIN; MORPHOGENESIS AB Tube formation is a widespread process during organogenesis. Specific cellular behaviors participate in the invagination of epithelial monolayers that form tubes. However, little is known about the evolutionary mechanisms of cell assembly into tubes during development. In Caenorhabditis elegans, the detailed step-to-step process of vulva formation has been studied in wild type and in several mutants. Here we show that cellular processes during vulva development, which involve toroidal cell formation and stacking of rings, are conserved between C elegans and Pristionchus pacificus, two species of nematodes that diverged approximately 100 million years ago. These cellular behaviors are divided into phases of cell proliferation, short-range migration, and cell fusion that are temporally distinct in C elegans but not in P. pacificus. Thus, we identify heterochronic changes in the cellular events of vulva development between these two species. We find that alterations in the division axes of two equivalent vulval cells from Left-Right cleavage in C. elegans to Anterior-Posterior division in P pacificus can cause the formation of an additional eighth ring. Thus, orthogonal changes in cell division axes with alterations in the number and sequence of cell fusion events result in dramatic differences in vulval shape and in the number of rings in the species studied. Our characterization of vulva formation in P. pacificus compared to C elegans provides an evolutionary-developmental foundation for molecular genetic analyses of organogenesis in different species within the phylum Nematoda. (C) 2003 Elsevier Inc. All rights reserved. C1 Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. RP Podbilewicz, B (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10, Room 10D10,10 Ctr Dr, Bethesda, MD 20892 USA. EM podbilew@tx.technion.ac.il RI Podbilewicz, Benjamin/N-4825-2014; OI Podbilewicz, Benjamin/0000-0002-0411-4182 NR 59 TC 10 Z9 10 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2004 VL 266 IS 2 BP 322 EP 333 DI 10.1016/j.ydbio.2003.10.029 PG 12 WC Developmental Biology SC Developmental Biology GA 776RA UT WOS:000189129300008 PM 14738880 ER PT J AU Lee, JS Kamijo, K Ohara, N Kitamura, T Miki, T AF Lee, JS Kamijo, K Ohara, N Kitamura, T Miki, T TI MgcRacGAP regulates cortical activity through RhoA during cytokinesis SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE MgcRacGAP; RhoA; cytokinesis; cortical activity ID GTPASE-ACTIVATING PROTEIN; MYOSIN LIGHT-CHAIN; ACTIN POLYMERIZATION; INDUCED APOPTOSIS; EXCHANGE FACTOR; CYTOCHALASIN-D; ROCK-I; CELLS; SPINDLE; PHOSPHORYLATION AB Although Rho GTPases regulate multiple cellular events, their role in cell division is still obscure. Here we show that expression of a GTPase-activating protein (GAP)-deficient mutant (R386A) of the Rho regulator MgcRacGAP induces abnormal cortical activity during cytokinesis in U20S cells. Multiple large blebs were observed in cells expressing MgcRacGAP R386A from the onset of anaphase to the late stage of cell division. When mitotic blebbing was excessive, cytokinesis was inhibited, and cells with micronuclei were generated. It has been reported that blebbing is caused by abnormal cortical activity. The MgcRacGAP R386A-induced abnormal cortical activity was inhibited by the dominant negative form of RhoA, but not Rac1 or Cdc42. Moreover, expression of constitutively active RhoA also induced drastic cortical activity during cytokinesis. Unlike apoptotic blebbing, MgcRacGAP R386A-induced blebbing was not inhibited by the ROCK inhibitor Y-27632, suggesting that MgcRacGAP regulates cortical activity during cytokinesis through a novel signaling pathway. We propose that MgcRacGAP plays a pivotal role in cytokinesis by regulating cortical movement through RhoA. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Mol Tumor Biol Sect, Basic Res Lab, Bethesda, MD 20892 USA. Univ Tokyo, Inst Med Sci, Div Hematopoiet Factors, Minato Ku, Tokyo 1088639, Japan. RP Lee, JS (reprint author), Seoul Natl Univ, Coll Med, ILCHUN, Inst Mol Med, Seoul 110799, South Korea. EM jaeslee@snu.ac.kr NR 33 TC 30 Z9 31 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2004 VL 293 IS 2 BP 275 EP 282 DI 10.1016/j.yexcr.2003.10.015 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 767QB UT WOS:000188462700010 PM 14729465 ER PT J AU Liang, XJ Yin, JJ Zhou, JW Wang, PC Taylor, B Cardarelli, C Kozar, M Forte, R Aszalos, A Gottesman, MM AF Liang, XJ Yin, JJ Zhou, JW Wang, PC Taylor, B Cardarelli, C Kozar, M Forte, R Aszalos, A Gottesman, MM TI Changes in biophysical parameters of plasma membranes influence cisplatin resistance of sensitive and resistant epidermal carcinoma cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE cisplatin resistance; heptadecanoic acid; plasma membrane fluidity; membrane potential; fluorescence polarization; human epidermal carcinoma KB cells ID MULTIDRUG-RESISTANCE; INDUCED APOPTOSIS; DNA DAMAGE; LINES; ACCUMULATION; PACKING; DRUGS; ACID AB The mechanism of resistance of cancer cells to the anticancer drug cisplatin is not fully understood. Using cisplatin-sensitive KB-3-1 and -resistant KCP-20 cells, we found that the resistant cells have higher membrane potential, as determined by membrane potential sensing oxonol dye. Electron spin resonance and fluorescence polarization studies revealed that the-resistant cells have more "fluid" plasma membranes than the sensitive cells. Because of this observed difference in membrane "fluidity," we attempted modification of the plasma membrane fluidity by the incorporation of heptadecanoic acid into KB-3-1 and KCP-20 cell membranes. We found that such treatment resulted in increased heptadecanoic acid content and increased fluidity in the plasma membranes of both cell types, and also resulted in increased cisplatin resistance in the KCP-20 cells. This finding is in accord with our results, which showed that the cisplatin-resistant KCP-20 cells have more fluid membranes than the cisplatin-sensitive KB-3-1 cells. It remains to be determined whether the observed differences in biophysical status and/or fatty acid composition alone, or the secondary effect of these differences on the structure or function of some transmembrane protein(s), is the reason for increased cisplatin resistance. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Instrumentat & Biophys Branch, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. Howard Univ, Dept Radiol, Washington, DC 20060 USA. Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Room 1A-09,37 Convent Dr, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Kozar, Michael/A-9155-2011; Yin, Jun Jie /E-5619-2014 NR 31 TC 18 Z9 26 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2004 VL 293 IS 2 BP 283 EP 291 DI 10.1016/j.yexcr.2003.10.012 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 767QB UT WOS:000188462700011 PM 14729466 ER PT J AU Patel, RP Gladwin, MT AF Patel, RP Gladwin, MT TI Physiologic, pathologic and therapeutic implications for hemoglobin interactions with nitric oxide SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review ID S-NITROSOHEMOGLOBIN; ERYTHROCYTES; DIFFUSION; NO C1 NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Free Rad Biol, Birmingham, AL 35294 USA. RP Gladwin, MT (reprint author), NIH, Crit Care Med Dept, Ctr Clin, Bldg 10,Room 7D-43,10 Ctr Dr, Bethesda, MD 20892 USA. EM patel@path.uab.edu; mgladwin@nih.gov OI Patel, Rakesh/0000-0002-1526-4303 NR 14 TC 13 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2004 VL 36 IS 4 BP 399 EP 401 DI 10.1016/j.freeradbiomed.2003.11.019 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 780FA UT WOS:000189360600001 PM 14975442 ER PT J AU Piccioni, F Roman, BR Fischbeck, KH Taylor, JP AF Piccioni, F Roman, BR Fischbeck, KH Taylor, JP TI A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor SO HUMAN MOLECULAR GENETICS LA English DT Article ID BULBAR MUSCULAR-ATROPHY; HUNTINGTONS-DISEASE; CELL-DEATH; CASPASE CLEAVAGE; SODIUM-PUMP; APOPTOSIS; INHIBITION; NEURODEGENERATION; MITOCHONDRIA; SULOCTIDIL AB Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na+K+-ATPase. The fourth compound, suloctidil, is a calcium channel blocker. C1 Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Taylor, JP (reprint author), Univ Penn, Sch Med, Dept Neurol, 3 W Gates Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM jpt@mail.med.upenn.edu FU NINDS NIH HHS [K22-NS44125-01] NR 37 TC 44 Z9 46 U1 1 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 FEB 15 PY 2004 VL 13 IS 4 BP 437 EP 446 DI 10.1093/hmg/ddh045 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 771PM UT WOS:000188795300008 PM 14709594 ER PT J AU Shanker, A AF Shanker, A TI Is thymus redundant after adulthood? SO IMMUNOLOGY LETTERS LA English DT Review DE adult thymus function; thymic atrophy; tumour; stress; thymic import and export; T cell reconstitution ID AGE-RELATED-CHANGES; T-CELL LYMPHOMA; BONE-MARROW-TRANSPLANTATION; MAREKS-DISEASE VIRUS; LYMPHOCYTES-T; TUMOR-BEARING; IMMUNE-SYSTEM; PROTEIN-PHOSPHORYLATION; ANTIRETROVIRAL THERAPY; PERIPHERAL SELECTION AB Thymus is considered to involute with age with a decline in thymic function. However, this generality is not universally and incontrovertibly true. Many studies performed in animals and men have proved to the contrary that thymic activity and function appear to be well maintained in the old age and may be indispensable for T cell reconstitution in different immunological settings. During some clinical situations where T cell pool needs to be regenerated, renewal of thymic activity and mass has been observed in an otherwise dormant thymic remnant. New studies have revealed a dynamic interplay between postnatal thymus output and peripheral T cell pool. Moreover, age-related loss of thymic function appears to be only quantitative and not qualitative. This review, thus, focuses on the different conditions that lead to thymic involution and attempts to bring about the emerging notion and the clinical relevance of continuous thymic activity well beyond the adulthood to optimise the function of the immune system in the context of cancer and infectious diseases. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Mediterranee, CNRS, INSERM, Ctr Immunol Marseille Luminy, F-13288 Marseille 09, France. RP Shanker, A (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Bldg 560,POB B, Frederick, MD 21702 USA. EM shankera@ncifcrf.gov OI Shanker, Anil/0000-0001-6372-3669 NR 116 TC 28 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB 15 PY 2004 VL 91 IS 2-3 BP 79 EP 86 DI 10.1016/j.imlet.2003.12.012 PG 8 WC Immunology SC Immunology GA 802QB UT WOS:000220176900001 PM 15019273 ER PT J AU Chantalat, S Park, SK Hua, ZL Liu, K Gobin, R Peyroche, A Rambourg, A Graham, TR Jackson, CL AF Chantalat, S Park, SK Hua, ZL Liu, K Gobin, R Peyroche, A Rambourg, A Graham, TR Jackson, CL TI The Arf activator Gea2p and the P-type ATPase Drs2p interact at the golgi in Saccharomyces cerevisiae SO JOURNAL OF CELL SCIENCE LA English DT Article DE Arf guanine nucleotide exchange factor (GEF); Arf GTPase; aminophospholipid translocase; golgi apparatus; secretory vesicles; secretory granules; membrane dynamics ID GUANINE-NUCLEOTIDE-EXCHANGE; ADP-RIBOSYLATION FACTOR; YEAST GOLGI; ENDOPLASMIC-RETICULUM; FACTORS GEA1P; PROTEIN; CLATHRIN; ENDOCYTOSIS; TRANSPORT; COMPLEX AB Arf GTPases regulate both the morphological and protein sorting events that are essential for membrane trafficking. Guanine nucleotide exchange factors (GEFs) specific for Arf proteins determine when and where Arf GTPases will be activated in cells. The yeast Gea2p Arf GEF is a member of an evolutionarily conserved family of high molecular mass Arf GEFs that are peripherally associated with membranes. Nothing is known about how these proteins are localized to membranes, and few direct binding partners have been identified. In yeast, Gea2p has been implicated in trafficking through the Golgi apparatus and in maintaining Golgi structure. A major function of the Golgi apparatus is the packaging of cargo into secretory granules or vesicles. This process occurs through a series of membrane transformation events starting with fenestration of a saccular membrane, and subsequent remodeling of the fenestrated membrane into a mesh-like tubular network. Concentration of secretory cargo into nodes of the tubular network leads to enlargement of the nodes, which correspond to forming vesicles/granules, and thinning of the surrounding tubules. The tubules eventually break to release the secretory vesicles/granules into the cytoplasm. This process is highly conserved at the morphological level from yeast to mammalian cells. Drs2p, a multi-span transmembrane domain protein and putative aminophospholipid translocase, is required for the formation of a class of secretory granules/vesicles in yeast. Here we show that Drs2p interacts directly with Gea2p, both in vitro and in vivo. We mapped the domain of interaction of Drs2p to a 20-amino-acid region of the C-terminal cytoplasmic tail of the protein, adjacent to a region essential for Drs2p function. Mutations in Gea2p that abolish interaction with Drs2p are clustered in the C-terminal third of the Sec? domain, and are important for Gea2p function. We characterize one such mutant that has a thermosensitive phenotype, and show that it has morphological defects along the secretory pathway in the formation of secretory granules/vesicles. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. CEA Saclay, Dept Biol Joliot Curie, F-91191 Gif Sur Yvette, France. Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. RP Jackson, CL (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM cathyj@helix.nih.gov RI Jackson, Catherine/A-3421-2013; PEYROCHE, Anne /C-5548-2014 OI Jackson, Catherine/0000-0002-0843-145X; PEYROCHE, Anne /0000-0002-8808-8785 FU NIGMS NIH HHS [GM62367] NR 37 TC 57 Z9 59 U1 0 U2 4 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 15 PY 2004 VL 117 IS 5 BP 711 EP 722 DI 10.1242/jcs.00896 PG 12 WC Cell Biology SC Cell Biology GA 778NV UT WOS:000189248400007 PM 14734650 ER PT J AU Liang, W Curran, PK Hoang, Q Moreland, RT Fishman, PH AF Liang, W Curran, PK Hoang, Q Moreland, RT Fishman, PH TI Differences in endosomal targeting of human beta(1)- and beta(2)-adrenergic receptors following clathrin-mediated endocytosis SO JOURNAL OF CELL SCIENCE LA English DT Article DE beta-adrenergic receptor; endocytosis; recycling; clathrin; arrestin ID PROTEIN-COUPLED RECEPTORS; BETA-ADRENERGIC-RECEPTOR; MUSCARINIC ACETYLCHOLINE-RECEPTOR; DOWN-REGULATION; CARDIAC MYOCYTES; PLASMA-MEMBRANE; BETA-2-ADRENERGIC RECEPTORS; TRANSFERRIN RECEPTORS; ADENYLYL-CYCLASE; CHOLERA-TOXIN AB The beta(2)-adrenergic receptor (beta(2)AR) undergoes agonist-mediated endocytosis via clathrin-coated pits by a process dependent on both arrestins and dynamin. Internalization of some G protein-coupled receptors, however, is independent of arrestins and/or dynamin and through other membrane microdomains such as caveolae or lipid rafts. The human beta(1)AR is less susceptible to agonist-mediated internalization than the beta(2)-subtype, and its endocytic route, which is unknown, may be different. We have found that (i) co-expression of arrestin-2 or -3 enhanced the internalization of both subtypes whereas co-expression of dominant-negative mutants of arrestin-2 or dynamin impaired their internalization, as did inhibitors of clathrin-mediated endocytosis. (ii) Agonist stimulation increased the phosphorylation of beta(2)AR but not beta(1)AR. (iii) In response to agonist, each subtype redistributed from the cell surface to a distinct population of cytoplasmic vesicles; those containing beta(1)AR were smaller and closer to the plasma membrane whereas those containing beta(2)AR were larger and more perinuclear. (iv) When subcellular fractions from agonist-treated cells were separated by sucrose density gradient centrifugation, all of the internalized beta(2)AR appeared in the lighter endosomal-containing fractions whereas some of the internalized beta(1)AR remained in the denser plasma membrane-containing fractions. (v) Both subtypes recycled with similar kinetics back to the cell surface upon removal of agonist; however, recycling of beta(2)AR but not beta(1)AR was inhibited by monensin. Based on these results, we propose that the internalization of beta(1)AR is both arrestin- and dynamin-dependent and follows the same