FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Graziewicz, MA Day, BJ Copeland, WC AF Graziewicz, MA Day, BJ Copeland, WC TI The mitochondrial DNA polymerase as a target of oxidative damage SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HYDROGEN-PEROXIDE; ACCESSORY SUBUNIT; CATALYTIC SUBUNIT; PROTEIN OXIDATION; NUCLEAR-DNA; GAMMA; CELLS; REPLICATION; RESIDUES; IDENTIFICATION AB The mitochondrial respiratory chain is a source of reactive oxygen species (ROS) that are responsible for oxidative modification of biomolecules, including proteins. Due to its association with mitochondrial DNA, DNA polymerase gamma (pol gamma) is in an environment to be oxidized by hydrogen peroxide and hydroxyl radicals that may be generated in the presence of iron ions associated with DNA. We tested whether human pol gamma was a possible target of ROS with H2O2 and investigated the effect on the polymerase activities and DNA binding efficiency. A 1 h treatment with 250 muM H2O2 significantly inhibited DNA polymerase activity of the p140 subunit and lowered its DNA binding efficiency. Addition of p55 to the p140 catalytic subunit prior to H2O2 treatment offered protection from oxidative inactivation. Oxidatively modified amino acid residues in pol gamma resulting from H2O2 treatment were observed in vitro as well as in vivo, in SV40-transfected human fibroblasts. Pol gamma was detected as one of the major oxidized mitochondrial matrix proteins, with a detectable decline in polymerase activity. These results suggest pol gamma as a target of oxidative damage, which may result in a reduction in mitochondrial DNA replication and repair capacities. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 41 TC 113 Z9 121 U1 0 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 JUL 1 PY 2002 VL 30 IS 13 BP 2817 EP 2824 DI 10.1093/nar/gkf392 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 569MW UT WOS:000176607000013 PM 12087165 ER PT J AU Martin, LJ Mahaney, MC Almasy, L Hixson, JE Cole, SA MacCluer, JW Jaquish, CE Blangero, J Comuzzie, AG AF Martin, LJ Mahaney, MC Almasy, L Hixson, JE Cole, SA MacCluer, JW Jaquish, CE Blangero, J Comuzzie, AG TI A quantitative trait locus on chromosome 22 for serum leptin levels adjusted for serum testosterone SO OBESITY RESEARCH LA English DT Article DE variance component linkage analysis; obesity; sex hormones ID PROLIFERATOR-ACTIVATED RECEPTOR; MIGRATION INHIBITORY FACTOR; PLASMA LEPTIN; BODY-FAT; MEXICAN-AMERICANS; LINKAGE ANALYSIS; SEX DIFFERENCE; OBESE; GENE; PEDIGREES AB Objective: Studies have reported the existence of marked sexual dimorphism in serum leptin levels in humans with women having approximately two to three times the levels of men. We have shown that this sexual dimorphism has a strong genetic component arising from a genotype by sex interaction, but adjusting leptin levels for testosterone eliminates this interaction. Because interactions such as genotype X sex can confound the detection of quantitative trait loci (QTLs), we wanted to determine if there are QTLs associated with the expression of leptin adjusted for testosterone. Research Methods and Procedures: We performed a genome-wide scan using multipoint linkage analysis and implemented a general pedigree-based variance-component approach to identify genes with measurable effects on variation in leptin levels independent of testosterone in 318 Mexican Americans from the San Antonio Family Heart Study. Results: We detected significant evidence of linkage (log of the odds ratio = 3.44) for a QTL on chromosome 22. Discussion: Given these results, we hypothesize that a QTL on chromosome 22 may influence the level of leptin adjusted for testosterone. C1 Childrens Hosp, Med Ctr, Ctr Biostat & Epidemiol, Cincinnati, OH 45229 USA. SW Fdn Biomed Res, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. RP Martin, LJ (reprint author), Childrens Hosp, Med Ctr, Ctr Biostat & Epidemiol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. RI Martin, Lisa/E-2425-2016 OI Martin, Lisa/0000-0001-8702-9946 FU NHLBI NIH HHS [HL45522]; NIDDK NIH HHS [DK44297]; NIGMS NIH HHS [GM15803]; NIMH NIH HHS [MH59490] NR 34 TC 9 Z9 9 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD JUL PY 2002 VL 10 IS 7 BP 602 EP 607 DI 10.1038/oby.2002.82 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 573YQ UT WOS:000176860900005 PM 12105281 ER PT J AU McDuffie, JR Calis, KA Uwaifo, GI Sebring, NG Fallon, EM Hubbard, VS Yanovski, JA AF McDuffie, JR Calis, KA Uwaifo, GI Sebring, NG Fallon, EM Hubbard, VS Yanovski, JA TI Three-month tolerability of orlistat in adolescents with obesity-related comorbid conditions SO OBESITY RESEARCH LA English DT Article DE obesity; weight loss; adolescence; pharmacotherapy; orlistat ID AIR-DISPLACEMENT PLETHYSMOGRAPHY; GASTROINTESTINAL LIPASE INHIBITOR; HUMAN-BODY COMPOSITION; WEIGHT-LOSS; VITAMIN-D; CARDIOVASCULAR RISK; CUTANEOUS SYNTHESIS; GLUCOSE-TOLERANCE; CONTROLLED TRIAL; HEALTHY-ADULTS AB Objective: To study the safety, tolerability, and potential efficacy of orlistat in adolescents with obesity and its comorbid conditions. Research Methods and Procedures: We studied 20 adolescents (age, 14.6 +/- 2.0 years; body mass index, 44.1 +/- 12.6 kg/m(2)). Subjects were evaluated before and after taking orlistat (120 mg three times daily) and a multivitamin for 3 months. Subjects were simultaneously enrolled in a 12-week program emphasizing diet, exercise, and strategies for behavior change. Results: Participants who completed treatment (85%) reported taking 80% of prescribed medication. Adverse effects were generally mild, limited to gastrointestinal effects observed in adults, and decreased with time. Three subjects required additional vitamin D supplementation despite the prescription of a daily multivitamin containing vitamin D. Weight decreased significantly (-4.4 +/- 4.6 kg p < 0.001 -3.8 +/- 4.1% of initial weight), as did body mass index (-1.9 +/- 2.5 kg/m(2); P < 0.0002). Total cholesterol (-21.3 +/- 24.7 mg/dL; p < 0.001), low-density lipoprotein-cholesterol (-17.3 +/- 15.8 mg/dL; p < 0.0001), fasting insulin 13.7 +/- 19.0 muU/mL; (p < 0.02), and fasting glucose 15.4 +/- 7.4 mg/dL; (p < 0.003) were also significantly lower after orlistat. Insulin sensitivity, assessed by a frequently sampled intravenous glucose-tolerance test, improved significantly (p < 0.02). Discussion: We conclude that, in adolescents, short-term treatment with orlistat, in the context of a behavioral program, is well-tolerated and has a side-effect profile similar to that observed in adults, but its true benefit versus conventional therapy remains to be determined in placebo-controlled trials. C1 NICHD, Unit Growth & Obes, DEB, NIH, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Drug Informat Serv, Dept Pharm, Bethesda, MD USA. Warren G Magnuson Clin Ctr, Dept Nutr, Bethesda, MD USA. NIDDKD, NIH, Div Nutr Res Coord, Bethesda, MD 20892 USA. RP McDuffie, JR (reprint author), NICHD, Unit Growth & Obes, DEB, NIH, 10 Ctr Dr,Bldg 10,Room 10N262,MSC 1862, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 FU NICHD NIH HHS [Z01-HD-00641] NR 56 TC 77 Z9 77 U1 0 U2 6 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD JUL PY 2002 VL 10 IS 7 BP 642 EP 650 DI 10.1038/oby.2002.87 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 573YQ UT WOS:000176860900010 PM 12105286 ER PT J AU Coady, SA Jaquish, CE Fabsitz, RR Larson, MG Cupples, LA Myers, RH AF Coady, SA Jaquish, CE Fabsitz, RR Larson, MG Cupples, LA Myers, RH TI Genetic variability of adult body mass index: A longitudinal assessment in Framingham families SO OBESITY RESEARCH LA English DT Article DE heritability; longitudinal; body mass index; family study ID CARDIOVASCULAR RISK-FACTORS; PEDIGREE ANALYSIS; RELATIVE WEIGHT; ENVIRONMENTAL CONTRIBUTIONS; TWINS; OBESITY; ADIPOSITY; DISEASE; FAT; HERITABILITY AB Objective: To explore the contribution of genetics to the mean, SD, maximum value, maximum less the mean, and change over time in body mass index (BMI) and the residual of body weight after adjustment for height. BMI is frequently used as a general indicator of obesity because of its ease and reliability in ascertainment. Cross-sectional twin and family studies have shown a moderate-to-substantial genetic component for BMI. However, the contribution of genetics to the long-term average, variability, or change over time in BMI is less clear. Research Methods and Procedures: Longitudinal data from the Framingham heart study were used to create pedigrees of age-matched individuals. Heritability estimates were derived using variance-decomposition methods on a total of 105 1 individuals from 380 extended pedigrees followed for a period of 20 years. All subjects were followed from approximately age 35 to 55 years. Results: Moderate heritability estimates were found for the mean BMI (h(2) = 0.37), maximum BMI (h(2) = 0.40), and the mean residual of body weight (h(2) = 0.36). Low heritability estimates (h(2) congruent to 0.20) were found for the maximum less the mean in BMI and the SDs of BMI and residual of body weight. No additive genetic contribution was found for the average change over time in BMI or the residual of body weight. Discussion: These findings suggest that there is a significant genetic component for the magnitude of BMI throughout an individual's middle-adult years; however, little evidence was found for a genetic contribution to the variability or rate of change in an individual's BMI. C1 NHLBI, Rockledge Ctr 2, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Coady, SA (reprint author), NHLBI, Rockledge Ctr 2, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,MSC 7934, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC38038] NR 44 TC 36 Z9 38 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD JUL PY 2002 VL 10 IS 7 BP 675 EP 681 DI 10.1038/oby.2002.91 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 573YQ UT WOS:000176860900014 PM 12105290 ER PT J AU Cornelison, TL Montz, FJ Bristow, RE Chou, B Bovicelli, A Zeger, SL AF Cornelison, TL Montz, FJ Bristow, RE Chou, B Bovicelli, A Zeger, SL TI Decreased incidence of cervical cancer in Medicare-eligible California women SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PAP SMEARS; ELDERLY WOMEN; OLDER WOMEN AB OBJECTIVE: To determine if the incidence of invasive cervical cancer relative to carcinoma in situ decreased in Medicare-eligible women. METHODS: A retrospective cohort was amassed from the California Cancer Registry database. The hypothesis was prospectively specified. Mean ratio of invasive (international Federation of Gynecology and Obstetrics Stages I-IV) to in situ cervical carcinoma in 1988-1990 versus 1991-1995 was stratified by age (24 or younger, 25-44, 45-64, 65 or older) and race (all races, whites, blacks, Hispanics, Asian/Pacific Islanders). RESULTS: The mean ratio of invasive to in situ cervical cancer incidence for women at least 65 years old was lower in 1991-1995 compared with 1988-1990 (P < .001, 95% confidence interval 0.893, 0.954); and had decreased more than observed for women aged 45-64 and 25-44, for all races combined, and for white women. The decreased ratio of invasive to in situ cancer for blacks, Hispanics, and Asian/Pacific Islanders at least 65 years old was no different than the decreased ratio in younger women. CONCLUSION: In California, in the 5 years after the 1990 change in Medicare funding statutes for cervical cytology screening, the ratio of invasive cervical cancer to in situ disease decreased more in Medicare-eligible patients than in younger women. (C) 2002 by The American College of Obstetricians and Gynecologists. C1 Johns Hopkins Med Inst, Kelly Gynecol Oncol Serv, Dept Gynecol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Kelly Gynecol Oncol Serv, Dept Obstet, Baltimore, MD USA. Johns Hopkins Med Inst, Kelly Gynecol Oncol Serv, Dept Biostat, Baltimore, MD USA. Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. RP Montz, FJ (reprint author), Johns Hopkins Med Inst, Kelly Gynecol Oncol Serv, Dept Gynecol, Baltimore, MD 21205 USA. NR 20 TC 8 Z9 8 U1 0 U2 0 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 JUL PY 2002 VL 100 IS 1 BP 79 EP 86 AR PII S0029-7844(02)02025-2 DI 10.1016/S0029-7844(02)02025-2 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568CG UT WOS:000176524400012 PM 12100807 ER PT J AU Rayburn, WF Zhang, J AF Rayburn, WF Zhang, J TI Rising rates of labor induction: Present concerns and future strategies SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID CESAREAN DELIVERY; UTERINE RUPTURE; WOMEN AB The rate of labor induction nationwide increased gradually from 9.5% to 19.4% between 1990 and 1998. Reasons for this doubling of inductions relate to widespread availability of cervical ripening agents, pressure from patients, conveniences to physicians, and litigious constraints. The increase in medically indicated inductions was slower than die overall increase, suggesting that induction for marginal or elective reasons has risen more rapidly. Data to support or refute the benefits of marginal or elective inductions are limited. Many trials of inductions for marginal indications are either nonexistent or retrospective with small sample sizes, thereby limiting definitive conclusions. Until prospective clinical trials can better validate reasons for the liberal use of labor induction, it would seem prudent to maintain a cautious approach, especially among nulliparous women. Strategies are proposed for developing evidence-based guidelines to reduce the presumed increase in health care costs, risk of cesarean delivery for nulliparas, and overscheduling in labor and delivery. (C) 2002 by The American College of Obstetricians and Gynecologists. C1 Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol,Div Maternal Fetal Med, Albuquerque, NM 87131 USA. Natl Inst Hlth & Human Dev, Epidemiol Branch, NIH, Bethesda, MD USA. RP Rayburn, WF (reprint author), Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol,Div Maternal Fetal Med, 2211 Lomas Blvd NE,ACC 4, Albuquerque, NM 87131 USA. NR 11 TC 106 Z9 107 U1 1 U2 5 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 JUL PY 2002 VL 100 IS 1 BP 164 EP 167 AR PII S0029-7844(02)02047-1 DI 10.1016/S0029-7844(02)02047-1 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568CG UT WOS:000176524400023 PM 12100818 ER PT J AU Wright, JJ Zerivitz, K Gravell, AE Cheson, BD AF Wright, JJ Zerivitz, K Gravell, AE Cheson, BD TI Clinical Trials Referral Resource: Current Clinical Trials of R115777 (Zarnestra) SO ONCOLOGY-NEW YORK LA English DT Article ID INHIBITOR R115777; FARNESYLTRANSFERASE C1 NCI, Bethesda, MD 20892 USA. RP Wright, JJ (reprint author), NCI, Bethesda, MD 20892 USA. NR 14 TC 4 Z9 4 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 JUL PY 2002 VL 16 IS 7 BP 930 EP + PG 5 WC Oncology SC Oncology GA 577GG UT WOS:000177052700017 PM 12164559 ER PT J AU Velez, G Boldt, HC Whitcup, SM Nussenblatt, RB Robinson, MR AF Velez, G Boldt, HC Whitcup, SM Nussenblatt, RB Robinson, MR TI Local methotrexate and dexamethasone phosphate for the treatment of recurrent primary intraocular lymphoma SO OPHTHALMIC SURGERY AND LASERS LA English DT Article ID NERVOUS-SYSTEM LYMPHOMA; PRIMARY CNS LYMPHOMA; RETICULUM-CELL SARCOMA; INTRAVITREAL CHEMOTHERAPY; GLUCOCORTICOID RECEPTORS; PHARMACOKINETICS; RADIOTHERAPY; INJECTION; THERAPY AB A 70-year-old patient with recurrent bilateral primary intraocular lymphoma (PIOL) was treated with local injections of methotrexate and periocular dexamethasone phosphate to both eyes over the course of 5 months. Local therapy consisted of a cycle to each eye of 3 intravitreal injections of methotrexate (200 mug in a total volume of 0.1 cc) administered on days 1, 5, and 8, followed by a sub-tenon injection of dexamethasone phosphate (7.5 mg in a total volume of 0.3 cc) on day 9. This treatment cycle was administered 4 times for the right eye and 3 times for the left eye, at 4 to 6 week intervals. Electroretinography was used to assess retinal function prior to and during each treatment regimen. Complete regression of the lymphomatous infiltrates and resolution of the vitritis was observed with preservation of visual acuity and no changes on electroretinography. The effect was sustained for 24 months after termination of treatment in the absence of systemic chemotherapy, radiation treatments, or maintenance intravitreal injections. Local combined chemotherapy can be used to treat recurrent PIOL, and can serve as successful palliative therapy in patients for whom further treatment with systemic chemotherapy or radiation is contraindicated. C1 NEI, NIH, Immunol Lab, Bethesda, MD USA. NEI, NIH, Off Clin Director, Bethesda, MD USA. Univ Iowa Hosp & Clin, Vitreoretinal Serv, Iowa City, IA 52242 USA. RP Velez, G (reprint author), 85 Washington Pk, Newton, MA 02460 USA. NR 27 TC 17 Z9 20 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0022-023X J9 OPHTHALMIC SURG LAS JI Ophthalmic Surg. Lasers PD JUL-AUG PY 2002 VL 33 IS 4 BP 329 EP 333 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 573KF UT WOS:000176828100014 PM 12134997 ER PT J AU Klein, R Sharrett, AR Klein, BEK Moss, SE Folsom, AR Wong, TY Brancati, FL Hubbard, LD Couper, D AF Klein, R Sharrett, AR Klein, BEK Moss, SE Folsom, AR Wong, TY Brancati, FL Hubbard, LD Couper, D CA ARIC Grp TI The association of atherosclerosis, vascular risk factors, and retinopathy in adult's with diabetes - The atherosclerosis risk in communities study SO OPHTHALMOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; CAROTID-ARTERY PLAQUE; VON-WILLEBRAND-FACTOR; MIDDLE-AGED ADULTS; WALL THICKNESS; CARDIOVASCULAR-DISEASE; MICROVASCULAR COMPLICATIONS; RETINAL ARTERY; BLOOD-PRESSURE; HARD EXUDATE AB Purpose: The aim of this report is to describe the prevalence of retinopathy and its associations with atherosclerosis and vascular risk factors in people with diabetes. Design: Cross-sectional study. Participants: Persons with diabetes, having gradable fundus photographs, from a biracial population-based cohort of adults (ages 51-72 years), and living in four United States communities (Forsyth County, North Carolina; the city of Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland) were studied from 1993 to 1995. Methods: Lesions typical of diabetic retinopathy were detected by grading a 450 color fundus photograph of one eye of each participant, using a modification of the Airlie House classification system. Main Outcome Measure: Severity of diabetic retinopathy (none, minimal nonproliferative, moderate nonproliferative, severe nonproliferative, and proliferative) and macular edema. Results: Retinopathy was detected in 328/1600 (20.5%) of those with diabetes; 114/1724 (6.6%) had hard exudate, 28/1600 (1.8%) had proliferative diabetic retinopathy, and 27/1662 (1.6%) had macular edema. The prevalence of diabetic retinopathy was higher in blacks (27.7%) compared with whites (16.7%). Controlling for duration of diabetes, serum glucose, systolic blood pressure, and type of diabetes medications taken, severity of retinopathy was associated with carotid artery intima-media wall thickness (odds ratio [OR]/0.1-mm thickness 1.09; 95% confidence interval [Cl], 1.01, 1.17; P = 0.01), serum albumin (OR/0.1 g/dl 0.94; 95% Cl, 0.88, 0.99; P = 0.02), but not race (OR blacks versus whites,1.24; 95% Cl, 0.88, 1.75; P = 0.21). Severity of diabetic retinopathy was not associated with coronary artery disease or stroke history or any of the plasma lipids studied. Controlling for age, gender, duration of diabetes, serum glucose, and type of diabetes medications taken, the presence of retinal hard exudates was associated with plasma low-density lipoprotein cholesterol (OR/10 mg/dl 1.18; 95% Cl, 1.09,1.29; P < 0.001), and plasma Lp(a) (OR/10 mg/dl 1.02; 95% Cl, 1.00, 1,05; P = 0.04) but not race or blood pressure. Conclusions. These data suggest that plasma lipids are associated with the presence of hard exudate and that carotid artery intima-media wall thickness is associated with retinopathy, but other manifestations of atherosclerosis and most of its risk factors are not associated with severity of diabetic retinopathy. Ophthalmology 2002;109:1225-1234 (C) 2002 by the American Academy of Ophthalmology. C1 NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, 610 N Walnut St,460 WARF, Madison, WI 53705 USA. FU NEI NIH HHS [EY 06594]; NHLBI NIH HHS [HL 59259, N01-HC 55015, R01-HC 35125, R01-HC 55018, R01-HC 55019, R01-HC 55020, R01-HC 55021] NR 62 TC 126 Z9 141 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2002 VL 109 IS 7 BP 1225 EP 1234 DI 10.1016/S0161-6420(02)01074-6 PG 10 WC Ophthalmology SC Ophthalmology GA 568BK UT WOS:000176522400013 PM 12093643 ER PT J AU Vitolo, JM Baum, BJ AF Vitolo, JM Baum, BJ TI The use of gene transfer for the protection and repair of salivary glands SO ORAL DISEASES LA English DT Article DE salivary glands; gene transfer; gene therapy; radiation; Sjogren's syndrome ID SUPEROXIDE-DISMUTASE TRANSGENE; COLLAGEN-INDUCED ARTHRITIS; CELLS IN-VITRO; SJOGRENS-SYNDROME; MEDIATED TRANSFER; INFLAMMATORY RESPONSES; GLUTATHIONE-PEROXIDASE; RHEUMATOID-ARTHRITIS; SUBMANDIBULAR GLANDS; IMMUNE-RESPONSES C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, NIH Bldg 10,Room 1N113,SC-1190, Bethesda, MD 20892 USA. NR 78 TC 23 Z9 23 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1354-523X J9 ORAL DIS JI Oral Dis. PD JUL PY 2002 VL 8 IS 4 BP 183 EP 191 DI 10.1034/j.1601-0825.2002.02865.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 570MR UT WOS:000176662500003 PM 12206399 ER PT J AU Canto, MT Horowitz, AM Drury, TF Goodman, HS AF Canto, MT Horowitz, AM Drury, TF Goodman, HS TI Maryland family physicians' knowledge, opinions and practices about oral cancer SO ORAL ONCOLOGY LA English DT Article DE oral cancer; screening; Maryland family phsicians; knowledge; practices ID SQUAMOUS-CELL CARCINOMA; BASE-LINE DATA; PHARYNGEAL CANCER; UNITED-STATES; DENTISTS; PREVENTION; TOBACCO; LESIONS; ADULTS; TONGUE AB The objective of this study was to assess family physicians' knowledge. opinions and practices regarding oral cancers in the state of Maryland, USA. A 40-item, self-administered questionnaire was mailed to all members of the Maryland Academy of Family Physicians. Unweighted data (n=240) were analyzed using SAS and SUDAAN software: results were evaluated using an alpha less than or equal to0.05. Family physicians (FPs) were aware of the major risk factors for oral cancers, but misinformation existed about the non-risk factors. Approximately 77% asked their patients the eight questions related to risk factors for oral cancer when taking a medical history but less than 24% provided an oral cancer examination to patients 40 years of age and over. Nearly 64% were interested in a continuing education course about oral cancer. This survey identified gaps in knowledge and practices among FPs but it is eucouraging that they expressed interest in continuing education courses on this topic. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Dental Craniofacial Res, Bethesda, MD 20892 USA. Maryland Dept Hlth & Mental Hyg, Off Oral Hlth, Baltimore, MD 21201 USA. RP Canto, MT (reprint author), Natl Inst Dental Craniofacial Res, 45 Ctr Dr,Bldg 45,Room 3 AN44, Bethesda, MD 20892 USA. NR 31 TC 37 Z9 37 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2002 VL 38 IS 5 BP 416 EP 424 AR PII S1368-8375(01)00080-X DI 10.1016/S1368-8375(01)00080-X PG 9 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 575HY UT WOS:000176941900002 PM 12110334 ER PT J AU Eliav, E Teich, S Benoliel, R Nahlieli, O Lewkowicz, AA Baruchin, A Gracely, R AF Eliav, E Teich, S Benoliel, R Nahlieli, O Lewkowicz, AA Baruchin, A Gracely, R TI Large myelinated nerve fiber hypersensitivity in oral malignancy SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID NUMB CHIN SYNDROME; SQUAMOUS-CELL CARCINOMA; NEUROPATHY; PAIN; CANCER AB Objectives. The purpose of this study was to assess the sensory function of trigeminal nerve A-beta fibers in suspected soft tissue oral malignancies. Study design. Twenty-three patients referred for the evaluation of an oral lesion suspected of malignancy were included in the study. All lesions were classified as in, near, or out of the nerve territory containing the lesion. Within these subgroups we assessed the sensitivity of A-beta primary afferents to weak electrical currents applied bilaterally to regions innervated by 3 peripheral branches of the trigeminal nerve. The ratio of electrical detection thresholds from the affected and the unaffected side was calculated. Electrical detection threshold ratios were contrasted with the results of physical examination, radiographic imaging, and biopsy. Results: For dermatomes containing the lesions, ratios were lower than 0.8 in 12 patients. Biopsy showed that the lesions in 10 of these 12 patients were malignant. No malignancy was found in the remaining 11 patients. Conclusions. A-beta primary afferent hypersensitivity is observed to occur in nerves exposed to soft tissue oral malignancy. C1 Hadassah Sch Dent Med, Dept Oral Diag Oral Med & Radiol, IL-91120 Jerusalem, Israel. Barzilia Med Ctr, Dept Maxillofacial Surg, Ashqelon, Israel. NIDCR, Clin Measurements & Mechanisms Unit, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD USA. RP Eliav, E (reprint author), Hadassah Sch Dent Med, Dept Oral Diag Oral Med & Radiol, POB 12272, IL-91120 Jerusalem, Israel. NR 17 TC 26 Z9 27 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD JUL PY 2002 VL 94 IS 1 BP 45 EP 50 DI 10.1067/moe.2002.126016 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 589GW UT WOS:000177751300010 PM 12193892 ER PT J AU Monge, P Wesseling, C Rodriguez, AC Cantor, KP Weiderpass, E Reutfors, J Ahlbom, A Partanen, T AF Monge, P Wesseling, C Rodriguez, AC Cantor, KP Weiderpass, E Reutfors, J Ahlbom, A Partanen, T TI Childhood leukaemia in Costa Rica, 1981-96 SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID LEUKEMIA; CANCER AB Childhood leukaemia incidence in Costa Rica during 1981-96, among the highest in the world, was analysed by histology, gender, birth year, time period of diagnosis, age at diagnosis and region. Numbers of cases were extracted from the database of the National Cancer Registry (RNT) of Costa Rica. Person-years at risk were calculated from census data and post-census population estimates. During the follow-up, 918 cases of leukaemia in children under 15 years (510 boys, 408 girls) were reported to the RNT (41% of all childhood malignancies), with an overall age-standardised incidence rate of 56 per million person-years. Acute lymphocytic leukaemia (ALL) represented 79% and acute non-lymphocytic leukaemia (ANLL) 16% of the cases, with rates of 43 and 9 per million person-years respectively. There were downward trends in incidence of total leukaemias, ALL and ANLL and 'not otherwise specified' (NOS) combined. Incidence of ALL was highest at 1-4 years of age in boys and girls, whereas ANLL peaked in girls during the first year of life. During 1991-96, the decrease in ALL was significant (P = 0.042). A multivariable Poisson regression model identified significant excesses of ALL for boys, for age groups 1-4 and 5-9 years and for three out of seven regions. Possible reasons for the high rates in Costa Rica are discussed. C1 Univ Nacl, Cent Amer Inst Studies Tox Subst IRET, Heredia, Costa Rica. Social Secur Costa Rica, San Jose, Costa Rica. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. Karolinska Inst, Stockholm, Sweden. RP Monge, P (reprint author), Univ Nacl, Cent Amer Inst Studies Tox Subst IRET, POB 86-3000, Heredia, Costa Rica. RI Weiderpass, Elisabete/M-4029-2016 OI Weiderpass, Elisabete/0000-0003-2237-0128 NR 22 TC 16 Z9 19 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2002 VL 16 IS 3 BP 210 EP 218 DI 10.1046/j.1365-3016.2002.00422.x PG 9 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 574TU UT WOS:000176906300005 PM 12123433 ER PT J AU Rosier, EM Iadarola, MJ Coghill, RC AF Rosier, EM Iadarola, MJ Coghill, RC TI Reproducibility of pain measurement and pain perception SO PAIN LA English DT Article DE pain measurement; reproducibility; pain perception; visual analogue scale; verbal descriptor scale ID VISUAL ANALOG; SCALES; TEMPERATURE; VALIDATION; STIMULI AB The reproducibility of both the conscious experience of pain and the reproducibility of psychophysical assessments of pain remain critical, yet poorly characterized factors in pain research and treatment. To assess the reproducibility of both the pain experience and two methods of pain assessment, 15 subjects evaluated experimental heat pain during four weekly sessions. In each session, both brief (5 s) and prolonged (90 s) heat stimuli were utilized to determine effects of stimulus duration on reproducibility. Multiple presentations of the brief heat stimuli in each session were used to evaluate effects of response averaging. Both visual analog scales (VAS) and randomized verbal descriptor scales (VDS) were employed to better distinguish variations in the pain experience from variations in pain scale usage. Subjects also rated the intensity of visual stimuli in order to provide an independent assessment of the session-to-session variation in the use of both types of scales. Within-subjects analyses revealed that ratings of visual stimuli exhibited significantly less session-to-session variation than ratings of heat pain. Thus, pain perceptions were more variable than perceptions of visual stimuli after controlling for session-to-session variations in scale usage. Comparisons between scales indicated that intensity ratings acquired with the VAS had significantly smaller session-to-session variation than those acquired with the VDS, although VDS ratings were spread across a larger range of the scale. For both scales, analyses of the effects of stimulus averaging and stimulus duration revealed that averaging multiple assessments of the same stimulus substantially reduces session-to-session variation and that multiple assessments of brief stimuli produce responses which are more reproducible than a single presentation of a prolonged stimulus. However, the VAS was significantly more sensitive to small differences in perceived pain intensity and pain unpleasantness, and did not exhibit some of the order effects present with the VDS. Taken together, these results indicate that the reproducibility of psychophysical ratings of pain can be maximized: (1) by averaging responses to multiple, brief stimuli; (2) by providing subjects with a training period distinct from the study period; and (3) by ensuring that interpretation of scale parameters remains constant over time. Thus, although the experiences of both experimental and clinical pain are highly variable, pain assessment procedures can be structured to minimize session-to-session variability. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Coghill, RC (reprint author), Wake Forest Univ, Sch Med, Dept Neurobiol & Anat, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NINDS NIH HHS [NS 39426] NR 16 TC 99 Z9 100 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2002 VL 98 IS 1-2 BP 205 EP 216 AR PII S0304-3959(02)00048-9 DI 10.1016/S0304-3959(02)00048-9 PG 12 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 579XN UT WOS:000177204300023 PM 12098633 ER PT J AU Dickens, DS Kozielski, R Khan, J Forus, A Cripe, TP AF Dickens, DS Kozielski, R Khan, J Forus, A Cripe, TP TI Cyclooxygenase-2 expression in pediatric sarcomas SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE Ewing sarcoma; osteosarcoma; rhabdomyosarcoma; cyclooxygenase-2 ID CELL-LINES; PROGNOSTIC-SIGNIFICANCE; ENHANCED EXPRESSION; EPITHELIAL-CELLS; COX-2 INHIBITOR; URINARY-BLADDER; BREAST-CANCER; COLON-CANCER; ASPIRIN USE; IN-VITRO AB Therapies for metastatic pediatric sarcomas have reached maximum tolerated doses, but continue to provide suboptimal cure rates. Additionally, these treatments are associated with numerous short- and long-term side effects. Therefore, the search for newer, less toxic therapeutic agents is warranted. Overexpression of the inducible enzyme, cyclooxygenase-2 (COX-2), has been discovered in a variety of adult solid tumors and numerous studies have shown COX-2 inhibitors to have significant antiproliferative effects. Therefore, we sought to determine the expression of COX-2 in pediatric sarcomas. We evaluated rhabdomyosarcoma (RMS), osteosarcoma (OS), and Ewing sarcoma (EWS) samples for COX-2 expression by immunohistochemical analysis as well as by cDNA microarray analysis. COX-2 expression was detected in 48/58 (82.8%) tumors by immunohistochemistry and in an additional 52/59 (88.1%) tumors tested by microarray gene analysis. There was a trend toward increased COX-2 expression in metastatic rhabdomyosarcoma and osteosarcoma, though it did not reach clinical significance. The degree of COX-2 immunoreactivity did not vary significantly with other clinicopathologic features such as age, gender, or histologic classification. We conclude that the majority of these pediatric sarcoma samples express COX-2 to varying degrees. Therefore, studies testing the efficacy of COX-2 inhibitors in the treatment of pediatric sarcomas are warranted. C1 Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Hematol Oncol, Cincinnati, OH 45229 USA. Cincinnati Childrens Hosp Med Ctr, Div Pathol & Lab Med, Cincinnati, OH 45229 USA. NCI, Pediat Oncol Branch, Gaithersburg, MD 20877 USA. Norwegian Radium Hosp, Dept Tumor Biol, N-0310 Oslo, Norway. RP Dickens, DS (reprint author), Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Hematol Oncol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Dickens, David/0000-0001-8821-6022 NR 45 TC 46 Z9 48 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD JUL-AUG PY 2002 VL 5 IS 4 BP 356 EP 364 DI 10.1007/s10024-002-005-1 PG 9 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 575FV UT WOS:000176937000004 PM 12024286 ER PT J AU Church, JA Cunningham, C Hughes, M Palumbo, P Mofenson, LM Delora, P Smith, E Wiznia, A Purdue, L Hawkins, E Sista, P AF Church, JA Cunningham, C Hughes, M Palumbo, P Mofenson, LM Delora, P Smith, E Wiznia, A Purdue, L Hawkins, E Sista, P CA PACTG P1005 Study Team TI Safety and antiretroviral activity of chronic subcutaneous administration of T-20 in human immunodeficiency virus 1-infected children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT 8th Conference on Retroviruses and Opportunistic Infections CY FEB 04-08, 2001 CL CHICAGO, ILLINOIS DE human immunodeficiency virus; antiretroviral therapy; T-20; human immunodeficiency virus entry inhibitor; human immunodeficiency virus fusion inhibitor ID HIV-1 GP41; THERAPY; TYPE-1; RESISTANCE; INHIBITOR AB Background. Entry inhibitors, a new class of antiretroviral agents, interfere with the attachment, coreceptor interaction or fusion of HIV-1 with host target cells. The fusion inhibitor T-20 is the first in this new class, and the present study is the first to examine chronic se administration of T-20 to HIV-1-infected children. Methods. Fourteen children, 4 to 12 years of age, with incompletely suppressed HIV-1 were studied. The median plasma viral load at baseline was 26 866 copies/ml (4.4 log(10)), and the median CD4 count was 523 cells/mm(3). T-20 was administered twice daily by sc injection at 30 or 60 mg per m(2) of body surface area per dose. For 7 days T-20 was added to the patients' background antiretroviral regimens; at Day 7 each subject's background therapy was changed to a regimen that was predicted to be virologically active, while T-20 was continued. Results are presented for the first 24 weeks of chronic T-20 dosing. Results. T-20 was generally well-tolerated. One child discontinued the drug because of aversion to injections, but no child discontinued because of adverse events. Eleven (79%) of 14 children had local injection site reactions at some time during the chronic T-20 dosing. Eleven of 14 subjects achieved the protocol-specified milestone of at least a 0.7-log(10) reduction in plasma HIV-1 RNA by Day 7. In 10 subjects (71%) virologic suppression of 1.0 log(10) or greater was achieved at 24 weeks; 6 subjects (43%) had viral loads <400 copies/ml and 3 (21%) had fewer than 50 copies/ml at 24 weeks. Conclusions. These results indicate that a 24-week regimen of twice daily sc dosing of T-20 in HIV-1-infected children is safe and tolerable and that it is associated with suppression of HIV-1 replication during 24 weeks of administration. C1 Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Dept Pediat, Los Angeles, CA 90027 USA. Trimeris Inc, Durham, NC USA. Jacobi Med Ctr, Bronx, NY USA. NIAID, Div Aids, Bethesda, MD 20892 USA. NIAID, Pediat Med Branch, Bethesda, MD 20892 USA. Hoffmann La Roche, Nutley, NJ USA. NICHD, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. Pediat AIDS Clin Trials Grp Operat Ctr, Rockville, MD USA. Univ Med & Dent New Jersey, Dept Pediat, Div Allergy Immunol & Infect Dis, Newark, NJ USA. Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. SUNY Syracuse, Upstate Med Univ, Syracuse, NY USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. RP Church, JA (reprint author), Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Dept Pediat, 4650 Sunset Blvd,Mail Stop 75, Los Angeles, CA 90027 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 20 TC 33 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2002 VL 21 IS 7 BP 653 EP 659 DI 10.1097/01.inf.0000020900.21870.0b PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 574NJ UT WOS:000176896200009 PM 12237598 ER PT J AU Bauman, LJ Wright, E Leickly, FE Carin, E Kurszon-Moran, D Wade, SL Visness, CM AF Bauman, LJ Wright, E Leickly, FE Carin, E Kurszon-Moran, D Wade, SL Visness, CM TI Relationship of adherence to pediatric asthma morbidity among inner-city children SO PEDIATRICS LA English DT Article DE adherence; asthma; morbidity; inner-city; child ID MEDICATION COMPLIANCE; DRUG-THERAPY; PATIENT; REGIMENS; PATTERNS; USAGE AB Objectives. Morbidity from asthma among children is one of the most important US health concerns. This study examines the relationship of baseline nonadherence to subsequent asthma morbidity among inner-city children. Methods. A multisite, prospective, longitudinal panel study was conducted of 1199 children who were aged 4 to 9 years and had asthma and their caregivers, most of whom were parents, in emergency departments and clinics at 8 research centers in 7 US metropolitan inner-city areas. Nine morbidity indicators were collected at 3, 6, and 9 months after baseline, including hospitalizations, unscheduled visits, days of wheeze/cough, and days of reduced activities. Results. Children whose caregivers scored high on a new measure, Admitted Nonadherence, experienced significantly worse morbidity on 8 of the 9 measures. Children who scored high on a new Risk for Nonadherence measure experienced significantly worse morbidity on all 9 morbidity measures. Multiple and logistic regressions found that the adherence measures had independent significant effects on morbidity. Combining the measures improved estimates of morbidity: children whose caregivers were poor on either adherence measure had worse morbidity than those with good adherence on both, eg, rate of hospitalization was twice as high, they missed more than twice as much school, had poorer overall functioning, and experienced more days of wheezing and more restricted days of activity. Conclusions. Risk for Nonadherence and Admitted Nonadherence independently and jointly predicted subsequent asthma morbidity. Targeting risks for nonadherence may be an effective intervention strategy. Most risks can be controlled by physicians through reducing the complexity of asthma regimens, communicating effectively with caregivers about medication use, and correcting family misconceptions about asthma medication side effects. C1 Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. Childrens Hosp Montefiore, Bronx, NY USA. New England Res Inst, Watertown, MA 02172 USA. James Whitcomb Riley Hosp Children, Dept Pediat, Indianapolis, IN 46202 USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Rho Fed Syst Div Inc, Chapel Hill, NC USA. RP Bauman, LJ (reprint author), NIAID, DAIT, Solar Bldg Rm 4A42,6003 Execut Blvd, Bethesda, MD 20892 USA. FU PHS HHS [A1-30772, A1-30753, A1-30756, A1-30773-01, A1-30779, A1-30780, A1-330777, N01-A1-15105, UO1 A1-30751] NR 42 TC 80 Z9 81 U1 2 U2 9 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 JUL PY 2002 VL 110 IS 1 AR e6 DI 10.1542/peds.110.1.e6 PG 7 WC Pediatrics SC Pediatrics GA 568TP UT WOS:000176560200006 PM 12093987 ER PT J AU Lee, G Pollard, HB Arispe, N AF Lee, G Pollard, HB Arispe, N TI Annexin 5 and apolipoprotein E2 protect against Alzheimer's amyloid-beta-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site SO PEPTIDES LA English DT Review DE Alzheimer's disease; amyloid-beta-protein; phosphatidylserine; annexin 5; apoE; cytotoxicity ID RECEPTOR-RELATED PROTEIN; ENZYME COMPLEX RECEPTOR; PLANAR LIPID BILAYERS; NEURONAL CELL-LINE; C-TERMINAL DOMAIN; NEURITE OUTGROWTH; CALCIUM CHANNELS; DOWNS-SYNDROME; E GENOTYPE; A-BETA AB Amyloid-beta-protein (betaA/4, AbetaP) accumulates in the brains of patients with Alzheimer's disease AD), regardless of genetic etiology, and is thought to be the toxic principle responsible for neuronal cell death. The epsilon4 allele of apoE has been linked closely to earlier onset of AD and increased deposition of the amyloid peptide. regardless of the clinical status of AD, while the apoE epsilon2 allele is generally protective. We have previously hypothesized that the cell target for amyloid peptide might be the apoptotic signal molecule phosphatidylserine (PS). We report here that annexin 5, a specific ligand for PS, not only blocks amyloid peptide AbetaP[1-40] cytotoxicity, but competitively inhibits AbetaP[1-40]-dependent aggregation of PS liposomes. In addition, we find that apoE2, but not apoE4, can not only perform the same protective effect on cells exposed to AbetaP[1-40], but can also competitively inhibit PS liposome aggregation and fusion by the amyloid peptide. Altogether, the in vivo and in vitro results reported here provide fundamental insight to the process by which amyloid targets specific neurons for destruction, and suggest that PS may be a surface "receptor" site for AbetaP binding. These results also provide a biochemical mechanism by which the apoE epsilon2 allele, but not apoE epsilon4, can be protective towards the incidence and progression of Alzheimer's disease. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIDDK, Lab Cell Biol & Biochem, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Inst Mol Med, Bethesda, MD 20814 USA. RP Arispe, N (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 101 TC 60 Z9 62 U1 1 U2 10 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 JUL PY 2002 VL 23 IS 7 BP 1249 EP 1263 AR PII S0196-9781(02)00060-8 DI 10.1016/S0196-9781(02)00060-8 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 586UG UT WOS:000177603400007 PM 12128082 ER PT J AU Tanus-Santos, JE Desai, M Deak, LR Pezzullo, JC Abernethy, DR Flockhart, DA Freedman, JE AF Tanus-Santos, JE Desai, M Deak, LR Pezzullo, JC Abernethy, DR Flockhart, DA Freedman, JE TI Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiol SO PHARMACOGENETICS LA English DT Article DE endothelial nitric oxide synthase; estradiol; genetics; platelets ID MISSENSE GLU298ASP VARIANT; CORONARY-ARTERY DISEASE; MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; 5'-FLANKING REGION; T-786->C MUTATION; VASCULAR-DISEASE; IN-VITRO; AGGREGATION; SPASM AB Impaired platelet-derived nitric oxide (NO) contributes to acute coronary syndromes by enhancing platelet recruitment and thrombus formation. Polymorphic variants of the endothelial NO synthase (eNOS) gene have been associated with cardiovascular diseases. To examine whether eNOS variants affect platelet-derived NO and platelet function, and to assess the effects of estradiol on platelet function, we studied platelets from 47 healthy caucasians who were genotyped for eNOS polymorphisms in the promoter region (T-786 C), in intron 4, and in exon 7 (Glu298Asp). Platelet aggregation, platelet-derived NO and superoxide production were measured in control samples and samples pretreated with 17-alpha-estradiol (10 nmol/l). The occurrence of variants in the promoter region (P= 0.002) or in exon 7 (P= 0.007), but not in intron 4 (P > 0.05), were associated with lower levels of platelet-derived NO. An increased (P= 0.047) release of superoxide was observed with platelets from subjects with the variant in the promoter region, but not with other eNOS genetic variants. The eNOS gene polymorphisms did not affect ADP-induced platelet aggregation (P> 0.05). However, estradiol significantly increased platelet aggregation (P = 0.004), and platelet-derived superoxide (P= 0.047) in individuals homozygous for the variant in exon 7, but not in subject with other genotypes. These data demonstrate that the eNOS variants in the promoter region and in exon 7 decrease platelet-derived NO and that estradiol significantly increases platelet aggregation in homozygous-for the variant in exon 7 but not in subjects with other genotypes, suggesting that eNOS variants may influence the thrombotic response. C1 Georgetown Univ, Sch Med, Div Clin Pharmacol, Washington, DC USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Tanus-Santos, JE (reprint author), NIDDK, Biol Chem Lab, Bldg 10,Room 9N-307, Bethesda, MD 20892 USA. RI Tanus-Santos, Jose/A-4451-2008 FU NHLBI NIH HHS [HL 62267]; NIA NIH HHS [AG 08226]; NIGMS NIH HHS [R01-GM56898-01, U01-GM61373]; PHS HHS [T32-9M08386] NR 38 TC 81 Z9 86 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JUL PY 2002 VL 12 IS 5 BP 407 EP 413 DI 10.1097/00008571-200207000-00008 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 582XK UT WOS:000177376300008 PM 12142730 ER PT J AU Schindler, CW Cannona, GN AF Schindler, CW Cannona, GN TI Effects of dopamine agonists and antagonists on locomotor activity in male and female rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE cocaine; dopamine; activity; sex; rat ID SEX-DIFFERENCES; BEHAVIORAL SENSITIZATION; COCAINE; QUINPIROLE; GBR-12909; FISCHER AB Male and female Sprague-Dawley rats were treated with cocaine, the specific dopamine uptake inhibitor GBR 12909, the doparnine D1 agonist SKF 82958 or the dopamine D2 agonist quinpirole. After treatment, the rats were placed in an activity chamber for 30 min and locomotor activity was monitored. Cocaine, GBR 12909 and SKF 82958 all increased locomotor activity in both males and females, but greater increases were observed in females. In contrast, quinpirole produced decreases in activity, with males showing greater decreases than females. Separate groups of animals were given SCH 23390 or eticlopride prior to cocaine. The D1 antagonist SCH 23390 reduced the locomotor activating effects of cocaine in both males and females, with females showing greater sensitivity to SCH 23390. The D2 antagonist eticlopride also reduced the locomotor activating effects of cocaine, with no clear differences between males and females. These results suggest that the differences between males and females in their locomotor response to cocaine can be at least partially attributed to differences in the function of dopamine D1 and D2 receptors. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIDA, Preclin Pharmacol Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 18 TC 65 Z9 67 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUL PY 2002 VL 72 IS 4 BP 857 EP 863 AR PII S0091-3057(02)00770-0 DI 10.1016/S0091-3057(02)00770-0 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 576EV UT WOS:000176990600012 PM 12062575 ER PT J AU Rothman, RB Baumann, MH AF Rothman, RB Baumann, MH TI Therapeutic and adverse actions of serotonin transporter substrates SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE fenfluramine; serotonin transporter; valvular heart disease; primary pulmonary hypertension; neurotoxicity ID PRIMARY PULMONARY-HYPERTENSION; BIOGENIC-AMINE TRANSPORTERS; APPETITE-SUPPRESSANT DRUGS; VALVULAR HEART-DISEASE; VASCULAR SMOOTH-MUSCLE; CENTRAL-NERVOUS-SYSTEM; D-FENFLURAMINE; RAT-BRAIN; NEUROTRANSMITTER TRANSPORTERS; SHORT-TERM AB A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and ( -) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and ( -)-norfenfluramine. Fenfluramines and norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT2B and 5-HT2C receptor agonist, The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 183 TC 109 Z9 111 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD JUL PY 2002 VL 95 IS 1 BP 73 EP 88 AR PII S0163-7258(02)00234-6 DI 10.1016/S0163-7258(02)00234-6 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 590BA UT WOS:000177796300005 PM 12163129 ER PT J AU Heinz, A Jones, DW Bissette, G Hommer, D Ragan, P Knable, M Wellek, S Linnoila, M Weinberger, DR AF Heinz, A Jones, DW Bissette, G Hommer, D Ragan, P Knable, M Wellek, S Linnoila, M Weinberger, DR TI Relationship between cortisol and serotonin metabolites and transporters in alcolholism SO PHARMACOPSYCHIATRY LA English DT Article ID I-123 BETA-CIT; PITUITARY-ADRENOCORTICAL AXIS; FLUID MONOAMINE METABOLITES; HEALTHY-HUMAN SUBJECTS; HUMAN BRAIN; IN-VIVO; RAT-BRAIN; DOPAMINE TRANSPORTERS; ALCOHOL-CONSUMPTION; DEPRESSED-PATIENTS AB Background: Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. Methods: The availability of serotonin transporters was measured with [1-123]beta-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. Results: Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. Conclusion: Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, Intramural Res Program, Bethesda, MD 20892 USA. Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MI USA. Univ Heidelberg, Ctr Inst Mental Hlth, D-6800 Mannheim, Germany. RP Heinz, A (reprint author), Dept Psychiat Charite, Schumannstr 20-21, D-10117 Berlin, Germany. NR 65 TC 43 Z9 45 U1 4 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD JUL PY 2002 VL 35 IS 4 BP 127 EP 134 DI 10.1055/s-2002-33197 PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 582XR UT WOS:000177376900001 PM 12163982 ER PT J AU McDuffie, JR Calis, KA Booth, SL Uwaifo, GI Yanovski, JA AF McDuffie, JR Calis, KA Booth, SL Uwaifo, GI Yanovski, JA TI Effects of orlistat on fat-soluble vitamins in obese adolescents SO PHARMACOTHERAPY LA English DT Article ID GASTROINTESTINAL LIPASE INHIBITOR; CUTANEOUS SYNTHESIS; HEALTHY-VOLUNTEERS; CONTROLLED TRIAL; DOUBLE-BLIND; K STATUS; ABSORPTION; CHOLESTEROL; REDUCTION; RETINOL AB Study Objectives. To determine whether orlistat causes fat-soluble vitamin deficiencies in African-American and Caucasian adolescents. Design. Prospective, open-label pilot study. Setting. Warren Grant Magnuson Clinical Center of the National Institutes of Health. Patients. Seventeen adolescents with body mass indexes above the 95th percentile for age, race, and gender who also had at least one obesity-related comorbid condition. Intervention. Subjects received orlistat 120 mg 3 times/day and a daily multivitamin supplement containing vitamin A 5000 IU, vitamin D 400 TU, vitamin E 300 IU, and vitamin K 25 mug. Measurements and Main Results. During 3-6 months of orlistat treatment, acute absorption of retinol (vitamin A) was not significantly altered, but absorption of a-tocopherol (vitamin E) was significantly reduced compared with baseline levels (p<0.001). Serum levels of vitamins A and E did not change significantly however, there was a nonsignificant decrease in vitamin K. Mean vitamin D levels were significantly reduced compared with baseline (p<0.02) after I month of orlistat, despite multivitamin supplementation. Conclusion. It may be prudent to monitor vitamin D concentrations in adolescents who take orlistat, even when a multivitamin is prescribed. C1 NICHD, Unit Growth & Obes, DEB, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Drug Informat Serv, Dept Pharm, Bethesda, MD 20892 USA. Tufts Univ, Ctr Aging, Jean Mayer US Dept Agr Human Nutr Res, Boston, MA 02111 USA. RP McDuffie, JR (reprint author), NICHD, Unit Growth & Obes, DEB, NIH, 10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 NR 49 TC 68 Z9 69 U1 1 U2 8 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2002 VL 22 IS 7 BP 814 EP 822 DI 10.1592/phco.22.11.814.33627 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 569RV UT WOS:000176616700002 PM 12126214 ER PT J AU An, KP Athar, M Tang, XW Katiyar, SK Russo, J Beech, J Aszterbaum, M Kopelovich, L Epstein, EH Mukhtar, H Bickers, DR AF An, KP Athar, M Tang, XW Katiyar, SK Russo, J Beech, J Aszterbaum, M Kopelovich, L Epstein, EH Mukhtar, H Bickers, DR TI Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: Implications for therapeutic approach SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID ARACHIDONIC-ACID METABOLISM; KINASE-C-ALPHA; COX-2 EXPRESSION; MOUSE SKIN; MULTISTAGE CARCINOGENESIS; MOLECULAR PATHOLOGY; COLORECTAL-CANCER; TUMOR-DEVELOPMENT; URINARY-BLADDER; TRANSGENIC MICE AB Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine,SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose X 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm(2)) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer. C1 Columbia Univ, Dept Dermatol, Coll Phys & Surg, New York, NY 10032 USA. Case Western Reserve Univ, Sch Med, Dept Dermatol, Cleveland, OH 44106 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, Dept Dermatol, Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. FU NCI NIH HHS [N01-CN-15109, U19 CA 81888]; NIAMS NIH HHS [P30 AR 44535]; NIEHS NIH HHS [R01 ES 01900] NR 51 TC 133 Z9 140 U1 0 U2 4 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL PY 2002 VL 76 IS 1 BP 73 EP 80 DI 10.1562/0031-8655(2002)076<0073:CEIMAH>2.0.CO;2 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 573XB UT WOS:000176856800010 PM 12126310 ER PT J AU Dagdug, L Berezhkovskii, AM Weiss, GH AF Dagdug, L Berezhkovskii, AM Weiss, GH TI Number of distinct sites visited by a random walker trapped by an absorbing boundary SO PHYSICAL REVIEW E LA English DT Article ID PHOTON MIGRATION; MEDICINE; MODEL; MEDIA AB The number of distinct sites visited by a lattice random walker is a subject of continuing interest in both mathematics and physics. All previous investigations have used the assumption that the lattice is unbounded. An assessment of the amount of tissue interrogated by a photon in reflectance measurements for diagnostic purposes suggests analyzing properties of the average number of distinct sites visited by a random walker trapped by an absorbing plane at time t. We show that for sufficiently large t this number is the same as the average number of distinct sites visited for this time when the surface is not present. A more complete analysis is possible for a random walk on a line terminated by an absorbing point. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Dagdug, L (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 17 TC 5 Z9 5 U1 0 U2 2 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD JUL PY 2002 VL 66 IS 1 AR 012901 DI 10.1103/PhysRevE.66.012901 PN 1 PG 4 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 579WF UT WOS:000177200500071 PM 12241402 ER PT J AU Shumway-Cook, A Patla, AE Stewart, A Ferrucci, L Ciol, MA Guralnik, JM AF Shumway-Cook, A Patla, AE Stewart, A Ferrucci, L Ciol, MA Guralnik, JM TI Environmental demands associated with community mobility in older adults with and without mobility disabilities SO PHYSICAL THERAPY LA English DT Article DE aging; disability; environment; mobility ID ATTENTIONAL DEMANDS; GAIT SPEED; FALLS; DISABLEMENT; STRENGTH AB Background and Purpose. In this study, the influence of 8 dimensions of the physical environment on mobility in older adults with and without mobility disability was measured. This was done in order to identify environmental factors that contribute to mobility disability. Subjects. Subjects were 36 older adults (greater than or equal to70 years of age) who were recruited from 2 geographic sites (Seattle, Wash, and Waterloo, Ontario, Canada) and were grouped according to level of mobility function (physically able [ability to walk 1/2mile (0.8 km) or climb stairs without assistance], physically disabled). Methods. Subjects were observed and videotaped during 3 trips into the community (trip to grocery store, physician visit, recreational trip). Frequency of encounters with environmental features within each of the 8 dimensions was recorded. Differences in baseline characteristics and environmental encounters were analyzed using an analysis of variance or the Fisher exact test, as appropriate. Results. Mobility disability among older adults was not associated with a uniform decrease in encounters with environmental challenges across all dimensions. Environmental dimensions that differed between subjects who were physically able and those with physical disability included temporal factors, physical load, terrain, and postural transition. Dimensions that were not different included distance, density, ambient conditions (eg, light levels and weather conditions), and attentional demands. Discussion and Conclusion. Understanding the relationship of the environment to mobility is crucial to both prevention and rehabilitation of mobility disability in older adults. Among older adults, certain dimensions of the environment may disable community mobility more than others. [Shumway-Cook A, Patla AE, Stewart A, et al. Environmental demands associated with community mobility in older adults with and without mobility disabilities. Phys Ther. 2002;82:670-681.] C1 Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. Univ Waterloo, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. Univ Calif San Francisco, Inst Hlth & Aging, San Francisco, CA 94143 USA. INRCA, Clin Epidemiol, Florence, Italy. Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD USA. RP Shumway-Cook, A (reprint author), Univ Washington, Dept Rehabil Med, Box 356490, Seattle, WA 98195 USA. NR 30 TC 141 Z9 146 U1 2 U2 13 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD JUL PY 2002 VL 82 IS 7 BP 670 EP 681 PG 12 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 569QN UT WOS:000176613700004 PM 12088464 ER PT J AU Mattson, MP Chan, SL Duan, WZ AF Mattson, MP Chan, SL Duan, WZ TI Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior SO PHYSIOLOGICAL REVIEWS LA English DT Review ID AMYLOID-BETA-PEPTIDE; AMYOTROPHIC-LATERAL-SCLEROSIS; GINKGO-BILOBA EXTRACT; PROTECTS HIPPOCAMPAL-NEURONS; PERTURBED CALCIUM HOMEOSTASIS; LONG-TERM POTENTIATION; TRANSGENIC MOUSE MODEL; EXPRESSING MUTANT PRESENILIN-1; MANGANESE SUPEROXIDE-DISMUTASE; PROSTATE APOPTOSIS RESPONSE-4 AB Multiple molecular, cellular, structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively, or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e. g., protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (alpha-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E-4, have more subtle effects on brain aging. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease. C1 NIA, Neurosci Lab, Gerontol Res Ctr 4F01, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr 4F01, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 399 TC 258 Z9 273 U1 10 U2 41 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2002 VL 82 IS 3 BP 637 EP 672 DI 10.1152/physrev.00004.2002 PG 36 WC Physiology SC Physiology GA 569AC UT WOS:000176576300003 PM 12087131 ER PT J AU Bianchi, DW Simpson, JL Jackson, LG Elias, S Holzgreve, W Evans, MI Dukes, KA Sullivan, LM Klinger, KW Bischoff, FZ Hahn, S Johnson, KL Lewis, D Wapner, RJ AF Bianchi, DW Simpson, JL Jackson, LG Elias, S Holzgreve, W Evans, MI Dukes, KA Sullivan, LM Klinger, KW Bischoff, FZ Hahn, S Johnson, KL Lewis, D Wapner, RJ TI Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data SO PRENATAL DIAGNOSIS LA English DT Article DE fetal cells in maternal blood; FISH; prenatal diagnosis; non-invasive ID PRENATAL-DIAGNOSIS; FLOW-CYTOMETRY; CIRCULATION; TRISOMY-21 AB Objectives The National Institute of Child Health and Human Development Fetal Cell Isolation Study (NIFTY) is a prospective, multicenter clinical project to develop non-invasive methods of prenatal diagnosis. The initial objective was to assess the utility of fetal cells in the peripheral blood of pregnant women to diagnose or screen for fetal chromosome abnormalities. Methods Results of fluorescence in situ hybridization (FISH) analysis on interphase nuclei of fetal cells recovered from maternal blood were compared to metaphase karyotypes of fetal cells obtained by amniocentesis or chorionic villus sampling (CVS). After the first 5 years of the study we performed a planned analysis of the data. We report here the data from 2744 fully processed pre-procedural blood samples; 1292 samples were from women carrying singleton male fetuses. Results Target cell recovery and fetal cell detection were better using magnetic-based separation systems (MACS) than with flow-sorting (FACS). Blinded FISH assessment of samples from women carrying singleton male fetuses found at least one cell with an X and Y signal in 41.4% of cases (95% Cl: 37.4%, 45.5%). The false-positive rate of gender detection was 11.1% (95% Cl: 6.1,16.1%). This was higher than expected due to the use of indirectly labeled FISH probes in one center. The detection rate of finding at least one aneuploid cell in cases of fetal aneuploidy was 74.4% (95% Cl: 76.0%, 99.0%,), with a false-positive rate estimated to be between 0.6% and 4.1%. Conclusions The sensitivity of aneuploidy detection using fetal cell analysis from maternal blood is comparable to single marker prenatal serum screening, but technological advances are needed before fetal cell analysis has clinical application as part of a multiple marker method for non-invasive prenatal screening. The limitations of the present study, i.e. multiple processing protocols, are being addressed in the ongoing study. Copyright (C) 2002 John Wiley Sons, Ltd. C1 Tufts Univ, Sch Med, Dept Pediat, Div Genet, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Obstet & Gynecol, Div Genet, Boston, MA 02111 USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Jefferson Med Coll, Dept Med, Div Med Genet, Philadelphia, PA USA. Jefferson Med Coll, Dept Obstet & Gynecol, Div Med Genet, Philadelphia, PA USA. Med Coll Penn & Hahnemann Univ, Philadelphia, PA USA. Univ Illinois, Dept Obstet & Gynecol, Chicago, IL USA. Univ Basel, Dept Obstet & Gynecol, Basel, Switzerland. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. DM STAT, Medford, MA USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Genzyme Genet, Framingham, MA USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. NICHHD, Mental Retardat Res Branch, Bethesda, MD 20892 USA. RP Bianchi, DW (reprint author), Tufts Univ New England Med Ctr, Div Genet, 750 Washington St,Box 394, Boston, MA 02111 USA. FU NICHD NIH HHS [HD4-3201, HD4-3202, HD4-3203, HD4-3204] NR 16 TC 177 Z9 186 U1 0 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD JUL PY 2002 VL 22 IS 7 BP 609 EP 615 DI 10.1002/pd.347 PG 7 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 577NK UT WOS:000177067500015 PM 12124698 ER PT J AU Chokkalingam, AP Gao, YT Deng, J Stanczyk, FZ Sesterhenn, IA Mostofi, FK Fraumeni, JF Hsing, AW AF Chokkalingam, AP Gao, YT Deng, J Stanczyk, FZ Sesterhenn, IA Mostofi, FK Fraumeni, JF Hsing, AW TI Insulin-like growth factors and risk of benign prostatic hyperplasia SO PROSTATE LA English DT Article DE IGF; growth factors; binding proteins; China; epidemiology ID FACTOR-BINDING-PROTEINS; I IGF-I; CANCER RISK; ANDROGENS; CHINA; INSULIN-LIKE-GROWTH-FACTOR-1; EXPRESSION; CELLS AB BACKGROUND. Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate tissue, whereas IGF binding proteins (IGFBI's) inhibit growth of prostatic tissue. The IGF axis has been implicated in prostate cancer risk, but its role in benign prostatic hyperplasia (BPH) is unclear. METHODS. Plasma levels of IGF-I, IGF II, IGFBP-1, and IGFBP-3 were determined from the fasting bloods of 206 BPH cases admitted for treatment and 306 randomly selected population controls in Shanghai, China. RESULTS. Relative to the lowest tertile, men in the highest tertile of IGF-I levels had a significantly elevated risk of BPH (odds ratio [OR]=2.80, 95% confidence interval [95%, CI] =1.60-4.92; P-trend < 0.001). Results for IGF-I were more pronounced after adjustment for serum androgens. In contrast, men in the highest IGFBP-3 tertile had a significantly reduced risk (OR=0.40; 95% CI=0.23-0.69; P-trend < 0.001). No associations of BPH with IGF-II and IGFBP-1 were observed. CONCLUSION. As has been previously observed for prostate cancer, we found that IGF-I and IGFBP-3 are associated with BPH risk in China. Further investigation is needed to elucidate the role of the IGF axis in BPH etiology. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Shanghai Canc Inst, Shanghai, Peoples R China. Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Chokkalingam, AP (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, EPS-MSC-7234,3120 Execut Blvd, Rockville, MD 20852 USA. NR 26 TC 53 Z9 57 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 0270-4137 J9 PROSTATE JI Prostate PD JUL 1 PY 2002 VL 52 IS 2 BP 98 EP 105 DI 10.1002/pros.10096 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 566MB UT WOS:000176431000002 PM 12111701 ER PT J AU Woo, JH Liu, YY Mathias, A Stavrou, S Wang, ZR Thompson, J Neville, DM AF Woo, JH Liu, YY Mathias, A Stavrou, S Wang, ZR Thompson, J Neville, DM TI Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID TRUNCATED DIPHTHERIA-TOXIN; SINGLE-CHAIN IMMUNOTOXIN; HIGH-LEVEL EXPRESSION; SACCHAROMYCES-CEREVISIAE; METHYLOTROPHIC YEAST; EFFICIENT SECRETION; CODON OPTIMIZATION; PROTEIN-L; LOW PH; FRAGMENT AB The bivalent anti-human anti-T cell immunotoxin A-dmDT390-bisFv(G(4)S) was developed for treatment of T cell leukemia, autommume diseases, and tolerance induction for transplantation. The multi-domain structure of the bivalent immunotoxin hinders efficient production in Escherichia coli and most eukaryotes are sensitive to the toxin. However, Pichia pastoris has a tolerance to levels of DT (diphtheria toxin) that were previously observed to intoxicate wild type eukaryotic cells, including Saccharomyces cerevisiae. This tolerance has permitted the optimization of the secreted expression of A-dmDT390-bisFv(G4S) in P. pastoris under the control of AOXI (alcohol oxidase 1) promoter. The original DNA sequence of A-dmDT390-bisFv(G4S) was not expressed in P. pastoris because of several AT-rich regions, which induce an early termination of transcription. After DNA rebuilding for abolishing AT-rich regions and codon optimization, the immunotoxin could be expressed up to 10 mg/L in the shake flask culture. No differences in the expression levels of immunotoxin were observed by using different secretional signal sequences, Mut(s) (methanol utilization slow phenotype) or Mut(+) (methanol utilization plus phenotype) phenotypes. Buffered complex medium (pH 7.0) having 1% casamino acids provided the highest expression in shake flask culture and PMSF (phenylmethylsulfonyl fluoride) in the range of 1 to 3 mM further improved the expression level presumably by inhibiting protein degradation. The immunotoxin was purified by DEAE (diethylaminoethyl) Sepharose ion exchange chromatography and Protein L affinity chromatography. The immunotoxin purified from P. pastoris culture was as fully functional as that expressed in a toxin resistant mutant CHO (Chinese hamster ovary) cell line. Our results demonstrate that P. pastoris is an ideal system for expression of toxin-based fusion proteins. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIMH, Mol Biol Lab, Sect Biophys Chem, Bethesda, MD 20892 USA. Fenske Lab, University Pk, PA 16802 USA. RP Neville, DM (reprint author), NIMH, Mol Biol Lab, Sect Biophys Chem, 36 RM 1 B08,36 Convent Dr, Bethesda, MD 20892 USA. NR 38 TC 67 Z9 74 U1 1 U2 8 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 JUL PY 2002 VL 25 IS 2 BP 270 EP 282 AR PII S1046-5928(02)00009-8 DI 10.1016/S1046-5928(02)00009-8 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 582XW UT WOS:000177377300009 PM 12135560 ER PT J AU Tsai, CJ de Laureto, PP Fontana, A Nussinov, R AF Tsai, CJ de Laureto, PP Fontana, A Nussinov, R TI Comparison of protein fragments identified by limited proteolysis and by computational cutting of proteins SO PROTEIN SCIENCE LA English DT Article DE folding intermediates; limited proteolysis; protein anatomy; protein flexibility; protein folding; protein fragments ID MOLTEN GLOBULE STATE; ALPHA-LACTALBUMIN; RIBONUCLEASE-A; FOLDING UNITS; DYNAMIC CHARACTERIZATION; TERMINAL FRAGMENT; NATIVE PROTEINS; COMPACT UNITS; FOLDED STATES; CYTOCHROME-C AB Here we present a comparison between protein fragments produced by limited proteolysis and those identified by computational cutting based on the building block folding model. The principles upon which the two methods are based are different. Limited proteolysis of natively folded proteins occurs at flexible sites and never at the level of chain segments of regular secondary structure such as alpha-helices. Therefore, the targets for limited proteolysis are locally unfolded regions. In contrast, the computational cutting algorithm considers the compactness of the fragments, their nonpolar buried surface area, and their isolatedness, that is, the surface area which was buried prior to the cutting and becomes exposed subsequently. Despite the different criteria, there is an overall correspondence between sites or regions of limited proteolysis with those identified by computational cutting. The Computational cutting method has been applied to several model proteins for which detailed limited proteolysis data are available, namely apomyoglobin, cytochrome c, ribonuclease A, alpha-lactalbumin, and thermolysin. As expected, more cuts are obtained computationally than experimentally and the agreement is better when a number of proteolytic enzymes are used. For example, cytochrome c is cleaved by thermolysin at 56-57, 45-46, and at 80-81, and by proteinase K at 48-49 and 50-51. Incubation of the noncovalent and native-like complex of cytochrome c fragments 1-56 and 57-104 with proteinase K yielded the gapped protein species 1-48/57-104 and finally 1-40/57-104. Computational cutting of cytochrome c reproduced the major experimental observations, with cuts at 47, 64-65 or 65-66 and 80-81 and an unstable 32-47 region not assigned to any building block. The next step, not addressed in this work, is to probe the ability of the generated fragments to fold independently. Since both the computational algorithm and limited proteolysis attempt to dissect the protein folding problem, the general agreement between the two procedures is gratifying. This consistency allows us to propose the use of limited proteolysis to produce protein fragments that can adopt an independent folding and, therefore, to study folding intermediates. The results of the present study appear to validate the building, block folding model and are in line with the proposal that protein folding is a hierarchical process, where parts constituting local minima of energy fold first, with their subsequent association and mutual stabilization to finally yield the global fold. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Univ Padua, CRIBI Biotechnol Ctr, I-35121 Padua, Italy. Tel Aviv Univ, Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU NCI NIH HHS [N01CO12400, N01 CO 12400] NR 85 TC 26 Z9 28 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2002 VL 11 IS 7 BP 1753 EP 1770 DI 10.1110/ps.4100102 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564QJ UT WOS:000176324800019 PM 12070328 ER PT J AU Aravind, L Anantharaman, V Koonin, EV AF Aravind, L Anantharaman, V Koonin, EV TI Monophyly of class I aminoacyl tRNA synthetase, USPA, ETFP, photolyase, and PP-ATPase nucleotide-binding domains: Implications for protein evolution in the RNA world SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE HUP domain; last universal common ancestor (LUCA); class I aminoacyl-tRNA synthetases ID ELECTRON-TRANSFER FLAVOPROTEIN; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; PSI-BLAST; CYTIDYLYLTRANSFERASE SUPERFAMILY; SEQUENCE; CLASSIFICATION; DATABASE; ALIGNMENT; ENZYME AB Protein sequence and structure comparisons show that the catalytic domains of Class I aminoacyl-tRNA synthetases, a related family of nucleotidyltransferases involved primarily in coenzyme biosynthesis, nucleotide-binding domains related to the UspA protein (USPA domains), photolyases, electron transport flavoproteins, and PP-loop-containing ATPases together comprise a distinct class of alpha/beta domains designated the HUP domain after HIGH-signature proteins, UspA, and PP-ATPase. Several lines of evidence are presented to support the monophyly of the HUP domains, to the exclusion of other three-layered alpha/beta folds with the generic "Rossmann-like" topology. Cladistic analysis, with patterns of structural and sequence similarity used as discrete characters, identified three major evolutionary lineages within the HUP domain class: the PP-ATPases; the HIGH superfamily, which includes class I aaRS and related nucleotidyltransferases containing the HIGH signature in their nucleotide-binding loop; and a previously unrecognized USPA-like group, which includes USPA domains, electron transport flavoproteins, and photolyases. Examination of the patterns of phyletic distribution of distinct families within these three major lineages suggests that the Last Universal Common Ancestor of all modern life forms encoded 15-18 distinct alpha/beta ATPases and nucleotide-binding proteins of the HUP class. This points to an extensive radiation of HUP domains before the last universal common ancestor (LUCA), during which the multiple class I aminoacyl-tRNA synthetases emerged only at a late stage. Thus, substantial evolutionary diversification of protein domains occurred well before the modern version of the protein-dependent translation machinery was established, i.e., still in the RNA world. (C) 2002 Wiley-Liss, Inc. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. OI Anantharaman, Vivek/0000-0001-8395-0009 NR 60 TC 82 Z9 85 U1 0 U2 4 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 JUL 1 PY 2002 VL 48 IS 1 BP 1 EP 14 DI 10.1002/prot.10064 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559AN UT WOS:000176002100001 PM 12012333 ER PT J AU Mahalingam, B Boross, P Wang, YF Louis, JM Fischer, CC Tozser, J Harrison, RW Weber, IT AF Mahalingam, B Boross, P Wang, YF Louis, JM Fischer, CC Tozser, J Harrison, RW Weber, IT TI Combining mutations in HIV-1 protease to understand mechanisms of resistance SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE HIV-1 protease; mutants; catalysis; structure, function ID HUMAN-IMMUNODEFICIENCY-VIRUS; INHIBITOR CROSS-RESISTANCE; TYPE-1 PROTEASE; DRUG-RESISTANCE; DIMER STABILITY; IN-VIVO; SUBSTRATE; GAG; SPECIFICITY; MUTANTS AB HIV-1 develops resistance to protease inhibitors predominantly by selecting mutations in the protease gene. Studies of resistant mutants of HIV-1 protease with single amino acid substitutions have shown a range of independent effects on specificity, inhibition, and stability. Four double mutants, K45I/L90M, K45I/V82S, D30N/V82S, and N88D/L90M were selected for analysis on the basis of observations of increased or decreased stability or enzymatic activity for the respective single mutants. The double mutants were assayed for catalysis, inhibition, and stability. Crystal structures were analyzed for the double mutants at resolutions of 2.2-1.2 Angstrom to determine the associated molecular changes. Sequence-dependent changes in protease-inhibitor interactions were observed in the crystal structures. Mutations D30N, K45I, and V82S showed altered interactions with inhibitor residues at P2/P2', P3/P3'/P4/P4', and P1/P1', respectively. One of the conformations of Met90 in K45I/L90M has an unfavorably close contact with the carbonyl oxygen of Asp25, as observed previously in the L90M single mutant. The observed catalytic efficiency and inhibition for the double mutants depended on the specific substrate or inhibitor. In particular, large variation in cleavage of p6(pol)-PR substrate was observed, which is likely to result in defects in the maturation of the protease from the Gag-Pol precursor and hence viral replication. Three of the double mutants showed values for stability that were intermediate between the values observed for the respective single mutants. D30N/V82S mutant showed lower stability than either of the two individual mutations, which is possibly due to concerted changes in the central P2-P2' and S2-S2' sites. The complex effects of combining mutations are discussed. (C) 2002 Wiley-Liss, Inc. C1 Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. Debrecen Univ, Dept Biochem & Mol Biol, Fac Med, Debrecen, Hungary. NIDDK, Natl Inst Hlth, Chem Phys Lab, Bethesda, MD USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, 402 Kell Hall,24 Peachtree Ctr Ave, Atlanta, GA 30303 USA. RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU NIGMS NIH HHS [R01 GM062920, GM62920]; PHS HHS [A141380] NR 41 TC 41 Z9 44 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 JUL 1 PY 2002 VL 48 IS 1 BP 107 EP 116 DI 10.1002/prot.10140 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559AN UT WOS:000176002100010 PM 12012342 ER PT J AU Elvevag, B Fisher, JE Gurd, JM Goldberg, TE AF Elvevag, B Fisher, JE Gurd, JM Goldberg, TE TI Semantic clustering in verbal fluency: schizophrenic patients versus control participants SO PSYCHOLOGICAL MEDICINE LA English DT Article ID HEALTHY-ADULTS; TASKS; MEMORY AB Background. Schizophrenic patients generate fewer words than healthy controls during verbal fluency tasks. The structure of output may explain why patients generate fewer exemplars. Methods. Twenty-four healthy controls and 24 patients with schizophrenia participated in six, 3 min semantic fluency tasks. In a subsequent session, participants were given cards, each printed with one of their own words generated from previous fluency tasks. Participants were to sort the cards into categories (e.g. subcategories of 'animals'), thus defining their own semantic subcategories of words, and thereby eliminating experimenter assumptions about word relatedness. These clusters were matched with fluency output of each participant. The time spent searching through semantic networks within clusters and switching to other clusters when locating and producing associated words were measured. Results. Patients produced fewer words and spent more time switching to words within clusters and to different clusters than controls, but otherwise response profiles were similar. Although controls returned more frequently to clusters and consequently made more switches between these clusters than patients, this group difference disappeared when the total number of words produced was covaried. Conclusions. Consistent with previous literature, patients produced fewer words and made more errors than controls. The absence of a group difference in number of different clusters or mean number of items per cluster suggests that patients are similar to controls with respect to number of ideas in their semantic network. Patients' longer between-cluster switching times indicate a general slowness that may be attributed to difficulties finding new words within a semantic field. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Oxford, Dept Clin Neurol, Neuropsychol Unit, Oxford, England. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4S235,MSC 1379, Bethesda, MD 20892 USA. NR 28 TC 28 Z9 29 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2002 VL 32 IS 5 BP 909 EP 917 DI 10.1017/S0033291702005597 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 583FX UT WOS:000177397000014 PM 12171385 ER PT J AU Butterweck, V Nahrstedt, A Evans, J Hufeisen, S Rauser, L Savage, J Popadak, B Ernsberger, P Roth, BL AF Butterweck, V Nahrstedt, A Evans, J Hufeisen, S Rauser, L Savage, J Popadak, B Ernsberger, P Roth, BL TI In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs SO PSYCHOPHARMACOLOGY LA English DT Article DE St. John's wort; Hypericum perforatum; hyperforin; hypericin; flavonoids; receptor screening ID TRICYCLIC ANTIDEPRESSANT DESIPRAMINE; SEROTONIN REUPTAKE INHIBITORS; ATYPICAL ANTIPSYCHOTIC AGENTS; RANDOMIZED CONTROLLED TRIAL; BETA-ADRENERGIC RECEPTORS; FORCED SWIMMING TEST; HYPERICUM-PERFORATUM; NEUROTRANSMITTER TRANSPORTERS; IN-VITRO; DOPAMINE-RECEPTORS AB Rationale: Hypericum perforatum L. (St. John's wort; SJW) is one of the leading psychotherapeutic phytomedicines and great effort has been devoted to clarifying its mechanism of action. Objective: We have undertaken a comprehensive analysis of several pure compounds isolated from the crude extract to gain further insight into the molecular actions of various substituents of SJW. Methods: We characterized the in vitro pharmacology of the naphthodianthrones hypericin and pseudohypericin, the phloroglucinol derivative hyperforin, and several flavonoids at 42 biogenic amine receptors and transporters using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. Results: The biflavonoid amentoflavone significantly inhibited binding at serotonin (5-HT1D, 5-HT2C), D-3-dopamine, delta-opiate, and benzodiazepine receptors. The napthodianthrone hypericin had significant activity at D-3- and D-4-dopamine receptors and beta-adrenergic receptors. With the exception of the D-1-dopamine receptor, the phloroglucinol derivative hyperforin was less active than other SJW constituents tested on all screened receptors. Conclusion: Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically. C1 Univ Munster, Inst Pharmacol & Toxicol, D-48149 Munster, Germany. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program,Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program,Dept Psychiat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program,Dept Neurosci, Cleveland, OH 44106 USA. Univ Munster, Inst Pharmaceut Biol & Phytochem, Munster, Germany. Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. RP Butterweck, V (reprint author), Univ Munster, Inst Pharmacol & Toxicol, Domagkstr 12, D-48149 Munster, Germany. RI Roth, Bryan/F-3928-2010; Ernsberger, Paul/O-2702-2014 OI Ernsberger, Paul/0000-0003-2372-2500 FU NIMH NIH HHS [K02MH01366, N01MH80005] NR 69 TC 64 Z9 65 U1 0 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2002 VL 162 IS 2 BP 193 EP 202 DI 10.1007/s00213-002-1073-7 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 577NG UT WOS:000177067000011 PM 12110997 ER PT J AU Abdi, K AF Abdi, K TI IL-12: The role of p40 versus p75 SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material ID ANTIGEN-PRESENTING CELLS; NECROSIS-FACTOR-ALPHA; INTERFERON-GAMMA PRODUCTION; BLOOD MONONUCLEAR-CELLS; STIMULATORY FACTOR NKSF; MURINE DENDRITIC CELLS; NATURAL-KILLER-CELLS; IFN-GAMMA; IN-VIVO; MESSENGER-RNA AB Interleukin (IL)-12p75 is a heterodimeric cytokine composed of the product of two different genes that specify p35 and p40 subunits. The prevailing view is that IL-12 acts as a proinflammatory cytokine that bridges the innate and adaptive immune responses and skews T-cell reactivity toward a T(H)1 cytokine pattern. Though the terms IL-12 and IL-12p40 are often used interchangeably, and measurements of the p40 chain are often interpreted as measurements of the intact p75 heterodimer, such interchangeable usage may be incorrect. In the following discussion, I will delineate an alternative hypothesis for the roles of the p40 and p75 proteins, suggesting specifically, that: (1) in vivo, secretion of free p40 precedes that of p75 in response to pathogens; (2) induction of p40 is a T-independent response by antigen presenting cells (APCs) to early host-pathogen interactions; and (3) IL-12p75 is a late product, whose induction requires T-dependent signals. It is made as a result, rather than as a cause, of T(H)1 differentiation. Thus, it is the p40 protein, either alone or paired with other polypeptides, rather than p75, that acts as an interface between the innate and adaptive immune responses. C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Abdi, K (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 111,MSC-0420, Bethesda, MD 20892 USA. NR 106 TC 65 Z9 70 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 JUL PY 2002 VL 56 IS 1 BP 1 EP 11 DI 10.1046/j.1365-3083.2002.01101.x PG 11 WC Immunology SC Immunology GA 568GA UT WOS:000176533000001 PM 12100467 ER PT J AU Alving, BM AF Alving, BM TI Introduction: New treatment strategies for thrombotic disorders SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Alving, BM (reprint author), NHLBI, Bldg 31,Room 5A47,MSC 2490,31 Ctr Dr, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2002 VL 39 IS 3 BP 143 EP 144 DI 10.1053/shem.2002.34094 PG 2 WC Hematology SC Hematology GA 574CQ UT WOS:000176871200001 ER PT J AU Boesen, CC Radaev, S Motyka, SA Patamawenu, A Sun, PD AF Boesen, CC Radaev, S Motyka, SA Patamawenu, A Sun, PD TI The 1.1 angstrom crystal structure of human TGF-beta type II receptor ligand binding domain SO STRUCTURE LA English DT Article ID TRANSFORMING GROWTH-FACTOR-BETA-2; PROTEIN STRUCTURES; ECTODOMAIN; REFINEMENT; SYSTEM AB Transforming growth factor beta (TGF-beta) is involved in a wide range of biological functions including development, carcinogenesis, and immune regulation. Here we report the 1.1 Angstrom resolution crystal structure of human TGF-beta type II receptor ectodomain (TBRII). The overall structure of TBRII is similar to that of activin type II receptor ectodomain (ActRII) and bone morphogenic protein receptor type IA (BRIA). It displays a three-finger toxin fold with fingers formed by the beta strand pairs beta1-beta2, beta3-beta4, and beta5-beta6. The first finger in the TBRII is significantly longer than in ActRII and BRIA and folds tightly between the second finger and the C terminus. Surface charge distributions and hydrophobic patches predict potential TBRII binding sites. C1 NIAID, Immunogenet Lab, Struct Biol Sect, NIH, Rockville, MD 20852 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Sun, PD (reprint author), NIAID, Immunogenet Lab, Struct Biol Sect, NIH, Rockville, MD 20852 USA. NR 27 TC 36 Z9 45 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 JUL PY 2002 VL 10 IS 7 BP 913 EP 919 AR PII S0969-2126(02)00780-3 DI 10.1016/S0969-2126(02)00780-3 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 569LF UT WOS:000176603300005 PM 12121646 ER PT J AU Martin, TW Dauter, Z Devedjiev, Y Sheffield, P Jelen, F He, M Sherman, DH Otlewski, J Derewenda, ZS Derewenda, U AF Martin, TW Dauter, Z Devedjiev, Y Sheffield, P Jelen, F He, M Sherman, DH Otlewski, J Derewenda, ZS Derewenda, U TI Molecular basis of mitomycin C resistance in Streptomyces: Structure and function of the MRD protein SO STRUCTURE LA English DT Article ID CRYSTAL-STRUCTURE; LAVENDULAE; DIOXYGENASE; MECHANISM; BINDING; DNA; REFINEMENT; BLEOMYCIN; MODEL; 2,7-DIAMINOMITOSENE AB Mitomycin C (MC) is a potent anticancer agent. Streptomyces lavendulae, which produces MC, protects itself from the lethal effects of the drug by expressing several resistance proteins. One of them (MRD) binds MC and functions as a drug exporter. We report the crystal structure of MRD and its complex with an MC metabolite, 1,2-cis-1-hydroxy-2,7-diaminomitosene, at 1.5Angstrom resolution. The drug is sandwiched by pi-stacking interactions of His-38 and Trp-108. MRD is a dimer. The betaalphabetabetabeta fold of the MRD molecule is reminiscent of methylmalonyl-CoA epimerase, bleomycin resistance proteins, glyoxalase 1, and extradiol dioxygenases. The location of the binding site is identical to the ones in evolutionarily related enzymes, suggesting that the protein may have been recruited from a different metabolic pathway. C1 Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. NCI, Frederick & Natl Brookhaven Lab, Upton, NY 11973 USA. Univ Wroclaw, Inst Biochem & Mol Biol, PL-50137 Wroclaw, Poland. Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. Univ Minnesota, Inst Biotechnol, Minneapolis, MN 55455 USA. RP Derewenda, U (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RI Otlewski, Jacek/B-6340-2008 FU NCI NIH HHS [CA81172] NR 44 TC 15 Z9 16 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUL PY 2002 VL 10 IS 7 BP 933 EP 942 AR PII S0969-2126(02)00778-5 DI 10.1016/S0969-2126(02)00778-5 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 569LF UT WOS:000176603300007 PM 12121648 ER PT J AU Vally, H Taylor, ML Thompson, PJ AF Vally, H Taylor, ML Thompson, PJ TI The prevalence of aspirin intolerant asthma (AIA) in Australian asthmatic patients SO THORAX LA English DT Article ID MECHANICAL VENTILATION; POPULATION; DRUGS; EPIDEMIOLOGY; MANAGEMENT; DIAGNOSIS; CHALLENGE AB Background: Aspirin intolerant asthma (AIA) is a clinically distinct syndrome characterised by the precipitation of asthma attacks following the ingestion of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). The prevalence of AIA among Australian asthmatic patients has not previously been reported. Methods: Three populations were surveyed to establish the prevalence of AIA among Australian asthmatics. Two surveys were completed in patients recruited from the metropolitan area in Perth, Western Australia, one comprising 150 recruited from hospital based sources (hospital cohort) and the second comprising 366 from the membership of the Asthma Foundation of Western Australia (Asthma Foundation cohort). In a third study 1298 individuals were randomly selected from the rural community of Busselton in Western Australia. Results: The prevalence of AIA in the hospital and Asthma Foundation cohorts was found to be 10.7% and 10.4%, respectively. Univariate analyses in the Asthma Foundation cohort indicated that AIA was associated with more severe asthma (OR=2.4, 95% CI 1.18 to 4.86), nasal polyposis (OR=3.19 95% CI 1.52 to 6.68), atopy (OR=2.96, 95% CI 1.48 to 5.89), sulfite sensitivity (OR=3.97, 95% CI 1.87 to 8.41), and sensitivity to wine (OR=3.27, 95% CI 1.65 to 6.47). Multivariate analyses indicated that atopy (OR=2.80, 95% CI 1.38 to 5.70), nasal polyposis (OR=3.39, 95% CI 1.57 to 7.29), and the number of asthma attacks in the previous 12 months (OR=1.20, 95% CI 1.02 to 1.42) were independent predictors for AIA, as was wine sensitivity (OR=2.20, 95% CI 1.02 to 4.72). The prevalence of AIA among asthmatic patients in the Busselton cohort was 10.9%. In addition, 2.5% of non-diagnosed asthmatics in this cohort reported asthma symptoms following aspirin ingestion. Conclusion: The prevalence of respiratory symptoms triggered by aspirin/NSAID use was found to be 10-11% in patients with asthma and 2.5% in non-asthmatics. Aspirin sensitivity appears to be a significant problem in the community and further investigations of the mechanisms of these responses and the possible link between this syndrome and other food and chemical sensitivities are required. C1 Univ Western Australia, Asthma & Allergy Res Inst Inc, Perth, WA 6009, Australia. Univ Western Australia, Cooperat Res Ctr Asthma, Perth, WA 6009, Australia. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Vally, H (reprint author), Sir Charles Gairdner Hosp, Asthma & Allergy Res Inst, Ground Floor,E Bloock, Nedlands, WA 6009, Australia. NR 30 TC 100 Z9 101 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD JUL PY 2002 VL 57 IS 7 BP 569 EP 574 DI 10.1136/thorax.57.7.569 PG 6 WC Respiratory System SC Respiratory System GA 575MM UT WOS:000176950100003 PM 12096197 ER PT J AU Benvenga, S Alesci, S Trimarchi, F AF Benvenga, S Alesci, S Trimarchi, F TI High-density lipoprotein-facilitated entry of thyroid hormones into cells: A mechanism different from the low-density lipoprotein-facilitated entry SO THYROID LA English DT Article ID THYROXINE-BINDING-SITES; PLASMA-LIPOPROTEINS; CONFORMATIONAL CHANGE; CHOLESTEROL ESTERS; HUMAN-FIBROBLASTS; A-I; RECEPTOR; APOLIPOPROTEINS; TRANSPORT; IDENTIFICATION AB In human skin fibroblasts incubated with interstitial fluid concentrations of low-density lipoproteins (LDL) (22 mug/mL) that had been preincubated with [I-125] thyroid hormone (TH), thyroxine (T-4) whole-cell saturable uptake (CSU) is approximately 40% greater than in control fibroblasts. This effect of the LDL, which requires upregulation of low-density lipoprotein-receptors (LDL-R; K-d approximate to 20 mug/mL), is less for [I-125]triiodothyronine (T-3)We have evaluated high-density lipoproteins (HDL), and assessed whether lipoproteins target TH to the nucleus. In some experiments, fibroblasts were cholesterol-deprived (chol(-)) or cholesterol-enriched (chol(+)) to upregulate LDL-R or high-density lipoprotein-receptors (HDL-R), respectively. In chol- fibroblasts, 25 mug/mL of LDL increased both T4 CSU and T4 nuclear saturable uptake (NSU) by 48% or 30%, respectively; the latter becoming appreciable at approximately 180 minutes. Interstitial fluid concentrations of HDL (280 mug/mL or approximate to50-fold greater than K-d of the HDL-R) inhibited both T-4 and T-3 CSU even in chol(+) fibroblasts. However, when chol(+) fibroblasts were incubated first with HDL, and after cell washings with [I-125]T-4 or [I-125]T-3, T-4 or T-3 CSU increased by 24% or 12%, respectively. The corresponding increase in chol(-) fibroblasts was 8% or 0%, and in nonmanipulated fibroblasts was 15% or 4%. Unlike LDL, the magnitude of the increase in T-4 or T-3 NSU caused by HDL matched the corresponding CSU, and was already evident at 30 minutes. In conclusion, cells have a LDL-facilitated, LDL-R-mediated mode of entry of TH (T-4 much greater than T-3) that targets relatively late only part of TH to the nucleus, and an HDL-facilitated mode of entry (T-4 > T-3) that targets immediately to the nucleus all of the TH, suggesting entry of TH in free form. This effect of HDL represents facilitated diffusion of TH through the cell membrane. C1 Univ Messina Policlin, Sch Med, Dipartimento Clin Sperimentale Med & Farmacol, Sez Endocrinol, I-98125 Messina, Italy. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Benvenga, S (reprint author), Univ Messina Policlin, Sch Med, Dipartimento Clin Sperimentale Med & Farmacol, Sez Endocrinol, Padigl H,4 Piano, I-98125 Messina, Italy. NR 35 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2002 VL 12 IS 7 BP 547 EP 556 DI 10.1089/105072502320288384 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 578YR UT WOS:000177149100003 PM 12193297 ER PT J AU Moyer, CF Kodavanti, UP Haseman, JK Costa, DL Nyska, A AF Moyer, CF Kodavanti, UP Haseman, JK Costa, DL Nyska, A TI Systemic vascular disease in male B6C3F1 mice exposed to particulate matter by inhalation: Studies conducted by the National Toxicology Program SO TOXICOLOGIC PATHOLOGY LA English DT Article DE air pollution; indium phosphide; cobalt sulfate heptahydrate; mouse; heart; arteritis ID AIR-POLLUTION; MORTALITY; MODEL; RATS AB Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate- matter- induced inflammation and vascular disease, a 2- phase retrospective study was conducted. Phase one included the review of heart, lung, and kidney tissues from high- dose and control male B6C3F1 mice exposed by inhalation to 9 particulate compounds for a 2- year period. The results showed that high- dose males developed significantly increased incidences of coronary and renal arteritis over controls in 2 of the 9 studies (indium phosphide and cobalt sulfate heptahydrate), while marginal increases in arteritis incidence was detected in 2 additional studies (vanadium pentoxide and gallium arsenide). In contrast, arteritis of the muscular arteries of the lung was not observed. Morphological features of arteritis in these studies included an influx of mixed inflammatory cells including neutrophils, lymphocytes, and macrophages. Partial and complete effacement of the normal vascular wall architecture, often with extension of the inflammatory process into the periarterial connective tissue, was observed. Phase 2 evaluated the heart, lung, kidney, and mesentery of male and female B6C3F1 mice from the 90- day studies of the 4 compounds demonstrating arteritis after a 2- year period. The results showed arteritis did not develop in the 90- day studies, suggesting that long- term chronic exposure to lower- dose metallic particulate matter may be necessary to induce or exacerbate arteritis. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Pathol Associates Inc, Raleigh, NC 27606 USA. US EPA, Pulm Toxicol Branch, Expt Toxicol Div, Natl Hlth & Environm Effectts Res Lab, Res Triangle Pk, NC 27711 USA. NIEHS, Biostat Branch, Res Branch, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 14 Z9 14 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 JUL-AUG PY 2002 VL 30 IS 4 BP 427 EP 434 DI 10.1080/01926230290105631 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YG UT WOS:000178193600003 PM 12187935 ER PT J AU Hamadeh, HK Knight, BL Haugen, AC Sieber, S Amin, RP Bushel, PR Stoll, R Blanchard, K Jayadev, S Tennant, RW Cunningham, ML Afshari, CA Paules, RS AF Hamadeh, HK Knight, BL Haugen, AC Sieber, S Amin, RP Bushel, PR Stoll, R Blanchard, K Jayadev, S Tennant, RW Cunningham, ML Afshari, CA Paules, RS TI Methapyrilene toxicity: Anchorage of pathologic observations to gene expression alterations SO TOXICOLOGIC PATHOLOGY LA English DT Article DE toxicogenomics; gene expression; methapyrilene; toxicity classification; rat liver; histopathology; phenotypic anchorage; hepatotoxicity ID POTENT HEPATOCARCINOGEN METHAPYRILENE; F344 RATS; SPECIES-DIFFERENCES; LIVER-REGENERATION; OXIDATIVE STRESS; PROTEIN; CELLS; IDENTIFICATION; HYDROCHLORIDE; INVITRO AB Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression patterns, and 3) to gain insight into mechanism( s) of methapyrilene hepatotoxicity. Large- scale differential gene expression levels associated with the exposure of male Sprague- Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/ kg/ day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low- dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. RP Paules, RS (reprint author), NIEHS, POB 12233,MD D2-03,111 Alexander Dr,Bldg 101, Res Triangle Pk, NC 27709 USA. NR 62 TC 86 Z9 91 U1 1 U2 7 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 JUL-AUG PY 2002 VL 30 IS 4 BP 470 EP 482 DI 10.1080/01926230290105712 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YG UT WOS:000178193600006 PM 12187938 ER PT J AU Ghanayem, BI Nyska, A Haseman, JK Bucher, JR AF Ghanayem, BI Nyska, A Haseman, JK Bucher, JR TI Acrylonitrile is a multisite carcinogen in male and female B6C3F1 mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE acrylonitrile; B6C3F1 mice; carcinogenicity; Harderian gland; forestomach; lung; ovary ID FORESTOMACH CELL-PROLIFERATION; 2-CYANOETHYLENE OXIDE; FISCHER-344 RATS; OXIDATIVE STRESS; METABOLISM; MORTALITY; TESTS; METHACRYLONITRILE; MUTAGENICITY; ACRYLAMIDE AB Acrylonitrile is a heavily produced unsaturated nitrile, which is used in the production of synthetic fibers, plastics, resins, and rubber. Acrylonitrile is a multisite carcinogen in rats after exposure via gavage, drinking water, or inhalation. No carcinogenicity studies of acrylonitrile in a second animal species were available. The current studies were designed to assess the carcinogenicity of acrylonitrile in B6C3F1 mice of both sexes. Acrylonitrile was administered by gavage at 0, 2.5, 10, or 20 mg/kg/day, 5 days per week, for 2 years. Urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine were measured as markers of exposure to acrylonitrile. In general, there were dose-related increases in urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine concentrations in all dosed groups of mice and at all time points. Survival was significantly (p < 0.001) reduced in the top dose (20 mg/kg) group of male and female mice relative to controls. The incidence of forestomach papillomas and carcinomas was increased in mice of both sexes in association with an increase in forestomach epithelial hyperplasia. The incidence of Harderian gland adenomas and carcinomas was also markedly increased in the acrylonitrile-dosed groups. In female mice, the incidence of benign or malignant granulosa cell tumors (combined) in the ovary in the 10 mg/kg dose group was greater than that in the vehicle control group, but because of a lack of dose response, this was considered an equivocal finding. In addition, the incidences of atrophy and cysts in the ovary of the 10 and 20 mg/kg dose groups were significantly increased. The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in female mice treated with acrylonitrile at 10 mg/kg/day for 2 years. This was also considered an equivocal result. In conclusion, these studies demonstrated that acrylonitrile causes multiple carcinogenic effects after gavage administration to male and female B6C3F1 mice for 2 years. C1 NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Ghanayem, BI (reprint author), NIEHS, Environm Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 45 TC 27 Z9 28 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2002 VL 68 IS 1 BP 59 EP 68 DI 10.1093/toxsci/68.1.59 PG 10 WC Toxicology SC Toxicology GA 569DL UT WOS:000176585200009 PM 12075111 ER PT J AU Bolan, CD Cecco, SA Wesley, RA Horne, M Yau, YY Remaley, AT Childs, RW Barrett, AJ Rehak, NN Leitman, SF AF Bolan, CD Cecco, SA Wesley, RA Horne, M Yau, YY Remaley, AT Childs, RW Barrett, AJ Rehak, NN Leitman, SF TI Controlled study of citrate effects and response to IV calcium administration during allogeneic peripheral blood progenitor cell donation SO TRANSFUSION LA English DT Article ID PARATHYROID-HORMONE; IONIZED CALCIUM; PLASMA-EXCHANGE; TRANSPLANTATION; GLUCONATE; PLATELETPHERESIS; ELECTROLYTES; CHLORIDE; INFUSION AB BACKGROUND: Leukapheresis procedures are generally performed at citrate anticoagulation rates extrapolated from shorter plateletpheresis procedures. However, neither the metabolic effects nor the management of associated symptoms have been critically evaluated during leukapheresis in healthy donors. STUDY DESIGN AND METHODS: Symptom assessments (n = 315) and laboratory analyses (n = 49) were performed during 244 procedures performed with and 71 without prophylactic calcium (Ca) chloride or Ca gluconate given at a dose linked to the citrate infusion rate (1.0-2.2 mg/kg/min). RESULTS: During leukapheresis of 12 to 25 L processed, ionized Ca and ionized magnesium (Mg) decreased as much as 35 and 56 percent, respectively, each exhibiting a tight negative correlation with marked increases in serum citrate levels. Significant increases in urinary Ca and Mg excretion accompanied the renal excretion of a large citrate load. Serum divalent cation levels remained depressed 24 hours after leukapheresis. Symptoms were more frequent in donors who were women, had low initial total Mg levels, and underwent procedures in which larger volumes were processed at higher citrate infusion rates. Ca infusions reduced clinically significant paresthesias by 96 percent and also attenuated decreases in serum potassium. Ca chloride maintained higher Ca levels than Ca gluconate. CONCLUSIONS: Prophylactic Ca infusions safely attenuate the marked metabolic effects of citrate administration and promote faster, more comfortable, leukapheresis procedures. C1 NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Lab Med, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Biostat Serv, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RP Bolan, CD (reprint author), NHLBI, Dept Transfus Med, NIH, Bldg 10,Room 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. NR 24 TC 48 Z9 51 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2002 VL 42 IS 7 BP 935 EP 946 DI 10.1046/j.1537-2995.2002.00151.x PG 12 WC Hematology SC Hematology GA 576FN UT WOS:000176992300019 PM 12375668 ER PT J AU Dixon, D Flake, GP Moore, AB He, H Haseman, JK Risinger, JI Lancaster, JM Berchuck, A Barrett, JC Robboy, SJ AF Dixon, D Flake, GP Moore, AB He, H Haseman, JK Risinger, JI Lancaster, JM Berchuck, A Barrett, JC Robboy, SJ TI Cell proliferation and apoptosis in human uterine leiomyomas and myometria SO VIRCHOWS ARCHIV LA English DT Article DE leiomyoma; proliferation; apoptosis; Bcl-2; Bax; immunohistochemistry ID BCL-2 FAMILY PROTEINS; MENSTRUAL-CYCLE; IMMUNOHISTOCHEMICAL ANALYSIS; EXPRESSION; DEATH; BAX; PROTOONCOGENE; PROGESTERONE; MITOCHONDRIA; TUMORS AB To determine the role of cell proliferation and apoptosis in uterine leiomyoma growth, we studied protein expression of two major regulatory proteins of apoptosis - Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) and two endogenous markers of cell replication - proliferating cell nuclear antigen (PCNA) and Ki-67 - in tumors and matched myometrium from premenopausal women. Conventional mitotic indices also were determined, and all proliferation data were correlated to tumor size. In situ end-labeling of fragmented DNA and routine histology were used to assess apoptosis. Our results showed that the apoptosis-regulating proteins (Bcl-2 and Bax) were expressed in the cytoplasm of the leiomyoma and myometrial smooth muscle cells throughout the menstrual cycle. Bax expression differed from Bcl-2 in that it also was found in the cytoplasm of vascular smooth muscle cells of the myometria and tumors. Both tumors and myometrial samples expressed 26-kDa and 21-kDa proteins that reacted with antibodies directed towards Bcl-2 and Bax, respectively. Apoptosis was not a prominent feature of uterine leiomyomas or myometrium. PCNA- and Ki-67-labeling and mitotic counts were significantly (P<0.05) higher in leiomyomas than in matched myometrial samples. Proliferative activity was variable for individual tumors of the same patient and independent of tumor size. Our results suggest that altered apoptosis by overexpression of Bcl-2 or by decreased expression of Bax does not appear to be a major factor in uterine leiomyoma growth. We conclude that increased cell proliferation is the most significant contributor to growth and that the proliferative state is autonomous for each tumor in a given patient and is independent of tumor size. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Stat & Biomath Branch, Res Triangle Pk, NC 27709 USA. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Dixon, D (reprint author), NIEHS, Lab Expt Pathol, POB 12233,MDC2-09, Res Triangle Pk, NC 27709 USA. NR 33 TC 38 Z9 47 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD JUL PY 2002 VL 441 IS 1 BP 53 EP 62 DI 10.1007/s00428-001-0568-7 PG 10 WC Pathology SC Pathology GA 597VA UT WOS:000178240400008 PM 12111201 ER PT J AU Sheliga, BM Brown, VJ Miles, FA AF Sheliga, BM Brown, VJ Miles, FA TI Voluntary saccadic eye movements in humans studied with a double-cue paradigm SO VISION RESEARCH LA English DT Article DE saccadic eye movements; double-step paradigm; cognitive cues ID DOUBLE-STEP STIMULI; COUNTERMANDING SACCADES; RESPONSES; AMPLITUDE; MACAQUE; SYSTEM AB In the classic double-step paradigm, subjects are required to make a saccade to a visual target that is briefly presented at one location and then shifted to a new location before the subject has responded. The saccades in this situation are "reflexive" in that they are made in response to the appearance of the target itself. In the present experiments we adapted the double-step paradigm to study "voluntary" saccades. For this, several identical targets were always visible and subjects were given a cue to indicate that they should make a saccade to one of them. This cue was then changed to indicate another of the targets before the subject had responded: double-cue (DC) paradigm. The saccadic eye movements in our DC paradigm had many features in common with those in the double-step paradigm and we show that apparent differences can be attributed to the spatio-temporal arrangements of the cues/targets rather than to any intrinsic differences in the programming of these two kinds of eye movements. For example, a feature of our DC paradigm that is not seen in the usual double-step paradigm is that the second cue could cause transient delays of the initial saccade, and these delays still occurred when the second cue was reflexive-provided that it was at the fovea (as in our DC paradigm) and not in the periphery (as in the usual double-step paradigm). Thus, the critical factor for the delay was the retinal (foveal) location of the second cue/target-not whether it was cognitive or reflexive-and we argue that the second cue/target is here acting as a distractor. We conclude that the DC paradigm can be used to study the programming of voluntary saccades in the same way that the double-step paradigm can be used to study reflexive saccades. Published by Elsevier Science Ltd. C1 NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. Univ St Andrews, Sch Psychol, St Andrews KY16 9JU, Fife, Scotland. RP Sheliga, BM (reprint author), NEI, Lab Sensorimotor Res, NIH, Bldg 49,Rm 2A50,49 Convent Dr, Bethesda, MD 20892 USA. RI Brown, Verity/A-5235-2011 OI Brown, Verity/0000-0001-5762-1797 FU NEI NIH HHS [Z01 EY000153-22] NR 29 TC 7 Z9 8 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUL PY 2002 VL 42 IS 15 BP 1897 EP 1915 AR PII S0042-6989(02)00101-3 DI 10.1016/S0042-6989(02)00101-3 PG 19 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 587VW UT WOS:000177664800008 PM 12128020 ER PT J AU Caruccio, L Byrne, K Procter, J Stroncek, D AF Caruccio, L Byrne, K Procter, J Stroncek, D TI A novel method using formamide for the elution of antibodies from erythrocytes SO VOX SANGUINIS LA English DT Article DE DAT; elution; formamide sensitization; RBC ID RED-BLOOD-CELLS; ACID-ELUTION; DISSOCIATION AB Background and Objectives Accurate identification of antibodies that sensitize red blood cells (RBCs) involves dissociating them from RBCs using an in vitro elution method that does not alter their antigen-binding properties, and analysis of the eluates against a panel of RBCs. Materials and Methods A method was developed that allowed efficient RBC antibody elution. Human polyclonal anti-D was used to sensitize Rh-positive RBCs, and known antigen-antibody disruptive reagents were tested using these RBCs. The best reagent conditions were optimized. Eluates made were tested and compared to results obtained with a glycine-acid-based commercial elution kit to determine efficacy. Patient samples that were positive with direct antiglobulin tests (DATs), and in vitro commercial antisera-sensitized RBCs representing clinically significant antibodies, were used for evaluating the new method. Results The formamide method was efficient at removing antibodies from RBCs. The patient samples with a positive DAT had antibodies recovered with the same specificity when compared to the acid-based technique. The length of preparation time was similar for both formamide and acid-based methods. Results of testing the eluates made from reagent RBCs sensitized with commercial antisera were distinct with antigen-positive and -negative erythrocytes. Conclusions The formamide method compares well with acid techniques and may be an alternative choice of elution method. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Caruccio, L (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NR 13 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2002 VL 83 IS 1 BP 63 EP 69 DI 10.1046/j.1423-0410.2002.00181.x PG 7 WC Hematology SC Hematology GA 570MQ UT WOS:000176662400010 PM 12100391 ER PT J AU Petersen, EF Spencer, RGS McFarland, EW AF Petersen, EF Spencer, RGS McFarland, EW TI Microengineering neocartilage scaffolds SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE cartilage; photolithography; micropattern; scaffold; tissue engineering ID MAGNETIC-RESONANCE MICROSCOPY; HOLLOW-FIBER BIOREACTOR; ARTICULAR CHONDROCYTES; CARTILAGE; CULTURE; SPECTROSCOPY; EXPRESSION; ALGINATE; COLLAGEN; SYSTEM AB Advances in micropatterning methodologies have made it possible to create structures with precise architecture on the surface of cell culture substrata. We applied these techniques to fabricate microfeatures (15-65 mum wide; 40 mum deep) on the surface of a flexible, biocompatible polysaccharide gel. The micropatterned polymer gels were subsequently applied as scaffolds for chondrocyte culture and proved effective in maintaining key aspects of the chondrogenic phenotype. These were rounded cell morphology and a positive and statistically significant (p < 0.0001) immunofluorescence assay for the production of type II collagen throughout the maximum culture time of 10 days after cell seeding. Further, cells housed within individual surface features were observed to, proliferate, while serial application of chondrocytes resulted in the formation of cellular aggregates. These methods represent a novel approach to the problem of engineering reparative cartilage in vitro. (C) 2002 Wiley Periodicals, Inc. C1 NIA, NMR Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Cartilage Restorat Ctr, Baltimore, MD USA. Univ Calif Santa Barbara, Dept Chem Engn, Santa Barbara, CA 93106 USA. RP Spencer, RGS (reprint author), NIA, NMR Unit, NIH, Gerontol Res Ctr, Room 4D-06,5600 Nathan Shock Drive, Baltimore, MD 21224 USA. RI McFarland, Eric/G-1763-2014 NR 20 TC 9 Z9 11 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD JUN 30 PY 2002 VL 78 IS 7 BP 801 EP 804 DI 10.1002/bit.10256 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 558KK UT WOS:000175965000010 PM 12001172 ER PT J AU Zhang, L Li, BS Zhao, WQ Chang, YH Ma, W Dragan, M Barker, JL Hu, Q Rubinow, DR AF Zhang, L Li, BS Zhao, WQ Chang, YH Ma, W Dragan, M Barker, JL Hu, Q Rubinow, DR TI Sex-related differences in MAPKs activation in rat astrocytes: effects of estrogen on cell death SO MOLECULAR BRAIN RESEARCH LA English DT Article DE estrogen; kinases; astrocyte; proliferation; cell death; sexual dimorphism ID HUMAN BREAST-CANCER; PROTEIN-KINASE ACTIVITY; NERVE GROWTH-FACTOR; SYNAPTIC PLASTICITY; SIGNALING PATHWAYS; NEURAL DEVELOPMENT; DOPAMINE RELEASE; BASAL FOREBRAIN; ESTRADIOL; NEURONS AB Gender-related differences in the unstimulated and estrogen-induced activation of the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2, cell proliferation, and cell death were examined using rat cortical astrocytes in culture. Females have higher unstimulated levels of phosphorylated ERK1 and ERK2 than males. 17beta-Estradiol (E-2) decreases activation of ERK1 and ERK2, with females showing a greater response than males. Further, E-2 results in more inhibition of DNA synthesis and greater increase in cell death in females than in males. The inhibitory effects of E-2 on DNA synthesis are mimicked and enhanced by a specific MAPK kinase (MEK) inhibitor, PD98059. Finally, the inhibitory effects of E-2 are blocked by the estrogen receptor antagonist tamoxifen in astrocytes from females but not males, with ER-alpha (estrogen receptor alpha) present in the former but not the latter. Taken together, these results suggest that the sex differences in unstimulated and estrogen-modulated activation of MAPKs may result in differential regulation of cell proliferation and death in astrocytes and possibly contribute to sexual dimorphisms in brain development. Published by Elsevier Science B.V. C1 NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. NINDS, Neurochem Lab, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), NIMH, Behav Endocrinol Branch, NIH, Bldg 10,Room 3N238,10 Ctr Dr MSC 1276, Bethesda, MD 20892 USA. NR 47 TC 42 Z9 43 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 30 PY 2002 VL 103 IS 1-2 BP 1 EP 11 AR PII S0169-328X(02)00130-4 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 583YV UT WOS:000177440400001 ER PT J AU Chinta, SJ Pai, HV Upadhya, SC Boyd, MR Ravindranath, V AF Chinta, SJ Pai, HV Upadhya, SC Boyd, MR Ravindranath, V TI Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE human brain; drug metabolism; cytochrome p450; psychoactive drug; monooxygenase; cytochrome P4502D ID PARKINSONS-DISEASE; RAT-BRAIN; PLASMA-MEMBRANE; MICROSOMES; OXIDATION; PROTEINS; CYP2D6; GENE; POLYMORPHISMS; BINDING AB Cytochrome P4502D6, an important isoform of cytochrome P450, mediates the metabolism of several psychoactive drugs in liver. Quantitatively, liver is the major drug metabolizing organ, however metabolism of drugs in brain could modulate pharmacological and pharmacodynamic effects of psychoactive drugs at their site of action and explain some of the variation typically seen in patient population. We have measured cytochrome P450 content and examined constitutive expression of CYP2D mRNA and protein in human brain regions by reverse transcription polymerase chain reaction, Northern and immunoblotting and localized it by in situ hybridization and immunohistochemistry. CYP2D mRNA was expressed constitutively in neurons of cerebral cortex, Purkinje and granule cell layers of cerebellum, reticular neurons of midbrain and pyramidal neurons of CA1, CA2 and CA3 subfields of hippocampus. Immunoblot studies demonstrated the presence of cytochrome P4502D protein in cortex, cerebellum, midbrain, striatum and thalamus of human brain. Immunohistochemical localization showed the predominant presence of cytochrome P4502D not only in neuronal soma but also in dendrites of Purkinje and cortical neurons. These studies demonstrate constitutive expression of cytochrome P4502D in neuronal cell population in human brain, indicating its possible role in metabolism of psychoactive drugs directly at or near their site of action, in neurons, in human brain. (C) 2002 Elsevier Science BY. All rights reserved. C1 Natl Brain Res Ctr, New Delhi 110067, India. Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Mol Targets Drug Discovery Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Brain Res Ctr, ICGEB Campus,Aruna Asaf Ali Marg, New Delhi 110067, India. NR 36 TC 45 Z9 47 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 30 PY 2002 VL 103 IS 1-2 BP 49 EP 61 AR PII S0169-328X(02)00177-8 DI 10.1016/S0169-328X(02)00177-8 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 583YV UT WOS:000177440400005 ER PT J AU Kim, UK Chae, JJ Lee, SH Lee, CC Namkoong, Y AF Kim, UK Chae, JJ Lee, SH Lee, CC Namkoong, Y TI Molecular diagnosis of Duchenne/Becker muscular dystrophy by polymeirase chain reaction and microsatellite analysis SO MOLECULES AND CELLS LA English DT Article DE dystrophin gene; Korean population; polymerase chain reaction ID PRENATAL-DIAGNOSIS; KOREAN POPULATION; CARRIER DETECTION; GENE DELETIONS; CACA REPEAT; DNA; POLYMORPHISMS; AMPLIFICATION; POLYMERASE AB Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive genetic disorders resulting from mutations in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5' and central region of the gene. The remaining DMD/BMD cases show no deletions, so they cannot be easily identified by current strategies. In these DMD/BMD families, a linkage analysis that involves DNA markers of the flanking and intragenic dystrophin gene are necessary for carrier and prenatal diagnosis. We analyzed eighteen deletion-prone exons of the gene by a polymerase chain reaction (PCR) in order to characterize the molecular defects of the dystrophin gene in Korean DMD/BMD families. We also performed a linkage analysis to assess the usefulness and application of six short tandem repeat markers for molecular diagnosis in the families. We observed a deletion that eliminated the exon 50. Also, a linkage analysis in the families with six short tandem repeat (STR) markers showed heterozygosity at most of the STR markers. The haplotype analysis was useful for detecting the carrier status. This study will be helpful for a molecular diagnosis of DMD/BMD families in the Korean population. C1 Kangnung Natl Univ, Dept Biol, Kangnung 210702, South Korea. Seoul Natl Univ, Dept Mol Biol, Seoul 151742, South Korea. NIAMSD, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. Pochon CHA Univ, CHA Gen Hosp, Infertil Med Ctr, Coll Med, Seoul 135080, South Korea. RP Namkoong, Y (reprint author), Kangnung Natl Univ, Dept Biol, Kangnung 210702, South Korea. NR 16 TC 7 Z9 11 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD JUN 30 PY 2002 VL 13 IS 3 BP 385 EP 388 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 568RT UT WOS:000176557400005 PM 12132577 ER PT J AU Steinberg, SM Venzon, DJ AF Steinberg, SM Venzon, DJ TI Early selection in a randomized phase II clinical trial SO STATISTICS IN MEDICINE LA English DT Article DE selection theory; randomized phase II trial; two-stage phase II trial ID DURATION; SURVIVAL; DESIGNS; SIZE AB A randomized phase II clinical trial design can be employed when one wishes to be able to select one of several similar therapies or variants of a therapy for inclusion in a subsequent, definitive, phase III trial. It is not necessary in this type of trial to formally identify a superior arm using the usual parameters and stringent criteria employed for hypothesis testing. Simon, Wittes and Ellenberg have described methods and sample sizes for selecting the superior arm from among k possible arms. In this paper, we describe an approach based on statistical selection theory which allows one to potentially make a decision to end accrual to a randomized phase II trial at an interim point of the trial, and to select one of two arms as being worthy of further evaluation in a subsequent study. This method requires that an adequate gap in the number of responses between the two arms be observed at the interim point in order to limit the probability that the selected ann is actually inferior by more than an indifference amount. Published in 2002 by John Wiley Sons, Ltd. C1 NCI, Biostat & Data Management Sect, Off Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Steinberg, SM (reprint author), NCI, Biostat & Data Management Sect, Off Director, Ctr Canc Res,NIH, 6116 Execut Blvd,Room 702,MSC 8325, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 17 TC 22 Z9 23 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2002 VL 21 IS 12 BP 1711 EP 1726 DI 10.1002/sim.1150 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 565FX UT WOS:000176360000005 PM 12111907 ER PT J AU Thakurta, AG Yoon, JH Dhar, R AF Thakurta, AG Yoon, JH Dhar, R TI Schizosaccharomyces pombe spPABP, a homologue of Saccharomyces cerevisiae Pab1p, is a non-essential, shuttling protein that facilitates mRNA export SO YEAST LA English DT Article DE Schizosaccaromyces pombe; PABP; poly(A)-binding protein; mRNA export ID MESSENGER-RNA EXPORT; POLY(A)-BINDING PROTEIN; FISSION YEAST; TRANSLATION INITIATION; BINDING; GENE; EXPRESSION; POLYADENYLATION; NUCLEAR; DOMAIN AB Poly(A)-binding proteins play important roles in mRNA metabolism in eukaryotic cells. We examined the role of the Schizosaccharomyces pombe homologue of the Saccharomyces cerevisiae poly(A)-binding protein, Pab1p, in cellular growth and mRNA export. In contrast to PAB1, the sppabp gene is not essential for cellular viability. Like the human hPABP1 protein, spPABP is cytoplasmically localized and can shuttle between the nucleus and the cytoplasm. We found that a spPABP-GFP fusion protein expressed from a multicopy plasmid could suppress the growth and mRNA export defect of rae1-16 7 nup184-1 synthetic lethal mutations. However, about 20-25% of cells in the population exhibited a pronounced nuclear accumulation of poly(A)(+) RNA. The same cells also localized the spPABP-GFP fusion to the nucleus, suggesting that the shuttling ability of spPABP is related to its function in mRNA export. When a heterologous nuclear export activity from spMex67p was fused to spPABP-GFP fusion protein, it overcame the nuclear retention but did not increase nuclear mRNA export. We discuss the implications of these observations in relation to how spPABP could function in mRNA export. Published in 2002 by John Wiley Sons, Ltd. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP NCI, Basic Res Lab, NIH, Bldg 37,Rm 6138B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dharr@mail.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0749-503X EI 1097-0061 J9 YEAST JI Yeast PD JUN 30 PY 2002 VL 19 IS 9 BP 795 EP 802 DI 10.1002/yea.876 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 568RU UT WOS:000176557600006 ER PT J AU Davis, RL Shrimpton, AE Carrell, RW Lomas, DA Gerhard, L Baumann, B Lawrence, DA Yepes, M Kim, TS Ghetti, B Piccardo, P Takao, M Lacbawan, F Muenke, M Sifers, RN Bradshaw, CB Kent, PF Collins, GH Larocca, D Holohan, PD AF Davis, RL Shrimpton, AE Carrell, RW Lomas, DA Gerhard, L Baumann, B Lawrence, DA Yepes, M Kim, TS Ghetti, B Piccardo, P Takao, M Lacbawan, F Muenke, M Sifers, RN Bradshaw, CB Kent, PF Collins, GH Larocca, D Holohan, PD TI Association between conformational mutations in neuroserpin and onset and severity of dementia SO LANCET LA English DT Article ID SERINE-PROTEASE INHIBITOR; NEURODEGENERATIVE DISEASE; CRYSTAL-STRUCTURE; INCLUSION-BODIES; SERPINS; ALPHA(1)-ANTITRYPSIN; ENCEPHALOPATHY; ACCUMULATION; MECHANISM; MYOCLONUS AB Background The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations. Methods Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted. Findings Each of the families was heterozygous for an aminoacid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons. Interpretation The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation. C1 Univ Cambridge, Dept Haematol, Cambridge Inst Med Res, Cambridge, England. Univ Cambridge, Dept Med, Cambridge Inst Med Res, Cambridge CB2 2QQ, England. Upstate Med Univ, Dept Pathol, Syracuse, NY USA. Univ Witten Herdecke, Inst Clin Neurosurg, Witten, Germany. Univ Magdeburg, Dept Psychiat, D-39106 Magdeburg, Germany. Amer Red Cross, Holland Lab, Dept Vasc Biol, Rockville, MD USA. Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. Indiana Univ, Sch Med, Div Neuropathol, Alzheimer Dis Ctr, Indianapolis, IN USA. Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Upstate Med Univ, Dept Neurol, Syracuse, NY USA. Upstate Med Univ, Dept Pharmacol, Syracuse, NY USA. RP Carrell, RW (reprint author), Univ Cambridge, Dept Haematol, Cambridge Inst Med Res, Cambridge, England. RI Yepes, Manuel/C-3576-2011 FU NIA NIH HHS [AG10133]; NINDS NIH HHS [NS14426, NS40722] NR 33 TC 101 Z9 103 U1 0 U2 5 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 29 PY 2002 VL 359 IS 9325 BP 2242 EP 2247 DI 10.1016/S0140-6736(02)09293-0 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 567YJ UT WOS:000176514500010 PM 12103288 ER PT J AU Kapust, RB Tozser, J Copeland, TD Waugh, DS AF Kapust, RB Tozser, J Copeland, TD Waugh, DS TI The P1 ' specificity of tobacco etch virus protease SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE TEV protease; fusion protein; affinity tag; N-end rule ID MALTOSE-BINDING-PROTEIN; POLYPROTEIN CLEAVAGE SITE; ESCHERICHIA-COLI; FUSION PROTEINS; PROTEOLYTIC DEGRADATION; YERSINIA-PESTIS; EXPRESSION; PURIFICATION; POLYPEPTIDES; BACTERIA AB Affinity tags have become indispensable tools for protein expression and purification. Yet, because they have the potential to interfere with structural and functional studies, it is usually desirable to remove them from the target protein. The stringent sequence specificity of the tobacco etch virus (TEV) protease has made it a useful reagent for this purpose. However, a potential limitation of TEV protease is that it is believed to require a Gly or Ser residue in the P1' position of its substrates to process them with reasonable efficiency. Consequently, after an N-terminal affinity tag is removed by TEV protease, the target protein will usually retain a non-native Ser or Gly residue on its N-terminus, and in some cases this may affect its biological activity. To investigate the stringency of the requirement for Gly or Ser in the P1' position of a TEV protease recognition site, we constructed 20 variants of a fusion protein substrate with an otherwise optimal recognition site, each containing a different amino acid in the P1' position. The efficiency with which these fusion proteins were processed by TEV protease was compared both in vivo and in vitro. Additionally, the kinetic parameters K-M and k(cat) were determined for a representative set of peptide substrates with amino acid substitutions in the P1' position. The results indicate that many side-chains can be accommodated in the P1' position of a TEV protease recognition site with little impact on the efficiency of processing. (C) 2002 Published by Elsevier Science (USA). C1 NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. Univ Debrecen, Dept Biochem & Mol Biol, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM waughd@ncifcrf.gov RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 29 TC 179 Z9 188 U1 2 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 28 PY 2002 VL 294 IS 5 BP 949 EP 955 AR PII S0006-291X(02)00574-0 DI 10.1016/S0006-291X(02)00574-0 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 568PJ UT WOS:000176550900005 PM 12074568 ER PT J AU Khurana, RN Maddala, RL Shimokawa, H Zigler, JS Epstein, DL Rao, PV AF Khurana, RN Maddala, RL Shimokawa, H Zigler, JS Epstein, DL Rao, PV TI Inhibition of Rho-kinase induces alpha B-crystallin expression in lens epithelial cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE alpha B-crystallin; Rho GTPase; Rho kinase; actin; cytoskeleton; p38 MAPK; lens epithelial cells ID HEAT-SHOCK PROTEIN; CENTRAL-NERVOUS-SYSTEM; ACTIN CYTOSKELETON; FAMILY GTPASES; STRESS CONDITIONS; FOCAL ADHESIONS; DOWN-REGULATION; GROWTH-FACTOR; INDUCTION; ACTIVATION AB The small heat shock protein, alphaB-crystallin, has been shown to interact with actin and intermediate filament proteins. However, little is known regarding the cellular mechanisms regulating such interactions. In this study, we explored the role of the Rho/Rho-kinase pathway in alphabeta-crystallin distribution and expression in porcine lens epithelial cells. alphaB-crystallin was distributed uniformly throughout the cytoplasm and did not exhibit any unique redistribution in response to actin depolymerization induced by Rho/Rho-kinase inhibitors (C3-exoenzyme or Y-27632) or by overexpression. of the dominant negative mutant of Rho-kinase (DNRK) in porcine lens epithelial cells. Interestingly, alphaB-crystallin levels markedly increased in lens epithelial cells treated with the inhibitors of Rho/Rho-kinase proteins (lovastatin, Y-27632 or DNRK) while a protein kinase C inhibitor (GF109203x) was found to have no effect. Further, Y-27632 showed a dose (2-50 muM) response effect on alphaB-crystallin induction. Nocodazole, a microtubule-depolymerizing agent, elicited an increase in alphaB-crystallin levels but latrunculin, an actin depolymerizing agent, did not show any significant effect. Pretreatment with cycloheximide or genistein blocked the Rho-kinase inhibitor-induced increase in alphaB-crystallin protein levels. Rho-kinase inhibitor-induced increases in alphabeta-crystallin levels were found to be associated with activation of P38 mitogen-activated protein kinase (MAPK). These results suggest that Rho/Rho-kinase negatively regulates alphaB-crystallin expression, and this response appears to be dependent on tyro sine-protein kinase and P38 MAPK function. Finally, alphaB-crystallin induction appears to be better correlated with the direct inhibition of Rho/Rho-kinase than with actin depolymerization per se. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka, Japan. NEI, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc, Durham, NC 27710 USA. RP Rao, PV (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. FU NEI NIH HHS [R01 EY 12201] NR 46 TC 6 Z9 6 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 JUN 28 PY 2002 VL 294 IS 5 BP 981 EP 987 AR PII S0006-291X(02)00583-1 DI 10.1016/S0006-291X(02)00583-1 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 568PJ UT WOS:000176550900010 PM 12074573 ER PT J AU Dobbins, DE Sood, R Hashiramoto, A Hansen, CT Wilder, RL Remmers, EF AF Dobbins, DE Sood, R Hashiramoto, A Hansen, CT Wilder, RL Remmers, EF TI Mutation of macrophage colony stimulating factor (Csf1) causes osteopetrosis in the tl rat SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE osteopetrosis; osteoclasts; osteoblasts; colony stimulating factor 1; bone disease; tl rats; bone homeostasis; growth factors ID BONE-RESORPTION; FACTOR-I; TOOTHLESS; OSTEOCLASTS; EXPRESSION; SURVIVAL; RNA AB Osteopetrosis results from a heterogeneous group of congenital bone diseases that display inadequate osteoclastic bone resorption. We recently mapped tl (toothless), a mutation that causes osteopetrosis in rats, to a genetic region predicted to include the rat Csf1 gene. In this study, we sequenced the coding sequence of the rat Csf1 gene to determine if a mutation in Csf1 could be responsible for the tl phenotype. Sequencing revealed a 10-base insertion in the coding sequence of mutant animals that produces a frameshift and generates a stop codon early in the mutant Csf1 coding sequence. The 41 amino acid polypeptide predicted to be produced from the Csf1 promoter would have only the first nine amino acids of the wild-type rat protein. These data suggest that osteopetrosis develops in tl/tl rats because they cannot produce functional mCsf, a growth factor required for osteoclast differentiation and activation. (C) 2002 Published by Elsevier Science (USA). C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Medimmune Inc, Gaithersburg, MD 20878 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Dobbins, DE (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 20 TC 27 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 28 PY 2002 VL 294 IS 5 BP 1114 EP 1120 AR PII S0006-291X(02)00598-3 DI 10.1016/S0006-291X(02)00598-3 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 568PJ UT WOS:000176550900029 PM 12074592 ER PT J AU Zhou, FC Lesch, KP Murphy, DL AF Zhou, FC Lesch, KP Murphy, DL TI Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative SO BRAIN RESEARCH LA English DT Article DE transgenic mouse; gene knockout; serotonin transporter; dopamine transporter; paroxetine; GBR-12935; false transmission ID KNOCK-OUT MICE; 5-HT TRANSPORTER; BRAIN; EXPRESSION; MONOAMINE; RECEPTORS; TRANSMISSION; LOCALIZATION; TERMINALS; REDUCTION AB Monoamine neurons are believed to use neuronal-specific transporters to remove their own transmitters from the extracellular space and thus terminate transmission to postsynaptic neurons. We report here, for the first time, conclusive evidence that a cross clearance of serotonin into dopamine neurons exists. Such alternative uptake by different neurons is adopted under circumstances when their own transporter function is no longer adequate. When the serotonin transporter (5-HTT) is disrupted in 5-HTT knockout mice, serotonin (5-HT) is found in doparmine (DA) neurons of homozygous (-/-) but not of heterozygous (+/-) mutant mice or their normal littermates. DA neurons containing 5-HT are seen in the substantia nigra and ventral tegmental area (VTA), but not in other brain areas of 5-HTT -/- mice. Normal rats treated with a 5-HT uptake blocker paroxetine also showed situilar result. To verify the role of the DA transporter in such ectopic uptake, 5-HTT -/- mice were treated with DA uptake blocker GBR-12935, ectopic 5-HT in DA neurons was disappeared. These data indicate that: (a) 5-HT can be taken into DA neurons in rats and mice when the 5-HTT is not functionally adequate to remove extracellular 5-HT; (b) the 5-14T uptake into DA neurons is not affected by the 5-HT uptake blocker paroxetine; and (c) the DA transporter is responsible for the 5-HT uptake into DA neurons. This study thus demonstrates that cross neuronal type uptake exists and serves as a compensatory backup when a specific transporter is dysfunctional, This study also demonstrates that DA neurons can store 5-14T for possible 'false neurotransmitter' or other usage. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Indiana Univ, Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. NIMH, Clin Sci Lab, IRP, Bethesda, MD 20892 USA. RP Zhou, FC (reprint author), Indiana Univ, Sch Med, Dept Anat & Cell Biol, 635 Barnhill Dr, Indianapolis, IN 46202 USA. RI Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X FU NIAAA NIH HHS [R01 AA 12406] NR 26 TC 64 Z9 66 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 28 PY 2002 VL 942 IS 1-2 BP 109 EP 119 AR PII S0006-8993(02)02709-9 DI 10.1016/S0006-8993(02)02709-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 565YK UT WOS:000176397900013 PM 12031859 ER PT J AU Rothman, RB Katsnelson, M Vu, N Partilla, JS Dersch, CM Blough, BE Baumann, MH AF Rothman, RB Katsnelson, M Vu, N Partilla, JS Dersch, CM Blough, BE Baumann, MH TI Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE phendimetrazine; phenmetrazine; dopamine; norepinephrine; microdialysis ID BIOGENIC-AMINE TRANSPORTERS; RHESUS-MONKEYS; AMPHETAMINE; DOPAMINE; DRUGS; FENFLURAMINE; PHENTERMINE; SEROTONIN; RELEASE; ABUSE AB Phendimetrazine is an effective and widely prescribed appetite suppressant. Preclinical findings show that phendimetrazine displays stimulant properties similar to amphetamine, but few studies have examined the neurochemical mechanism of the drug. In the present work, we characterize the activity of phendimetrazine and its putative metabolites [phenmetrazine, pseudophenmetrazine, and associated stereoisomers] at biogenic amine transporters. All drugs were tested in vitro using assays to measure uptake and release of [H-3]dopamine, [H-3]norepinephrine, and [H-3]serotonin ([H-3]5-HT) in rat brain synaptosomes. Selected drugs were tested in vivo using microdialysis to measure extracellular dopamine and serotonin (5-HT) in rat nucleus accumbens. Phendimetrazine itself had no effect on uptake or release of any transmitter. In contrast, the trans-configured N-demethylated metabolite, phenmetrazine, was a potent releaser of [H-3]norepinephrine (EC50 = 50 nM) and [H-3]dopamine (EC50 = 131 nM). The cis N-demethylated metabolite, pseudophenmetrazine, displayed modest potency at releasing [H-3]norepinephrine (EC50 514 nM) and blocking [H-3]dopamine re-uptake (IC50 = 2630 nM). All drugs tested were inactive or weak in the [H-3]5-HT assays. When injected intravenously, phendimetrazine had minimal effects on extracellular transmitter levels, whereas phenmetrazine produced dose-related elevations in extracellular dopamine. The collective findings suggest that phendimetrazine is a "prodrug" that is converted to the active metabolite phenmetrazine, a potent substrate for norepinephrine and dopamine transporters. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 18 TC 41 Z9 42 U1 0 U2 2 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 JUN 28 PY 2002 VL 447 IS 1 BP 51 EP 57 AR PII S0014-2999(02)01830-7 DI 10.1016/S0014-2999(02)01830-7 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 574XU UT WOS:000176916100006 PM 12106802 ER PT J AU Chrambach, A Griffith, AL AF Chrambach, A Griffith, AL TI Reflections on the first anniversary of N. Catsimpoolas' death SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article ID ELECTROPHORESIS; SEPARATION C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Room 9D50, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 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 JUN 28 PY 2002 VL 52 IS 1 BP 1 EP 10 AR PII S0165-022X(02)00028-3 DI 10.1016/S0165-022X(02)00028-3 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 580WB UT WOS:000177258700001 PM 12184272 ER PT J AU Brosh, RM Waheed, J Sommers, JA AF Brosh, RM Waheed, J Sommers, JA TI Biochemical characterization of the DNA substrate specificity of Werner syndrome helicase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STALLED REPLICATION FORKS; SINGLE-STRANDED-DNA; SYNDROME PROTEIN; SYNDROME CELLS; SYNDROME GENE; FLAP ENDONUCLEASE-1; POLYMERASE-DELTA; REPEAT SEQUENCE; HOLLIDAY JUNCTIONS; S-PHASE AB Werner syndrome is a hereditary premature aging disorder characterized by genome instability. The product of the gene defective in WS, WRN, is a helicase/exonuclease that presumably functions in DNA metabolism. To understand the DNA structures WRN acts upon in vivo, we examined its substrate preferences for unwinding. WRN unwound a 3'-single-stranded (ss)DNA-tailed duplex substrate with streptavidin bound to the end of the 3'-ssDNA tail, suggesting that WRN does not require a free DNA end to unwind the duplex; however, WRN was completely blocked by streptavidin bound to the 3'-ssDNA tail 6 nucleotides upstream of the single-stranded/double-stranded DNA junction. WRN efficiently unwound the forked duplex with streptavidin bound just upstream of the junction, suggesting that WRN recognizes elements of the fork structure to initiate unwinding. WRN unwound two important intermediates of replication/repair, a 5'-ssDNA flap substrate and a synthetic replication fork. WRN was able to translocate on the lagging strand of the synthetic replication fork to unwind duplex ahead of the fork. For the 5'-flap structure, WRN specifically displaced the 5'-flap oligonucleotide, suggesting a role of WRN in Okazaki fragment processing. The ability of WRN to target DNA replication/repair intermediates may be relevant to its role in genome stability maintenance. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 51 TC 101 Z9 103 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 28 PY 2002 VL 277 IS 26 BP 23236 EP 23245 DI 10.1074/jbc.M111446200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700020 PM 11956187 ER PT J AU Parkin, SE Baer, M Copeland, TD Schwartz, RC Johnson, PF AF Parkin, SE Baer, M Copeland, TD Schwartz, RC Johnson, PF TI Regulation of CCAAT/enhancer-binding protein (C/EBP) activator proteins by heterodimerization with C/EBP gamma (Ig/EBP) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; ACUTE-PHASE RESPONSE; DNA-BINDING; TRANSCRIPTION FACTORS; LEUCINE ZIPPER; HEPATOCYTE PROLIFERATION; CELL-PROLIFERATION; MESSENGER-RNA; IN-VITRO; BETA AB The CCAAT/enhancer-binding proteins (C/EBPs) are basic leucine zipper transcription factors that play important roles in regulating cell growth and differentiation. C/EBP proteins form leucine zipper-mediated homodimers but are also capable of heterodimerizing with other C/EBPs in vitro. Here we show that C/EBPbeta occurs predominantly as a heterodimer that displays rapid mobility in gel shift assays. Biochemical fractionation and antibody supershift assays demonstrate that the C/EBPbeta heterodimeric partner is C/EBPgamma (Ig/EBP), a C/EBP protein that has been implicated as an inhibitor of other family members. Although most cell types express C/EBPbeta.C/EBPgamma heterodimers, macrophages contain a C/EBPbeta partner that is serologically distinct from C/EBPgamma. We found that C/EBPgamma blocked the ability of C/EBPbeta and C/EBPgamma to activate a reporter gene in L cell fibroblasts but did not inhibit a chimeric C/EBPbeta protein containing the GCN4 leucine zipper. Repression by C/EBPgamma occurs at the level of transactivation and requires heterodimerization with the C/EBP partner. C/EBPgamma was an ineffective repressor in HepG2 hepatoma cells despite forming C/EBP heterodimers, and C/EBPalpha was not effectively inhibited in either L or HepG2 cells. Our findings demonstrate that C/EBPgamma modulates C/EBP activity in a cell- and isoform-specific manner. C1 NCI Frederick, Basic Res Lab, Regulat Cell Growth Lab, Frederick, MD 21702 USA. NCI Frederick, Basic Res Lab, Eukaryot Transcript Regulat Sect, Frederick, MD 21702 USA. Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. RP Johnson, PF (reprint author), NCI Frederick, Basic Res Lab, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 51 TC 44 Z9 45 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 JUN 28 PY 2002 VL 277 IS 26 BP 23563 EP 23572 DI 10.1074/jbc.M202184200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700061 PM 11980905 ER PT J AU Zrachia, A Dobroslav, M Blass, M Kazimirsky, G Kronfeld, I Blumberg, PM Kobiler, D Lustig, S Brodie, C AF Zrachia, A Dobroslav, M Blass, M Kazimirsky, G Kronfeld, I Blumberg, PM Kobiler, D Lustig, S Brodie, C TI Infection of glioma cells with sindbis virus induces selective activation and tyrosine phosphorylation of protein kinase C delta - Implications for sindbis virus-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERSISTENT ALPHAVIRUS INFECTION; PROTEOLYTIC ACTIVATION; SIGNAL-TRANSDUCTION; GROWTH-FACTOR; PKC-DELTA; TRANSLOCATION; EXPRESSION; PATHWAY; FAMILY; BCL-2 AB Sindbis virus (SV) is an alpha virus used as a model for studying the role of apoptosis in virus infection. In this study, we examined the role of protein kinase C (PKC) in the apoptosis induced by SVNI, a virulent strain of SV. Infection of C6 cells with SVNI induced a selective translocation of PKCdelta to the endoplasmic reticulum and its tyrosine phosphorylation. The specific PKCdelta inhibitor rottlerin and a PKCdelta kinase-dead mutant increased the apoptosis induced by SVNI. To examine the role of the tyrosine phosphorylation of PKCS in the apoptosis induced by SVNI we used a PKCdelta mutant in which five tyrosine residues were mutated to phenylalanine (PKCdelta5). PKCdelta5-overexpressing cells exhibited increased apoptosis in response to SVNI as compared with control cells and to cells overexpressing PKCdelta. SVNI also increased the cleavage of caspase 3 in cells overexpressing PKCdelta5 but did not induce cleavage of PKCdelta or PKCdelta5. Using single tyrosine mutants, we identified tyrosines 52, 64, and 155 as the phosphorylation sites associated with the apoptosis induced by SVNI. We conclude that PKCdelta exerts an inhibitory effect on the apoptosis induced by SV and that phosphorylation of PKCdelta on specific tyrosines is required for this function. C1 Bar Ilan Univ, Fac Life Sci, Med Diag Res Ctr, IL-52900 Ramat Gan, Israel. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Israel Inst Biol Res, Dept Infect Dis, IL-74100 Ness Ziona, Israel. RP Brodie, C (reprint author), Bar Ilan Univ, Fac Life Sci, Med Diag Res Ctr, IL-52900 Ramat Gan, Israel. NR 53 TC 50 Z9 52 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 JUN 28 PY 2002 VL 277 IS 26 BP 23693 EP 23701 DI 10.1074/jbc.M111658200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700078 PM 11927579 ER PT J AU Walters, RW Pilewski, JM Chiorini, JA Zabner, J AF Walters, RW Pilewski, JM Chiorini, JA Zabner, J TI Secreted and transmembrane mucins inhibit gene transfer with AAV4 more efficiently than AAV5 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; ADENOASSOCIATED VIRUS VECTORS; AIRWAY EPITHELIA; SIALIC-ACID; TRACHEAL EPITHELIUM; FACTOR-IX; C VIRUS; CELLS; TRANSDUCTION; GLYCOPROTEINS AB Adeno-associated virus (AAV) is a promising vector for gene transfer in cystic fibrosis. AAV4 and AAV5 both bind to the apical surface of differentiated human airway epithelia, but only AAV5 infects. Both AAV4 and AAV5 require 2,3-linked sialic acid for binding. However, AAV5 interacts with sialic acid on N-linked carbohydrates, whereas AAV4 interacts with sialic acid on O-linked carbohydrates. Because mucin is decorated with O-linked carbohydrates, we hypothesized that mucin binds AAV4 and inhibits gene transfer. To evaluate the effect of secreted mucin, we studied mucin binding and gene transfer to COS cells and the basolateral membrane of well differentiated human airway epithelia. AAV4 bound mucin more efficiently than AAV5, and mucin inhibited gene transfer with AAV4. Moreover, O-glycosidase-pretreated mucin did not block gene transfer with AAV4. Similar to secreted mucin, the transmembrane mucin MUC1 inhibited gene transfer with AAV4 but not AAV5. MUC1 inhibited AAV4 by blocking internalization of the virus. Thus, O-linked carbohydrates of mucin are potent inhibitors of AAV4. Furthermore, whereas mucin plays an important role in innate host defense, its activity is specific; some vectors or pathogens are more resistant to its effects. C1 NIDCR, Gene Therapeut Branch, NIH, Bethesda, MD 20902 USA. Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Physiol & Biophys, Iowa City, IA 52242 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. RP Zabner, J (reprint author), NIDCR, Gene Therapeut Branch, NIH, 10-1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20902 USA. FU NIDDK NIH HHS [T30DK54759] NR 43 TC 45 Z9 45 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 JUN 28 PY 2002 VL 277 IS 26 BP 23709 EP 23713 DI 10.1074/jbc.M200292200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700080 PM 11925433 ER PT J AU Dubois, E Scherens, B Vierendeels, F Ho, MMW Messenguy, F Shears, SB AF Dubois, E Scherens, B Vierendeels, F Ho, MMW Messenguy, F Shears, SB TI In Saccharomyces cerevisiae, the inositol polyphosphate kinase activity of Kcs1p is required for resistance to salt stress, cell wall integrity, and vacuolar morphogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA EXPORT; ARGININE METABOLISM; HEXAKISPHOSPHATE KINASE; PHOSPHOLIPASE-C; LEUCINE-ZIPPER; YEAST VACUOLE; PROTEIN; FAMILY; BIOGENESIS; ARGRIII AB A problem for inositol signaling is to understand the significance of the kinases that convert inositol hexakisphosphate to diphosphoinositol polyphosphates. This kinase activity is catalyzed by Kcs1p in the yeast Saccharomyces cerevisiae. A kcs1Delta yeast strain that was transformed with a specifically "kinase-dead" kcs1p mutant did not synthesize diphosphoinositol polyphosphates, and the cells contained a fragmented vacuolar compartment. Biogenesis of the yeast vacuole also required another functional domain in Kcs1p, which contains two leucine heptad repeats. The kinase activity of Kcs1p was also found to sustain cell growth and integrity of the cell wall and to promote adaptive responses to salt stress. Thus, the synthesis of diphosphoinositol polyphosphates has wide ranging physiological significance. Furthermore, we showed that these phenotypic responses to Kcs1p deletion also arise when synthesis of precursor material for the diphosphoinositol polyphosphates is blocked in arg82Delta cells. This metabolic block was partially bypassed, and the phenotype was partially rescued, when Kcs1p was overexpressed in the arg82Delta cells. This was due, in part, to the ability of Kcs1p to phosphorylate a wider range of substrates than previously appreciated. Our results show that diphosphoinositol polyphosphate synthase activity is essential for biogenesis of the yeast vacuole and the cell's responses to certain environmental stresses. C1 Free Univ Brussels, Inst Rech Microbiol Jean Marie Wiame, B-1070 Brussels, Belgium. NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Dubois, E (reprint author), Free Univ Brussels, Inst Rech Microbiol Jean Marie Wiame, 808 Route Lennik, B-1070 Brussels, Belgium. NR 43 TC 74 Z9 76 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 JUN 28 PY 2002 VL 277 IS 26 BP 23755 EP 23763 DI 10.1074/jbc.M202206200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700086 PM 11956213 ER PT J AU Fan, JF Dolensky, B Kim, IH Kirk, KL AF Fan, JF Dolensky, B Kim, IH Kirk, KL TI Syntheses of E- and Z-2- and 4-fluorourocanic acids SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE fluoroimidazoles; Homer-Wadsworth-Emmons olefination; urocanic acid; tritylation ID UROCANIC ACID; SUPPRESSION AB Homer-Wadsworth-Emmons olefination of ring-fluorinated N-trityl-imidazole carboxaldehydes with dialkyphosphonoacetic acid esters produced ring-fluorinated imidazolyl-E- and Z-acrylate esters. Stereochemistry was controlled by choice of phoshonate. Acid catalyzed removal of trityl followed by ester saponification gave the target 2- and 4-fluoro-E- and Z-urocanic acid derivatives. These are being investigated as potential mediators of photo-immunosupression. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20982 USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20982 USA. NR 14 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD JUN 28 PY 2002 VL 115 IS 2 BP 137 EP 142 AR PII S0022-1139(02)00045-3 DI 10.1016/S0022-1139(02)00045-3 PG 6 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 569NF UT WOS:000176607900006 ER PT J AU Johnson, JD Reichelderfer, D Zutshi, A Graves, S Walters, D Smith, C AF Johnson, JD Reichelderfer, D Zutshi, A Graves, S Walters, D Smith, C TI Toxicokinetics of 2-methylimidazole in male and female F344 rats SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article AB The toxicokinetics of 2-methylimidazole (2-MI) were studied in male and female Fischer 344 rats after a single iv dose of 10 mg/kg or gavage dose of 25, 50, or 100 mg/kg. The 2-MI was formulated in 0.05 M phosphate-buffeted saline (pH 7.4). The iv profiles could be best described by a two-compartment model with first-order elimination. The terminal elimination half-life, volume of distribution at steady state, and clearance values were 0.78 and 0.8-5 h(-1), 1.5 and 1.9 L, and 4.97 and 12.0 L/h/kg for males and females, respectively. After a gavage dose, the plasma concentration time profiles could be best described by a one-compartment model, no lag phase, and first-order absorption and elimination. The peak 2-MI plasma concentrations increased proportionately with close and were reached within 35 to 50 min (T-max) for all groups. The estimated half-life value for 2-MI was about I h for the iv group and the male 25-, 50-, or 100-mg/kg groups and female 25-mg/kg groups. Clearance increased for the male 100- and female 50- and 100-mg/kg groups. For a given dose group, clearance was also two to three times greater for female rats when compared to male rats. Absolute bioavailability tot 2-MI was estimated to approach 97%. The results of this study indicated that 2-MI was (1) rapidly and completely absorbed, (2) quickly eliminated, (3) cleated differently for females than for males, (4) affected somewhat by dose for females, and (5) unlikely to undergo tissue accumulation following repeated exposure. C1 Battelle Mem Inst, Columbus, OH 43201 USA. Whitehall Robins, Richmond, VA USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Johnson, JD (reprint author), Battelle Mem Inst, Room 6-1-47C,505 King Ave, Columbus, OH 43201 USA. NR 17 TC 4 Z9 4 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD JUN 28 PY 2002 VL 65 IS 12 BP 869 EP 879 DI 10.1080/00984100290071135 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 563XC UT WOS:000176281800004 PM 12079612 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Calcium-induced volume transition in polyacrylate hydrogels swollen in physiological salt solutions SO MACROMOLECULAR BIOSCIENCE LA English DT Article DE hydrogels; ion exchange; osmotic pressure; small-angle neutron scattering; swelling ID ANGLE NEUTRON-SCATTERING; THERMODYNAMIC OBSERVATIONS; POLYMER GELS; ACID) GELS; NETWORKS; SANS AB Osmotic and small-angle neutron-scattering measurements are performed to study the volume transition that occurs in sodium polyacrylate gels swollen in sodium chloride solutions when calcium ions are introduced. In the presence of calcium ions, the osmotic pressure depends sensitively on the sodium chloride concentration, indicating that calcium preferentially replaces condensed sodium ions. This substitution modifies the effective attractive interaction between polymer chains. Analysis of the osmotic data in terms of the Flory-Huggins reveals a sharp increase in the third-order ternary thermodynamic interaction parameter upon introduction of calcium ions. The neutron-scattering response at low scattering vectors q displays power-law behavior with a slope of approximately - 3.6, consistent with scattering from surfaces of large objects. These results are in agreement with the development of dense polymer-rich regions dispersed in a soft polymer matrix. At larger q, a region with slope - 1 is observed, characteristic of rigid linear structures. C1 NICHD, Lab Integrat & Med Biophys, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, UMR 5588, Spectrometrie Phys Lab, F-38402 St Martin Dheres, France. RP Horkay, F (reprint author), NICHD, Lab Integrat & Med Biophys, Sect Tissue Biophys & Biomimet, NIH, 13 South Dr, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 32 TC 8 Z9 8 U1 0 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1616-5187 J9 MACROMOL BIOSCI JI Macromol. Biosci. PD JUN 28 PY 2002 VL 2 IS 5 BP 207 EP 213 DI 10.1002/1616-5195(200206)2:5<207::AID-MABI207>3.0.CO;2-5 PG 7 WC Biochemistry & Molecular Biology; Materials Science, Biomaterials; Polymer Science SC Biochemistry & Molecular Biology; Materials Science; Polymer Science GA 574HU UT WOS:000176883900004 ER PT J AU Cummings, KJ Gray, SL Simmons, CJT Kozak, CA Sherwood, NM AF Cummings, KJ Gray, SL Simmons, CJT Kozak, CA Sherwood, NM TI Mouse pituitary adenylate cyclase-activating polypeptide (PACAP): gene, expression and novel splicing SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE neuropeptide; hormone; PACAP; Adcyapl gene; postnatal expression ID HORMONE-RELEASING HORMONE; MESSENGER-RIBONUCLEIC-ACID; MOLECULAR-CLONING; PEPTIDE PACAP; INDUCED APOPTOSIS; RAT TESTIS; RNA; RECEPTOR; CELLS; PRECURSOR AB PACAP is a conserved neuropeptide present in all vertebrates. In the mouse, the PACAP gene and various mRNAs have been isolated. To further characterize the mouse PACAP gene (Adcyap1), we have confirmed its sequence, identified its chromosomal location on distal chromosome 17 and used RT-PCR and 5'RACE in various tissues to identify eight PACAP mRNAs, four of which are novel. Three of these novel transcripts have alternate 5'UTRs, whereas the fourth is altered within the coding region. This is the first report of alternate splicing within the coding region of the PACAP gene. The expression pattern of PACAP in the mouse during embryonic development and adulthood is known. Here, expression of PACAP in the mouse at four postnatal stages in 12 tissues is assessed. We identify continuous expression of PACAP in the brain and eye and stage-specific expression in the gonads and thymus. The complex splicing of PACAP transcripts may regulate the tissue-and stage-specific expression. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Victoria, Dept Biol, Victoria, BC V8W 2Y2, Canada. NIAID, NIH, Bethesda, MD 20892 USA. RP Sherwood, NM (reprint author), Univ Victoria, Dept Biol, POB 1700, Victoria, BC V8W 2Y2, Canada. NR 61 TC 11 Z9 11 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 28 PY 2002 VL 192 IS 1-2 BP 133 EP 145 AR PII S0303-7207(02)00028-X DI 10.1016/S0303-7207(02)00028-X PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 571MF UT WOS:000176720600015 PM 12088875 ER PT J AU Nabel, G Makgoba, W Esparza, J AF Nabel, G Makgoba, W Esparza, J TI HIV-1 diversity and vaccine development SO SCIENCE LA English DT Letter C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. S African MRC, ZA-7505 Tygerberg, South Africa. WHO, Joint UN Programme HIV AIDS, CH-1211 Geneva, Switzerland. RP Nabel, G (reprint author), NIH, Vaccine Res Ctr, MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. NR 3 TC 29 Z9 29 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 JUN 28 PY 2002 VL 296 IS 5577 BP 2335 EP 2335 DI 10.1126/science.296.5577.2335 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567CE UT WOS:000176467200020 PM 12090274 ER PT J AU McCune, AR Fuller, RC Aquilina, AA Dawley, RM Fadool, JM Houle, D Travis, J Kondrashov, AS AF McCune, AR Fuller, RC Aquilina, AA Dawley, RM Fadool, JM Houle, D Travis, J Kondrashov, AS TI A low genomic number of recessive lethals in natural populations of bluefin killifish and zebrafish SO SCIENCE LA English DT Article ID DROSOPHILA-MELANOGASTER; MUTANTS AB Despite the importance of selection against deleterious mutations in natural populations, reliable estimates of the genomic numbers of mutant alleles in wild populations are scarce. We found that, in wild-caught bluefin killifish Lucania goodei (Fundulidae) and wild-caught zebrafish Danio rerio (Cyprinidae), the average numbers of recessive lethal alleles per individual are 1.9 (95% confidence limits 1.3 to 2.6) and 1.4 (95% confidence limits 1.0 to 2.0), respectively. These results, together with data on several Drosophila species and on Xenopus laevis, show that phylogenetically distant animals with different genome sizes and numbers of genes carry similar numbers of lethal mutations. C1 Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. Ursinus Coll, Dept Biol, Collegeville, PA 19426 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP McCune, AR (reprint author), Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. NR 24 TC 33 Z9 34 U1 2 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 28 PY 2002 VL 296 IS 5577 BP 2398 EP 2401 DI 10.1126/science.1071757 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567CE UT WOS:000176467200043 PM 12089444 ER PT J AU Pollock, PM Meltzer, PS AF Pollock, PM Meltzer, PS TI Cancer - Lucky draw in the gene raffle SO NATURE LA English DT Editorial Material ID ACTIVATION C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Pollock, PM (reprint author), NHGRI, Canc Genet Branch, NIH, 50 S Dr MSC 8000, Bethesda, MD 20892 USA. EM pmeltzer@nhgri.nih.gov NR 7 TC 15 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 27 PY 2002 VL 417 IS 6892 BP 906 EP 907 DI 10.1038/417906a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566RC UT WOS:000176441200023 PM 12087387 ER PT J AU Marchbanks, PA McDonald, JA Wilson, HG Folger, SG Mandel, MG Daling, JR Bernstein, L Malone, KE Ursin, G Strom, BL Norman, SA Weiss, LK Wingo, PA Burkman, RT Berlin, JA Simon, MS Spirtas, R Weiss, LK AF Marchbanks, PA McDonald, JA Wilson, HG Folger, SG Mandel, MG Daling, JR Bernstein, L Malone, KE Ursin, G Strom, BL Norman, SA Weiss, LK Wingo, PA Burkman, RT Berlin, JA Simon, MS Spirtas, R Weiss, LK TI Oral contraceptives and the risk of breast cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID UNITED-STATES; WOMEN; PROGNOSIS; BLACK; WHITE AB Background: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. Methods: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. Results: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. Conclusions: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer. C1 Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Wayne State Univ, Karmanos Canc Inst, Div Epidemiol, Detroit, MI USA. Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. Bay State Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. Wayne State Univ, Karmanos Canc Inst, Div Hematol & Oncol, Detroit, MI USA. NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD 20892 USA. RP Marchbanks, PA (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. FU NCI NIH HHS [N01-PC-67006, N01-CN-0532, N01-CN-65064, N01-PC-67010]; NICHD NIH HHS [N01-HD-2-3166, N01-HD-3-3168, N01-HD-3-3174, N01-HD-3-3175, N01-HD-3-3176, Y01-HD-7022] NR 27 TC 259 Z9 277 U1 1 U2 9 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 JUN 27 PY 2002 VL 346 IS 26 BP 2025 EP 2032 DI 10.1056/NEJMoa013202 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 566DN UT WOS:000176411900002 PM 12087137 ER PT J AU Yanovski, SZ AF Yanovski, SZ TI Pharmacotherapy for obesity - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Yanovski, SZ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM sy29f@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 27 PY 2002 VL 346 IS 26 BP 2093 EP 2093 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 566DN UT WOS:000176411900028 ER PT J AU Manzano, RG Montuenga, LM Dayton, M Dent, P Kinoshita, I Vicent, S Gardner, GJ Nguyen, PM Choi, YH Trepel, J Auersperg, N Birrer, MJ AF Manzano, RG Montuenga, LM Dayton, M Dent, P Kinoshita, I Vicent, S Gardner, GJ Nguyen, PM Choi, YH Trepel, J Auersperg, N Birrer, MJ TI CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential SO ONCOGENE LA English DT Article DE MKP-1; ovarian; cancer; phosphatases; growth; motility ID PROTEIN-TYROSINE PHOSPHATASES; IMMEDIATE-EARLY GENE; MAP KINASE; IN-VIVO; CONSTITUTIVE ACTIVATION; EXTRACELLULAR-MATRIX; DNA-SYNTHESIS; CELL-LINES; GROWTH; MKP-1 AB Although early stage ovarian cancer can be effectively treated with surgery and chemotherapy, the majority of cases present with advanced disease, which remains essentially incurable. Unfortunately, little is known about the genes important for the development and progression of this disease. In this study, the expression of 68 phosphatases was determined in immortalized ovarian epithelial cells (IOSE) and compared to ovarian cancer cell lines. CL100, a dual specificity phosphatase, displayed 10-25-fold higher expression in normal compared to malignant ovarian cell lines. Immunohistochemical staining of normal ovaries and 68 ovarian cancer specimens confirmed this differential expression. Re-expression of CL100 in ovarian cancer cells decreased adherent and nonadherent cell growth and induced phenotypic changes including loss of filopodia and lamellipodia with an associated decrease in cell motility. Induced expression of CL100 in ovarian cancer cells suppressed intraperitoneal tumor growth in nude mice. These results show for the first time that CL100 expression is altered in human ovarian cancer, that CL100 expression changes cell morphology and motility, and that it suppresses intraperitoneal growth of human ovarian epithelial cancer. These data suggest that down-regulation of CL100 may play a role in the progression of human ovarian cancer. C1 NCI, Cell & Canc Biol Dept, Rockville, MD 20850 USA. Louisiana State Univ, Med Ctr, Dept Med, Shreveport, LA 71130 USA. Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Dept Radiat Oncol, Richmond, VA 23298 USA. Univ British Columbia, Dept Obstet & Gynecol, Vancouver, BC V6H 3V5, Canada. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Dept, 9610 Med Ctr Dr, Rockville, MD 20850 USA. OI Vicent, Silvestre/0000-0002-9457-6881 FU NCI NIH HHS [CA88906]; NIDDK NIH HHS [DK52825] NR 37 TC 40 Z9 42 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 27 PY 2002 VL 21 IS 28 BP 4435 EP 4447 DI 10.1038/sj.onc.1205542 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 564MA UT WOS:000176317100009 PM 12080474 ER PT J AU Wei, ZL Sakamuri, S Petukhov, PA George, C Lewin, NE Blumberg, PM Kozikowski, AP AF Wei, ZL Sakamuri, S Petukhov, PA George, C Lewin, NE Blumberg, PM Kozikowski, AP TI Synthesis and modeling study of (2S,5R,6R)- and (2S,5R,6S)-6-hydroxy-8-(1-decynyl)-benzolactam-V8 as protein kinase C modulators SO ORGANIC LETTERS LA English DT Article ID ACTIVATOR-BINDING DOMAIN; BIOLOGICAL EVALUATION; SIGNAL-TRANSDUCTION; TUMOR PROMOTERS; STRUCTURAL BASIS; LYNGBYATOXIN-A; INDOLACTAM-V; PKC-DELTA; ANALOGS; TELEOCIDIN AB [GRAPHICS] Both (2S,5R,6R)- and (2S,5R,6S)-6-hydroxy-8-(1-decynyl)benzolactam-V8 were designed and synthesized as PKC modulators. Biological assays reveal the (6R)-ligand to be 20-fold more potent than its (6S)-counterpart in binding to PKCalpha. C1 Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. USN, Res Lab, Washington, DC 20375 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Kozikowski, AP (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, 3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NCI NIH HHS [CA 79601] NR 34 TC 5 Z9 5 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD JUN 27 PY 2002 VL 4 IS 13 BP 2169 EP 2172 DI 10.1021/ol026013u PG 4 WC Chemistry, Organic SC Chemistry GA 565DY UT WOS:000176354700014 PM 12074659 ER PT J AU Mukhopadhyay, M Pelka, P DeSousa, D Kablar, B Schindler, A Rudnicki, MA Campos, AR AF Mukhopadhyay, M Pelka, P DeSousa, D Kablar, B Schindler, A Rudnicki, MA Campos, AR TI Cloning, genomic organization and expression pattern of a novel Drosophila gene, the disco-interacting protein 2 (dip2), and its murine homolog SO GENE LA English DT Article DE nervous system; development; genetics ID DISCONNECTED GENE; VISUAL-SYSTEM; CELLS; CLASSIFICATION; MELANOGASTER; SEQUENCE AB We report the cloning and initial characterization of a novel gene encoding the Disco interacting protein 2 (Dip2). dip2 DNA complementary to RNA (cDNA) showed a high degree of sequence similarity to cDNAs of unknown function previously identified in humans and Caenorhabditis elegans. We have cloned the mouse homolog of the dip2 cDNA and characterized the expression of this gene by Northern blotting analysis and in situ hybridization to whole mount embryos. Our observations demonstrate that there is a remarkable degree of sequence conservation at the dip2 locus that is reflected in the nervous system-specific expression of both the Drosophila and mouse homologs. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Ottawa Hlth Res Inst, Mol Med Programme, Ottawa, ON, Canada. Dalhousie Univ, Dept Anat & Neurobiol, Halifax, NS, Canada. McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Canji Inc, San Diego, CA 92121 USA. NIH, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Campos, AR (reprint author), Ottawa Hlth Res Inst, Mol Med Programme, Ottawa, ON, Canada. NR 21 TC 13 Z9 15 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 JUN 26 PY 2002 VL 293 IS 1-2 BP 59 EP 65 AR PII S0378-1119(02)00694-7 DI 10.1016/S0378-1119(02)00694-7 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 584JC UT WOS:000177462600006 PM 12137943 ER PT J AU Sopko, G AF Sopko, G TI Preventing cardiac events and restenosis after percutaneous coronary intervention SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID SMOOTH-MUSCLE CELLS; ARTERY DISEASE; DENSITY-LIPOPROTEIN; GROWTH-FACTOR; ANGIOPLASTY; LOVASTATIN; ENDOTHELIUM; OXIDATION; THERAPY; PROTEIN C1 NHLBI, Bethesda, MD 20892 USA. RP Sopko, G (reprint author), NHLBI, 6701 Rockledge Dr,MSC 7190, Bethesda, MD 20892 USA. NR 45 TC 6 Z9 6 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 JUN 26 PY 2002 VL 287 IS 24 BP 3259 EP 3261 DI 10.1001/jama.287.24.3259 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 566FF UT WOS:000176415800032 PM 12076224 ER PT J AU Foley, DJ White, LR AF Foley, DJ White, LR TI Dietary intake of antioxidants and risk of Alzheimer disease - Food for thought SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID IMPACT C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Foley, DJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. NR 11 TC 22 Z9 22 U1 1 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 JUN 26 PY 2002 VL 287 IS 24 BP 3261 EP 3263 DI 10.1001/jama.287.24.3261 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 566FF UT WOS:000176415800033 PM 12076225 ER PT J AU Chu, RA Pei, WH Takei, J Bai, YW AF Chu, RA Pei, WH Takei, J Bai, YW TI Relationship between the native-state hydrogen exchange and folding pathways of a four-helix bundle protein SO BIOCHEMISTRY LA English DT Article ID STABILITY; EQUILIBRIUM; TOPOLOGY; BARNASE; ABSENCE AB The hydrogen exchange behavior of a four-helix bundle protein in low concentrations of denaturant reveals some partially unfolded forms that are significantly more stable than the fully unfolded state. Kinetic folding of the protein, however, is apparently two-state in the absence of the accumulation of early folding intermediates. The partially unfolded forms are either as folded as or more folded than the rate-limiting transition state and appear to represent the major intermediates in a folding and unfolding reaction. These results are consistent with the suggestion that partially unfolded intermediates may form after the rate-limiting step for small proteins with apparent two-state folding kinetics. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. NR 25 TC 78 Z9 78 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 JUN 25 PY 2002 VL 41 IS 25 BP 7998 EP 8003 DI 10.1021/bi025872n PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564QA UT WOS:000176324000017 PM 12069590 ER PT J AU Dunigan, CD Hoang, Q Curran, PK Fishman, PH AF Dunigan, CD Hoang, Q Curran, PK Fishman, PH TI Complexity of agonist- and cyclic AMP-mediated downregulation of the human beta(1)-adrenergic receptor: Role of internalization, degradation, and mRNA destabilization SO BIOCHEMISTRY LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; PROTEIN-COUPLED RECEPTORS; INDUCED DOWN-REGULATION; BETA(2)-ADRENERGIC RECEPTOR; MESSENGER-RNA; BETA-2-ADRENERGIC RECEPTOR; BETA-1-ADRENERGIC RECEPTOR; NEUROTUMOR CELLS; DESENSITIZATION; SEQUESTRATION AB Prolonged agonist exposure often induces downregulation of G protein-coupled receptors (GPCRs). Although downregulation of the prototypical beta(2)-adrenergic receptor (beta(2)AR) has been extensively studied, the underlying mechanisms have yet to be resolved. As even less is known about the beta(1)-subtype, we investigated the downregulation of human beta(1)AR stably expressed in Chinese hamster fibroblasts in response to the agonist isoproterenol or the cell-permeable, chlorophenylthio-cAMP (CPT-cAMP). While either effector mediated decreases in both beta(1)AR binding activity and steady-state beta(1)AR mRNA levels, there were significant differences in their actions. Whereas agonist-mediated downregulation of beta(1)AR followed first-order kinetics, that induced by CPT-cAMP was delayed for several hours and similar to50% of the former. Furthermore, agonist but not CPT-cAMP induced beta(1)AR internalization, and inhibiting internalization also suppressed agonist-mediated downregulation. The latter, however, was more sensitive than the former to agonist concentration (EC50 of 0.3 vs 48 nM). Thus, at less than or equal to1 nM agonist, downregulation occurred without internalization and with a pattern similar to that mediated by CPT-cAMP. The amounts of beta(1)AR downregulated or internalized were proportional to initial receptor levels but reached saturation at similar to2 and 3 pmol/mg of protein, respectively. The fate of beta(1)AR protein during downregulation was determined by immunoblotting with anti-C-terminal antibodies. In agonist-treated cells, beta(1)AR protein disappeared with time and without any immunoreactive degradation products. Agonist-mediated downregulation of the human beta(1)AR appears to be a complex process that consists of both agonist- and cAMP-specific components. The former involves both receptor internalization and degradation whereas the latter involves a reduction in receptor mRNA. C1 NINCDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Fishman, PH (reprint author), NINCDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bldg 49,Room 2A28,49 Convent Drive,MSC 4440, Bethesda, MD 20892 USA. NR 40 TC 20 Z9 20 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 25 PY 2002 VL 41 IS 25 BP 8019 EP 8030 DI 10.1021/bi025538r PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564QA UT WOS:000176324000020 PM 12069593 ER PT J AU Brown, P AF Brown, P TI Drug therapy in human and experimental transmissible spongiform encephalopathy SO NEUROLOGY LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; RESISTANT PRION PROTEIN; INFECTED NEUROBLASTOMA-CELLS; FOLLICULAR DENDRITIC CELLS; CONGO RED; ALZHEIMERS-DISEASE; SCRAPIE PRION; INCUBATION PERIOD; PRP ACCUMULATION; AMPHOTERICIN-B AB During the past 30 years, over 60 different chemical compounds have been used to treat experimental animals infected with transmissible spongiform encephalopathies (TSE), including a wide variety of anti-infectious agents, immunomodulating drugs, and chemicals interacting with the lympho-reticular system. Some compounds achieved a prolongation of the incubation period, but this effect decreased or disappeared when they were administered at or near the onset of symptomatic disease. Recent in vitro and tissue culture studies support earlier speculation about the importance of a chemical structure containing both water-soluble and lipid-soluble components, evidently as a means of interaction with the misfolded membrane-bound 'prion' protein. A number of compounds shown to eliminate the protein (or infectivity) in TSE-infected tissue cultures are the subject of ongoing studies in animals, and are under consideration for human drug trials. As with other recalcitrant infections, combinations of drugs with different modes of action are likely to be necessary for any effective therapy. Also, very recent work in developing antibodies that can neutralize in vitro infection (and, in conjunction with genetic engineering, in vivo infection) has renewed interest in the strategies of both active and passive immunization. C1 NINDS, Lab Cent Nervous Syst Studies, NIH, Bethesda, MD 20892 USA. RP Brown, P (reprint author), NINDS, Lab Cent Nervous Syst Studies, NIH, Bldg 36,Room 4A-19 MSC-4123, Bethesda, MD 20892 USA. NR 48 TC 37 Z9 38 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 25 PY 2002 VL 58 IS 12 BP 1720 EP 1725 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 566LN UT WOS:000176429700003 PM 12088013 ER PT J AU Ment, LR Bada, HS Barnes, P Grant, PE Hirtz, D Papile, LA Pinto-Martin, J Rivkin, M Slovis, TL AF Ment, LR Bada, HS Barnes, P Grant, PE Hirtz, D Papile, LA Pinto-Martin, J Rivkin, M Slovis, TL TI Practice parameter: Neuroimaging of the neonate - Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society SO NEUROLOGY LA English DT Review ID BIRTH-WEIGHT INFANTS; HYPOXIC-ISCHEMIC ENCEPHALOPATHY; MAGNETIC-RESONANCE SPECTROSCOPY; CRANIAL ULTRASOUND ABNORMALITIES; APPARENT DIFFUSION-COEFFICIENT; PROTON MR SPECTROSCOPY; REAL-TIME ULTRASOUND; PRETERM INFANTS; INTRAVENTRICULAR HEMORRHAGE; BRAIN INJURY AB Objective: The authors reviewed available evidence on neonatal neuroimaging strategies for evaluating both very low birth weight preterm infants and encephalopathic term neonates. Imaging for the preterm neonate: Routine screening cranial ultrasonography (US) should be performed on all infants of <30 weeks' gestation once between 7 and 14 days of age and should be optimally repeated between 36 and 40 weeks' postmenstrual age. This strategy detects lesions such as intraventricular hemorrhage, which influences clinical care, and those such as periventricular leukomalacia and low-pressure ventriculomegaly, which provide information about long-term neurodevelopmental outcome. There is insufficient evidence for routine MRI of all very low birth weight preterm infants with abnormal results of cranial US. Imaging for the term infant: Noncontrast CT should be performed to detect hemorrhagic lesions in the encephalopathic term infant with a history of birth trauma, low hematocrit, or coagulopathy. If CT findings are inconclusive, MRI should be performed between days 2 and 8 to assess the location and extent of injury. The pattern of injury identified with conventional MRI may provide diagnostic and prognostic information for term infants with evidence of encephalopathy. In particular, basal ganglia and thalamic lesions detected by conventional MRI are associated with poor neurodevelopmental outcome. Diffusion-weighted imaging may allow earlier detection of these cerebral injuries. Recommendations: US plays an established role in the management of preterm neonates of <30 weeks' gestation. US also provides valuable prognostic information when the infant reaches 40 weeks' postmenstrual age. For encephalopathic term infants, early CT should be used to exclude hemorrhage; MRI should be performed later in the first postnatal week to establish the pattern of injury and predict neurologic outcome. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. NINDS, Clin Trials Sect, Bethesda, MD 20892 USA. Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI USA. RP Ment, LR (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. NR 117 TC 193 Z9 204 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 25 PY 2002 VL 58 IS 12 BP 1726 EP 1738 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 566LN UT WOS:000176429700004 PM 12084869 ER PT J AU Williams, MC Gorelick, RJ Musier-Forsyth, K AF Williams, MC Gorelick, RJ Musier-Forsyth, K TI Specific zinc-finger architecture required for HIV-1 nucleocapsid protein's nucleic acid chaperone function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MURINE LEUKEMIA-VIRUS; RNA PACKAGING SIGNAL; MINUS-STRAND; REVERSE TRANSCRIPTION; GENOME RECOGNITION; DNA; BINDING; SEQUENCES; ELEMENTS; REGION AB The nucleocapsid protein (NC) of HIV type 1 (HIV-1) is a nucleic acid chaperone that facilitates the rearrangement of nucleic acid secondary structure during reverse transcription. HIV-1 NC contains two CCHC-type zinc binding domains. Here, we use optical tweezers to stretch single lambda-DNA molecules through the helix-to-coil transition in the presence of wild-type and several mutant forms of HIV-1 NC with altered zinc-finger domains. Although all forms of NC lowered the cooperativity of the DNA helix-coil transition, subtle changes in the zinc-finger structures reduced NC's effect on the transition. The change in cooperativity of the DNA helix-coil transition correlates strongly with in vitro nucleic acid chaperone activity measurements and in vivo HIV-1 replication studies using the same NC mutants. Moreover, Moloney murine leukemia virus NC, which contains a single zinc finger, had little effect on transition cooperativity. These results suggest that a specific two-zinc-finger architecture is required to destabilize nucleic acids for optimal chaperone activity during reverse transcription in complex retroviruses such as HIV-1. C1 Northeastern Univ, Dana Res Ctr 111, Dept Phys, Boston, MA 02115 USA. Northeastern Univ, Dana Res Ctr 111, Ctr Interdisciplinary Res Complex Syst, Boston, MA 02115 USA. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. RP Williams, MC (reprint author), Northeastern Univ, Dana Res Ctr 111, Dept Phys, Boston, MA 02115 USA. OI Williams, Mark C./0000-0003-3219-376X FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [AI43231] NR 33 TC 83 Z9 84 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 JUN 25 PY 2002 VL 99 IS 13 BP 8614 EP 8619 DI 10.1073/pnas.132128999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567GZ UT WOS:000176478200029 PM 12084921 ER PT J AU Horwitz, EM Gordon, PL Koo, WKK Marx, JC Neel, MD McNall, RY Muul, L Hofmann, T AF Horwitz, EM Gordon, PL Koo, WKK Marx, JC Neel, MD McNall, RY Muul, L Hofmann, T TI Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEMATOPOIETIC STEM-CELLS; STROMAL CELLS; PROGENITOR CELLS; PAMIDRONATE TREATMENT; ADHERENT CELLS; RAT; DIFFERENTIATION; TRANSPLANTATION; EXPRESSION; CULTURES AB Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors. C1 St Jude Childrens Res Hosp, Transplantat & Gene Therapy Program, Memphis, TN 38105 USA. Wayne State Univ, Detroit, MI 48201 USA. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Horwitz, EM (reprint author), St Jude Childrens Res Hosp, 332 N Lauderdale,Room D-2058, Memphis, TN 38101 USA. EM edwin.horwitz@stjude.org FU NCI NIH HHS [P30 CA021765, P30 CA21765] NR 35 TC 998 Z9 1052 U1 4 U2 65 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 25 PY 2002 VL 99 IS 13 BP 8932 EP 8937 DI 10.1073/pnas.132252399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567GZ UT WOS:000176478200083 PM 12084934 ER PT J AU Lee, MK Stirling, W Xu, YQ Xu, XY Qui, D Mandir, AS Dawson, TM Copeland, NG Jenkins, NA Price, DL AF Lee, MK Stirling, W Xu, YQ Xu, XY Qui, D Mandir, AS Dawson, TM Copeland, NG Jenkins, NA Price, DL TI Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 -> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MULTIPLE SYSTEM ATROPHY; LEWY BODIES; NEUROFILAMENT SUBUNIT; IN-VIVO; PRESENILIN-1; DEMENTIA; DISORDERS; OLIGOMERIZATION; INCLUSIONS; PATHOLOGY AB Mutations in alpha-synuclein (alpha-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, alpha-Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of alpha-Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 --> Pro (A30P) or Ala-53 --> Thr (A53T) human alpha-Syns. The mice expressing the A53T human alpha-Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of alpha-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of alpha-Syn, brain regions with pathology exhibit increases in detergent-insoluble alpha-Syn and alpha-Syn aggregates. Our results demonstrate that the A53T mutant alpha-Syn causes significantly greater in vivo neurotoxicity as compared with other alpha-Syn variants. Further, alpha-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble alpha-Syn. C1 Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Johns Hopkins Udall Parkinsons Dis Res Ctr, Baltimore, MD 21205 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Lee, MK (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol, 558 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Lee, Michael/D-9491-2013 OI Lee, Michael/0000-0001-5865-9682 FU NIA NIH HHS [AG14248, P01 AG014248]; NINDS NIH HHS [R56 NS038065, NS38065, NS38377, P01 NS038065, P50 NS038377, R01 NS038065] NR 41 TC 376 Z9 389 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 25 PY 2002 VL 99 IS 13 BP 8968 EP 8973 DI 10.1073/pnas.132197599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567GZ UT WOS:000176478200089 PM 12084935 ER PT J AU Chen, CC Zimmer, A Sun, WH Hall, J Brownstein, MJ Zimmer, A AF Chen, CC Zimmer, A Sun, WH Hall, J Brownstein, MJ Zimmer, A TI A role for ASIC3 in the modulation of high-intensity pain stimuli SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GATED CATION CHANNELS; SENSING ION CHANNELS; NA+ CHANNEL; ACID; SUBUNIT; NEURONS; FAMILY; CELLS; MICE; NOCICEPTION AB Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins/epithelial sodium channel (DEG/ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50degreesC), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate- to high-intensity pain sensation. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. Univ Bonn, Dept Psychiat, Mol Neurobiol Lab, D-53105 Bonn, Germany. RP Zimmer, A (reprint author), NIMH, Genet Lab, 36 Convent Dr 3D06, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009 NR 30 TC 194 Z9 206 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 25 PY 2002 VL 99 IS 13 BP 8992 EP 8997 DI 10.1073/pnas.122245999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567GZ UT WOS:000176478200093 PM 12060708 ER PT J AU Saka, E Iadarola, M Fitzgerald, DJ Graybiel, AM AF Saka, E Iadarola, M Fitzgerald, DJ Graybiel, AM TI Local circuit neurons in the striatum regulate neural and behavioral responses to dopaminergic stimulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUBSTANCE-P; C-FOS; NEUROKININ-1 RECEPTOR; PROJECTION NEURONS; BASAL GANGLIA; RAT STRIATUM; CHOLINERGIC INTERNEURONS; MATRIX COMPARTMENTS; DEPLETED STRIATUM; NEOSTRIATUM AB Interneurons are critical for shaping neuronal circuit activity in many parts of the central nervous system. To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum. Our findings demonstrate that the neurotoxin SP-PE35, a substance P-Pseudomonas exotoxin conjugate, selectively targets striatal cholinergic and nitric oxide synthase/somatostatinergic interneurons when injected locally into the striatum. The effects of this selective cell targeting encompassed alterations in both behavioral and neural responses to dopaminergic stimulation, including altered patterns of early-gene response in striosomes and matrix. We conclude that NK-1-bearing local circuit neurons of the striatum regulate the differential responses of striatal projection neurons to dopamine-mediated signaling. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. NIH, Neural Gene Express Unit, Pain & Neurosensory Mech Branch, Bethesda, MD 20892 USA. NCI, Biotherapy Sect, Mol Biol Lab, Bethesda, MD 20892 USA. RP Graybiel, AM (reprint author), MIT, Dept Brain & Cognit Sci, E25-618,45 Carleton St, Cambridge, MA 02139 USA. FU NIMH NIH HHS [MH60379, R01 MH060379]; NINDS NIH HHS [NS38372, P50 NS038372] NR 38 TC 59 Z9 61 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 JUN 25 PY 2002 VL 99 IS 13 BP 9004 EP 9009 DI 10.1073/pnas.132212499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 567GZ UT WOS:000176478200095 PM 12060713 ER PT J AU Hunyady, L Baukal, AJ Gaborik, Z Olivares-Reyes, JA Bor, M Szaszak, M Lodge, R Catt, KJ Balla, T AF Hunyady, L Baukal, AJ Gaborik, Z Olivares-Reyes, JA Bor, M Szaszak, M Lodge, R Catt, KJ Balla, T TI Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT(1) angiotensin receptor SO JOURNAL OF CELL BIOLOGY LA English DT Article DE angiotensin II receptor recycling; endosomal sorting; G protein-coupled receptor; PI 3-kinase; Rab proteins ID PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; GREEN FLUORESCENT PROTEIN; GROWTH-FACTOR RECEPTOR; MULTIVESICULAR BODY; PLASMA-MEMBRANE; BETA-ARRESTIN; II RECEPTOR; INTRACELLULAR TRAFFICKING; PHOSPHOINOSITIDE 3-KINASE; MEDIATED ENDOCYTOSIS AB Agonist-induced endocytosis and processing of the G protein-coupled AT, angiotensin 11 (Ang 11) receptor (AT(1)R) was studied in HEK 293 cells expressing green fluorescent protein (GFP)- or hemagglutinin epitope-tagged forms of the receptor. After stimulation with Ang 11, the receptor and its ligand colocalized with Rab5-GFP and Rab4-GFP in early endosomes, and subsequently with Rab11-GFP in pericentriolar recycling endosomes. Inhibition of phosphaticlylinositol (PI) 3-kinase by wortmannin (WT) or LY294002 caused the formation of large endosomal vesicles of heterogeneous Rab composition, containing the ligand-receptor complex in their limiting membranes and in small associated vesicular structures. In contrast to Alexa((R))-transferrin, which was mainly found in small vesicles associated with the outside of large vesicles in WT-treated cells, rhodamine-Ang 11 was also segregated into small internal vesicles. In cells labeled with I-125-Ang 11, WT treatment did not impair the rate of receptor endocytosis, but significantly reduced the initial phase of receptor recycling without affecting its slow component. Similarly, WT inhibited the early, but not the slow, component of the recovery of AT(1)R at the cell surface after termination of Ang 11 stimulation. These data indicate that internalized AT, receptors are processed via vesicles that resemble multivesicular bodies, and recycle to the cell surface by a rapid PI 3-kinase-dependent recycling route, as well as by a slower pathway that is less sensitive to PI 3-kinase inhibitors. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Dept Physiol, H-1444 Budapest, Hungary. RP Balla, T (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 49,Rm 6A35,49 Convent Dr, Bethesda, MD 20892 USA. EM tambal@box-t.nih.gov RI Szaszak, Marta/G-7957-2011; OI Balla, Tamas/0000-0002-9077-3335 NR 50 TC 119 Z9 120 U1 0 U2 4 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 JUN 24 PY 2002 VL 157 IS 7 BP 1211 EP 1222 DI 10.1083/jcb.200111013 PG 12 WC Cell Biology SC Cell Biology GA 568EA UT WOS:000176528400010 PM 12070129 ER PT J AU Nacro, K Lee, J Barchi, JJ Lewin, NE Blumberg, PM Marquez, VE AF Nacro, K Lee, J Barchi, JJ Lewin, NE Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). Part 19: Asymmetric syntheses of (3R)- and (3S)-3-hydroxy-4,4-disubstituted heptono-1,4-lactones as protein kinase C (PK-C) ligands with increased hydrophilicity SO TETRAHEDRON LA English DT Article DE protein kinase C; diacylglycerol; DAG-lactones; carbohydrate chernistry; log P ID TEMPLATE AB The stereospecific introduction of (R)- and (S)-OH groups at position C-3 of two diacylglycerol gamma-lactones (DAG-lactones) previously identified as strong protein kinase C (PK-C) ligands is presented. The compounds were designed to investigate whether the extra OH group in a specific orientation could establish an additional hydrogen bond with the C1 domain of PK-C, thus providing a DAG analogue with reduced lipophilicity. The OH groups were introduced following two different diastereoselective multistep syntheses starting from diacetone-D-glucose. The PK-C binding affinities for the new compounds were weaker in comparison to those of the parent compounds, suggesting that the extra OH does not engage efficiently in hydrogen bonding at the receptor. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, 376 Boyles St,Bldg 376 Rm104, Frederick, MD 21702 USA. RI Barchi Jr., Joseph/N-3784-2014 NR 15 TC 12 Z9 12 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD JUN 24 PY 2002 VL 58 IS 26 BP 5335 EP 5345 AR PII S0040-4020(02)00477-5 DI 10.1016/S0040-4020(02)00477-5 PG 11 WC Chemistry, Organic SC Chemistry GA 568JT UT WOS:000176539200017 ER PT J AU Salvatore, G Nagata, S Billaud, M Santoro, M Vecchio, G Pastan, I AF Salvatore, G Nagata, S Billaud, M Santoro, M Vecchio, G Pastan, I TI Generation and characterization of novel monoclonal antibodies to the Ret receptor tyrosine kinase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ret/antibody ID NEUROBLASTOMA CELL-LINES; PROTOONCOGENE; EXPRESSION; DIFFERENTIATION; SPERMATOGONIA; CARCINOMAS; LEUKEMIA; CANCER; GDNF; GENE AB Ret is a tyrosine kinase receptor involved in several human diseases germ-line mutations are responsible for multiple endocrine neoplasia type 2 syndromes while somatic mutations of Ret are found in sporadic medullary thyroid carcinomas. In the present work, we describe the generation and characterization of a panel of novel monoclonal antibodies to Ret obtained by immunizing mice with a Ret-FC fusion protein. Fifty-five independent monoclonal antibodies recognize Ret-FC by enzyme linked immunosorbent assay but not a non-related FC fusion protein. Twenty antibodies further characterized recognize Ret expressing cells by flow cytometry. Finally, immunoprecipitation analysis showed that these antibodies recognize Ret mature glycosylated and immature forms. Thus, these monoclonal antibodies could be used as diagnostic tools to detect Ret expression, as well as therapeutic tools to downmodulate Ret or to deliver cytotoxic drugs to malignancies that overexpress Ret as neuroblastomas, medullary and papillary thyroid carcinomas, seminomas, and leukemia. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Naples Federico II, Ctr Endocrinol & Oncol Sperimentale, CNR,Fac Med & Chirurg, Dipartimento Biol & Patol Cellulare & Mol, I-80131 Naples, Italy. CNRS, Genet Lab, UMR 5641, F-69373 Lyon, France. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. RI Billaud, Marc/M-6954-2013 NR 21 TC 8 Z9 9 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 JUN 21 PY 2002 VL 294 IS 4 BP 813 EP 817 AR PII S000-6291(X0)20056-0 DI 10.1016/S0006-291X(02)00560-0 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 567ND UT WOS:000176490100011 PM 12061779 ER PT J AU Lin, Y Martin, J Gruendler, C Farley, J Meng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, V Wang, TW AF Lin, Y Martin, J Gruendler, C Farley, J Meng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, V Wang, TW TI A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs) SO BMC CELL BIOLOGY LA English DT Article ID E3 UBIQUITIN LIGASE; FACTOR-BETA FAMILY; 20S PROTEASOME; DEPENDENT DEGRADATION; PRECURSOR COMPLEXES; SMAD PROTEINS; I RECEPTOR; INTERACTS; ACTIVATION; SUBUNIT AB Background The intracellular signaling events of the Bone Morphogenetic Proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and sown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300. Currently, the detailed molecular mechanisms that allow R-Smads and Co-Smad to co-operatively modulate transcription events are not fully understood. Results Here we report a novel physical and functional link between Smad1 and the 26S proteasome that contributes to Smad1- and Smad4-mediated transcriptional regulation. Smad1 forms a complex wit a proteasome beta subunit HsN3 and the ornithine decarboxylase antizyme (Az). T e interaction is enhanced upon BMP type I receptor activation and occur prior to the incorporation of HsN3 into the mature 20S proteasome. Furthermore, BMPs trigger the translocation of Smad1, HsN3 and Az into the nucleus, where the novel CBP/p300 repressor protein SNIP1 is further recruited to Smad1/HsN3/Az complex and degraded in a Smad1-, Smad4- and Az-dependent fashion. The degradation of the CBP/p300 repressor SNIP1 is likely an essential step for Smad1-, Smad4- mediated transcriptional activation, since increased SNIP1 expression inhibits BMP-induced gene responses. Conclusions Our studies thus add two additional important functional partners of Smad1 into the signaling web of BMPs and also suggest a novel mechanism for Smad1 and Smad4 to co-modulate transcription via regulating proteasomal degradation of CBP/p300 repressor SNIP1. C1 Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Genet, Boston, MA 02114 USA. Pfizer Inc, Dept Cardiovasc Metab Dis, Groton, CT 06340 USA. NCI, Chemoprevent Lab, Bethesda, MD 20892 USA. RP Wang, TW (reprint author), Virginia Mason Res Ctr, 1201 9th Ave, Seattle, WA 98101 USA. NR 55 TC 53 Z9 65 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUN 21 PY 2002 VL 3 AR 15 DI 10.1186/1471-2121-3-15 PG 55 WC Cell Biology SC Cell Biology GA 565RQ UT WOS:000176383600001 PM 12097147 ER PT J AU Ten Hagen, KG Tran, DT AF Ten Hagen, KG Tran, DT TI A UDP-GalNAc : polypeptide N-acetylgalactosaminyltransferase is essential for viability in Drosophila melanogaster SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACETYL-D-GALACTOSAMINE; ALPHA-D-GALACTOSAMINE; CDNA CLONING; MOLECULAR-CLONING; EXPRESSION; GLYCOSYLATION; HOMOLOG; FAMILY; GENE; N-ACETYLGALACTOSAMINYLTRANSFERASE-T3 AB We report the first demonstration that the activity of a member of the LTDP-GalNAc:polypeptide N-acetylgaIactosaminyltransferase gene family is necessary for viability in Drosophila melanogaster. Expression of the wild-type recombinant pgant35A gene in COS7 cells resulted in in vitro activity against peptide and glycopeptide substrates, demonstrating that this gene encodes a biochemically active transferase. Previous mutagenesis studies identified recessive lethal mutations that were rescued by a genomic fragment containing the pgant35A gene; however, the presence of additional open reading frames within this fragment left open the possibility that another gene was responsible for rescue of the observed lethality. Here, we have determined the molecular nature of the mutations in three independent mutant alleles. Two of the mutant alleles contain premature stop codons within the coding region of pgant35A. The third mutant contains an arginine to tryptophan amino acid change, which, when expressed in COS7 cells, resulted in a dramatic reduction of transferase activity in vitro. PCR amplification of this gene from Drosophila cDNA panels and Northern analysis revealed that it is expressed throughout embryonic, larval, and pupal stages as well as in adult males and females. This study provides the first direct evidence for the involvement of a member of this conserved multigene family in eukaryotic development and viability. C1 NIDDK, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), NIDDK, Sect Biol Chem, NIH, 9000 Rockville Pike,Bldg 50,Rm 4120, Bethesda, MD 20892 USA. NR 32 TC 65 Z9 67 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 JUN 21 PY 2002 VL 277 IS 25 BP 22616 EP 22622 DI 10.1074/jbc.M201807200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600068 PM 11925446 ER PT J AU Bartke, A Wright, JC Mattison, JA Ingram, DK Miller, RA Roth, GS AF Bartke, A Wright, JC Mattison, JA Ingram, DK Miller, RA Roth, GS TI Dietary restriction and life-span SO SCIENCE LA English DT Letter ID MICE C1 So Illinois Univ, Sch Med, Dept Physiol, Carbondale, IL 62901 USA. NIA, NIH, Anim Ctr, Poolesville, MD 20837 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Bartke, A (reprint author), So Illinois Univ, Sch Med, Dept Physiol, Carbondale, IL 62901 USA. RI Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X NR 3 TC 17 Z9 17 U1 0 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 21 PY 2002 VL 296 IS 5576 BP 2141 EP 2141 DI 10.1126/science.296.5576.2141 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565PQ UT WOS:000176379000023 PM 12094784 ER PT J AU Dunah, AW Jeong, H Griffin, A Kim, YM Standaert, DG Hersch, SM Mouradian, MM Young, AB Tanese, N Krainc, D AF Dunah, AW Jeong, H Griffin, A Kim, YM Standaert, DG Hersch, SM Mouradian, MM Young, AB Tanese, N Krainc, D TI Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease SO SCIENCE LA English DT Article ID MEDIATED TRANSCRIPTION; GLUTAMINE REPEATS; GENE-EXPRESSION; TRANSGENIC MICE; MAMMALIAN-CELLS; BINDING PROTEIN; NERVOUS-SYSTEM; RECEPTOR GENE; TFIID SUBUNIT; HUMAN BRAIN AB Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Ctr Aging Genet & Neurodegenerat, Charlestown, MA 02129 USA. NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Microbiol MSB258, New York, NY 10016 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Ctr Aging Genet & Neurodegenerat, Charlestown, MA 02129 USA. OI Tanese, Naoko/0000-0002-1946-3211; Mouradian, M. Maral/0000-0002-9937-412X; Standaert, David/0000-0003-2921-8348 FU NCCIH NIH HHS [AT00613]; NIA NIH HHS [5R37AG13617]; NINDS NIH HHS [NS02174, NS34361, NS35255] NR 42 TC 448 Z9 458 U1 2 U2 15 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 JUN 21 PY 2002 VL 296 IS 5576 BP 2238 EP 2243 DI 10.1126/science.1072613 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565PQ UT WOS:000176379000064 PM 11988536 ER PT J AU Deng, WP Wong, KA Kirk, KL AF Deng, WP Wong, KA Kirk, KL TI Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA SO TETRAHEDRON-ASYMMETRY LA English DT Article ID ALPHA-AMINO-ACIDS; L-DOPA; ASYMMETRIC-SYNTHESIS; METABOLISM; GLYCINE; 6-FLUORO-L-DOPA; FLUORINATION; RAT; RADIOFLUORODESTANNYLATION; IMINES AB Alkylation under phase transfer conditions of the chiral glycine synthon 2 (prepared from the commercially available Oppolzer chiral sultam) with fluorinated analogues of 3,4-dimethoxybenzyl chloride proceeded with high diastereoselectivity. Hydrolysis of the Schiff base, removal of the chiral auxiliary and HBr demethylation produced 2-, 5-, 6-fluoro- and 2,6-difluoro-L-DOPA in e.e. of >99%. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 29 TC 11 Z9 11 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0957-4166 J9 TETRAHEDRON-ASYMMETR JI Tetrahedron: Asymmetry PD JUN 21 PY 2002 VL 13 IS 11 BP 1135 EP 1140 AR PII S0957-4166(02)00321-X DI 10.1016/S0957-4166(02)00321-X PG 6 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic; Chemistry, Physical SC Chemistry GA 577QD UT WOS:000177072100004 ER PT J AU Vukovic, P Chen, K Liu, XQ Foley, M Boyd, A Kaslow, D Good, MF AF Vukovic, P Chen, K Liu, XQ Foley, M Boyd, A Kaslow, D Good, MF TI Single-chain antibodies produced by phage display against the C-terminal 19 kDa region of merozoite surface protein-1of Plasinodium yoelii reduce parasite growth following challenge SO VACCINE LA English DT Article DE malaria; vaccines; passive immunization ID PLASMODIUM-FALCIPARUM MALARIA; PROTECTIVE IMMUNE-RESPONSE; AOTUS MONKEYS; MONOCLONAL-ANTIBODY; ESCHERICHIA-COLI; FRAGMENT; RECOMBINANT; MICE; IMMUNIZATION; INHIBIT AB Antibodies have the potential to be therapeutic reagents for malaria. Here we describe the production of a novel phage antibody display library against the C-terminal 19 kDa region of the Plasmodium yoelii YM merozoite surface protein-1 (MSP1(19)). In vivo studies against homologous lethal malaria challenge show an anti-parasite effect in a dose dependent manner, and analysis by plasmon resonance indicates binding to the antigen is comparable to the binding of a protective monoclonal antibody. The data support the lack of a need for any antibody Fc-related function and hold great significance for the development of a therapeutic reagent for malaria. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 PO Royal Brisbane Hosp, Queensland Inst Med Res, Cooperat Res Ctr Vaccine Technol, Herston, Qld 4029, Australia. Latrobe Univ, CRC Diagnost Technol, Melbourne, Vic, Australia. Natl Inst Hlth, Washington, DC USA. RP Good, MF (reprint author), PO Royal Brisbane Hosp, Queensland Inst Med Res, Cooperat Res Ctr Vaccine Technol, Herston, Qld 4029, Australia. NR 30 TC 14 Z9 16 U1 0 U2 1 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 JUN 21 PY 2002 VL 20 IS 21-22 BP 2826 EP 2835 AR PII S0264-410X(02)00197-4 DI 10.1016/S0264-410X(02)00197-4 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 568JL UT WOS:000176538600024 PM 12034110 ER PT J AU Feng, YM Shi, JQ Goldstein, AM Tucker, MA Nelson, MA AF Feng, YM Shi, JQ Goldstein, AM Tucker, MA Nelson, MA TI Analysis of mutations and identification of several polymorphisms in the putative promoter region of the P34(CDC2)-related CDC2L1 gene located at 1P36 in melanoma cell lines and melanoma families SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE CDC2L1; PITSLRE; mutation; polymorphism; melanoma ID CUTANEOUS MALIGNANT-MELANOMA; CHROMOSOME 1P36.3; DYSPLASTIC NEVUS; BREAST-CANCER; PROTEIN; APOPTOSIS; DELETION; COMPLEX; NEUROBLASTOMA; ABNORMALITIES AB Chromosome I abnormalities are the most commonly detected aberrations in many cancers including malignant melanoma. Partial deletions and an allelic loss of the chromosome 1p36 region observed in melanoma indicate the presence of putative tumor suppressor gene(s) in this region. A candidate gene, CDC2L1, which encodes PITSLRE proteins related to p34(cdc2), is mapped to 1p36. To determine whether CDC2L1 mutation is involved in melanoma development, we examined 20 melanoma cell lines and 11 members of melanoma-prone families linked to chromosome 1p36. Mutation analysis throughout the entire coding region of the CDC2L1 gene revealed only 1 mutation (C-T at nucleotide location 97 of exon 7, Ser-->Leu) in the melanoma cell line UACC 903 out of 20 melanoma cell lines and 6 melanoma cases. However, 4 polymorphic nucleotide changes, C-48T, G-53C, T-103C and T-210C, in the putative promoter region of CDC2L1 were identified. The 4 variants were located within or beside the conserved binding sites of transcription factors TCF11, MZF1 and TAAC box, indicating their potential effects on the regulation of CDC2L1 expression. No aberrant methylation of the CDC2L1 CpG island in the promoter region was observed by sodium bisulfite genomic sequencing. These results indicate that mutations are rare in the CDC2L1 gene in these melanoma cell lines and melanoma families and that the aberrant cytosine methylation of the CDC2L1 CpG island is not the mechanism of CDC2L1 repression in melanoma. The contribution of 4 promoter polymorphisms to the transcriptional regulation of the gene and its association with melanoma warrants further investigation. (C) 2002 Wiley-Liss, Inc. C1 Arizona Canc Ctr, Tucson, AZ 85724 USA. Univ Arizona, Dept Pathol, Tucson, AZ USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Nelson, MA (reprint author), Arizona Canc Ctr, 1515N Campbell Ave, Tucson, AZ 85724 USA. RI Tucker, Margaret/B-4297-2015; OI Shi, Jiaqi/0000-0003-4893-1587 FU NCI NIH HHS [CA 70145] NR 39 TC 9 Z9 9 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 JUN 20 PY 2002 VL 99 IS 6 BP 834 EP 838 DI 10.1002/ijc.10422 PG 5 WC Oncology SC Oncology GA 557WL UT WOS:000175931700010 PM 12115485 ER PT J AU Brown, LL Kulkarni, S Pavlova, OA Koren, AO Mukhin, AG Newman, AH Horti, AG AF Brown, LL Kulkarni, S Pavlova, OA Koren, AO Mukhin, AG Newman, AH Horti, AG TI Synthesis and evaluation of a novel series of 2-chloro-5-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-3-(2-(4-pyridinyl)viny l)pyridine analogues as potential positron emission tomography imaging agents for nicotinic acetylcholine receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VIVO; BINDING-SITE; POISON FROG; EPIBATIDINE; PHARMACOPHORE; LIGAND; PET; BRAIN; FLUORINE-18-FPH; RADIOLIGAND AB Reportedly, 2-[F-18]fluoro-A-85380, 1, a promising radiotracer for imaging the nicotinic acetylcholine receptor (nAChR) by positron emission tomography (PET) in humans, exhibits slow penetration through the blood-brain barrier (BBB) due to its low lipophilicity. A ligand for nAChRs with greater lipophilicity than that of 1 would be potentially more favorable for PET imaging of nAChR due to its faster penetration through the BBB. Herein, a novel series of compounds has been developed based on the high affinity ligand for nAChRs, 2-chloro-5((1-methyl-2-(S)-pyrrolidinyl)methoxy)-3-(2-(4-pyridinyl)vinyl)pyridine, 3b. The in vitro binding affinities for the new series were found to be in the range of K-i = 9-331 pM. A molecular modeling study showed differences in the comformational profiles and the electronic properties of these compounds, which provides further insight into the structure-activity relationships at nAChR. Lipophilicities of the compounds 3b-6b have been found to be substantially higher than that of 1. As a result, compounds 3b-6b might exhibit a faster penetration through the BBB than the less lipophilic 1. The N-methyl derivatives 3b and 6b demonstrated very high affinities at nAChRs (Ki = 28 and 23 pM, respectively) and will be targets for development of (CH3)-C-11-labeled derivatives as radiotracers for PET imaging of nAChRs. C1 Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Intramural Res Program, Med Chem Sect, Baltimore, MD 21224 USA. RP Horti, AG (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 41 TC 27 Z9 29 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 JUN 20 PY 2002 VL 45 IS 13 BP 2841 EP 2849 DI 10.1021/jm010550n PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 562NH UT WOS:000176204300016 PM 12061886 ER PT J AU Rosenwald, A Wright, G Chan, WC Connors, JM Campo, E Fisher, RI Gascoyne, RD Muller-Hermelink, HK Smeland, EB Staudt, LM AF Rosenwald, A Wright, G Chan, WC Connors, JM Campo, E Fisher, RI Gascoyne, RD Muller-Hermelink, HK Smeland, EB Staudt, LM CA Lymphoma Leukemia Mol Profiling Pr TI The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENE-EXPRESSION; PROLIFERATION; THERAPY AB Background: The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. Methods: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. Results: Three gene-expression subgroups -- germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma -- were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. Conclusions: DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. British Columbia Canc Ctr, Vancouver, BC, Canada. Univ Barcelona, Hosp Clin, Barcelona, Spain. Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY USA. Univ Rochester, Sch Med, SW Oncol Grp, Rochester, NY USA. Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. Norwegian Radium Hosp, Dept Immunol, Oslo, Norway. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Arizona, Ctr Canc, Tucson, AZ USA. SW Oncol Grp, Tucson, AZ USA. SW Oncol Grp, Seattle, WA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Rm 4N114, Bethesda, MD 20892 USA. OI Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU NCI NIH HHS [UO1-CA84967] NR 17 TC 2052 Z9 2154 U1 5 U2 43 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 JUN 20 PY 2002 VL 346 IS 25 BP 1937 EP 1947 DI 10.1056/NEJMoa012914 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 563QC UT WOS:000176266200002 PM 12075054 ER PT J AU Oral, EA Ruiz, E Gorden, P AF Oral, EA Ruiz, E Gorden, P TI Leptin-replacement therapy in lipodystrophy - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID OBESITY C1 NIDDKD, Bethesda, MD 20892 USA. RP Oral, EA (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 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 JUN 20 PY 2002 VL 346 IS 25 BP 2009 EP 2010 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 563QC UT WOS:000176266200019 ER PT J AU Triyatni, M Vergalla, J Davis, AR Hadlock, KG Foung, SKH Liang, TJ AF Triyatni, M Vergalla, J Davis, AR Hadlock, KG Foung, SKH Liang, TJ TI Structural features of envelope proteins on hepatitis C virus-like particles as determined by anti-envelope monoclonal antibodies and CD81 binding SO VIROLOGY LA English DT Article DE anti-HCV envelope antibodies; conformational epitopes; viral receptor ID GLYCOPROTEIN E2; HYPERVARIABLE REGION-1; HYPERIMMUNE SERUM; INSECT CELLS; INFECTION; CHIMPANZEES; NEUTRALIZATION; HCV; GLYCOSYLATION; LOCALIZATION AB The envelope glycoprotein E2 of hepatitis C virus (HCV) is a major component of the viral envelope Knowledge of its topologic features and antigenic determinants in virions is crucial in understanding the viral binding sites to cellular receptor(s) and the induction of neutralizing antibodies. The lack of a robust cell culture system for virus propagation has hampered the characterization of E2 presented on the virion. Here we report the structural features of hepatitis C virus-like particles (HCV-LPs) of the la and 1b genotypes as determined by various mouse and human monoclonal anti-envelope antibodies. Our results show that the E2 protein of HCV-LPs reacts with human monoclonal antibodies recognizing conformational determinants. Monoclonal antibodies (mAbs) specific for the hypervariable region 1 (HVR-1) sequence reacted strongly with HCV-LPs, suggesting that the HVR-1 is exposed on the viral surface Several mAbs recognized both HCV-LPs with equally high affinity, indicating that the corresponding epitopes [amino acids (aa) 192-217 of El and aa 412-423, aa 522-531, and aa 640-663 of E2] are conserved in both genotypes and exposed on the surface of the HCV-LP The E2 and E1/E2 dimers of la bound strongly to the recombinant large extracellular loop (LEL) of CD81 (CD81- LEL) of human and African green monkey, while the HCV-LP of la bound weakly to human CD81-LEL. E1/E2 dinners and the HCV-LPs of 1b did not bind CD81-LEL, consistent with the notion that CD81 recognition by E2 is strain-specific and does not correlate with permissiveness of infection, A model of the topology and exposed antigenic determinants of the envelope proteins of HCV is proposed. (C) 2002 Elsevier Science (USA). C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Pathol, Stanford, CA 94304 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Sect, NIH, Bldg 10,Room 9806,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI47355]; NIDA NIH HHS [DA06596] NR 35 TC 65 Z9 68 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 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2002 VL 298 IS 1 BP 124 EP 132 DI 10.1006/viro.2002.1463 PG 9 WC Virology SC Virology GA 573HH UT WOS:000176822900014 PM 12093180 ER PT J AU Morcock, DR Katakam, S Kane, BP Casas-Finet, JR AF Morcock, DR Katakam, S Kane, BP Casas-Finet, JR TI Fluorescence and nucleic acid binding properties of bovine leukemia virus nucleocapsid protein SO BIOPHYSICAL CHEMISTRY LA English DT Article DE bovine leukemia virus; nucleocapsid; zinc finger; fluorescence ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENCAPSIDATION SIGNAL; GAG GENE; RNA; TYPE-1; SEQUENCE; COMPLEX; HIV-1 AB We used the intrinsic fluorescence of bovine leukemia virus p12, a nucleocapsid protein with two tryptophan-containing zinc fingers (ZFs), to study its conformation and binding to single-stranded nucleic acids. Spectral emission maxima suggested solvent-exposed tryptophans. A peptide derived from ZF1 had a higher quantum yield and longer average lifetime (tau) than ZF2. BLV p12 tau and rotational correlation time were greater than ZF values, but all de-metallated sequences gave similar results. Apo p12 showed reduced fluorescence intensity, T and loss of secondary structure. DNA-binding affinity of p12 was in the nanomolar range, and decreased 14-fold after Zn++ ejection. Nucleobase preference of BLV p12 was different from the closely related HTLV-1 but similar to HIV-1 and SIV nucleocapsids, both phylogenetically distant. (C) 2002 Elsevier Science B.V All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. Informax Inc, Bethesda, MD 20814 USA. Medimmune Inc, Gaithersburg, MD 20878 USA. RP Morcock, DR (reprint author), NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Bldg 535,5th Floor,POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 29 TC 6 Z9 6 U1 1 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 JUN 19 PY 2002 VL 97 IS 2-3 BP 203 EP 212 AR PII S0301-4622(02)00070-4 DI 10.1016/S0301-4622(02)00070-4 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 564AY UT WOS:000176292700009 PM 12050010 ER PT J AU Nguyen, DT Rovira, II Finkel, T AF Nguyen, DT Rovira, II Finkel, T TI Regulation of the Werner helicase through a direct interaction with a subunit of protein kinase A SO FEBS LETTERS LA English DT Article DE Werner syndrome; helicases; RecQ; aging; signal transduction ID DNA-POLYMERASE-DELTA; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL INTERACTION; SYNDROME CELLS; LIFE-SPAN; RAS; LOCALIZATION; NUCLEOLUS; GENE; MSI1 AB Werner syndrome is a hereditary disease characterized by cancer predisposition, genetic instability, and the premature appearance of features associated with normal aging. At the molecular level this syndrome has been related to mutations in the Werner helicase, a member of the RecQ family of DNA helicases which are required to maintain genomic stability in cells. Here we show by a yeast two-hybrid screen that the Werner helicase can directly, interact with the regulatory subunit (RIP) of cAMP protein kinase A (PKA). We confirm that this interaction occurs in vivo. Interestingly, serum withdrawal causes a redistribution of the Werner helicase within the nucleus of mammalian cells. Raising intracellular cAMP levels or increased expression of the regulatory but not the catalytic subunit of PKA inhibits this nuclear redistribution stimulated by serum deprivation. These results suggest that similar to lower organisms, gene products linked to genomic instability and aging may be directly regulated by growth factor-sensitive, PKA-dependent pathways. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10-6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 19 PY 2002 VL 521 IS 1-3 BP 170 EP 174 AR PII S0014-5793(02)02868-5 DI 10.1016/S0014-5793(02)02868-5 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 566TD UT WOS:000176443600034 PM 12067711 ER PT J AU Bishop, DT Demenais, F Goldstein, AM Bergman, W Bishop, JN Bressac-de Paillerets, B Chompret, A Ghiorzo, P Gruis, N Hansson, J Harland, M Hayward, N Holland, EA Mann, GJ Mantelli, M Nancarrow, D Platz, A Tucker, MA AF Bishop, DT Demenais, F Goldstein, AM Bergman, W Bishop, JN Bressac-de Paillerets, B Chompret, A Ghiorzo, P Gruis, N Hansson, J Harland, M Hayward, N Holland, EA Mann, GJ Mantelli, M Nancarrow, D Platz, A Tucker, MA CA Melanoma Genetics Consortium TI Geographical variation in the penetrance of CDKN2A mutations for melanoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; DYSPLASTIC NEVUS SYNDROME; FAMILIAL MELANOMA; GERMLINE MUTATIONS; PRONE FAMILIES; ANATOMIC SITE; SEGREGATION ANALYSIS; UNITED-STATES; P16 GENE; CDK4 AB Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance. C1 Canc Res UK Clin Ctr, Genet Epidemiol Div, Leeds, W Yorkshire, England. INSERM EMI 00 06, Evry, France. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. Inst Gustave Roussy, Villejuif, France. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. Karolinska Hosp, Dept Oncol Pathol, S-10401 Stockholm, Sweden. Queensland Canc Fund Res Unit, Brisbane, Qld, Australia. Westmead Inst Canc Res, Sydney, NSW, Australia. RP Bishop, DT (reprint author), St James Univ Hosp, Canc Res UK Clin Ctr, Genet Epidemiol Div, Canc Genet Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England. RI Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; OI Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Bishop, Tim/0000-0002-8752-8785 NR 59 TC 263 Z9 267 U1 1 U2 6 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 JUN 19 PY 2002 VL 94 IS 12 BP 894 EP 903 PG 10 WC Oncology SC Oncology GA 564PW UT WOS:000176323600007 PM 12072543 ER PT J AU Singh, GK Miller, BA Hankey, BF Feuer, EJ Pickle, LW AF Singh, GK Miller, BA Hankey, BF Feuer, EJ Pickle, LW TI Changing area socioeconomic patterns in US cancer mortality, 1950-1998: Part I - All cancers among men SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID UNITED-STATES; SOCIAL-CLASS; SPECIAL SECTION; LUNG-CANCER; ALL-CAUSE; DEPRIVATION; HEALTH; SCOTLAND; ENGLAND; SMOKING AB Background: Area socioeconomic deprivation indices are widely used to monitor health disparities in Europe. However, such indices have not been used in cancer surveillance in the United States. We developed an area socioeconomic index to examine area socioeconomic patterns in all-cancer mortality among U.S. men between 1950 and 1998. Methods: Principal components analysis on 11 census variables was used to develop an area socioeconomic index that was then used to stratify all U.S. counties into one of five socioeconomic categories. The index was linked to 1950-1998 county mortality data to generate annual mortality rates for each area socioeconomic group. Joinpoint regression analysis was used to model mortality trends, and Poisson regression analysis was used to estimate socioeconomic gradients in mortality over time. Results: Area socioeconomic patterns in U.S. male cancer mortality changed dramatically between 1950 and 1998. Throughout the 1950s and 1960s, there was a positive socioeconomic gradient, with higher cancer mortality rates in high area socioeconomic groups than in low area socioeconomic groups. For example, in 1950-1952, cancer mortality was 49% (95% confidence interval [CI] = 41% to 59%) greater in the highest area socioeconomic group than in the lowest. The positive gradient narrowed in the 1470s, and by the late 1980s, socioeconomic differences in cancer mortality began to reverse and widen. In 1997-1998, cancer mortality was 19 % (95 % CI = 11 % to 28 %) higher in the lowest area socioeconomic group than in the highest. Gradients were steeper for men aged 25-64 years than for men aged 65 years or older. Conclusions: Socioeconomic patterns in male cancer mortality have reversed over time in the United States, Area socioeconomic indices could serve as a powerful surveillance tool for monitoring health disparities in cancer outcomes. C1 NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. RP Singh, GK (reprint author), NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, 6116 Execut Blvd,Suite 504,MSC 8316, Bethesda, MD 20892 USA. NR 61 TC 63 Z9 64 U1 3 U2 5 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 JUN 19 PY 2002 VL 94 IS 12 BP 904 EP 915 PG 12 WC Oncology SC Oncology GA 564PW UT WOS:000176323600008 PM 12072544 ER PT J AU Singh, GK Miller, BA Hankey, BF AF Singh, GK Miller, BA Hankey, BF TI Changing area socioeconomic patterns in US cancer mortality, 1950-1998: Part II - Lung and colorectal cancers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID UNITED-STATES; SPECIAL SECTION; SOCIAL-CLASS; ALL-CAUSE; DEPRIVATION; SMOKING; RISK; SCOTLAND; TRENDS; HEALTH AB Background: Lung cancer and colorectal cancer are leading causes of U.S. cancer mortality. Because mortality rates for many cancers vary by socioeconomic characteristics, we used area socioeconomic indices to examine patterns in U.S. lung and colorectal cancer mortality between 1950 and 1998. Methods: A factor-based area socioeconomic index was linked to 1950-1998 county mortality data to generate annual lung and colorectal cancer mortality rates for each area socioeconomic group. Joinpoint regression analysis was used to model and identify statistically significant changes in the mortality trends. Results: Area socioeconomic patterns in U.S. lung cancer mortality changed dramatically between 1950 and 1998. Men aged 25-64 years and those aged 65 years or older in higher socioeconomic areas generally had higher lung cancer mortality than did those in lower socioeconomic areas during 1950-1964 and 1950-1980, respectively. Area socioeconomic differences in lung cancer mortality began to reverse and widen by the early 1970s for younger men and by the mid-1980s for older men. In 1998, lung cancer mortality was 56% (95% confidence interval [CI] = 49 % to 64 %) higher for younger men and 38 % higher (95% CI = 34% to 43%) for older men in the lowest area socioeconomic group than for the same age groups in the highest area socioeconomic group. Lung cancer mortality among older women in all socioeconomic groups increased sevenfold to eightfold between 1950 and 1998, with higher mortality in higher area socioeconomic groups. The positive socioeconomic gradient in colorectal cancer mortality diminished substantially over time. Although colorectal cancer mortality among women in all area socioeconomic groups showed a consistent downward trend, colorectal cancer mortality among men in low area socioeconomic groups, but not in high area socioeconomic groups, showed an upward trend. Conclusions: Socioeconomic gradients in male lung cancer mortality reversed between 1950 and 1998, and those in colorectal cancer mortality narrowed over that time. Area measures may be useful for monitoring socioeconomic disparities in cancer mortality and for identifying areas for potential cancer control interventions. C1 NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. RP Singh, GK (reprint author), NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, 6116 Execut Blvd,Suite 504,MSC 8316, Bethesda, MD 20892 USA. NR 69 TC 86 Z9 88 U1 4 U2 7 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 JUN 19 PY 2002 VL 94 IS 12 BP 916 EP 925 PG 10 WC Oncology SC Oncology GA 564PW UT WOS:000176323600009 PM 12072545 ER PT J AU Mohan, AK Hauptmann, M Linet, MS Ron, E Lubin, JH Freedman, DM Alexander, BH Boice, JD Doody, MM Matanoski, GM AF Mohan, AK Hauptmann, M Linet, MS Ron, E Lubin, JH Freedman, DM Alexander, BH Boice, JD Doody, MM Matanoski, GM TI Breast cancer mortality among female radiologic technologists in the United States SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ATOMIC-BOMB SURVIVORS; RADIATION; WORKERS; RISK AB We evaluated breast cancer mortality through 1997 among 69 525 female radiologic technologists who were certified in the United States from 1926 through 1982 and who responded to our questionnaire. Risk of breast cancer mortality was examined according to work history and practices and was adjusted for known risk factors. Breast cancer mortality risk was highest among women who were first employed as radiologic technologists prior to 1940 (relative risk [RR] = 2.92, 95% confidence interval [CI] = 1.22 to 7.00) compared with risk of those first employed in 1960 or later and declined with more recent calendar year of first employment (P for trend = .002). Breast cancer mortality risk increased with increasing number of years of employment as a technologist prior to 1950 (P for trend = .018). However, risk was not associated with the total number of years a woman worked as a technologist. Technologists who first performed fluoroscopy (RR = 1.69, 95% CI = 1.02 to 3.11) and multifilm procedures (RR = 1.87, 95% CI = 1.04 to 3.34) before 1950 had statistically significantly elevated risks compared with technologists who first performed these procedures in 1960 or later. The high risks of breast cancer mortality for women exposed to occupational radiation prior to 1950 and the subsequent decline in risk are consistent with the dramatic reduction in recommended radiation exposure limits over time. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Hauptmann, M (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01CP51016, N02CP81005, N02CP81121] NR 24 TC 28 Z9 29 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 19 PY 2002 VL 94 IS 12 BP 943 EP 948 PG 6 WC Oncology SC Oncology GA 564PW UT WOS:000176323600012 PM 12072548 ER PT J AU McDermott, MM Greenland, P Liu, K Guralnik, JM Celic, L Criqui, MH Chan, C Martin, GJ Schneider, J Pearce, WH Taylor, LM Clark, E AF McDermott, MM Greenland, P Liu, K Guralnik, JM Celic, L Criqui, MH Chan, C Martin, GJ Schneider, J Pearce, WH Taylor, LM Clark, E TI The ankle brachial index is associated with leg function and physical activity: The walking and leg circulation study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; LOWER-EXTREMITY FUNCTION; VASCULAR-DISEASE; INTERMITTENT CLAUDICATION; CARDIOVASCULAR HEALTH; SUBSEQUENT DISABILITY; CALTRAC ACCELEROMETER; SKELETAL-MUSCLE; WOMENS HEALTH; 6-MINUTE WALK AB Background: The ankle brachial index (ABI) is a noninvasive, reliable measure of lower-extremity ischemia. However, the relationship between ABI and lower-extremity function has not been well studied. Objective: To describe the association between the ABI and lower-extremity function. Design: Cross-sectional study. Setting: 3 academic medical centers in the Chicago area. Participants: 740 men and women (460 with peripheral arterial disease). Measurements: Accelerometer-measured physical activity over 7 days, 6-minute walk, 4-m walking velocity, standing balance, and ABI. Results: 33% of participants with peripheral arterial disease had intermittent claudication. Fewer than 40% of participants with an ABI less than 0.40 walked continuously for 6 minutes compared with more than 95% of participants with an ABI between 1.00 and 1.50. Compared with an ABI of 1.10 to 1.50, an ABI less than 0.50 was associated with shorter distance walked in 6 minutes (beta-regression coefficient = -523 ft [95% Cl, -592 to -454 ft]; P < 0.001), less physical activity (beta = -514.8 activity units [Cl, -657 to -373 activity units]; P < 0.001), slower 4-m walking velocity (beta = -0.21 m/s [Cl, -0.27 to -0.15 m/s]; P < 0.001), and less likelihood of maintaining a tandem stand for 10 seconds (odds ratio, 0.37 [Cl, 0.18 to 0.76]; P = 0.007), after adjustment for typical confounders. Associations between ABI and function were stronger than associations between leg symptoms and function. Conclusions: The ABI, a noninvasive test that can be performed in a medical office, is more closely associated with leg function in persons with peripheral arterial disease than is intermittent claudication or other leg symptoms. These data support the use of the ABI to identify abnormal lower-extremity function. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Catholic Hlth Partners, Chicago, IL USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. Evanston Hosp Corp, Skokie, IL USA. Oregon Hlth Sci Med Ctr, Portland, OR USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099] NR 47 TC 281 Z9 297 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 18 PY 2002 VL 136 IS 12 BP 873 EP 883 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 563JL UT WOS:000176252500004 PM 12069561 ER PT J AU Hamdan, FF Ward, SDC Siddiqui, NA Bloodworth, LM Wess, J AF Hamdan, FF Ward, SDC Siddiqui, NA Bloodworth, LM Wess, J TI Use of an in situ disulfide cross-linking strategy to map proximities between amino acid residues in transmembrane domains I and VII of the M-3 muscarinic acetylcholine receptor SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BETA(2) ADRENERGIC-RECEPTOR; LIGHT-DEPENDENT CHANGES; INDUCED CONFORMATIONAL-CHANGES; CYSTEINE ACCESSIBILITY METHOD; STATE TERTIARY STRUCTURE; CONSTITUTIVE ACTIVATION; DIRECTED MUTAGENESIS; CYTOPLASMIC DOMAIN; ANTAGONIST BINDING AB In this study, we employed an in situ disulfide cross-linking strategy to gain insight into the structure of the inactive and active state of the M-3 muscarinic acetylcholine receptor. Specifically, this study was designed to identify residues in TM I that are located in close to Cys532 (position 7.42), an endogenous cysteine residue present in the central portion of TM VII. Cysteine residues were substituted, one at a time, into 10 consecutive positions of TM I (Ala71-Va180) of a modified version of the M-3 muscarinic receptor that lacked most endogenous cysteine residues and contained a factor Xa cleavage site within the third intracellular loop. Following their expression in COS-7 cells, the 10 resulting cysteine mutant receptors were oxidized in their native membrane environment, either in the absence or in the presence of muscarinic ligands. Disulfide cross-link formation was monitored by examining changes in the electrophoretic mobility of oxidized and factor Xa-digested receptors on SDS gels. When molecular iodine was used as the oxidizing agent, the L77C receptor (position 1.42) was the only mutant receptor that displayed significant disulfide cross-linking, either in the absence or in the presence of muscarinic agonists or antagonists. On the other hand, when the Cu(II)-(1,10-phenanthroline)(3) complex served as the redox catalyst, muscarinic ligands inhibited disulfide cross-linking of the L77C receptor, probably because of impaired access of this relatively bulky oxidizing agent to the ligand binding crevice. The iodine cross-linking data suggest that M-3 muscarinic receptor activation is not associated with significant changes in the relative orientations of the outer and/or central segments of TM I and VII. In bovine rhodopsin, the residues present at the positions corresponding to Cys532 and Leu77 in the rat M-3 muscarinic receptor are not located directly adjacent to each other, raising the possibility that the relative orientations of TM I and VII are not identical among different class I GPCRs. Alternatively, dynamic protein backbone fluctuation may occur, enabling Cys532 to move within cross-linking distance of Leu77 (Cys77). C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Bioorgan Chem Lab, NIH, 8 Ctr Dr,Bldg 8A,Room B1A-05,MSC 0810, Bethesda, MD 20892 USA. NR 57 TC 26 Z9 26 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 18 PY 2002 VL 41 IS 24 BP 7647 EP 7658 DI 10.1021/bi016029c PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 561RP UT WOS:000176156700014 PM 12056896 ER PT J AU Puri, N Majumdar, A Cuenoud, B Natt, F Martin, P Boyd, A Miller, PS Seidman, MM AF Puri, N Majumdar, A Cuenoud, B Natt, F Martin, P Boyd, A Miller, PS Seidman, MM TI Minimum number of 2 '-O-(2-aminoethyl) residues required for gene knockout activity by triple helix forming oligonucleotides SO BIOCHEMISTRY LA English DT Article ID DOUBLE-STRANDED DNA; PHYSIOLOGICAL PH; MAMMALIAN-CELLS; 3RD STRAND; INHIBIT TRANSCRIPTION; DUPLEX DNA; STABILITY; RECOGNITION; SEQUENCE; BINDING AB Triple helix forming oligonucleotides (TFOs) that bind chromosomal targets in living cells may become tools for genome manipulation, including gene knockout, conversion, or recombination. However, triplex formation by DNA third strands, particularly those in the pyrimidine motif, requires nonphysiological pH and Mg2+ concentration, and this limits their development as gene-targeting reagents. Recent advances in oligonucleotide chemistry promise to solve these problems. For this study TFOs containin- 2'-O-methoxy (2'-OMe) and 2'-O-(2-aminoethyl) (2'-AE) ribose substitutions in varying proportion have been constructed. The TFOs were linked to psoralen and designed to tarcyet and mutaaenize a site in the hamster HPRT gene. T-m analyses showed that triplexes formed by these TFOs were more stable than the underlying duplex, regardless of 2'-OMe/2'-AE ratio. However, TFOs with 2'-AE residues were more stable in physiological pH than those with only 2'-OMe sugars, as a simple function of 2'-AE content. In contrast, gene knockout assays revealed a threshold requirement-TFOs with three or four 2'-AE residues were at least 10-fold more active than the TFO with two 2'-AE residues. The HPRT knockout frequencies with the most active TFOs were 300-400-fold above the background, whereas there was no activity against the APRT gene, a monitor of nonspecific mutagenesis. C1 NIA, LMG, NIH, Baltimore, MD 21224 USA. Novartis Horsham Res Ctr, Horsham RH12 4AB, W Sussex, England. Novartis Pharma Ltd, CH-4002 Basel, Switzerland. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. RP Seidman, MM (reprint author), NIA, LMG, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 64 TC 46 Z9 47 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 JUN 18 PY 2002 VL 41 IS 24 BP 7716 EP 7724 AR UNSP BI025734Y DI 10.1021/bi025734y PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 561RP UT WOS:000176156700021 PM 12056903 ER PT J AU Reis, SE Olson, MB Fried, L Reeser, V Mankad, S Pepine, CJ Kerensky, R Merz, CNB Sharaf, BL Sopko, G Rogers, WJ Holubkov, R AF Reis, SE Olson, MB Fried, L Reeser, V Mankad, S Pepine, CJ Kerensky, R Merz, CNB Sharaf, BL Sopko, G Rogers, WJ Holubkov, R TI Mild renal insufficiency is associated with angiographic coronary artery disease in women SO CIRCULATION LA English DT Article DE coronary artery disease; renal insufficiency; women ID SYNDROME EVALUATION WISE; FAILURE; INTERLEUKIN-6; MORTALITY; RISK AB Background-Mild renal insufficiency is associated with an increased risk for cardiovascular events in women with coronary artery disease (CAD). However, the relationship between mild renal insufficiency and atherosclerotic CAD in women is not known. Methods and Results-Women with chest pain who were referred for coronary angiography in the NHLBI Women's Ischemia Syndrome Evaluation (WISE) study underwent quantitative coronary angiography, blood measurements of creatinine, lipids, and homocysteine, and assessment of CAD risk factors. Fifty-six women had mild renal insufficiency (serum creatinine 1.2 to 1.9 mg/dL), and 728 had normal renal function (creatinine < 1.2 mg/dL). Creatinine correlated with angiographic CAD severity score (r=0.11, P<0.004) and maximum coronary artery stenosis (r=0.11, P<0.003). Compared with women with normal renal function, those with mild renal insufficiency were more likely to have significant angiographic CAD (greater than or equal to50% diameter stenosis in greater than or equal to1 coronary artery) (61% versus 37%; P<0.001) and CAD in multiple vessels (P<0.001 for association) and had greater maximum percent diameter coronary stenosis (59+/-35% versus 38+/-36%; P<0.001). Mild renal insufficiency was associated with significant angiographic CAD independent of age and risk factors (OR=1.9, 95%CI=1.1 to 3.5). After controlling for homocysteine in 509 women, mild renal insufficiency remained predictive of CAD (OR=3.2, 95%CI=1.4 to 7.2). Conclusions-In women with chest pain, mild renal insufficiency is an independent predictor of significant angiographic CAD. Mildly increased serum creatinine is probably a marker for unmeasured proatherogenic factors. C1 Univ Alabama, Div Cardiol, Birmingham, AL USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. Univ Florida, Div Cardiol, Gainesville, FL USA. W Penn Allegheny Hlth Syst, MCP Hahnemann Sch Med, Div Cardiol, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15213 USA. RP Reis, SE (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, 200 Lothrop St, Pittsburgh, PA 15213 USA. RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [U01-HL64829-01, U01-HL64914-01, N01-HV-68164, N01-HV-68163, N01-HV-68161, N01-HV-68162, U01-HL64924-01] NR 14 TC 83 Z9 86 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 JUN 18 PY 2002 VL 105 IS 24 BP 2826 EP 2829 DI 10.1161/01.CIR.0000021597.63026.65 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 573FH UT WOS:000176818300008 PM 12070108 ER PT J AU Eckel, RH Barouch, WW Ershow, AG AF Eckel, RH Barouch, WW Ershow, AG TI Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the Pathophysiology of Obesity-Associated Cardiovascular Disease SO CIRCULATION LA English DT Editorial Material DE hypertension; stroke; atherosclerosis; thrombosis; diabetes mellitus ID OBSTRUCTIVE SLEEP-APNEA; DENSITY-LIPOPROTEIN CHOLESTEROL; FOLLOW-UP; INSULIN-RESISTANCE; NEURAL MECHANISMS; TRANSGENIC MICE; LEPTIN LEVELS; RISK-FACTORS; OVERWEIGHT; WOMEN C1 Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Eckel, RH (reprint author), Univ Colorado, Hlth Sci Ctr, 4200 E 9th Ave,Box B-151, Denver, CO 80262 USA. NR 48 TC 152 Z9 158 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 JUN 18 PY 2002 VL 105 IS 24 BP 2923 EP 2928 DI 10.1161/01.CIR.0000017823.53114.4C PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 573FH UT WOS:000176818300024 PM 12070124 ER PT J AU Scheffer, GL de Jong, MC Monks, A Flens, MJ Hose, CD Izquierdo, MA Shoemaker, RH Scheper, RJ AF Scheffer, GL de Jong, MC Monks, A Flens, MJ Hose, CD Izquierdo, MA Shoemaker, RH Scheper, RJ TI Increased expression of beta 2-microglobulin in multidrug-resistant tumour cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE LMR-12; multidrug resistance; expression cloning; beta 2-microglobulin; MHC class I; TAP ID HLA CLASS-I; BREAST-CANCER; MONOCLONAL-ANTIBODIES; DRUG-RESISTANCE; DOWN-REGULATION; P-GLYCOPROTEIN; PROTEIN; LINES; TRANSPORTER; MOLECULES AB The rat monoclonal antibody LMR-12 was shown earlier to react with a plasma membrane protein, upregulated in multidrug-resistant cell lines, In this study, we observed distinct LMR-12 staining in 36 out of 55 non-drug-selected tumour cell lines, including melanomas, renal cell- colon- and lung carcinomas, whereas in other tumour types, such as leukaemia and ovarian cancer, LMR-12 staining was generally low or absent. The cDNA encoding the LMR-12 antigen was isolated from a library of the multidrug-resistant human fibrosarcoma cell line HT1080/DR4 by expression cloning in MOP8 cells. Sequence analysis showed that the LMR-12 antigen is identical to the major histocompatibility complex class l molecule beta 2-microglobulin (beta(2)-m). The LMR-12/beta(2)-m staining results were confirmed by mRNA microarray data from an independent National Cancer Institute study, as well as by newly obtained reverse transcriptase polymerase chain reaction data, Further analysis of the microarray data showed that beta(2)-m levels closely reflected levels of major histocompatibility complex class I heavy chains and the transporter associated with antigen processing. Since the ABC transporter associated with antigen processing was previously shown to contribute to multidrug-resistance, it may very well be that the observed LMR-12/beta(2)-m levels are secondary to (elevated) levels of the transporter associated with antigen processing. A perspective arising from the present study is that drug resistant tumour cells may, by having elevated levels of major histocompatibility complex related molecules, be particular good candidates for alternative therapeutic therapies, such as cytotoxic T cell mediated immune-therapies. (C) 2002 Cancer Research UK. C1 Free Univ Amsterdam, Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. NCI, Dev Therapeut Program, Screening Technol Branch, Frederick, MD 21701 USA. Catalan Inst Oncol, Dept Oncol, Barcelona, Spain. RP Scheper, RJ (reprint author), Free Univ Amsterdam, Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. NR 31 TC 12 Z9 12 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 JUN 17 PY 2002 VL 86 IS 12 BP 1943 EP 1950 DI 10.1038/sj.bjc.6600354 PG 8 WC Oncology SC Oncology GA 571VL UT WOS:000176739800020 PM 12085191 ER PT J AU Brookes, S Rowe, J Ruas, M Llanos, S Clark, PA Lomax, M James, MC Vatcheva, R Bates, S Vousden, KH Parry, D Gruis, N Smit, N Bergman, W Peters, G AF Brookes, S Rowe, J Ruas, M Llanos, S Clark, PA Lomax, M James, MC Vatcheva, R Bates, S Vousden, KH Parry, D Gruis, N Smit, N Bergman, W Peters, G TI INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence SO EMBO JOURNAL LA English DT Article DE anchorage independence; p14(ARF); p16(INK4a); Ras; senescence ID REPLICATIVE LIFE-SPAN; NORMAL HUMAN-CELLS; ONCOGENIC RAS; PREMATURE SENESCENCE; TUMOR SUPPRESSION; TELOMERASE ACTIVITY; DEPENDENT KINASES; INK4A LOCUS; DNA-DAMAGE; P53 AB The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by, aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14ARF. Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species. C1 Canc Res UK London Res Inst, Mol Oncol Lab, London WC2A 3PX, England. Canc Res UK London Res Inst, Human Cytogenet Labs, London WC2A 3PX, England. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. DNAX Res Inst Mol & Cellular Biol Inc, Palo Alto, CA 94304 USA. Leiden Univ, Med Ctr, Dept Dermatol, NL-2333 AL Leiden, Netherlands. RP Peters, G (reprint author), Canc Res UK London Res Inst, Mol Oncol Lab, Lincolns Inn Fields, London WC2A 3PX, England. NR 52 TC 169 Z9 173 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 17 PY 2002 VL 21 IS 12 BP 2936 EP 2945 DI 10.1093/emboj/cdf289 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569EL UT WOS:000176587600010 PM 12065407 ER PT J AU Kim, HP Leonard, WJ AF Kim, HP Leonard, WJ TI The basis for TCR-mediated regulation of the IL-2 receptor alpha chain gene: role of widely separated regulatory elements SO EMBO JOURNAL LA English DT Article DE AP-1; cyclosporin A; IL-2R alpha; NFAT; TCR ID DOMINANT-NEGATIVE MUTANT; T-CELL PROLIFERATION; INTERLEUKIN-2 RECEPTOR; GAMMA-CHAIN; BETA-CHAIN; TRANSCRIPTION FACTORS; CYTOPLASMIC DOMAINS; ANTIGEN RECEPTOR; NUCLEAR FACTOR; LYMPHOCYTES-T AB The interleukin-2 receptor alpha (IL-2Ralpha) chain is a component of high-affinity IL-2 receptors and thus is a key regulator of lymphocyte proliferation. Lineage-restricted and activation-dependent IL-2Ralpha transcription is controlled by four upstream positive regulatory regions (PRRs) and one downstream PRR. We now demonstrate that T-cell receptor (TCR) responsiveness requires both upstream sequences and an intronic region, PRRIV, previously identified as an IL-2 response element. Whereas IL-2 responsiveness requires Stat5 and HMG-I(Y) binding, TCR responsiveness of PRRIV requires two AP-1- and two NFAT-binding sites that bind Jun, Fos and NFAT family members in vitro and in vivo. Moreover, IL-2Ralpha induction is impaired in T lymphocytes from transgenic mice expressing a dominant-negative c-jun construct, or following treatment with cyclosporin A. Thus, our data indicate an important role for both A-P-1 and NFAT proteins for TCR-induced IL-2Ralpha expression and establish that both upstream and intronic sequences mediate TCR responsiveness of the IL-2Ralpha gene. Moreover, our data reveal a previously unappreciated link between the TCR-mediated upregulation of the IL-2 and IL-2Ralpha genes. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kim, HP (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N252, Bethesda, MD 20892 USA. NR 37 TC 47 Z9 54 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 17 PY 2002 VL 21 IS 12 BP 3051 EP 3059 DI 10.1093/emboj/cdf321 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569EL UT WOS:000176587600021 PM 12065418 ER PT J AU Mascarenhas, J Soppa, J Strunnikov, AV Graumann, PL AF Mascarenhas, J Soppa, J Strunnikov, AV Graumann, PL TI Cell cycle-dependent localization of two novel prokaryotic chromosome segregation and condensation proteins in Bacillus subtilis that interact with SMC protein SO EMBO JOURNAL LA English DT Article DE chromosome; condensation; Scp proteins; segregation; SMC protein ID REPLICATION ORIGIN REGIONS; STRAND BREAK REPAIR; ESCHERICHIA-COLI; STRUCTURAL MAINTENANCE; DNA-REPLICATION; CAULOBACTER-CRESCENTUS; BIPOLAR LOCALIZATION; ABC-ATPASE; GENE; BACTERIA AB Disruption of ypuG and ypuH open reading frames in Bacillus subtilis leads to temperature-sensitive slow growth, a defect in chromosome structure and formation of anucleate cells. The genes, which were named scpA and sepB, were found to be epistatic to the smc gene. Fusions of ScpA and ScpB to the fluorescent proteins YFP or CFP showed that both proteins colocalize to two or four discrete foci that were present at mid-cell in young cells, and within both cell halves, generally adjacent to chromosomal origin regions, in older cells. ScpA and ScpB foci are associated with DNA and depend on the presence of SMC and both Seps. ScpA and ScpB are associated with each other and with SMC in vivo, as determined using the FRET technique and immunoprecipitation assays. Genes similar to scpA and scpB are present in many bacteria and archaea, which suggests that their gene products form a condensation complex with SMC in most prokaryotes. The observed foci could constitute condensation factories that pull DNA away from mid-cell into both cell halves. C1 Univ Marburg, Fachbereich Chem, D-35032 Marburg, Germany. Univ Frankfurt, Biozentrum Niederursel, Inst Mikrobiol, D-60439 Frankfurt, Germany. NICHD, NIH, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Graumann, PL (reprint author), Univ Marburg, Fachbereich Chem, Hans Meerwein Str, D-35032 Marburg, Germany. OI Strunnikov, Alexander/0000-0002-9058-2256 NR 47 TC 113 Z9 116 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 17 PY 2002 VL 21 IS 12 BP 3108 EP 3118 DI 10.1093/emboj/cdf314 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569EL UT WOS:000176587600026 PM 12065423 ER PT J AU Rhee, EG Mendez, S Shah, JA Wu, CY Kirman, JR Turon, TN Davey, DF Davis, H Klinman, DM Coler, RN Sacks, DL Seder, RA AF Rhee, EG Mendez, S Shah, JA Wu, CY Kirman, JR Turon, TN Davey, DF Davis, H Klinman, DM Coler, RN Sacks, DL Seder, RA TI Vaccination with heat-killed Leishmania antigen or recombinant leishmanial protein and CpG oligodeoxynucleotides induces long-term memory CD4(+) and CD8(+) T cell responses and protection against Leishmania major infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD4(+) T cells; CD8(+) T cells; DNA vaccines; parasitic infection; Th cells ID IMMUNOSTIMULATORY DNA-SEQUENCES; MURINE LEISHMANIASIS; IN-VIVO; CUTANEOUS LEISHMANIASIS; INDEPENDENT MECHANISM; INTERFERON-GAMMA; DENDRITIC CELLS; IMMUNE-RESPONSE; BACTERIAL-DNA; TH1 IMMUNITY AB CpG oligodeoxynucleotides (ODN) have potent effects on innate and adaptive cellular immune responses,. In this report, the ability, of CpG ODN to confer long-term immunity and protection when used as a vaccine adjuvant with a clinical grade of leishmanial antigen, autoclaved Leishmania major (ALM), or a recombinant leishmanial protein was studied. In two different Mouse models of L. major infection, vaccination with ALM plus CpG ODN was able to control infection and markedly reduce lesion development in susceptible BALB/c and resistant C57BL/6 (B6) mice, respectively, up to 12 wk after immunization. Moreover, 136 mice immunized with ALM plus CpG ODNs were still protected against infectious challenge even 6 mo after vaccination. In terms of immune correlates of protection, ALM plus CpG ODN-vaccinated mice displayed L. major-specific T helper cell I and CD8(+) response,;. In addition. complete protection was markedly abrogated in mice depleted of CD8(+) T cells at the time of vaccination. Similarly, mice vaccinated with a recombinant leishmanial protein plus CpG ODN also had long-term protection that was dependent on CD8(+) T cells in vivo. Together, these data demonstrate that CpG ODN, when used as a vaccine adjuvant with either a recombinant protein or heat-killed leishmanial antigen, can induce long-term protection against an intracellular infection in a CDS-dependent manner. C1 NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Coley Pharmaceut Grp, Ottawa, ON K1Y 4S1, Canada. US FDA, Ctr Biol Evaluat & Res, Lab Retrovirol & Immunol, Bethesda, MD 20892 USA. Infect Dis Res Inst, Seattle, WA 98104 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bldg 40,Room 3512,40 Convent Dr,MSC 3025, Bethesda, MD 20892 USA. NR 36 TC 133 Z9 140 U1 0 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 JUN 17 PY 2002 VL 195 IS 12 BP 1565 EP 1573 DI 10.1084/jem.20020147 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565DR UT WOS:000176354100007 PM 12070284 ER PT J AU Panigada, M Porcellini, S Barbier, E Hoeflinger, S Cazenave, PA Gu, H Band, H von Boehmer, H Grassi, F AF Panigada, M Porcellini, S Barbier, E Hoeflinger, S Cazenave, PA Gu, H Band, H von Boehmer, H Grassi, F TI Constitutive endocytosis and degradation of the pre-T cell receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE c-Cbl; pre-TCR; T cell development; thymocyte; ubiquitin ID SYK TYROSINE KINASE; PHOSPHOTYROSINE-BINDING DOMAIN; CBL PROTOONCOGENE PRODUCT; GROWTH-FACTOR RECEPTOR; TCR ALPHA-CHAIN; GAMMA-DELTA; C-CBL; IMMATURE THYMOCYTES; NEGATIVE REGULATOR; ALLELIC EXCLUSION AB The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR, into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR, is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56(lck) actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the gammadeltaTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR- but riot gammadeltaTCR-expressing cells. A role of c-Cbl-mediated ubiquitination in pre-TCR, degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl-deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function. C1 Univ Milan, Dipartimento Biol & Genet Sci Med, I-20133 Milan, Italy. Inst Pasteur, Dept Immunol, F-75724 Paris 15, France. Univ Paris 06, F-75005 Paris, France. Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lymphocyte Biol Sect,Div Rheumatol Immunol & Alle, Boston, MA 02115 USA. NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. RP Grassi, F (reprint author), Dana Farber Canc Inst, Dept Pathol, 1 Jimmy Fund Way, Boston, MA 02115 USA. NR 84 TC 50 Z9 50 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 17 PY 2002 VL 195 IS 12 BP 1585 EP 1597 DI 10.1084/jem.20020047 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565DR UT WOS:000176354100009 PM 12070286 ER PT J AU Kele, P Orbulescu, J Calhoun, TL Gawley, RE Leblanc, RM AF Kele, P Orbulescu, J Calhoun, TL Gawley, RE Leblanc, RM TI Coumaryl crown ether based chemosensors: selective detection of saxitoxin in the presence of sodium and potassium ions SO TETRAHEDRON LETTERS LA English DT Article DE coumarin; saxitoxin; fluorescence ID CHARGE-TRANSFER; SENSORS; FLUORESCENCE; LUMINESCENCE; RECOGNITION; SWITCHES; LANGMUIR AB Two novel fluorescent chemosensors in which an aza-crown is linked to 4-coumaryl fluorophores by a methylene spacer have been synthesized for sensing saxitoxin. Fluorescence enhancement was observed upon binding of the dicationic toxin molecule, whereas several metal ions produced no effect. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Coral Gables, FL 33124 USA. RP Gawley, RE (reprint author), Univ Miami, Dept Chem, 1301 Mem Dr, Coral Gables, FL 33124 USA. EM rgawley@miami.edu; rml@miami.edu RI Orbulescu, Jhony/D-7829-2012 OI Orbulescu, Jhony/0000-0001-9408-9787 NR 18 TC 45 Z9 45 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JUN 17 PY 2002 VL 43 IS 25 BP 4413 EP 4416 AR PII S0040-4039(02)00853-5 DI 10.1016/S0040-4039(02)00853-5 PG 4 WC Chemistry, Organic SC Chemistry GA 562CW UT WOS:000176180700001 ER PT J AU Bennett, SK Smith, MF Gottlieb, SS Fisher, ML Bacharach, SL Dilsizian, V AF Bennett, SK Smith, MF Gottlieb, SS Fisher, ML Bacharach, SL Dilsizian, V TI Effect of metoprolol on absolute myocardial blood flow in patients with heart failure secondary to ischemic or nonischemic cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR FUNCTION; CONSCIOUS DOGS; BETA BLOCKADE; PROPRANOLOL C1 Univ Maryland, Med Ctr, Div Nucl Med Cardiol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Baltimore, MD USA. NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Dilsizian, V (reprint author), Univ Maryland, Med Ctr, Div Nucl Med Cardiol, 22 S Greene St,Room N2W78, Baltimore, MD 21201 USA. NR 13 TC 13 Z9 13 U1 1 U2 2 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 JUN 15 PY 2002 VL 89 IS 12 BP 1431 EP 1434 DI 10.1016/S0002-9149(02)02363-9 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 563GL UT WOS:000176247900021 PM 12062744 ER PT J AU Haffer, AST Rogers, JR Montello, MJ Frank, EC Ostroff, C AF Haffer, AST Rogers, JR Montello, MJ Frank, EC Ostroff, C TI 2001 anthrax crisis in Washington, DC: Clinic for persons exposed to contaminated mail SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE ambulatory care; anthrax; biological warfare; diagnosis; disaster planning; protocols; team AB An anthrax prophylaxis clinic is described. In October 2001, four workers from the U.S. Postal Service's Brentwood facility in Washington, D.C., were hospitalized with inhalational anthrax; many others may have been exposed to anthrax spores. U.S. Public Health Service (USPHS) teams were deployed to establish an anthrax prophylaxis clinic that would provide education and medication to workers and people who visited the mail facility. The temporary clinic was set up at D.C. General Hospital and was staffed primarily by health care professionals from USPHS. The protocol at the clinic involved three major phases. Phase 1 consisted of gathering information from the patient and distributing educational materials. Phase 2 involved presentations by a physician and a pharmacist concerning anthrax, followed by a question-and-answer session. In phase 3, a pharmacist selected the most appropriate prophylactic agent, dispensed the medication, counseled the patient, and referred patients with flu-like symptoms or skin lesions to a physician. Two floor plans were used to maximize the number of patients seen per hour without jeopardizing patient care. The clinic operated 14 hours a day for 14 days. The 136-member health care team included 52 pharmacists, and medication was dispensed to more than 18,000 patients. The clinic may serve as a model for pharmacists and other professionals in designing and implementing disaster plans. A multidisciplinary team established and operated a clinic to treat persons who may have been exposed to anthrax through contaminated mail. C1 US FDA, Div Drug Mkt Advertising & Commun, Rockville, MD 20852 USA. US PHS, PHS Diaster Med Assistance Team 1, Washington, DC 20201 USA. NCI, Canc Therapy Evaluat Program, Protocol & Informat Off, Rockville, MD USA. US PHS, Commissioned Corps Readiness Force, Washington, DC 20201 USA. US FDA, Div Special Pathogen & Immunol Drug Prod, Rockville, MD 20857 USA. US FDA, Div Pulm & Allergy Drug Prod, Rockville, MD 20857 USA. RP Haffer, AST (reprint author), US FDA, Div Drug Mkt Advertising & Commun, HFD-042,5600 Fishers Lane,Room 17B-17, Rockville, MD 20852 USA. NR 4 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 15 PY 2002 VL 59 IS 12 BP 1189 EP 1192 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 561ZY UT WOS:000176174000011 PM 12073860 ER PT J AU Montello, MJ Ostroff, C Frank, EC Haffer, AST Rogers, JR AF Montello, MJ Ostroff, C Frank, EC Haffer, AST Rogers, JR TI 2001 anthrax crisis in Washington, DC: Pharmacists' role in screening patients and selecting prophylaxis SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE ambulatory care; anthrax; biological warfare; ciprofloxacin; diagnosis; disaster planning; doxycycline; pharmacists; protocols; quinolones; tetracyclines AB Pharmacists' development and use of a worksheet facilitating their rapid selection of patient-appropriate prophylactic antimicrobials in an anthrax clinic is described. A clinic housed at D.C. General Hospital, in Washington, D.C., treated most of the people-many of them postal workers-who may have been exposed to anthrax in that city during the 2001 anthrax crisis. A form was needed to assist pharmacists in the rapid selection of prophylactic antimicrobials and in patient education and counseling. A team of pharmacists collaborated on the development of a form tailored to the clinical and logistical needs of the operation. The questions on the form were based largely on the two antianthrax agents most likely to be used, ciprofloxacin and doxycycline, and were designed to identify the circumstances that would most frequently require a medication change or a modification of patient education. Yes-or-no check boxes allowed pertinent data to be captured most efficiently. A positive response to any question triggered a personal interview and assessment by a pharmacist. A treatment algorithm was also developed to ensure consistent pharmacist selection of agents in the face of potentially changing policies and staff. The worksheet questions sought to establish treatment objectives, document allergies and concomitant therapies, and identify patients who were pregnant or lactating. Pharmacists developed a patient-screening worksheet that helped determine their choice of treatment for people who may have been exposed to anthrax in Washington, D.C., during the 2001 anthrax crisis. C1 US PHS, Disaster Med Assistance Team 1, Rockville, MD 20852 USA. NCI, Protocol & Informat Off, Canc Therapeut Evaluat Program, Rockville, MD USA. US FDA, Div Pulm & Allergy Drug Prod, Rockville, MD 20857 USA. US PHS, Commissioned Corps Readiness Force, Washington, DC 20201 USA. US FDA, Div Special Pathogen & Immunol Drug Prod, Rockville, MD 20857 USA. US FDA, Div Drug Mkt Advertising & Commun, Rockville, MD 20857 USA. RP Montello, MJ (reprint author), US PHS, Disaster Med Assistance Team 1, 6130 Execut Blvd,Execut Plaza N,Room 6118, Rockville, MD 20852 USA. NR 7 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 15 PY 2002 VL 59 IS 12 BP 1193 EP 1199 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 561ZY UT WOS:000176174000012 PM 12073861 ER PT J AU Etzioni, A Sturla, L Antonellis, A Green, ED Gershoni-Baruch, R Berninsone, PM Hirschberg, CB Tonetti, M AF Etzioni, A Sturla, L Antonellis, A Green, ED Gershoni-Baruch, R Berninsone, PM Hirschberg, CB Tonetti, M TI Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE leukocyte adhesion defect; fucose; Golgi apparatus ID GDP-FUCOSE TRANSPORTER; GOLGI; GLYCOSYLATION AB Leukocyte adhesion deficiency (LAD) type II is a rare autosomal recessive syndrome characterized by recurrent infections, typical dysmorphic features, the Bombay blood phenotype and severe growth and psychomotor retardation. It is attributed to a general absence of fucosylated glycans on the cell surface. Three Arab Israeli patients and one Turkish child have been reported so far. The primary defect in a specific GDP-L-fucose transporter of the Golgi apparatus has been disclosed recently. All three children reported by us are homozygous for one single founder mutation, different from that reported in the Turkish child. The amount of mRNA of the GDP-L-fucose transporter in cells from Arab patients and their parents are comparable to controls. Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes. (C) 2002 Wiley-Liss, Inc. C1 Technion Israel Inst Technol, B Rapapport Sch Med, Rambam Med Ctr, Dept Pediat & Immunol, Haifa, Israel. G Gaslini Inst Children, Genoa, Italy. NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. George Washington Univ, Grad Program Genet, Washington, DC USA. Boston Univ, Sch Dent Med, Dept Mol & Cell Biol, Boston, MA 02215 USA. Univ Genoa, Dept Expt Med, Genoa, Italy. RP Etzioni, A (reprint author), Rambam Med Ctr, Dept Pediat, IL-31096 Haifa, Israel. OI TONETTI, MICHELA/0000-0002-8829-7173 FU NIGMS NIH HHS [GM 30365] NR 18 TC 37 Z9 38 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 15 PY 2002 VL 110 IS 2 BP 131 EP 135 DI 10.1002/ajmg.10423 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 558UZ UT WOS:000175986300006 PM 12116250 ER PT J AU Lei, TC Virador, VM Vieira, WD Hearing, VJ AF Lei, TC Virador, VM Vieira, WD Hearing, VJ TI A melanocyte-keratinocyte coculture model to assess regulators of pigmentation in vitro SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE coculture; melanocyte; keratinocyte; tyrosinase; melanin ID SKIN EQUIVALENT MODEL; ULTRAVIOLET-LIGHT; EPIDERMAL-KERATINOCYTES; TYROSINASE ACTIVITY; MELANOGENESIS; EXPRESSION; CULTURE; GROWTH; CELLS; DIFFERENTIATION AB Many melanocyte or skin equivalent models have been used to evaluate the potential efficacy of melanogenic compounds to regulate pigmentation, but there has been great variation in results, partially stemming from the use of different cell lines and diverse conditions for the melanogenic assays. In an earlier report, we optimized a microtiter format assay system to screen potential bioactive compounds using immortalized melan-a melanocytes. That assay system, termed the STOPR protocol, allowed effects on melanocyte proliferation and differentiation to be assessed in a highly sensitive, reproducible, and cost-effective manner. However, in the skin and hair, melanocytes interact with keratinocytes, fibroblasts, and other cell types, and testing of putative bioactive compounds on melanocytes alone in culture does not allow one to observe the interactions with those other cell types, such as would occur in vivo. Therefore, we developed a melanocyte-keratinocyte coculture protocol that allows testing of compounds for potential effects on pigmentation in a more physiologically relevant context. It is a sensitive, reproducible, and reliable model for testing melanogenic regulators, and we have standardized it with known melanogenic inhibitors (hydroquinone, arbutin, kojic acid, and niacinamide) and stimulators (alpha-melanocyte-stimulating hormone, 8-methoxypsoralen, and 3,4-dihydroxyphenylalanine). This coculture system allows for large-scale screening of candidate compounds in conjunction with the STOPR protocol and provides a more physiologically relevant system to study melanocyte-keratinocyte interactions and to elucidate the regulatory mechanisms of melanogenic compounds. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lei, TC (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 53 TC 50 Z9 69 U1 2 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2002 VL 305 IS 2 BP 260 EP 268 DI 10.1006/abio.2002.5665 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 565HM UT WOS:000176363900016 PM 12054455 ER PT J AU Dikalov, SI Dikalova, AE Mason, RP AF Dikalov, SI Dikalova, AE Mason, RP TI Noninvasive diagnostic tool for inflammation-induced oxidative stress using electron spin resonance spectroscopy and an extracellular cyclic hydroxylamine SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE inflammation; oxidative stress; reactive oxygen species; superoxide; hydroxylamine; nitroxide; lipopolysaccharide; free radicals ID IN-VITRO; POLYMORPHONUCLEAR LEUKOCYTES; SUPEROXIDE RADICALS; OXYGEN; PEROXYNITRITE; QUANTIFICATION; NEUTROPHILS; GENERATION; ADHERENT; OXIDE AB Inflammation is one of the leading causes of the many pathological states associated with oxidative stress. A crucial role in the development of inflammation-induced oxidative stress is played by reactive oxidant species (ROS), which are very difficult to detect in vivo. One of the most sensitive and definitive methods in the detection of ROS is electron spin resonance, especially as used in conjunction with spin trapping. Unfortunately, the commonly used nitrone spin traps have a very low efficacy for trapping superoxide radicals, and their radical adducts are not stable. To address this deficiency, we have developed negatively charged cyclic hydroxylamines such as 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidine (PP-H) for the detection of reactive oxidant species as a diagnostic tool for extracellular inflammation-induced oxidative stress. We used inflammation induced by a bacterial endotoxin lipopolysaccharide (LPS) as a model. ROS formation was tested in cultured macrophages, in blood and in vivo. PP-H reacts with reactive oxidant species generating the stable nitroxide radical 4-phosphonooxy-TEMPO. It was shown that a 5-h treatment of macrophages with LPS (1 mug/ml) leads to a threefold increase in superoxide formation as demonstrated using superoxide dismutase. Formation of reactive oxidant species 5 h after LPS (1 mg/kg) treatment of Fischer rats was analyzed in arterial blood; formation of reactive oxidant species in LPS-treated animals increased by a factor of 2.2 and was dependent upon the LPS dose. Diphenyleneiodonium (0.1 mM) inhibited formation of LPS-stimulated reactive oxidant species by 80%. We suggest that this test could be used as a noninvasive diagnostic tool for inflammation-induced oxidative stress. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Mason, RP (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 Alexander Dr,POB 12233,Mail Drop F0-01, Res Triangle Pk, NC 27709 USA. NR 23 TC 51 Z9 52 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2002 VL 402 IS 2 BP 218 EP 226 AR PII S0003-9861(02)00064-4 DI 10.1016/S0003-9861(02)00064-4 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 567NH UT WOS:000176490500008 PM 12051666 ER PT J AU Nekhai, S Zhou, M Fernandez, A Lane, WS Lamb, NJC Brady, J Kumar, A AF Nekhai, S Zhou, M Fernandez, A Lane, WS Lamb, NJC Brady, J Kumar, A TI HIV-1 Tat-associated RNA polymerase C-terminal domain kinase, CDK2, phosphorylates CDK7 and stimulates Tat-mediated transcription SO BIOCHEMICAL JOURNAL LA English DT Article DE microinjection; protein microsequencing ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEIN-KINASE; P-TEFB; HIGH-AFFINITY; CAK ACTIVITY; IN-VITRO; ELONGATION; CELL; ACTIVATION; BINDING AB HIV-1 gene expression is regulated by a viral transactivator protein (Tat) which induces transcriptional elongation of HIV-1 long tandem repeat (LTR). This induction requires hyperphosphorylation of the C-terminal domain (CTD) repeats of RNA polymerase 11 (Pol 11). To achieve CTD hyperphosphorylation. Tat stimulates CTD kinases associated with general transcription factors of the promoter complex, specifically TFIIH-associated CDK7 and positive transcription Factor b-associated CDK9 (cyclin-dependent kinase 9). Other studies indicate that Tat may bind an additional CTD kinase that regulates the target-specific phosphorylation of RNA Pol 11 CTD, We previously reported that Tat-associated T-cell-derived kinase (TTK), purified from human primary T-cells, stimulates Tat-dependent transcription of HIV-1 LTR in vivo [Nekhai. Shukla. Fernandez, Kumar and Lamb (2000) Virology 266, 246-256]. In the work presented here. we characterized the components of TTK by biochemical fractionation and the function of TTK in transcription assays in vitro. TTK uniquely co-purified with CDK2 and not with either CDK9 or CDK7. Tat induced the TTK-associated CDK2 kinase to phosphorylate CTD. specifically at Ser-2 residues, The TTK fraction restored Tat-mediated transcription activation of HIV-1 LTR in a HeLa nuclear extract immunodepleted of CDK9. but not in the HeLa nuclear extract double-depleted of CDK9 and CDK7. Direct microinjection of the TTK fraction augmented Tat transactivation of HIV-1 LTR in human primary HS68 fibroblasts. The results argue that TTK-associated CDK2 may function to maintain target-specific phosphorylation of RN,A Pol II that is essential for Tat transactivation of HIV-1 promoter. They are also consistent with the observed cell-cycle-specific induction of viral gene transactivation. C1 George Washington Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20037 USA. Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. Howard Univ, Dept Biochem, Washington, DC 20059 USA. IGH CNRS, Cell Biol Unit, Montpellier, France. Harvard Univ, Microchem Fac, Cambridge, MA 02138 USA. NCI, Virus Turmor Biol Sect, Bethesda, MD 20892 USA. RP George Washington Univ, Sch Med, Dept Biochem & Mol Biol, 2300 Eye St NW, Washington, DC 20037 USA. EM akumar@gwu.edu NR 34 TC 51 Z9 54 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUN 15 PY 2002 VL 364 BP 649 EP 657 DI 10.1042/BJ20011191 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568QA UT WOS:000176552600008 PM 12049628 ER PT J AU Nguyen, DH Taub, D AF Nguyen, DH Taub, D TI Cholesterol is essential for macrophage inflammatory protein 1 beta binding and conformational integrity of CC chemokine receptor 5 SO BLOOD LA English DT Article ID SMALL-MOLECULE INHIBITOR; LIPID RAFTS; HIV-1 ENTRY; MEMBRANE CHOLESTEROL; CXCR4 CORECEPTOR; VIRUS; TYPE-1; CELLS; MICRODOMAINS; INFECTION AB The chemokine receptor, CCR5, is used as a human immunodeficiency virus coreceptor in combination with CD4 during transmission and early infection. CCR5 has been shown to be palmitoylated and targeted to cholesterol- and sphingolipid-rich membrane microdomains termed "lipid rafts." However, the role of cholesterol and lipid rafts on chemokine binding and signaling through CCR5 remains unknown. We found that cholesterol extraction by hydroxypropyl-p-cyclodextrin (BCD) significantly reduced the binding and signaling of macrophage inflammatory protein 1beta (MIP-1beta) using CCR5-expressing CEM-NKR T cells. Reloading treated cells with cholesterol but not 4-cholesten-3-one, an oxidized form of cholesterol, restored MIP-1beta binding to BCD-treated cells. Antibodies specific for distinct CCR5 epitopes lost their ability to bind to the cell surface after cholesterol extraction to varying degrees. Moreover, cells stained with fluorescently labeled MIP-1beta extensively colocalized with the GM1 lipid raft marker while using anti-CCR5 antibodies; most of CCR5 on these cells only partially colocalized with GM1, suggesting that active ligand binding facilitates receptor association with lipid rafts or that raft association promotes a higher affinity conformation of CCR5. Together, these data demonstrate that cholesterol and lipid rafts are important for the maintenance of the CCR5 conformation and are necessary for both the binding and function of this chemokine receptor. (Blood. 2002;99:4298-4306) (C) 2002 by The American Society of Hematology. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Taub, D (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 42 TC 82 Z9 83 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2002 VL 99 IS 12 BP 4298 EP 4306 DI 10.1182/blood-2001-11-0087 PG 9 WC Hematology SC Hematology GA 559WA UT WOS:000176047800006 PM 12036855 ER PT J AU Ghosh, P Buchholz, MA Yano, S Taub, D Longo, DL AF Ghosh, P Buchholz, MA Yano, S Taub, D Longo, DL TI Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway SO BLOOD LA English DT Article ID MESSENGER-RNA TRANSLATION; ACCESSORY MOLECULE CD28; T-CELL PROLIFERATION; 70-KDA S6 KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; ACTIVATION PATHWAY; MAMMALIAN PROTEIN; SIGNALING PATHWAY; IL-2 PRODUCTION; INTERLEUKIN-2 AB The consequences of T-cell activation depend exclusively on costimulation during antigen-T-cell receptor Interaction. Interaction between the T-cell coreceptor CD28 and its ligand B7 during antigen-antigen receptor engagement results in full activation of T cells, the outcomes of which are proliferation and effector functions. The ability of CD28 to costimulate the production of interleukin-2 (IL-2) explains the importance of this costimulation. The signaling event mediated by CD28 engagement has been proposed to have 2 components: one is sensitive to the immunosuppressive drug cyclosporin A (CsA), and the other one is CsA-resistant. In this report, we demonstrate that the CsA-resistant pathway is sensitive to the immunosuppressive drug rapamycin. Treatment with rapamycin blocked IL-2 production after activation of human peripheral blood T cells with phorbol ester (PMA) and anti-CD28 (CsA-resistant pathway), whereas this drug did not have any effect on PIVIA plus lonomycin stimulation (CsA-sensitive pathway). The inhibitory effect of rapamycin was on messenger RNA stability and translation, rather than on IL-2 transcription or protein turnover. (C) 2002 by The American Society of Hematology. C1 NIA, Gerontol Res Ctr, Lymphocyte Cell Biol Sect, Immunol Lab,NIH, Baltimore, MD 21224 USA. RP Ghosh, P (reprint author), NIA, Gerontol Res Ctr, Lymphocyte Cell Biol Sect, Immunol Lab,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 53 TC 29 Z9 32 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 JUN 15 PY 2002 VL 99 IS 12 BP 4517 EP 4524 DI 10.1182/blood-2001-11-0062 PG 8 WC Hematology SC Hematology GA 559WA UT WOS:000176047800034 PM 12036883 ER PT J AU Bolan, CD Leitman, SF Griffith, LM Barrett, AJ Childs, RW AF Bolan, CD Leitman, SF Griffith, LM Barrett, AJ Childs, RW TI Parameters of erythropoietic function after major ABO-incompatible hematopoietic stem cell transplantation: implications following nonmyeloablative conditioning - Response SO BLOOD LA English DT Letter ID BONE-MARROW TRANSPLANTATION; CHIMERISM; APLASIA C1 NIH, Dept Transfus Med, LTC USA MC, Bethesda, MD 20892 USA. RP Bolan, CD (reprint author), NIH, Dept Transfus Med, LTC USA MC, Bldg 10,Rm 1C711,MSC 1184, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 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 JUN 15 PY 2002 VL 99 IS 12 BP 4643 EP 4644 PG 2 WC Hematology SC Hematology GA 559WA UT WOS:000176047800054 ER PT J AU Tucker, MA Fraser, MC Goldstein, AM Struewing, JP King, MA Crawford, JT Chiazze, EA Zametkin, DP Fontaine, LS Clark, WH AF Tucker, MA Fraser, MC Goldstein, AM Struewing, JP King, MA Crawford, JT Chiazze, EA Zametkin, DP Fontaine, LS Clark, WH TI A natural history of melanomas and dysplastic nevi - An atlas of lesions in melanoma-prone families SO CANCER LA English DT Article; Proceedings Paper CT 5th Internatinal Conference on Melanoma CY FEB 28, 2001 CL VENICE, ITALY DE melanoma; dysplastic nevi; genetics; familial melanoma ID CUTANEOUS MALIGNANT-MELANOMA; ATYPICAL-MOLE SYNDROME; NONFAMILIAL MELANOMA; GERMLINE MUTATIONS; TUMOR PROGRESSION; CDKN2A MUTATIONS; RISK-FACTORS; PRECURSOR LESIONS; COMMON; CDK4 AB BACKGROUND. Few long-term clinical and histologic data for melanocytic lesions have been available based on the mutation status of families at an increased risk of melanoma. In the current study, the authors describe the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A, CDK4, or not yet identified genes. METHODS. Thirty-three families with > 2 living members with invasive melanoma were evaluated clinically and followed prospectively for up to 25 years. All the participants were evaluated by the same study team at the Clinical Center of the National Institutes of Health or in local clinics. After informed consent was obtained, family members (n = 844) were examined and photographed. Blood was obtained for genetic studies; genotyping for CDKN2A and CDK4 was performed. Sequential photographs of melanocytic lesions were taken as part of the clinical evaluations. When melanocytic lesions were removed, the histology was reviewed. Representative photographs and photo micrographs were selected for six classes of lesions and three mutation groups. RESULTS. All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either gene identified. The majority of dysplastic nevi either remain stable or regress; few change in a manner that should cause concern for melanoma. With careful surveillance, melanomas can be found early. CONCLUSIONS. The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families. (C) 2002 American Cancer Society. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. NIH, Div Intramural Res Serv, Med Arts & Photo Branch, Photog Sect, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. RP Tucker, MA (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Lab Populat Genet,Ctr Canc Res, Execut Plaza S,Room 7122 MSC 7236,6120 Execut Blv, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 45 TC 67 Z9 68 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2002 VL 94 IS 12 BP 3192 EP 3209 DI 10.1002/cncr.10605 PG 18 WC Oncology SC Oncology GA 564GA UT WOS:000176305600016 PM 12115352 ER PT J AU McCusker, ME Cote, TR Clegg, LX Sobin, LH AF McCusker, ME Cote, TR Clegg, LX Sobin, LH TI Primary malignant neoplasms of the appendix - A population-based study from the surveillance, epidemiology and end-results program, 1973-1998 SO CANCER LA English DT Article DE adenocarcinoma; appendix; carcinoid tumor; goblet cell carcinoid; epidemiology; incidence; mucinous adenocarcinoma; signet ring cell carcinoma; SEER; survival ID TUMORS; ADENOCARCINOMA; LESIONS AB BACKGROUND. Cancer of the appendix is an uncommon disease that is rarely suspected rarely before surgery. Although several case series of these tumors have been published, little research has been anchored in population-based data on cancer of the appendix. METHODS. This analysis included all actively followed cases of appendiceal neoplasms reported to the National Cancer Institute's Surveillance, Epidemiology and End-Results (SEER) program between 1973 and 1998. Tumors were classified as "colonic type" adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, goblet cell carcinoid, and "malignant carcinoid" (SEER only collects data on carcinoids specifically classified as malignant). We compared incidence, overall survival and survival rates by extent of disease at diagnosis. RESULTS. Between 1973 and 1998, 2117 appendiceal malignancies were reported to the SEER program, of which 1645 cases were included in the analysis. Age-adjusted incidence of cancer of the appendix was 0.12 cases per 1,000,000 people per year. Demographic characteristics of patients with goblet cell carcinoid tumors were midway between those of patients with malignant carcinoid and all types of adenocarcinomas. After controlling for age and extent of disease at diagnosis, the overall survival rate for patients diagnosed between 1983 and 1997 (n = 1061) was significantly worse for those with signet ring cell carcinoma than for those with any other tumor type (P < 0.01). In addition, overall survival rates were better for patients with malignant carcinoid (P = 0.01). CONCLUSIONS. Demographic characteristics of patients with cancer of the appendix vary by histology. Except for signet ring cell carcinoma and malignant carcinoid, the extent of disease at time of diagnosis is a more important predictor of survival than histology. (C) 2002 American Cancer Society. C1 Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Hepat & Gastrointestinal Pathol, Washington, DC 20306 USA. RP McCusker, ME (reprint author), Univ Maryland, Dept Epidemiol & Prevent Med, 660 W Redwood St, Baltimore, MD 21201 USA. NR 21 TC 172 Z9 187 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2002 VL 94 IS 12 BP 3307 EP 3312 DI 10.1002/cncr.10589 PG 6 WC Oncology SC Oncology GA 564GA UT WOS:000176305600029 PM 12115365 ER PT J AU Fujii, T Dracheva, T Player, A Chacko, S Clifford, R Strausberg, RL Buetow, K Azumi, N Travis, WD Jen, J AF Fujii, T Dracheva, T Player, A Chacko, S Clifford, R Strausberg, RL Buetow, K Azumi, N Travis, WD Jen, J TI A preliminary transcriptome map of non-small cell lung cancer SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; TUMOR-SUPPRESSOR GENE; HOMOZYGOUS DELETION REGION; ANALYSIS DETECTS FREQUENT; CHROMOSOMAL ALTERATIONS; CYTOGENETIC ANALYSIS; ALLELIC IMBALANCE; DNA-SEQUENCES; CARCINOMAS; HEAD AB We constructed a genome-wide transcriptome map of non-small cell lung carcinomas based on gene-expression profiles generated by serial analysis of gene expression (SAGE) using primary tumors and bronchial epithelial cells of the lung. Using the human genome working draft and the public databases, 25,135 nonredundant UniGene clusters were mapped onto unambiguous chromosomal positions. Of the 23,056 SAGE tags that appeared more than once among the nine SAGE libraries, 11,156 tags representing 7,097 UniGene clusters were positioned onto chromosomes. A total of 43 and 55 clusters of differentially expressed genes were observed in squamous cell carcinoma and adenocarcinoma, respectively. The number of genes in each cluster ranged from 18 to 78 in squamous cell carcinomas and from 20 to 165 in adenocarcinomas. The size of these clusters varied from 1.8 Mb to 65.5 Mb in squamous cell carcinomas and from 1.6 Mb to 98.1 Mb in adenocarcinomas. Overall, the clusters with genes over-represented in tumors had an average of 3-4-fold increase in gene expression compared with the normal control. In contrast, clusters of genes with reduced expression had about 50-65% of the gene expression level compared with the normal. Examination of clusters identified in squamous cell lung cancer suggested that 9 of 15 clusters with overexpressed genes and 13 of 28 clusters with underexpressed genes were concordant with previously reported cytogenetic, comparative genomic hybridization or loss of heterozygosity studies. Therefore, at least a portion of the gene clusters identified via the transcriptome map most likely represented the transcriptional or genetic alterations occurred in the tumors. Integrating chromosomal mapping information with gene expression profiles may help reveal novel molecular changes associated with human lung cancer. C1 NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Canc Genom Off, NIH, Bethesda, MD 20892 USA. Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. RP Jen, J (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, NIH, 41 Liberty Dr,Bldg 41 Room D702, Bethesda, MD 20892 USA. EM jenj@mail.nih.gov OI Fujii, Takeshi/0000-0001-7237-1183 NR 45 TC 51 Z9 53 U1 0 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 JUN 15 PY 2002 VL 62 IS 12 BP 3340 EP 3346 PG 7 WC Oncology SC Oncology GA 562NB UT WOS:000176203500003 PM 12067970 ER PT J AU Tiano, HF Loftin, CD Akunda, J Lee, CA Spalding, J Sessoms, A Dunson, DB Rogan, EG Morham, SG Smart, RC Langenbach, R AF Tiano, HF Loftin, CD Akunda, J Lee, CA Spalding, J Sessoms, A Dunson, DB Rogan, EG Morham, SG Smart, RC Langenbach, R TI Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; CHEMOPREVENTIVE ACTIVITY; COLON CARCINOGENESIS; GENE-EXPRESSION; TUMOR PROMOTION; MICE; CANCER; DISRUPTION; CELECOXIB; INHIBITOR AB Nonsteroidal anti-inflammatory drugs are widely reported to inhibit carcinogenesis in humans and in rodents. These drugs are believed to act by inhibiting one or both of the known isoforms of cyclooxygenase (COX). However, COX-2, and not COX-1, is the isoform most frequently reported to have a key role in tumor development. Here we report that homozygous deficiency of either COX-1 or COX-2 reduces skin tumorigenesis by 75% in a multistage mouse skin model. Reduced tumorigenesis was observed even though the levels of stable 7,12-dimethylbenz(a)anthracene-DNA adducts were increased about 2-fold in the COX-deficient mice compared with wild-type mice. The premature onset of keratinocyte terminal differentiation appeared to be the cellular event leading to the reduced tumorigenesis because keratin 1 and keratin 10, two keratins that indicate the commitment of keratinocytes to differentiate, were expressed 8-13-fold and 10-20-fold more frequently in epidermal basal cells of the COX-1-deficient and COX-2-deficient mice, respectively, than in wildtype mice. Papillomas on the COX-deficient mice also displayed the premature onset of keratinocyte terminal differentiation. However, loricrin, a late marker of epidermal differentiation, was not significantly altered, suggesting that it was the early stages of keratinocyte differentiation that were primarily affected by COX deficiency. Because keratin 5, a keratin associated with basal cells, was detected differently in papillomas of COX-1-deficient as compared with COX-2-deficient mice, it appears that the isoforms do not have identical roles in papilloma development. Interestingly, apoptosis, a cellular process associated with nonsteroidal anti-inflammatory drug-induced inhibition of tumorigenesis, was not significantly altered in the epidermis or in papillomas of the COX-deficient mice. Thus, both COX-1 and COX-2 have roles in keratinocyte differentiation, and we propose that the absence of either isoform causes premature terminal differentiation of initiated keratinocytes and reduced tumor formation. C1 Natl Inst Environm Hlth Sci, Lab Expt Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Myriad Genet Inc, Salt Lake City, UT 84108 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Langenbach, R (reprint author), Natl Inst Environm Hlth Sci, Lab Expt Carcinogenesis & Mutagenesis, POB 12233, Res Triangle Pk, NC 27709 USA. NR 43 TC 270 Z9 280 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3395 EP 3401 PG 7 WC Oncology SC Oncology GA 562NB UT WOS:000176203500014 PM 12067981 ER PT J AU Casanova, ML Larcher, F Casanova, B Murillas, R Fernandez-Acenero, MJ Villanueva, C Martinez-Palacio, J Ullrich, A Conti, CJ Jorcano, JL AF Casanova, ML Larcher, F Casanova, B Murillas, R Fernandez-Acenero, MJ Villanueva, C Martinez-Palacio, J Ullrich, A Conti, CJ Jorcano, JL TI A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis SO CANCER RESEARCH LA English DT Article ID VASCULAR-PERMEABILITY FACTOR; EGF RECEPTOR; ENDOTHELIAL-CELLS; TUMOR-DEVELOPMENT; HAIR FOLLICLE; FACTOR-ALPHA; IN-VITRO; EXPRESSION; CANCER; MICE AB Epidermal growth factor receptor (EGFR) plays a critical role in epidermal biology. Abnormal EGFR function has been described in eplthelial tumors including those induced by two-stage chemical carcinogenesis in mouse skin. A large body of evidence indicates that in this model, activation of Ha-ras is the critical event in papilloma formation, a process that involves epidermal proliferation and stroma remodeling, which includes angiogenesis. This study reports that activated Ha-ras results in a dramatic induction of EGFR in epidermal tumor cells and provides experimental evidence that EGFR signaling is responsible for Ha-ras-dependent vascular endothelial growth factor (VEGF) induction, as well as for the repression of other angiogenic factors such as angiopoietin 1. The pivotal role of functional EGFR in throwing the angiogenic switch necessary for tumor growth was confirmed by s.c. injection of immunodeficient mice with epidermal tumor cells carrying a dominant negative (dn) EGFR and by in vivo chemical skin carcinogenesis assays in transgenic mice expressing the same dn EGFR form in the epidermis. Immunohistochemical analysis of the tumors obtained by both ex vivo and in vivo approaches showed that dn EGFR expression abolished the changes in blood vessels that occurred during tumor progression. A strong reduction of VEGF expression in dn EGFR tumors appears to be the key event responsible for angiogenesis and tumor growth suppression. The apoptotic rate was increased, and Akt activity was decreased, suggesting that impaired nutrient and oxygen supply might contribute to diminished cell survival in dn EGFR tumors. Support for this mechanism is provided by the fact that the ectopic expression of VEGF in dn EGFR-expressing tumor cell lines restored tumor growth capacity. Although ras activation might suffice for epidermal transformation and the stroma-remodeling events of tumor induction, such effects may not be operative without a functional upstream EGFR. It is tempting to speculate that EGFR family members may function as angiogenic regulators in other epithelial tumors such as those of the colon, breast, and prostate, reinforcing their value as targets for therapeutic intervention. C1 CIEMAT, Project Cell & Mol Biol & Gene Therapy, Ctr Invest Energet Medioambientales & Tecnol, E-28040 Madrid, Spain. GENOTEK, Barcelona 08206, Spain. NCI, NIH, Bethesda, MD 20892 USA. Hosp Gen Mostoles, Madrid 28935, Spain. Max Planck Inst Biochem, D-82152 Martinsried, Germany. Univ Texas, MD Anderson Canc Ctr, Smithville, TX 78957 USA. RP Jorcano, JL (reprint author), CIEMAT, Project Cell & Mol Biol & Gene Therapy, Ctr Invest Energet Medioambientales & Tecnol, Avenida Complutense 22, E-28040 Madrid, Spain. RI Martinez, Jesus/M-3791-2014; Larcher, Fernando/J-1527-2016 OI Martinez, Jesus/0000-0002-9521-8744; Larcher, Fernando/0000-0002-6771-3561 FU NCI NIH HHS [R01 CA 76540] NR 33 TC 84 Z9 91 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3402 EP 3407 PG 6 WC Oncology SC Oncology GA 562NB UT WOS:000176203500015 PM 12067982 ER PT J AU Kuzmin, I Gillespie, JW Protopopov, A Geil, L Dreijerink, K Yang, YF Vocke, CD Duh, FM Zabarovsky, E Minna, JD Rhim, JS Emmert-Buck, MR Linehan, WM Lerman, MI AF Kuzmin, I Gillespie, JW Protopopov, A Geil, L Dreijerink, K Yang, YF Vocke, CD Duh, FM Zabarovsky, E Minna, JD Rhim, JS Emmert-Buck, MR Linehan, WM Lerman, MI TI The RASSF1A tumor suppressor gene is inactivated in prostate tumors and suppresses growth of prostate carcinoma cells SO CANCER RESEARCH LA English DT Article ID FREQUENT EPIGENETIC INACTIVATION; HUMAN-CHROMOSOME 3P21.3; HUMAN-PAPILLOMAVIRUS; PROMOTER HYPERMETHYLATION; EPITHELIAL-CELLS; CANCER; LUNG; RAS; REGION; TRANSFORMATION AB We analyzed expression status of the recently identified tumor suppressor gene RASSF1A in primary prostate carcinomas and in prostate cell lines. We found complete methylation of the RASSF1A promoter in 63 % of primary microdissected prostate carcinomas (7 of 11 samples). The remaining 4 samples (37 %) were partially methylated, possibly because of contamination with normal cells. No promoter methylation was observed in matching normal prostate tissues. High levels of RASSF1A transcript and no methylation of RASSF1A promoter were found in explanted primary normal prostate epithelial and stromal cells. Complete silencing and methylation of RASSFIA promoter was observed in five widely used prostate carcinoma cell lines, which acquired the ability to grow in culture spontaneously, including LNCaP, PC-3, ND-1, DU-145, 22Rv1 and one primary prostate carcinoma immortalized by overexpression of the human telomerase catalytic subunit (RC-58T/hTERT). However, no silencing of RASSF1A was found in four other prostate carcinoma cell lines, which were adapted for cell culture after transformation with human papillomaviral DNA. Suppression of cell growth in vitro was demonstrated after the reintroduction of RASSF1A-expressing construct into LNCaP prostate carcinoma cells. Our data implicate the RASSF1A gene in human prostate tumorigenesis. C1 SAIC Frederick Inc, NCI, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Ft Detrick, MD 21702 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Karolinska Inst, MTC & CGR, S-17177 Stockholm, Sweden. VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. Uniformed Serv Univ Hlth Sci, Ctr Prostate Dis Res, Bethesda, MD 20814 USA. RP Kuzmin, I (reprint author), SAIC Frederick Inc, NCI, Intramural Res Support Program, Bldg 560,Room 12-34, Frederick, MD 21702 USA. RI Zabarovsky, Eugene/A-6645-2010 FU NCI NIH HHS [P50 CA70907, N01-CO-12400, CA71618] NR 23 TC 125 Z9 138 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3498 EP 3502 PG 5 WC Oncology SC Oncology GA 562NB UT WOS:000176203500027 PM 12067994 ER PT J AU Hoffmann, TK Donnenberg, AD Finkelstein, SD Donnenberg, VS Friebe-Hoffmann, U Myers, EN Appella, E DeLeo, AB Whiteside, TL AF Hoffmann, TK Donnenberg, AD Finkelstein, SD Donnenberg, VS Friebe-Hoffmann, U Myers, EN Appella, E DeLeo, AB Whiteside, TL TI Frequencies of tetramer(+) T cells specific for the wild-type sequence p53(264-272) peptide in the circulation of patients with head and neck cancer SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; TARGETING P53; LYMPHOCYTES; CARCINOMA; MUTATIONS; EPITOPE; COMPLEX; PAPILLOMAVIRUS; IMMUNOTHERAPY; RECOGNITION AB Immunization with wild-type sequence (wt) p53 epitopes represents a novel therapeutic strategy for cancer patients with tumors accumulating mutant p53. To evaluate usefulness of p53-derived peptides as future cancer vaccines, frequencies of wt p53(264-272) peptide-specific CD8(+) T cells were determined in the peripheral circulation of patients with squamous cell carcinoma of the head and neck (SCCHN). T cells of 30 HLA-A2.1(+) patients and 31 HLA-A2.1(+) healthy individuals were evaluated by multicolor flow cytometry analysis using peptide-HLA-A2.1 complexes (tetramers). T cells specific for an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were studied in parallel. Patients with SCCHN had a significantly higher mean frequency of CD8(+) T cells specific for wt p53(264-272) than normal donors (P = 0.0041). Surprisingly, the frequency of epitope-specific T cells in the circulation of patients did not correlate with p53 accumulation in the tumor. In patients whose tumors had normal p53 expression or had p53 gene mutations preventing presentation of this epitope, high frequencies of wt p53(264-272)-specific CD8(+) T cells were found, of which many were memory T cells. In contrast, patients whose tumors accumulated p53 had low frequencies of wt p53(264-272)-specific CD8(+) T cells, which predominantly had a naive phenotype and were unable to proliferate ex vivo in response to the epitope, as reported by us previously IT. K. Hoffmann, J. Immunol., 165: 5938-5944, 2000). This seemingly contradictory relationship between the high frequency of epitope-specific T cells and wt p53 expression in the tumor suggests that other factors may contribute to the observed anti-p53 responses. Human papillomavirus-16 E6/E7 expression is common in SCCHN, and E6 is known to promote presentation of wt p53 epitopes. Although human papillomavirus-16 E6/E7 expression was detected in 46% of the tumors, it did not correlate with the frequency of wt p53264-272-specific CD8(+) T cells or with p53 expression in the tumor. These findings emphasize the complexity of interactions between the tumor and the host immune system, and, thus, have particularly important implications for future p53-based immunization strategies. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Immunol & Infect Dis, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Magee Res Inst, Dept Pathol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15213 USA. NCI, Bethesda, MD 20892 USA. RP Whiteside, TL (reprint author), Univ Pittsburgh, Inst Canc, W1041 Biomed Sci Tower,211 Lothrop St, Pittsburgh, PA 15213 USA. FU NIAID NIH HHS [R01 AI14870, 1P01 AI43664, R01 AI41408]; NIDCR NIH HHS [P0-1 DE-12321] NR 39 TC 68 Z9 72 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3521 EP 3529 PG 9 WC Oncology SC Oncology GA 562NB UT WOS:000176203500032 PM 12067999 ER PT J AU Engbring, JA Hoffman, MP Karmand, AJ Kleinman, HK AF Engbring, JA Hoffman, MP Karmand, AJ Kleinman, HK TI The B16F10 cell receptor for a metastasis-promoting site on laminin-1 is a heparan sulfate/chondroitin sulfate-containing proteoglycan SO CANCER RESEARCH LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; AMINO-ACID-SEQUENCE; SYNTHETIC PEPTIDES; MELANOMA-CELLS; TUMOR-CELLS; ADHESION; IDENTIFICATION; ANGIOGENESIS; BINDING; CHAIN AB Exposure to AG73, a synthetic peptide (LQVQLSIR) from the COOH-terminal region of the laminin alpha1 chain, induces a malignant phenotype in B16F10 melanoma cells. Coinjection of this peptide with the cells results in an increase of lung tumors and also the formation of liver tumors in similar to50% of the mice (W. H. Kim et al., Int. J. Cancer, 77: 632-639, 1998). Here we have characterized the cell surface receptor and its functional groups on B16F10 cells. Peptide affinity chromatography identified a cell surface protein eluting with I vi NaCl, which ran in SDS gels as a broad band Of M-r similar to150,000-200,000. Digestion with heparitinase and chondroitinase produced a core protein of lower molecular weight M-r similar to90,000). Involvement of the glycosaminoglycan (GAG) side chains was demonstrated by inhibition of cell binding to the peptide by heparin, heparan sulfate, and chondroitin sulfate B, but not by chondroitin sulfates A or C, or hyaluronic acid. The IC50 for heparin was the lowest, followed by heparan sulfate, then chondroitin sulfate B, suggesting that the overall sulfation of the GAG side chain is critical. This was confirmed by inhibition of attachment with chemically modified heparin and heparan sulfate, which also showed that N or O linkages were not important for function. Using sized heparin fragments to inhibit cell binding to the peptide demonstrated that 16-mer is the minimum length required. B16F10 cells form a network when grown on Matrigel, and this is prevented by addition of the AG73 peptide. The GAGs alone did not affect network formation, but heparin, heparan sulfate, and chondroitin sulfate B reversed the inhibitory effect of the peptide, whereas other GAGs were inactive. Furthermore, removal of cell surface GAGs inhibited cell attachment to the peptide. Cells treated with glycosidases and coinjected with the peptide formed liver tumors equal to the control group receiving no peptide, suggesting that the GAGs play an early role in peptide-mediated tumor metastasis. These data indicate that the B16F10 cell receptor for a laminin metastasis-promoting sequence is a heparan sulfate/chondroitin sulfate-containing proteoglycan, and these GAG side chains are functionally important in the cell-peptide interaction. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, 30-433,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. NR 31 TC 29 Z9 30 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3549 EP 3554 PG 6 WC Oncology SC Oncology GA 562NB UT WOS:000176203500036 PM 12068003 ER PT J AU Pise-Masison, CA Radonovich, M Mahieux, R Chatterjee, P Whiteford, C Duvall, J Guillerm, C Gessain, A Brady, JN AF Pise-Masison, CA Radonovich, M Mahieux, R Chatterjee, P Whiteford, C Duvall, J Guillerm, C Gessain, A Brady, JN TI Transcription profile of cells infected with human T-cell leukemia virus type I compared with activated lymphocytes SO CANCER RESEARCH LA English DT Article ID KAPPA-B SITE; HTLV-I; GENE-EXPRESSION; SPASTIC PARAPARESIS; SIGNALING COMPLEX; PROTEIN-KINASE; P12(I) PROTEIN; TAX PROTEIN; FRAME-II; NF-Y AB Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent for adult T-cell leukemia and the neurological disorder tropical spastic paraparesis/HTLV-I-associated myelopathy. CD4+ T lymphocytes, the primary hosts for HTLV-1, undergo a series of changes that lead to T-cell activation, immortalization, and transformation. To gain insight into the genetic differences between activated and HTLV-I-infected lymphocytes, we performed Affymetrix GeneChip analysis of activated and HTLV-I-infected cells. Using the Hu6800 GeneChip, we identified similar to763 genes that had differentially regulated expression in at least three of five HTLV-1 cell lines. Classification of these genes into functional groups including cellular receptors, kinases, phosphatases, cytokines, signal proteins, and transcription factors provides insight into genes and pathways that are differentially regulated during HTLV-I transformation. C1 NCI, Basic Res Lab, Tumor Virus Biol Sect, Bethesda, MD 20892 USA. Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, F-75724 Paris 15, France. NIH, Ctr Adv Technol, Gaithersburg, MD USA. RP Brady, JN (reprint author), NCI, Basic Res Lab, Tumor Virus Biol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 60 TC 53 Z9 53 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3562 EP 3571 PG 10 WC Oncology SC Oncology GA 562NB UT WOS:000176203500038 PM 12068005 ER PT J AU Hisada, M Maloney, EM Sawada, T Miley, WJ Palmer, P Hanchard, B Goedert, JJ Manns, A AF Hisada, M Maloney, EM Sawada, T Miley, WJ Palmer, P Hanchard, B Goedert, JJ Manns, A TI Virus markers associated with vertical transmission of human T lymphotropic virus type 1 in Jamaica SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID CELL LEUKEMIA-VIRUS; HIGH PROVIRAL LOAD; CHILD TRANSMISSION; HTLV-I; ANTIBODY; SEROCONVERSION; TRANSFUSION; MOTHERS; ASSAY; JAPAN AB In a prospective study involving 150 mothers and their offspring in Jamaica, we examined maternal viral factors associated with the risk of transmission of human T lymphotropic virus type 1 (HTLV-1). Overall, the incidence of HTLV-1 infection among children was 8.3 occurrences per 1000 person-months. A higher maternal provirus level (odds ratio [OR], 1.9 per quartile) and a higher HTLV-1 antibody titer (OR, 2.2 per quartile) were independently associated with transmission to children, whereas the presence of anti-Tax antibody was not. Higher maternal antibody titers also were associated with older age at infection among children who were breast-fed for less than or equal to12 months, which suggests that passively transferred maternal antibodies confer protection against infection while they persist. These data imply that mothers who have high provirus loads should be encouraged not to breast-feed. Alternatively, the successful reduction of maternal provirus loads or maintenance of passive antibody levels in infants during breast-feeding may lower the risk of transmission. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Sci Applicat Int Corp, HIV Vaccine Program, Frederick, MD USA. Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 30026, Japan. Univ W Indies, Kingston 7, Jamaica. RP Hisada, M (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-8008, Rockville, MD 20852 USA. FU NCI NIH HHS [N01-CP-40548] NR 21 TC 35 Z9 37 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2002 VL 34 IS 12 BP 1551 EP 1557 DI 10.1086/340537 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 559CC UT WOS:000176006400002 PM 12032888 ER PT J AU Mutskov, VJ Farrell, CM Wade, PA Wolffe, AP Felsenfeld, G AF Mutskov, VJ Farrell, CM Wade, PA Wolffe, AP Felsenfeld, G TI The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation SO GENES & DEVELOPMENT LA English DT Article DE chromatin; histone acetylation; DNA methylation; insulator; methyl-binding domain (MBD) proteins; silencing ID DE-NOVO METHYLATION; BETA-GLOBIN LOCUS; CHROMATIN STRUCTURE; BINDING-PROTEINS; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; TRANSCRIPTION; COMPLEX; DEMETHYLATION; BOUNDARIES AB Stably integrated transgenes flanked by the chicken beta-globin HS4 insulator are protected against chromosomal position effects and gradual extinction of expression during long-term propagation in culture. To investigate the mechanism of action of this insulator, we used bisulfite genomic sequencing to examine the methylation of individual CpG sites within insulated transgenes, and compared this with patterns of histone acetylation. Surprisingly, although the histones of the entire insulated transgene are highly acetylated, only a specific region in the promoter, containing binding sites for erythroid-specific transcription factors, is highly protected from DNA methylation. This critical region is methylated in noninsulated and inactive lines. MBD3 and Mi-2, subunits of the Mi-2/NuRD repressor complex, are bound in vivo to these silenced noninsulated transgenes. In contrast, insulated cell lines do not show any enrichment of Mi-2/NuRD proteins very late in culture. In addition to the high levels of histone acetylation observed across the entire insulated transgene, significant peaks of H3 acetylation are present over the HS4 insulator elements. Targeted histone acetylation by the chicken beta-globin insulator occurs independently of gene transcription and does not require the presence of a functional enhancer. We suggest that this acetylation is in turn responsible for the maintenance of a region of unmethylated DNA over the promoter. Whereas DNA methylation often leads to histone deacetylation, here acetylation appears to prevent methylation. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 44 TC 135 Z9 139 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2002 VL 16 IS 12 BP 1540 EP 1554 DI 10.1101/gad.988502 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 566XJ UT WOS:000176453300010 PM 12080092 ER PT J AU McHugh, RS Shevach, EM AF McHugh, RS Shevach, EM TI Cutting edge: Depletion of CD4(+)CD25(+) regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HOMEOSTASIS; EXPANSION; GASTRITIS; COMPARTMENT; LYMPHOCYTES; ANTIBODY; INHIBIT AB Thymectomy of BALB/c mice on day 3 of life results in the development of autoimmune gastritis (AIG) due to the absence of CD4(+)CD25(+) regulatory T cells. However, depletion of CD4(+)CD25(+) T cells by treatment with anti-CD25 rarely resulted in AIG. Depletion was efficient, as transfer of splenocytes from depleted,mice induced AIG in nu/nu mice. One explanation for this result is that CD4(+)CD25(+) T cells upon transfer to nude recipients undergo lymphopenia-induced proliferation, providing a signal for T cell activation. Cotransfer of CD25(+) T cells did not inhibit initial proliferation but did suppress AIG. Surprisingly, immunization with the AIG target Ag, H/K ATPase, in IFA failed to induce disease in normal animals but induced severe AIG in CD25-depleted mice. These results demonstrate that second signals (nonspecific proliferation, TCR activation, or inflammation) are needed for induction of autoimmunity in the absence of CD25(+) regulatory T cells. C1 NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 11N311,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 238 Z9 246 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 JUN 15 PY 2002 VL 168 IS 12 BP 5979 EP 5983 PG 5 WC Immunology SC Immunology GA 561MT UT WOS:000176145300001 PM 12055202 ER PT J AU Scanga, CA Aliberti, J Jankovic, D Tilloy, F Bennouna, S Denkers, EY Medzhitov, R Sher, A AF Scanga, CA Aliberti, J Jankovic, D Tilloy, F Bennouna, S Denkers, EY Medzhitov, R Sher, A TI Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IFN-GAMMA; IMMUNE-RESPONSE; MICE; PROTEIN; INTERLEUKIN-12; INDUCTION; IL-1-BETA; LIPOPOLYSACCHARIDE; NEUTROPHILS; STIMULATION AB Host resistance to the intracellular protozoan Toxoplasma gondii is highly dependent on early IL-12 production by APC. We demonstrate here that both host resistance and T. gondii-induced IL-12 production are dramatically reduced in mice lacking the adaptor molecule MyD88, an important signaling element used by Toll-like receptor (TLR) family members. Infection of MyD88-deficient mice with T. gondii resulted in uncontrolled parasite replication and greatly reduced plasma IL-12 levels. Defective IL-12 responses to T. gondii Ags (soluble tachyzoite Ag (STAg)) were observed in MyD88(-/-) peritoneal macrophages, neutrophils, and splenic dendritic cells (DC). In contrast, DC from TLR2- or TLR4-deficient animals developed normal IL-12 responses to STAg. In vivo treatment with pertussis toxin abolished the residual IL-12 response displayed by STAg-stimulated DC from MyD88(-/-) mice. Taken together, these data suggest that the induction of IL-12 by T. gondii depends on a unique mechanism involving both MyD88 and G protein-coupled signaling pathways. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA. Howard Hughes Med Inst, New Haven, CT 06520 USA. Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. RP Scanga, CA (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6148,50 S Dr, Bethesda, MD 20892 USA. RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 31 TC 294 Z9 306 U1 1 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2002 VL 168 IS 12 BP 5997 EP 6001 PG 5 WC Immunology SC Immunology GA 561MT UT WOS:000176145300005 PM 12055206 ER PT J AU Hodge, DL Schill, WB Wang, JM Blanca, I Reynolds, DA Ortaldo, JR Young, HA AF Hodge, DL Schill, WB Wang, JM Blanca, I Reynolds, DA Ortaldo, JR Young, HA TI IL-2 and IL-12 alter NK cell responsiveness to IFN-gamma-inducible protein 10 by down-regulating CXCR3 expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; INTERFERON-GAMMA; GENE-EXPRESSION; CHEMOKINE RECEPTORS; CYTOKINE PRODUCTION; STIMULATORY FACTOR; LYMPHOCYTES; ACTIVATION; VIRUS; REPLICATION AB Cytokine treatment of NK cells results in alterations in multiple cellular responses that include cytotoxicity, cytokine production, proliferation, and chemotaxis. To understand the molecular mechanisms underlying these responses, microarray analysis was performed and the resulting gene expression patterns were compared between unstimulated, IL-2, IL-2 plus IL-12, and IL-2 plus IL-18-stimulated NK92 cells. RNase protection assays and RT-PCR confirmed microarray predictions for changes in mRNA expression for nine genes involved in cell cycle progression, signal transduction, transcriptional activation, and chemotaxis. Multiprobe RNase protection assay also detected changes in the expression of CCR2 mRNA, a gene that was not imprinted on the microarray. We subsequently expanded our search for other chemokine receptor genes absent from the microarray and found an IL-2- and IL-12-dependent decrease in CXCR3 receptor mRNA expression in NK92 cells. A detailed analysis of CXCR3 expression in primary NK cells revealed that an IL-2 and an IL-12 together significantly decreased the CXCR3 receptor mRNA and receptor surface expression by 6 and 24 h of treatment, respectively. This decrease in receptor expression was associated with a significant reduction in chemotaxis in the presence of IFN-gamma-inducible protein-10. The decline in CXCR3 mRNA was due to transcriptional and posttranscriptional mechanisms as the addition of actinomycin D to IL-2- and IL-12-treated NK92 slightly altered the half-life of the CXCR3 mRNA. Collectively, these data suggest that IL-2 and IL-12 directly affect NK cell migratory ability by rapid and direct down-regulation of chemokine receptor mRNA expression. C1 NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. US Geol Survey, Natl Fish Hlth Res Lab, Leetown Sci Ctr, Kearneysville, WV 25430 USA. RP Young, HA (reprint author), NCI, Expt Immunol Lab, Ctr Canc Res, Bldg 560,Room 31-23, Frederick, MD 21702 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NCI NIH HHS [N01-CO-12400] NR 37 TC 42 Z9 44 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 JUN 15 PY 2002 VL 168 IS 12 BP 6090 EP 6098 PG 9 WC Immunology SC Immunology GA 561MT UT WOS:000176145300018 PM 12055219 ER PT J AU Smeltz, RB Chen, J Ehrhardt, R Shevach, EM AF Smeltz, RB Chen, J Ehrhardt, R Shevach, EM TI Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN T-CELLS; HELPER CELL-TYPE-1 PHENOTYPE; TYPE-1 CYTOKINE RESPONSES; SELECTIVE EXPRESSION; FUNCTIONAL IL-18; CHAIN EXPRESSION; INTERLEUKIN-12; MICE; INFECTION; BALB/C AB Two key events occur during the differentiation of IFN-gamma-secreting Th1 cells: up-regulation of IL-12Rbeta2 and IL-12-driven upregulation of IL-18Ralpha. We previously demonstrated that IL-12-driven up-regulation of IL-18Ra expression is severely impaired in IFN-gamma(-/-) mice. However, it was unclear from these studies how IFN-gamma influenced IL-18Ralpha since IFN-gamma alone had no direct effect on IL-18Ra expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Ralpha/IL-12Rbeta2 was independent of IFN-gamma. However, in the presence of IL-4, IFN-gamma functions to limit the negative effects of IL-4 on both IL-18Ralpha and IL-12Rbeta2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18ralpha/IL-12Rbeta2 in an IFN-gamma-independent fashion. In the absence of both IL-12 and IL-4, IFN-gamma up-regulates IL-12beta2 expression and primes IFN-gamma-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Ra or the IL-12Rbeta2 and the capacity of these cells to produce IFN-gamma, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-gamma in regulation of IL-18Ralpha/IL-12Rbeta2 during both IL-12-dependent and IL12-independent Th1 differentiation. C1 NIAID, Immunol Lab, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, NIH, Hlth Res Scholars Program, Bethesda, MD 20814 USA. Bioseek, Burlingame, CA 94010 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, Cellular Immunol Sect, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 38 TC 54 Z9 57 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 JUN 15 PY 2002 VL 168 IS 12 BP 6165 EP 6172 PG 8 WC Immunology SC Immunology GA 561MT UT WOS:000176145300028 PM 12055229 ER PT J AU Alexander, J Oseroff, C Dahlberg, C Qin, MS Ishioka, G Beebe, M Fikes, J Newman, M Chesnut, RW Morton, PA Fok, K Appella, E Sette, A AF Alexander, J Oseroff, C Dahlberg, C Qin, MS Ishioka, G Beebe, M Fikes, J Newman, M Chesnut, RW Morton, PA Fok, K Appella, E Sette, A TI A decaepitope polypeptide primes for multiple CD8(+) IFN-gamma and Th lymphocyte responses: Evaluation of multiepitope polypeptides as a mode for vaccine delivery SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; RECOMBINANT SUBUNIT VACCINES; DENDRITIC CELLS; TRANSGENIC MICE; SURFACE-ANTIGEN; EXOGENOUS ANTIGEN; CTL EPITOPES; VIRUS ANKARA; DNA VACCINES AB Proteins are generally regarded as ineffective immunogens for CTL responses. We synthesized a 100-mer decaepitope polypeptide and tested its capacity to induce multiple CD8(+) IFN-gamma and Th lymphocyte (HTL) responses in HLA transgenic mice. Following a single immunization in the absence of adjuvant, significant IFN-gamma in vitro recall responses were detected for all epitopes included in the construct (six A2.1-, three All-restricted CTL epitopes, and one universal HTL epitope). Immunization with truncated forms of the decaepitope polypeptide was used to demonstrate that optimal immunogenicity was associated with a size of at least 30-40 residues (3-4 epitopes). Solubility analyses of the truncated constructs were used to identify a correlation between immunogenicity for IFN-gamma responses and the propensity of these constructs to form particulate aggregates. Although the decaepitope polypeptide and a pool of epitopes emulsified in IFA elicited similar levels of CD8(+) responses using fresh splenocytes, we found that the decaepitope polypeptide more effectively primed for in vitro recall CD8(+) T cell responses. Finally, immunogenicity comparisons were also made between the decaepitope polypeptide and a corresponding gene encoding the same polypeptide delivered by naked DNA immunization. Although naked DNA immunization induced somewhat greater direct ex vivo and in vitro recall responses 2 wk after a single immunization, only the polypeptide induced significant in vitro recall responses 6 wk following the priming immunization. These studies support further evaluation of multiepitope polypeptide vaccines for induction of CD8(+) IFN-gamma and HTL responses. C1 Epimmune, San Diego, CA 92121 USA. Pharmacia, St Louis, MO 63198 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Alexander, J (reprint author), Epimmune, 5820 Nancy Ridge Drive,Suite 100, San Diego, CA 92121 USA. FU NIAID NIH HHS [N01-AI-95362] NR 74 TC 45 Z9 48 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2002 VL 168 IS 12 BP 6189 EP 6198 PG 10 WC Immunology SC Immunology GA 561MT UT WOS:000176145300031 PM 12055232 ER PT J AU Faure, M Long, EO AF Faure, M Long, EO TI KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; TYROSINE-PHOSPHATASE 1C; IG-LIKE RECEPTORS; HLA-G EXPRESSION; HUMAN TROPHOBLASTS; CUTTING EDGE; ANTIGEN; RECRUITMENT; NKG2D; PHOSPHORYLATION AB KIR2DL4 (CD158d) is an unusual member of the killer cell Ig-like receptor family expressed in all NK cells and some T cells. KIR2DL4 activates the cytotoxicity of NK cells, despite the presence of an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic tail. The role of this ITIM on the activating function of KIR2DL4, and whether it can provide inhibitory signals, is not known. Mutated forms of KIR2DL4 were engineered that lacked either the tyrosine in the ITIM or an arginine-tyrosine motif in the transmembrane region that is required for the activation signal. The activity of the mutated KIR2DL4 molecules was tested in a redirected lysis assay. The ITIM was not necessary for activation of lysis by KIR2DL4. The activation signal of KIR2DL4 was sensitive to inhibition by another ITIM-containing receptor. The activation-deficient mutant of KIR2DL4 inhibited the signal delivered by the activating receptor CD16. In pull-down experiments with GST fusion proteins, the tyrosine-phosphorylated cytoplasmic tail of KIR2DL4 bound the Src homology 2-containing phosphatases 1 and 2, as did the tail of the inhibitory receptor KIR2DL1. Therefore, KIR2DL4 has inhibitory potential in addition to its activating function. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Drive, Rockville, MD 20852 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 44 TC 128 Z9 134 U1 2 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 JUN 15 PY 2002 VL 168 IS 12 BP 6208 EP 6214 PG 7 WC Immunology SC Immunology GA 561MT UT WOS:000176145300033 PM 12055234 ER PT J AU Dybul, M Bolan, R Condoluci, D Cox-Iyamu, R Redfield, R Hallahan, CW Folino, M Sathasivam, K Weisberg, M Andrews, M Hidalgo, B Vasquez, J Fauci, AS AF Dybul, M Bolan, R Condoluci, D Cox-Iyamu, R Redfield, R Hallahan, CW Folino, M Sathasivam, K Weisberg, M Andrews, M Hidalgo, B Vasquez, J Fauci, AS TI Evaluation of initial CD4(+) T cell counts in individuals with newly diagnosed human immunodeficiency virus infection, by sex and race, in urban settings SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; VIRAL LOAD; DISEASE PROGRESSION; DRUG-THERAPY; HIV; COMMUNITY; SURVIVAL AB The CD4(+) T cell count is an important determinant of disease stage and prognosis in human immunodeficiency virus (HIV)-infected individuals. This study evaluated the CD4(+) T cell counts in individuals at the time of diagnosis of HIV infection at 4 community clinics in large urban settings with relatively high frequencies of HIV infection. Of 2223 individuals, 57% and 36% had CD4(+) T cell counts, 350 and, 200 cells/mm(3), respectively, at the time of diagnosis. There were no clear differences by sex or race. Enhanced educational efforts regarding the importance of HIV testing for at-risk individuals across sex and race strata in community settings may be important for early identification of individuals with HIV infection. This in turn could impact efforts to reduce transmission, and it could impact the prognosis for patients who receive antiretroviral therapy. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. LA Gay & Lesbian Ctr, Lambda Med Grp, Jeffrey Goodman Special Care Program Clin, Los Angeles, CA USA. Garden State Infect Dis Associates Clin, Voorhees, NJ USA. Whitman Walker Clin, Washington, DC USA. RP Dybul, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-13, Bethesda, MD 20892 USA. NR 15 TC 58 Z9 60 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 JUN 15 PY 2002 VL 185 IS 12 BP 1818 EP 1821 DI 10.1086/340650 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 558AA UT WOS:000175940800020 PM 12085332 ER PT J AU Gerfen, CR Miyachi, S Paletzki, R Brown, P AF Gerfen, CR Miyachi, S Paletzki, R Brown, P TI D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; striatum; Parkinson's disease; gene regulation; signal transduction; MAP kinase; protein kinase ID ACTIVATED PROTEIN-KINASE; EARLY GENE-EXPRESSION; LONG-TERM-MEMORY; C-FOS; SIGNALING PATHWAY; BASAL GANGLIA; RAT STRIATUM; MAP KINASE; IN-VIVO; NEURONS AB Dopamine effects in the striatum are mediated principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons. After degeneration of the nigrostriatal dopamine system, direct pathway neurons display a supersensitive response to D1 dopamine receptor agonists, which is demonstrated by the induction of immediate early genes (IEGs), such as c-fos. Here we show, using analysis of receptor-mediated signal transduction, including protein phosphorylation and induction of IEGs, that D1 dopamine receptor supersensitivity is attributable to a switch to ERK1/2/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) in direct pathway neurons. Normally, in the dopamine-intact striatum, activation of ERK1/2/MAP kinase is shown to be restricted to indirect and not direct pathway neurons in response to stimulation of corticostriatal afferents. Moreover, in the dopamine-intact striatum, treatment with full D1 dopamine receptor agonists or stimulation of nigrostriatal dopaminergic afferents, both of which result in the induction of IEGs in direct striatal projection neurons, does not activate ERK1/2/MAP kinase. However, after degeneration of the nigrostriatal dopaminergic pathway, ERK1/2/MAP kinase is activated in direct pathway neurons in response to D1 dopamine receptor agonists either alone or when combined with stimulation of corticostriatal afferents. Inhibitors of MEK (MAP kinase kinase), which is responsible for phosphorylation of ERK1/2/MAP kinase, blocks D1 dopamine receptor agonist activation of ERK1/2/MAP kinase in the dopamine-depleted striatum, as well as the supersensitive induction of IEGs. These results demonstrate that dopamine input to the striatum maintains distinct forms of protein kinase-mediated gene regulation in the direct and indirect striatal projection neurons. C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Gerfen, CR (reprint author), Bldg 36,Room 2D-30,36 Convent Dr, Bethesda, MD 20892 USA. NR 41 TC 230 Z9 234 U1 1 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 15 PY 2002 VL 22 IS 12 BP 5042 EP 5054 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 564KE UT WOS:000176312900031 PM 12077200 ER PT J AU Coe, B Tomihara, K Matsuzawa, M Hikosaka, O AF Coe, B Tomihara, K Matsuzawa, M Hikosaka, O TI Visual and anticipatory bias in three cortical eye fields of the monkey during an adaptive decision-making task SO JOURNAL OF NEUROSCIENCE LA English DT Article DE frontal eye fields; supplementary eye fields; lateral intraparietal cortex; single-cell activity; attention; intention; decision making; free-choice task; saccade ID SUPPLEMENTARY MOTOR AREA; CONDITIONAL OCULOMOTOR ASSOCIATIONS; LATERAL INTRAPARIETAL AREA; DORSOLATERAL PREFRONTAL CORTEX; SACCADE-RELATED ACTIVITY; NEURONAL-ACTIVITY; PARIETAL CORTEX; RHESUS-MONKEYS; BEHAVIORAL ENHANCEMENT; SUPERIOR COLLICULUS AB To examine the role of three cortical eye fields during internally guided decision-making processes, we recorded neuronal activities in the frontal eye field (FEF), supplementary eye field (SEF), and lateral intraparietal cortex (LIP) using a free-choice delayed saccade task with two synchronized targets. Although the monkeys must perform the task in a time-locked manner, they were free to choose either the receptive field (RF) target or the nonreceptive field (nRF) target to receive reward. In all three areas we found neurons with stronger activation during trials when the monkey was going to make a saccade to the RF target (RF trials) than to the nRF target (nRF trials). Modulation occurred not only during target presentation (visual bias) but also before target presentation (anticipatory bias). The visual bias was evident as an attenuated visual response to the RF stimulus in nRF trials. The anticipatory bias, however, was seen as an enhancement of pretarget activity in the RF trials. We analyzed the activity during the 500 msec before target presentation and found that 22.5% of FEF and 31.3% of LIP neurons and 49.1% of SEF neurons showed higher activity during the RF trials. To more accurately determine when each neuron started to show preferential activity, we used a new inverse interspike interval analysis procedure. Our results suggest that although all three cortical eye fields reflect attentional and intentional aspects of sensorimotor processing, SEF plays an earlier and perhaps more cognitive role in internally guided decision-making processes for saccades. C1 Juntendo Univ, Sch Med, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. NR 76 TC 139 Z9 141 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 15 PY 2002 VL 22 IS 12 BP 5081 EP 5090 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 564KE UT WOS:000176312900034 PM 12077203 ER PT J AU Bernardini, N Roza, C Sauer, SK Gomeza, J Wess, J Reeh, PW AF Bernardini, N Roza, C Sauer, SK Gomeza, J Wess, J Reeh, PW TI Muscarinic M2 receptors on peripheral nerve endings: A molecular target of antinociception SO JOURNAL OF NEUROSCIENCE LA English DT Article DE primary afferents; cholinergic; desensitization; noxious heat; mechanosensitivity; M2 knock-out; M4 knockout; pain; analgesia ID DORSAL-ROOT GANGLIA; ISOLATED RAT SKIN; ACETYLCHOLINE-RECEPTORS; NOCICEPTIVE NEURONS; C-NOCICEPTORS; CLASSIFICATION; NEOSTIGMINE; EXPRESSION; SYNTHESIZE; ANALGESIA AB We recently described a novel endogenous mechanism of peripheral antinociception, possibly involving activation of muscarinic M2 acetylcholine receptors that are expressed on nociceptive nerve endings and decrease their sensitivity. In the present study, this mechanism was scrutinized in skin taken from mice with targeted deletions of the muscarinic M2 receptor gene and, for control purposes, of the M4 receptor gene. Two different approaches were taken. Electrophysiologically the effects of muscarine on nociceptive afferents were investigated using the mouse skin-saphenous nerve preparation, in vitro. Muscarine did not excite nociceptors in the wild-type litter-mates (WT) and M4 knock-out (M4 KO) mice, but almost all fibers exhibited marked desensitization to mechanical and heat stimuli. Surprisingly, in the M2 KO mice, muscarine was able to excite C-nociceptors and to induce a mild sensitization to heat but caused no alteration in mechanical responsiveness tested with von Frey hairs. In the second, neurochemical approach, the heat-induced cutaneous release of calcitonin gene-related peptide (CGRP) was investigated to gain comparative data on the neurosecretory (vasodilatory) functions of the primary afferent neurons. The substantial increase of CGRP release evoked by noxious heat (47degreesC) was diminished under muscarine by >50% in the WT and M4 KO animals but remained unaltered in the M2 KO mice. Together, these data provide direct evidence that M2 receptors on cutaneous nerve endings mediate effective depression of nociceptive responsiveness. This observation should be of interest for the development of novel classes of analgesic agents. C1 Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, D-91054 Erlangen, Germany. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Reeh, PW (reprint author), Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, Univ Str 17, D-91054 Erlangen, Germany. RI Reeh, Peter/J-8981-2012; Sauer, Susanne /K-1145-2012; Roza, Carolina/H-3992-2015 OI Reeh, Peter/0000-0002-4367-094X; Roza, Carolina/0000-0001-5757-9066 NR 29 TC 28 Z9 31 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 15 PY 2002 VL 22 IS 12 AR RC229 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 564KE UT WOS:000176312900002 PM 12045234 ER PT J AU Ariano, MA Aronin, N Difiglia, M Tagle, DA Sibley, DR Leavitt, BR Hayden, MR Levine, MS AF Ariano, MA Aronin, N Difiglia, M Tagle, DA Sibley, DR Leavitt, BR Hayden, MR Levine, MS TI Striatal neurochemical changes in transgenic models of Huntington's disease SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE Huntington's disease; dopamine receptors; cyclic AMP; striatal projection pathways; transgenic mice ID NEURONAL INTRANUCLEAR INCLUSIONS; DEPENDENT PROTEIN-KINASE; EXPANDED CAG REPEAT; ANTIRECEPTOR ANTISERA; CELLULAR-DISTRIBUTION; FUNCTIONAL-ANATOMY; MUTANT HUNTINGTIN; PREFERENTIAL LOSS; NMDA RECEPTORS; BASAL GANGLIA AB Transgenic mouse models of Huntington's disease (HD) were examined following the onset of overt behavioral symptoms. The HD transgenic mice demonstrated profound striatal losses in D1, D2, and D3 dopamine (DA) receptor proteins in comparison with their nonsymptomatic, age-matched littermate controls. In parallel, a robust increase in the striatal D5 DA receptor subtype occurred in the transgenic compared with the wild-type control mice. This receptor elevation was accompanied by heightened cyclic AMP levels, which may be induced by the adenylyl cyclase-linked D5 receptor. This is a unique result; normal striatal D5 protein levels are modest and not thought to contribute substantially to cyclic AMP-mediated DA signaling mechanisms. Simple compensatory up-regulation of D5 DA receptors in response to D1 receptor subtype loss does not explain our findings, because genetic inactivation of the D1 DA receptor does not alter levels of D5 DA receptor expression. Immunofluorescent detection of tyrosine hydroxylase showed that nigrostriatal DA containing terminals were reduced, further supporting that disturbances in DA signaling occurred in HD transgenic models. The substance P-containing striatal efferent pathway was more resistant to the HD mutation than met-enkephalin-producing striatal projection neurons in the transgenics, based on neuropeptide immunofluorescent staining. Analogous findings in multiple transgenic models suggest that these changes are due to the presence of the transgene and are not dependent on its composition, promotor elements, or mouse strain background. These findings suggest modifications in the striatal DA system and that its downstream signaling through cyclic AMP mechanisms is disrupted severely in HD following onset of motor symptoms. (C) 2002 Wiley-Liss, Inc. C1 CMS, FUHS, Dept Neurosci, N Chicago, IL 60064 USA. Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 1M9, Canada. NINCDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. MGH Harvard, Dept Neurol, Boston, MA USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. Univ Calif Los Angeles, Mental Retardat Res Ctr, Los Angeles, CA 90024 USA. RP Ariano, MA (reprint author), CMS, FUHS, Dept Neurosci, 3333 Green Bay Rd, N Chicago, IL 60064 USA. RI Leavitt, Blair/G-1934-2012; Hayden, Michael/D-8581-2011 OI Hayden, Michael/0000-0001-5159-1419 FU NINDS NIH HHS [NS33538] NR 54 TC 53 Z9 54 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 15 PY 2002 VL 68 IS 6 BP 716 EP 729 DI 10.1002/jnr.10272 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 559AU UT WOS:000176002600007 PM 12111832 ER PT J AU Lederman, RJ Mendelsohn, FO Anderson, RD Saucedo, JF Tenaglia, AN Hermiller, JB Hillegass, WB Rocha-Singh, K Moon, TE Whitehouse, MJ Annex, BH AF Lederman, RJ Mendelsohn, FO Anderson, RD Saucedo, JF Tenaglia, AN Hermiller, JB Hillegass, WB Rocha-Singh, K Moon, TE Whitehouse, MJ Annex, BH CA TRAFFIC Investigators TI Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial SO LANCET LA English DT Article ID PROPIONYL-L-CARNITINE; DOUBLE-BLIND TRIAL; ARTERIAL-DISEASE; HEART-DISEASE; PENTOXIFYLLINE; PHVEGF(165); MULTICENTER; CILOSTAZOL; INJECTION; ISCHEMIA AB Background Recombinant fibroblast growth factor-2 (rFGF-2) improves perfusion in models of myocardial and hindlimb ischaemia. We investigated whether one or two doses of intra-arterial rFGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. Methods 190 patients with intermittent claudication caused by infra-inguinal atherosclerosis were randomly assigned (1:1:1) bilateral intra-arterial infusions of placebo on days 1 and 30 (n=63); rFGF-2 (30 mug/kg) on day 1 and placebo on day 30 (single-dose, n=66); or rFGF-2 (30 mug/kg) on days I and 30 (double-dose, n=61). Primary outcome was 90-day change in peak walking time. Secondary outcomes included ankle-brachial pressure index and safety. The main analysis was per protocol. Findings Before 90 days, six patients had undergone peripheral revascularisation and were excluded, and ten withdrew or had missing data. 174 were therefore assessed for primary outcome. Peak walking time at 90 days was increased by 0.60 min with placebo, by 1.77 min with single-dose, and by 1.54 min with double-dose. By ANOVA, the difference between groups was p=0.075. In a secondary intention-to-treat analysis, in which all 190 patients were included, the difference was p=0.034. Pairwise comparison showed a significant difference between placebo and single-dose (p=0.026) but placebo and double-dose did not differ by much (p=0.45). Serious adverse events were similar in all groups. Interpretation Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion. The findings of TRAFFIC provide evidence of clinical therapeutic angiogenesis by intra-arterial infusion of an angiogenic protein. C1 Univ Michigan Hlth Syst, Div Cardiol, Ann Arbor, MI USA. Sarasota Mem Hosp, Sarasota, FL USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Tulane Univ, Med Ctr, New Orleans, LA USA. Nasser Smith & Pinckerton, Indianapolis, IN USA. Heart Grp, Evansville, IN USA. Prairie Cardiovasc Consultants, Springfield, IL USA. Chiron Corp, Emeryville, CA 94608 USA. Duke Univ, Durham, NC USA. Vet Affairs Med Ctr, Durham, NC USA. RP Lederman, RJ (reprint author), NHLBI, NIH, 10 Ctr Dr,Bldg 10,Room 2C713, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 NR 27 TC 301 Z9 320 U1 0 U2 8 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 15 PY 2002 VL 359 IS 9323 BP 2053 EP 2058 DI 10.1016/S0140-6736(02)08937-7 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 562JX UT WOS:000176194600005 PM 12086757 ER PT J AU Yu, EZ Hallenbeck, JM Cai, DC McCarron, RM AF Yu, EZ Hallenbeck, JM Cai, DC McCarron, RM TI Elevated arylalkylamine-N-acetyltransferase (AA-NAT) gene expression in medial habenular and suprachiasmatic nuclei of hibernating ground squirrels SO MOLECULAR BRAIN RESEARCH LA English DT Article DE epithalamus; extra-pineal; hibernation; hypothalamus; in situ hybridization; melatonin biosynthesis ID MESSENGER-RNA EXPRESSION; PINEAL-GLAND; BODY-TEMPERATURE; MAMMALIAN HIBERNATION; MELATONIN SYNTHESIS; CIRCADIAN-RHYTHMS; SERUM MELATONIN; GOLDEN-HAMSTERS; SYRIAN-HAMSTER; SEROTONIN AB Hibernation. an adaptive response for energy conservation in mammals, involves a variety of physiological changes. Melatonin is linked with the regulation of core body temperature and intervenes in generating circadian cycles; its role in seasonal (circannual) rhythms of hibernation is explored here. Melatonin is primarily produced in the pineal gland. Since arylalkylamine-N-acetyltransferase (AA-NAT) is the rate-limiting enzyme for synthesizing melatonin, AA-NAT gene expression was investigated to assess the possible role of melatonin in hibernation. The findings presented here utilized combined in situ hybridization and immunohistochemistry methodologies to evaluate the AA-NAT mRNA expression in brains of both hibernating and non-hibernating ground squirrels, Brains were examined for the expression of AA-NAT mRNA using a oligonucleotide AA-NAT probe: antibody against neurofilament-70 (NF-70) was used as a neuronal marker. All hibernating animals expressed significantly (P<0.01) elevated levels of AA-NAT mRNA in both the epithalamic medial habenulax nuclei (MHb) area and the hypothalamic suprachiasmatic nuclei (SCN), which is also known as the master biologic clock. These findings represent the first demonstration of the expression of mRNA encoding for AA-NAT in the extra-pineal (i.e. SCN and MHb) sites of thirteen-lined ground squirrels and indicate that the habenular nucleus may be an important supplementary location for melatonin biosynthesis. The data presented here indicate that AA-NAT gene is one of the few specific genes up-regulated during hibernation and suggest that elevation of its expression in SCN and MHb may play an essential role in the generation and maintenance of hibernation, Published by Elsevier Science B.V. C1 USN, Med Res Ctr, Resuscitat Med Dept, Silver Spring, MD 20910 USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP McCarron, RM (reprint author), USN, Med Res Ctr, Resuscitat Med Dept, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM McCarronR@nmrc.navy.mil NR 53 TC 23 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 15 PY 2002 VL 102 IS 1-2 BP 9 EP 17 AR PII S0169-328X(02)00138-9 DI 10.1016/S0169-328X(02)00138-9 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 570FQ UT WOS:000176648600002 ER PT J AU Wistow, G AF Wistow, G TI A project for ocular bioinformatics: NEIBank SO MOLECULAR VISION LA English DT Article ID GENE-EXPRESSION; PAX-6; LENS; CRYSTALLIN; SEQUENCES; REGION; INTRON; CELLS C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov NR 26 TC 33 Z9 33 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 JUN 15 PY 2002 VL 8 IS 21 BP 161 EP 163 PG 3 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300001 PM 12107408 ER PT J AU Wistow, G Berstein, SL Touchman, JW Bouffard, G Wyatt, MK Peterson, K Behal, A Gao, J Buchoff, P Smith, D AF Wistow, G Berstein, SL Touchman, JW Bouffard, G Wyatt, MK Peterson, K Behal, A Gao, J Buchoff, P Smith, D TI Grouping and identification of sequence tags (GRIST): Bioinformatics tools for the NEIBank database SO MOLECULAR VISION LA English DT Article ID HUMAN GENES; COLLECTION; PROTEINS; CDH23; 1D AB NEIBank is a project to develop and organize genomics and bioinformatics resources for the eye. As part of this effort, tools have been developed for bioinformatics analysis and web based display of data from expressed sequence tag (EST) analyses. EST sequences are identified and formed into groups or clusters representing related transcripts from the same gene. This is carried out by a rules-based procedure called GRIST (GRouping and Identification of Sequence Tags) that uses sequence match parameters derived from BLAST programs. Linked procedures are used to eliminate non-mRNA contaminants. All data are assembled in a relational database and assembled for display as web pages with annotations and links to other informatics resources. Genome projects generate huge amounts of data that need to be classified and organized to become easily accessible to the research community. GRIST provides a useful tool for assembling and displaying the results of EST analyses. The NEIBank web site contains a growing set of pages cataloging the known transcriptional repertoire of eye tissues, derived from new NEIBank cDNA libraries and from eye-related data deposited in the dbEST section of GenBank. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. NR 15 TC 22 Z9 23 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 JUN 15 PY 2002 VL 8 IS 21 BP 164 EP 170 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300002 PM 12107414 ER PT J AU Wistow, G Bernstein, SL Wyatt, MK Behal, A Touchman, J Bouffard, G Smith, D Peterson, K AF Wistow, G Bernstein, SL Wyatt, MK Behal, A Touchman, J Bouffard, G Smith, D Peterson, K TI Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: Over 6000 non-redundant transcripts, novel genes and splice variants SO MOLECULAR VISION LA English DT Review ID INTRINSIC MEMBRANE-PROTEIN; FIBER CELL-DIFFERENTIATION; LENS EPITHELIAL-CELLS; DNA-BINDING; BOVINE LENS; MOLECULAR-CLONING; ANTERIOR SEGMENT; CRYSTALLIN GENES; OXIDATIVE STRESS; INDUCED CATARACT AB Purpose: To explore the expression profile of the human lens and to provide a resource for microarray studies, expressed sequence tag (EST) analysis has been performed on cDNA libraries from adult lenses. Methods: A cDNA library was constructed from two adult (40 year old) human lenses. Over two thousand clones were sequenced from the unamplified, un-normalized library. The library was then normalized and a further 2200 sequences were obtained. All the data were analyzed using GRIST (GRouping and Identification of Sequence Tags), a procedure for gene identification and clustering. Results: The lens library (by) contains a low percentage of non-mRNA contaminants and a high fraction (over 75%) of apparently full length cDNA clones. Approximately 2000 reads from the unamplified library yields 810 clusters, potentially representing individual genes expressed in the lens. After normalization, the content of crystallins and other abundant cDNAs is markedly reduced and a similar number of reads from this library (fs) yields 1455 unique groups of which only two thirds correspond to named genes in GenBank. Among the most abundant cDNAs is one for a novel gene related to glutamine synthetase, which was designated "lengsin" (LGS). Analyses of ESTs also reveal examples of alternative transcripts, including a major alternative splice form for the lens specific membrane protein MP19. Variant forms for other transcripts, including those encoding the apoptosis inhibitor Livin and the armadillo repeat protein ARVCF, are also described. Conclusions: The lens cDNA libraries are a resource for gene discovery, full length cDNAs for functional studies and microarrays. The discovery of an abundant, novel transcript, lengsin, and a major novel splice form of MP19 reflect the utility of unamplified libraries constructed from dissected tissue. Many novel transcripts and splice forms are represented, some of which may be candidates for genetic diseases. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. NIH, Intramural Sequencing Ctr, Gaithersburg, MD USA. RP NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov NR 114 TC 71 Z9 77 U1 0 U2 4 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 15 PY 2002 VL 8 IS 21 BP 171 EP 184 PG 14 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300003 PM 12107413 ER PT J AU Wistow, G Berstein, SL Ray, S Wyatt, MK Behal, A Touchman, JW Bouffard, G Smith, D Peterson, K AF Wistow, G Berstein, SL Ray, S Wyatt, MK Behal, A Touchman, JW Bouffard, G Smith, D Peterson, K TI Expressed sequence tag analysis of adult human iris for the NEIBank Project: Steroid-response factors and similarities with retinal pigment epithelium SO MOLECULAR VISION LA English DT Article ID LEUCINE-ZIPPER PROTEINS; GTP-BINDING PROTEINS; OPEN-ANGLE GLAUCOMA; NEURAL CREST CELLS; GROWTH-FACTOR; CILIARY BODY; MOLECULAR-CLONING; GENE-EXPRESSION; AQUEOUS-HUMOR; IDENTIFICATION AB Purpose: The iris is a specialized tissue with important roles in the development and function of the eye. It is involved in diseases, including glaucoma and ocular melanoma, and its pigmented cells share an origin with the retinal pigment epithelium (RPE). Expressed sequence tag (EST) analysis of human iris has been performed to explore the repertoire of genes expressed in this tissue. Methods: An unamplified, un-normalized cDNA library (designated bx) was constructed from pooled (4-80 years old) human iris tissue. Over 2000 clones were picked and sequenced. Sequences were analyzed and clustered using GRIST (GRouping and Identification of Sequence Tags). The library was then normalized (and designated fg) and a further 2200 clones were sequenced for deeper examination of rarer sequence. Some sequences of interest were investigated further by standard methods. Results: From bx and fg libraries respectively, 1263 and 1604 clusters of expressed genes have been identified, giving a combined total of almost 2700 potentially unique genes. The most abundant novel transcript in bx is oculoglycan/opticin. Others include glucocorticoid induced leucine zipper protein (GILZ), Ris, a novel member of the Ras family, Iris Ring Finger (IRF), a member of the midline family, melastatin 2 (MLSN2), a member of the transient receptor potential calcium channel family, and iris expressed growth factor (IEGF), a member of the VEGF/PDGF family. Several factors involved in steroid responses are also represented. Conclusions: The iris libraries are a rich source of novel as well as known genes, including molecular markers for pigmented cells that are also shared with RPE. A number of transcripts code for proteins involved in steroid response, with interesting implications for control of intraocular pressure. These sequence verified clones provide a nonredundant set for micro-array construction. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. NIH, Intramural Sequencing Ctr, Gaithersburg, MD USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. NR 65 TC 34 Z9 38 U1 0 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 15 PY 2002 VL 8 IS 21 BP 185 EP 195 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300004 PM 12107412 ER PT J AU Wistow, G Berstein, SL Wyatt, MK Ray, S Behal, A Touchman, JW Bouffard, G Smith, D Peterson, K AF Wistow, G Berstein, SL Wyatt, MK Ray, S Behal, A Touchman, JW Bouffard, G Smith, D Peterson, K TI Expressed sequence tag analysis of human retina for the NEIBank Project: Retbindin, an abundant, novel retinal cDNA and alternative splicing of other retina-preferred gene transcripts SO MOLECULAR VISION LA English DT Article ID SYNDROME TYPE 1D; USHER-SYNDROME; MOLECULAR-GENETICS; C-MAF; DEGENERATION; NRL; DIFFERENTIATION; CRYSTALLIN; MUTATION; CADHERIN AB Purpose: Expressed sequence tag (EST) analysis was performed on un-normalized, unamplified cDNA libraries constructed from adult human retina to examine the expression profile of the tissue and to contribute resources for functional genomics studies. Methods: Two size fractionated cDNA libraries (designated hd and he) were constructed from human retina RNA. Clones were randomly selected for sequencing and analyzed using the bioinformatics program GRIST (GRouping and Identification of Sequence Tags). PCR, Northern blotting and other techniques have been used to examine selected novel transcripts. Results: After informatics analysis, 2200 retina cDNAs yield 1254 unique clusters, potentially representing individual genes. Opsin is the most abundant transcript and other retina transcripts are prominently represented. One abundant cluster of cDNAs encodes retbindin, a novel, retina preferred transcript which has sequence similarity to riboflavin binding proteins and whose gene is on chromosome 19. Variant transcripts of known retina genes are also observed, including an alternative exon in the coding sequence of the transcription factor NRL and a skipped coding sequence exon in the phosphodiesterase gammasubunit (PDE6G). Conclusions: The new retina cDNA libraries compare favorably in quality with those already represented in public databases. They are rich in retina specific sequences and include abundant cDNAs for a novel protein, retbindin. The function of retbindin remains to be determined, but it is a candidate for flavinoid or carotenoid binding. Analysis of multiple clones for highly expressed retina genes reveals several alternative splice variants in both coding and noncoding sequences which may have functional significance. The validated set of retina cDNAs will contribute to a nonredundant set for microarray construction. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. NIH, Intramural Sequencing Ctr, Gaithersburg, MD USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. NR 45 TC 48 Z9 54 U1 0 U2 4 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 15 PY 2002 VL 8 IS 21 BP 196 EP 204 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300005 PM 12107411 ER PT J AU Wistow, G Berstein, SL Wyatt, MK Farriss, RN Behal, A Touchman, J Bouffard, G Smith, D Peterson, K AF Wistow, G Berstein, SL Wyatt, MK Farriss, RN Behal, A Touchman, J Bouffard, G Smith, D Peterson, K TI Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: Over 6000 non-redundant transcripts, novel genes and splice variants SO MOLECULAR VISION LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; DOMINANT RETINITIS-PIGMENTOSA; REPEAT PROTEIN FAMILY; MACULAR DEGENERATION; MOLECULAR-CLONING; MESSENGER-RNA; GLUTAMINE-SYNTHETASE; CONGENITAL AMAUROSIS; TIGHT JUNCTIONS; IN-VITRO AB Purpose: The retinal pigment epithelium (RPE) and choroid comprise a functional unit of the eye that is essential to normal retinal health and function. Here we describe expressed sequence tag (EST) analysis of human RPE/choroid as part of a project for ocular bioinformatics. Methods: A cDNA library (cs) was made from human RPE/choroid and sequenced. Data were analyzed and assembled using the program GRIST (GRouping and Identification of Sequence Tags). Complete sequencing, Northern and Western blots, RH mapping, peptide antibody synthesis and immunofluorescence (IF) have been used to examine expression patterns and genome location for selected transcripts and proteins. Results: Ten thousand individual sequence reads yield over 6300 unique gene clusters of which almost half have no matches with named genes. One of the most abundant transcripts is from a gene (named "alpha") that maps to the BBS1 region of chromosome 11. A number of tissue preferred transcripts are common to both RPE/choroid and iris. These include oculoglycan/opticin, for which an alternative splice form is detected in RPE/choroid, and "oculospanin" (Ocsp), a novel tetraspanin that maps to chromosome 17q. Antiserum to Ocsp detects expression in RPE, iris, ciliary body, and retinal ganglion cells by IF. A newly identified gene for a zinc-finger protein (TIRC) maps to 19q13.4. Variant transcripts of several genes were also detected. Most notably, the predominant form of Bestrophin represented in cscontains a longer open reading frame as a result of splice junction skipping. Conclusions: The unamplified cs library gives a view of the transcriptional repertoire of the adult RPE/choroid. A large number of potentially novel genes and splice forms and candidates for genetic diseases are revealed. Clones from this collection are being included in a large, nonredundant set for cDNA microarray construction. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Neurobiol & Genet, Baltimore, MD 21201 USA. NIH, Intramural Sequencing Ctr, Gaithersburg, MD USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Room 331, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov NR 98 TC 57 Z9 63 U1 0 U2 3 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 15 PY 2002 VL 8 IS 21 BP 205 EP 220 PG 16 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 571EF UT WOS:000176701300006 PM 12107410 ER PT J AU Groll, AH Walsh, TJ AF Groll, AH Walsh, TJ TI Antifungal chemotherapy: advances and perspectives SO SWISS MEDICAL WEEKLY LA English DT Review DE mycoses; antifungal agents; treatment; prevention ID INVASIVE FUNGAL-INFECTIONS; LIPOSOMAL AMPHOTERICIN-B; BONE-MARROW TRANSPLANTATION; PLACEBO-CONTROLLED TRIAL; STEM-CELL TRANSPLANTATION; DOUBLE-BLIND; PULMONARY ASPERGILLOSIS; NEUTROPENIC PATIENTS; FLUCONAZOLE PROPHYLAXIS; IMMUNOCOMPROMISED PATIENTS AB Invasive fungal infections have emerged as important causes of morbidity and mortality in immunocompromised patients. In response to this challenge, the field of antifungal chemotherapy has considerably expanded. Fluconazole and itraconazole, introduced in the late 1980s, were the first durably useful alternatives to amphotericin B deoxycholate. The clinical development of the lipid formulations of amphotericin B, and, more recently, that of novel echinocandin derivatives and improved antifungal triazoles each represent milestones in antifungal drug research that have further amplified our therapeutic options. Major progress has been made in harmonising disease definitions, in defining the paradigms of antifungal intervention, and in designing and implementing clinical trials. Standardised methods for in vitro susceptibility testing of yeasts and filamentous fungi have become available, and pharmacodynamic concepts have entered preclinical and clinical drug development. This article reviews the evolution of therapeutic options over the past decade, advances in chemoprevention and empirical antifungal therapy, progress in early diagnosis and pre-emptive therapy, the promise of the new echinocandins and second generation triazoles, as well as perspectives for combination therapies and,adjuvant immunoreconstitution. Invasive fungal infections will remain a frequent and important complication of modem medicine; the current momentum in the field of laboratory and clinical antifungal drug research provides hope for substantial progress in prevention and management of these life-threatening infections in the near future. C1 Univ Munster, Ctr Med, Ctr Bone Marrow Transplanat, Dept Pediat Haematol Oncol, D-48129 Munster, Germany. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Groll, AH (reprint author), Univ Munster, Ctr Med, Ctr Bone Marrow Transplanat, Dept Pediat Haematol Oncol, Domagkstr 9A, D-48129 Munster, Germany. NR 102 TC 53 Z9 60 U1 0 U2 1 PU E M H SWISS MEDICAL PUBLISHERS LTD PI BASEL PA STEINENTORSTRASSE 13, CH-4-10 BASEL, SWITZERLAND SN 1424-7860 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD JUN 15 PY 2002 VL 132 IS 23-24 BP 303 EP 311 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 600VP UT WOS:000178412700002 PM 12362280 ER PT J AU Cadet, JL McCoy, MT Ladenheim, B AF Cadet, JL McCoy, MT Ladenheim, B TI Distinct gene expression signatures in the striata of wild-type and heterozygous c-fos knockout mice following methamphetamine administration: Evidence from cDNA array analyses SO SYNAPSE LA English DT Article DE methamphetamine; neurotoxicity; c-fos mutant; cDNA array; DNA repair ID BASE-EXCISION-REPAIR; DNA-POLYMERASE-BETA; DISMUTASE TRANSGENIC MICE; SUPEROXIDE-DISMUTASE; APURINIC/APYRIMIDINIC ENDONUCLEASE; DAMAGING AGENTS; MISMATCH REPAIR; NULL MUTATION; APURINIC ENDONUCLEASE; INDUCED NEUROTOXICITY AB Methamphetamine (METH) is a drug of abuse which can cause apoptosis and degeneration of monoaminergic terminals in the mammalian brain. c-fos appears to play a protective role against METH-induced damage because METH toxicity is exacerbated in c-fos heterozygous knockout mice. In the present study, we used the comprehensive technique of cDNA array to test the idea that heterozygous c-fos knockout mice might show differential METH-induced molecular responses in comparison to wild-type (WT) animals. Of 1,176 genes examined, the expression of 195 genes in either of the two groups of mice was affected by at least 2-fold at 2 or 12 h after METH treatment. More genes were either up- or downregulated in the WT mice. Moreover, there were substantial differences in the pattern of responses between the two genotypes, with more genes involved in DNA repair and protective processes being upregulated in WT mice after METH administration. These results support the idea that the c-fos knockout genotype may render the animals unable to trigger multicomponent responses in order to protect against the multifaceted toxic effects of this illicit neurotoxin. (C) 2002 Wiley-Liss, Inc. C1 NIA, Mol Neuropsychiat Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIA, Mol Neuropsychiat Sect, NIH, Intramural Res Program, POB 5160, Baltimore, MD 21224 USA. NR 56 TC 22 Z9 22 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 0887-4476 J9 SYNAPSE JI Synapse PD JUN 15 PY 2002 VL 44 IS 4 BP 211 EP 226 DI 10.1002/syn.10074 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 546ZF UT WOS:000175306600002 PM 11984857 ER PT J AU Parham, FM Matthews, HB Portier, CJ AF Parham, FM Matthews, HB Portier, CJ TI A physiologically based pharmacokinetic model of p,p '-dichlorodiphenylsulfone SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE physiologically based pharmacokinetic model; PBPK; DDS; dichlorodiphenylsulfone ID CHLORINATED BIPHENYLS; RATS; DISPOSITION; ABSORPTION; TCDD AB A physiologically based pharmacokinetic model of the absorption, distribution, metabolism, and elimination of p,p'-dichlorodiphenylsulfone (DDS) in male and female rats and mice is presented. Data used in constructing the model come from single-dose intravenous administration of DDS to male Fischer 344 rats (10 mg/kg, with data taken up to 504 h after administration), from single-dose gavage administration to male rats (10, 100, or 1000 mg/kg, with data up to 72 h after administration), and from chronic feed studies in male and female rats and male and female B6C3F(1) mice (studies of duration from 2 weeks up to 18 months, with feed concentrations of DDS up to 300 ppm). The model uses diffusion-limited kinetic for the distribution of the parent compound. Because fewer data are available for the metabolites of DDS (at least five of which are known to exist in the data), the model groups the metabolites into one metabolic pathway and uses simpler flow-limited kinetics for the metabolites. The data show that the kinetics of DDS are nonlinear. Possible sources of nonlinearity considered in the model were nonlinear (Michaelis-Menten) metabolism, nonlinear absorption of DDS from the gut, and induction by DDS of its own metabolism. A model using Michaelis-Menten metabolism was not found to give a significantly better fit than one using first-order linear metabolism, but omitting either of the other nonlinear effects was found to give a significantly poorer fit to the data. Because the data from mice are limited compared to those from rats, there is more confidence in the model's description of DDS kinetics in rats than in its description of kinetics in mice. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Parham, FM (reprint author), NIEHS, POB 12233,MD A3-06, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 21 TC 8 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2002 VL 181 IS 3 BP 153 EP 163 DI 10.1006/taap.2002.9410 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 568KD UT WOS:000176540200001 PM 12079424 ER PT J AU Guo, TL White, KL Brown, RD Delclos, KB Newbold, RR Weis, C Germolec, DR McCay, JA AF Guo, TL White, KL Brown, RD Delclos, KB Newbold, RR Weis, C Germolec, DR McCay, JA TI Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F-0 and F-1 generations of Sprague-Dawley rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE genistein; developmental immunotoxicity; NK cell activity; antibody-forming cell responses ID IN-VITRO; SOYBEAN ISOFLAVONES; PHYTO-ESTROGENS; MAMMARY-CANCER; MELANOMA-CELLS; EXPOSURE; DAIDZEIN; MICE; PHYTOESTROGENS; INHIBITION AB The potential effects of the phytoestrogen genistein (GEN) on the immune system were evaluated in both F, (dams) and F, generations of Sprague-Dawley rats exposed to a soy-free diet containing low (L: 25 ppm), middle (M: 250 ppm), and high (H: 1250 ppm) levels of GEN. In dams, exposure to GEN from Gestation Day 7 to Postpartum Day 51 (totally 65 days) produced a significant increase in NK cell activity (M and H), while a decrease in the percentage of helper T cells (H). In F, males, exposure to GEN gestationally, lactationally, and through feed from Postnatal Days 22 to 64 (total 78 days) produced an increase in the relative weights (% body) of spleen (L and H) and thymus (L). Furthermore, exposure to GEN increased the number of splenic B cells (H), T cells (L, M, and H), and T-cell subsets (L, M, and H). Although GEN decreased the percentages of splenic NK cells (L, M, and H), no effect on the activity of NK cells was observed. In F, females, exposure to GEN produced a decrease in terminal body weight (H), with an increase in the relative weight of spleen (L, M, and 11). Exposure to GEN also increased the number of splenic B cells (L), macrophages (L and M), T cells (H), helper T cells (L and H), and cytotoxic T cells (M and H). Additionally, exposure to GEN increased the percentages of T cells (M and H), helper T cells (H), and cytotoxic T cells (M and H). Moreover, the spleen IgM antibody-forming cell response to sheep red blood cells was enhanced (H), although the percentages of B cells were decreased (M and H). No effect on the activity of NK cells was observed; however, the percentages of splenic NK cells were decreased by GEN (L and H). In conclusion, these results demonstrate that exposure to GEN can modulate the immune responses in Sprague-Dawley rats. Furthermore, the sexual dimorphic effects of GEN in F-1 male and female rats suggest that there may be interactions between GEN and the responses modulated by sex hormones. (C) 2002 Elsevier Science (USA). C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP White, KL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, POB 980613, Richmond, VA 23298 USA. FU NIEHS NIH HHS [ES 55094] NR 40 TC 43 Z9 47 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 JUN 15 PY 2002 VL 181 IS 3 BP 219 EP 227 DI 10.1006/taap.2002.9418 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 568KD UT WOS:000176540200008 PM 12079431 ER PT J AU Gondois-Rey, F Grivel, JC Biancotto, A Pion, M Vigne, R Margolis, LB Hirsch, I AF Gondois-Rey, F Grivel, JC Biancotto, A Pion, M Vigne, R Margolis, LB Hirsch, I TI Segregation of R5 and X4 HIV-1 variants to memory T cell subsets differentially expressing CD62L in ex vivo infected human lymphoid tissue SO AIDS LA English DT Article DE CD62L-selectin; HIV-1 persistent infection; lymphoid tissue; memory T cells; pathogenesis; receptor; virus-cell interaction ID HUMAN-IMMUNODEFICIENCY-VIRUS; MOLECULAR CLONE; LYMPHOCYTES; HISTOCULTURES; REPLICATION; PHENOTYPE; DEPLETION; TYPE-1 AB Objective: The mechanisms of HIV-triggered immunodeficiency were examined by determining the segregation of R5 and X4 HIV-1 variants into memory T cell subsets expressing differentially a homing receptor, CD62L-selectin, in human lymphoid tissue. Methods: Subpopulations of CD3 and intracellular p24 gag-positive cells in human lymphoid tissue infected ex vivo with X4 HIV-1 variant NL4-3 and R5 HIV-1 variant AD8 were analysed for expression of the T cell memory markers CD45RO and CD45RA, the T cell homing receptor for lymphoid tissue CD62L, and the HIV-1 coreceptors CCR5 and CXCR4. Results: Memory CD4 T cells were the predominant targets for productive infection of lymphoid tissue ex vivo with both R5 and X4 HIV-1. R5 HIV-1 predominantly infected CD62L-negative memory T cells, which selectively express CCR5. In contrast, X4 HIV-1 variants predominantly infected CD62L+ memory T cells, although CXCR4 coreceptor was equally expressed by memory T cells of both CD62L-positive and CD62L-negative subsets. A high proportion of X4 HIV-1, but not of R5 HIV-1, productively infected T cells, displayed a CD45RA+CD45RO+ phenotype. Conclusion: The selective expression of the CCR5 coreceptor by CD62L-negative terminally differentiated memory T cells correlates with the preferential productive infection of these cells with the R5 HIV-1 variant. The predominance of X4 HIV-1 variants in less-differentiated memory T cells may be related to their recent activation state, as suggested by the coexpression of both CD45RA and CD45RO molecules on their surface. Differential homing of CD62L-positive and CD62L-negative cells suggests different routes of dissemination of X4 and R5 viruses. (C) 2002 Lippincott Williams Wilkins. C1 INSERM, Lab Pathogenie Infect Lentivirus, U372, Unite Pathogene Infect Lentivirus, F-13276 Marseille 9, France. NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. RP Hirsch, I (reprint author), INSERM, Lab Pathogenie Infect Lentivirus, U372, Unite Pathogene Infect Lentivirus, 163 Ave Luminy,BP 178, F-13276 Marseille 9, France. RI Pion, Marjorie/D-8139-2012; Hirsch, Ivan/J-7726-2015; OI Pion, Marjorie/0000-0002-6406-747X; Hirsch, Ivan/0000-0003-1701-1438 NR 20 TC 20 Z9 20 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 JUN 14 PY 2002 VL 16 IS 9 BP 1245 EP 1249 DI 10.1097/00002030-200206140-00006 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 565KR UT WOS:000176369600008 PM 12045489 ER PT J AU O'Hanlon, TP Miller, FW AF O'Hanlon, TP Miller, FW TI Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE histidyl-tRNA synthetase; transcript mapping; genomic structure; HARS; HARSL ID TRANSFER-RNA-SYNTHETASE; LOCALIZATION; EXPRESSION; CONTAINS; MYOSITIS; MAMMALS; EPITOPE; ENCODES; MOTIF AB Histidyl-tRNA synthetase catalyses the covalent ligation of histidine to its cognate tRNA as an early step in protein biosynthesis. In humans, the histidyl-tRNA synthetase gene (HARS) is oriented opposite of a synthetase-like gene (HARSL) that bears striking homology to HARS. In this report, we describe the genomic organization of the HARS/HARSL locus and map multiple transcripts originating from a bi-directional promoter controlling the differential expression of these genes. The HARS and HARSL genes each contain 13 exons with strong structural and sequence homology over exons 3-12. HARS transcripts originate from two distinct promoters; a cluster of short transcripts map 15-65 bp upstream of the HARS ORF while a single, longer transcript (352 bp 5'-UTR) maps to a distal promoter. Similarly, multiple HARSL transcripts (mapping 10-198 bp upstream of its ORF) are produced by the shared bi-directional promoter. Human and rodent HARS/HARSL loci are homologous and support a model of inverted gene duplication to explain the emergence of HARSL during mammalian evolution. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD 20892 USA. RP O'Hanlon, TP (reprint author), NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD 20892 USA. OI Miller, Frederick/0000-0003-2831-9593 NR 26 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 14 PY 2002 VL 294 IS 3 BP 609 EP 614 AR PII S0006-291X(02)00525-9 DI 10.1016/S0006-291X(02)00525-9 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 565HW UT WOS:000176364700016 PM 12056811 ER PT J AU Kanungo, J AF Kanungo, J TI Prolonged incubation in seawater induces a DNA-dependent protein phosphorylation activity in Arbacia punctulata eggs SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE egg activation; DNA-inducible kinase; early development ID KINASE-ACTIVITY; FERTILIZATION; EXTRACTS; EMBRYOS AB Various protein kinases are activated in eggs in response to fertilization. We have previously shown that the induction of DNA-dependent protein phosphorylation activity in the sea urchin eggs is triggered by fertilization. The present study demonstrates that the activation of a DNA-dependent serine/threonine kinase in unfertilized eggs of Arbacia punctulata can be achieved without fertilization. Prolonged incubation in seawater resulted in the activation of the eggs with concomitant induction of DNA-dependent protein phosphorylation activity. The activated eggs when fertilized show a slight increase in the phosphorylation activity 10-min post-insemination. The activity gradually declines as the first and second cleavages proceed. The cytoplasmic extracts of the blastulae, gastrulae, and plutei lack the enzyme activity. These findings reveal that not only fertilization but also egg activation serves as a signal for the induction of a DNA-dependent protein phosphorylation activity in sea urchin eggs suggesting that spermentry is not required for the induction of the enzyme activity. Published by Elsevier Science (USA). C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kanungo, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 15 TC 2 Z9 2 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 JUN 14 PY 2002 VL 294 IS 3 BP 667 EP 671 AR PII S0006-291X(02)00539-9 DI 10.1016/S0006-291X(02)00539-9 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 565HW UT WOS:000176364700026 PM 12056821 ER PT J AU Trebak, M Bird, GSJ McKay, RR Putney, JW AF Trebak, M Bird, GSJ McKay, RR Putney, JW TI Comparison of human TRPC3 channels in receptor-activated and store-operated modes - Differential sensitivity to channel blockers suggests fundamental differences in channel composition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE CELLS; INOSITOL TRISPHOSPHATE RECEPTOR; CAPACITATIVE CALCIUM-ENTRY; STIMULATES CA2+ INFLUX; 2-AMINOETHOXYDIPHENYL BORATE; ENDOTHELIAL-CELLS; CATION CHANNELS; HTRP3 CHANNELS; DEPLETION; RELEASE AB Capacitative calcium entry or store-operated calcium entry in nonexcitable cells is a process whereby the activation of calcium influx across the plasma membrane is signaled by depletion of intracellular calcium stores. Transient receptor potential (TRP) proteins have been proposed as candidates for store-operated calcium channels. Human TRPC3 (hTRPC3), an extensively studied member of the TRP family, is activated through a phospholipase C-dependent mechanism, not by store depletion, when expressed in HEK293 cells. However, store depletion by thapsigargin is sufficient to activate hTRPC3 channels when expressed in DT40 avian B-lymphocytes. To gain further insights into the differences between hTRPC3 channels generated in these two expression systems and further understand the role of hTRPC3 in capacitative calcium entry, we examined the effect of two well characterized inhibitors of capacitative calcium entry, Gd3+ and 2-aminoethoxydiphenyl borane (2APB). We confirmed that in both DT40 cells and HEK293 cells, 1 muM Gd3+ or 30 mum 2APB completely blocked calcium entry due to receptor activation or store depletion. In HEK293 cells, 1 mum Gd3+ did not block receptor-activated hTRPC3-mediated cation entry, whereas 2APB had a partial (similar to60%) inhibitory effect. Interestingly, store-operated hTRPC3-mediated cation entry in DT40 cells was also partially inhibited by 2APB, whereas 1 mum Gd3+ completely blocked store-operated hTRPC3 activity in these cells. Furthermore, the sensitivity of store-operated hTRPC3 channels to Gd3+ in DT40 cells was similar to the endogenous store-operated channels, with essentially 100% block of activity at concentrations as low as 0.1 mum. Finally, Gd3+ has a rapid inhibitory effect when added to fully developed hTRPC3-mediated calcium entry, suggesting a direct action of Gd3+ on hTRPC3 channels. The distinct action of these inhibitors on hTRPC3-mediated cation entry in these two cell types may result from their different modes of activation and may also reflect differences in basic channel structure. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Trebak, M (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,MD F2-02, Res Triangle Pk, NC 27709 USA. RI Trebak, Mohamed/E-7405-2014 NR 41 TC 170 Z9 179 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 14 PY 2002 VL 277 IS 24 BP 21617 EP 21623 DI 10.1074/jbc.M202549200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000067 PM 11943785 ER PT J AU Szaszak, M Gaborik, Z Turu, G McPherson, PS Clark, AJL Catt, KJ Hunyady, L AF Szaszak, M Gaborik, Z Turu, G McPherson, PS Clark, AJL Catt, KJ Hunyady, L TI Role of the proline-rich domain of dynamin-2 and its interactions with Src homology 3 domains during endocytosis of the AT(1) angiotensin receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; PROTEIN-COUPLED RECEPTORS; SIGNAL-TRANSDUCTION; BETA-ARRESTIN; SH3 DOMAIN; VESICLE FORMATION; BINDING PARTNERS; COATED PITS; AMPHIPHYSIN; INTERNALIZATION AB In nonneural tissues, the dynamin-2 isoform. participates in the formation of clathrin-coated vesicles during receptor endocytosis. In this study, the mechanism of dynamin-2 action was explored during endocytosis of the G protein-coupled AT(1A) angiotensin receptor expressed in Chinese hamster ovary cells. Dynamin-2 molecules with mutant pleckstrin homology domains or deleted proline-rich domains (PRD) exerted dominant negative inhibition on the endocytosis of radiolabeled angiotensin II. However, only the PRD mutation interfered with the localization of the dynamin-2 molecule to clathrin-coated pits and reduced the inhibitory effect of the GTPase-deficient K44A mutant dynamin-2. Green fluorescent protein-tagged Src homology 3 (SH3) domains of endophilin I and amphiphysin II, two major binding partners of dynamins, also inhibited AT(1A) receptor-mediated endocytosis of angiotensin II. These effects were partially or fully, respectively, restored by the overexpression of dynamin-2. Transient overexpression of these SH3 domains also reduced the localization of dynamin-2 to clathrin-coated pits. These data indicate that, similar to the recruitment of dynamin-1 during the recycling of synaptic vesicles, interaction of the dynamin-2 PRD with SH3 domains of proteins such as the amphiphysins and endophilins is essential for AT(1A) receptor endocytosis. This mechanism could be of general importance in dynamin-dependent endocytosis of other G protein-coupled receptors in nonneural tissues. C1 Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest 8, Hungary. McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. Univ London, Queen Mary, Barts & London, Dept Endocrinol, London EC1A 7BE, England. NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, PBO 259, H-1444 Budapest 8, Hungary. EM Hunyady@puskin.sote.hu RI Szaszak, Marta/G-7957-2011; OI Turu, Gabor/0000-0002-4421-3812 NR 64 TC 22 Z9 22 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 JUN 14 PY 2002 VL 277 IS 24 BP 21650 EP 21656 DI 10.1074/jbc.M200778200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000072 PM 11925437 ER PT J AU Pedersen, LC Darden, TA Negishi, M AF Pedersen, LC Darden, TA Negishi, M TI Crystal structure of beta 1,3-glucuronyltransferase I in complex with active donor substrate UDP-GlcUA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN LINKAGE REGION; HEPARAN-SULFATE; GLUCURONOSYLTRANSFERASE-I; N-ACETYLGLUCOSAMINE; CATALYTIC MECHANISM; MOLECULAR-CLONING; MAST-CELLS; BIOSYNTHESIS; PROTEOGLYCANS; EXPRESSION AB beta1,3-Glucuronyltransferase (GlcAT-I) is an essential enzyme involved in heparan sulfate and chondroitin sulfate biosynthesis. GlcAT-I is an inverting glycosyltransferase that catalyzes the transfer of glucuronic acid (GlcUA) to the common growing linker region Galbeta1-3Galbeta1-4Xyl that is attached to a serine side chain of a core protein. Previously the structure of GlcAT-I has been solved in the presence of the donor product UDP and an acceptor analog Galbeta1-3GalX1-4Xyl (Pedersen, L. C., Tsuchida, K., Kitagawa, H., Sugahara, K., Darden, T. A. & Negishi, M. (2000) J. Biol. Chem. 275, 34580-34585). Here we report the x-ray crystal structure of GIcAT-I in complex with the complete donor UDP-Glc-UA, thereby providing structures of an inverting glycosyltransferase in which both the complete donor and acceptor substrates are present in the active site. This structure supports the in-line displacement reaction mechanism previously proposed. It also provides information on the essential amino acid residues that determine donor substrate specificity. C1 NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. NR 28 TC 53 Z9 56 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 JUN 14 PY 2002 VL 277 IS 24 BP 21869 EP 21873 DI 10.1074/jbc.M112343200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000097 PM 11950836 ER PT J AU von Kobbe, C Karmakar, P Dawut, L Opresko, P Zeng, XM Brosh, RM Hickson, ID Bohr, VA AF von Kobbe, C Karmakar, P Dawut, L Opresko, P Zeng, XM Brosh, RM Hickson, ID Bohr, VA TI Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYNDROME GENE-PRODUCT; DNA HELICASE; CELL-CYCLE; FLAP ENDONUCLEASE-1; HOLLIDAY JUNCTIONS; WRN HELICASE; TELOMERASE; BINDING; COMPLEX; 3'->5'-EXONUCLEASE AB The RecQ helicase family comprises a conserved group of proteins implicated in several aspects of DNA metabolism. Three of the family members are defective in heritable diseases characterized by abnormal growth, premature aging, and predisposition to malignancies. These include the WRN and BLM gene products that are defective in Werner and Bloom syndromes, disorders which share many phenotypic and cellular characteristics including spontaneous genomic instability. Here, we report a physical and functional interaction between BLM and WRN. These proteins were coimmunoprecipitated from a nuclear matrix-solubilized fraction, and the purified recombinant proteins were shown to interact directly. Moreover, BLM and WRN colocalized to nuclear foci in three human cell lines. Two regions of WRN that mediate interaction with BLM were identified, and one of these was localized to the exonuclease domain of WRN. Functionally, BLM inhibited the exonuclease activity of WRN. This is the first demonstration of a physical and functional interaction between RecQ helicases. Our observation that RecQ family members interact provides new insights into the complex phenotypic manifestations resulting from the loss of these proteins. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Oxford, Inst Mol Med, Imperial Canc Res Fund Labs, Oxford OX3 9DS, England. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. OI Opresko, Patricia/0000-0002-6470-2189 NR 45 TC 97 Z9 97 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 JUN 14 PY 2002 VL 277 IS 24 BP 22035 EP 22044 DI 10.1074/jbc.M200914200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000116 PM 11919194 ER PT J AU Chen, J Kaul, S Simons, SS AF Chen, J Kaul, S Simons, SS TI Structure/activity elements of the multifunctional protein, GMEB-1 - Characterization of domains relevant for the modulation of glucocorticoid receptor transactivation properties SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE AMINOTRANSFERASE GENE; ESTROGEN-REGULATED RNAS; TRANSCRIPTION FACTOR; AGONIST ACTIVITY; BINDING PROTEIN; KDWK FAMILY; INDUCTION PROPERTIES; BIOLOGICAL-ACTIVITY; HORMONE RECEPTORS; NUCLEAR RECEPTORS AB GMEB-1 was initially described as a component of a 550-kDa heteromeric DNA binding complex that is involved in the modulation of two properties of glucocorticoid receptor (GR) transactivation, the dose-response curve of agonists and the partial agonist activity of antagonists. Subsequently, GMEB-1 was also found to bind to hsp27, to associate with the coactivator TIF2 in yeast cells, and to participate in Parvovirus replication. To understand these multiple activities of GMEB-1 at a molecular level, we have now determined which regions are associated with the various activities associated with the modulation of GR transactivation properties. These activities include, homooligomerization, heterooligomerization, DNA binding, binding to GR and the transcriptional cofactor CBP, and GR modulation. Complex activities such as DNA binding and GR modulation, are found to require the physical combination of those domains that would be predicted from the involved biochemical processes. We have previously documented that GMEB-1 possesses both GR modulatory and intrinsic transactivation activity. However, the domains for these two activities of GMEB-1 are found not to overlap. This separation of activities provides a structural basis for our prior biological observations that the modulation of the dose-response curve and partial agonist activity of GR complexes is independent of the total levels of gene activation by the same GR complexes. C1 NIDDK, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bldg 8,Rm B2A-07, Bethesda, MD 20892 USA. NR 65 TC 15 Z9 15 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 JUN 14 PY 2002 VL 277 IS 24 BP 22053 EP 22062 DI 10.1074/jbc.M202311200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000118 PM 11934901 ER PT J AU Bautista, AP Wang, EZ AF Bautista, AP Wang, EZ TI Acute ethanol administration downregulates human immunodeficiency virus-1 glycoprotein 120-induced KC and RANTES production by murine Kupffer cells and splenocytes SO LIFE SCIENCES LA English DT Article DE CC chemokines; CXC chemokines; gene expression; Balb/c mice ID MACROPHAGE INFLAMMATORY PROTEIN-2; ACUTE ALCOHOL-INTOXICATION; BETA-CHEMOKINE PRODUCTION; MYELOID PROGENITOR CELLS; NF-KAPPA-B; CXC-CHEMOKINE; EPITHELIAL-CELLS; GENE-EXPRESSION; HUMAN MONOCYTES; HIV-INFECTION AB Glycoprotein 120 from HIV-1, HIV-2 and SIV is known to stimulate secretion of chemokines by mononuclear cells. Thus, this work tests the hypothesis that acute ethanol intoxication suppresses HIV-1 gp120-induced chemokine production by murine Kupffer cells and splenocytes. Male Balb/c mice were given ethanol (1.70 g/Kg) by intragastric gavage in 0.1 ml volume of saline. Five minutes after ethanol administration, mice received an intravenous injection of HIV-1 gp120 (5 mug/Kg). After 24 hr, serum samples, splenocytes and Kupffer cells were obtained. Isolated cells were cultured in DMEM for 24 hr to determine production of chemokines and cytokines in vitro. Chemokines (MIP-2, KC, RANTES, MIP-1alpha and MCP-1) and cytokines (IL-1beta, TNFalpha, IL-10, gamma-IFN) were measured by ELISA. M-RNA abundance of these mediators was determined by RT-PCR. Results show that HIV-1 gp120 treatment was associated with significant elevations in serum KC and RANTES. No changes were observed with regard to other chemokines and cytokines. Oral administration of ethanol significantly suppressed HIV-1gp120-induced KC and RANTES release. KC and RANTES-mRNA expression and protein release by splenocytes and Kupffer cells were up-regulated by HIV-1 gp120. Such up-regulation was attenuated by ethanol treatment. These data show that acute ethanol administration attenuates HIV-1 gp120-induced chemokine release in vivo by isolated splenocytes and Kupffer cells. Through this mechanism, previous in vivo ethanol use may compromise the ability of HIV-1 gp120 to induce chemokine-mediated inhibition of HIV-1 entry into target cells. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, New Orleans, LA 70112 USA. Louisiana State Univ, Hlth Sci Ctr, NIAAA, Sponsored Alcohol Res Ctr, New Orleans, LA 70112 USA. RP Bautista, AP (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, 1901 Perdido St,Box P7-3, New Orleans, LA 70112 USA. FU NIAAA NIH HHS [R01 AA 08846, P50 AA 09803, R01 AA 10746] NR 46 TC 5 Z9 5 U1 0 U2 1 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 JUN 14 PY 2002 VL 71 IS 4 BP 371 EP 382 AR PII S0024-3205(02)01687-9 DI 10.1016/S0024-3205(02)01687-9 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 569VZ UT WOS:000176624300002 PM 12044837 ER PT J AU Asanuma, M Miyazaki, I Higashi, Y Cadet, JL Ogawa, N AF Asanuma, M Miyazaki, I Higashi, Y Cadet, JL Ogawa, N TI Methamphetamine-induced increase in striatal p53 DNA-binding activity is attenuated in Cu,Zn-superoxide dismutase transgenic mice SO NEUROSCIENCE LETTERS LA English DT Article DE methamphetamine; p53; DNA-binding activity; superoxide dismutase; reactive oxygen species ID FREE-RADICALS; APOPTOSIS; EXPRESSION; TERMINALS; TOXICITY; SYSTEMS; BRAIN; ROLES; GENE; BAX AB The striatal DNA-binding activities of p53 as a transcription factor were gradually increased at several days after a single methamphetamine (METH) injection, while they were more rapidly increased within several hours after repeated METH injections (x 4 with a 2 h interval). The elevation of striatal p53 DNA-binding after repeated METH injections was markedly attenuated in Cu,Zn-superoxide dismutase transgenic mice, but not affected by treatments with N-methyl-Daspartate or D1 receptor antagonists. The present results suggest that METH-induced production of reactive oxygen species activates striatal p53 DNA-binding activity; this, in turn, may activate other downstream pathways that are responsible for chronic neurotoxicity of METH. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Okayama Univ, Grad Sch Med & Dent, Dept Brain Sci, Okayama 7008558, Japan. NIDA, Mol Neuropsychiat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Asanuma, M (reprint author), Okayama Univ, Grad Sch Med & Dent, Dept Brain Sci, 2-5-1 Shikatacho, Okayama 7008558, Japan. NR 16 TC 9 Z9 9 U1 0 U2 0 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 JUN 14 PY 2002 VL 325 IS 3 BP 191 EP 194 AR PII S0304-3940(02)00291-4 DI 10.1016/S0304-3940(02)00291-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 569VC UT WOS:000176622200012 PM 12044653 ER PT J AU Taylor, JP Hardy, J Fischbeck, KH AF Taylor, JP Hardy, J Fischbeck, KH TI Biomedicine - Toxic proteins in neurodegenerative disease SO SCIENCE LA English DT Review ID FAMILIAL ALZHEIMERS-DISEASE; AMYLOID PRECURSOR PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC MOUSE MODEL; PARKINSONS-DISEASE; HUNTINGTONS-DISEASE; EXPANDED POLYGLUTAMINE; ALPHA-SYNUCLEIN; NUCLEAR-LOCALIZATION; SUSCEPTIBILITY LOCUS AB A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders. C1 NINCDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Taylor, JP (reprint author), NINCDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM taylorjp@ninds.nih.gov RI Hardy, John/C-2451-2009 NR 74 TC 666 Z9 697 U1 5 U2 65 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 JUN 14 PY 2002 VL 296 IS 5575 BP 1991 EP 1995 DI 10.1126/science.1067122 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563UD UT WOS:000176273300042 PM 12065827 ER PT J AU Sommers, CL Park, CS Lee, J Feng, CG Fuller, CL Grinberg, A Hildebrand, JA Lacana, E Menon, RK Shores, EW Samelson, LE Love, PE AF Sommers, CL Park, CS Lee, J Feng, CG Fuller, CL Grinberg, A Hildebrand, JA Lacana, E Menon, RK Shores, EW Samelson, LE Love, PE TI A LAT mutation that inhibits T cell development yet induces lymphoproliferation SO SCIENCE LA English DT Article ID TYROSINE RESIDUES; CD5 EXPRESSION; ACTIVATION; RECEPTOR; LINKER; RAS; PHOSPHORYLATION; SELECTION; APOPTOSIS AB Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma 1 (PLC-gamma1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. EM pel@helix.nih.gov NR 20 TC 197 Z9 206 U1 0 U2 1 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 JUN 14 PY 2002 VL 296 IS 5575 BP 2040 EP 2043 DI 10.1126/science.1069066 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563UD UT WOS:000176273300057 PM 12065840 ER PT J AU Lamas, GA Lee, KL Sweeney, MO Silverman, R Leon, A Yee, R Marinchak, RA Flaker, G Schron, E Orav, EJ Hellkamp, AS Goldman, L Greer, S McAnulty, J Ellenbogen, K Ehlert, F Freedman, RA Estes, NAM Greenspon, A AF Lamas, GA Lee, KL Sweeney, MO Silverman, R Leon, A Yee, R Marinchak, RA Flaker, G Schron, E Orav, EJ Hellkamp, AS Goldman, L Greer, S McAnulty, J Ellenbogen, K Ehlert, F Freedman, RA Estes, NAM Greenspon, A CA Mode Select Trial Sinus-Node Dysfunct TI Ventricular pacing or dual-chamber pacing for sinus-node dysfunction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TERM FOLLOW-UP; MYOCARDIAL-INFARCTION; PACEMAKER SYNDROME; RANDOMIZED TRIAL; CLINICAL-TRIALS; MODE SELECTION; ATRIAL; MORBIDITY; SURVIVAL; LIFE AB Background: Dual-chamber (atrioventricular) and single-chamber (ventricular) pacing are alternative treatment approaches for sinus-node dysfunction that causes clinically significant bradycardia. However, it is unknown which type of pacing results in the better outcome. Methods: We randomly assigned a total of 2010 patients with sinus-node dysfunction to dual-chamber pacing (1014 patients) or ventricular pacing (996 patients) and followed them for a median of 33.1 months. The primary end point was death from any cause or nonfatal stroke. Secondary end points included the composite of death, stroke, or hospitalization for heart failure; atrial fibrillation; heart-failure score; the pacemaker syndrome; and the quality of life. Results: The incidence of the primary end point did not differ significantly between the dual-chamber group (21.5 percent) and the ventricular-paced group (23.0 percent, P=0.48). In patients assigned to dual-chamber pacing, the risk of atrial fibrillation was lower (hazard ratio, 0.79; 95 percent confidence interval, 0.66 to 0.94; P=0.008), and heart-failure scores were better (P<0.001). The differences in the rates of hospitalization for heart failure and of death, stroke, or hospitalization for heart failure were not significant in unadjusted analyses but became marginally significant in adjusted analyses. Dual-chamber pacing resulted in a small but measurable increase in the quality of life, as compared with ventricular pacing. Conclusions: In sinus-node dysfunction, dual-chamber pacing does not improve stroke-free survival, as compared with ventricular pacing. However, dual-chamber pacing reduces the risk of atrial fibrillation, reduces signs and symptoms of heart failure, and slightly improves the quality of life. Overall, dual-chamber pacing offers significant improvement as compared with ventricular pacing. C1 Univ Miami, Sch Med, Miami Beach, FL USA. Mt Sinai Med Ctr, Div Cardiol, Miami Beach, FL 33140 USA. Duke Univ, Sch Med, Durham, NC USA. Duke Clin Res Inst, Durham, NC USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Heart Care Ctr, Fayetteville, AR USA. Emory Univ, Atlanta, GA 30322 USA. Crawford W Long Mem Hosp, Atlanta, GA USA. Univ Hosp London, London, ON, Canada. Lankenau Hosp, Wynnewood, PA USA. Univ Missouri Hosp & Clin, Columbia, MO USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Baptist Med Ctr, Little Rock, AR USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. St Lukes Roosevelt Hosp, New York, NY USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. RP Lamas, GA (reprint author), Cardiovasc Associates Miami, 4300 Alton Rd,Suite 207, Miami Beach, FL 33140 USA. FU NHLBI NIH HHS [U01 HL 53973, U01 HL 49804, U01 HL 55981] NR 33 TC 463 Z9 490 U1 0 U2 6 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 JUN 13 PY 2002 VL 346 IS 24 BP 1854 EP 1862 DI 10.1056/NEJMoa013040 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100003 PM 12063369 ER PT J AU Tuomala, RE Shapiro, DE Mofenson, LM Bryson, Y Culnane, M Hughes, MD O'Sullivan, MJ Scott, G Stek, AM Wara, D Bulterys, M AF Tuomala, RE Shapiro, DE Mofenson, LM Bryson, Y Culnane, M Hughes, MD O'Sullivan, MJ Scott, G Stek, AM Wara, D Bulterys, M TI Antiretroviral therapy during pregnancy and the risk of an adverse outcome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MATERNAL-INFANT TRANSMISSION; PERINATAL TRANSMISSION; WOMEN; HIV; ZIDOVUDINE; PREVENTION; TRENDS; IMPACT; BIRTH AB Background: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. Methods: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. Results: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). Conclusions: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation. C1 Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Pediat AIDS Clin Trials Grp Study 076, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Management Ctr, Pediat AIDS Clin Trials Grp, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Women & Infants Transmiss Study, Boston, MA 02115 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Pediat AIDS Clin Trials Grp Study 185, Los Angeles, CA USA. Univ Calif Los Angeles, Maternal Infant HIV Transmiss Study, Los Angeles, CA USA. NIAID, Pediat Med Branch, Div AIDS, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Pediat AIDS Clin Trials Grp Study 076, Miami, FL USA. Univ Miami, Sch Med, Dept Obstet, Miami, FL USA. Univ Miami, Sch Med, Dept Pediat, Miami, FL USA. Univ Miami, Infants HIV Seropost Mothers Study 1, Miami, FL USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. Univ So Calif, Los Angeles Cty Perinatal Transmiss Study, Los Angeles, CA 90033 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Bay Area Pediat AIDS Consortium, Atlanta, GA USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. RP Tuomala, RE (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NCRR NIH HHS [M01 RR-43]; NIAID NIH HHS [AI-34841, AI-27541, AI-27550, AI-27560, AI-34840, AI-34842, AI-34858, AI-41110]; NICHD NIH HHS [HD-2-5714, HD-33162, HD-36117, HD-82913, R01 HD 30629]; NIDA NIH HHS [DA-15054]; PHS HHS [M015501271, R01 A123524] NR 28 TC 221 Z9 232 U1 0 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 JUN 13 PY 2002 VL 346 IS 24 BP 1863 EP 1870 DI 10.1056/NEJMoa991159 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100004 PM 12063370 ER PT J AU Watts, DH AF Watts, DH TI Drug therapy - Management of human immunodeficiency virus infection in pregnancy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID MOTHER-TO-CHILD; MATERNAL-INFANT TRANSMISSION; PERINATAL TRANSMISSION; CESAREAN-SECTION; VERTICAL TRANSMISSION; HIV TRANSMISSION; ANTIRETROVIRAL THERAPY; RISK-FACTORS; VIRAL LOAD; HIV-1-INFECTED WOMEN C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. RP Watts, DH (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, 6100 Execut Blvd,Rm 4B11, Bethesda, MD 20892 USA. NR 98 TC 57 Z9 63 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 JUN 13 PY 2002 VL 346 IS 24 BP 1879 EP 1891 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100007 PM 12063373 ER PT J AU Yeh, IC Hummer, G AF Yeh, IC Hummer, G TI Peptide loop-closure kinetics from microsecond molecular dynamics simulations in explicit solvent SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TRIPLET ENERGY-TRANSFER; PARTICLE MESH EWALD; CONTACT FORMATION; INTRACHAIN REACTIONS; CYTOCHROME-C; DNA HAIRPIN; DIFFUSION; PROTEIN; WATER; PROGRAM AB End-to-end contact formation rates of several peptides were recently measured by tryptophan triplet quenching (Lapidus et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7220). Motivated by these experiments, we study loop-closure kinetics for two peptides of different lengths, Cys-(Ala-Gly-Gln)(n)-Trp (n = 1, 2), in multiple all-atom explicit-solvent molecular dynamics simulations with different initial conditions and force fields. In 150 simulations of approximately 20 ns each, we collect data covering 1.0 and 0.8 mus for the penta-peptide simulated with the AMBER and CHARMM force fields, respectively, and about 0.5 us each with the two force fields for the octa-peptide. These extensive simulations allow us to analyze the dynamics of peptides in the unfolded state with atomic resolution, thus probing early events in protein folding, and to compare molecular dynamics simulations directly with experiment. The calculated lifetimes of the tryptophan triplet state are in the range of 50-100 ns, in agreement with experimental measurements. However, end-to-end contacts form more rapidly, with characteristic times less than 10 ns. The contact formation rates for the two force fields are similar despite differences in the respective ensembles of peptide conformations. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 46 TC 97 Z9 97 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 12 PY 2002 VL 124 IS 23 BP 6563 EP 6568 DI 10.1021/ja025789n PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 560AM UT WOS:000176059100026 PM 12047175 ER PT J AU Nagababu, E Ramasamy, S Rifkind, JM AF Nagababu, E Ramasamy, S Rifkind, JM TI Site-specific cross-linking of human and bovine hemoglobins differentially alters oxygen binding and redox side reactions producing rhombic heme and heme degradation SO BIOCHEMISTRY LA English DT Article ID HYDROGEN-PEROXIDE; BLOOD SUBSTITUTES; FERRYL INTERMEDIATE; HIGH COOPERATIVITY; LINKED HEMOGLOBIN; ENDOTHELIAL-CELLS; DISTAL POCKET; METHEMOGLOBIN; CARRIERS; AUTOXIDATION AB Chemically modified human or bovine hemoglobins (Hb) have been developed as oxygen-carrying therapeutics and are currently under clinical evaluation. Oxidative processes, which are in many cases enhanced when modifications are introduced that lower the oxygen affinity, can limit the safety of these proteins. We have carried out a systematic evaluation of two modified human Hbs (O-R-polyHbA(0) and DBBF-Hb) and one bovine Hb (polyHbBv). We have both measured the oxidative products present in the Hb preparations and followed the oxidative reactions during 37 degreesC incubations. Autoxidation, the primary oxidative reaction which initiates the oxidative cascade, is highly correlated with P-50 (R = 0.987; p < 0.002). However, when the results for the other oxidative processes are compared, two different classes of oxidative reactions are identified. The formation of oxyferrylHb, like the rate of autoxidation, increases for all modified Hbs. However, the subsequent reactions, which lead to heme damage and eventually heme degradation, are enhanced for the modified human Hbs but are actually suppressed for bovine-modified Hbs. The rhombic heme measured by electron paramagnetic resonance, which is the initial step that causes irreversible damage to the heme, is found to be a reliable measure of the stability of ferrylHb and has the tendency to produce degradation products. DBBF-Hb, a Hb-based oxygen carrier (HBOC) for which toxic side effects have been well documented, has the highest level of rhombic heme (41-fold greater than for HbA(0)), even though its rate of autoxidation is relatively low. These findings establish the importance of these secondary oxidative reactions over autoxidation in evaluating the toxicity of HBOCs. C1 NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Nagababu, E (reprint author), US FDA, NIH, Bldg 29,Room 112,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 40 TC 76 Z9 78 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 11 PY 2002 VL 41 IS 23 BP 7407 EP 7415 DI 10.1021/bi0121048 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 559ZU UT WOS:000176057300027 PM 12044174 ER PT J AU Baek, SH Hrabie, JA Keefer, LK Hou, DM Fineberg, N Rhoades, R March, KL AF Baek, SH Hrabie, JA Keefer, LK Hou, DM Fineberg, N Rhoades, R March, KL TI Augmentation of intrapericardial nitric oxide level by a prolonged-release nitric oxide donor reduces luminal narrowing after porcine coronary angioplasty SO CIRCULATION LA English DT Article DE angioplasty; restenosis; pericardium; nitric oxide; coronary disease ID MUSCLE CELL-PROLIFERATION; BALLOON ANGIOPLASTY; SYNTHASE GENE; IN-VIVO; RESTENOSIS; INJURY; DELIVERY AB Background-Nitric oxide (NO) is a potent vasodilator and antiplatelet agent that suppresses vascular smooth muscle cell proliferation. Hypothesizing that generating NO in the pericardial space would reduce luminal narrowing after coronary angioplasty without affecting systemic hemodynamics, we have determined the effect of a novel NO donor on vascular healing after balloon overstretch. Methods and Results-Diazeniumdiolated bovine serum albumin (D-BSA; molecular weight 74 kDa, half-life for NO release 20 days) was radioiodinated and found by intravital gamma-imaging to have a longer residence time in pig pericardium than a low-molecular-weight (0.5 kDa) analogue (22 versus 4.6 hours, respectively). Intrapericardial injection of D-BSA immediately before 30% overstretch of normal left anterior descending and left circumflex coronary arteries dose dependently reduced the intimal/medial area ratio by up to 50% relative to controls treated with underivatized albumin when measured 2 weeks after intervention. Positive remodeling was also noted, which increased luminal area relative to control. Conclusions-Perivascular exposure of coronary arteries to NO via intrapericardial D-BSA administration reduced flow-restricting lesion development after angioplasty in pigs without causing significant systemic effects. The data suggest that intrapericardial delivery of NO donors for which NO release rates and pericardial residence times are matched and optimized might be a beneficial adjunct to coronary angioplasty. C1 Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21701 USA. Indiana Univ, Med Ctr, Dept Physiol, Indianapolis, IN USA. Indiana Univ, Med Ctr, Dept Med, Div Cardiol, Indianapolis, IN USA. RP March, KL (reprint author), Indiana Ctr Vasc Biol & Med, 1B441,975 W Walnut St, Indianapolis, IN 46202 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 20 TC 39 Z9 41 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 11 PY 2002 VL 105 IS 23 BP 2779 EP 2784 DI 10.1161/01.CIR.0000017432.19415.3E PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 562GT UT WOS:000176189600025 PM 12057994 ER PT J AU Pfeifer, LA White, LR Ross, GW Petrovitch, H Launer, LJ AF Pfeifer, LA White, LR Ross, GW Petrovitch, H Launer, LJ TI Cerebral amyloid angiopathy and cognitive function The HAAS autopsy study SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE CERAD; MINI-MENTAL STATE; CLINICAL-DIAGNOSIS; CRITERIA; DEMENTIA; CALIFORNIA; CONSORTIUM; ESTABLISH; REGISTRY; HAWAII AB Objective: To investigate the relationship between cerebral amyloid angiopathy (CAA), dementia, and cognitive function in an autopsy sample of 211 Japanese-American men from the population-based Honolulu-Asia Aging Study. Methods: Starting in 1991, participants were assessed with the Cognitive Abilities Screening Instrument (CASI) and diagnosed with dementia (including subtype) based on published criteria. At autopsy, neuropathologists blinded to clinical data examined brains for neurofibrillary tangles (NFT), neuritic plaques (NP), and a number of vascular pathologies, including CAA. CAA was detected by immunostaining for betaA4 amyloid in parenchymal vessels in the neocortex and semiquantitatively rated. Linear regression models were used to examine the association of CASI score, dementia subtype, and CAA controlling for age at death, time between CASI administration and death, education, NP and NFT counts, infarcts, hemorrhage, and APOE genotype. Results: A total of 44.1% of subjects had CAA in at least one neocortical area. The presence of CAA was associated with higher mean NFT and NP counts and having at least one APOE-epsilon4 allele. The interaction between CAA and AD on the adjusted mean CASI score was significant; compared with nondemented men without CAA, the CASI score was 16.6% lower in men with AD and no CAA and 45.9% lower in men with AD plus CAA. Conclusions: CAA may contribute to the clinical presentation of dementia by interacting with other neuronal pathologies, leading to more severe cognitive impairment in men with both CAA and AD compared with men with only AD or CAA. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Pacific Ctr Hlth Res, Honolulu, HI USA. Dept Vet Affairs, Honolulu, HI USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [N01-AG-42149] NR 37 TC 181 Z9 185 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 11 PY 2002 VL 58 IS 11 BP 1629 EP 1634 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 561CN UT WOS:000176119500011 PM 12058090 ER PT J AU Roy, SK Hu, JB Meng, QJ Xia, Y Shapiro, PS Reddy, SPM Platanias, LC Lindner, DJ Johnson, PF Pritchard, C Pages, G Pouyssegur, J Kalvakolanu, DV AF Roy, SK Hu, JB Meng, QJ Xia, Y Shapiro, PS Reddy, SPM Platanias, LC Lindner, DJ Johnson, PF Pritchard, C Pages, G Pouyssegur, J Kalvakolanu, DV TI MEKK1 plays a critical role in activating the transcription factor gene expression in C/EBP-beta-dependent response to IFN-gamma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokines; cell growth; differentiation; antiviral; immune response ID INTERFERON-GAMMA; PROTEIN-KINASE; MAP KINASE; KAPPA-B; PHOSPHORYLATION; RAF-1; MACROPHAGES; INDUCTION; NF-IL6; ALPHA AB IFN-gamma induces a number of genes to up-regulate cellular responses by using specific transcription factors and the cognate elements. We recently discovered that CCAAT/enhancer-binding protein-beta (C/EBP-P) induces gene transcription through an IFN-response element called gamma-IFN-activated transcriptional element (GATE). Using mutant cells, chemical inhibitors, and specific dominant negative inhibitors, we show that induction of GATE-driven gene expression depends on MEK1 (mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase) and ERKs (extracellular signal-regulated protein kinases) but is independent of Raf-1. interestingly in cells lacking the MEKK1 gene or expressing the dominant negative MEKK1, ERK activation, and GATE dependent gene expression is inhibited. A dominant negative MEKK1 blocks C/EBP-beta-driven gene expression stimulated by IFN-gamma. These studies describe an IFN-gamma-stimulated pathway that involves MEKK1-MEK1-ERK1/2 kinases to regulate C/EBP-beta-dependent gene expression. C1 Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA. Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Toxicol, Baltimore, MD 21205 USA. Univ Illinois, Dept Hematol & Oncol, Chicago, IL 60612 USA. Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH 44195 USA. NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. Inst Signaling Dev Biol & Canc Res, F-06189 Nice, France. RP Kalvakolanu, DV (reprint author), Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NCI NIH HHS [CA 71401, CA 73881, CA 77816, CA 78282, R01 CA077816, R01 CA078282]; NHLBI NIH HHS [HL 58122, R01 HL058122, R29 HL058122] NR 54 TC 64 Z9 65 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 JUN 11 PY 2002 VL 99 IS 12 BP 7945 EP 7950 DI 10.1073/pnas.122075799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562UQ UT WOS:000176217700028 PM 12048245 ER PT J AU Hough, RB Avivi, A Davis, J Joel, A Nevo, E Piatigorsky, J AF Hough, RB Avivi, A Davis, J Joel, A Nevo, E Piatigorsky, J TI Adaptive evolution of small heat shock protein/alpha B-crystallin promoter activity of the blind subterranean mole rat, Spalax ehrenbergi SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ALPHA-A-CRYSTALLIN; LENS CRYSTALLINS; GENE-EXPRESSION; TRANSGENIC MICE; IDENTIFICATION; ENHANCER; SYSTEM; MUSCLE; PAX-6; MUTATION AB Blind mole rats have degenerated subcutaneous eyes that are visually nonfunctional. In this investigation, we have compared the tissue specificity of the small heat shock protein (shsp)/alphaB-crystallin promoter of the mole rat superspecies, Spalax ehrenbergi, with that of the mouse. Earlier experiments showed that mouse shsp/alphaB-crystallin promoter/enhancer activity is high in the lens and moderate in the heart and skeletal muscle of transgenic mice. Here, we show in transgenic mouse experiments using the firefly luciferase reporter gene that, despite relatively few changes in sequence, the mole rat shsp/alphaB-crystallin promoter/enhancer has selectively lost lens activity after 13.5 days of embryogenesis (E13.5). The ratios of mole rat/mouse promoter activity were 0.01 for lens, 1.7 for heart, and 13.6 for skeletal muscle in 8-wk-old transgenic mice. Our data indicate that the shsp/aB-crystallin promoter/enhancer has undergone adaptive changes corresponding to the subterranean evolution of the blind mole rat. We speculate that selective pressures on metabolic economy may have contributed to these tissue-specific modifications of promoter/enhancer function during adaptation to life underground. C1 NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. Univ Haifa, Inst Evolut, IL-31905 Haifa, Israel. RP NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. EM nevo@research.haifa.ac.il; joramp@nei.nih.gov NR 35 TC 20 Z9 20 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 11 PY 2002 VL 99 IS 12 BP 8145 EP 8150 DI 10.1073/pnas.122231099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562UQ UT WOS:000176217700063 PM 12060761 ER PT J AU Paone, G Wada, A Stevens, LA Matin, A Hirayama, T Levine, RL Moss, J AF Paone, G Wada, A Stevens, LA Matin, A Hirayama, T Levine, RL Moss, J TI ADP ribosylation of human neutrophil peptide-1 regulates its biological properties SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; BRONCHIAL EPITHELIAL-CELLS; MOLECULAR CHARACTERIZATION; ANTIMICROBIAL PEPTIDES; CYSTIC-FIBROSIS; SKELETAL-MUSCLE; HOST-DEFENSE; T-CELLS; RIBOSYLTRANSFERASE; PROTEINS AB In human airways, epithelial cells lining the lumen and intraluminal cells (e.g., polymorphonuclear cells) participate in the innate immune response. These cells secrete or express on their surfaces arginine-specific ADP ribosyltransferases. Defensins, antimicrobial proteins secreted by immune cells, are arginine-rich, leading us to hypothesize that ADP ribosylation could modify their biological activities. We found that an arginine-specific ADP ribosyltransferase-1 present on airway epithelial cells modifies Arg-14 of alpha defensin-1. ADP-ribosylated defensin-1 had decreased antimicrobial and cytotoxic activities but still stimulated T cell chemotaxis and IL-8 release from A549 cells. Further, ADP-ribosylated defensin-1 inhibited cytotoxic and antimicrobial activities of unmodified defensin-1. We identified ADP-ribosylated defensin-1 in bronchoal-veolar lavage fluid from smokers but not from nonsmokers, confirming its existence in vivo. Thus, airway mono-ADP-ribosyltransferases could have an important regulatory role in the innate immune response through modification of alpha defensin-1 and perhaps other basic molecules, with alteration of their biological properties. C1 NHLBI, Pulmonary Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Sect Prot Funct Dis, NIH, Bethesda, MD 20892 USA. Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. RP Moss, J (reprint author), NHLBI, Pulmonary Crit Care Med Branch, NIH, Bldg 10,Rm 6D30,10 Ctr Dr,MSC1590, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 35 TC 86 Z9 88 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 JUN 11 PY 2002 VL 99 IS 12 BP 8231 EP 8235 DI 10.1073/pnas.122238899 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562UQ UT WOS:000176217700078 PM 12060767 ER PT J AU Sha, BE Valdez, H Gelman, RS Landay, AL Agosti, J Mitsuyasu, R Pollard, RB Mildvan, D Namkung, A Ogata-Arakaki, DM Fox, L Estep, S Erice, A Kilgo, P Walker, RE Bancroft, L Lederman, MM AF Sha, BE Valdez, H Gelman, RS Landay, AL Agosti, J Mitsuyasu, R Pollard, RB Mildvan, D Namkung, A Ogata-Arakaki, DM Fox, L Estep, S Erice, A Kilgo, P Walker, RE Bancroft, L Lederman, MM TI Effect of etanercept (Enbrel) on interleukin 6, tumor necrosis factor alpha, and markers of immune activation in HIV-infected subjects receiving interleukin 2 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article; Proceedings Paper CT 8th Conference on Retroviruses and Opportunistic Infections CY FEB 04-08, 2001 CL CHICAGO, ILLINOIS ID RHEUMATOID-ARTHRITIS; FACTOR RECEPTOR; CYTOKINES; THERAPY; INHIBITION; TRIAL; TNF AB The effect of etanercept, a soluble p75 tumor necrosis factor (TNF) receptor:Fc fusion protein (Enbrel; Immunex, Seattle, WA) on plasma cytokines was evaluated in 11 HIV-infected subjects receiving highly active antiretroviral therapy (HAART) for 28 weeks with or without subcutaneous or intravenous recombinant human interleukin 2 (rhIL-2). Plasma IL-6 and C-reactive protein (CRP) levels increased after rhIL-2 treatment. Etanercept pretreatment attenuated these increases. Median plasma IL-6 levels were 20.29 pg/ml 4 days after rhIL-2 and 7.87 pg/ml 4 days after etanercept and rhIL-2 (p = 0.22); median CRP levels were 78.73 and 46.16 mug/ml, respectively (p = 0.03). An effect on TNF bioactivity could not be assessed as all measurements were below limits of detection. No significant changes were seen in temperature or plasma levels of IL-4, IL-10, IL-12, interferon gamma, or HIV-1 RNA levels. All subjects had undetectable or low-level HIV-1 RNA levels before etanercept dosing. One subject died; however, her death was thought to be unrelated to etanercept. Pretreatment with etanercept may blunt activation of IL-6 and CRP expression induced by rhIL-2. The safety and utility of etanercept in HIV-infected persons should be explored further. C1 Rush Med Coll, Dept Med, Infect Dis Sect, Chicago, IL 60612 USA. Rush Med Coll, Dept Immunol Microbiol, Chicago, IL 60612 USA. Case Western Reserve Univ, Ctr AIDS Res, Dept Med, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. Univ Calif Los Angeles, Los Angeles, CA 90095 USA. Univ Texas, Galveston, TX 77555 USA. Beth Israel Med Ctr, Dept Med, Div Infect Dis, New York, NY 10003 USA. Adult AIDS Clin Trials Grp Operat Ctr, Silver Spring, MD 20910 USA. Univ Hawaii Manoa, Honolulu, HI 96816 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med & Pathol, Div Infect Dis, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY 14226 USA. RP Sha, BE (reprint author), Rush Med Coll, Dept Med, Infect Dis Sect, 600 S Paulina Suite 143, Chicago, IL 60612 USA. FU NIAID NIH HHS [AI 38858, AI 25879, AI 27660, AI 36219, AI 46370] NR 15 TC 31 Z9 32 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2002 VL 18 IS 9 BP 661 EP 665 DI 10.1089/088922202760019365 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 560WP UT WOS:000176104600007 PM 12079562 ER PT J AU Takahashi, M Barrett, JC Tsutsui, T AF Takahashi, M Barrett, JC Tsutsui, T TI Transformation by inorganic arsenic compounds of normal Syrian hamster embryo cells into a neoplastic state in which they become anchorage-independent and cause tumors in newborn hamsters SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE arsenic; Syrian hamster embryo cell; anchorage independence; neoplastic transformation; senescence; DNA hypomethylation ID INDUCED MALIGNANT TRANSFORMATION; FETAL LUNG FIBROBLASTS; PROTEIN CROSS-LINKS; CYTO-TOXICITY; MORPHOLOGICAL TRANSFORMATION; SODIUM ARSENITE; DNA; MECHANISM; HYPOMETHYLATION; CARCINOGENESIS AB Arsenic is a known human carcinogen, but little evidence exists for its carcinogenicity in animals. In order to investigate the ability of inorganic arsenics to transform normal cells into a neoplastic state, mass cultures of normal, diploid Syrian hamster embryo (SHE) cells exposed to various concentrations of sodium arsenite or sodium arsenate for 48 hr were continually passaged and tested for neoplastic transformation, as determined by anchorage-independent growth in semisolid agar and tumorigenicity in newborn hamsters. Twenty-one of 22 (96%) untreated, control cultures senesced by 20 passages. While I culture escaped senescence, it did not acquire the ability to either grow in semisolid agar or form tumors in animals. Ten of 14 (71%) cultures exposed to sodium arsenite or sodium arsenate escaped senescence. Nine of the 10 (90%) arsenic-treated immortal cultures acquired the anchorage-independent phenotype. Five of 5 anchorage-independent cultures examined were tumorigenic. Two of 3 morphologically transformed colonies induced by sodium arsenate also acquired the ability to grow in semisolid agar when isolated. Amplification of the c-myc or c-Ha-ras oncogene was detected in 3 of 5 and 4 of 5 tumorigenic cell lines, respectively. Both c-myc and c-Ha-ras were amplified even in a preneoplastic, anchorage-dependent cell line, but neither was amplified in 6 of 9 anchorage-independent cell lines. Overexpression of c-myc and c-Ha-ras mRNA was observed in most of the neoplastically transformed cell lines but not in the preneoplastic cell line. Experiments using the methylation-sensitive restriction endonuclease isoschizomers Hpall and MspI revealed hypomethylation of c-myc and c-Ha-ras in the 5'-CCGG sequence of arsenic-exposed cell lines but not in the parental SHE cells or a spontaneously transformed cell line. Thus, inorganic arsenics induce neoplastic transformation of normal, diploid mammalian cells. Overexpression of onco-genes by DNA hypomethylation may participate in the arsenic-induced neoplastic transformation of mammalian cells. Published 2002 Wiley-Liss, Inc.(dagger). C1 NCI, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Nippon Dent Univ Tokyo, Dept Pharmacol, Tokyo, Japan. RP Barrett, JC (reprint author), NCI, Ctr Canc Res, Lab Biosyst & Canc, 9000 Rockville Pike,Bldg 40,Rm 26, Bethesda, MD 20892 USA. NR 30 TC 27 Z9 32 U1 1 U2 1 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 JUN 10 PY 2002 VL 99 IS 5 BP 629 EP 634 DI 10.1002/ijc.10407 PG 6 WC Oncology SC Oncology GA 555YU UT WOS:000175821300001 PM 12115494 ER PT J AU Rapella, A Negrioli, A Melillo, G Pastorino, S Varesio, L Bosco, MC AF Rapella, A Negrioli, A Melillo, G Pastorino, S Varesio, L Bosco, MC TI Flavopiridol inhibits vascular endothelial growth factor production induced by hypoxia or picolinic acid in human neuroblastoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE neuroblastoma; flavopiridol; picolinic acid; vascular endothelial growth factor; hypoxia ID DEPENDENT KINASE INHIBITOR; OXIDE SYNTHASE PROMOTER; HUMAN NEURO-BLASTOMA; N-MYC AMPLIFICATION; ACTIVITY IN-VIVO; TUMOR-GROWTH; CELL-LINE; RESPONSIVE ELEMENT; FACTOR EXPRESSION; CARCINOMA-CELLS AB Human neuroblastoma (NB) tumors elaborate angiogenic peptides, and enhanced angiogenesis correlates with their aggressive behavior, metastatic spread and poor clinical outcome. Hence, inhibition of angiogenic factor production may represent a potential therapeutic target for NB treatment. There is currently little information regarding the stimuli that control NB production of angiogenic mediators. In this study, we analyzed the effects of hypoxia, a common feature of solid tumors and a major drive to tumor angiogenesis, and of PA, a tryptophan catabolite produced under inflammatory conditions and endowed with several biologic properties, on the production of the angiogenic activator VEGF by advanced-stage human NB cell lines. We demonstrate that both stimuli are potent inducers of VEGF expression and secretion. VEGF upregulation by PA involved iron chelation because iron sulfate prevented this effect whereas the iron-chelating agent DFX induced VEGF production. Conversely, the CDK inhibitor Flp completely blocked VEGF induction by hypoxia. This effect occurred as early as 3 hr after stimulation and did not require de novo protein synthesis. Moreover, Flp exerted similar inhibitory activity on VEGF induction by PA or DFX, suggesting that this compound targets an essential step in the signaling pathway that leads to VEGF expression. Our findings demonstrate that PA can modulate angiogenic factor production by tumor cells and establish the importance of Flp as an inhibitor of VEGF production by human NB. (C) 2002 Wiley-Liss, Inc. C1 Ist Giannina Gaslini, Mol Biol Lab, I-16147 Genoa, Italy. NCI, Sci Applicat Int Corp, Dev Therapeut Program, Tumor Hypoxia Program,Frederick Canc Res & Dev Ct, Frederick, MD USA. RP Bosco, MC (reprint author), Ist Giannina Gaslini, Mol Biol Lab, L Go Gerolamo Gaslini 5, I-16147 Genoa, Italy. EM mcbosco@tin.it RI Bosco, Maria Carla/J-7928-2016; varesio, luigi/J-8261-2016 OI Bosco, Maria Carla/0000-0003-1857-7193; varesio, luigi/0000-0001-5659-2218 NR 47 TC 34 Z9 38 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 10 PY 2002 VL 99 IS 5 BP 658 EP 664 DI 10.1002/ijc.10392 PG 7 WC Oncology SC Oncology GA 555YU UT WOS:000175821300005 PM 12115498 ER PT J AU Grigoriev, IV Makhnovskii, YA Berezhkovskii, AM Zitserman, VY AF Grigoriev, IV Makhnovskii, YA Berezhkovskii, AM Zitserman, VY TI Kinetics of escape through a small hole SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-MOTION; FLUCTUATING BOTTLENECKS; DYNAMIC DISORDER; LIGAND AB We study the time dependence of the survival probability of a Brownian particle that escapes from a cavity through a round hole. When the hole is small the escape is controlled by an entropy barrier and the survival probability decays as a single exponential. We argue that the rate constant is given by k=4Da/V, where a and V are the hole radius and the cavity volume and D is the diffusion constant of the particle. Brownian dynamics simulations for spherical and cubic cavities confirmed both the exponential decay of the survival probability and the expression for the rate constant for sufficiently small values of a. (C) 2002 American Institute of Physics. C1 Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Russian Acad Sci, Inst High Temp, Thermophys Ctr, Moscow 127412, Russia. RP Berezhkovskii, AM (reprint author), Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Leninsky Pr 29, Moscow 117912, Russia. RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X NR 11 TC 105 Z9 106 U1 0 U2 11 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 JUN 8 PY 2002 VL 116 IS 22 BP 9574 EP 9577 DI 10.1063/1.1475756 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 554PL UT WOS:000175744600003 ER PT J AU Berezhkovskii, AM Pustovoit, MA Bezrukov, SM AF Berezhkovskii, AM Pustovoit, MA Bezrukov, SM TI Channel-facilitated membrane transport: Transit probability and interaction with the channel SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ESCHERICHIA-COLI; DIFFUSION AB Transport of metabolites between cells and between subcellular compartments is facilitated by special protein channels that form aqueous pores traversing biological membranes. Accumulating evidence demonstrates that solute-specific channels display pronounced binding to the corresponding solutes. In this paper we rationalize this observation by showing that a wide and deep potential well inside the channel is able to greatly increase the transit probability of the particle through the channel. Using a one-dimensional diffusion model with radiation boundary conditions, we give exact analytical expressions for the particle translocation probabilities. We also run Brownian dynamics simulations to verify the model and the quantitative predictions of our theory. (C) 2002 American Institute of Physics. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, CIT, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Bezrukov, SM (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bldg 9,Room 1E-122, Bethesda, MD 20892 USA. RI Pustovoit, Mark/B-5249-2008 NR 11 TC 79 Z9 79 U1 1 U2 8 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 JUN 8 PY 2002 VL 116 IS 22 BP 9952 EP 9956 DI 10.1063/1.1475758 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 554PL UT WOS:000175744600045 ER PT J AU Bourdi, M Reilly, TP Elkahloun, AG George, JW Pohl, LR AF Bourdi, M Reilly, TP Elkahloun, AG George, JW Pohl, LR TI Macrophage migration inhibitory factor in drug-induced liver injury: a role in susceptibility and stress responsiveness SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE acetaminophen; adverse drug reactions; halothane; heat shock proteins; hepatotoxicity; interferon-gamma; macrophage migration inhibitory factor; stress response ID TUMOR-NECROSIS-FACTOR; TNF-ALPHA; MICE; ACETAMINOPHEN; EXPRESSION; PROTECTION; APOPTOSIS; HEPATOTOXICITY; PATHOGENESIS; INFLAMMATION AB Idiosyncratic drug-induced hepatitis may depend upon many factors including a balance between pro- and anti-inflammatory mediator production levels. Using a guinea pig model of liver injury induced by bioactivation of the anesthetic drug, halothane, we found that toxicity was commensurate with an increase in serum macrophage migration inhibitory factor (MIF), a pro-inflammatory signal and counter-regulator of glucocorticoids, but only in susceptible animals. The pathogenic role of MIF was further investigated using a murine model in which liver injury was induced by the reactive metabolite of another drug, acetaminophen (APAP). MIF leakage from the liver into the sera preceded peak increases in toxicity following APAP administration. MIF null (-/-) mice were significantly less susceptible to this toxicity at 8 h. At 48 h following a 300 mg/kg dose, complete lethality was observed in wild-type mice, while 46% survival was noted in MIF-/- mice. The decreased hepatic injury in MIF-/- mice correlated with a reduction in mRNA levels of interferon-gamma and a significant increase in heat shock protein expression, but was unrelated to the APAP-protein adduct formation in the liver. These findings support MIF as a critical pro-toxicant signal in drug-induced liver injury with potentially important and novel effects on heat shock protein responsiveness. (C) 2002 Published by Elsevier Science (USA). C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD USA. RP Bourdi, M (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike,Bldg 10,Rm 8N110, Bethesda, MD 20892 USA. NR 37 TC 38 Z9 42 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 7 PY 2002 VL 294 IS 2 BP 225 EP 230 AR PII S0006-291X(02)00466-7 DI 10.1016/S0006-291X(02)00466-7 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 564YH UT WOS:000176340800006 PM 12051698 ER PT J AU Xu, D Finkel, T AF Xu, D Finkel, T TI A role for mitochondria as potential regulators of cellular life span SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID DROSOPHILA-MELANOGASTER; SUPEROXIDE-DISMUTASE; CALORIC RESTRICTION; OXIDATIVE STRESS; OVEREXPRESSION; SENESCENCE; EXTENSION; CELLS; BIOGENESIS; OXIDANTS AB We demonstrate that by simply raising extracellular pyruvate levels, and hence increasing metabolic supply, human diploid fibroblasts undergo a concentration-dependent induction of cellular senescence. Fibroblasts treated with pyruvate undergo a rapid growth arrest accompanied by elevated levels of the cell-cycle regulatory molecules p53, p21, and p16. These cells also exhibit arise in mitochondrial oxidant production and a fall in intracellular glutathione levels. Exposure of pyruvate treated cells to the antioxidant and glutathione precursor N-acetylcysteine restores cell growth and reverses the increase in senescence-associated beta-galactosidase activity. Similarly, we demonstrate that by increasing mitochondrial number via retroviral-mediated expression of the mitochondrial biogenesis regulator PGC-1 there is also a reduction in cell growth and the more rapid induction of senescence. These results suggest that mitochondria appear to play a central role in regulating cellular life span. (C) 2002 Published by Elsevier Science (USA). C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10-6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 22 TC 50 Z9 54 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 7 PY 2002 VL 294 IS 2 BP 245 EP 248 AR PII S0006-291X(02)00464-3 DI 10.1016/S0006-291X(02)00464-3 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 564YH UT WOS:000176340800009 PM 12051701 ER PT J AU Corpe, CP Bovelander, FJ Munoz, CM Hoekstra, JH Simpson, IA Kwon, O Levine, M Burant, CF AF Corpe, CP Bovelander, FJ Munoz, CM Hoekstra, JH Simpson, IA Kwon, O Levine, M Burant, CF TI Cloning and functional characterization of the mouse fructose transporter, GLUT5 SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE fructose transporter; GLUT5; 5 ' RACE; dietary; developmental ID SMALL-INTESTINE; MESSENGER-RNA; EXPRESSION; LOCALIZATION; SEQUENCE; PROTEIN; KIDNEY; TISSUE AB Mouse GLUT5 cDNA and a 7.7-kb genomic fragment have been isolated and characterized. The cDNA sequence suggests mouse GLUT5 is composed of 501 amino acids, and has 69-88% amino acid identity with human, rat, and rabbit GLUT5. Expression of mouse GLUT5 cRNA in Xenopus laevis oocytes showed that GLUT5 mediated fructose transport, with a K-I of 13 mM, Northern blot studies detected GLUT5 mRNA expression in mouse small intestine, kidney, and testis, with transcript sizes of approximately 2.1, 2.1, and 2.8 kb, respectively. 5'Rapid Amplification of cDNA Ends (5'RACE) determined that the differences in transcript sizes occurred because GLUT5 possessed alternative transcriptional initiation sites in somatic and germ cells. In agreement with studies in rats and rabbits, mouse small intestinal GLUT5 mRNA expression levels were increased following exposure to a 65% fructose-enriched diet, In addition, developmental studies showed a significant increase in GLUT5 mRNA expression levels in adult mouse testis when compared to prepubertal mouse testis. To begin to identify the cis-acting domains responsible for GLUT5 expression characteristics, a 7.7-kb GLUT5 genomic fragment was isolated from a mouse lambdafix11 library and sequenced. The clone contained exons 1-4 and 5' flanking regions. Moreover, caudal homeobox gene (CdxA), upstream stimulatory factor (USF), and sex-determining region of Y (SRY) binding sites were identified in the 5' flanking region that may be responsible for GLUT5's expression characteristics: tissue distribution, sensitivity to dietary fructose in the small intestine, and developmental expression in the testis. (C) 2002 Published by Elsevier Science B,V. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Bosch Medicentrum, Dept Pediat, sHertogenbosch, Netherlands. RP Corpe, CP (reprint author), NIDOK, Natl Inst Hlth, Digest Dis Branch, Mol & Clin Nutr, Bethesda, MD 20892 USA. OI Burant, Charles/0000-0001-9189-5003 FU NIDDK NIH HHS [DK-02170] NR 20 TC 40 Z9 45 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JUN 7 PY 2002 VL 1576 IS 1-2 BP 191 EP 197 AR PII S0167-4781(02)00284-1 DI 10.1016/S0167-4781(02)00284-1 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 560BE UT WOS:000176060700024 PM 12031501 ER PT J AU Deroo, BJ Archer, TK AF Deroo, BJ Archer, TK TI Proteasome inhibitors reduce luciferase and beta-galactosidase activity in tissue culture cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; GLUCOCORTICOID RECEPTOR; HEAT-SHOCK; PROTEIN DENATURATION; CHROMATIN STRUCTURE; MAMMALIAN-CELLS; 26S PROTEASOME; DEGRADATION; PROGESTINS; APOPTOSIS AB Reporter enzymes are commonly used in cell biology to study transcriptional activity of genes. Recently, reporter enzymes in combination with compounds that inhibit proteasome function have been used to study the effect of blocking transcription factor degradation on gene activation. While investigating the effect of proteasome inhibition on steroid receptor activation of the mouse mammary tumor virus (MMTV) promoter, we found that treatment with proteasome inhibitors enhanced glucocorticoid activation of the promoter attached to a chloramphenicol acetyltransferase (CAT) reporter, but inhibited activation of MMTV attached to a firefly luciferase or beta-galactosidase reporter. MMTV RNA levels under these conditions correlated with the promoter activity observed using the CAT reporter, suggesting that proteasome inhibitor treatment interfered with luciferase or beta-galactosidase reporter assays. Washout experiments demonstrated that the majority of luciferase activity was lost if the proteasome inhibitor was added at the same time luciferase was produced, not once the functional protein was made, suggesting that proteasome inhibition interferes with production of luciferase protein. Indeed, we found that proteasome inhibitor treatment dramatically reduced the levels of luciferase and beta-galactosidase protein produced, as determined by Western blot. Thus, treatment with proteasome inhibitors interferes with luciferase and beta-galactosidase reporter assays, possibly by inhibiting production of a functional reporter protein. C1 NIEHS, Reprod & Dev Toxicol Lab, Chromatin & Gene Express Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Chromatin & Gene Express Sect, NIH, MD E4-06, Res Triangle Pk, NC 27709 USA. NR 27 TC 38 Z9 38 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 JUN 7 PY 2002 VL 277 IS 23 BP 20120 EP 20123 DI 10.1074/jbc.C200173200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500003 PM 11959849 ER PT J AU Oubrahim, H Chock, PB Stadtman, ER AF Oubrahim, H Chock, PB Stadtman, ER TI Manganese(II) induces apoptotic cell death in NIH3T3 cells via a caspase-12-dependent pathway. SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; DOUBLE-STRANDED-RNA; HYDROGEN-PEROXIDE; ACTIVATION; PROTEASE; MECHANISM; CASPASES; COMPLEX; ROLES AB Under physiological conditions, manganese(II) exhibits catalase-like activity. However, at elevated concentrations, it induces apoptosis via a non-mitochondria-mediated mechanism (Oubrahim, H., Stadtman, E. R., and Chock, P. B. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 9505-9510). In this study, we show that the Mn(II)-induced apoptosis, as monitored by caspase-3-like activity, in NIH3T3 cells was inhibited by calpain inhibitors I and II or the p38 MAP kinase inhibitor, SB202190. The control experiments showed that each of these inhibitors in the concentration ranges used exerted no effect on activated caspase-3-like activity. Furthermore, caspase-12 was cleaved in Mn(II)-treated cells, suggesting that the Mn(II)-induced apoptosis is mediated by caspase-12. This notion is confirmed by the observations that pretreatment of NIH3T3 cells with either caspase-12 antisense RNA or dsRNA corresponding to the full-length caspase-12 led to a dramatic decrease in caspase-3-like activity induced by Mn(II). The precise mechanism by which Mn(II) induced the apoptosis is not clear. Nevertheless, Mn(II), in part, exerts its effect via its ability to replace Ca(II) in the activation of m-calpain, which in turn activates caspase-12 and degrades Bcl-xL. In addition, the dsRNA, method serves as an effective technique for knocking out caspase-12 in NIH3T3 cells without causing apoptosis. C1 NHLBI, LB, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, LB, NIH, Bldg 10,Rm 2140,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. NR 27 TC 53 Z9 58 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 JUN 7 PY 2002 VL 277 IS 23 BP 20135 EP 20138 DI 10.1074/jbc.C200226200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500007 PM 11964391 ER PT J AU Niu, SL Mitchell, DC Litman, BJ AF Niu, SL Mitchell, DC Litman, BJ TI Manipulation of cholesterol levels in rod disk membranes by methyl-beta-cyclodextrin. Effects on receptor activation. SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHAIN PHOSPHATIDYLCHOLINE VESICLES; PROTEIN-COUPLED RECEPTOR; OUTER SEGMENT MEMBRANES; HIGHER-ORDER ANALYSIS; LIPID-COMPOSITION; METARHODOPSIN-II; ANISOTROPY DECAY; MOLECULAR ORDER; RHODOPSIN; EQUILIBRIUM AB The effect of cholesterol on rod outer segment disk membrane structure and rhodopsin activation was investigated. Disk membranes with varying cholesterol concentrations were prepared using methyl-beta-cyclodextrin as a cholesterol donor or acceptor. Cholesterol exchange followed a simple equilibrium partitioning model with a partition coefficient of 5.2 +/- 0.8 in favor of the disk membrane. Reduced cholesterol in disk membranes resulted in a higher proportion of photolyzed rhodopsin being converted to the G protein-activating metarhodopsin II (MII) conformation, whereas enrichment of cholesterol reduced the extent of MII formation. Time-resolved fluorescence anisotropy measurements using 1,6-diphenyl-1,3,5-hexatriene showed that increasing cholesterol reduced membrane acyl chain packing free volume as characterized by the parameter f(v).. The level of MII formed showed a positive linear correlation with f(v) over the range of 4 to 38 mol % cholesterol. In addition, the thermal stability of rhodopsin increased with mol % of cholesterol in disk membranes. No evidence was observed for the direct interaction of cholesterol with rhodopsin in either its agonist- or antagonist-bound form. These results indicate that cholesterol mediates the function of the G protein-coupled receptor, rhodopsin, by influencing membrane lipid properties, i.e. reducing acyl chain packing free volume, rather than interacting specifically with rhodopsin. C1 NIAAA, Lab Membrane Biochem & Biophys, Sect Fluorescences Studies, NIH, Rockville, MD 20852 USA. RP Litman, BJ (reprint author), 12420 Parklawn Dr,Rm 158, Rockville, MD 20852 USA. NR 39 TC 91 Z9 94 U1 3 U2 7 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 JUN 7 PY 2002 VL 277 IS 23 BP 20139 EP 20145 DI 10.1074/jbc.M200594200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500008 PM 11889130 ER PT J AU Lee, SR Yang, KS Kwon, J Lee, C Jeong, W Rhee, SG AF Lee, SR Yang, KS Kwon, J Lee, C Jeong, W Rhee, SG TI Reversible inactivation of the tumor suppressor PTEN by H2O2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; MAMMALIAN THIOREDOXIN REDUCTASE; TYROSINE-PHOSPHATASE 1B; AIRWAY SMOOTH-MUSCLE; HYDROGEN-PEROXIDE; PHOSPHATIDYLINOSITOL 3-KINASE; TRANSCRIPTIONAL ACTIVATION; PHOSPHOINOSITIDE 3-KINASE; AKT PHOSPHORYLATION; CATALYTIC DOMAIN AB The tumor suppressor PTEN regulates cell migration, growth, and survival by removing the T-phosphate of phosphoinositides. Exposure of purified PTEN or of cells to H2O2 resulted in inactivation of PTEN in a time-and H2O2 concentration-dependent manner. Analysis of various cysteine mutants, including mass spectrometry of tryptic peptides, indicated that the essential Cys(124) residue in the active site of PTEN specifically forms a disulfide with Cys(71) during oxidation by H2O2. The reduction of H2O2-oxidized PTEN in cells appears to be mediated predominantly by thioredoxin. Thus, thioredoxin was more efficient than glutaredoxin, glutathione, or a 14-kDa thioredoxin-like protein with regard to the reduction of oxidized PTEN in vitro. Thioredoxin co-immunoprecipitated with PTEN from cell lysates; and incubation of cells with 2,4-dinitro-1-chlorobenzene (an inhibitor of thioredoxin reductase) delayed the reduction of oxidized PTEN, whereas incubation with buthioninesulfoximine (an inhibitor of glutathione biosynthesis) did not. These results suggest that the reversible inactivation of PTEN by H2O2 might be important for the accumulation of 3'-phosphorylated phosphoinositides and that the uncontrolled generation of H2O2 associated with certain pathological conditions might contribute to cell proliferation by inhibiting PTEN function. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 50,Rm 3523, Bethesda, MD 20892 USA. NR 54 TC 550 Z9 566 U1 0 U2 17 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 JUN 7 PY 2002 VL 277 IS 23 BP 20336 EP 20342 DI 10.1074/jbc.M111899200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500032 PM 11916965 ER PT J AU Sandhoff, R Hepbildikler, ST Jennemann, R Geyer, R Gieselmann, V Proia, RL Wiegandt, H Grone, HJ AF Sandhoff, R Hepbildikler, ST Jennemann, R Geyer, R Gieselmann, V Proia, RL Wiegandt, H Grone, HJ TI Kidney sulfatides in mouse models of inherited glycosphingolipid disorders - Determination by nano-electrospray ionization tandem mass spectrometry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LINKED GLYCOPROTEIN OLIGOSACCHARIDES; CAPILLARY GAS-CHROMATOGRAPHY; NORMAL HUMAN-LEUKOCYTES; LEUKEMIA HL60 CELLS; LOW PICOMOLE LEVEL; COMPLEX GANGLIOSIDES; EMBRYONIC ANTIGEN-1; NERVOUS-SYSTEM; E-SELECTIN; TAY-SACHS AB Sulfatides show structural, and possibly physiological similarities to gangliosides. Kidney dysfunction might be correlated with changes in sulfatides, the major acidic glycosphingolipids in this organ. To elucidate their in vivo metabolic pathway these compounds were analyzed in mice afflicted with inherited glycosphingolipid disorders. The mice under study lacked the genes encoding either beta-hexosaminidase alpha-subunit (Hexa-/-), the beta-hexosaminidase beta-subunit (Hexb-/-), both beta-hexosaminidase a and beta-subunits (Hexa-/- and Hexb-/-), GD3 synthase (GD3S-/-), GD3 synthase and Ga1NAc transferase (GD3S-/- and GaINAcT-/-), GNU activator protein (Gm2a-/-), or arylsulfatase A (ASA-/-). Quantification of the sulfatides, (ISO3)-S-3--GalCer (SM4s), (IISO3-)-S-3. LacCer (SM3), (IISO3-)-S-3-Gg(3)Cer (SM2a), and IV3, II3-(SO3-)(2)-Gg(4)Cer (SB1a), was performed by nano-electrospray tandem mass spectrometry. We conclude for the in vivo situation in mouse kidneys that: 1) a single enzyme (GalNAc transferase) is responsible for the synthesis of SM2a and GNU from SM3 and GM3, respectively. 2) In analogy to GD1a, SB1a is degraded via SM2a. 3) SM2a is hydrolyzed to SM3 by beta-hexosaminidase S (Hex S) and Hex A, but not Hex B. Both enzymes are supported by GNU-activator protein. 4) Arylsulfatase A is required to degrade SB1a. It is probably the sole sphingolipid-sulfatase cleaving the galactosyl-3-sulfate bond. In addition, a human Tay-Sachs patient's liver was investigated, which showed accumulation of SM2a along with GNU storage. The different ceramide compositions of both compounds indicated they were probably derived from different cell types. These data demonstrate that in vivo the sulfatides of the ganglio-series follow the same metabolic pathways as the gangliosides with the replacement of sulfotransferases and sulfatases by sialyltransferases and sialidases. Furthermore, a novel neutral GSL, IV(6)GlcNAcbeta-Gb(4)Cer, was found to accumulate only in Hexa-/- and Hexb-/- mouse kidneys. From this we conclude that Hex S also efficiently cleaves terminal beta1-6-linked HexNAc residues from neutral GSLs in vivo. C1 Deutsch Krebsforschungszentrum, Abt Zellulare & Mol Pathol, D-69120 Heidelberg, Germany. Univ Bonn, Kekule Inst Organ Chem & Biochem, D-53121 Bonn, Germany. Univ Giessen Klinikum, Inst Biochem, D-35392 Giessen, Germany. Univ Bonn, Inst Physiol Chem, D-53115 Bonn, Germany. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deutsch Krebsforschungszentrum, Abt Zellulare & Mol Pathol, INF 280, D-69120 Heidelberg, Germany. EM r.sandhoff@dkfz-heidelberg.de RI Proia, Richard/A-7908-2012 NR 55 TC 39 Z9 40 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2002 VL 277 IS 23 BP 20386 EP 20398 DI 10.1074/jbc.M110641200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500038 PM 11919180 ER PT J AU Savitsky, PA Finkel, T AF Savitsky, PA Finkel, T TI Redox regulation of Cdc25C SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGE CHECKPOINT; CELL-CYCLE; SUPEROXIDE-DISMUTASE; CRYSTAL-STRUCTURE; PROTEIN-KINASE; ARREST; G(2); PHOSPHATASE; INHIBITION; PATHWAY AB The Cdc25 family of dual specific phosphatases are critical components of cell cycle progression and checkpoint control. Certain stresses such as ultraviolet light stimulate the rapid and selective destruction of Cdc25A protein through a Chk1 protein kinase-dependent pathway. We demonstrate that in contrast to cellular stresses previously examined, hydrogen peroxide exposure affects Cdc25C but not Cdc25A levels. Pharmacological inhibition of Chk1 activity or a mutant of Cdc25C that lacks the Chk1 phosphorylation site still undergoes degradation in response to oxidants. We also demonstrate that in vitro hydrogen peroxide stimulates an intramolecular disulfide bond between the active site cysteine at position 377 and another invariant cysteine at position 330. The in vivo stability of Cdc25C is substantially reduced by the mutation of either of these two cysteine residues. In contrast, a double (C2) mutant of both cysteine 330 and cysteine 377 results in a protein that is more stable than wild type Cdc25C and is resistant to oxidative stress-induced degradation. In addition, the C2 mutant, which is unable to form an intramolecular disulfide bond, has reduced binding to 14-3-3 in vitro and in vivo. These results suggest that oxidative stress may induce cell cycle arrest in part through the degradation of Cdc25C. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10 6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 27 TC 154 Z9 156 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2002 VL 277 IS 23 BP 20535 EP 20540 DI 10.1074/jbc.M201589200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500057 PM 11925443 ER PT J AU Lim, JH Bustin, M Ogryzko, VV Postnikov, YV AF Lim, JH Bustin, M Ogryzko, VV Postnikov, YV TI Metastable macromolecular complexes containing high mobility group nucleosome-binding chromosomal proteins in HeLa nuclei SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE ACETYLASE COMPLEX; SELF-ORGANIZATION; CHROMATIN; HMG-14; DOMAIN; PHOSPHORYLATION; ARCHITECTURE; COMPONENTS; ACTIVATION; DISTINCT AB High mobility group nucleosome-binding (HMGN) proteins belong to a family of nuclear proteins that bind to nucleosomes and enhance transcription from chromatin templates by altering the structure of the chromatin fiber. The intranuclear organization of these proteins is dynamic and related to the metabolic state of the cell. Here we report that similar to50% of the HMGN proteins are organized into macromolecular complexes in a fashion that is similar to that of other nuclear activities that modify the structure of the chromatin fiber. We identify several distinct HMGN-containing complexes that are relatively unstable and find that the inclusion of HMGN in the complexes varies according to the metabolic state of the cell. The nucleosome binding ability of HMGN in the complex is stronger than that of the free HMGN. We suggest that the inclusion of HMGN proteins into metastable multiprotein complexes serves to target the HMGN proteins to specific sites in chromatin and enhances their interaction with nucleosomes. C1 NCI, CCR, Prot Sect, NIH, Bethesda, MD 20892 USA. CNRS, UPR 9079, Inst Andre Lwoff, Lab Oncogenese, F-94801 Villejuif, France. RP Postnikov, YV (reprint author), NCI, CCR, Prot Sect, NIH, Bldg 37 Rm 3E-24, Bethesda, MD 20892 USA. RI Ogryzko, Vasily/M-6665-2015; Bustin, Michael/G-6155-2015 OI Ogryzko, Vasily/0000-0002-8548-1389; NR 43 TC 26 Z9 26 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 JUN 7 PY 2002 VL 277 IS 23 BP 20774 EP 20782 DI 10.1074/jbc.M200404200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500087 PM 11909857 ER PT J AU Ramakrishnan, B Qasba, PK AF Ramakrishnan, B Qasba, PK TI Structure-based design of beta 1,4-galactosyltransferase I (beta 4GaI-T1) with equally efficient N-acetylgalactosaminyltransferase activity - Point mutation broadens beta 4GaI-T1 donor specificity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-LACTALBUMIN; CRYSTAL-STRUCTURE; BOVINE; ACCEPTOR; EXPRESSION AB beta1,4-Galactosyltransferase I (Gal-T1) normally transfers Gal from LTDP-Gal to GlcNAc in the presence of Mn2+ ion. In the presence of alpha-lactalbumin (LA), the Gal acceptor specificity is altered from GlcNAc to Glc. Gal-T1 also transfers GaINAc from UDP-Ga1NAc to Glc-NAc, but with only similar to0.1% of Gal-T activity. To understand this low GaINAc-transferase activity, we have carried out the crystal structure analysis of the Gal-T1(.)LA complex with UDP-GalNAc at 2.1-Angstrom resolution. The crystal structure reveals that the LTDP-GalNAc binding to Gal-T1 is similar to the binding of LTDP-Gal to Gal-T1, except for an additional hydrogen bond formed between the N-acetyl group of GaINAc moiety with the Tyr-289 side chain hydroxyl group. Elimination of this additional hydrogen bond by mutating Tyr-289 residue to Leu, Ile, or Asn enhances the GaINAc-transferase activity. Although all three mutants exhibit enhanced GalNAc-transferase activity, the mutant Y289L exhibits GalNAc-transferase activity that is nearly 100% of its Gal-T activity, even while completely retaining its Gal-T activity. The steady state kinetic analyses on the Leu-289 mutant indicate that the K-m for GlcNAc has increased compared to the wild type. On the other hand, the catalytic constant (k(cat)) in the Gal-T reaction is comparable with the wild type, whereas it is 3-5-fold higher in the GaINAc-T reaction. Interestingly, in the presence of LA, these mutants also transfer GaINAc to Glc instead of to GlcNAc. The present study demonstrates that, in the Gal-T family, the Tyr-289/Phe-289 residue largely determines the sugar donor specificity. C1 NCI, Struct Glycobiol Sect, LECB, CCR,NIH, Frederick, MD 21702 USA. NCI, Intramural Res Support Program SAIC, LECB, CCR,NIH, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, LECB, CCR,NIH, Bldg 469,Rm 221, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 27 TC 109 Z9 115 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2002 VL 277 IS 23 BP 20833 EP 20839 DI 10.1074/jbc.M111183200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500094 PM 11916963 ER PT J AU Liu, J Tian, ZG Gao, B Kunos, G AF Liu, J Tian, ZG Gao, B Kunos, G TI Dose-dependent activation of antiapoptotic and proapoptotic pathways by ethanol treatment in human vascular endothelial cells - Differential involvement of adenosine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; GLYCOGEN-SYNTHASE KINASE-3; NF-KAPPA-B; MODERATE ALCOHOL-CONSUMPTION; CORONARY HEART-DISEASE; NITRIC-OXIDE SYNTHASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; MOLECULAR-CLONING; INDUCED APOPTOSIS AB Moderate but not heavy drinking has been found to have a protective effect against cardiovascular morbidity. We investigated the effects of ethanol (EtOH) treatment on the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt pathway in cultured human umbilical vein endothelial cells (HUVEC). Exposure of cells to 2-20 mm EtOH resulted in rapid (< 10 min) induction of Akt phosphorylation that could be prevented by pertussis toxin or the PI3K inhibitors wortmannin and LY294002. Among the downstream effectors of PI3K/Akt, p70S6 kinase, glycogen synthase kinase 3alpha/p, and IKB-alpha were phosphorylated, the latter resulting in 3-fold activation of NF-kappaB. EtOH also activated p44/42 mitogenactivated protein kinase in a PI3K-dependent manner. Low concentrations of EtOH increased endothelial nitric-oxide synthase activity, which could be blocked transfection of HUVEC with dominant-negative Akt, implicating the PI3K/Akt pathway in this effect. The adenosine Al receptor antagonist 1,3-dipopyleyclopentylxanthine prevented the phosphorylation of Akt observed in the presence of EtOH, adenosine, or the Al agonist N-6-cyclopentyladenosine. Incubation of HUVEC with 50100 mm EtOH resulted in mitochondrial permeability transition and caspase-3 activation followed by apoptosis, as documented by DNA fragmentation and TUNEL assays. EtOH-induced apoptosis was unaffected by DPCPX and was potentiated by wortmannin or LY294002. We conclude that treatment with low concentrations of EtOH activates the cell survival promoting PI3K/Akt pathway in endothelial cells by an adenosine receptor-dependent mechanism and activation of the proapoptotic caspase pathway by higher concentrations of EtOH via an adenosine-independent mechanism can mask or counteract such effects. C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP NIAAA, Lab Physiol Studies, NIH, 12420 Parklawn Dr,Rm 120,MSC 8115, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov RI Tian, Zhigang/J-3512-2013 NR 57 TC 45 Z9 45 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2002 VL 277 IS 23 BP 20927 EP 20933 DI 10.1074/jbc.M110712200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500106 PM 11919181 ER PT J AU Kang, SG Ortega, J Singh, SK Wang, N Huang, NN Steven, AC Maurizi, MR AF Kang, SG Ortega, J Singh, SK Wang, N Huang, NN Steven, AC Maurizi, MR TI Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI CLPP; SACCHAROMYCES-CEREVISIAE; SPASTIC PARAPLEGIA; BACTERIAL CLPX; PIM1 PROTEASE; HUMAN HOMOLOG; PROTEINS; DEGRADATION; CHAPERONE; SEQUENCE AB Human mitochondrial ClpP (hClpP) and ClpX (hClpX) were separately cloned, and the expressed proteins were purified. Electron microscopy confirmed that hClpP forms heptameric rings and that hClpX forms a hexameric ring. Complexes of a double heptameric ring of hClpP with hexameric hClpX rings bound on each side are stable in the presence of ATP or adenosine 5'-(3-thiotriphosphate) (ATPgammaS), indicating that a symmetry mismatch is a universal feature of Clp proteases. hClpXP displays both ATP-dependent proteolytic activity and ATP- or ATPgammaS-dependent peptidase activity. hClpXP cannot degrade lambdaO protein or GFP-SsrA, specific protein substrates recognized by Escherichia coli (e) ClpXP. However, eClpX interacts with hClpP, and, when examined by electron microscopy, the resulting heterologous complexes are indistinguishable from homologous eClpXP complexes. The hybrid eClpX-hClpP complexes degrade eClpX-specific protein substrates. In contrast, eClpA can neither associate with nor activate hClpP. hClpP has an extra C-terminal extension of 28 amino acids. A mutant lacking this C-terminal extension interacts more tightly with both hClpX and eClpX and shows enhanced enzymatic activities but still does not interact with eCIpA. Our results establish that human ClpX and ClpP constitute a bone fide ATP-dependent protease and confirm that substrate selection, which differs between human and E. coli ClpX, is dependent solely on the Clp ATPase. Our data also indicate that human ClpP has conserved sites required for interaction with eClpX but not eCIpA, implying that the modes of interaction with ClpP may not be identical for ClpA and ClpX. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37 Room 1B09,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 41 TC 66 Z9 69 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 7 PY 2002 VL 277 IS 23 BP 21095 EP 21102 DI 10.1074/jbc.M201642200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500125 PM 11923310 ER PT J AU Gu, YJ Reshetnikova, L Li, Y Wu, Y Yan, HG Singh, S Ji, XH AF Gu, YJ Reshetnikova, L Li, Y Wu, Y Yan, HG Singh, S Ji, XH TI Crystal structure of shikimate kinase from Mycobacterium tuberculosis reveals the dynamic role of the LID domain in catalysis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE shikimate pathway; shikimate kinase; X-ray crystallography; phosphoryl transfer; drug design ID NUCLEOSIDE MONOPHOSPHATE KINASES; ESCHERICHIA-COLI; ADENYLATE KINASE; DIFFRACTION DATA; SUBSTRATE-SPECIFICITY; GUANYLATE KINASE; URIDYLATE KINASE; PATHWAY; COMPLEX; BINDING AB Shikimate kinase (SK) and other enzymes in the shikimate pathway are potential targets for developing non-toxic antimicrobial agents, herbicides, and anti-parasite drugs, because the pathway is essential in the above species but is absent from mammals. The crystal structure of Mycobacterium tuberculosis SK (MtSK) in complex with MgADP has been determined at 1.8 Angstrom resolution, revealing critical information for the structure-based design of novel anti-M. tuberculosis agents. MtSK, with a five-stranded parallel beta-sheet flanked by eight alpha-helices, has three domains: the CORE domain, the shikimate-binding domain (SB), and the LID domain. The ADP molecule is bound with its adenine moiety sandwiched between the side-chains of Arg110 and Pro155, its beta-phosphate group in the P-loop, and the alpha and beta-phosphate groups hydrogen bonded to the guanidinium group of Arg117. Arg117 is located in the LID domain, is strictly conserved in SK sequences, is observed for the first time to interact with any bound nucleotide, and appears to be important in both substrate binding and catalysis. The crystal structure of MtSK (this work) and that of Erwinia chrysanthemi SK suggest a concerted conformational change of the LID and SB domains upon nucleotide binding. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Pittsburgh, Univ Pittsburgh Canc Inst, Sch Med, Pittsburgh, PA 15620 USA. Univ Pittsburgh, Dept Pharmacol, Sch Med, Pittsburgh, PA 15620 USA. Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NCI NIH HHS [CA 55589, R01 CA 76348]; NIGMS NIH HHS [GM 51901] NR 38 TC 52 Z9 58 U1 1 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 JUN 7 PY 2002 VL 319 IS 3 BP 779 EP 789 DI 10.1016/S0022-2836(02)00339-X PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 565QB UT WOS:000176380000015 PM 12054870 ER PT J AU Stoll, S Delon, J Brotz, TM Germain, RN AF Stoll, S Delon, J Brotz, TM Germain, RN TI Dynamic imaging of T cell-dendritic cell interactions in lymph nodes SO SCIENCE LA English DT Article ID IN-VIVO; ANTIGEN PRESENTATION; IMMUNOLOGICAL SYNAPSE; LYMPHOCYTES; ACTIVATION; CD4; REDISTRIBUTION; INFECTION; IMMUNITY; MOESIN AB T cell immune responses begin within organized lymphoid tissues. The pace, topology, and outcomes of the cellular interactions that underlie these responses have, so far, been inferred from static imaging of sectioned tissue or from studies of cultured cells. Here we report dynamic visualization of antigen-specific T cells interacting with dendritic cells within intact explanted lymph nodes. We observed immunological synapse formation and prolonged interactions between these two coil types, followed by the activation, dissociation, and rapid migration of T cells away from the antigenic stimulus. This high-resolution spatiotemporal analysis provides insight into the nature of cell interactions critical to early immune responses within lymphoid structures. C1 NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Brotz, Tilmann/R-6599-2016 OI Brotz, Tilmann/0000-0001-8212-459X NR 28 TC 458 Z9 480 U1 2 U2 25 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 JUN 7 PY 2002 VL 296 IS 5574 BP 1873 EP 1876 DI 10.1126/science.1071065 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559YP UT WOS:000176054300050 PM 12052961 ER PT J AU Pettit, GR Grealish, MP Jung, MK Hamel, E Pettit, RK Chapuis, JC Schmidt, JM AF Pettit, GR Grealish, MP Jung, MK Hamel, E Pettit, RK Chapuis, JC Schmidt, JM TI Antineoplastic agents. 465. Structural modification of resveratrol: Sodium resverastatin phosphate SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TRANS-RESVERATROL; RED WINE; CELLS; DERIVATIVES; PHYTOALEXIN; GROWTH; 3,5,4'-TRIHYDROXYSTILBENE; PTEROSTILBENE; AGGREGATION; COLCHICINE AB As an extension of structure/activity investigations of resveratrol (1), phenstatin (2c), and the cancer antiangiogenesis drug sodium combretastatin A-4 phosphate (2b), syntheses of certain related stilbenes (14) and benzophenones (16) were undertaken. The trimethyl ether derivative of (Z)-resveratrol (4a) exhibited the strongest activity (GI(50) = 0.01-0.001 mug/mL) against a minipanel of human cancer cell lines. A monodemethylated derivative (14c) was converted to prodrug 14n (sodium resverastatin phosphate) for further biological evaluation. The antitubulin and antimicrobial activities of selected compounds were also evaluated. C1 Arizona State Univ, Inst Canc Res, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Ft Detrick, MD 21702 USA. NCI, Sci Applicat Int Corp, NIH, Frederick, MD 21702 USA. RP Pettit, GR (reprint author), Arizona State Univ, Inst Canc Res, POB 872404, Tempe, AZ 85287 USA. FU NCI NIH HHS [N01-CO-56000, CA 44344-05-12, R01 CA 90441-01] NR 45 TC 133 Z9 135 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 6 PY 2002 VL 45 IS 12 BP 2534 EP 2542 DI 10.1021/jm010119y PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 558GJ UT WOS:000175957700021 PM 12036362 ER PT J AU Flynn, BL Hamel, E Jung, MK AF Flynn, BL Hamel, E Jung, MK TI One-pot synthesis of benzo[b]furan and indole inhibitors of tubulin polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COMBRETASTATIN A4 PHOSPHATE; SOLID TUMOR-THERAPY; ANTINEOPLASTIC AGENTS; COUPLING APPROACH; BINDING-AGENTS; ARYL HALIDES; IN-VITRO; A-4; COLCHICINE; CYCLIZATION AB Benzo[b]furan and indole analogues of some recently identified benzo[b]thiophene inhibitors of tubulin polymerization have been prepared, and their biological activity has been assessed. Several very potent analogues were identified. C1 Australian Natl Univ, Dept Chem, Canberra, ACT 0200, Australia. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, NIH, Frederick, MD 21702 USA. RP Flynn, BL (reprint author), Australian Natl Univ, Dept Chem, Canberra, ACT 0200, Australia. FU NCI NIH HHS [N01-CO-1240] NR 32 TC 186 Z9 191 U1 2 U2 22 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 JUN 6 PY 2002 VL 45 IS 12 BP 2670 EP 2673 DI 10.1021/jm020077t PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 558GJ UT WOS:000175957700037 PM 12036378 ER PT J AU Klar, AJS AF Klar, AJS TI Fibonacci's flowers SO NATURE LA English DT Editorial Material ID INHERITANCE; PATTERN C1 NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NR 4 TC 16 Z9 16 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 6 PY 2002 VL 417 IS 6889 BP 595 EP 595 DI 10.1038/417595a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559AE UT WOS:000176001200025 PM 12050641 ER PT J AU Saftlas, AF Levine, RJ AF Saftlas, AF Levine, RJ TI The interval between pregnancies and preeclampsia. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ABORTION; RISK C1 Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. NICHHD, Bethesda, MD 20892 USA. RP Saftlas, AF (reprint author), Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. NR 5 TC 3 Z9 3 U1 0 U2 1 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 JUN 6 PY 2002 VL 346 IS 23 BP 1831 EP 1832 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 559EK UT WOS:000176012500028 PM 12050350 ER PT J AU Skjaerven, R Wilcox, AJ Lie, RT AF Skjaerven, R Wilcox, AJ Lie, RT TI The interval between pregnancies and preeclampsia. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RISK; PATERNITY C1 Univ Bergen, N-5021 Bergen, Norway. NIEHS, Res Triangle Pk, NC 27709 USA. RP Skjaerven, R (reprint author), Univ Bergen, N-5021 Bergen, Norway. NR 6 TC 0 Z9 0 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 JUN 6 PY 2002 VL 346 IS 23 BP 1832 EP 1832 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 559EK UT WOS:000176012500029 ER PT J AU Yu, CY Wang, LH Khaletskiy, A Farrar, WL Larner, A Colburn, NH Li, JH AF Yu, CY Wang, LH Khaletskiy, A Farrar, WL Larner, A Colburn, NH Li, JH TI STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells SO ONCOGENE LA English DT Article DE transcription factor; STAT3; transformation response; matrix metalloproteinase; mouse skin cells ID NF-KAPPA-B; EPIDERMAL GROWTH-FACTOR; ANCHORAGE-INDEPENDENT GROWTH; BREAST-CANCER CELLS; TRANSCRIPTION FACTORS; MATRIX METALLOPROTEINASES; TYROSINE PHOSPHORYLATION; CELLULAR-TRANSFORMATION; INTRACELLULAR DOMAIN; SIGNAL-TRANSDUCTION AB STAT3, a member of signal transducers and activators of transcription (STATs) originally discovered as mediators in cytokine signaling pathways, plays an active role in oncogenesis. However, the function of STAT3 in signaling multistage carcinogenesis, especially in transformation of tumor-promotion sensitive epithelial cells has not been elucidated. The present study demonstrates that STAT3 is activated in interleukin-6 induced transformation in mouse skin epithelial cells. DNA binding and transcriptional activities of STAT3 were significantly increased by interleukin-6. This induced anchorage-independent transformation in tumor-promotion sensitive JB6 mouse skin P+ cells but not in the resistant variant P- cells. Two forms of dominant negative STAT3 (mutant of transcriptional domain, mF, or DNA-binding domain, mD) were stably transfected into P+ cells. Activation of STAT3 was abolished and importantly, interleukin-6 induced anchorage-independent growth was absent in both mutant STAT3 transfectants. To determine the genes targeted by STAT3, three matrix metalloproteinase proteins linked with carcinogenesis of epithelial cells were analysed. Both basal and interleukin-6 induced expression of collagenase I and stromelysin I, but not gelatinase A, were inhibited in the mutant STAT3 transfectants. Furthermore, transfection of a wild type STAT3 restored STAT3 transactivation and response to interleukin-6 induced transformation in mutant STAT3 transfectants, which up-regulated collagenase I and stromelysin I as well. Together, these results provide the first evidence that STAT3 activation is required in the progression of multistage carcinogenesis of mouse skin epithelial cells, and matrix metalloproteinases are actively involved in STAT3-mediated cell transformation. C1 City Hope Natl Med Ctr, Beckman Res Inst, Div Radiat Oncol, Duarte, CA 91010 USA. NCI, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. NCI, Cytokine Mol Mech Sect, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. NCI, Lab Basic Res, NIH, Frederick, MD 21702 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, Cleveland, OH 44106 USA. RP Li, JH (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Div Radiat Oncol, Halper S Bldg,H115,1500 Duarte Rd, Duarte, CA 91010 USA. NR 67 TC 28 Z9 28 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 JUN 6 PY 2002 VL 21 IS 25 BP 3949 EP 3960 DI 10.1038/js.onc.1205499 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 556VP UT WOS:000175869900001 PM 12037677 ER PT J AU Zeng, XC Wang, SX AF Zeng, XC Wang, SX TI Evidence that BmTXK beta-BmKCT cDNA from Chinese scorpion Buthus martensii Karsch is an artifact generated in the reverse transcription process SO FEBS LETTERS LA English DT Letter ID MOLECULAR-CLONING; PEPTIDES C1 Wuhan Univ, Coll Life Sci, Inst Virol, Dept Biotechnol, Wuhan 430072, Peoples R China. RP Zeng, XC (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2529,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 6 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 5 PY 2002 VL 520 IS 1-3 BP 183 EP 184 AR PII S0014-5793(02)02812-0 DI 10.1016/S0014-5793(02)02812-0 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 561QL UT WOS:000176153000036 PM 12044895 ER PT J AU Zujewski, JA AF Zujewski, JA TI "Build quality in" - HER2 testing in the real world SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID NEGATIVE BREAST-CANCER; PROGNOSTIC-SIGNIFICANCE; MONOCLONAL-ANTIBODY; NEU ONCOGENE; OVEREXPRESSION; ERBB-2; CHEMOTHERAPY; EXPRESSION; RECEPTOR; AMPLIFICATION C1 NCI, Ctr Canc Res, NIH, Med Branch, Bethesda, MD 20892 USA. RP Zujewski, JA (reprint author), NCI, Ctr Canc Res, NIH, Med Branch, 10 Ctr Dr,Bldg 10,Rm 12N-226, Bethesda, MD 20892 USA. NR 19 TC 10 Z9 10 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 JUN 5 PY 2002 VL 94 IS 11 BP 788 EP 789 PG 2 WC Oncology SC Oncology GA 558UG UT WOS:000175984600002 PM 12048261 ER PT J AU Parmiani, G Castelli, C Dalerba, P Mortarini, R Rivoltini, L Marincola, FM Anichini, A AF Parmiani, G Castelli, C Dalerba, P Mortarini, R Rivoltini, L Marincola, FM Anichini, A TI Cancer immunotherapy with peptide-based vaccines: What have we achieved? - Where are we going? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID CYTOLYTIC T-LYMPHOCYTES; COLONY-STIMULATING FACTOR; HUMAN-MELANOMA ANTIGEN; ANTITUMOR IMMUNE-RESPONSES; TUMOR-REACTIVE CTL; PHASE-I TRIAL; PERIPHERAL-BLOOD LYMPHOCYTES; INCOMPLETE FREUNDS-ADJUVANT; AUTOLOGOUS DENDRITIC CELLS; NECROSIS-FACTOR-ALPHA AB Many human tumor-associated antigens (TAAs) have recently been identified and molecularly characterized. When bound to major histocompatibility complex molecules, TAA peptides are recognized by, T cells. Clinical studies have therefore been initiated to assess the therapeutic potential of active immunization or vaccination with TAA peptides in patients with metastatic cancer. So far, only a limited number of TAA peptides, mostly those recognized by CD8(+) T cells in melanoma patients, have been clinically tested. In some clinical trials, partial or complete tumor regression was observed in approximately 10%-30% of patients. No serious side effects have been reported. The clinical responses, however, were often not associated with a detectable T-cell-specific antitumor immune response when patients' T cells were evaluated in ex vivo assays. In this review, we analyze the available human TAA peptides, the potential immunogenicity (i.e., the ability to trigger a tumor-specific T-cell response) of TAA peptides in vitro and ex vivo, and the potential to construct slightly modified forms of TAA peptides that have increased T-cell stimulatory activity. We discuss the available data from clinical trials of TAA peptide-based vaccination (including those that used dendritic cells to present TAA peptides), identify possible reasons for the limited clinical efficacy of these vaccines, and suggest ways to improve the clinical outcome of TAA peptide-based vaccination for cancer patients. C1 Ist Nazl Studio & Cura Tumori, Unit Immunotherapy Human Tumors, I-20133 Milan, Italy. Ist Nazl Studio & Cura Tumori, Unit Immunobiol Human Tumors, I-20133 Milan, Italy. NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Parmiani, G (reprint author), Ist Nazl Studio & Cura Tumori, Unit Immunotherapy Human Tumors, Via Venezian 1, I-20133 Milan, Italy. RI Anichini, Andrea/K-1434-2016; Mortarini, Roberta/C-9483-2017; castelli, chiara/K-6899-2012; OI Anichini, Andrea/0000-0001-5096-5538; Mortarini, Roberta/0000-0001-7732-0561; castelli, chiara/0000-0001-6891-8350; Rivoltini, Licia/0000-0002-2409-6225; Dalerba, Piero/0000-0002-8815-4981 NR 143 TC 275 Z9 291 U1 1 U2 31 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 JUN 5 PY 2002 VL 94 IS 11 BP 805 EP 818 PG 14 WC Oncology SC Oncology GA 558UG UT WOS:000175984600008 PM 12048268 ER PT J AU Lan, Q Chapman, RS Schreinemachers, DM Tian, LW He, XZ AF Lan, Q Chapman, RS Schreinemachers, DM Tian, LW He, XZ TI Household stove improvement and risk of lung cancer in Xuanwei, China SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INDOOR AIR-POLLUTION; WOOD COMBUSTION EMISSIONS; MALE BRITISH DOCTORS; DEVELOPING-COUNTRIES; RESPIRATORY-INFECTIONS; SMOKING CESSATION; FUEL COMBUSTION; COOKING FUEL; MORTALITY; WOMEN AB Background: Lung cancer rates in rural Xuanwei County, Yunnan Province, are among the highest in China. Residents traditionally burned "smoky" coal in unvented indoor firepits that generated very high levels of air pollution. Since the 1970s, most residents have changed from firepits to stoves with chimneys. This study assessed whether lung cancer incidence decreased after this stove improvement. Methods: A cohort of 21232 farmers, born from 1917 through 1951, was followed retrospectively from 1976 through 1992. All subjects were users of smoky coal who had been born into homes with unvented firepits. During their lifetime, 17184 subjects (80.9%) changed permanently to stoves with chimneys. A hospital record search detected 1384 cases of lung cancer (6.5%) during follow-up. Associations of stove improvement with lung cancer incidence were analyzed with product-limit plots and multivariable Cox models. In 1995, indoor concentrations of airborne particles and benzo[a]pyrene were compared in Xuanwei homes during smoky coal burning in stoves with chimneys and in unvented stoves or firepits. Results: A long-term reduction in lung cancer incidence was noted after stove improvement. In Cox models, risk ratios (RRs) for lung cancer after stove improvement were 0.59 (95% confidence interval [CI] = 0.49 to 0.71) in men and 0.54 (95% CI = 0.44 to 0.65) in women (for both, P<.001). Incidence reduction became unequivocal about 10 years after stove improvement. Levels of indoor air pollution during burning with chimneys were less than 35% of levels during unvented burning. Conclusion: Changing from unvented to vented stoves appears to benefit the health of people in China and may do so in other developing countries as well. C1 US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. Chinese Acad Prevent Med, Inst Environm Hlth & Engn, Beijing, Peoples R China. NCI, NIH, Bethesda, MD 20892 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. RP Chapman, RS (reprint author), US EPA, Natl Ctr Environm Assessment, MD-52, Res Triangle Pk, NC 27711 USA. RI Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 NR 47 TC 141 Z9 155 U1 3 U2 34 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 JUN 5 PY 2002 VL 94 IS 11 BP 826 EP 835 PG 10 WC Oncology SC Oncology GA 558UG UT WOS:000175984600010 PM 12048270 ER PT J AU Paik, S Bryant, J Tan-Chiu, E Romond, E Hiller, W Park, K Brown, A Yothers, G Anderson, S Smith, R Wickerham, DL Wolmark, N AF Paik, S Bryant, J Tan-Chiu, E Romond, E Hiller, W Park, K Brown, A Yothers, G Anderson, S Smith, R Wickerham, DL Wolmark, N TI Real-world performance of HER2 testing - National surgical adjuvant breast and bowel project experience SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IN-SITU HYBRIDIZATION; PROTEIN OVEREXPRESSION; GENE AMPLIFICATION; IMMUNOHISTOCHEMISTRY; CARCINOMA; CANCER; REPRODUCIBILITY AB Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest(TM) IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide. C1 NSABP, Allegheny Ctr 4, Div Pathol, Operat Ctr, Pittsburgh, PA 15212 USA. NSABP, Ctr Biostat, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Kentucky, Div Hematol Oncol, Lucille P Markey Canc Ctr, Lexington, KY USA. Amer Holdings, Lab Corp, Ctr Mol Biol & Pathol, Res Triangle Pk, NC USA. RP Paik, S (reprint author), NSABP, Allegheny Ctr 4, Div Pathol, Operat Ctr, 5th Floor,E Commons,Profess Bldg, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10CA12027, U10CA37377, U10CA69651, U10CA69974] NR 16 TC 342 Z9 355 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 5 PY 2002 VL 94 IS 11 BP 852 EP 854 PG 3 WC Oncology SC Oncology GA 558UG UT WOS:000175984600013 PM 12048273 ER PT J AU Gail, MH Katki, HA AF Gail, MH Katki, HA TI Re: All-cause mortality in randomized trials of cancer screening SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 8032, Bethesda, MD 20892 USA. RI Katki, Hormuzd/B-4003-2015 NR 2 TC 10 Z9 10 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 JUN 5 PY 2002 VL 94 IS 11 BP 862 EP 862 PG 1 WC Oncology SC Oncology GA 558UG UT WOS:000175984600018 PM 12048278 ER PT J AU Shchelkunov, SN Totmenin, AV Safronov, PF Mikheev, MV Gutorov, VV Ryazankina, OI Petrov, NA Babkin, IV Uvarova, EA Sandakhchiev, LS Sisler, JR Esposito, JJ Damon, IK Jahrling, PB Moss, B AF Shchelkunov, SN Totmenin, AV Safronov, PF Mikheev, MV Gutorov, VV Ryazankina, OI Petrov, NA Babkin, IV Uvarova, EA Sandakhchiev, LS Sisler, JR Esposito, JJ Damon, IK Jahrling, PB Moss, B TI Analysis of the monkeypox virus genome SO VIROLOGY LA English DT Review ID DEPENDENT RNA-POLYMERASE; TEMPERATURE-SENSITIVE MUTANTS; EXTRACELLULAR ENVELOPED VIRUS; INVERTED TERMINAL REPETITION; EARLY TRANSCRIPTION FACTOR; THYMIDINE KINASE GENE; TRIPHOSPHATE PHOSPHOHYDROLASE-I; NUCLEOTIDE-SEQUENCE ANALYSIS; COMPLEMENT CONTROL PROTEINS; ACTIN-CONTAINING MICROVILLI AB Monkeypox virus (MPV) belongs to the orthopoxvirus genus of the family Poxviridae, is endemic in parts of Africa, and causes a human disease that resembles smallpox. The 196,858-by MPV genome was analyzed with regard to structural features and open reading frames. Each end of the genome contains an identical but oppositely oriented 6379-bp terminal inverted repetition, which similar to that of other orthopoxviruses, includes a putative telomere resolution sequence and short tandem repeats. Computer-assisted analysis was used to identify 190 open reading frames containing greater than or equal to60 amino acid residues. Of these, four were present within the inverted terminal repetition. MPV contained the known essential orthopoxvirus genes but only a subset of the putative immunomodulatory and host range genes. Sequence comparisons confirmed the assignment of MPV as a distinct species of orthopoxvirus that is not a direct ancestor or a direct descendent of variola virus, the causative agent of smallpox. C1 State Res Ctr Virol & Biotechnol Vector, Koltsov 630559, Russia. NIAID, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Moss, B (reprint author), State Res Ctr Virol & Biotechnol Vector, Koltsov 630559, Russia. RI Sandakhchiev, Lev/B-7035-2012; Babkin, Igor/R-1598-2016 NR 224 TC 52 Z9 59 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 JUN 5 PY 2002 VL 297 IS 2 BP 172 EP 194 DI 10.1006/viro.2002.1446 PG 23 WC Virology SC Virology GA 573HG UT WOS:000176822800002 PM 12083817 ER PT J AU Sadqi, M Hernandez, F Pan, UM Perez, M Schaeberle, MD Avila, J Munoz, V AF Sadqi, M Hernandez, F Pan, UM Perez, M Schaeberle, MD Avila, J Munoz, V TI alpha-helix structure in Alzheimer's disease aggregates of tau-protein SO BIOCHEMISTRY LA English DT Article ID AMYLOID FIBRIL FORMATION; X-RAY-DIFFRACTION; CIRCULAR-DICHROISM; BETA-STRUCTURE; NEUROFIBRILLARY TANGLES; SECONDARY STRUCTURE; FILAMENTS; STABILITY; CORE; FIBERS AB The discovery of beta-sheet structure in Alzheimer's amyloid fibrils, and then in many other disease-related protein fibrils, has led to the widely believed view that beta-sheet formation is the general mechanism of aberrant protein aggregation leading to disease. This notion is further reinforced by recent findings, which indicate that normal proteins can be induced to form beta-sheet fibrils in vitro. Alzheimer's disease, a paradigm proteopathy, is accompanied by the formation of two distinct aggregates, amyloid fibrils and paired helical filaments (PHFs). Electron microscope images of PHFs show pairs of twisted ribbons with 80 nm periodicity. However, there is little information of the molecular structure of PHFs, as previous studies have failed to identify signs of regular structure. Using far-UV circular dichroism and Fourier-transformed infrared spectroscopy, we find that PHFs are comprised of alpha-helices. This is remarkable as tau-protein, PHF's primary constituent, has a high abundance of helix-breaking amino acids and is unstructured in solution. We also find that PHFs are very stable, as judged by their high melting temperature and resistance to protease digestion. PHFs are the first example of pathological aggregation associated to the formation of alpha-helix. C1 Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. Univ Maryland, Ctr Biomol Struct & Org, College Pk, MD 20742 USA. Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Munoz, V (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RI Hernandez, Felix/L-2114-2015 OI Hernandez, Felix/0000-0001-8753-8249 NR 42 TC 76 Z9 77 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 4 PY 2002 VL 41 IS 22 BP 7150 EP 7155 DI 10.1021/bi025777e PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 558LC UT WOS:000175966900031 PM 12033949 ER PT J AU Chow, YH Wei, OL Phogat, S Sidorov, IA Fouts, TR Broder, CC Dimitrov, DS AF Chow, YH Wei, OL Phogat, S Sidorov, IA Fouts, TR Broder, CC Dimitrov, DS TI Conserved structures exposed in HIV-1 envelope glycoproteins stabilized by flexible linkers as potent entry inhibitors and potential immunogens SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INTERMOLECULAR DISULFIDE BOND; MONOCLONAL-ANTIBODIES; HUMORAL RESPONSE; GP41 SUBUNITS; BINDING; GP120; FUSION; CD4; COMPLEX AB The HIV-1 envelope glycoprotein (Env) undergoes conformational changes while driving entry. We hypothesized that some of the intermediate Env conformations could be represented in tethered constructs where gp120 and the ectodomain of gp41 are joined by flexible linkers. Tethered Envs with long linkers (gp140-14 with 15 aa and gp140-24 with 26 aa) were stable and recognized by conformationally dependent anti-gp120 and anti-ap41 monoclonal antibodies (mAbs). Surprisingly, these proteins potently inhibited membrane fusion mediated by R5, X4, and R5X4 Envs with 5-100-fold lower IC50 than a tethered Env with short linker (gp140-4 with 4 aa), gp 120, gp 140, soluble CD4, or DP178 (T20). Compared to gp 140, gp140-14,24 exhibited increased binding to anti-gp41 cluster II mAbs but not to cluster I mAbs. Cluster II mAbs but not cluster I, IV, or V mAbs reversed the inhibitory effect of gp140-14,24 suggesting a rote of exposed conserved gp41 structures for the mechanism of inhibition. These findings suggest the existence of conserved gp41 structures that are important for HIV-1 entry and can be stably exposed in the native environment of the Env even in the absence of receptor-mediated activation. Thus, tethered Envs with long linkers may not only be important as HIV-1 inhibitors but also for elucidation of viral entry mechanisms and development of novel vaccine immunogens. C1 NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. RP Dimitrov, DS (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bldg 469,Rm 246,POB B,Miller Dr, Frederick, MD 21702 USA. RI Chow, Yen-Hung /E-3863-2010; OI Fouts, Timothy/0000-0002-2429-2859; Sidorov, Igor/0000-0001-6519-4983 FU NHLBI NIH HHS [R01 HL59796]; NIAID NIH HHS [AI47490, AI47697, AI47066] NR 38 TC 14 Z9 14 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 JUN 4 PY 2002 VL 41 IS 22 BP 7176 EP 7182 DI 10.1021/bi025646d PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 558LC UT WOS:000175966900034 PM 12033952 ER PT J AU Spooner, PM Zipes, DP AF Spooner, PM Zipes, DP TI Sudden death predictors - An inflammatory association SO CIRCULATION LA English DT Editorial Material DE editorials; death, sudden; inflammation; protein, C-reictive ID BLOOD-INSTITUTE WORKSHOP; C-REACTIVE PROTEIN; CARDIAC DEATH; NATIONAL-HEART; RISK FACTOR; POPULATION; LUNG; ARRHYTHMOGENESIS; ARRHYTHMIAS; GENES C1 Indiana Univ, Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Zipes, DP (reprint author), Indiana Univ, Sch Med, Krannert Inst Cardiol, 1800 N Capitol Ave,Suite E475, Indianapolis, IN 46202 USA. OI Zipes, Douglas/0000-0001-7141-6829 NR 18 TC 10 Z9 10 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 JUN 4 PY 2002 VL 105 IS 22 BP 2574 EP 2576 DI 10.1161/01.CIR.0000017821.98250.25 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559UE UT WOS:000176043100002 PM 12045156 ER PT J AU Germain, RN AF Germain, RN TI Two hats too many SO CURRENT BIOLOGY LA English DT Editorial Material AB My Word: Ronald N. Germain believes it's time scientists eliminated splits in their personality between researching and reviewing. C1 NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bldg 10,Rm 11N311,10 Ctr Dr,MSC-1892, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 4 PY 2002 VL 12 IS 11 BP R376 EP R376 DI 10.1016/S0960-9822(02)00875-8 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 560MH UT WOS:000176085500002 ER PT J AU Caplan, S Naslavsky, N Hartnell, LM Lodge, R Polishchuk, RS Donaldson, JG Bonifacino, JS AF Caplan, S Naslavsky, N Hartnell, LM Lodge, R Polishchuk, RS Donaldson, JG Bonifacino, JS TI A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane SO EMBO JOURNAL LA English DT Article DE Arf6; clathrin-independent; EHD1; MHC class I; recycling ID RECEPTOR-MEDIATED ENDOCYTOSIS; ADAPTER-LIKE PROTEIN; COATED VESICLES; CELL-SURFACE; CLATHRIN; PATHWAY; ARF6; EH; TRAFFICKING; ASSOCIATION AB The Eps15 homology (EH) domain-containing protein, EHD1, has recently been ascribed a role in the recycling of receptors internalized by clathrin-mediated endocytosis. A subset of plasma membrane proteins can undergo internalization by a clathrin-independent pathway regulated by the small GTP-binding protein ADP-ribosylation factor 6 (Arf6). Here, we report that endogenous EHD proteins, as well as transgenic tagged EHD1, are associated with long, membrane-bound tubules containing Arf6. EHD1 appears to induce tubule formation, which requires nucleotide cycling on Arf6 and intact microtubules. Mutations in the N-terminal P-loop domain or deletion of the C-terminal EH domain of EHD1 prevent association of EHD1 with tubules or induction of tubule formation. The EHD1 tubules contain internalized major histocompatibility complex class I (MHC-I) molecules that normally traffic through the Arf6 pathway. Recycling assays show that overexpression of EHD1 enhances MHC-I recycling. These observations suggest an additional function of EHD1 as a tubule-inducing factor in the Arf6 pathway for recycling of plasma membrane proteins internalized by clathrin-independent endocytosis. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Consorzio Mario Negri Sud, Ist Ric Farmacol Mario Negri, Dept Cell Biol & Oncol, Chieti, Italy. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 53 TC 190 Z9 191 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 3 PY 2002 VL 21 IS 11 BP 2557 EP 2567 DI 10.1093/emboj/21.11.2557 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 557MN UT WOS:000175912500006 PM 12032069 ER PT J AU Dorr, A Kiermer, V Pedal, A Rackwitz, HR Henklein, P Schubert, U Zhou, MM Verdin, E Ott, M AF Dorr, A Kiermer, V Pedal, A Rackwitz, HR Henklein, P Schubert, U Zhou, MM Verdin, E Ott, M TI Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain SO EMBO JOURNAL LA English DT Article DE acetylation; bromodomain; HIV; PCAF; Tat ID RNA-POLYMERASE-II; ADENOVIRAL ONCOPROTEIN E1A; HIV-1 TAT; HISTONE ACETYLTRANSFERASES; COACTIVATORS P300; IN-VIVO; ACTIVATION; PROTEIN; COMPLEX; INTERACTS AB The human immunodeficiency virus (HIV) Tat protein plays an essential role in promoting efficient transcriptional elongation of viral transcripts. We report that the transcriptional co-activator PCAF and Tat interact and synergize to activate the HIV promoter. The binding of Tat and PCAF in vitro and in vivo is dependent on the acetylated state of Lys50 of Tat and on the PCAF bromodomain. Structural analysis of the acetylated Tat peptide bound to the PCAF bromodomain defined amino acids Y47 and R53 in Tat and V763, Y802, and Y809 in PCAF as critical interaction points between the two proteins. Mutation of each of these residues in either Tat or PCAF inhibited in a cumulative manner the Tat-PCAF interaction in vitro and in vivo, and abrogated the synergistic activation of the HIV promoter by both proteins. These observations demonstrate that acetylation of Tat establishes a novel protein-protein interaction domain at the surface of Tat that is necessary for the transcriptional activation of the HIV promoter. C1 Deutsch Krebsforschungszentrum, D-69120 Heidelberg, Germany. Humboldt Univ, Inst Biochem, D-10115 Berlin, Germany. Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA. NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Physiol & Biophys, Struct Biol Program, New York, NY 10029 USA. RP Ott, M (reprint author), Deutsch Krebsforschungszentrum, D-69120 Heidelberg, Germany. OI Verdin, Eric/0000-0003-3703-3183; Kiermer, Veronique /0000-0001-8771-7239 FU NIAID NIH HHS [AI 40847] NR 30 TC 98 Z9 102 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 3 PY 2002 VL 21 IS 11 BP 2715 EP 2723 DI 10.1093/emboj/21.11.2715 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 557MN UT WOS:000175912500021 PM 12032084 ER PT J AU Wang, HY Zhou, YH Zhu, KC Riker, AI Marincola, FM Wang, RF AF Wang, HY Zhou, YH Zhu, KC Riker, AI Marincola, FM Wang, RF TI Identification of a mutated fibronectin as a tumor antigen recognized by CD4(+) T cells: Its role in extracellular matrix formation and tumor metastasis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cancer vaccines; cancer biology; CD4(+) T cells; antitumor immunity; immunotherapy ID HLA-DR MOLECULES; TRANSGENIC MICE; IN-VIVO; MELANOMA; LYMPHOCYTES; EPITOPES; RESPONSES; RECEPTOR; CANCER; ASSOCIATION AB CD4(+) T cells play an important role in orchestrating host immune responses against cancer, particularly by providing critical help for priming and extending the survival of CD8(+) T cells. However, relatively little is known about major histocompatibility complex class II-restricted human tumor antigens capable of activating CD4(+) T cells. Here, we describe the identification of a mutated fibronectin (FN) as a tumor antigen recognized by human histocompatibility leukocyte antigen-DR2-restricted CD4(+) T cells. Deoxyribonucleic acid (DNA) sequencing analysis indicated that this gene contains a mutation that results in the substitution of lysine for glutamic acid and gives rise to a new T cell epitope recognized by CD4(+) T cells. Tumor cells harboring the mutant FN resulted in the loss of FN matrix formation and the gain of metastatic potential based on the migration pattern compared with that of tumor cells that express wildtype FN. Additional experiments using cell lines stably expressing the mutated FN cDNA demonstrated that the point mutation in FN was responsible for the loss of FN staining in extracellular matrices and the enhancement of tumor cell migration. These findings represent the first demonstration that a mutated gene product recognized by CD4(+) T cells is directly involved in tumor metastasis, which indicates the importance of CD4(+) T cells in controlling the spread of tumor cells to distant anatomic sites. C1 Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. Loyola Univ, Dept Surg, Maywood, IL 60153 USA. NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Rockville, MD 20852 USA. RP Wang, RF (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, ALKEK Bldg N1120,1Baylor Plaza, Houston, TX 77030 USA. RI Riker, Adam/A-6065-2011 FU NCI NIH HHS [R01 CA090327, R01 CA 90327] NR 40 TC 25 Z9 26 U1 0 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 JUN 3 PY 2002 VL 195 IS 11 BP 1397 EP 1406 DI 10.1084/jem.20020141 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 561DE UT WOS:000176121800004 PM 12045238 ER PT J AU Travis, LB AF Travis, LB TI Therapy-associated solid tumors SO ACTA ONCOLOGICA LA English DT Review ID 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; NON-HODGKINS-LYMPHOMA; LUNG-CANCER; BREAST-CANCER; TESTICULAR CANCER; OVARIAN-CANCER; RADIATION-THERAPY; ATAXIA-TELANGIECTASIA; GENOMIC INSTABILITY AB As survival after a diagnosis of cancer improves, characterization of the late sequelae of treatment becomes critical. The development of second malignant neoplasms represents one of the most serious side effects of treatment with radiation and chemotherapy. Although secondary leukemia was the first reported carcinogenic effect resulting from cancer treatment, solid tumors now comprise the largest second tumor burden in some populations of survivors. It should be recognized, however, that solid cancers do not necessarily represent an adverse effect of therapy, but may also reflect the operation of shared etiologic factors, host determinants, gene-environment interactions, and other influences. Quantification of second cancer risk is important in terms of patient management, enabling clinicians to make informed decisions with regard to optimal treatment of the initial cancer, balancing efficacy against acute and chronic sequelae. This article focuses on selected highlights and recent developments in treatment-associated solid malignancies, with emphasis on radiotherapy and chemotherapy in adults, and summarizes areas for future research. Although cancer therapy represents a double-edged sword, it should always be recognized that it is advances in treatment that are largely responsible for the tremendous improvement in patient survival. Thus, the benefit derived from many cancer therapies far outweighs any risk of developing a second cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 7086 MS 7238, Bethesda, MD 20892 USA. NR 114 TC 88 Z9 89 U1 0 U2 3 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PD JUN 1 PY 2002 VL 41 IS 4 BP 323 EP 333 PG 11 WC Oncology SC Oncology GA 583HE UT WOS:000177400600001 PM 12234023 ER PT J AU Korhonen, P Malila, N Pukkala, E Teppo, L Albanes, D Virtamo, J AF Korhonen, P Malila, N Pukkala, E Teppo, L Albanes, D Virtamo, J TI The Finnish Cancer Registry as follow-up source of a large trial cohort - Accuracy and delay SO ACTA ONCOLOGICA LA English DT Article AB We evaluated the accuracy and time to reporting of cancer diagnoses obtained through the Finnish Cancer Registry (FCR) for the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study in 1985-1997. In the ATBC Study suspect neoplasms were cent rally reviewed through medical records and pathology specimens. The FCR data were compared against the reviewed data for 3600 cancers of eight sites. For most sites, 95% of the cases were reported to the FCR within 0.9 years with longer delays for lung and pancreatic cancers. Ninety-six percent of all FCR cases received the same primary site diagnosis in the ATBC review, and in 1.4% no malignancy was found. Conversely, 97% of cancers ascertained in the ATBC review had the same primary site in the FCR and 0.8% were unknown to the Registry. The accuracy of the FCR data is high but the delay in case notification should be considered in epidemiological studies. C1 Orion Phama, Dept Biostat & Data Management, FIN-02101 Espoo, Finland. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, FIN-00170 Helsinki, Finland. NCI, Bethesda, MD 20892 USA. RP Korhonen, P (reprint author), Orion Phama, Dept Biostat & Data Management, POB 65, FIN-02101 Espoo, Finland. RI Albanes, Demetrius/B-9749-2015 NR 8 TC 107 Z9 107 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PD JUN 1 PY 2002 VL 41 IS 4 BP 381 EP 388 PG 8 WC Oncology SC Oncology GA 583HE UT WOS:000177400600009 PM 12234031 ER PT J AU Chang, KT Min, KT AF Chang, KT Min, KT TI Regulation of lifespan by histone deacetylase SO AGEING RESEARCH REVIEWS LA English DT Article DE lifespan; histone deacetylase; aging ID ORAL SODIUM PHENYLBUTYRATE; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; SUPEROXIDE-DISMUTASE; GENE-EXPRESSION; SILENCING PROTEINS; CLINICAL-TRIAL; SPAN EXTENSION; EXTENDED LIFE AB Aging is a universal biological phenomenon in eukaryotes, but why and how we age still remain mysterious. It would be of great biological interest and practical importance if we could uncover the molecular mechanism of aging, and find a way to delay the aging process while maintaining physical and mental strengths of youth. Histone deacetylases (HDACs) such as SIR2 and RPD3 are known to be involved in the extension of lifespan in yeast and Caenorhabditis elegans. An inhibitor of HDACs, phenylbutyrate, also can significantly increase the lifespan of Drosophila, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. Alteration in the pattern of gene expression, including induction or repression of numerous genes involved in longevity by changing the level and the pattern of histone acetylation may be an important factor in determining the longevity of animals. Published by Elsevier Science Ireland Ltd. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Min, KT (reprint author), NINDS, Neurogenet Branch, NIH, MSC 1250,Bldg 10,Room 3B12, Bethesda, MD 20892 USA. OI min, kyung-tai/0000-0003-0983-4258 NR 73 TC 61 Z9 70 U1 0 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD JUN PY 2002 VL 1 IS 3 BP 313 EP 326 AR PII S1568-1637(02)00003-X DI 10.1016/S1568-1637(02)00003-X PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AP UT WOS:000178536900001 PM 12067588 ER PT J AU Mattson, MP Mattson, EP AF Mattson, MP Mattson, EP TI Amyloid peptide enhances nail rusting: novel insight into mechanisms of aging and Alzheimer's disease SO AGEING RESEARCH REVIEWS LA English DT Editorial Material DE aggregation; Alzheimer's disease; free radicals; iron; neurons; protein oxidation ID BETA-PEPTIDE; NEUROTOXICITY; HOMEOSTASIS; PROTEIN; NEURONS; DEATH AB Oxidative stress is believed to play a major role in the dysfunction and degeneration of neurons that occurs in Alzheimer's disease (AD). Amyloid beta-peptide forms insoluble aggregates in the brains of AD patients and it has been shown that the neurotoxic actions of amyloid beta-peptide involve membrane lipid peroxidation. However, it is not known how amyloid beta-peptide induces oxidative stress. Here we describe a simple experiment that we performed 6 years ago that demonstrates that amyloid beta-peptide is itself a source of oxyradicals. The weights of iron nails were recorded and the nails were then incubated in one of three different solutions: water (control), 1 mM amyloid beta-peptide (1-40) in water, and 1 mM bovine serum albumin in water. After 1 month of incubation the nails were then removed, allowed to dry, and then their weights determined. The weights of all the nails decreased, but the amount of weight decrease in the nails that had been incubated in the presence of amyloid beta-peptide was approximately twice that of the nails incubated in the control solutions. These data provide direct evidence that amyloid beta-peptide generates, or facilitates the production of, oxyradicals thereby enhancing metal oxidation. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 12 TC 11 Z9 12 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD JUN PY 2002 VL 1 IS 3 BP 327 EP 330 AR PII S1568-1637(02)00002-8 DI 10.1016/S1568-1637(02)00002-8 PG 4 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AP UT WOS:000178536900002 PM 12067589 ER PT J AU Bandinelli, S Lauretani, F Benvenuti, E Corsi, A De Marco, MF Bartali, B Ruotolo, G Miniati, B Macchi, C Russo, CR Guralnik, JM Ferrucci, L AF Bandinelli, S Lauretani, F Benvenuti, E Corsi, A De Marco, MF Bartali, B Ruotolo, G Miniati, B Macchi, C Russo, CR Guralnik, JM Ferrucci, L TI Understanding the physiological and functional consequences of menopause: The PROSALMEN study SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE aging; menopause; older women; physical performance; prevention; PROSALMEN Study ID BONE LOSS; OLDER WOMEN; HEALTH; LIFE; AGE; DETERMINANTS; DISABILITY; STRENGTH; PROTOCOL; DENSITY AB Background and aims: Women live longer and are more often affected by disability and poor health than men. The mechanism underlying this sex-related "mortality-morbidity" paradox is still unclear but it has been suggested that the physiological and functional changes occurring during the menopausal transition play an important role. The aim of PROSALMEN (PROgetto SALute MENopausa: Health in Menopause Project) is to study in great detail how these changes affect the integrity and function of the physiologic subsystems that are relevant to the maintenance of an active and healthy life-style during the aging process. Methods: PROSALMEN is a cross-sectional comparison of age-matched pre- and post-menopausal women. Thirty post-menopausal women, aged 48-58 years, were enrolled in the study together with 30 age-matched pre-menopausal controls. A number of clinical, biological and functional parameters were collected assessing the integrity and level of function of the physiological subsystems that are important for mobility. Furthermore, we collected information on risk factors, medical conditions and symptoms that frequently develop or become clinically evident after menopause, including the most important elements of the classical post-menopausal syndrome. Conclusions: This rich dataset will be used to start dissecting the causal pathway leading from menopause to damages in the musculoskeletal system and, in turn, to reduced physical function. The final goal is to understand how and to what extent changes in health behavior and pharmacological treatments in addition to hormone replacement therapy (HRT) may counteract these processes. C1 INRCA Geriatr Dept, Lab Clin Epidemiol, I-50127 Florence, Italy. Univ Florence, Unit Gerontol & Geriatr Med, I-50121 Florence, Italy. S Raffaele Hosp, Lab Lipid Metab & Prevent Cardiovasc Dis, Milan, Italy. Don Gnocchi Fdn, Florence, Italy. NIA, Epidemiol Demog & Biometry Lab, NIH, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), INRCA Geriatr Dept, Lab Clin Epidemiol, Viale Michelangiolo 41, I-50127 Florence, Italy. NR 31 TC 1 Z9 1 U1 1 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD JUN PY 2002 VL 14 IS 3 BP 170 EP 177 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 603JE UT WOS:000178555200003 PM 12387523 ER PT J AU Martin, SE Snyder, LB Hamilton, M Fleming-Milici, F Slater, MD Stacy, A Chen, MJ Grube, JW AF Martin, SE Snyder, LB Hamilton, M Fleming-Milici, F Slater, MD Stacy, A Chen, MJ Grube, JW TI Alcohol advertising and youth SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol advertising; children; adolescents; alcohol consumption ID AMERICAN COMMUNITY; DRINKING; ADVERTISEMENTS; EXPECTANCIES; MEMORY; ADOLESCENTS; MEDIA; RESPONSES; CHILDREN AB This article presents the proceedings of a symposium at tire 2001 Research Society on Alcoholism meeting in Montreal, Canada. The symposium was organized and chaired by Joel W. Grube. The presentations and presenters were (1) Introduction and background, by Susan E. Martin; (2)The effect of alcohol ads on youth 15-26 years old, by Leslie Snyder, Mark Hamilton, Fran Fleming-Mitici, and Michael D. Slater; (3) A comparison of exposure to alcohol advertising and drinking behavior in elementary versus middle school children, by Phyllis L Ellickson and Rebecca L. Collins,; (4) USC health and advertising project: assessment study on alcohol advertisement memory and exposure, by Alan Stacy; and (5) TV beer and soft drink advertising: what young people like and what effects? by Meng-Jinn Chen and Joel W, Grube. C1 NIAAA, Bethesda, MD USA. Univ Connecticut, Dept Commun Sci, Storrs, CT 06268 USA. Colorado State Univ, Dept Journalism & Tech Commun, Ft Collins, CO 80523 USA. Univ So Calif, Dept Prevent Med, Costa Mesa, CA USA. Prevent Res Ctr, Berkeley, CA 94704 USA. RP Grube, JW (reprint author), Prevent Res Ctr, 2150 Shattuck Ave,Ste 900, Berkeley, CA 94704 USA. RI Slater, Michael/A-5450-2011; Stacy, Alan/G-5406-2016 OI Slater, Michael/0000-0003-4279-346X; FU NIAAA NIH HHS [AA12136, R01 AA11551, R01 AA12128] NR 35 TC 42 Z9 42 U1 6 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2002 VL 26 IS 6 BP 900 EP 906 DI 10.1111/j.1530-0277.2002.tb02620.x PG 7 WC Substance Abuse SC Substance Abuse GA 566HR UT WOS:000176421700020 PM 12068260 ER PT J AU Stuebing, KK Fletcher, JM LeDoux, JM Lyon, GR Shaywitz, SE Shaywitz, BA AF Stuebing, KK Fletcher, JM LeDoux, JM Lyon, GR Shaywitz, SE Shaywitz, BA TI Validity of IQ-discrepancy classifications of reading disabilities: A meta-analysis SO AMERICAN EDUCATIONAL RESEARCH JOURNAL LA English DT Review DE IQ-discrepancy; IQ tests; learning disabilities; meta-analysis; reading disabilities ID LOW ACHIEVEMENT DEFINITIONS; LEARNING-DISABILITIES; POOR READERS; INDIVIDUAL-DIFFERENCES; PROCESSING ABILITIES; DEFICIT HYPOTHESIS; PHONOLOGICAL-CORE; CHILDREN; DYSLEXIA; STUDENTS AB According to federal regulations, children with reading difficulties are eligible for special education services under the learning disability category if they display reading skills that are significantly lower than their scores on intelligence (IQ) tests. Children who are poor readers but do not display this discrepancy are not eligible for special education. A meta-analysis involving 46 studies addressing the validity of this classification of poor readers revealed substantial overlap between the IQ-discrepant and Q-consistent poor readers. Aggregated effect sizes were in the negligible range for the Behavior (-.05) and Achievement (-.12) domains but in the small range for the Cognitive Ability domain (.30). The latter effects were heterogeneous, with, larger estimates showing higher performance by the IQ-discrepant poor readers. The size of the effects could be largely explained by the selection criteria used to form groups, indicating that variation in group definitions across studies accounted for variability in effect size estimates. These results provide little evidence supporting the validity of the IQ-discrepancy classification fundamental to public policy concerning students with learning disabilities and cast doubt on the need for IQ tests in identifying these students. C1 Univ Texas, Hlth Sci Ctr, Dept Pediat, Houston, TX USA. FSD Data Serv Inc, Houston, TX 77098 USA. NICHHD, Child Dev & Behav Branch, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pediat, Yale Ctr Study Learning & Attent, New Haven, CT 06510 USA. RP Stuebing, KK (reprint author), FSD Data Serv Inc, 2020 SW Freeway,Suite 206, Houston, TX 77098 USA. NR 106 TC 141 Z9 143 U1 5 U2 34 PU AMER EDUCATIONAL RESEARCH ASSOC PI WASHINGTON PA 1230 17TH ST NW, WASHINGTON, DC 20036-3078 USA SN 0002-8312 J9 AM EDUC RES J JI Am. Educ. Res. J. PD SUM PY 2002 VL 39 IS 2 SI SI BP 469 EP 518 DI 10.3102/00028312039002469 PG 50 WC Education & Educational Research SC Education & Educational Research GA 571YU UT WOS:000176747400009 ER PT J AU Murabito, JM Evans, JC Nieto, K Larson, MG Levy, D Wilson, PWF AF Murabito, JM Evans, JC Nieto, K Larson, MG Levy, D Wilson, PWF TI Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study SO AMERICAN HEART JOURNAL LA English DT Article ID ANKLE-ARM INDEX; BLOOD-PRESSURE INDEX; INTERMITTENT CLAUDICATION; RISK-FACTORS; ELDERLY WOMEN; CARDIOVASCULAR-DISEASE; VASCULAR-DISEASE; HEART-DISEASE; MORTALITY; ATHEROSCLEROSIS AB Background Peripheral arterial disease (PAD) is associated with an increased risk for mortality. We sought to assess the prevalence of PAD and its risk factors in a population-based sample. Methods We examined 1554 males and 1759 females with a mean age of 59 years who attended a Framingham Offspring Study examination from 1995 to 1998. PAD was defined by an ankle-brachial blood pressure index of <0.9. Age- and sex-adjusted and multivariable logistic regression analyses were performed to identify factors associated with PAD. Results The prevalences of PAD, current intermittent claudication, lower extremity bruits and surgical intervention were 3.9%, 1.9%, 2.4% and 1.4% in males and 3.3%, 0.8%, 2.3% and 0.5% in females. Hypercholesterolemia, high-density lipoprotein cholesterol, triglyceride, diabetes, hypertension, current smoking, pack-years of smoking, body mass index, fibrinogen, and prevalent coronary disease were associated with PAD in age- and sex-adjusted analyses. Odds ratios and 95% Cls for significant associations identified from multivariable analyses are as follows: each 10 years of age, 2.6 (2.0, 3.4); hypertension, 2.2 (1.4, 3.5); smoking, 2.0 (1.1, 3.4); 10 pack-years of smoking, 1.3 (1.2, 1.4); 50 mg/dL of fibrinogen, 1.2 (1.1, 1.4); 5 mg/dL of high-density lipoprotein, 0.9 (0.8, 1.0); coronary disease, 2.6 (1.6, 4.1). Conclusions Smoking cessation and hypertension control are important goals in the aim to reduce PAD and its associated impact on quality of life, functional decline, and risk for subsequent cardiovascular disease. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Murabito, Joanne/0000-0002-0192-7516; Larson, Martin/0000-0002-9631-1254 NR 26 TC 234 Z9 251 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2002 VL 143 IS 6 BP 961 EP 965 DI 10.1067/mhj.2002.122871 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 568CT UT WOS:000176525400009 PM 12075249 ER PT J AU Dendi, R Goldstein, DS AF Dendi, R Goldstein, DS TI Meta-analysis of nonselective versus beta-1 adrenoceptor-selective blockade in prevention of tilt-induced neurocardiogenic syncope SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID NEURALLY-MEDIATED SYNCOPE; VASOVAGAL SYNCOPE; CONTROLLED TRIAL; VASODEPRESSOR SYNCOPE; ADRENERGIC-BLOCKADE; UNEXPLAINED SYNCOPE; DOUBLE-BLIND; METOPROLOL; TABLE; EFFICACY AB Beta-adrenoceptor blockers are frequently used to treat patients predisposed to neurocardiogenic syncope. Beta-2 adrenoceptor-mediated skeletal vasodilation might contribute to neurocardiogenic syncope, and consistent with this notion, meta-analysis of published reports indicates that nonselective beta blockers are more effective than beta-1-selective blockers in preventing tilt-induced syncope. C1 Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. NINCDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Dendi, R (reprint author), Univ Iowa Hosp & Clin, Room S416GH,200 Hawkins Dr, Iowa City, IA 52242 USA. NR 32 TC 19 Z9 22 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 JUN 1 PY 2002 VL 89 IS 11 BP 1319 EP + DI 10.1016/S0002-9149(02)02338-X PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300020 PM 12031740 ER PT J AU Aranda, JM Krause-Steinrauf, HJ Greenberg, BH Heng, MK Kosolcharoen, PK Renlund, DG Thaneemit-Chen, S White, M Cintron, GB AF Aranda, JM Krause-Steinrauf, HJ Greenberg, BH Heng, MK Kosolcharoen, PK Renlund, DG Thaneemit-Chen, S White, M Cintron, GB CA BEST Investigators TI Comparison of the beta blocker bucindolol in younger versus older patients with heart failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ADRENERGIC-RECEPTOR BLOCKADE; AGE AB The elderly population in the Beta-Blocker Evaluation of Survival Trial is a sicker cohort of patients characterized by increased duration of heart failure, more coronary artery disease, and higher mortality. Compared with younger patients, older patients with heart failure safely tolerate the beta blocker bucindolol with similar physiologic effects; advanced age should not be the sole reason for avoiding beta blockers in elderly patients with heart failure. C1 Univ Florida, Coll Med, Gainesville, FL 32610 USA. Gainesville Vet Adm Med Ctr, Gainesville, FL USA. NHLBI, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Sepulveda Vet Adm Med Ctr, Sepulveda, CA USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. Dept Vet Affairs Palo Alto Hlth Care Syst, CSPCC, Palo Alto, CA USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Tampa Vet Adm Med Ctr, Tampa, FL USA. RP Aranda, JM (reprint author), Univ Florida, Coll Med, 1600 SW Archer Rd,Room 10-539, Gainesville, FL 32610 USA. NR 11 TC 11 Z9 11 U1 0 U2 1 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 JUN 1 PY 2002 VL 89 IS 11 BP 1322 EP + DI 10.1016/S0002-9149(02)02339-1 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300021 PM 12031741 ER PT J AU Freed, LA Levy, D Levine, RA Evans, JC Larson, MG Fuller, DL Lehman, B Benjamin, EJ AF Freed, LA Levy, D Levine, RA Evans, JC Larson, MG Fuller, DL Lehman, B Benjamin, EJ TI Mitral valve prolapse and atrial septal aneurysm: An evaluation in the Framingham heart study SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; PATENT FORAMEN OVALE; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; CEREBROVASCULAR EVENTS; DIAGNOSIS; PREVALENCE; EMBOLISM; MEMBRANE; ADULT AB Mitral valve prolapse and atrial septal aneurysms have been linked in previous studies. The results of this study demonstrate that atrial septal aneurysms, examined for the first time in a community-based sample, the Framingham Heart Study, occur with similar frequency in subjects with and without mitral valve prolapse. C1 NHLBI, Framington Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA 02215 USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framington Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01-HL-38176, K24-HL-67434, N01 HC-38038, R01-HL-53702]; NINDS NIH HHS [5-R01-NS-17950-16] NR 20 TC 6 Z9 6 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 JUN 1 PY 2002 VL 89 IS 11 BP 1326 EP + DI 10.1016/S0002-9149(02)02340-8 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300022 PM 12031742 ER PT J AU Del Parigi, A Chen, KW Gautier, JF Salbe, AD Pratley, RE Ravussin, E Reiman, EM Tataranni, PA AF Del Parigi, A Chen, KW Gautier, JF Salbe, AD Pratley, RE Ravussin, E Reiman, EM Tataranni, PA TI Sex differences in the human brain's response to hunger and satiation SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE sex; hunger; satiation; eating behavior; positron emission tomography; human brain ID POSITRON-EMISSION-TOMOGRAPHY; ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; GENDER; RECEPTOR; OBESITY; EMOTION; SKILLS; FOOD; AGE AB Background: Sex differences in eating behavior are well documented, but it is not known whether these differences have neuroanatomical correlates. Recent neuroimaging studies have provided functional maps of the human cerebral areas activated in response to hunger and satiation. Objective: The objective of this study was to assess whether the brain's response to a meal is sex-specific. Design: Using positron emission tomography, we measured regional cerebral blood flow, a marker of neuronal activity, to investigate the functional neuroanatomy of hunger (36-h fast) and satiation (in response to a liquid meal) in 22 women and 22 men. Results: We observed extensive similarities, as well as some differences, between the sexes. In response to hunger, the men tended to have greater activation in the frontotemporal and paralimbic areas than did the women (P < 0.005). In response to satiation, the women tended to have greater activation in the occipital and parietal sensory association areas and in the dorsolateral prefrontal cortex than did the men (P < 0.005); in contrast, the men tended to have greater activation in the ventromedial prefrontal cortex than did the women (P < 0.005). Conclusions: Despite extensive similarities in the brain responses to hunger and satiation between the men and women, our study showed sex-specific brain responses to a meal that indicate possible differences between men and women in the cognitive and emotional processing of hunger and satiation. This study provides a foundation for investigating the brain regions and cognitive processes that distinguish normal and abnormal eating behavior in men and women. C1 NIDDK, CDNS, NIH, Phoenix, AZ 85016 USA. Univ Arizona, Dept Psychiat, Tucson, AZ USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Good Samaritan Reg Med Ctr, Positron Emiss Tomog Ctr, Phoenix, AZ USA. RP Del Parigi, A (reprint author), NIDDK, CDNS, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 NR 39 TC 72 Z9 73 U1 2 U2 13 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2002 VL 75 IS 6 BP 1017 EP 1022 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 555FH UT WOS:000175783200010 PM 12036808 ER PT J AU Breathnach, OS Kasturi, V Kaye, F Herscher, L Georgiadis, MS Edison, M Schuler, BS Pizzella, P Steinberg, SM O'Neil, K Johnson, BE AF Breathnach, OS Kasturi, V Kaye, F Herscher, L Georgiadis, MS Edison, M Schuler, BS Pizzella, P Steinberg, SM O'Neil, K Johnson, BE TI Phase II neoadjuvant trial of paclitaxel by 96-hour continuous infusion (CIVI) in combination with cisplatin followed by chest radiotherapy for patients with stage III non-small-cell lung cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE lung neoplasm; carcinoma; non-small-cell lung cancer; clinical trial; phase II; neoadjuvant ID THERAPY ONCOLOGY GROUP; HYPERFRACTIONATED RADIATION-THERAPY; RANDOMIZED TRIAL; CONCURRENT CHEMOTHERAPY; BREAST-CANCER; I/II TRIAL; CARCINOMA; PATTERNS; SURVIVAL; FAILURE AB Sixteen patients with untreated locally advanced (n = 15) or recurrent (n = 1) non-small-cell lung cancer (NSCLC) were enrolled in this study between July 1996 and March 1999. Eight patients had stage IIIA NSCLC, seven had stage = disease, and one had recurrent disease after prior resection of stage I disease. Patients were treated with paclitaxel 30 mg/rm(2) /d for 4 days by continuous intravenous infusion followed by cisplatin 80 mg/m(2) on day 5. Therapy was administered every 3 weeks until disease progression or a maximum of four cycles. Thoracic radiation was started within 3 to 4 weeks of day I of the last cycle of paclitaxel and cisplatin. Fourteen patients (87.5%) received all four cycles of chemotherapy and subsequent radiation therapy. Forty-four percent of patients achieved a partial response, and 1 patient complete response (overall response rate, 50%). The median progression-free survival was 8.8 months. At a median potential follow-up of 3.7 years, the median survival for all 16 enrolled patients was 13.2 months and the actuarial 1-, 2-, and 3-year survivals were 62.5%: 43.8%, and 21.9%. In contrast to predictions from in vitro cytotoxicity models, the sequential use of prolonged infusional paclitaxel and bolus cisplatin followed by thoracic radiation does not appear to have a greater impact over shorter chemotherapy infusion schedules. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. NCI, Natl Naval Med Ctr, Med Branch, Bethesda, MD 20892 USA. NCI, Natl Naval Med Ctr, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Natl Naval Med Ctr, Radiat Oncol Branch, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD USA. Natl Naval Med Res Inst, Dept Pulm Med, Bethesda, MD USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Suite 1234,44 Binney St, Boston, MA 02115 USA. RI kaye, frederic/E-2437-2011 NR 25 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD JUN PY 2002 VL 25 IS 3 BP 269 EP 273 DI 10.1097/00000421-200206000-00013 PG 5 WC Oncology SC Oncology GA 559VG UT WOS:000176045900013 PM 12040286 ER PT J AU Filie, AC Wilder, AM Brosky, K Kopp, JB Miller, KD Abati, A AF Filie, AC Wilder, AM Brosky, K Kopp, JB Miller, KD Abati, A TI Urinary cytology associated with human polyomavirus and indinavir therapy in HIV-infected patients SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 23-31, 2000 CL NEW ORLEANS, LOUISIANA SP US & Canadian Acad Pathol DE urinary cytology; hematuria; indinavir sulfate; BK virus; polyomavirus; urine; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; BONE-MARROW TRANSPLANTATION; BK VIRUS; HEMORRHAGIC CYSTITIS; HEMATURIA; FAILURE; DISEASE AB We retrospectively analyzed 155 urine cytology samples (78 from patients treated with indinavir; 77, no indinavir) from 90 HIV+ patients to evaluate possible association between human polyomavirus and hematuria and to describe indinavir-associated urinary cytologic findings. The CD4 count also was recorded. Variables studied included the presence of cellular viral changes consistent with polyomavirus infection (PVCs), microscopic hematuria, multinucleated cells, indinavir crystals, neutrophils, and eosinophils. Twenty-two samples (15.8%) from patients with CD4 counts of more than 200/muL (>200 x 10(6)/L) showed PVCs. Multinucleated cells, of presumed histiocytic origin based on morphologic features and selective immunocytochemical findings, were present in a higher percentage of samples from indinavir-treated patients. Neutrophils were present in a higher percentage of indinavir-treated patients. Indinavir crystals were identified in 9 samples (12%) from patients receiving indinavir. The lower percentage of PVC's in HIV+ patients with high CD4 counts likely represents an indirect antipolyomavirus indinavir effect by boosting immunity. Multinucleated cells (presumably histocytic) and acute inflammation are associated with indinavir therapy. Indinavir crystals have a characteristic fan or circular lamellae appearance. Because indinavir crystals may be associated with genitourinary disease, recognizing and reporting them is clinically relevant in HIV+ patients. C1 Cytopathol Sect, Lab Pathol, NCI, Bethesda, MD 20892 USA. Natl Inst Diabet & Digest & Kidney Dis, Metab Dis Branch, Bethesda, MD USA. Warren Grant Magnuson Clin Ctr, Crit Ctr Med Dept, Bethesda, MD USA. RP Filie, AC (reprint author), Cytopathol Sect, Lab Pathol, NCI, 10 Ctr Dr Bldg 10 R2A19, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 18 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUN PY 2002 VL 117 IS 6 BP 922 EP 926 PG 5 WC Pathology SC Pathology GA 555MR UT WOS:000175798300011 PM 12047144 ER PT J AU Vogt, TM Mayne, ST Graubard, BI Swanson, CA Sowell, AL Schoenberg, JB Swanson, GM Greenberg, RS Hoover, RN Hayes, RB Ziegler, RG AF Vogt, TM Mayne, ST Graubard, BI Swanson, CA Sowell, AL Schoenberg, JB Swanson, GM Greenberg, RS Hoover, RN Hayes, RB Ziegler, RG TI Serum lycopene, other serum carotenoids, and risk of prostate cancer in US blacks and whites SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Blacks; carotenoids; case-control studies; nutrition; prostatic neoplasms ID PLASMA LYCOPENE; UNITED-STATES; FRUIT CONSUMPTION; BETA-CAROTENE; RETINOL; HUMANS; DIET; BIOMARKERS; VEGETABLES; JAPANESE AB Epidemiologic studies investigating the relation between individual carotenoids and risk of prostate cancer have produced inconsistent results. To further explore these associations and to search for reasons prostate cancer incidence is over 50% higher in US Blacks than Whites, the authors analyzed the serum levels of individual carotenoids in 209 cases and 228 controls in a US multicenter, population-based case-control study (1986-1989) that included comparable numbers of Black men and White men aged 40-79 years. Lycopene was inversely associated with prostate cancer risk (comparing highest with lowest quartiles, odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.36, 1.15; test for trend, p = 0.09), particularly for aggressive disease (comparing extreme quartiles, OR = 0.37, 95% CI: 0.15, 0.94; test for trend, p = 0.04). Other carotenoids were positively associated with risk. For all carotenoids, patterns were similar for Blacks and Whites. However, in both the controls and the Third National Health and Nutrition Examination Survey, serum lycopene concentrations were significantly lower in Blacks than in Whites, raising the possibility that differences in lycopene exposure may contribute to the racial disparity in incidence. In conclusion, the results, though not statistically significant, suggest that serum lycopene is inversely related to prostate cancer risk in US Blacks and Whites. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Chamblee, GA USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. Michigan State Univ, Coll Human Med, E Lansing, MI 48824 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Vogt, TM (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CN-05225, N01-CN-05227, N01-CN-31022, N01-CP-51087, N01-CP-51089, N01-CP-5109, N01-CP-51092] NR 50 TC 55 Z9 57 U1 0 U2 1 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 JUN 1 PY 2002 VL 155 IS 11 BP 1023 EP 1032 DI 10.1093/aje/155.11.1023 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 557MY UT WOS:000175913400006 PM 12034581 ER PT J AU Bernstein, J Haile, R Stern, M Berwick, M Conti, C De Roos, A AF Bernstein, J Haile, R Stern, M Berwick, M Conti, C De Roos, A TI DNA repair pathways in cancer epidemiology. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Los Angeles, CA 90089 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 118 BP s30 EP s30 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500117 ER PT J AU Carr, Z Kleinerman, R Land, C Mabuchi, K Stovall, M Weinstock, R Griem, M AF Carr, Z Kleinerman, R Land, C Mabuchi, K Stovall, M Weinstock, R Griem, M TI Coronary heart disease after radiotherapy for peptic ulcer. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 082 BP s21 EP s21 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500082 ER PT J AU Hartman, T Lanza, E Albert, P Schatzkin, A AF Hartman, T Lanza, E Albert, P Schatzkin, A CA Polyp Prevention Trial Study Grp TI Calcium and recurrence of colorectal adenomas. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 JUN 1 PY 2002 VL 155 IS 11 SU S MA 221 BP s56 EP s56 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500217 ER PT J AU Hisada, M Gold, B Kim, N Owens, M Cranston, B El-Omar, E Hanchard, B AF Hisada, M Gold, B Kim, N Owens, M Cranston, B El-Omar, E Hanchard, B TI Risk factors of Helicobacter pylori infection in the Jamaica mother-infant cohort study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 417 BP s105 EP s105 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500411 ER PT J AU Huang, WY Kang, D Weissfeld, JL Bresalier, RS Hayes, RB AF Huang, WY Kang, D Weissfeld, JL Bresalier, RS Hayes, RB TI DNA repair polymorphisms and risk of colorectal adenoma in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 014 BP s4 EP s4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500016 ER PT J AU Kipnis, V Izmirlian, G AF Kipnis, V Izmirlian, G TI The impact of categorization of continuous exposure measured with error. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 111 BP s28 EP s28 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500108 ER PT J AU Kipnis, V Izmirlian, G Midthune, D Subar, A Schatzkin, A AF Kipnis, V Izmirlian, G Midthune, D Subar, A Schatzkin, A TI Misclassification of dietary exposure and its implications: Results from the Observing Protein and Energy Nutrition (OPEN) biomarker study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 110 BP s28 EP s28 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500109 ER PT J AU Longnecker, MP Magnus, P Olsen, J Stanley, F AF Longnecker, MP Magnus, P Olsen, J Stanley, F TI Rationale, strengths, and strategies for new large birth cohort studies. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 117 BP s30 EP s30 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500115 ER PT J AU Mulherin, SA O'Brien, TR Ioannidis, JPA Goedert, JJ Buchbinder, SP Coutinho, RA Margolick, JB Meyer, L Michael, NL Pantaleo, G Rizzardi, GP Schuitemaker, H Sheppard, HW Theodorou, ID Vlahov, D Rosenberg, PS AF Mulherin, SA O'Brien, TR Ioannidis, JPA Goedert, JJ Buchbinder, SP Coutinho, RA Margolick, JB Meyer, L Michael, NL Pantaleo, G Rizzardi, GP Schuitemaker, H Sheppard, HW Theodorou, ID Vlahov, D Rosenberg, PS TI Effects of CCR5-Delta 32 and CCR2-641 alleles on HIV-1 disease progression: The protection varies with duration of infection. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RI Ioannidis, John/G-9836-2011; Pantaleo, Giuseppe/K-6163-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 156 BP s39 EP s39 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500154 ER PT J AU Rao, RS Sigurdson, AJ Doody, MM Graubard, BI AF Rao, RS Sigurdson, AJ Doody, MM Graubard, BI TI Weighting methods to adjust for nonresponse in cohort studies. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 261 BP s66 EP s66 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500257 ER PT J AU Schatzkin, A Kipnis, V Subar, A Troiano, R Midthune, D Bingham, S Schoeller, D AF Schatzkin, A Kipnis, V Subar, A Troiano, R Midthune, D Bingham, S Schoeller, D TI Food frequency questionnaires may seriously attenuate associations between diet and disease: Results from the OPEN (Observing Protein and Energy Nutrition) biomarker study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 109 BP s28 EP s28 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500107 ER PT J AU Tooze, J Subar, A Thompson, F Troiano, R Schatzkin, A Kipnis, V AF Tooze, J Subar, A Thompson, F Troiano, R Schatzkin, A Kipnis, V TI Psychosocial predictors of energy underreporting in a large doubly labeled water study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 222 BP s56 EP s56 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500219 ER PT J AU Wegienka, G Baird, DD Hertz-Picciotto, I AF Wegienka, G Baird, DD Hertz-Picciotto, I TI An examination of the association between uterine leiomyomas (fibroids) and menstrual gushing. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 284 BP s71 EP s71 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500280 ER PT J AU Wilson, RT Ward, MH Pickle, LW AF Wilson, RT Ward, MH Pickle, LW TI Kidney cancer incidence in relation to water source type among American Indian, Hispanic and white racial/ethnic groups in New Mexico, 1989-1998. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 059 BP s15 EP s15 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500057 ER PT J AU Breuer, DK Yashar, BM Filippova, E Hiriyanna, S Lyons, RH Mears, AJ Asaye, B Acar, C Vervoort, R Wright, AF Musarella, MA Wheeler, P MacDonald, I Iannaccone, A Birch, D Hoffman, DR Fishman, GA Heckenlively, JR Jacobson, SG Sieving, PA Swaroop, A AF Breuer, DK Yashar, BM Filippova, E Hiriyanna, S Lyons, RH Mears, AJ Asaye, B Acar, C Vervoort, R Wright, AF Musarella, MA Wheeler, P MacDonald, I Iannaccone, A Birch, D Hoffman, DR Fishman, GA Heckenlively, JR Jacobson, SG Sieving, PA Swaroop, A TI A comprehensive mutation analysis of RP2 and RPGR in a north American cohort of families with x-linked retinitis pigmentosa SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; GTPASE REGULATOR; CHROMOSOME CONDENSATION; POSITIONAL CLONING; LINKAGE ANALYSIS; VISUAL FUNCTION; GENE-THERAPY; PROTEIN; MOUSE; RCC1 AB X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5 upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in ! 10% and 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy. C1 Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48105 USA. Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48105 USA. Univ Michigan, Sequencing Core Facil, Ann Arbor, MI 48105 USA. Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. Suny Downstate Med Ctr, Dept Ophthalmol, Brooklyn, NY 11203 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Univ Alberta, Dept Ophthalmol, Edmonton, AB, Canada. Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN USA. Retina Fdn SW, Dallas, TX USA. Univ Illinois, Chicago, IL USA. Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. NEI, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. RI Acar, Ceren/B-5758-2008; OI Swaroop, Anand/0000-0002-1975-1141; Birch, David/0000-0002-6594-2897; MacDonald, Ian/0000-0001-7472-8385 FU NEI NIH HHS [R01 EY005235, EY 05235, EY 05627, EY 07003, EY 07961, F31 EY007003, P30 EY007003, R01 EY007961] NR 49 TC 135 Z9 143 U1 1 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 2002 VL 70 IS 6 BP 1545 EP 1554 DI 10.1086/340848 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 549LP UT WOS:000175445700015 PM 11992260 ER PT J AU Greenberg, JH AF Greenberg, JH TI The National Institutes of Health announces online availability of "Points to Consider When Planning a Genetic Study That Involves Members of Named Populations" SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 NIGMS, NIH, Div Genet & Dev Biol, Bethesda, MD 20892 USA. RP Greenberg, JH (reprint author), NIGMS, NIH, Div Genet & Dev Biol, Bldg 45,Room 2As25,45 Ctr Dr,MSC-6200, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 2002 VL 70 IS 6 BP 1602 EP 1602 AR UNSP 0002-9297/2002/7006-0027 DI 10.1086/340851 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 549LP UT WOS:000175445700026 PM 11992270 ER PT J AU Kovac, JA Patel, SS Peterson, RA Kimmel, PL AF Kovac, JA Patel, SS Peterson, RA Kimmel, PL TI Patient satisfaction with care and behavioral compliance in end-stage renal disease patients treated with hemodialysis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE patient satisfaction; depression; social support; compliance; functional status ID BECK DEPRESSION INVENTORY; SOCIAL SUPPORT; PSYCHOSOCIAL FACTORS; DIALYSIS PATIENTS; FAMILY SUPPORT; MORTALITY; SURVIVAL; PREDICTORS AB Compliance with the hemodialysis (HD) prescription is an important predictor of patient outcome. Although there is interest in the concept of patient satisfaction with medical care and caregivers, relatively few such data exist regarding HD patients. We examined whether associations exist between patient satisfaction with medical personnel and depressive affect and social support levels and behavioral compliance with prescribed HD treatment. Seventy-nine HD patients were interviewed, assessing depression, social support, and perception of satisfaction with dialysis staff. Medical and treatment data, Karnofsky functioning and severity of illness scores, and behavioral and laboratory compliance measures were determined. There was no association between patient satisfaction with care and level of depressive affect. A relationship was found between patient satisfaction with care with their nephrologist and attendance at dialysis sessions. Patients who had a poor perception of satisfaction with their nephrologist had poorer attendance at dialysis sessions. There was no relationship between behavioral compliance and patient perception of ancillary HD staff. In addition, patient perception of satisfaction with staff was related to perception of social support, protein catabolic rate, and serum albumin concentration, all of which have been linked to survival. We conclude that a nephrologist has a crucial role in patient compliance. These results suggest interventions that improve patient perception of physician support may improve patient adjustment and possibly survival. (C) 2002 by the National Kidney Foundation, Inc. C1 George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Dept Psychol, Washington, DC 20037 USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. NR 28 TC 55 Z9 58 U1 1 U2 7 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2002 VL 39 IS 6 BP 1236 EP 1244 DI 10.1053/ajkd.2002.33397 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 565ZC UT WOS:000176399600016 PM 12046037 ER PT J AU Xu, K Liu, XH Nagarajan, S Gu, XY Goldman, D AF Xu, K Liu, XH Nagarajan, S Gu, XY Goldman, D TI Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE delta-opioid receptor gene; heroin dependence; case-control study; genomic control loci ID SINGLE-NUCLEOTIDE POLYMORPHISM; OPIATE; POPULATION; ASSOCIATION; DEPENDENCE; ALCOHOL; MEN AB Pharmacological and electrophysiological evidence has shown that opioid receptors are involved in the mechanism of heroin dependence. Thus, opioid receptors are appropriate candidate genes for case-control association studies of heroin dependence. Previously, two single nucleotide polymorphisms (SNPs), OPRD1 921T > C and 80G > T, of the human,5 opioid receptor gene were used in population-based studies of heroin dependence. One study in a German population found that OPRD1 921T > C was associated with heroin dependence. This finding, however, was not replicated in a different German sample. To test the hypothesis that OPRD1 or a closely linked gene is associated with heroin dependence, we used 5' nuclease assays to genotype both OPRD1 SNPs in 450 Chinese heroin dependent patients and 304 unaffected controls from the same population. In addition, five SNPs distributed in four other genes: ADH2, ALDH2, OPRM1, and DRD1, were used as genomic control loci to test the case and control populations for stratification bias. Genotype and allele frequencies at OPRD1 921T > C were not significantly different, and the OPRD1 80G was absent from both Chinese opioid dependence patients and controls. Based on the genotype and allele frequencies of the genomic control loci, there was no evidence for stratification bias capable of masking an association of OPRD1 to heroin dependence in this large and homogenous Chinese sample. Therefore, these data do not support an association between the OPRD1 gene and heroin dependence in the Chinese population. Published 2002 Wiley-Liss, Inc. C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. W China Univ Med Sci, Dept Psychiat, Chengdu 610041, Sichuan, Peoples R China. LeShan Mental Hlth Ctr, LeShan, Sichuan, Peoples R China. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, 12420 Parklawn Dr,Suite 451,MSC 8110, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 22 TC 28 Z9 30 U1 0 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 JI Am. J. Med. Genet. PD JUN 1 PY 2002 VL 110 IS 1 BP 45 EP 50 DI 10.1002/ajmg.10374 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 552WQ UT WOS:000175643400008 PM 12116270 ER PT J AU Mittendorf, R Dambrosia, J Pryde, PG Lee, KS Gianopoulos, JG Besinger, RE Tomich, PG AF Mittendorf, R Dambrosia, J Pryde, PG Lee, KS Gianopoulos, JG Besinger, RE Tomich, PG TI Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE magnesium; adverse outcomes ID TOTAL PEDIATRIC MORTALITY; CEREBRAL-PALSY; HEMORRHAGE; INFECTION AB OBJECTIVE: The purpose of this study was to determine whether the use of antenatal magnesium sulfate prevents adverse outcomes (neonatal intraventricular hemorrhage, periventricular leucomalacia, death, and cerebral palsy). STUDY DESIGN: In a controlled trial, we randomized mothers in preterm labor to magnesium sulfate, "other" tocolytic, or placebo. At delivery, umbilical cord blood was collected for the later determination of serum ionized magnesium levels. Neonatal cranial ultrasound scans were obtained periodically for the diagnosis of intraventricular hemorrhage and periventricular leucomalacia. Among survivors, the diagnosis of cerebral palsy was made at age 18 months. RESULTS: Children with adverse outcomes had higher umbilical cord magnesium levels at delivery. In regression models that controlled for confounders, which included very low birth weight, magnesium remained a significant risk factor (adjusted odds ratio, 3.7; 95% CI, 1.1-11.9; P=.03). CONCLUSION: Contrary to original hypotheses, this randomized trial found that the use of antenatal magnesium sulfate was associated with worse, not better, perinatal outcome in a dose-response fashion. C1 Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. NINCDS, Biostat Branch, NIH, Bethesda, MD USA. Univ Wisconsin, Dept Obstet & Gynecol, Div Maternal Fetal Med, Madison, WI 53706 USA. Univ Chicago, Dept Pediat, Sect Neonatol, Chicago, IL 60637 USA. RP Mittendorf, R (reprint author), Loyola Univ, Med Ctr, Dept Obstet & Gynecol, 2160 S 1st Ave, Maywood, IL 60153 USA. NR 25 TC 118 Z9 125 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2002 VL 186 IS 6 BP 1111 EP 1118 DI 10.1067/mob.2002.123544 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 565TF UT WOS:000176385000001 PM 12066082 ER PT J AU Chaiworapongsa, T Romero, R Kim, JC Kim, YM Blackwell, SC Yoon, BH Gomez, R AF Chaiworapongsa, T Romero, R Kim, JC Kim, YM Blackwell, SC Yoon, BH Gomez, R TI Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE inflammation; chorioamnionitis; fetus; cerebral palsy ID INTRA-AMNIOTIC INFECTION; IMMEDIATE POSTPARTUM TREATMENT; UMBILICAL-CORD PLASMA; NECROSIS-FACTOR-ALPHA; INFLAMMATORY RESPONSE; NEONATAL SEPSIS; INTERLEUKIN-6 CONCENTRATIONS; BRONCHOPULMONARY DYSPLASIA; INTRAPARTUM; INFANTS AB OBJECTIVE: Clinical and histologic chorioamnionitis have recently been identified as risk factors for cerebral palsy. Proinflammatory cytokines have been implicated in the mechanisms that are responsible for brain injury in cases of intrauterine infection. The purpose of this study was to determine whether clinical chorioamnionitis, which is a maternal syndrome, is associated with an elevation in the fetal plasma interleukin-6 (IL-6) that is indicative of fetal inflammation. STUDY DESIGN: A cross-sectional study was designed to determine plasma concentrations of IL-6 in umbilical venous blood from patients with clinical chorioamnionitis (n = 26) and a control group (n = 111). Umbilical cord blood was obtained at the time of delivery. Plasma concentrations of IL-6 were measured with a sensitive and specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: Plasma concentrations of IL-6 were detectable in all samples of umbilical venous plasma. The median concentration of plasma IL-6 was higher in neonates born to mothers with clinical chorioamnionitis than in neonates born to mothers in the control group (clinical chorioamnionitis: median, 27.46 pg/mL; range, 1.3-5550.0 pg/mL; vs control: median, 2.13 pg/mL; range, 0.6-812.3 pg/mL; P < .001). Sixty-two percent of neonates (16/26) who were born to women with clinical chorioamnionitis had fetal plasma concentrations of IL-6 >11 pg/mL and 54% (14/26) had fetal plasma concentrations of IL-6 >18 pg/mL (these cutoff points have been used previously to define the fetal inflammatory response syndrome). CONCLUSION: Umbilical vein plasma concentrations of interleukin-6 are elevated in the neonates who were born to mothers with clinical chorioamnionitis, which suggests that the inflammatory process that is responsible for the maternal syndrome of clinical chorioamnionitis frequently involves the human fetus. C1 Wayne State Univ, Perinatol Res Branch, NICHHD, Hutzel Hosp,Dept Obstet & Gynecol, Detroit, MI 48201 USA. Seoul Natl Univ, Seoul 151, South Korea. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHHD, Hutzel Hosp,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. RI Yoon, Bo Hyun/H-6344-2011 NR 26 TC 67 Z9 70 U1 1 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2002 VL 186 IS 6 BP 1178 EP 1182 DI 10.1067/mob.2002.124042 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 565TF UT WOS:000176385000013 PM 12066094 ER PT J AU Ewan, KB Shyamala, G Ravani, SA Tang, Y Akhurst, R Wakefield, L Barcellos-Hoff, MH AF Ewan, KB Shyamala, G Ravani, SA Tang, Y Akhurst, R Wakefield, L Barcellos-Hoff, MH TI Latent transforming growth factor-beta activation in mammary gland - Regulation by ovarian hormones affects ductal and alveolar proliferation SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TGF-BETA; EPITHELIAL-CELLS; BREAST-CANCER; IN-SITU; GROWTH-FACTOR-BETA-1 TRANSGENE; RECEPTOR EXPRESSION; TUMOR SUPPRESSION; II RECEPTOR; MOUSE; TGF-BETA-1 AB Transforming growth factor-beta1 (TGF-beta1) is a pluripotent cytokine that can inhibit epithelial proliferation and induce apoptosis, but is also widely implicated in breast cancer progression. Understanding its biological action in mammary development is critical for understanding its role in cancer. TGF-beta1 is produced as a latent complex that requires extracellular activation before receptor binding. To better understand the spatial and temporal regulation of its action during mammary gland development, we examined the pattern of activation in situ using antibodies selected to distinguish between latent and active TGF-beta. Activation was highly restricted. TGF-beta1 activation was localized primarily to the epithelium, and within the epithelium it was restricted to luminal epithelial cells but absent from either cap or myoepithelial cells. Within the luminal epithelium, we noted a further restriction. During periods of proliferation (ie, puberty, estrus and pregnancy), which are stimulated by ovarian hormones, TGF-beta1 activation decreased in some cells, consistent with preparation for proliferation. Paradoxically, other cells simultaneously increase TGF-beta1 immunoreactivity, which suggests that TGF-beta1 differentially restrains epithelial subpopulations from responding to hormonal signals to proliferate. These data suggest that endogenous TGF-beta1 activation and thus activity are regulated by ovarian hormones. To determine the specific consequences of TGF-beta1 activity, we manipulated TGF-beta1 levels in vivo using Tgfbeta1 knockout mice and undertook tissue recombination experiments with heterozygous tissue. In Tgfbeta1 heterozygous mice, which have <10% wildtype levels of TGF-beta1, ductal development during puberty and alveolar development during pregnancy were accelerated, consistent with, its role as a growth inhibitor. The proliferative index of Tgfbeta1 +/- epithelium. was increased approximately twofold in quiescent tissue and fourfold in proliferating tissue but both ducts and alveoli were grossly and histologically normal. To test whether epithelial TGF-beta1 was critical to the proliferative phenotype, Tgfbeta1 +/+ and +/- epithelium were transplanted into +/+ mammary stroma. The outgrowth 4 of Tgfbeta1 +/- epithelium was accelerated in wild-type hosts, indicating that the phenotype was intrinsic to the epithelium. Moreover, proliferation was 15-fold greater in Tgfbeta1 +/- than wild-type mice after ovariectomy and treatment with estrogen and progesterone, suggesting that TGF-beta1 acts in an autocrine or juxtacrine manner to regulate epithelial proliferation. Together these data indicate that ovarian hormones regulate TGF-beta1 activation, which in turn restricts proliferative response to hormone signaling. C1 Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. Univ Calif San Francisco, Mt Zion Canc Res Inst, San Francisco, CA 94143 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Barcellos-Hoff, MH (reprint author), Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Bldg 74-174,1 Cyclotron Rd, Berkeley, CA 94720 USA. EM mhbarcellos-hoff@lbl.gov RI Ewan, Kenneth/N-3554-2015 OI Ewan, Kenneth/0000-0001-6622-9009 FU NCI NIH HHS [CA66541] NR 66 TC 109 Z9 112 U1 1 U2 5 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2002 VL 160 IS 6 BP 2081 EP 2093 DI 10.1016/S0002-9440(10)61158-3 PG 13 WC Pathology SC Pathology GA 559ZQ UT WOS:000176056900020 PM 12057913 ER PT J AU Fernandez-Cobo, M Agostini, HT Britez, G Ryschkewitsch, CF Stoner, GL AF Fernandez-Cobo, M Agostini, HT Britez, G Ryschkewitsch, CF Stoner, GL TI Strains of JC virus in Amerind-speakers of North America (Salish) and South America (Guarani), Na-Dene-speakers of New Mexico (Navajo), and modern Japanese suggest links through an ancestral Asian population SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE Native Americans; Tupi-Guarani; human migration; Japan; polyomavirus; virus evolution; phylogenetics ID HUMAN POLYOMAVIRUS JC; PAPUA-NEW-GUINEA; NEW-WORLD; COMPLETE GENOMES; Y-CHROMOSOME; NATIVE-AMERICANS; AFRICAN-AMERICANS; SEQUENCE-ANALYSIS; VIRAL EVOLUTION; MTDNA VARIATION AB Previously we showed that strains of human polyoma virus JC among the Navajo in New Mexico, speakers of an Athapaskan language in the Na-Dene language phylum, and among the Salish people in Montana, speakers of a language of the Salishan group in the Amerind family, were mainly of a northeast Asian genotype found in Japan (type 2A). We now report partial VP1-gene, regulatory region, and complete genome sequences of JC virus (JCV) from the Guarani Indians of Argentina. The Tupi-Guarani language represents the Equatorial branch of the Amerind language family proposed by Greenberg ([1987] Language in the Americas, Stanford: Stanford University Press), The partial VP1 gene sequences of the Guarani revealed several variants of strains found in northeast Asia (Japan), as did the Salish. In contrast, the strains in the Navajo largely conformed to the prototype type 2A sequence (MY). Phylogenetic reconstruction with both the neighbor-joining and maximum parsimony methods utilized three complete Guarani JCV genome sequences, three genomes from the Salish people, and 27 other complete JCV genomes, including three from the Navajo and three from Japan. Both trees showed that all type 2A JCV strains from the North and South Americans are closely related phylogenetically to strains in present-day Japan. However, variant sites in the coding regions, the T-antigen intron, and the regulatory region link the type 2A strains in Amerind groups (Guarani and Salish), but differentiate them from those in a Na-Dene-speaking (Navajo) population. The data suggest separation from a population ancestral to modern Japanese, followed by a second division within the ancestral group that led to Amerind- and Na-Dene-speaking groups. The data cannot, however, localize the latter split to the Asian mainland (two migrations) or to North America (one migration). Published 2002 Wiley-Liss, Inc. C1 NINCDS, Neurotoxicol, NIH, Bethesda, MD 20892 USA. INEI, ANLIS, Dept Virus, Natl Biol Serv, RA-1281 Buenos Aires, DF, Argentina. Univ Freiburg, Dept Ophthalmol, D-79106 Freiburg, Germany. Hosp Jardin Amer, RA-3328 Jardin America, Misiones, Argentina. RP Stoner, GL (reprint author), NINCDS, Neurotoxicol, NIH, 36 Convent Dr,Room 4A-27, Bethesda, MD 20892 USA. NR 62 TC 18 Z9 18 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD JUN PY 2002 VL 118 IS 2 BP 154 EP 168 DI 10.1002/ajpa.10085 PG 15 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 553ET UT WOS:000175663300007 PM 12012368 ER PT J AU Montgomery, DE Wolska, BM Pyle, WG Roman, BB Dowell, JC Buttrick, PM Koretsky, AP Del Nido, P Solaro, RJ AF Montgomery, DE Wolska, BM Pyle, WG Roman, BB Dowell, JC Buttrick, PM Koretsky, AP Del Nido, P Solaro, RJ TI alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE protein kinase C; troponin I ID PROTEIN-KINASE-C; ACTOMYOSIN MGATPASE ACTIVITY; MYOSIN LIGHT CHAIN-2; TROPONIN-I; VENTRICULAR MYOCYTES; RAT; EXPRESSION; CELLS; HYPERTROPHY; FORCE AB Protein kinase C (PKC)-mediated phosphorylation of cardiac myofilament (MF) proteins has been shown to depress the actomyosin interaction and may be important during heart failure. Biochemical studies indicate that phosphorylation of Ser(43) and Ser(45) of cardiac troponin I (cTnI) plays a substantial role in the PKC-mediated depression. We studied intact and detergent-extracted papillary muscles from nontransgenic (NTG) and transgenic (TG) mouse hearts that express a mutant cTnI (Ser43Ala, Ser45Ala) that lacks specific PKC-dependent phosphorylation sites. Treatment of NTG papillary muscles with phenylephrine (PE) resulted in a transient increase and a subsequent 62% reduction in peak twitch force. TG muscles showed no transient increase and only a 45% reduction in force. There was a similar difference in maximum tension between NTG and TG fiber bundles that had been treated with a phorbol ester and had received subsequent detergent extraction. Although levels of cTnI phosphorylation correlated with these differences, the TG fibers also demonstrated a decrease in phosphorylation of cardiac troponin T. The PKC-specific inhibitor chelerythrine inhibited these responses. Our data provide evidence that specific PKC-mediated phosphorylation of Ser(43) and Ser(45) of cTnI plays an important role in regulating force development in the intact myocardium. C1 Univ Illinois, Coll Med, Dept Physiol & Biophys, Program Cardiovasc Sci, Chicago, IL 60612 USA. Univ Illinois, Coll Med, Dept Med, Cardiol Sect, Chicago, IL 60612 USA. NINCDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Solaro, RJ (reprint author), Univ Illinois, Coll Med, Dept Physiol & Biophys, Program Cardiovasc Sci, 835 S Wolcott M-C 901, Chicago, IL 60612 USA. RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NHLBI NIH HHS [P01 HL-62426, R01 HL-58591, R37 HL-22231] NR 29 TC 49 Z9 49 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2002 VL 282 IS 6 BP H2397 EP H2405 DI 10.1152/ajpheart.00714.2001 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 550YC UT WOS:000175531800055 PM 12003851 ER PT J AU Talukder, MAH Morrison, RR Jacobson, MA Jacobson, KA Ledent, C Mustafa, SJ AF Talukder, MAH Morrison, RR Jacobson, MA Jacobson, KA Ledent, C Mustafa, SJ TI Targeted deletion of adenosine A(3) receptors augments adenosine-induced coronary flow in isolated mouse heart SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE coronary vasodilation; knockout mice; A(2A) receptor knockout mice ID A(2B) RECEPTORS; FUNCTIONAL-CHARACTERIZATION; BLOOD-PRESSURE; ANTAGONISTS; VASODILATION; ARTERIES; MICE; CIRCULATION; RELAXATION; RESISTANCE AB To determine whether adenosine A(3) receptors participate in adenosine-induced changes in coronary flow, isolated hearts from wild-type (WT) and A(3) receptor knockout (A(3)KO) mice were perfused under constant pressure and effects of nonselective and selective agonists were examined. Adenosine and the selective A(2A) agonist 2-[p-(2-carboxyethyl)] phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A3KO hearts compared with WT hearts. Selective activation of A(3) receptors with 2-chloro-N-6 ( 3-iodobenzyl)-adenosine-5'- N-methyluronamide (Cl-IB-MECA) at nanomolar concentrations did not effect coronary flow, but at higher concentrations it produced coronary vasodilation both in WT and A3KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A(2A) receptors. Because deletion or blockade of adenosine A(3) receptors augmented coronary flow induced by nonselective adenosine and the selective A(2A) receptor agonist CGS-21680, we speculate that this is due to removal of an inhibitory influence associated with the A(3) receptor subtype. These data indicate that the presence of adenosine A(3) receptors may either inhibit or negatively modulate coronary flow mediated by other adenosine receptor subtypes. C1 E Carolina Univ, Brody Sch Med, Dept Pharmacol, Greenville, NC 27858 USA. E Carolina Univ, Brody Sch Med, Dept Pediat, Greenville, NC 27858 USA. Merck Res Labs, W Point, PA 19486 USA. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20814 USA. Free Univ Brussels, B-1070 Brussels, Belgium. RP Mustafa, SJ (reprint author), E Carolina Univ, Brody Sch Med, Dept Pharmacol, Greenville, NC 27858 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [HL-27339] NR 37 TC 34 Z9 34 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2002 VL 282 IS 6 BP H2183 EP H2189 DI 10.1152/ajpheart.00964.2001 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 550YC UT WOS:000175531800031 PM 12003827 ER PT J AU Frank, AE Wingo, CS Andrews, PM Ageloff, S Knepper, MA Weiner, ID AF Frank, AE Wingo, CS Andrews, PM Ageloff, S Knepper, MA Weiner, ID TI Mechanisms through which ammonia regulates cortical collecting duct net proton secretion SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE intracellular calcium; 1,2-bis(2-aminophenoxy)ethane-N,N,N '; N '-tetraacetic acid acetoxymethyl ester; microtubule; soluble N-ethylmaleimide-sensitive fusion attachment receptor protein; hydrogen-potassium-adenosine triphosphatase ID BLOCK NEUROTRANSMITTER RELEASE; GASTRIC PARIETAL-CELLS; ACID-SECRETION; BICARBONATE TRANSPORT; INTRACELLULAR PH; AQUAPORIN-2 TRAFFICKING; PLASMA-MEMBRANE; H+/K+-ATPASE; H+-ATPASE; RABBIT AB Ammonia stimulates cortical collecting duct (CCD) net bicarbonate reabsorption by activating an apical H(+)-K(+)-ATPase through mechanisms that are independent of ammonia's known effects on intracellular pH and active sodium transport. The present studies examined whether this stimulation occurs through soluble N-ethylmaleimide-sensitive fusion attachment receptor (SNARE) protein-mediated vesicle fusion. Rabbit CCD segments were studied using in vitro microperfusion, and transepithelial bicarbonate transport was measured using microcalorimetry. Ammonia's stimulation of bicarbonate reabsorption was blocked by either chelating intracellular calcium with 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester or by inhibiting microtubule polymerization with colchicine compared with parallel studies performed in the absence of these inhibitors. An inactive structural analog of colchicine, lumicolchicine, did not alter ammonia's stimulation of bicarbonate reabsorption. Tetanus toxin, a zinc endopeptidase specific for vesicle-associated SNARE (v-SNARE) proteins, prevented ammonia from stimulating net bicarbonate reabsorption. Consistent with the functional evidence for v-SNARE involvement, antibodies directed against a conserved region of isoforms 1-3 of the tetanus toxin-sensitive, vesicle-associated membrane protein (VAMP) members of v-SNARE proteins labeled the apical and subapical region of collecting duct intercalated cells. Similarly, antibodies to NSF protein, a protein involved in activation of SNARE proteins for subsequent vesicle fusion, localized to the apical and subapical region of collecting duct intercalated cells. These results indicate that ammonia stimulates CCD bicarbonate reabsorption through an intracellular calcium-dependent, microtubule-dependent, and v-SNARE-dependent mechanism that appears to involve insertion of cytoplasmic vesicles into the apical plasma membrane of CCD intercalated cells. C1 Univ Florida, Div Nephrol Hypertens & Transplantat, Gainesville, FL 32610 USA. Georgetown Univ, Dept Cell Biol, Washington, DC 20007 USA. Vet Affairs Med Ctr, Gainesville, FL 32610 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Weiner, ID (reprint author), Univ Florida, Div Nephrol Hypertens & Transplantat, POB 100224, Gainesville, FL 32610 USA. EM WeineID@ufl.edu RI Weiner, Irving/G-6333-2016 OI Weiner, Irving/0000-0002-0046-0600 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NIDDK NIH HHS [DK-45788, DK-49750, R01 DK045788, R01 DK049750] NR 53 TC 21 Z9 22 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2002 VL 282 IS 6 BP F1120 EP F1128 DI 10.1152/ajprenal.00266.2001 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 549JN UT WOS:000175440900018 PM 11997329 ER PT J AU Michea, L Combs, C Andrews, P Dmitrieva, N Burg, MB AF Michea, L Combs, C Andrews, P Dmitrieva, N Burg, MB TI Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE caspase; endonuclease G; cytochrome c; mitochondria membrane potential; murine inner medullary collecting duct; sodium chloride ID ADENINE-NUCLEOTIDE TRANSLOCATOR; LASER-SCANNING CYTOMETRY; RAT-LIVER MITOCHONDRIA; BCL-2 FAMILY PROTEINS; CYTOCHROME-C RELEASE; BAX TRANSLOCATION; EPITHELIAL-CELLS; ENDONUCLEASE-G; MATRIX VOLUME; DEATH AB Raising osmolality to 700 mosmol/kgH(2)O by the addition of NaCl rapidly kills most murine inner renal medullary collecting duct cells (mIMCD3), but they survive at 500 mosmol/kgH(2)O. At 300 and 500 mosmol/kgH(2)O, NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 s to 30 min at 700 mosmol/kgH(2)O, the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased tetramethylrhodamine methyl ester perchlorate (TMRM) fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within 1-6 h. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning 1 h after osmolality is raised to 700, but not to 500, mosmol/kgH(2)O. General caspase activity and caspase-9 activity increase only after 6 h at 700 mosmol/kgH(2)O. The mitochondrial Bcl-2/Bax ratio decreases within 1-3 h, but no cytochrome c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kgH(2)O does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Light Microscopy Facil, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Cell Biol, Washington, DC 20002 USA. RP Burg, MB (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N262, Bethesda, MD 20892 USA. EM maurice_burg@nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 55 TC 39 Z9 39 U1 2 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2002 VL 282 IS 6 BP F981 EP F990 DI 10.1152/ajprenal.00301.2001 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 549JN UT WOS:000175440900003 PM 11997314 ER PT J AU Luoma, JB Martin, CE Pearson, JL AF Luoma, JB Martin, CE Pearson, JL TI Contact with mental health and primary care providers before suicide: A review of the evidence SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID ADOLESCENT SUICIDE; COMPLETED SUICIDE; PSYCHOLOGICAL AUTOPSY; GENERAL-PRACTITIONERS; CLINICAL ASPECTS; SERVICES; AGE; INPATIENTS; DISORDERS; CHILDREN AB Objective: This study examined rates of contact with primary care and mental health care professionals by individuals before they died by suicide. Method: The authors reviewed 40 studies for which there was information available on rates of health care contact and examined age and gender differences among the subjects. Results: Contact with primary care providers in the time leading up to suicide is common. While three of four suicide victims had contact with primary care providers within the year of suicide, approximately one-third of the suicide victims had contact with mental health services. About one in five suicide victims had contact with mental health services within a month before their suicide. On average, 45% of suicide victims had contact with primary care providers within 1 month of suicide. Older adults had higher rates of contact with primary care providers within 1 month of suicide than younger adults. Conclusions: While it is not known to what degree contact with mental health care and primary care providers can prevent suicide, the majority of individuals who die by suicide do make contact with primary care providers, particularly older adults, Given that this pattern is consistent with overall health-service-seeking, alternate approaches to suicide-prevention efforts may be needed for those less likely to be seen in primary care or mental health specialty care, specifically young men. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Catholic Univ Amer, Washington, DC USA. RP Pearson, JL (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Rm 7160,MSC 9635, Bethesda, MD 20892 USA. OI Luoma, Jason/0000-0002-3601-7037 FU Intramural NIH HHS [Z99 MH999999] NR 61 TC 439 Z9 452 U1 5 U2 34 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2002 VL 159 IS 6 BP 909 EP 916 DI 10.1176/appi.ajp.159.6.909 PG 8 WC Psychiatry SC Psychiatry GA 558DQ UT WOS:000175951300003 PM 12042175 ER PT J AU Tohen, M Baker, RW Altshuler, LL Zarate, CA Suppes, T Ketter, TA Milton, DR Risser, R Gilmore, JA Breier, A Tollefson, GA AF Tohen, M Baker, RW Altshuler, LL Zarate, CA Suppes, T Ketter, TA Milton, DR Risser, R Gilmore, JA Breier, A Tollefson, GA TI Olanzapine versus divalproex in the treatment of acute mania SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RATING-SCALE; VALPROATE; PLACEBO; EFFICACY AB Objective: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. Method: A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (5002500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively, Safety was assessed with several measures. Results: The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (greater than or equal to50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale less than or equal to12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups, Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. Conclusions: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex. C1 Lilly Res Labs, Indianapolis, IN 46285 USA. Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA USA. McLean Hosp, Belmont, MA USA. Univ Calif Los Angeles, Neuropsychiat Inst & Hosp, Los Angeles, CA 90024 USA. NIMH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Stanford Univ, Stanford, CA 94305 USA. RP Tohen, M (reprint author), Lilly Res Labs, Indianapolis, IN 46285 USA. NR 22 TC 192 Z9 196 U1 4 U2 6 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2002 VL 159 IS 6 BP 1011 EP 1017 DI 10.1176/appi.ajp.159.6.1011 PG 7 WC Psychiatry SC Psychiatry GA 558DQ UT WOS:000175951300019 PM 12042191 ER PT J AU Fee, E Brown, TM Lazarus, J Theerman, P AF Fee, E Brown, TM Lazarus, J Theerman, P TI The smoke nuisance SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. Univ Rochester, Dept Hist, Rochester, NY 14642 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14642 USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2002 VL 92 IS 6 BP 931 EP 931 DI 10.2105/AJPH.92.6.931 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 555NM UT WOS:000175800200013 PM 12036778 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI John Harvey Kellogg, MD - Health reformer and antismoker crusader SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. RP Fee, E (reprint author), Natl Lib Med, Hist Med Div, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2002 VL 92 IS 6 BP 935 EP 935 DI 10.2105/AJPH.92.6.935 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 555NM UT WOS:000175800200015 PM 12036780 ER PT J AU Jones, TR Stroncek, DF Gozalo, AS Obaldia, N Andersen, EM Lucas, C Narum, DL Magill, AJ Sim, BKL Hoffman, SL AF Jones, TR Stroncek, DF Gozalo, AS Obaldia, N Andersen, EM Lucas, C Narum, DL Magill, AJ Sim, BKL Hoffman, SL TI Anemia in parasite- and recombinant protein-immunized Aotus monkeys infected with Plasmodium falciparum SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID BINDING DOMAIN; MALARIA; CHILDREN AB Plasmodium falciparum-induced anemia was characterized in Aotus monkeys repeatedly immunized by infection with P. falciparum (FVO strain) parasites, then cross-challenged with CAMP strain, or in monkeys receiving blood stage challenges as part of malaria vaccine trials. In 4 studies, 25 (30.5%) of 82 monkeys had at least a 50% reduction in hematocrit; mean day of maximum parasitemia was 12.5, whereas the mean day of minimum hematocrit was 18.8 (P < 0.0009). Decreased hematocrit levels were not associated with reticulocytosis until parasite densities decreased significantly from peak levels. Direct antibody tests to detect IgG and C3d on the surface of erythrocytes were negative. Nonantibody/noncomplement-mediated lysis of uninfected erythrocytes seems to be the principal cause of the anemia, and it also seems that bone marrow suppression and lysis of infected erythrocytes contributed to the anemia. Partial immunity-whether induced by repeated immunization with whole parasites or with vaccine-seems important to the development of anemia. C1 USN, Med Res Ctr, Silver Spring, MD 20910 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Naval Med Res Ctr Detachment, Lima, Peru. ProMed Trading SA, Panama City, Panama. Gorgas Mem Lab, Panama City, Panama. EntreMed Inc, Rockville, MD 20850 USA. RP Jones, TR (reprint author), USN, Med Res Ctr, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. RI Obaldia, Nicanor/O-8460-2015; OI Obaldia, Nicanor/0000-0002-3711-9449 FU NIAID NIH HHS [AI36758-02] NR 24 TC 29 Z9 29 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2002 VL 66 IS 6 BP 672 EP 679 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 587UB UT WOS:000177660700008 PM 12224573 ER PT J AU Banerjee, RK Sung, C Bungay, PM Dedrick, RL Van Osdol, WW AF Banerjee, RK Sung, C Bungay, PM Dedrick, RL Van Osdol, WW TI Antibody penetration into a spherical prevascular tumor nodule embedded in normal tissue SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE monoclonal antibody; tumor antigen; diffusion; pharmacokinetics; finite-element mathematical model ID BINDING-SITE BARRIER; BIOTINYLATED MONOCLONAL-ANTIBODY; RADIOLABELED BIOTIN; TREATMENT PROTOCOLS; MODELING ANALYSIS; XENOGRAFT MODEL; SOLID TUMORS; STREPTAVIDIN AB A finite-element (FE) method is used to numerically solve a pharmacokinetic model that describes the uptake of systemically administered antibody (mAb) in a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, lymphatic clearance, interstitial diffusion in both the normal tissue and tumor, and binding reactions. We use results from the FE analysis to assess previous predictions that employed either a Dirichlet boundary condition (b.c.), or an approximate, composite (Dirichlet and Neumann) b.c. at the tumor surface. We find that the Dirichlet b.c. significantly overpredicted the mean total tumor mAb concentration. In contrast, the composite b.c. yielded good agreement with FE predictions, except at early times. We also used the FE model to investigate the influence of the approximately 30-fold difference in the values of mAb diffusion coefficient measured by Clauss and Jain (Cancer Res. 50:3487-3492, 1990) and Berk et al. (Proc. Natl. Acad. Sci. U.S.A. 94:1785-1790, 1997). For low diffusivity, diffusional resistance slows both mAb uptake by and efflux from the tumor. For high diffusivity at the same mAb dose, more rapid uptake produces earlier and higher peak mAb levels in the tumor, while the efflux rate is limited by the dissociation of the mAb-tumor antigen complex. The differences in spatial and temporal variation in mAb concentration between low and high diffusivities are of sufficient magnitude to be experimentally observable, particularly at short times after antibody administration. (C) 2002 Biomedical Engineering Society. C1 NIH, Div Bioengn & Phys Sci, DBEPS, Off Res Serv, Bethesda, MD 20892 USA. Human Genome Sci Inc, Rockville, MD USA. ALZA Corp, Mt View, CA USA. RP Bungay, PM (reprint author), NIH, Div Bioengn & Phys Sci, DBEPS, Off Res Serv, Bldg 13-3N17, Bethesda, MD 20892 USA. NR 23 TC 7 Z9 7 U1 0 U2 1 PU BIOMEDICAL ENGINEERING SOC AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD JUN PY 2002 VL 30 IS 6 BP 828 EP 839 DI 10.1114/1.1496087 PG 12 WC Engineering, Biomedical SC Engineering GA 587LA UT WOS:000177640900008 PM 12220082 ER PT J AU Dalakas, MC AF Dalakas, MC TI Blockade of blocking antibodies in Guillain-Barre syndromes: "Unblocking" the mystery of action of intravenous immunoglobulin SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID IGG ANTI-GM1 ANTIBODY; AUTOIMMUNE; NEUROPATHY; RECOVERY; DEGENERATION; GANGLIOSIDES; MECHANISM; INFECTION; DISEASES; PROGRESS C1 NINCDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINCDS, Neuromuscular Dis Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 24 TC 14 Z9 17 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 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUN PY 2002 VL 51 IS 6 BP 667 EP 669 DI 10.1002/ana.10259 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 556RX UT WOS:000175863700001 PM 12112069 ER PT J AU Bertelli, G Venturini, M Del Mastro, L Bergaglio, M Sismondi, P Biglia, N Venturini, S Porcile, G Pronzato, P Costantini, M Rosso, R AF Bertelli, G Venturini, M Del Mastro, L Bergaglio, M Sismondi, P Biglia, N Venturini, S Porcile, G Pronzato, P Costantini, M Rosso, R TI Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study SO ANNALS OF ONCOLOGY LA English DT Article DE breast cancer; hot flashes; medroxyprogesterone acetate; megestrol acetate; postmenopausal symptoms; tamoxifen ID MENOPAUSAL SYMPTOMS; SURVIVORS; ACETATE; TRIAL; PREVALENCE; MANAGEMENT; WOMEN; LIFE AB Background: Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. Patients and methods: Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a greater than or equal to50% decrease in the number and severity of hot flashes. Results: At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). Conclusions: Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol. C1 S Croce Gen Hosp, I-12100 Cuneo, Italy. Natl Canc Inst, Genoa, Italy. Univ Turin, Turin, Italy. City Hosp, Massa, Italy. City Hosp, Alba, Italy. S Andrea Hosp, La Spezia, Italy. RP Bertelli, G (reprint author), S Croce Gen Hosp, Via Coppino 26, I-12100 Cuneo, Italy. RI costantini, massimo/G-1443-2012; Biglia, Nicoletta/F-8801-2013 NR 15 TC 52 Z9 54 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2002 VL 13 IS 6 BP 883 EP 888 DI 10.1093/annonc/mdf151 PG 6 WC Oncology SC Oncology GA 568RW UT WOS:000176557900016 PM 12123333 ER PT J AU Heck, AM Calis, KA McDuffie, JR Carobene, SE Yanovski, JA AF Heck, AM Calis, KA McDuffie, JR Carobene, SE Yanovski, JA TI Additive gastrointestinal effects with concomitant use of olestra and orlistat SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE gastrointestinal effects; olestra; orlistat ID OBJECTIVE MEASURES; SYMPTOMS; CONSUMPTION; STOOL AB Objective: To report a case of significant additive gastrointestinal effects with concomitant use of orlistat and an olestra-containing snackfood. Case Summary: A 16-year-old African American girl with type 2 diabetes, hypercholesterolemia, and hypertension was participating in a pilot study that tested the safety and efficacy of orlistat. After 2 weeks of orlistat treatment, the patient presented to the clinic with complaints of soft, fatty/oily stools, flatus with discharge, abdominal pain, increased flatus, and fecal incontinence. On further questioning, it was determined that she was also consuming approximately 5 ounces of olestra-containing potato chips on a daily basis. The patient eliminated olestra from her diet and returned to the clinic with substantially diminished gastrointestinal adverse effects, despite continuing to take orlistat. Discussion: This is the first published case describing additive gastrointestinal effects after concurrent use of orlistat and olestra. Education about the potential for serious additive gastrointestinal adverse effects is important to prevent premature and unnecessary discontinuation of orlistat therapy. Awareness of this potential interaction could be especially important for patients with underlying disease states in which severe gastrointestinal symptoms could result in significant complications. Conclusions: This case illustrates that significant gastrointestinal distress may result after olestra consumption during orlistat therapy. All patients receiving orlistat for the management of obesity should be properly educated about this potential drug-food interaction. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Indianapolis, IN USA. Clarian Hlth Partners, Indianapolis, IN USA. NIH, Drug Informat Serv, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nutr, Bethesda, MD 20892 USA. NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Heck, AM (reprint author), Purdue Pharm Programs Indianapolis, Wishard Hlth Serv, D711 Myers Bldg,1001 W 10th St, Indianapolis, IN 46202 USA. NR 12 TC 8 Z9 8 U1 0 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUN PY 2002 VL 36 IS 6 BP 1003 EP 1005 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 556FE UT WOS:000175838100008 PM 12022901 ER PT J AU Vitali, C Bombardieri, S Jonsson, R Moutsopoulos, HM Alexander, EL Carsons, SE Daniels, TE Fox, PC Fox, RI Kassan, SS Pillemer, SR Talal, N Weisman, MH AF Vitali, C Bombardieri, S Jonsson, R Moutsopoulos, HM Alexander, EL Carsons, SE Daniels, TE Fox, PC Fox, RI Kassan, SS Pillemer, SR Talal, N Weisman, MH CA European Study Grp Classification TI Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID RHEUMATIC DISEASE; ASSOCIATION AB Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria. C1 Univ Pisa, Clin Immunol Unit, Pisa, Italy. Univ Pisa, Rheumatol Unit, Pisa, Italy. Univ Bergen, Broegelmann Res Lab, Bergen, Norway. Athens Med Sch, Dept Pathophysiol, Athens, Greece. Arena Pharmaceut Inc, Expt & Clin Res, San Diego, CA USA. Winthrop Univ Hosp, Div Rheumatol Allergy & Immunol, Mineola, NY 11501 USA. SUNY Stony Brook, Hlth Sci Ctr, Dept Med, Stony Brook, NY 11794 USA. Univ Calif San Francisco, Sch Dent, San Francisco, CA 94143 USA. Amarillo Biosci Inc, Res & Dev, Amarillo, TX USA. Scripps Clin & Hosp, La Jolla, CA USA. Univ Colorado, Hlth Sci Ctr, Div Rheumatol, Denver, CO USA. NIDCR, NIH, Bethesda, MD USA. Univ Texas, Dept Med, San Antonio, TX 78285 USA. Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA. RP Vitali, C (reprint author), Osped Villamarina, Dept Internal Med & Rheumatol, I-57025 Piombino, LI, Italy. NR 21 TC 2526 Z9 2759 U1 6 U2 49 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2002 VL 61 IS 6 BP 554 EP 558 DI 10.1136/ard.61.6.554 PG 5 WC Rheumatology SC Rheumatology GA 555AH UT WOS:000175769200020 PM 12006334 ER PT J AU Xu, ZY Chen, ZP Malapetsa, A Alaoui-Jamali, M Bergeron, J Monks, A Myers, TG Mohr, G Sausville, EA Scudiero, DA Aloyz, R Panasci, LC AF Xu, ZY Chen, ZP Malapetsa, A Alaoui-Jamali, M Bergeron, J Monks, A Myers, TG Mohr, G Sausville, EA Scudiero, DA Aloyz, R Panasci, LC TI DNA repair protein levels vis-a-vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program SO ANTI-CANCER DRUGS LA English DT Article DE bifunctional alkylating agent; DNA repair; drug resistance; endogenous protein; National Cancer Institute human cell line panel; nucleotide excision repair; xeroderma pigmentosum complementary group D ID NUCLEOTIDE EXCISION-REPAIR; MESSENGER-RNA LEVELS; CHLOROETHYLNITROSOUREA RESISTANCE; XERODERMA-PIGMENTOSUM; COCKAYNES-SYNDROME; MAMMALIAN-CELLS; P-GLYCOPROTEIN; DAMAGED DNA; CISPLATIN; EXPRESSION AB Nucleotide excision repair (NER) is a multi-enzyme DNA repair pathway in eukaryotes. Several NER genes in this pathway including XPB, XPD, XPA and ERCC-1 have been implicated in anticancer drug resistance in human tumor cells. In this study, we assessed the levels of the above-mentioned proteins in the NCI panel of 60 human tumor cell lines in relation to the cytotoxicity patterns of 170 compounds that constitute the standard agent (SA) database. The database consists of drugs used in the clinic for which a mechanism of action has been at least partially defined. The ERCC-1, XPD and XPB protein expression patterns yielded significant negative Pearson correlations with 13, 32 and 17 out of the 170 compounds, respectively (using p < 0.05). XPA produced a random assortment of negative and positive correlations, and did not appear to confer an overall resistance or sensitivity to these drugs. Protein expression was also compared with a pre-defined categorization of the standard agents into six mechanism-of-action groups resulting in an Inverse association between XPD and alkylating agent sensitivity. Our present data demonstrate that XPD protein levels correlate with resistance to alkylating agents in human tumor cell lines suggesting that XPD is implicated in the development of this resistance. NER activity, using the in vitro cell-free system repair assay, revealed no correlation between NER activity and the level of XPD protein in four cell lines with widely varying XPD protein levels. This lack of correlation may be due to the contribution of XPD to other functions including interactions with the Rad51 repair pathway. [(C) 2002 Lippincott Williams & Wilkins.]. C1 Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Informat Technol Branch, Rockville, MD 20852 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Panasci, LC (reprint author), Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, 3755 Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada. RI Xu, Zhiyuan/B-3762-2012; Xu, Zhiyuan/J-8698-2013 FU NCI NIH HHS [R03CA78205] NR 40 TC 35 Z9 36 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD JUN PY 2002 VL 13 IS 5 BP 511 EP 519 DI 10.1097/00001813-200206000-00010 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 563BD UT WOS:000176232800010 PM 12045463 ER PT J AU Petraitis, V Petraitiene, R Groll, AH Roussillon, K Hemmings, M Lyman, CA Sein, T Bacher, J Bekersky, I Walsh, TJ AF Petraitis, V Petraitiene, R Groll, AH Roussillon, K Hemmings, M Lyman, CA Sein, T Bacher, J Bekersky, I Walsh, TJ TI Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID BONE-MARROW TRANSPLANTATION; AMPHOTERICIN-B; (1,3)-BETA-D-GLUCAN SYNTHASE; IMMUNOCOMPROMISED PATIENTS; ECHINOCANDIN LIPOPEPTIDE; NOSOCOMIAL PNEUMONIA; FUNGAL-INFECTIONS; MOUSE MODELS; EFFICACY; ALBICANS AB Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Fujisawa Healthcare Inc, Deerfield, IL USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,Ctr Dr, Bethesda, MD 20892 USA. NR 43 TC 121 Z9 124 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2002 VL 46 IS 6 BP 1857 EP 1869 DI 10.1128/AAC.46.6.1857-1869.2002 PG 13 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 553EM UT WOS:000175662800036 PM 12019101 ER PT J AU Roilides, E Lyman, CA Filioti, J Akpogheneta, O Sein, T Lamaignere, CG Petraitiene, R Walsh, TJ AF Roilides, E Lyman, CA Filioti, J Akpogheneta, O Sein, T Lamaignere, CG Petraitiene, R Walsh, TJ TI Amphotericin B formulations exert additive antifungal activity in combination with pulmonary alveolar macrophages and polymorphonuclear leukocytes against Aspergillus fumigatus SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; HUMAN NEUTROPHILS; MONONUCLEAR PHAGOCYTES; RHIZOPUS-ORYZAE; HOST DEFENSES; INVITRO; ACTIVATION; INVIVO; CYTOKINES; CONIDIA AB Deoxycholate amphotericin B (DAMB) and amphotericin B lipid complex (ABLC) additively augmented the fungicidal activity of pulmonary alveolar macrophages against the conidia of Aspergillus fumigatus. DAMB, ABLC, and liposomal amphotericin B similarly displayed additive effects with polymorphonuclear leukocytes in damaging the hyphal elements of A. fumigatus. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, GR-54642 Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. NR 28 TC 29 Z9 29 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2002 VL 46 IS 6 BP 1974 EP 1976 DI 10.1128/AAC.46.6.1974-1976.2002 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 553EM UT WOS:000175662800053 PM 12019118 ER PT J AU Qin, SF Chock, PB AF Qin, SF Chock, PB TI Tyrosine phosphatase CD45 regulates hydrogen peroxide-induced calcium mobilization in B cells SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID RECEPTOR SIGNAL-TRANSDUCTION; ANTIGEN RECEPTOR; TRANSFORMING GROWTH-FACTOR-BETA-1; PHOSPHATIDYLINOSITOL 3-KINASE; OXIDATIVE STRESS; T-CELLS; PROTEIN; KINASE; PHOSPHORYLATION; ACTIVATION AB By taking advantage of established CD45-deficient DT40 cells, the roles of CD45 in oxidative stress signaling were investigated. Using p-nitrophenyl phosphate as substrate, it was found that CD45 constituted nearly 40% of the total protein - tyrosine phosphatase activity. Almost 90% of the phosphatase activity was rapidly inactivated upon hydrogen peroxide treatment. Hydrogen peroxide-induced tyrosine phosphorylation of cellular proteins and c-jun N-terminal kinase activation were markedly enhanced in CD45-deficient cells relative to that in its parental cells. In comparison, hydrogen peroxide-induced inositol 1,4,5-trisphosphate production and Ca2+ mobilization were impaired in CD45-deficient DT40 cells. However, hydrogen peroxide-induced tyrosine phosphorylation of phospholipase Cgamma2 (PLCgamma2), phosphatidylinositol 3-kinase activity precipitated by anti-phosphotyrosine antibody and activation of Bruton's tyrosine kinase appeared intact in CD45-deficient DT40 cells. This suggests that CD45 mediates the ability of hydrogen peroxide-activated PLCgamma2 to hydrolyze its substrate via a mechanism independent of both tyrosine phosphorylation of PLCgamma2 and phosphatidylinositol 3-kinase, as well as activation of Bruton's tyrosine kinase. Taken together, our observations demonstrated that, in addition to its negative regulatory or phosphatase activity, CD45 has a positive role in oxidative stress signaling. C1 NHLBI, LB, NIH, Bethesda, MD 20892 USA. RP NHLBI, LB, NIH, Bldg 50,Room 2134,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. EM pbc@helix.nih.gov NR 52 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2002 VL 4 IS 3 BP 481 EP 490 DI 10.1089/15230860260196281 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 569ZP UT WOS:000176633600014 PM 12215216 ER PT J AU Kim, HS Kang, HS Messam, CA Min, KW Park, CS AF Kim, HS Kang, HS Messam, CA Min, KW Park, CS TI Comparative evaluation of angiogenesis in gastric adenocarcinoma by nestin and CD34 SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE angiogenesis; CD34; gastric cancer; nestin ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; TUMOR ANGIOGENESIS; MICROVESSEL DENSITY; PATHOLOGICAL STAGE; BREAST-CARCINOMA; NERVOUS-SYSTEM; EXPRESSION; PROGNOSIS; METASTASIS AB Tumor angiogenesis has been shown to be important for growth and metastasis in human neoplasms. Angiogenesis is usually detemined by immunohistochemical staining of tumor tissue using various antibodies specific for endothelial cells. CD34 has been the one most commonly used in studies of tumor angiogenesis. Nestin, a class VI intermediate filament protein, was reported to be a good angiogenic marker in animal models. The aim of the current study was to compare the predictive value of angiogenesis as determined by CD34 and nestin on the same group of patients with advanced gastric carcinomas and to evaluate the possibility of nestin being a newer, better angiogenesis marker. Immunohistochemical staining using anti-nestin polyclonal antibody and anti-CD34 monoclonal antibody was carried out on surgical specimens from 61 patients with advanced gastric adenocarcinomas. The sensitivity of each of the two antibodies was evaluated by microvessel density (MVD) measurement by counting vessels in three 200x fields of intense neovascularization ("hot spots") of invasive tumors using a digital image analyzer. Immunoreactivity for nestin and CD34 was seen in the endothelial cells, and no stain was noted in the negative controls. MVD determined by nestin [87.74 +/- 29.30 (mean standard deviation)] staining was significantly greater than that obtained by CD34 (82.48 +/- 32.27), and the difference was statistically significant. There was no correlation between MVD and patient clinical outcome with either antibody. Interestingly, in patients with larger carcinomas, MVD determined by nestin correlated better with longer survival than CD34. The difference was statistically significant. These results indicate that nestin is the better marker to evaluate neovascularity in endothelial cells. Evaluation of MVD determined by immunchistochemistry has limited value in patients with gastric carcinomas. C1 Chonnam Natl Univ, Sch Med, Dept Pathol, Dong Ku, Kwangju 501190, South Korea. Seonam Univ, Coll Med, Dept Pathol, Chonju, South Korea. NINCDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. Deaconess Hosp, Dept Pathol, Oklahoma City, OK USA. RP Park, CS (reprint author), Chonnam Natl Univ, Sch Med, Dept Pathol, Dong Ku, 5 Hakdong, Kwangju 501190, South Korea. NR 41 TC 26 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-3345 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD JUN PY 2002 VL 10 IS 2 BP 121 EP 127 DI 10.1097/00022744-200206000-00005 PG 7 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA 555CA UT WOS:000175774500005 PM 12051629 ER PT J AU Brockow, K Scott, LM Worobec, AS Kirshenbaum, A Akin, C Huber, MM Metcalfe, DD AF Brockow, K Scott, LM Worobec, AS Kirshenbaum, A Akin, C Huber, MM Metcalfe, DD TI Regression of urticaria pigmentosa in adult patients with systemic mastocytosis - Correlation with clinical patterns of disease SO ARCHIVES OF DERMATOLOGY LA English DT Article AB Objectives To determine clinical correlates of urticaria pigmentosa (UP) regression in adult patients with systemic mastocytosis (SM). Design: Cohort study of the natural history of mastocytosis. Setting: National Institute of Health Clinical Center. Patients: In a study of adult patients referred to the National Institutes of Health after 1980 and observed for a minimum of 10 years, 12 of 106 adult patients experienced clearance or fading of UP. Main Outcome Measures: Data from each patient's history and results of physical examination, laboratory evaluation, and organ biopsy at presentation to the National Institutes of Health were compared with findings at the patient's most recent visit. Results: In the patients in whom clearance of (n = 5) or a decrease in skin lesions (n=7) was noted, UP had persisted from 4 to 34 years (median, 17 years). Older age was a prognostic feature for regression of UP. Despite improvement of UP, the 2 patients with SM with an associated hematologic disorder experienced a deterioration in clinical condition, In the 10 patients with indolent SM, severity and frequency of symptoms decreased as the UP regressed. However, bone marrow changes consistent with SM remained. Conclusions: Urticaria pigmentosa regresses in approximately 10% of the older patients who have SM. In patients with an associated hematologic disorder such as myelodysplasia, this regression may be accompanied by disease progression. In contrast, regression of UP in patients with indolent SM parallels a decrease in disease intensity, although bone marrow findings of indolent SM remain. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C213,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. NR 13 TC 22 Z9 22 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUN PY 2002 VL 138 IS 6 BP 785 EP 790 DI 10.1001/archderm.138.6.785 PG 6 WC Dermatology SC Dermatology GA 563ZG UT WOS:000176287700009 PM 12056960 ER PT J AU Weinberger, DR McClure, RK AF Weinberger, DR McClure, RK TI Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry - What is happening in the schizophrenic brain? SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID PROLONGED GLUCOCORTICOID EXPOSURE; CHILDHOOD-ONSET SCHIZOPHRENIA; TEMPORAL-LOBE EPILEPSY; APOPTOTIC CELL-DEATH; 3-YEAR FOLLOW-UP; VENTRICULAR ENLARGEMENT; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; STRUCTURAL-CHANGE; MAJOR DEPRESSION AB In an era of dramatic discoveries in neuroscience and genetics, it is likely that many popular theories and formulations about mental illness will need to be revised, if not discarded. The "neurodevelopmental hypothesis" is one of the popular theories about the origins of schizophrenia, which posits that abnormalities of early brain development increase risk for the subsequent emergence of the clinical syndrome.(1-3) An early piece of evidence in support of this hypothesis was the apparent lack of progression of cerebral ventricular enlargement observed with computed tomography during illness.(4-9) An important assumption of the neuro developmental hypothesis is that the putative primary pathologic condition of the brain is a reflection of abnormalities of early development. The neuro developmental hypothesis thus assumes that developmental neuropathologic conditions should arrest early in life and not continue to progress. The computed tomography results showing no apparent progression seemed consistent with this assumption. However, a recent series of magnetic resonance imaging (MRI) studies has called into question this assumption, by revealing changes in measurements of brain structures over short periods in patients who have been ill for varying durations and at various stages of life. These recent studies'(10-14) have generated enthusiasm for a "neurodegenerative hypothesis," harkening back to proposals of Kraepelin and other neuropathologists during the first quarter of the 20th century that there is destruction of neural tissue associated with psychosis. In fact, results of MRI measurements have been cited as support for a much broader conceptual revolution in psychiatry, a "neurotoxicity hypothesis" for many psychiatric illnesses, including affective disorders(15,16) and anxiety and stress disorders(17-19) and even jet lag.(20) This recent trend has been bolstered by basic discoveries about the adaptability of neuronal connections(21) and the viability and reproducibility of neurons in the adult brain (eg, apoptosis and neurogenesis).(22,23) These developments have led some to opine that the neurodegenerative hypothesis of schizophrenia may have been unjustly overshadowed by the ascendancy of the neuro developmental hypothesis.(24) C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 3C-101,MSc 1255, Bethesda, MD 20892 USA. NR 75 TC 190 Z9 197 U1 5 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JUN PY 2002 VL 59 IS 6 BP 553 EP 558 DI 10.1001/archpsyc.59.6.553 PG 6 WC Psychiatry SC Psychiatry GA 559ZA UT WOS:000176055400010 PM 12044198 ER PT J AU Shuren, JE Grafman, J AF Shuren, JE Grafman, J TI The neurology of reasoning SO ARCHIVES OF NEUROLOGY LA English DT Review ID ORBITOFRONTAL CORTEX; DECISION-MAKING; HUMAN AMYGDALA; HEMISPHERE; EMOTION; BRAIN C1 US FDA, Off Policy Planning & Legislat, Rockville, MD 20857 USA. NINCDS, Cognit Neurosci Sect, NIH, Rockville, MD USA. RP Shuren, JE (reprint author), US FDA, Off Policy Planning & Legislat, HF-11,Room 14-101,5600 Fishers Ln, Rockville, MD 20857 USA. OI Grafman, Jordan H./0000-0001-8645-4457 NR 20 TC 20 Z9 21 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JUN PY 2002 VL 59 IS 6 BP 916 EP 919 DI 10.1001/archneur.59.6.916 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 561TK UT WOS:000176158600002 PM 12056926 ER PT J AU Ellwein, LB Urato, CJ AF Ellwein, LB Urato, CJ TI Use of eye care and associated charges among the medicare population - 1991-1998 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CATARACT-SURGERY; UNDERTREATMENT; AMERICANS; GLAUCOMA; SERVICES AB Objective: To examine trends in the utilization and cost of eve care in the Medicare population. Methods: Data were obtained from fee-for-service physician claims (Part B) from a 5% sample of Medicare beneficiaries 65 years and older. Use of eye care services and procedures, frequency of ocular diagnoses, and allowed charges were compared for each year from 1991 through 1998, Results: The proportion of beneficiaries receiving eye care increased from 41.4% to 48.1% during the 8-year period. Part B charges attributable to eye care decreased from 12.5% to 10.4%, with annual inflation-adjusted charges per beneficiary decreasing from $235 to $176 (1998 dollars). The proportion of beneficiaries with cataract-related claims increased from 23.4% to 27.3%, accounting for approximately 60% of eye care charges each year; beneficiaries with retinal disease claims increased from 7.8% to 11.4%, capturing 15.4% of eye care charges in 1998, up from 10.7% in 1991; and beneficiaries with glaucoma claims increased from 6.8% to 9.5%, accounting for nearly 10% of eye care charges each year. Conclusions: the proportion of the Medicare popularion receiving eye care increased between 1991 and 1998. Nevertheless, eye care costs did not increase, primarily because of constraints in charges associated with the management of cataract. C1 NEI, NIH, Bethesda, MD 20892 USA. Hlth Econ Res Inc, Waltham, MA USA. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 16 TC 85 Z9 87 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2002 VL 120 IS 6 BP 804 EP 811 PG 8 WC Ophthalmology SC Ophthalmology GA 561MV UT WOS:000176145500014 PM 12049587 ER PT J AU Bella, JN MacCluer, JW Roman, MJ Almasy, L North, KE Welty, TK Lee, ET Fabsitz, RR Howard, BV Devereux, RB AF Bella, JN MacCluer, JW Roman, MJ Almasy, L North, KE Welty, TK Lee, ET Fabsitz, RR Howard, BV Devereux, RB TI Genetic influences on aortic root size in American Indians - The strong heart study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE genetics; epidemiology; echocardiography; aorta ID LEFT-VENTRICULAR STRUCTURE; RISK-FACTORS; DISSECTING ANEURYSM; ASCENDING AORTA; REGURGITATION; HYPERTENSION; PREVALENCE; DISEASE; INHERITANCE; COMPONENTS AB Aortic root dilatation is a major pathophysiological mechanism for aortic regurgitation and predisposes the aortic root to dissection or rupture. However, only a small proportion of the variance of aortic root size can be explained by its known clinical and demographic correlates. The present study was undertaken to determine the heritability of echocardiographically derived aortic root diameter in the American Indian participants in the second Strong Heart Study examination. Echocardiograms were analyzed in 1373 SHS participants who had greater than or equal to1 family member in the cohort. Heritability calculations were performed by using variance component analysis as implemented in SOLAR, a computer analysis program. In a polygenic model, the variables entered and identified as covariates of larger aortic root diameter were older age, male sex, and center (P<0.001), which accounted for 35% of the overall variability of aortic root diameter. After simultaneous adjustment was made for these significant covariates, the proportion of phenotypic variance due to additive genetic contribution or residual heritability (h(2)) was 0.51 (SE=0.08, P<0.001). Additionally, simultaneous adjustment for height, weight, and systolic and diastolic Bps yielded slightly lower residual h(2) of aortic root diameter (h(2) = 0.44, SE=0.08, P<0.001), which accounted for 26% of the overall variance of aortic root size. Because center effects were identified as significant covariates in the analyses, h 2 analyses were performed separately in Arizona, Oklahoma, and North/South Dakota centers, which confirmed that a significant proportion of the phenotypic variance of aortic root diameter is due to additive genetic contribution. Heredity explains a substantial proportion of the variability of aortic root size that is not accounted for by age, sex, body size, and blood pressure. Echocardiographic screening of family members with aortic root dilatation may identify other individuals predisposed to aortic dissection or rupture. C1 Cornell Univ, Weill Med Coll, Dept Med, New York, NY USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Univ Oklahoma, Sch Publ Hlth Serv, Oklahoma City, OK USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. FU NCRR NIH HHS [M10RR0047-34]; NHLBI NIH HHS [U01-HL-41652, U01-HL-41654, U01-HL-41642] NR 38 TC 18 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUN PY 2002 VL 22 IS 6 BP 1008 EP 1011 DI 10.1161/01.ATV.0000017473.78775.F6 PG 4 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 565YV UT WOS:000176398900022 PM 12067912 ER PT J AU Cottington, EM LaMantia, C Stabler, SP Allen, RH Tangerman, A Wagner, C Zeisel, SH Mudd, SH AF Cottington, EM LaMantia, C Stabler, SP Allen, RH Tangerman, A Wagner, C Zeisel, SH Mudd, SH TI Adverse event associated with methionine loading test - A case report SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE methionine load elevation; cerebral death ID PLASMA HOMOCYSTEINE; ENDOTHELIAL DYSFUNCTION; FOLATE-DEFICIENCY; S-ADENOSYLHOMOCYSTEINE; SYNTHASE DEFICIENCY; VASCULAR-DISEASE; ORAL METHIONINE; FOLIC-ACID; SERUM; COBALAMIN AB The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care. C1 NIMH, Mol Biol Lab, DIRP, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Colorado, Hlth Sci Ctr, Div Hematol, Denver, CO USA. Univ Med Ctr Nijmegen, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. Dept Vet Affairs Med Ctr, Nashville, TN 37212 USA. Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. RP Mudd, SH (reprint author), NIMH, Mol Biol Lab, DIRP, Bldg 36,Room 1B-08,36 Convent Dr MSC 4034, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK-55865] NR 40 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUN PY 2002 VL 22 IS 6 BP 1046 EP 1050 DI 10.1161/01.ATV.0000020400.25088.A7 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 565YV UT WOS:000176398900029 PM 12067919 ER PT J AU Grammer, AC Lipsky, PE AF Grammer, AC Lipsky, PE TI CD154-CD40 interactions mediate differentiation to plasma cells in healthy individuals and persons with systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Review ID REACTIVE B-CELLS; IMMUNOGLOBULIN-SECRETING CELLS; ANTIGEN RECEPTOR ENGAGEMENT; HUMORAL IMMUNE-RESPONSE; CD40 LIGAND; T-CELL; AUTOIMMUNE-DISEASE; GERMINAL-CENTERS; PERIPHERAL-BLOOD; DEFICIENT MICE C1 NIAMS, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Grammer, AC (reprint author), NIAMS, Autoimmun Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 6D45A, Bethesda, MD 20892 USA. NR 119 TC 44 Z9 50 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2002 VL 46 IS 6 BP 1417 EP 1429 DI 10.1002/art.10287 PG 13 WC Rheumatology SC Rheumatology GA 562LX UT WOS:000176199200001 PM 12115170 ER PT J AU Hamano, M Kuramochi, H Nihei, N Kamiya, N Suzuki, H Igarashi, T Barrett, JC