clathrin-mediated endocytic pathway as beta(2)AR. But during or after endocytosis, beta(1)AR and beta(2)AR are sorted into different endosomal compartments. C1 NINDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Fishman, PH (reprint author), NINDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM fishmanp@ninds.nih.gov NR 59 TC 22 Z9 22 U1 0 U2 2 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 15 PY 2004 VL 117 IS 5 BP 723 EP 734 DI 10.1242/jcs.00878 PG 12 WC Cell Biology SC Cell Biology GA 778NV UT WOS:000189248400008 PM 14734649 ER PT J AU Podgornik, R Parsegian, VA AF Podgornik, R Parsegian, VA TI van der Waals interactions across stratified media SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID SYSTEMS; FILMS AB Working at the Lifshitz level, we investigate the van der Waals interactions across a series of layers with a periodic motif. We derive the complete form of the van der Waals interaction as an explicit function of the number of periodic layers. We then compare our result with an approximation based on an anisotropic-continuum representation of the stratified medium. Satisfactory agreement between discrete-layer and continuum models is reached only for thicknesses of ten or more layers. (C) 2004 American Institute of Physics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, Ljubljana, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, Ljubljana, Slovenia. RP Podgornik, R (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM rudi@helix.nih.gov RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 15 TC 15 Z9 15 U1 1 U2 7 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 15 PY 2004 VL 120 IS 7 BP 3401 EP 3405 DI 10.1063/1.1640338 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 773CV UT WOS:000188880900042 PM 15268496 ER PT J AU Citron, ML Berry, DA Cirrincione, C Hudis, C Norton, L Winer, EP Gradishar, WJ Davidson, NE Martino, S Livingston, R Ingle, JN Carpenter, J Hurd, D Holland, JF Smith, B Sartor, CI Leung, EH Abrams, J Schilsky, RL Muss, HB AF Citron, ML Berry, DA Cirrincione, C Hudis, C Norton, L Winer, EP Gradishar, WJ Davidson, NE Martino, S Livingston, R Ingle, JN Carpenter, J Hurd, D Holland, JF Smith, B Sartor, CI Leung, EH Abrams, J Schilsky, RL Muss, HB TI Dose density by any other name - In Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST-CANCER; INTENSITY C1 ProHlth Care Associates LLP, Lake Success, NY 11020 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Canc & Leukemia Grp B Stat Off, Durham, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Northwestern Univ, Chicago, IL 60611 USA. Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. John Wayne Canc Inst, Santa Monica, CA USA. Univ Washington, Seattle, WA 98195 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Univ Alabama, Birmingham, AL USA. Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. Ohio State Univ, Columbus, OH 43210 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27514 USA. Canc & Leukemia Grp B Data Off, Durham, NC USA. NCI, Bethesda, MD 20892 USA. Canc & Leukemia Grp B Cent Off, Chicago, IL USA. Univ Vermont, Burlington, VT USA. RP Citron, ML (reprint author), ProHlth Care Associates LLP, Lake Success, NY 11020 USA. NR 6 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2004 VL 22 IS 4 BP 751 EP 753 DI 10.1200/JCO.2004.99.272 PG 3 WC Oncology SC Oncology GA 775AP UT WOS:000189018800032 ER PT J AU Sheikh, F Baurin, VV Antes, A Shah, NK Smirnov, SV Anantha, S Dickensheets, H Dumoutier, L Renauld, JC Zdanov, A Donnelly, RP Kotenko, SV AF Sheikh, F Baurin, VV Antes, A Shah, NK Smirnov, SV Anantha, S Dickensheets, H Dumoutier, L Renauld, JC Zdanov, A Donnelly, RP Kotenko, SV TI Cutting edge: IL-26 signals through a novel receptor complex composed of IEL-20 receptor 1 and IL-10 receptor 2 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID II CYTOKINE RECEPTOR; INDUCIBLE FACTOR; INTERLEUKIN-10; IDENTIFICATION; CLONING; FAMILY; HOMOLOG; CHAIN; CELLS C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. NCI, Prot Struct Sect, Macromol Crystallog Lab, Canc Res Ctr,NIH, Ft Detrick, MD 21702 USA. Univ Louvain, Ludwig Inst Canc Res, Brussels, Belgium. Univ Louvain, Expt Med Unit, Christian De Duvre Inst Cellular Pathol, Brussels, Belgium. RP Kotenko, SV (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, 185 S Orange Ave,Room E-641, Newark, NJ 07103 USA. EM kotenkse@umdnj.edu FU NIAID NIH HHS [R01 AI51139, R01 AI051139] NR 22 TC 93 Z9 106 U1 1 U2 7 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 15 PY 2004 VL 172 IS 4 BP 2006 EP 2010 PG 5 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600004 PM 14764663 ER PT J AU Sugaya, M Lore, K Koup, RA Douek, DC Blauvelt, A AF Sugaya, M Lore, K Koup, RA Douek, DC Blauvelt, A TI HIV-infected Langerhans cells preferentially transmit virus to proliferating autologous CD4(+) memory T cells located within Langerhans cell-T cell clusters SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; DENDRITIC CELLS; INTRAVAGINAL INOCULATION; PRODUCTIVE INFECTION; VIRAL REPLICATION; CCR5; TAT; LYMPHOCYTES; MACROPHAGES; MATURATION AB Langerhans cells (LC) are likely initial targets for HIV following sexual exposure to virus and provide an efficient means for HIV to gain access to lymph node T cells. The purpose of this study was to examine the nature of the CD4(+) T cell that becomes infected by HIV-infected LC. We infected human LC within tissue explants ex vivo and then, 3 days later, cocultured HIV-infected LC with different subsets of autologous CD4(+) T cells. Using multicolor flow cytometric analyses of LC-CD4(+) T cell cocultures, we documented that HIV-infected LC preferentially infected memory (as compared with naive) CD4(+) T cells. Proliferating and HIV-infected CD4(+) memory T cells were more frequently detected in conjugates of LC and autologous CD4(+) T cells, suggesting that T cells become activated and preferentially get infected through cluster formation with infected LC, rather than getting infected with free virus produced by single HIV-infected LC or T cells. p24(+) Memory CD4(+) T cells proliferated well in the absence of superantigen; by contrast, p24(+) T cells did not divide or divided only once in the presence of staphylococcal enterotoxin B, suggesting that virus production was rapid and induced apoptosis in these cells before significant proliferation could occur. These results highlight that close interactions between dendritic cells, in this case epidermal LC, and T cells are important for optimal HIV replication within specific subsets of CD4(+) T cells. Disrupting cluster formation between LC and memory CD4(+) T cells may be a novel strategy to interfere with sexual transmission of HIV. C1 NCI, Dermatol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Blauvelt, A (reprint author), NCI, Dermatol Branch, Canc Res Ctr, Bldg 10,Room 12N238,10 Ctr Dr,Mail Stop Code 1908, Bethesda, MD 20892 USA. EM blauvelt@mail.nih.gov NR 27 TC 47 Z9 48 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 15 PY 2004 VL 172 IS 4 BP 2219 EP 2224 PG 6 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600030 PM 14764689 ER PT J AU Jackson, SH Yu, CR Mahdi, RM Ebong, S Egwuagu, CE AF Jackson, SH Yu, CR Mahdi, RM Ebong, S Egwuagu, CE TI Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCED MACROPHAGE ACTIVATION; COLONY-STIMULATING FACTOR; BONE-MARROW CULTURES; NEGATIVE REGULATION; IMMUNE-RESPONSES; T-CELLS; IL-6; DIFFERENTIATION; GENERATION; PROTEINS AB In this study we show that activation of STAT pathways is developmentally regulated and plays a role in dendritic cell (DC) differentiation and maturation. The STAT6 signaling pathway is constitutively activated in immature DC (iDC) and declines as iDCs differentiate into mature DCs (mDCs). However, down-regulation of this pathway during DC differentiation is accompanied by dramatic induction of suppressors of cytokine signaling 1 (SOCS1), SOCS2, SOCS3, and cytokine-induced Sire homology 2-containing protein expression, suggesting that inhibition of STAT6 signaling may be required for DC maturation. In contrast, STAT1 signaling is most robust in mDCs and is not inhibited by the up-regulated SOCS proteins, indicating that STAT1 and STAT6 pathways are distinctly regulated in maturing DC. Furthermore, optimal activation of STAT1 during DC maturation requires both IL-4 and GM-CSF, suggesting that synergistic effects of both cytokines may in part provide the requisite STAT1 signaling intensity for DC maturation. Analyses of STAT1(-/-) DCs reveal a role for STAT1 in repressing CD86 expression in precursor DCs and up-regulating CD40, CD11c, and SOCS1 expression in mDCs. We further show that SOCS proteins are differentially induced by IL-4 and GM-CSF in DCs. SOCS1 is primarily induced by IL-4 through a STAT1-dependent mechanism, whereas SOCS3 is induced mainly by GM-CSF. Taken together, these results suggest that cytokine-induced maturation of DCs is under feedback regulation by SOCS proteins and that the switch from constitutive activation of the STAT6 pathway in iDCs to predominant use of STAT1 signals in mDC is mediated in part by STAT1-induced SOCS expression. C1 NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov NR 50 TC 85 Z9 93 U1 1 U2 7 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 15 PY 2004 VL 172 IS 4 BP 2307 EP 2315 PG 9 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600040 PM 14764699 ER PT J AU Matsuyama, W Wang, LH Farrar, WL Faure, M Yoshimura, T AF Matsuyama, W Wang, LH Farrar, WL Faure, M Yoshimura, T TI Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages: Role of p38 mitogen-activated protein kinase and NF-kappa B SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MONOCYTE-CHEMOATTRACTANT PROTEIN-1; TUMOR-NECROSIS-FACTOR; TYROSINE KINASE; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; MESSENGER-RNA; CELLS; TAK1; P38-ALPHA; PATHWAY AB Macrophages produce an array of proinflammatory mediators at sites of inflammation and contribute to the development of inflammatory responses. Important roles for cytokines, such as IL-1 or TNF-alpha, and bacterial products, such as LPS, in this process have been well documented; however, the role for the extracellular matrix proteins, such as collagen, remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed during differentiation of human monocytes into macrophages, and the interaction of the DDR1b isoform with collagen facilitates their differentiation via the p38 mitogen-activated protein kinase (MAPK) pathway. In this study, we report that the interaction of DDR1b with collagen up-regulates the production of IL-8, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1 in human macrophages in a p38 MAPK- and NF-kappaB-dependent manner. p38 MAPK was critical for DDR1b-mediated, increased NF-kappaB trans-activity, but not for IkappaB degradation or NF-kappaB nuclear translocation, suggesting a role for p38 MAPK in the modification of NF-kappaB, DDR1b-mediated IkappaB degradation was mediated through the recruitment of the adaptor protein Shc to the LXNPXY motif of the receptor and the downstream TNFR-associated factor 6/NF-kappaB activator 1 signaling cascade. Taken together, our study has identified NF-kappaB as a novel target of DDR1b signaling and provided a novel mechanism by which tissue-infiltrating macrophages produce large amounts of chemokines during the development of inflammatory diseases. Intervention of DDR1b signaling may be useful to control inflammatory diseases in which these proteins play an important role. C1 NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. SUGEN, San Francisco, CA 94080 USA. RP Yoshimura, T (reprint author), NCI, Mol Immunoregulat Lab, Bldg 559,Room 9, Frederick, MD 21702 USA. EM yoshimur@mail.ncifcrf.gov NR 46 TC 69 Z9 72 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2004 VL 172 IS 4 BP 2332 EP 2340 PG 9 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600043 PM 14764702 ER PT J AU Morimoto, M Morimoto, M Whitmire, J Xiao, SY Anthony, RM Mirakami, H Star, RA Urban, JF Gause, WC AF Morimoto, M Morimoto, M Whitmire, J Xiao, SY Anthony, RM Mirakami, H Star, RA Urban, JF Gause, WC TI Peripheral CD4 T cells rapidly accumulate at the host : parasite interface during an inflammatory Th2 memory response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GASTROINTESTINAL NEMATODE PARASITE; HELIGMOSOMOIDES-POLYGYRUS; PROTECTIVE IMMUNITY; SCHISTOSOMA-MANSONI; IN-VIVO; EFFECTOR FUNCTIONS; TYPE-2 RESPONSE; IL-4 PRODUCTION; MICE; INFECTION AB Memory peripheral Th2 immune responses to infectious pathogens are not well studied due to the lack of suitable models and the difficulty of assessing Th2 cytokine expression at sites of inflammation. We have examined the localized immune response to a nematode parasite that encysts in the small intestine. An unexpected architecture was observed on day 4 of the memory response, with granulocytes and macrophages infiltrating the cyst and CD4(+), TCR-alphabeta(+) T cells surrounding the cyst. Laser capture microdissection analysis showed a pronounced CD4-dependent Th2 cytokine pattern at the cyst region only during the memory response, demonstrating that the Th2 memory response is readily distinguished from the primary response by the rapid accumulation of Th2 effector cells at the host:parasite interface. The Journal of Immunology, 2004, 172: 2424-2430. C1 Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. USDA, Beltsville Human Nutr Res Ctr, Nutrient Requirements & Funct Lab, Beltsville, MD 20705 USA. NIH, Renal Diagnost & Therapeut Unit, Bethesda, MD 20892 USA. RP Gause, WC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wgause@usuhs.mil OI Urban, Joseph/0000-0002-1590-8869 FU NIAID NIH HHS [AI31678] NR 44 TC 50 Z9 50 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 15 PY 2004 VL 172 IS 4 BP 2424 EP 2430 PG 7 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600054 PM 14764713 ER PT J AU Mitre, E Taylor, RT Kubofcik, J Nutman, TB AF Mitre, E Taylor, RT Kubofcik, J Nutman, TB TI Parasite antigen-driven basophils are a major source of IL-4 in human filarial infections SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SCHISTOSOMA-MANSONI; ALLERGIC SENSITIZATION; ONCHOCERCA-VOLVULUS; HISTAMINE-RELEASE; IMMUNE-RESPONSES; PERIPHERAL-BLOOD; CALCIUM-BINDING; T-CELLS; IGE; INTERLEUKIN-4 AB Basophil contribution to the IL-4 pool in filarial infections was assessed using PBMC from 20 patients with active filarial infections and from 9 uninfected subjects. Patient basophils released histamine in response to Brugia malayi Ag (BmAg). They also released IL-4 within 2 h after exposure to BmAg, as assessed by intracellular cytokine flow cytometry. This IL-4 induction was Ag specific, as IL-4 was not detected in BmAg-exposed basophils obtained from uninfected subjects. Although there were, on average, 64 times more CD4(+) T cells than basophils in the peripheral circulation of filaria-infected patients, the absolute numbers of basophils and CD4(+) T cells producing IL-4 per 100,000 PBMC were equivalent (geometric mean: 16 IL-4-producing basophils/100,000 PBMC vs 22 IL-4-producing CD4(+) T cells/100,000 PBMC). Basophils also released IL-4 in response to both low and high concentrations of BmAg, whereas CD4(+) T cells released IL-4 only after incubation with a high concentration of BmAg, raising the possibility that basophils, due to their lower threshold for activation, may actually release IL-4 more frequently than CD4(+) T cells in vivo. Furthermore, IL-4 production in vitro by Ag-stimulated purified basophils or CD4(+) T cells provided evidence that basophils release greater quantities of IL-4 per cell than CD4(+) T cells in response to BmAg. These results suggest that, when Ag-specific IgE is present in a filaria-infected individual, basophils function to amplify the ongoing Th2 response by releasing IL-4 in greater amounts and possibly more frequently than CD4(+) T cells in response to filarial Ag. The Journal of Immunology, 2004, 172: 2439-2445. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Lane,Room 4-126, Bethesda, MD 20892 USA. EM emitre@niaid.nih.gov NR 29 TC 70 Z9 75 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 15 PY 2004 VL 172 IS 4 BP 2439 EP 2445 PG 7 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600056 PM 14764715 ER PT J AU Zhang, R Fichtenbaum, CJ Hildeman, DA Lifson, JD Chougnet, C AF Zhang, R Fichtenbaum, CJ Hildeman, DA Lifson, JD Chougnet, C TI CD40 ligand dysregulation in HIV infection: HIV glycoprotein 120 inhibits signaling cascades upstream of CD40 ligand transcription SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; NF-KAPPA-B; MESSENGER-RNA; INTERLEUKIN-12 PRODUCTION; ENVELOPE GLYCOPROTEIN; IL-12 PRODUCTION; DENDRITIC CELLS; CROSS-LINKING; PROTEASE INHIBITOR AB IL-12 production and up-regulation of CD40 ligand (CD40L) expression are impaired in the PBMC of HIV-infected donors, and exogenous CD40L rescues IL-12 production by such cells. In this study, we implicate dysregulation of CD40L expression in the IL-12 defect associated with HIV by demonstrating that induction of CD40L expression by anti-CD3/CD28 stimulation was directly correlated with the IL-12 productive capacity of PBMC. Further, we demonstrate marked decreases in the induction of CD40L protein and mRNA following anti-CD3/CD28 stimulation in HIV-infected donors compared with uninfected donors, with a tight association between these two levels. Inhibition of CD40L up-regulation was selective, as induction of CD69 or OX40 was. not as severely affected. Increased instability of CD40L mRNA did not constitute a major mechanism in CD40L dysregulation, thus suggesting a potential defect in the signaling cascades upstream of transcription. The mechanisms by which HIV infection affects the induction of CD40L expression appear to involve HIV gp120-mediated engagement of CD4. Indeed, anti-CD4 mAb or inactivated HIV virions that harbor a conformationally intact gp120 significantly inhibited CD40L up-regulation at both the protein and mRNA levels. This inhibition was due to the native, virion-associated gp120, as coculture with soluble CD4 or heat treatment of inactivated HIV abolished their effect. These in vitro models mirror the CD40L defect seen in cells from HIV-infected donors and thus provide a suitable model to investigate HIV-induced CD40L dysregulation. Clear elucidation of mechanism(s) may well lead to the development of novel immunotherapeutic approaches to HIV infection. C1 Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH 45229 USA. Childrens Hosp, Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. Univ Cincinnati, Med Ctr, Ctr Infect Dis, Cincinnati, OH 45267 USA. NCI, AIDS Vaccine Program, Sci Appl Int Corp Frederick, Frederick, MD 21702 USA. RP Chougnet, C (reprint author), Childrens Hosp, Med Ctr, Div Mol Immunol, 3333 Burnet Ave,Mail Locat Code 7021, Cincinnati, OH 45229 USA. EM Claire.Chougnet@cchmc.org RI Hildeman, David/I-4884-2015 OI Hildeman, David/0000-0002-0421-8483 FU NIAID NIH HHS [AI-25897]; NIAMS NIH HHS [1 P30 AR47363]; PHS HHS [N01-C0-124000] NR 67 TC 37 Z9 37 U1 0 U2 1 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 15 PY 2004 VL 172 IS 4 BP 2678 EP 2686 PG 9 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600084 PM 14764743 ER PT J AU La Montagne, JR Simonsen, L Taylor, RJ Turnbull, J AF La Montagne, JR Simonsen, L Taylor, RJ Turnbull, J CA SARS Res Working Grp Co-Chairs TI Severe acute respiratory syndrome: Developing a research response SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SARS-CORONAVIRUS; INFECTION; OUTBREAK; TORONTO AB When severe acute respiratory syndrome (SARS) first came to world attention in March 2003, it was immediately perceived to be a global threat with a pandemic potential. To help coordinate international research efforts, the National Institute of Allergy and Infectious Diseases convened a colloquium entitled SARS: Developing a Research Response on 30 May 2003. Breakout sessions intended to identify unmet research needs in 5 areas of SARS research-clinical research, epidemiology, diagnostics, therapeutics, and vaccines-are summarized here. Since this meeting, however, the identified research needs have been only partially met. Needs that have yet to be realized include reliable methods for early identification of individuals with SARS, a full description of SARS pathogenesis and immune response, and animal models that faithfully mimic SARS respiratory symptoms. It is also of the utmost importance that the global scientific community enhance mechanisms for international cooperation and planning for SARS research, as well as for other emerging infectious disease threats that are certain to arise in the future. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP La Montagne, JR (reprint author), NIAID, NIH, Bldg 31,Rm 7A03, Bethesda, MD 20892 USA. EM jlamontagn@niaid.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 NR 25 TC 7 Z9 7 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 15 PY 2004 VL 189 IS 4 BP 634 EP 641 DI 10.1086/382225 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 772GF UT WOS:000188832900010 PM 14767816 ER PT J AU Kirk, S Frank, JA Karlik, S AF Kirk, S Frank, JA Karlik, S TI Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon? SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Review DE angiogenesis; multiple sclerosis; experimental allergic encephalomyelitis; neuroinflammation; VEGF; CNS pathology ID ENDOTHELIAL GROWTH-FACTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; COLLAGEN-INDUCED ARTHRITIS; SPINAL-CORD-INJURY; PROLIFERATIVE RETINOPATHY; CHRONIC INFLAMMATION; NERVOUS-SYSTEM; WHITE-MATTER; IN-VITRO; INHIBITION AB Characteristic pathological features of multiple sclerosis (MS) include inflammation, demyelination and axonal and oligodendrocyte loss. In addition, lesions can also have a significant vascular component. In this review, morphological, biochemical and radiological evidence is presented suggesting angiogenesis as a potential focus for investigation in MS. We hypothesize that angiogenesis plays a significant role in the MS lesion, perpetuating disease progression. Thus, treatment strategies that inhibit angiogenesis may decrease clinical and pathological signs of disease. Several approaches for testing this hypothesis are outlined. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Western Ontario, Dept Pathol, London, ON, Canada. Ctr Clin, Lab Diagnost Radiol Res, Expt Neuroimaging Sect, NIH, Bethesda, MD USA. Univ Western Ontario, Dept Diagnost Radiol, London, ON, Canada. Univ Western Ontario, Dept Physiol, London, ON, Canada. RP Karlik, S (reprint author), London Hlth Sci Ctr, Univ Campus,339 Windermere Rd,Diagnost Imaging Ro, London, ON N6A 5A5, Canada. EM skarlik@uwo.ca NR 74 TC 36 Z9 39 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2004 VL 217 IS 2 BP 125 EP 130 DI 10.1016/j.jns.2003.10.016 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 765NP UT WOS:000188290100002 PM 14706213 ER PT J AU Navizet, I Lavery, R Jernigan, RL AF Navizet, I Lavery, R Jernigan, RL TI Myosin flexibility: Structural domains and collective vibrations SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE motor proteins; Gaussian network model; structural blocks; B-factors ID FLUCTUATION DYNAMICS; MOTOR DOMAIN; PROTEINS; MOTIONS; MODEL; S1 AB The movement of the myosin motor along an actin filament involves a directed conformational change within the cross-bridge formed between the protein and the filament. Despite the structural data that has been obtained on this system, little is known of the mechanics of this conformational. change. We have used existing crystallographic structures of three conformations of the myosin head, containing the motor domain and the lever arm, for structural comparisons and mechanical studies with a coarse-grained elastic network model. The results enable us to define structurally conserved domains within the protein and to better understand myosin flexibility. Notably they point to the role of the light chains in rigidifying the lever arm and to changes in flexibility as a consequence of nucleotide binding. (C) 2003 Wiley-Liss, Inc. C1 NCI, Mol Struct Sect, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. CNRS, UPR 9080, Lab Biochim Theor, Inst Biol Physico Chim, F-75005 Paris, France. RP Jernigan, RL (reprint author), NCI, Mol Struct Sect, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. EM jernigan@iastate.edu RI Lavery, Richard/G-1422-2011; Jernigan, Robert/A-5421-2012; Navizet, Isabelle/M-2113-2016 OI Lavery, Richard/0000-0001-9901-6640; Navizet, Isabelle/0000-0002-2158-6157 NR 23 TC 41 Z9 42 U1 0 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD FEB 15 PY 2004 VL 54 IS 3 BP 384 EP 393 DI 10.1002/prot.10476 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 770AA UT WOS:000188699400002 PM 14747987 ER PT J AU Kanaan, RAA McGuire, PK Barker, GJ Chitnis, X Jones, DK Shergill, SS AF Kanaan, RAA McGuire, PK Barker, GJ Chitnis, X Jones, DK Shergill, SS TI A diffusion tensor imaging study of schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 Inst Psychiat, Sect Neuroimaging, London, England. NICHD, Bethesda, MD USA. EM r.kanaan@iop.kcl.ac.uk RI Barker, Gareth/C-9616-2009 OI Barker, Gareth/0000-0002-5214-7421 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 3 EP 4 PG 2 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100004 ER PT J AU Cohen, JR Elvevag, B Goldberg, TE AF Cohen, JR Elvevag, B Goldberg, TE TI Semantic information processing in schizophrenia: An examination of the distance and congruency effect SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 NIMH, Clin Brain Disorders Branch, DHHS, Bethesda, MD 20892 USA. EM cohenj@intra.nimh.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 88 EP 88 PG 1 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100208 ER PT J AU Elvevag, B Foltz, PW Weinberger, DR Goldberg, TE AF Elvevag, B Foltz, PW Weinberger, DR Goldberg, TE TI A novel approach to measuring coherence and incoherence in speech SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. New Mexico State Univ, Dept Psychol, Las Cruces, NM 88003 USA. EM elvevaab@intra.nimh.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 88 EP 88 PG 1 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100209 ER PT J AU Lauronen, E Veijola, J Miettunen, J Jones, PB Fenton, WS Koskinen, J Alaraisanen, A Karhu, M Jarvelin, MR Isohanni, M AF Lauronen, E Veijola, J Miettunen, J Jones, PB Fenton, WS Koskinen, J Alaraisanen, A Karhu, M Jarvelin, MR Isohanni, M TI Outcome and its predictors in schizophrenia before 35 years of age within the Northern Finland 1966 Birth Cohort SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 Univ Oulu, Dept Psychiat, Oulu, Finland. Univ Cambridge, Dept Psychiat, Cambridge CB2 1TN, England. NIMH, Bethesda, MD 20892 USA. EM llaurone@paju.oulu.fi NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 198 EP 198 PG 1 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100474 ER PT J AU Keefe, RSE Goldberg, TE Harvey, PD Gold, JM Poe, M Coughenour, L AF Keefe, RSE Goldberg, TE Harvey, PD Gold, JM Poe, M Coughenour, L TI The brief assessment of cognition in schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 Duke Univ, Med Ctr, Durham, NC 27706 USA. NIMH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, New York, NY USA. EM richard.keefe@duke.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 263 EP 263 PG 1 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100633 ER PT J AU Trachsel, D Tschudi, P Portier, CJ Kuhn, M Thormann, W Scholtysik, G Mevissen, M AF Trachsel, D Tschudi, P Portier, CJ Kuhn, M Thormann, W Scholtysik, G Mevissen, M TI Pharmacokinetics and pharmacodynamic effects of amiodarone in plasma of ponies after single intravenous administration SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE pharmacokinetics; amiodarone; single intravenous administration ID REFRACTORY ATRIAL-FIBRILLATION; PIG VENTRICULAR MYOCYTES; ORAL AMIODARONE; SINUS RHYTHM; HEALTHY DOGS; HORSES; CONVERSION; QUINIDINE; EFFICACY; SERUM AB Atrial fibrillation is a well-known heart disease in horses. The common therapy consists of administration of quinidine. More potent antiarrhythmic drugs have become available for human therapy and the use of these as alternatives to quinidine for equine antiarrhythmic therapy is a matter of interest. Amiodarone (AMD) is used in human medicine for treatment of many arrhythmias, including atrial fibrillation. Its disposition in horses has not yet been investigated. The purpose of this study was to measure the effect of single intravenous doses of amiodarone (5 and 7 mg/kg) on the surface electrocardiogram (ECG) of healthy minishetland ponies during the first 2 days after drug administration and to calculate pharmacokinetic parameters with a physiologically based pharmacokinetic model (PBPK) using amiodarone and desethylamiodarone (DAMD) plasma levels that were determined by high-performance liquid chromatography (HPLC). As expected for a K+-channel-blocker, the main effect on the measured ECG could be seen on the ventricular complex, as the QT interval and the T wave showed statistically significant alterations. The doses investigated were well tolerated clinically. Results from the pharmacokinetic model were found to compare well with literature data of rats, dogs, and humans. It showed a rapid distribution in the tissue, beginning with the rapidly perfused tissue, like the heart, followed by slowly perfused tissues, and finally an accumulation in fat. The half-life for total elimination was calculated to be 16.3 days with 99% eliminated by 97 days. The model predicts that approximately 96% of amiodarone is eliminated as desethylamiodarone in mine, 2% eliminated as desethylamiodarone in bile, and 2% as other metabolites. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Bern, Dept Vet Pharmacol, CH-3012 Bern, Switzerland. Univ Bern, Dept Vet Clin Med, CH-3012 Bern, Switzerland. Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Univ Bern, Dept Clin Pharmacol, CH-3010 Bern, Switzerland. RP Mevissen, M (reprint author), Univ Bern, Dept Vet Pharmacol, Laenggassstr 124, CH-3012 Bern, Switzerland. EM meike.mevissen@vpi.unibe.ch RI Portier, Christopher/A-3160-2010; Trachsel, Dagmar/A-3097-2016 OI Portier, Christopher/0000-0002-0954-0279; Trachsel, Dagmar/0000-0001-5103-8402 NR 68 TC 11 Z9 11 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 15 PY 2004 VL 195 IS 1 BP 113 EP 125 DI 10.1016/j.taap.2003.11.009 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 780KG UT WOS:000189379400012 PM 14962511 ER PT J AU Walker, N Kim, AH AF Walker, N Kim, AH TI Response to letter to the editor SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Letter ID 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; RATS C1 Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Walker, N (reprint author), Natl Inst Environm Hlth Sci, Environm Toxicol Program, Room D454A,Rall Bldg 101,111 Alexander Dr,POB 122, Res Triangle Pk, NC 27709 USA. EM walker3@niehs.nih.gov NR 4 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 15 PY 2004 VL 195 IS 1 BP 127 EP 128 DI 10.1016/j.taap.2003.11.004 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 780KG UT WOS:000189379400014 ER PT J AU Abraham, EG Islam, S Srinivasan, P Ghosh, AK Valenzuela, JG Ribeiro, JMC Kafatos, FC Dimopoulos, G Jacobs-Lorena, M AF Abraham, EG Islam, S Srinivasan, P Ghosh, AK Valenzuela, JG Ribeiro, JMC Kafatos, FC Dimopoulos, G Jacobs-Lorena, M TI Analysis of the Plasmodium and Anopheles transcriptional repertoire during ookinete development and midgut invasion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MALARIA PARASITE; IN-VITRO; IMMUNE-RESPONSE; MOSQUITO; EXPRESSION; GAMBIAE; FALCIPARUM; BERGHEI; CELLS; INFECTION AB Plasmodium, the causative agent of malaria, has to undergo sexual differentiation and development in anopheline mosquitoes for transmission to occur. To isolate genes specifically induced in both organisms during the early stages of Plasmodium differentiation in the mosquito, two cDNA libraries were constructed, one enriched for sequences expressed in differentiating Plasmodium berghei ookinetes and another enriched for sequences expressed in Anopheles stephensi guts containing invading ookinetes and early oocysts. Sequencing of 457 ookinete library clones and 652 early oocyst clones represented 175 and 346 unique expressed sequence tags, respectively. Nine of 13 Plasmodium and four of the five Anopheles novel expressed sequence tags analyzed on Northern blots were induced during ookinete differentiation and mosquito gut invasion. Ancaspase-7, an Anopheles effector caspase, is proteolytically activated during Plasmodium invasion of the midgut. WARP, a gene encoding a Plasmodium surface protein with a von Willebrand factor A- like adhesive domain, is expressed only in ookinetes and early oocysts. An anti- WARP polyclonal antibody strongly inhibits ( 70 - 92%) Plasmodium development in the mosquito, making it a candidate antigen for transmission blocking vaccines. The present results and those of an accompanying report ( Srinivasan, P., Abraham, E. G., Ghosh, A. K., Valenzuela, J., Ribeiro, J. M. C., Dimopoulos G., Kafatos, F. C., Adams, J. H., and Jacobs- Lorena, M. ( 2004) J. Biol. Chem. 279, 5581 - 5587) provide the foundation for further analysis of Plasmodium differentiation in the mosquito and of mosquito responses to the parasite. C1 Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. European Mol Biol Lab, D-69117 Heidelberg, Germany. RP Jacobs-Lorena, M (reprint author), Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM mlorena@jhsph.edu OI Dimopoulos, George/0000-0001-6755-8111; Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [R01 AI031478] NR 36 TC 61 Z9 62 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 FEB 13 PY 2004 VL 279 IS 7 BP 5573 EP 5580 DI 10.1074/jbc.M307582200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500066 PM 14627712 ER PT J AU Srinivasan, P Abraham, EG Ghosh, AK Valenzuela, J Ribeiro, JMC Dimopoulos, G Kafatos, FC Adams, JH Fujioka, H Jacobs-Lorena, M AF Srinivasan, P Abraham, EG Ghosh, AK Valenzuela, J Ribeiro, JMC Dimopoulos, G Kafatos, FC Adams, JH Fujioka, H Jacobs-Lorena, M TI Analysis of the Plasmodium and Anopheles transcriptomes during oocyst differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ERYTHROCYTE-BINDING-PROTEIN; CIRCUMSPOROZOITE PROTEIN; MALARIA PARASITES; GENOME SEQUENCE; FALCIPARUM; MOSQUITO; GAMBIAE; SPOROZOITES; INFECTION; IDENTIFICATION AB Understanding the life cycle of the malaria parasite in its mosquito vector is essential for developing new strategies to combat this disease. Subtractive hybridization cDNA libraries were constructed that are enriched for Plasmodium berghei and Anopheles stephensi genes expressed during oocyst differentiation on the midgut. Sequencing of 1485 random clones led to the identification of 1137 unique expressed sequence tags. Of the 608 expressed sequence tags with data base hits, 320 ( 53%) had significant matches to the non- redundant protein data base, whereas 288 ( 47%) with matches only to genomic data bases represent novel Plasmodium and Anopheles genes. Transcription of six novel parasite genes and two previously identified asexual stage genes was up- regulated during oocyst differentiation. In addition, the mRNA for an Anopheles fibrinogen domain gene was induced on day 2 after an infectious blood meal, at the time of ookinete to oocyst differentiation. The subcellular distribution of MAEBL, a sporozoite surface protein, is developmentally regulated from presumed storage organelles in day 15 oocysts to uniform distribution on the surface in day 22 oocysts. This redistribution may reflect a sporozoite maturation program in preparation for salivary gland invasion. Furthermore, apical membrane antigen 1, another parasite surface molecule, is translationally regulated late in sporozoite development, suggesting a role during infection of the vertebrate host. The present results and those of an accompanying report ( Abraham, E. G., Islam, S., Srinivasan, P., Ghosh, A. K., Valenzuela, J., Ribeiro, J. M., Kafatos, F. C., Dimopoulos, G., & Jacobs- Lorena, M. ( 2003) J. Biol. Chem. 279, 5573 - 5580) provide the foundation for studies seeking to understand at the molecular level Plasmodium development and its interactions with the mosquito. C1 Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. European Mol Biol Lab, D-69117 Heidelberg, Germany. Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. RP Jacobs-Lorena, M (reprint author), Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM mlorena@jhsph.edu RI Adams, John/G-1800-2015; OI Adams, John/0000-0003-3707-7979; Dimopoulos, George/0000-0001-6755-8111; Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [R01 AI033656, R01 AI031478] NR 31 TC 50 Z9 52 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 FEB 13 PY 2004 VL 279 IS 7 BP 5581 EP 5587 DI 10.1074/jbc.M307587200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500067 PM 14627711 ER PT J AU Wei, SJ Trempus, CS Ali, RC Hansen, LA Tennant, RW AF Wei, SJ Trempus, CS Ali, RC Hansen, LA Tennant, RW TI 12-O-tetradecanoylphorbol-13-acetate and UV radiation-induced nucleoside diphosphate protein kinase B mediates neoplastic transformation of epidermal cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METASTASIS-SUPPRESSOR GENES; ENERGY PHOSPHATE TRANSFER; HETEROTRIMERIC G-PROTEINS; MYELOID-LEUKEMIA CELLS; TRANSGENIC TG.AC MICE; STEM-CELLS; NM23 GENE; PAPILLOMA DEVELOPMENT; SKIN CARCINOGENESIS; FUNCTIONAL-ANALYSIS AB The molecular changes associated with early skin carcinogenesis are largely unknown. We have previously identified 11 genes whose expression was up- or down-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin keratinocyte progenitor cells (Wei, S.-J., Trempus, C. S., Cannon, R. E., Bortner, C. D., and Tennant, R. W. (2003) J. Biol. Chem. 278, 1758-1768). Here, we show an induction of a nucleoside diphosphate protein kinase B (NDPK-B) gene in response to TPA or UV radiation (UVR). TPA or UVR significantly induced the expression of NDPK-B both in vivo hyperplastic mouse skin and in vitro mouse JB6 Cl 41-5a epidermal cells. Indeed, this gene was also up- regulated in TPA or UVR-mediated skin tumors including papillomas, spindle cell tumors, and squamous cell carcinomas, relative to adjacent normal skins. Functional studies by constitutive expression of nm23-M2/NDPK-B in TPA susceptible JB6 Cl 41-5a and TPA-resistant JB6 Cl 30-7b preneoplastic epidermal cell lines showed a remarkable gene dosage-dependent increase in foci-forming activity, as well as an enhancement in the efficiency of neoplastic transformation of these cells in soft agar but no effect on proliferation in monolayer cultures. Interestingly, stable transfection of the nm23-M2/NDPK-B delRGD or G106A mutant gene in JB6 Cl 41-5a cells selectively abrogated NDPK-B-induced cellular transformation, implicating a possible Arg(105)-Gly(106)-Asp(107) regulatory role in early skin carcinogenesis. C1 NIEHS, Natl Ctr Toxicogenom, NIH, Res Triangle Pk, NC 27709 USA. Creighton Univ, Sch Med, Dept Biomed Sci, Omaha, NE 68178 USA. RP Wei, SJ (reprint author), NIEHS, Natl Ctr Toxicogenom, NIH, Bldg 101,Rm F-149,MD F1-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM wei2@niehs.nih.gov FU NIEHS NIH HHS [K22 ES000365] NR 71 TC 10 Z9 12 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 FEB 13 PY 2004 VL 279 IS 7 BP 5993 EP 6004 DI 10.1074/jbc.M310820200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500115 PM 14623877 ER PT J AU Sharma, S Sathyanarayana, BK Bird, JG Hoskins, JR Lee, B Wickner, S AF Sharma, S Sathyanarayana, BK Bird, JG Hoskins, JR Lee, B Wickner, S TI Plasmid P1 RepA is homologous to the F plasmid RepE class of initiators SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEINS; ESCHERICHIA-COLI; REPLICATION INITIATOR; DNA-REPLICATION; CLPA CHAPERONE; COPY NUMBER; HOST-RANGE; ORIGIN; BINDING; MUTANTS AB DNA replication of plasmid P1 requires a plasmid-encoded origin DNA-binding protein, RepA. RepA is an inactive dimer and is converted by molecular chaperones into an active monomer that binds RepA binding sites. Although the sequence of RepA is not homologous to that of F plasmid RepE, we found by using fold-recognition programs that RepA shares structural homology with RepE and built a model based on the RepE crystal structure. We constructed mutants in the two predicted DNA binding domains to test the model. As expected, the mutants were defective in P1 DNA binding. The model predicted that RepA binds the first half of the binding site through interactions with the C-terminal DNA binding domain and the second half through interactions with the N-terminal domain. The experiments supported the prediction. The model was further supported by the observation that mutants defective in dimerization map to the predicted subunit interface region, based on the crystal structure of pPS10 RepA, a RepE family member. These results suggest P1 RepA is structurally homologous to plasmid initiators, including those of F, R6K, pSC101, pCU1, pPS10, pFA3, pGSH500, Rts1, RepHI1B, RepFIB, and RSF1010. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Rm 5144,37 Convent Dr,MSC37-4264, Bethesda, MD 20892 USA. EM suewick@helix.nih.gov NR 45 TC 26 Z9 27 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 FEB 13 PY 2004 VL 279 IS 7 BP 6027 EP 6034 DI 10.1074/jbc.M310917200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500118 PM 14634015 ER PT J AU Barac, A Basile, J Vazquez-Prado, J Gao, YA Zheng, Y Gutkind, JS AF Barac, A Basile, J Vazquez-Prado, J Gao, YA Zheng, Y Gutkind, JS TI Direct interaction of p21-activated kinase 4 with PDZ-RhoGEF, a G protein-linked Rho guanine exchange factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANCHORAGE-INDEPENDENT GROWTH; LEUKEMIA-ASSOCIATED RHOGEF; HETEROTRIMERIC G-PROTEINS; SERINE/THREONINE KINASE; ACTIN CYTOSKELETON; SIGNALING PATHWAY; COUPLED RECEPTORS; FAMILY GTPASES; CDC42 GTPASES; PAK4 AB Rho GTPases regulate a wide variety of cellular processes, ranging from actin cytoskeleton remodeling to cell cycle progression and gene expression. Cell surface receptors act through a complex regulatory molecular network that includes guanine exchange factors (GEFs), GTPase activating proteins, and guanine dissociation inhibitors to achieve the coordinated activation and deactivation of Rho proteins, thereby controlling cell motility and ultimately cell fate. Here we found that a member of the RGL-containing family of Rho guanine exchange factors, PDZ RhoGEF, which, together with LARG and p115RhoGEF, links the G(12/13) family of heterotrimeric G proteins to Rho activation, binds through its C-terminal region to the serine-threonine kinase p21-activated kinase 4 (PAK4), an effector for Cdc42. This interaction results in the phosphorylation of PDZ RhoGEF and abolishes its ability to mediate the accumulation of Rho-GTP by Galpha(13). Moreover, when overexpressed, active PAK4 was able to dramatically decrease Rho-GTP loading in vivo and the formation of actin stress fibers in response to serum or LPA stimulation. Together, these results provide evidence that PAK4 can negatively regulate the activation of Rho through a direct protein-protein interaction with G protein-linked Rho GEFs, thus providing a novel potential mechanism for cross-talk among Rho GTPases. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. IPN, Ctr Invest & Estudios Avanzados, Dept Pharmacol, Mexico City 07360, DF, Mexico. Childrens Hosp Res Fdn, Cincinnati, OH 45229 USA. RP Gutkind, JS (reprint author), NIDR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Zheng, Yi/J-7235-2015; VAZQUEZ-PRADO, JOSE/C-1630-2017; OI Zheng, Yi/0000-0001-7089-6074; Barac, Ana/0000-0002-9935-8904 NR 33 TC 41 Z9 43 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 FEB 13 PY 2004 VL 279 IS 7 BP 6182 EP 6189 DI 10.1074/jbc.M309579200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500134 PM 14625312 ER PT J AU Borde, V Lin, W Novikov, E Petrini, JH Lichten, M Nicolas, A AF Borde, V Lin, W Novikov, E Petrini, JH Lichten, M Nicolas, A TI Association of Mre11p with double-strand break sites during yeast meiosis SO MOLECULAR CELL LA English DT Article ID SYNAPTONEMAL COMPLEX-FORMATION; RECOMBINATION INITIATION SITES; MEIOTIC DNA-REPLICATION; SACCHAROMYCES-CEREVISIAE; CHROMATIN-STRUCTURE; REPAIR; CHECKPOINT; MUTATION; SYNAPSIS; INTERMEDIATE AB The repair of DNA double-strand breaks (DSBs) requires the activity of the Mre11/Rad50/Xrs2(Nbs1) complex. In Saccharomyces cerevisiae, this complex is required for both the initiation of meiotic recombination by Spo11p-catalyzed programmed DSBs and for break end resection, which is necessary for repair by homologous recombination. We report that Mre11p transiently associates with the chromatin of Spo11-dependent DSB regions throughout the genome. Mutant analyses show that Mre11p binding requires the function of all genes required for DSB formation, with the exception of RAD50. However, Mre11p binding does not require DSB formation itself, since Mre11p transiently associates with DSB regions in the catalysis-negative mutant spo11-Y135F. Mre11p release from chromatin is blocked in mutants that accumulate unresected DSBs. We propose that Mre11p is a component of a pre-DSB complex that assembles on the DSB sites, thus ensuring a tight coupling between DSB formation by Spo11p and the processing of break ends. C1 Inst Curie, Sect Rech, UMR144 CNRS, F-75248 Paris 05, France. Inst Curie, Serv Bioinformat, Med Sect, F-75248 Paris, France. Cornell Univ, Grad Sch Med Sci, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Nicolas, A (reprint author), Inst Curie, Sect Rech, UMR144 CNRS, 26 Rue Ulm, F-75248 Paris 05, France. EM alain.nicolas@curie.fr RI Borde, Valerie/G-5228-2012; Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 45 TC 92 Z9 95 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 13 PY 2004 VL 13 IS 3 BP 389 EP 401 DI 10.1016/S1097-2765(04)00034-6 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 774BC UT WOS:000188959000011 PM 14967146 ER PT J AU Hickman, AB Ronning, DR Perez, ZN Kotin, RM Dyda, F AF Hickman, AB Ronning, DR Perez, ZN Kotin, RM Dyda, F TI The nuclease domain of adeno-associated virus rep coordinates replication initiation using two distinct DNA recognition interfaces SO MOLECULAR CELL LA English DT Article ID SITE-SPECIFIC INTEGRATION; ATPASE ACTIVITIES; TERMINAL REPEATS; GENE-THERAPY; HUMAN GENOME; SEQUENCE REQUIREMENTS; CRYSTAL-STRUCTURES; HELICASE ACTIVITY; BINDING-SITES; ACTIVE GENES AB Integration into a particular location in human chromosomes is a unique property of the adeno-associated virus (AAV). This reaction requires the viral Rep protein and AAV origin sequences. To understand how Rep recognizes DNA, we have determined the structures of the Rep endonuclease domain separately complexed with two DNA substrates: the Rep binding site within the viral inverted terminal repeat and one of the terminal hairpin arms. At the Rep binding site, five Rep monomers bind five tetranucleotide direct repeats-each repeat is recognized by two Rep monomers frog opposing faces of the DNA. Stem-loop binding involves a protein interface on the opposite side of the molecule from the active site where ssDNA is cleaved. Rep therefore has three distinct binding sites within its endonuclease domain for its different DNA substrates. Use of these different interfaces generates the structural asymmetry necessary to regulate later events in viral replication and integration. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM dyda@ulti.niddk.nih.gov RI kotin, robert/B-8954-2008 NR 58 TC 58 Z9 58 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 13 PY 2004 VL 13 IS 3 BP 403 EP 414 DI 10.1016/S1097-2765(04)00023-1 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 774BC UT WOS:000188959000012 PM 14967147 ER PT J AU McNeil, JG Johnston, MI Birx, DL Tramont, EC AF McNeil, JG Johnston, MI Birx, DL Tramont, EC TI Policy rebuttal - HIV vaccine trial justified SO SCIENCE LA English DT Editorial Material ID RECOMBINANT CANARYPOX; RESPONSES; ADULTS; GP120 C1 NIAID, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. RP McNeil, JG (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jomcneil@mail.nih.gov NR 12 TC 25 Z9 27 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 13 PY 2004 VL 303 IS 5660 BP 961 EP 961 DI 10.1126/science.1096161 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773JJ UT WOS:000188918000027 PM 14963313 ER PT J AU Li, LG Jin, RC Kok, PL Wan, HH AF Li, LG Jin, RC Kok, PL Wan, HH TI Pseudo-periodic partitions of biological sequences SO BIOINFORMATICS LA English DT Article ID N-ACETYLGLUCOSAMINE ACYLTRANSFERASE; CRYSTAL-STRUCTURE; REPEATS; PATTERNS; PROTEIN; APOLIPOPROTEIN(A); COAGULATION; PLASMINOGEN; COMPLEXITY; EVOLUTION AB Motivation: Algorithm development for finding typical patterns in sequences, especially multiple pseudo-repeats (pseudo-periodic regions), is at the core of many problems arising in biological sequence and structure analysis. In fact, one of the most significant features of biological sequences is their high quasi-repetitiveness. Variation in the quasi-repetitiveness of genomic and proteomic texts demonstrates the presence and density of different biologically important information. It is very important to develop sensitive automatic computational methods for the identification of pseudo-periodic regions of sequences through which we can infer, describe and understand biological properties, and seek precise molecular details of biological structures, dynamics, interactions and evolution. Results: We develop a novel, powerful computational tool for partitioning a sequence to pseudo-periodic regions. The pseudo-periodic partition is defined as a partition, which intuitively has the minimal bias to some perfect-periodic partition of the sequence based on the evolutionary distance. We devise a quadratic time and space algorithm for detecting a pseudo-periodic partition for a given sequence, which actually corresponds to the shortest path in the main diagonal of the directed (acyclic) weighted graph constructed by the Smith-Waterman self-alignment of the sequence. We use several typical examples to demonstrate the utilization of our algorithm and software system in detecting functional or structural domains and regions of proteins. A big advantage of our software program is that there is a parameter, the granularity factor, associated with it and we can freely choose a biological sequence family as a training set to determine the best parameter. In general, we choose all repeats (including many pseudo-repeats) in the SWISS-PROT amino acid sequence database as a typical training set. We show that the granularity factor is 0.52 and the average agreement accuracy of pseudo-periodic partitions, detected by our software for all pseudo-repeats in the SWISS-PROT database, is as high as 97.6%. C1 Maryland Inst Dynam Gen, Lab Bioinformat, Silver Spring, MD 20906 USA. Second Army Med Univ, Nanjing Army Med Coll, Dept Protect Med, Nanjing 210099, Jiangsu, Peoples R China. Temple Univ, Dept Comp & Informat Sci, Philadelphia, PA 19139 USA. Huazhong Univ Sci & Technol, Sch Comp Sci & Technol, Wuhan 430074, Peoples R China. Natl Ctr Genome Resources, Global Bioinformat Lab, Santa Fe, NM 87505 USA. NIEHS, Natl Ctr Toxicogen, NIH, Res Triangle Pk, NC 27709 USA. RP Wan, HH (reprint author), Maryland Inst Dynam Gen, Lab Bioinformat, 3910 Jeffry St, Silver Spring, MD 20906 USA. EM hwan@mindgen.org RI Jin, Renchao/C-3377-2008 OI Jin, Renchao/0000-0002-1591-3510 FU NIGMS NIH HHS [R01-GM00028] NR 29 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 12 PY 2004 VL 20 IS 3 BP 295 EP 306 DI 10.1093/bioinformatics/btg404 PG 12 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 774PD UT WOS:000188990900001 PM 14960455 ER PT J AU Kowalski, J Drake, C Schwartz, RH Powell, J AF Kowalski, J Drake, C Schwartz, RH Powell, J TI Non-parametric, hypothesis-based analysis of microarrays for comparison of several phenotypes SO BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION; NFAT AB Motivation: We present a statistical framework for the analysis of high-dimensional microarray data, where the goal is to compare intensities among several groups based on as few as a single sample from each group. In this setting, it is of interest to compare gene expression among several phenotypes to define candidate genes that simultaneously characterize several criteria, simultaneously, among the comparison groups. We motivate the approach by a comparative microarray experiment in which clones of a cell were singly exposed to several distinct but related conditions. The experiment was conducted to elucidate genes involved in pathways leading to T cell clonal anergy. Results: By integrating inference principles within a bioinformatics setting, we introduce a two-stage approach to select candidate genes that characterize several criteria. The method is unified in its non-parametric approach to inference and description. For inference, we construct a testable hypothesis based on the criteria of interest in a high-dimensional space, while preserving the dependence among genes. Upon rejecting the null, we estimate the cardinality of a set of individual candidate genes (or gene pairs) that depict the events of interest. With this estimate, we then select individual genes (or gene pairs) based upon a two-dimensional ranking that examines relations within and between genes, among comparison groups, using singular value decomposition in combination with inner product concepts. C1 Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Immunol & Hematopoiesis, Baltimore, MD 21205 USA. NIH, Cellular & Mol Immunol Lab, Bethesda, MD 20892 USA. RP Kowalski, J (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Oncol & Biostat, 550 N Broadway,Suite 1103, Baltimore, MD 21205 USA. EM jkowals1@jhmi.edu FU NCI NIH HHS [5P30 CA06973-40]; NIAID NIH HHS [K22AI01773-02, K22AI51186-01] NR 15 TC 19 Z9 20 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 12 PY 2004 VL 20 IS 3 BP 364 EP 373 DI 10.1093/bioinformatics/btg418 PG 10 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 774PD UT WOS:000188990900009 PM 14960463 ER PT J AU Nguyen, TH Liu, CY Gershon, ES McMahon, FJ AF Nguyen, TH Liu, CY Gershon, ES McMahon, FJ TI Frequency Finder: a multi-source web application for collection of public allele frequencies of SNP markers SO BIOINFORMATICS LA English DT Article ID DATABASE; POLYMORPHISMS; POPULATIONS AB Publicly available single nucleotide polymorphism (SNP) allele frequencies are an important resource for the selection of genetic markers that may be most useful for gene mapping and association studies. Data mining these allele frequencies through disparate public databases and Websites is time consuming and can result in inconsistent findings. We have developed a web-based software tool, Frequency Finder, to acquire SNP allele frequencies from multiple public data sources and return a summarized result to the user. Our software optimizes and automates the search of candidate markers, decreasing the amount of time it would take to extract pertinent data manually. We have included several methods to output the data, including on-screen and as a compressed text file. We show that Frequency Finder accurately retrieves available frequency data from the available sources. Using this tool, we detect significant differences between Asian, African and Caucasian populations in the allele frequency spectra of 246 097 SNPs. While limited to public databases that provide web-based access to allele frequencies, Frequency Finder provides a single, user-friendly interface for retrieving allele frequencies for large batches of SNPs from multiple data sources. C1 Univ Chicago, Dept Psychiat, Chicago, IL 60616 USA. Cent S Univ, Natl Lab Med Genet China, Changsha 410078, Peoples R China. NIMH, Mood & Anxiety Disorder Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Nguyen, TH (reprint author), Knapp Res Ctr, 924E 57th St, Chicago, IL 60637 USA. EM tnguyen@yoda.bsd.uchicago.edu RI McMahon, Francis/A-7290-2009 FU NIMH NIH HHS [R01 MH065560, R01 MH61613] NR 10 TC 6 Z9 6 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 FEB 12 PY 2004 VL 20 IS 3 BP 439 EP 443 DI 10.1093/bioinformatics/btg446 PG 5 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 774PD UT WOS:000188990900024 PM 14960477 ER PT J AU Shi, ZD Lee, K Wei, CQ Roberts, LR Worthy, KM Fisher, RJ Burke, TR AF Shi, ZD Lee, K Wei, CQ Roberts, LR Worthy, KM Fisher, RJ Burke, TR TI Synthesis of a 5-methylindolyl-containing macrocycle that displays ultrapotent Grb2 SH2 domain-binding affinity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID OLEFIN METATHESIS; LIGANDS; DESIGN; RECOGNITION; INHIBITOR; PEPTIDES AB The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. Here, a ring-closing metathesis approach is utilized to synthesize a 5-methylindolyl-containing tetrapeptide mimetic (6) that exhibits unprecedented in vitro Grb2 SH2 domain-binding affinity (K-d = 93 pM). Key to the preparation of 6 is the enantioselective synthesis of (2S)-2-(3-(5-methylindolyl)methyl)pent-4-enylamine (12) as one of two ring-closing segments. C1 NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Ft Detrick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Burke, Terrence/N-2601-2014 NR 16 TC 32 Z9 32 U1 1 U2 1 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 FEB 12 PY 2004 VL 47 IS 4 BP 788 EP 791 DI 10.1021/jm030440b PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 772FR UT WOS:000188831300002 PM 14761181 ER PT J AU Liu, SQ Brown, CW Berlin, KD Dhar, A Guruswamy, S Brown, D Gardner, GJ Birrer, MJ Benbrook, DM AF Liu, SQ Brown, CW Berlin, KD Dhar, A Guruswamy, S Brown, D Gardner, GJ Birrer, MJ Benbrook, DM TI Synthesis of flexible sulfur-containing heteroarotinoids that induce apoptosis and reactive oxygen species with discrimination between malignant and benign cells SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACID RECEPTOR-GAMMA; TRANS-RETINOIC ACID; BIOLOGICAL-ACTIVITY; NUCLEAR RECEPTOR; STRUCTURAL BASIS; CARCINOMA-CELLS; CANCER; RAR; IDENTIFICATION; SELECTIVITY AB Regulation of growth, differentiation, and apoptosis by synthetic retinoids can occur through mechanisms that are dependent and independent of their ability to bind and activate nuclear retinoic acid receptors. The objective of this study was to determine if increasing flexibility of the heteroarotinoid structure would affect the specificity of the synthetic retinoids for the receptors and for their regulation of cancerous and nonmalignant cells. Methods were developed to produce the first examples of heteroarotinoids 15a-15h, which contain urea and/or thiourea linking groups between two aryl rings. Substituents at the para position of the single phenyl ring were either an ester, a nitro group, or a sulfonamide group. Ovarian cancer cell lines Caov-3, OVCAR-3, SK-OV-3, UCI-101, and 222 were utilized, and the inhibitory prowess of the heteroarotinoids was referenced to that of 4-HPR (25). Similar to 4-HPR (25), the heteroarotinoids inhibited growth of all cell lines at micromolar concentrations. Although the heteroarotinoids did not activate retinoic acid receptors, the agents induced potent growth inhibition against the cancer cells with weak activity against normal and benign cells. The growth inhibition was associated with cell loss and induction of reactive oxygen species. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. NCI, Cell & Canc Biol Dept, Ctr Canc Res, Rockville, MD 20850 USA. Oklahoma State Univ, Dept Chem, Stillwater, OK 74078 USA. RP Benbrook, DM (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, POB 26901, Oklahoma City, OK 73190 USA. EM Doris-Benbrook@uhsc.edu FU NCI NIH HHS [F3CA83168, 1F31 CA83168, CA-077711, CA-73639]; NIGMS NIH HHS [5 R25 GM55244-02] NR 42 TC 35 Z9 35 U1 0 U2 0 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 FEB 12 PY 2004 VL 47 IS 4 BP 999 EP 1007 DI 10.1021/jm030346v PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 772FR UT WOS:000188831300023 PM 14761202 ER PT J AU Thomas, JB Fix, SE Rothman, RB Mascarella, SW Dersch, CM Cantrell, BE Zimmerman, DM Carroll, FI AF Thomas, JB Fix, SE Rothman, RB Mascarella, SW Dersch, CM Cantrell, BE Zimmerman, DM Carroll, FI TI Importance of phenolic address groups in opioid kappa receptor selective antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID N-SUBSTITUENT; NORBINALTORPHIMINE; POTENT; MU; (+)-(3R,4R)-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE; IDENTIFICATION; PHARMACOPHORE; AGENTS AB In vitro characterization and comparison of JDTic, its dehydroxy analogue and nor-BNI, and its dehydroxy analogue demonstrates that the N-substituted 3,4-dimethyl-(3-hydroxyphenyl)-piperidine-derived antagonist, JDTic, relies more heavily on its phenol address group for affinity and antagonist activity relative to the corresponding naltrexone derived antagonists, nor-BNI. The structural flexibility of the former class of compound relative to the latter is postulated to underlie the difference. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH, Baltimore, MD 21224 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. EM fic@rti.org OI Mascarella, Wayne/0000-0003-0092-8178 FU NIDA NIH HHS [DA09045] NR 12 TC 19 Z9 20 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 12 PY 2004 VL 47 IS 4 BP 1070 EP 1073 DI 10.1021/jm030467v PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 772FR UT WOS:000188831300030 PM 14761209 ER PT J AU Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Omland, T Wolf, PA Vasan, RS AF Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Omland, T Wolf, PA Vasan, RS TI Plasma natriuretic peptide levels and the risk of cardiovascular events and death SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGESTIVE-HEART-FAILURE; VENTRICULAR SYSTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; ATRIAL-FIBRILLATION; DIASTOLIC DYSFUNCTION; PROGNOSTIC VALUE; MORTALITY; DISEASE; STROKE; HYPERTROPHY AB Background: The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established. Methods: We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. Results: During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro-atrial natriuretic peptide. Conclusions: In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Med Ctr, Cardiol Sect, Boston, MA USA. Boston Med Ctr, Dept Neurol, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Akershus Hosp, Dept Med, Oslo, Norway. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,2, Framingham, MA 01702 USA. EM vasan@fram.nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23-HL074077-01, K24-HL-04334, N01-HC-25195] NR 45 TC 800 Z9 839 U1 1 U2 17 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 12 PY 2004 VL 350 IS 7 BP 655 EP 663 DI 10.1056/NEJMoa031994 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500006 PM 14960742 ER PT J AU Levine, RJ Maynard, SE Qian, C Lim, KH England, LJ Yu, KF Schisterman, EF Thadhani, R Sachs, BP Epstein, FH Sibai, BM Sukhatme, VP Karumanchi, SA AF Levine, RJ Maynard, SE Qian, C Lim, KH England, LJ Yu, KF Schisterman, EF Thadhani, R Sachs, BP Epstein, FH Sibai, BM Sukhatme, VP Karumanchi, SA TI Circulating angiogenic factors and the risk of preeclampsia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED-TRIAL; FACTOR RECEPTOR; SERUM LEVELS; 2ND-TRIMESTER; BEVACIZUMAB; EXPRESSION; CALCIUM; CANCER AB Background: The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. Methods: We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. Results: During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Conclusions: Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Allied Technol Grp, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Obstet, Boston, MA 02114 USA. Univ Cincinnati, Coll Med, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. RP Levine, RJ (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. EM levinerj@mail.nih.gov; sananth@bidmc.harvard.edu OI Schisterman, Enrique/0000-0003-3757-641X NR 25 TC 1597 Z9 1679 U1 6 U2 49 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 12 PY 2004 VL 350 IS 7 BP 672 EP 683 DI 10.1056/NEJMoa031884 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500008 PM 14764923 ER PT J AU Miller, FG AF Miller, FG TI End-of-life care for patients with dementia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20815 USA. RP Miller, FG (reprint author), NIH, Bethesda, MD 20815 USA. EM fmiller@nih.gov NR 5 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 12 PY 2004 VL 350 IS 7 BP 733 EP 733 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500028 PM 14960754 ER PT J AU Zhou, XL Thorgeirsson, SS Popescu, NC AF Zhou, XL Thorgeirsson, SS Popescu, NC TI Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells SO ONCOGENE LA English DT Article DE DLC-1 function; cell growth inhibition; cell migration inhibition; apoptosis reduction of tumorigenicity ID CHROMOSOME 8P DELETION; RHO GTPASES; IN-VIVO; METASTASIS; PROTEINS; LINES; DISEASE; DOMAIN; START; DEATH AB The gene deleted in liver cancer-1 (DLC-1) is located on human chromosome 8p21-22, a region thought to harbor tumor suppressor genes on the basis of its frequent deletion or loss of heterozygosity in a variety of human cancers, including hepatocellular carcinoma (HCC). Deletion or altered expression of DLC-1 is common in HCC. In the current study, the subcellular localization of Dlc-1 protein was determined by immunostaining with antibody to DLC-1 and the possible tumor growth suppressor activity of DLC-1 was investigated by examining the effects of of DLC-1 cDNA transfection in two human HCC cell lines lacking expression of the endogenous gene. The results show that Dlc-1protein is localized in the cell cytoplasm, and the restoration of DLC-1 expression in HCC cells resulted in caspase-3-mediated apoptosis, inhibition of cell growth and invasiveness in vitro as well as in reduction of the ability of the cells to form tumors in athymic nude mice. These observations thus support the notion that Dlc-1 protein is involved in hepatocarcinogenesis and has oncosuppressive activity in HCC. C1 NCI, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Ctr Canc Res, Expt Carcinogenesis Lab, Bldg 37,Room 4128,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM popescun@mail.nih.gov NR 27 TC 106 Z9 119 U1 1 U2 1 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 12 PY 2004 VL 23 IS 6 BP 1308 EP 1313 DI 10.1038/sj.onc.1207246 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 773HH UT WOS:000188892200016 PM 14647417 ER PT J AU Wendler, D Emanuel, E AF Wendler, D Emanuel, E TI Assessing the ethical and practical wisdom of surrogate consent for living organ donation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PERSISTENT VEGETATIVE STATE; SUBSTITUTED JUDGMENTS; ADVANCE DIRECTIVES; ATTITUDES; DONORS; CARE; PREFERENCES; ACCURACY; DEATH C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 32 TC 3 Z9 3 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 11 PY 2004 VL 291 IS 6 BP 732 EP 735 DI 10.1001/jama.291.6.732 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 772AY UT WOS:000188819200028 PM 14871918 ER PT J AU Tsutsui, S Schnermann, J Noorbakhsh, F Henry, S Yong, VW Winston, BW Warren, K Power, C AF Tsutsui, S Schnermann, J Noorbakhsh, F Henry, S Yong, VW Winston, BW Warren, K Power, C TI A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE EAE; cytokines; MMPs; demyelination; adenosine amine congener; caffeine ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MONOCLONAL-ANTIBODIES O1; CENTRAL-NERVOUS-SYSTEM; MATRIX METALLOPROTEINASES; CYTOKINE EXPRESSION; GENE-EXPRESSION; HUMAN MONOCYTES; MESSENGER-RNAS; A(1) RECEPTOR; MICE LACKING AB The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR(-/-)) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR(+/+)) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR(-/-) animals. In addition, spinal cords from A1AR(-/-) mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR(+/+) animals. Macrophages from A1AR(-/-) animals exhibited increased expression of the proinflammatory genes, interleukin-1beta, and matrix metalloproteinase-12 on immune activation when matched with A1AR(+/+) control cells. A1AR(-/-) macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR(+/+) mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis ( MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases. C1 Univ Calgary, Dept Clin Neurosci, Neurosci Res Grp, Calgary, AB T2N 4N1, Canada. Univ Calgary, Dept Crit Care Med, Calgary, AB T2N 4N1, Canada. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Med, Edmonton, AB T6G 2B7, Canada. RP Power, C (reprint author), Univ Calgary, Dept Clin Neurosci, Neurosci Res Grp, Heritage Med Res Bldg,Room 150,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM power@ucalgary.ca RI Power, Christopher/C-7181-2013; OI Power, Christopher/0000-0002-5131-9711 NR 53 TC 153 Z9 159 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 11 PY 2004 VL 24 IS 6 BP 1521 EP 1529 DI 10.1523/JNEUROSCI.4271-03.2004 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 773JF UT WOS:000188896100030 PM 14960625 ER PT J AU Puri, N Majumdar, A Cuenoud, B Miller, PS Seidman, MM AF Puri, N Majumdar, A Cuenoud, B Miller, PS Seidman, MM TI Importance of clustered 2 '-O-(2-aminoethyl) residues for the gene targeting activity of triple helix-forming oligonucleotides SO BIOCHEMISTRY LA English DT Article ID DOUBLE-STRANDED DNA; 2'-AMINOETHOXY-MODIFIED OLIGONUCLEOTIDES; GLUCOCORTICOID-RECEPTOR; DUAL RECOGNITION; MAMMALIAN-CELLS; 3RD STRAND; DUPLEX DNA; CHROMATIN; STABILITY; DYNAMICS AB We are developing triple helix-forming oligonucleotides (TFOs) as gene targeting reagents in living mammalian cells. We have described psoralen-linked TFOs with 2'-O-methyl and 2'-O-(2-aminoethyl) (2'-AE) substitutions that are active in a gene knockout assay in cultured cells. The assay is based on mutagenesis by psoralen, a photoactive DNA cross-linker. Previous work showed that TFOs with three or four 2'-AE residues were disproportionately more active than those with one or two substitutions. Here we demonstrate that for optimal bioactivity the 2'-AE residues must be clustered rather than dispersed. We have further characterized bioactive and inactive TFOs in an effort to identify biochemical and biophysical correlates of biological activity. While thermal stability is a standard monitor of TFO biophysical activity, we find that T-m values do not distinguish bioactive and inactive TFOs. In contrast, measurements of TFO association rates appear to correlate well with bioactivity, in that triplex formation occurs disproportionately faster with the TFOs containing three or four 2'-AE residues. We asked if extending the incubation time prior to photoactivation would enhance the bioactivity of a TFO with a slow on rate relative to the TFO with a faster association rate. However, there was no change in bioactivity differential. These results are compatible with a model in which TFO binding in vivo is followed by relatively rapid elution by cellular functions, similar to that described for transcription factors. Under these circumstances, TFOs with faster on rates would be favored because they would be more likely to be in triplexes at the time of photoactivation. C1 NIA, LMG, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. Novartis Pharmaceut Ltd, CH-4002 Basel, Switzerland. RP Seidman, MM (reprint author), NIA, LMG, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov NR 55 TC 37 Z9 37 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 10 PY 2004 VL 43 IS 5 BP 1343 EP 1351 DI 10.1021/bi035808l PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 772HA UT WOS:000188835300023 PM 14756571 ER PT J AU George, SE Wolf, DC Brooks, LR Bailey, KC Hooth, MJ Nelson, GM AF George, SE Wolf, DC Brooks, LR Bailey, KC Hooth, MJ Nelson, GM TI Changes in cecal microbial metabolism of rats induced by individual and a mixture of drinking water disinfection by-products SO CANCER LETTERS LA English DT Article DE water; disinfection; mixture; colon; bacterial metabolism ID EVANS EKER RATS; INTESTINAL MICROFLORA; FISCHER-344 RATS; 2,6-DINITROTOLUENE GENOTOXICITY; MUTAGENIC ACTIVITY; AZO DYES; GUT; LACTOBACILLUS; POTENTIATION; PRETREATMENT AB Disinfection of drinking water has been one of the greatest public health successes. Numerous halogenated disinfection by-products (DBPs) occur and chronic ingestion has been associated with an increased risk for colorectal cancer in human populations. Because the intestinal microbiota can bioactivate xenobiotics, studies have been performed to examine the effects of individual DBPs on intestinal microbial metabolism. No studies have been conducted on a defined mixture of DBPs to determine if there is an enhancement of response to a mixture. Ten-week-old male Long-Evans rats were treated in their drinking water for 17 weeks with 0.4 g/l potassium bromate, 1.8 g/l chloroform, 0.7 g/l bromodichloromethane (BDCM), 0.07 g/l 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or a mixture of the four chemicals or distilled water. Cecal nitroreductase (NR), azoreductase (AR), dechlorinase (DC), beta-glucuronidase (GLR), beta-galactosidase (GAL), and beta-glucosidase (GLU) were assayed. No change in GLU or GLR activity was detected after treatment. BDCM treatment reduced DC and GAL activities and elevated NR and AR activity. GAL, AR, and NR activities were significantly different after treatment with bromate, chloroform, BDCM, and MX, but not the mixture. DC activity after chloroform-, MX-, or BDCM-treatment was significantly below control levels. The present study shows that changes in intestinal microbial metabolism do occur after treatment with individual and a mixture of DBPs but the changes were not additive in the mixture group. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 US EPA, Natl Hlth & Environm Effects Res Lab, Div Environm Carcinogenesis, Off Res & Dev, Res Triangle Pk, NC 27711 USA. N Carolina Cent Univ, Dept Biol, Durham, NC USA. Dept Energy, Washington, DC USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Wolf, DC (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Div Environm Carcinogenesis, Off Res & Dev, MD-B143-06, Res Triangle Pk, NC 27711 USA. EM wolf.doug@epa.gov NR 23 TC 7 Z9 8 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD FEB 10 PY 2004 VL 204 IS 1 BP 15 EP 21 DI 10.1016/j.canlet.2003.09.019 PG 7 WC Oncology SC Oncology GA 774JG UT WOS:000188975900003 PM 14744530 ER PT J AU Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Wilson, PWF Vasan, RS AF Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Wilson, PWF Vasan, RS TI Impact of obesity on plasma natriuretic peptide levels SO CIRCULATION LA English DT Article DE natriuretic peptides; obesity; epidemiology ID BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; RECEPTOR EXPRESSION; ADIPOSE-TISSUE; HEART; BRAIN; DISEASE; GENE AB Background-The mechanisms linking obesity to hypertension have not been established, but sodium retention and excessive sympathetic tone are key contributors. The natriuretic peptides are important regulators of sodium homeostasis and neurohormonal activation, raising the possibility that obese individuals have an impaired natriuretic peptide response. Methods and Results-We examined the relations of plasma B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide (N-ANP) to body mass index in 3389 Framingham Study participants (1803 women) without heart failure. Multivariable regression analyses were performed, adjusting for clinical and echocardiographic covariates. BNP levels below the assay detection limit and N-ANP levels in the lowest sex-specific quartile were categorized as low. Multivariable-adjusted mean plasma BNP levels in lean (<25 kg/m(2)), overweight (25 to 29.9 kg/m(2)), and obese (&GE;30 kg/m(2)) men were 21.4, 15.5, and 12.7 pg/mL, respectively (trend P<0.0001). Corresponding values in women were 21.1, 16.3, and 13.1 pg/mL (trend P<0.001). A similar pattern was noted for plasma N-ANP. Obese individuals had higher odds of having low plasma BNP (multivariable-adjusted odds ratios: men, 2.51; 95% CI, 1.71 to 3.68; women, 1.84; 95% CI, 1.32 to 2.58) and low plasma N-ANP (odds ratios: men, 4.81; 95% CI, 2.98 to 7.76; women, 2.85; 95% CI, 2.01 to 4.04) compared with lean individuals. Diabetes also was associated with low plasma natriuretic peptide levels, and the negative effects of obesity and diabetes on natriuretic peptide levels were additive. Conclusions-Obese individuals have low circulating natriuretic peptide levels, which may contribute to their susceptibility to hypertension and hypertension-related disorders. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston Med Ctr, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston Med Ctr, Sect Prevent Med, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,2, Framingham, MA 01702 USA. EM vasan@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23 HL074077-01, K24-HL-04334, N01-HC-25195] NR 32 TC 465 Z9 491 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 10 PY 2004 VL 109 IS 5 BP 594 EP 600 DI 10.1161/01.CIR.0000112582.16683.EA PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772HM UT WOS:000188836600009 PM 14769680 ER PT J AU Volpato, S Pahor, M Ferrucci, L Simonsick, EM Guralnik, JM Kritchevsky, SB Fellin, R Harris, TB AF Volpato, S Pahor, M Ferrucci, L Simonsick, EM Guralnik, JM Kritchevsky, SB Fellin, R Harris, TB TI Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitior-1 in well-functioning older adults - The Health, Aging, and Body Composition study SO CIRCULATION LA English DT Article DE alcohol; inflammation; aging; epidemiology; interleukins ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; NECROSIS-FACTOR-ALPHA; CARDIOVASCULAR RISK; FIBRINOGEN LEVELS; CONSUMPTION; INTERLEUKIN-6; MECHANISMS; OBESITY; INHIBITOR-1 AB Background-Increased levels of acute-phase reactants predict the onset of poor health outcomes. A U-shaped association has been reported between alcohol intake and health outcomes, which suggests that alcohol intake may modify levels of acute-phase reactants. We investigated the relationship between weekly alcohol intake and interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1). Methods and Results-Data are from year 1 of the Health, Aging, and Body Composition study, a biracial cohort of 3075 well-functioning men and women aged 70 to 79 years, living in Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2574 persons (51.2% women; 40.1% black) with complete data. After adjustment for age, race, smoking status, history of diabetes, history of cardiovascular disease, physical activity, high-density lipoprotein cholesterol, antiinflammatory medications, statins, and total fat mass, alcohol intake showed a J-shaped relationship with mean IL-6 (P for quadratic term <0.001) and CRP (P=0.014) levels. The association was consistent in both men and women. Compared with subjects who consumed 1 to 7 drinks per week, those who never drank had an increased likelihood of having high levels of both IL-6 and CRP, as did those who drank 8 or more drinks per week. We found no relationship between alcohol intake and levels of TNF-α and PAI-1 (P=0.137 and 0.08, respectively). Conclusions-In well-functioning older persons, light alcohol consumption is associated with lower levels of IL-6 and CRP. These results might suggest an additional biological explanation to the epidemiological link between moderate alcohol consumption and cardiovascular events. C1 Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. NIA, Lab Epidemiol, Bethesda, MD 20892 USA. Wake Forest Univ Hlth Sci, Dept Internal Med, Sticht Ctr Aging, Winston Salem, NC USA. INRCA, I Fraticini, Dept Geriatr, Florence, Italy. NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Volpato, S (reprint author), Univ Ferrara, Dept Clin & Expt Med, Via Savonarola 9, I-44100 Ferrara, Italy. EM vlt@unife.it RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU NIA NIH HHS [N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106, P60 AG 10484-07] NR 25 TC 107 Z9 110 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 FEB 10 PY 2004 VL 109 IS 5 BP 607 EP 612 DI 10.1161/01.CIR.0000109503.13955.00 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772HM UT WOS:000188836600011 PM 14769682 ER PT J AU Benjamin, EJ Larson, MG Keyes, MJ Mitchell, GF Vasan, RS Keaney, JF Lehman, BT Fan, SX Osypiuk, E Vita, JA AF Benjamin, EJ Larson, MG Keyes, MJ Mitchell, GF Vasan, RS Keaney, JF Lehman, BT Fan, SX Osypiuk, E Vita, JA TI Clinical correlates and heritability of flow-mediated dilation in the community - The Framingham Heart Study SO CIRCULATION LA English DT Article DE endothelium; epidemiology; risk factors; genetics ID ENDOTHELIUM-DEPENDENT VASODILATION; LIPOPROTEIN CHOLESTEROL LEVELS; BRACHIAL-ARTERY REACTIVITY; CARDIOVASCULAR RISK; NITRIC-OXIDE; VITAMIN-C; DYSFUNCTION; DISEASE; WOMEN; DILATATION AB Background-Studies in selected samples have linked impaired endothelial function with cardiovascular disease and its risk factors. The clinical correlates and heritability of endothelial function in the community have not been described. Methods and Results-We examined a measure of endothelial function, brachial artery flow-mediated dilation (FMD), expressed as both percent (FMD%) and actual dilation by ultrasound with the occlusion cuff below the elbow in 2883 Framingham Study participants (52.9% women; mean age, 61 years). A subset of 1096 participants performed a 6-minute walk test before FMD determination. Mean FMD% was 3.3+/-3.0% in women and 2.4+/-2.4% in men. In stepwise multivariable linear regression models, FMD% was inversely related to age, systolic blood pressure, body mass index (BMI), lipid-lowering medication, and smoking, whereas it was positively related to female gender, heart rate, and prior walk test. The estimated heritability of FMD% was 0.14. FMD actual dilation findings were similar, except that female sex and BMI were not significantly associated. Conclusions-Increasing age, systolic blood pressure, BMI, and smoking were associated with lower FMD% in our community-based sample, whereas prior exercise and increasing heart rate were associated with higher FMD%. The estimated heritability of FMD was modest. Future research will permit more complete characterization of the genetic and environmental determinants of endothelial function and its prognostic value in the community. C1 Boston Univ, Sch Med, Evans Dept Med, Framingham Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Framingham, MA 01702 USA. Boston Univ, Sch Med, Prevent Med Sect, Framingham, MA 01702 USA. Cardiovasc Engn Inc, Holliston, MA USA. NHLBI, Framingham Study, Framingham, MA USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Evans Dept Med, Framingham Study, 73 Mt Wayte Ave 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24-HL-04334, HL60040, HL70100, N01-HC-38038] NR 38 TC 326 Z9 333 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 10 PY 2004 VL 109 IS 5 BP 613 EP 619 DI 10.1161/01.CIR.0000112565.60887.1E PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772HM UT WOS:000188836600012 PM 14769683 ER PT J AU Mahabir, S Leitzmann, MF Pietinen, P Albanes, D Virtamo, J Taylor, PR AF Mahabir, S Leitzmann, MF Pietinen, P Albanes, D Virtamo, J Taylor, PR TI Physical activity and renal cell cancer risk in a cohort of male smokers SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE physical activity; RCC; smokers ID SPONTANEOUS TUMORIGENESIS; CALORIE RESTRICTION; P53-DEFICIENT MICE; DIABETES-MELLITUS; INSULIN-LIKE; CARCINOMA; WEIGHT; REGISTRY; OBESITY; ADULTS AB Few studies have examined exercise in relation to risk of renal cell cancer. We examined the association between leisure-time and occupational physical activity and renal cell cancer in a cohort of 29,133 male smokers 50-69 years of age in the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study. Physical activity was assessed at baseline using a self-administered questionnaire that inquired about usual level of physical activity during leisure-time and at work during the past year. Cox proportional hazards modeling was used to adjust simultaneously for known or suspected risk factors for renal cell cancer. During 12 years (354,407 person-years) of follow-up, 2 10 incident cases of renal cell cancer were identified. In age-adjusted analysis, the RRs of renal cell cancer in increasing categories of leisure-time physical activity (light, moderate and heavy) were 1.0, 0.89 (95% CI = 0.67-1.17) and 0.38 (95% CI = 0.15-0.94), respectively (p-value for trend = 0.06). After adjustment for body mass index, energy intake, smoking, hypertension, education and fruit and vegetable intake, the multivariate RRs of renal cell cancer in increasing categories of leisure-time physical activity (light, moderate and heavy), were 1.0, 0.89 (95% Cl = 0.66-1.19), and 0.46 (95% CI = 0.18-1.13) (p-value for trend = 0.12). Occupational physical activity was unrelated to renal cell cancer risk. These data suggest that recreational physical activity may play a role in the prevention of renal cell cancer in men. (C) 2003 Wiley-Liss, Inc. C1 NCI, Ctr Canc Res, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. RP Mahabir, S (reprint author), NCI, Ctr Canc Res, Canc Prevent Studies Branch, 6116 Execut Blvd,Suite 705,MSC 8314, Bethesda, MD 20892 USA. RI Mahabir, Somdat/A-9788-2008; Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01 CN45165, N01 CN45035] NR 36 TC 32 Z9 33 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 10 PY 2004 VL 108 IS 4 BP 600 EP 605 DI 10.1002/ijc.11580 PG 6 WC Oncology SC Oncology GA 759JM UT WOS:000187734600018 PM 14696127 ER PT J AU Warach, S Kidwell, CS AF Warach, S Kidwell, CS TI The redefinition of TIA - The uses and limitations of DWI in acute ischemic cerebrovascular syndromes SO NEUROLOGY LA English DT Editorial Material ID DIFFUSION-WEIGHTED MR; ACUTE HUMAN STROKE; ATTACKS; DIAGNOSIS; EMERGENCY; CT C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20824 USA. Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Med Ctr, Dept Neurol, Los Angeles, CA 90024 USA. RP Warach, S (reprint author), NINDS, Stroke Branch, NIH, Bethesda, MD 20824 USA. EM warachs@ninds.nih.gov NR 15 TC 25 Z9 30 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 10 PY 2004 VL 62 IS 3 BP 359 EP 360 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 778JQ UT WOS:000189238800004 PM 14872012 ER PT J AU Oh, U Gupta, R Krakauer, JW Khandji, AG Chin, SS Elkind, MSV AF Oh, U Gupta, R Krakauer, JW Khandji, AG Chin, SS Elkind, MSV TI Reversible leukoencephalopathy associated with cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID SUBACUTE DEMENTIA; MASS AB The authors describe three patients with reversible leukoencephalopathy associated with cerebral amyloid angiopathy (CAA). Rapid progression of neurologic symptoms was followed by dramatic clinical and radiographic improvement. Pathologically, CAA was associated with varying degrees of inflammation ranging from none to transmural granulomatous infiltration. In the appropriate clinical context, the MRI finding of lobar white matter edema with evidence of prior hemosiderin deposition may indicate the presence of a reversible CAA leukoencephalopathy. C1 Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD USA. Cleveland Clin Fdn, Dept Vasc Neurol, Cleveland, OH USA. Columbia Univ, Dept Neurol, New York, NY USA. Columbia Univ, Dept Radiol, New York, NY USA. Columbia Univ, Dept Pathol, New York, NY USA. Columbia Univ Coll Phys & Surg, Sergievsky Ctr, New York, NY 10032 USA. RP Elkind, MSV (reprint author), Neurol Inst, 710 W 168th St,Room 641, New York, NY 10032 USA. EM mse13@columbia.edu NR 10 TC 58 Z9 59 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 10 PY 2004 VL 62 IS 3 BP 494 EP 497 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 778JQ UT WOS:000189238800034 PM 14872042 ER PT J AU Fernandez-Capetillo, O Nussenzweig, A AF Fernandez-Capetillo, O Nussenzweig, A TI Linking histone deacetylation with the repair of DNA breaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; GENOMIC INSTABILITY; COMPLEX; H2AX; CHROMATIN; RECOMBINATION; RAD54 C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 NR 24 TC 26 Z9 26 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 FEB 10 PY 2004 VL 101 IS 6 BP 1427 EP 1428 DI 10.1073/pnas.0307342101 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773JT UT WOS:000188921200001 PM 14757822 ER PT J AU Karle, IL Yagi, H Sayer, JM Jerina, DM AF Karle, IL Yagi, H Sayer, JM Jerina, DM TI Crystal and molecular structure of a benzo[a]pyrene 7,8-diol 9,10-epoxide N-2-deoxyguanosine adduct: Absolute configuration and conformation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSITION-MOMENT DIRECTIONS; DIOL EPOXIDE; BENZOPYRENE 7,8-DIOL-9,10-EPOXIDES; CARCINOGEN BENZOPYRENE; DEOXYGUANOSINE ADDUCTS; DNA-ADDUCTS; STEREOCHEMISTRY; NUCLEOTIDES; ENANTIOMERS; ADENOSINE AB Benzo[a]pyrene 7,8-diol 9,10-epoxide adducts in DNA are implicated in mutagenesis, and their formation from the diol epoxides and subsequent incorrect replication by human DNA polymerases provide an attractive mechanism for the induction of cancer by this highly carcinogenic hydrocarbon and its diol epoxide metabolites. Here, we describe the crystal structure of such an adduct at the exocyclic amino group of a purine nucleoside. The present adduct derives from trans opening at C10 of the (-)-(7S,8R)-diol (9R,10S)-epoxide enantiomer by the exocyclic N-2-amino group of deoxyguanosine. In the crystal, the pyrene rings of adjacent molecules stack with each other, but the guanine bases do not stack either intermolecularly with each other or intramolecularly with the pyrene. The most notable features of the molecular structure are (i) independent and unambiguous proof of the absolute configuration of the adduct based on the spatial relationship between the known chiral carbon atoms of the deoxyribose and the four asymmetric centers in the hydrocarbon moiety; (it) visualization of the relative orientations of the pyrene and guanine ring systems as well as the conformation of the partially saturated hydrocarbon ring (comprising carbon atoms 7, 8, 9, and 10), both of which conformational features in the crystal are in good agreement with deductions from NMR and CD measurements in solution; and (iii) the presence in the crystal of a syn glycosidic torsion angle, a conformation that is unusual in B-DNA but that may be involved in error-prone replication of these benzo[a]pyrene 7,8-diol 9,10-epoxide deoxyguanosine adducts by DNA polymerases. C1 USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NIDDK, Bioorgan Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Karle, IL (reprint author), USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. EM williams@harker.nri.navy.mil NR 34 TC 19 Z9 19 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 FEB 10 PY 2004 VL 101 IS 6 BP 1433 EP 1438 DI 10.1073/pnas.0307305101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773JT UT WOS:000188921200004 PM 14757823 ER PT J AU Nogueira, ML Wang, VEH Tantin, D Sharp, PA Kristie, TM AF Nogueira, ML Wang, VEH Tantin, D Sharp, PA Kristie, TM TI Herpes simplex virus infections are arrested in Oct-1-deficient cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELLULAR TRANSCRIPTION FACTORS; COACTIVATOR C1 HCF; VP16-INDUCED COMPLEX; SENSORY NEURONS; DNA-REPLICATION; HOMEO DOMAIN; PROTEIN; VP16; OCT-1; ACTIVATION AB Expression of the herpes simplex virus (HSV) immediate early (IE) genes is regulated by a multiprotein complex that is assembled on the TAATGARAT enhancer core element. The complex contains the cellular POU domain protein Oct-1, the viral transactivator VP16, and the cellular cofactor host cell factor 1. The current model suggests that the assembly depends on recognition of the core element by Oct-1. Here, HSV infection of Oct-l-deficient mouse embryonic fibroblast cells demonstrates that Oct-1 is critical for IE gene expression at low multiplicities of infection (moi). However, the protein is not essential for IE gene expression at high moi, indicating that VP16-mediated transcriptional induction through other IE regulatory elements is also important. This induction depends, at least in part, on the GA-binding protein binding elements that are present in each IE enhancer domain. Surprisingly, whereas the viral IE genes are expressed after high moi infection of Oct-l-deficient cells, the assembly of viral replication factories is severely impaired, revealing a second critical role for Oct-1 in HSV replication. The results have implications for both the HSV lytic and latency-reactivation cycles. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. MIT, Ctr Canc Res, Cambridge, MA 02139 USA. MIT, McGovern Inst, Cambridge, MA 02139 USA. RP Kristie, TM (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4-131,4 Ctr Dr, Bethesda, MD 20892 USA. EM thomas_kristie@nih.gov RI Nogueira, Mauricio/B-7599-2012 OI Nogueira, Mauricio/0000-0003-1102-2419 FU NCI NIH HHS [P01 CA 42063, P01 CA042063, P30 CA 14051, P30 CA014051] NR 44 TC 26 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 FEB 10 PY 2004 VL 101 IS 6 BP 1473 EP 1478 DI 10.1073/pnas.0307300101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773JT UT WOS:000188921200011 PM 14745036 ER PT J AU Backman, SA Ghazarian, D So, K Sanchez, O Wagner, KU Hennighausen, L Suzuki, A Tsao, MS Chapman, WB Stambolic, V Mak, TW AF Backman, SA Ghazarian, D So, K Sanchez, O Wagner, KU Hennighausen, L Suzuki, A Tsao, MS Chapman, WB Stambolic, V Mak, TW TI Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR GENE; LHERMITTE-DUCLOS-DISEASE; TRANSGENIC MICE; CONDITIONAL LOSS; COWDEN-DISEASE; CELL-SURVIVAL; MOUSE MODEL; SOMA SIZE; CANCER; LEADS AB PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase/protein kinase B signaling. Using the Cre-IoxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ. C1 Univ Toronto, Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. Univ Toronto, Ontario Canc Inst, Dept Lab Med & Pathobiol, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Med Biophys, Hlth Network, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Lab Med & Pathobiol, Hlth Network, Toronto, ON M5G 2M9, Canada. Univ Toronto, Toronto Gen Hosp, Clin Res Program, Hlth Network, Toronto, ON M5G 2C4, Canada. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Akita Univ, Dept Biochem, Sch Med, Akita 0108543, Japan. RP Mak, TW (reprint author), Univ Toronto, Ontario Canc Inst, Dept Med Biophys, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM tmak@uhnres.utoronto.ca RI Wagner, Kay-Uwe/B-6044-2009 NR 46 TC 110 Z9 114 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 FEB 10 PY 2004 VL 101 IS 6 BP 1725 EP 1730 DI 10.1073/pnas.0308217100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773JT UT WOS:000188921200055 PM 14747659 ER PT J AU Kodato, S Linders, JTM Gu, XH Yamada, K Flippen-Anderson, JL Deschamps, JR Jacobson, AE Rice, KC AF Kodato, S Linders, JTM Gu, XH Yamada, K Flippen-Anderson, JL Deschamps, JR Jacobson, AE Rice, KC TI Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2 ,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID RECEPTOR-MEDIATED PHENOMENA; PROBES; 5-(META-HYDROXYPHENYL)MORPHAN; ANTAGONISTS AB In an attempt to obtain the para-f isomer, rac-(IR,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9alpha-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyloctahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(IR,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans, that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor. C1 NIDDKD, Med Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, US Dept HHS, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. EM kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 NR 19 TC 12 Z9 12 U1 0 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD FEB 7 PY 2004 VL 2 IS 3 BP 330 EP 336 DI 10.1039/b312633c PG 7 WC Chemistry, Organic SC Chemistry GA 776YC UT WOS:000189146100011 PM 14747861 ER PT J AU Wlodawer, A Li, M Gustchina, A Oyama, H Oda, K Beyer, BB Clemente, J Dunn, BM AF Wlodawer, A Li, M Gustchina, A Oyama, H Oda, K Beyer, BB Clemente, J Dunn, BM TI Two inhibitor molecules bound in the active site of Pseudomonas sedolisin: a model for the bi-product complex following cleavage of a peptide substrate SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE serine-carboxyl proteinases; substrate specificity; inhibitor binding; reaction products ID INSENSITIVE CARBOXYL PROTEINASE; NEURONAL CEROID-LIPOFUSCINOSIS; CRYSTAL-STRUCTURE; PURIFICATION; IDENTIFICATION; KUMAMOLYSIN; REFINEMENT; EXPRESSION; RESIDUES; CLONING AB High-resolution crystallographic analysis of a complex of the serine-carboxyl proteinase sedolisin with pseudo-iodotyrostatin revealed two molecules of this inhibitor bound in the active site of the enzyme, marking subsites from S3 to S3'. The mode of binding represents two products of the proteolytic reaction. Substrate specificity of sedolisin was investigated using peptide libraries and a new peptide substrate for sedolisin, MCA-Lys-Pro-Pro-Leu-Glu#Tyr-Arg-Leu-Gly-Lys(DNP)-Gly, was synthesized based on the results of the enzymatic and crystallographic studies and was shown to be efficiently cleaved by the enzyme. The kinetic parameters for the substrate, measured by the increase in fluorescence upon relief of quenching, were: k(cat) = 73 +/- 5 s(-1), K-m = 0.12 +/- 0.011 muM, and k(cat)/K-m = 608 +/- 85 s(-1) muM(-1). Published by Elsevier Inc. C1 NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@nciferf.gov FU NCI NIH HHS [N01-CO12400]; NIAID NIH HHS [AI39211]; NIDDK NIH HHS [DK18865] NR 24 TC 12 Z9 13 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 6 PY 2004 VL 314 IS 2 BP 638 EP 645 DI 10.1016/j.bbrc.2003.12.130 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 769EE UT WOS:000188612800051 PM 14733955 ER PT J AU Gunasekaran, K Nussinov, R AF Gunasekaran, K Nussinov, R TI Modulating functional loop movements: The role of highly conserved residues in the correlated loop motions SO CHEMBIOCHEM LA English DT Article; Proceedings Paper CT 86th International Titisee Conference CY OCT 23-27, 2002 CL Titisee, GERMANY SP Boehringer Ingelheim Fonds DE conformation analysis; correlated motions; function design; ligand binding mechanism; proteins; transferases ID MOLECULAR-DYNAMICS SIMULATIONS; CRYSTAL-STRUCTURE; DIHYDROFOLATE-REDUCTASE; CONFORMATIONAL-CHANGES; PROTEIN FLEXIBILITY; ENZYME CATALYSIS; COMPLEX; BINDING; RESOLUTION; FAMILIES AB Loop flexibility in enzymes plays a vital role in correctly positioning catalytically important residues. This strong relationship between enzyme flexibility and function provides an opportunity to engineer new substrates and inhibitors. It further allows the design of site-directed mutagenesis experiments to explore enzymatic activity through the control of flexibility of a functional loop. Earlier, we described a novel mechanism in which a small loop triggers the motions of a functional loop in three enzymes (beta-1,4-galactosyltransferase, lipase, and enolase) unrelated in sequence, structure, or function. Here, we further address the question of how the interactions between various flexible loops modulate the movements of the functional loop. We examine beta-1,4-galactosyltransferase as a model system in which a Long loop undergoes a large conformational change (moves in space up to 20 Angstrom) upon substrate binding in addition to a small loop (Trp loop) that shows a considerably smaller conformational change. Our molecular-dynamics simulations carried out in implicit and explicit solvent show that, in addition to these two loops, two other neighboring loops are also highly flexible. These loops are in contact with either the Long loop or the Trp loop. Analysis of the covariance of the spatial displacement of the residues reveals that coupled motions occur only in one of these two loops. Sequence analysis indicates that loops correlated in their motions also have highly conserved residues involved in the loop-loop interactions. Further, analysis of, crystal structures and simulations in explicit water open the possibility that the Trp loop that triggers the movement of the Long loop in the unbound conformation may also play the same role in the substrate-bound conformation through its contact with the conserved and correlated third loop. Our proposition is supported by the observation that four of the five conserved positions in the third loop are at the interface with the Trp loop. Evolution appears to Select residues that drive the functional Long loop to a large conformational change. These observations suggest that altering selected loop-loop interactions might modulate the movements of the functional loop. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 36 TC 16 Z9 16 U1 1 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI Chembiochem PD FEB 6 PY 2004 VL 5 IS 2 BP 224 EP 230 DI 10.1002/cbic.200300732 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 777NQ UT WOS:000189184800012 PM 14760744 ER PT J AU Chu, GX Egnaczyk, GF Zhao, W Jo, SH Fan, GC Maggio, JE Xiao, RP Kranias, EG AF Chu, GX Egnaczyk, GF Zhao, W Jo, SH Fan, GC Maggio, JE Xiao, RP Kranias, EG TI Phosphoproteome analysis of cardiomyocytes subjected to beta-adrenergic stimulation - Identification and characterization of a cardiac heat shock protein p20 SO CIRCULATION RESEARCH LA English DT Article DE beta-adrenergic receptor signaling; protein phosphorylation; cardiomyocytes; heat shock proteins; proteomics ID RAT SKELETAL; TROPONIN-I; PHOSPHORYLATION; PHOSPHOLAMBAN; MYOCYTES; FAILURE; INSULIN; GENE; TRANSLOCATION; ACTIVATION AB Posttranslational modification of target substrates underlies biological processes through activation/inactivation of signaling cascades. To concurrently identify the phosphoprotein substrates associated with cardiac beta-adrenergic signaling, the mouse myocyte phosphoproteome was analyzed using 2-D gel electrophoresis in combination with P-32 autoradiography. Phosphoprotein spots, detected by silver staining, were identified using MALDI-TOF mass spectrometry in conjunction with computer-assisted protein spot matching. Stimulation with isoproterenol (1 mumol/L for 5 minutes) was associated with maximal increases in myocyte contractile parameters, and significant stimulation of the phosphorylation of troponin I (190+/-23%) and succinyl CoA synthetase (160+/-16%), whereas the phosphorylation of pyruvate dehydrogenase (48+/-10%), NADH-ubiquinone oxidoreductase (46+/-6%), heat shock protein 27 (18+/-3%), alphaB-crystallin (20+/-3%), and an unidentified 26-kDa protein (29+/-7%) was significantly decreased, compared with unstimulated cells (100%). After sustained (30 minutes) stimulation with isoproterenol, only the alterations in the phosphorylation levels of troponin I and NADH-ubiquinone oxidoreductase were maintained and de novo phosphorylation of a phosphoprotein (approximate to20 kDa and pI 5.5) was observed. The tryptic peptide fragments of this phosphoprotein were sequenced using postsource decay mass spectrometry, and the protein was subsequently cloned and designated as p20, based on its high sequence homology with rat and human skeletal p20. The mouse cardiac p20 contains the conserved domain sequences for heat shock proteins, and the RRAS consensus sequence for cAMP-PKA substrates. LC-MS/MS phosphorylation mapping confirmed phosphorylation of Ser(16) in p20 on beta-agonist stimulation. Adenoviral gene transfer of p20 was associated with significant increases in contractility and Ca transient peak in adult rat cardiomyocytes, suggesting an important role of p20 in cardiac function. These findings suggest that cardiomyocytes undergo significant posttranslational modification via phosphorylation in a multitude of proteins to dynamically fine-tune cardiac responses to beta-adrenergic signaling. C1 Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Kranias, EG (reprint author), Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, 231 Albert B Sabin Way, Cincinnati, OH 45267 USA. EM litsa.kranias@uc.edu FU NHLBI NIH HHS [HL-64018, HL-26057, HL-52318]; NIA NIH HHS [AG-12853] NR 25 TC 49 Z9 53 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 6 PY 2004 VL 94 IS 2 BP 184 EP 193 DI 10.1161/01.RES.0000107198.90218.21 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 771AH UT WOS:000188763000010 PM 14615292 ER PT J AU Zhang, JW Klemm, DJ Vinson, C Lane, MD AF Zhang, JW Klemm, DJ Vinson, C Lane, MD TI Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOTIC CLONAL EXPANSION; GROWTH FACTOR-I; ADIPOCYTE DIFFERENTIATION; 3T3-L1 CELLS; CYCLIC-AMP; ADIPOSE CONVERSION; PREADIPOCYTE DIFFERENTIATION; INHIBITS ADIPOGENESIS; TRANSGENIC MICE; KINASE AKT/PKB AB The proximal promoter of the C/EBPbeta gene possesses dual cis regulatory elements (TGA1 and TGA2), both of which contain core CREB binding sites. Comparison of the activities of C/EBPbeta promoter-reporter genes with 5'-truncations or site-directed mutations in the TGA elements showed that both are required for maximal promoter function. Electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) analyses with antibodies specific to CREB and ATF1 showed that these CREB family members associate with the proximal promoter both in vitro and ex vivo. Immunoblotting and ChIP analysis revealed that other CREB family members, CREM and ATF1, are up-regulated and associate with the proximal C/EBPbeta promoter in mouse embryonic fibroblasts (MEFs) from CREB(-/-) mice. ChIP analysis of wild-type MEFs and 3T3-L1 preadipocytes revealed that interaction of phospho-CREB, the active form of CREB, with the C/EBPbeta gene promoter occurs only after induction of differentiation of 3T3-L1 preadipocytes and MEFs. Consistent with the interaction of CREB and ATF1 at the TGA regulatory elements, expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required. Conversely, expression of a dominant-negative CREB blocked promoter-reporter activity, expression of C/EBPbeta, and adipogenesis. When subjected to the standard adipocyte differentiation protocol, wild-type MEFs differentiate into adipocytes at high frequency, whereas CREB(-/-) MEFs exhibit greatly reduced expression of C/EBPbeta and differentiation. The low level of expression of C/EBPbeta and differentiation in CREB(-/-) MEFs appears to be due to up-regulation of other CREB protein family members, i.e. ATF1 and CREM. C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Biochem Cellular & Mol Biol Program, Baltimore, MD 21205 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Cardiovasc Pulm Res Lab, Denver, CO 80262 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Lane, MD (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Rm 512 WBSB, Baltimore, MD 21205 USA. EM dlane@jhmi.edu RI Zhang, Jiangwen/A-7654-2013 FU NHLBI NIH HHS [HLHL14985]; NIDDK NIH HHS [DK38418, DK53969] NR 51 TC 120 Z9 127 U1 2 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2004 VL 279 IS 6 BP 4471 EP 4478 DI 10.1074/jbc.M311327200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300067 PM 14593102 ER PT J AU Tanaka, M Kim, YM Lee, G Junn, E Iwatsubo, T Mouradian, MM AF Tanaka, M Kim, YM Lee, G Junn, E Iwatsubo, T Mouradian, MM TI Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN-PROTEASOME SYSTEM; SPORADIC PARKINSONS-DISEASE; INCLUSION-BODY FORMATION; CORTICAL LEWY BODIES; NEURODEGENERATIVE DISORDERS; RETROGRADE TRANSPORT; DROSOPHILA MODEL; TRANSGENIC MICE; WILD-TYPE; DEGRADATION AB Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing alpha-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, gamma-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of alpha-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of non-apoptotic cells but only in 10% of apoptotic cells. Additionally, alpha-synuclein-induced apoptosis was not coupled with increased prevalence of aggresome-bearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of alpha-synuclein and synphilin-1. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, Piscataway, NJ 08854 USA. NINDS, Genet Pharmacol Unit, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan. RP Mouradian, MM (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, 683 Hoes Lane,Room 180, Piscataway, NJ 08854 USA. EM Mouradian@umdnj.edu OI Mouradian, M. Maral/0000-0002-9937-412X NR 63 TC 250 Z9 261 U1 2 U2 10 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 FEB 6 PY 2004 VL 279 IS 6 BP 4625 EP 4631 DI 10.1074/jbc.M310994200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300084 PM 14627698 ER PT J AU Suh, KS Mutoh, M Nagashima, K Fernandez-Salas, E Edwards, LE Hayes, DD Crutchley, JM Marin, KG Dumont, RA Levy, JM Cheng, C Garfield, S Yuspa, SH AF Suh, KS Mutoh, M Nagashima, K Fernandez-Salas, E Edwards, LE Hayes, DD Crutchley, JM Marin, KG Dumont, RA Levy, JM Cheng, C Garfield, S Yuspa, SH TI The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-CLONING; INTRACELLULAR PH; ANION CHANNEL; CLIC FAMILY; EXPRESSION; P64; MEMBRANES; BIOLOGY; COMPLEX; KINASE AB CLIC4/mtCLIC, a chloride intracellular channel protein, localizes to the mitochondria and cytoplasm of keratinocytes and participates in the apoptotic response to stress. We now show that multiple stress inducers cause the translocation of cytoplasmic CLIC4 to the nucleus. Immunogold electron microscopy and confocal analyses indicate that nuclear CLIC4 is detected prior to the apoptotic phenotype. CLIC4 associates with the Ran, NTF2, and Importin-a nuclear import complexes in immunoprecipitates of lysates from cells treated with apoptotic/stress-inducing agents. Deletion or mutation of the nuclear localization signal in the C terminus of CLIC4 eliminates nuclear translocation, whereas N terminus deletion enhances nuclear localization. Targeting CLIC4 to the nucleus via adenoviral transduction accelerates apoptosis when compared with cytoplasmic CLIC4, and only nuclear-targeted CLIC4 causes apoptosis in Apaf null mouse fibroblasts or in Bcl-2-overexpressing keratinocytes. These results indicate that CLIC4 nuclear translocation is an integral part of the cellular response to stress and may contribute to the initiation of nuclear alterations that are associated with apoptosis. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Confocal Microscopy Core Facil, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Electron Microscope Facil, Image Anal Lab, NIH,Sci Applicat Int Corp Inc, Frederick, MD 21702 USA. RP Yuspa, SH (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. EM yuspas@dc37a.nci.nih.gov NR 37 TC 79 Z9 85 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 FEB 6 PY 2004 VL 279 IS 6 BP 4632 EP 4641 DI 10.1074/jbc.M311632200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300085 PM 14610078 ER PT J AU Ikehata, JI Shinomiya, K Kobayashi, K Ohshima, H Kitanaka, S Ito, Y AF Ikehata, JI Shinomiya, K Kobayashi, K Ohshima, H Kitanaka, S Ito, Y TI Effect of Coriolis force on counter-current chromatographic separation by centrifugal partition chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE centrifugal partition chromatography; Coriolis force; efficiency AB The effect of Coriolis force on the counter-current chromatographic separation was studied using centrifugal partition chromatography (CPC) with four different two-phase solvent systems including n-hexane-acetonitrile (ACN); tert-butyl methyl ether (MtBE)-aqueous 0.1% trifluoroacetic acid (TFA) (1:1); MtBE-ACN-aqueous 0.1% TFA (2:2:3); and 12.5% (w/w) polyethylene glycol (PEG) 1000-12.5% (w/w) dibasic potassium phosphate. Each separation was performed by eluting either the upper phase in the ascending mode or the lower phase in the descending mode, each in clockwise (CW) and counterclockwise column rotation. Better partition efficiencies were attained by the CW rotation in both mobile phases in all the two-phase solvent systems examined. The mathematical analysis also revealed the Coriolis force works favorably under the CW column rotation for both mobile phases. The overall results demonstrated that the Coriolis force produces substantial effects on CPC separation in both organic-aqueous and aqueous-aqueous two-phase systems. (C) 2003 Elsevier B.V. All rights reserved. C1 Nihon Univ, Div Analyt Chem, Coll Pharm, Funabashi, Chiba 2748555, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Div Analyt Chem, Coll Pharm, 7-7-1 Narashinodai 7 Chome, Funabashi, Chiba 2748555, Japan. EM kshino@pha.nihon-u.ac.jp NR 10 TC 12 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 6 PY 2004 VL 1025 IS 2 BP 169 EP 175 DI 10.1016/j.chroma.2003.10.107 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 762DD UT WOS:000187954700004 PM 14763801 ER PT J AU Merrill, GN Webb, SP AF Merrill, GN Webb, SP TI The application of the effective fragment potential method to molecular anion solvation: A study of ten oxyanion-water clusters, A(-)(H2O)(1-4) SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID DENSITY-FUNCTIONAL THEORY; GAUSSIAN-TYPE BASIS; ORBITAL METHODS; AB-INITIO; GAS-PHASE; BASIS-SETS; VIBRATIONAL FREQUENCIES; ORGANIC-MOLECULES; MOLLER-PLESSET; HYDRATION AB The performance of the effective fragment potential (EFP) method, a quantum mechanical-molecular mechanical (QM-MM) method, to reproduce fully quantum mechanical results has been investigated. The enthalpies of hydration for 10 oxyanions (ClO4-, HSO4-, NO3-, H2PO4-, HCO3-, HCO2-, SO42-, HPO42-, CO32-, and PO43-) by one to four water molecules were studied. For monohydrate systems exhibiting small to moderate amounts of charge transfer (ClO4-, HSO4-, NO3-, H2PO4- HCO3-, and HCO2-), the EFP method reproduces Hartree-Fock (HF) differential enthalpies of hydration remarkably well (mean difference = -0.1 and standard deviation = 0.9 kcal/mol). The EFP and HF calculations also successfully reproduce the available experimental data (EFP: mean difference = 2.0 and standard deviation = 0.8 kcal/mol; HF: mean difference = 1.8 and standard deviation = 1.0 kcal/mol). MP2 calculations show only a slight improvement in agreement with experiment over the HF calculations, indicating a small electron correlation effect. For the high charge transfer monohydrate systems (SO42-, HPO42-, CO32-, and PO43-), the EFP method is less successful in reproducing HF differential enthalpies of hydration. The agreement between EFP and HF results improves, however, with the number of water molecules. These results suggest reduced variational space (RVS) analysis can be used to predict which systems may pose (charge transfer) problems for the EFP method. C1 NCI, SAIC Frederick, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. RP Merrill, GN (reprint author), 2155 29th Ave, San Francisco, CA 94116 USA. NR 56 TC 18 Z9 18 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD FEB 5 PY 2004 VL 108 IS 5 BP 833 EP 839 DI 10.1021/jp030970j PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 768UG UT WOS:000188553000017 ER EF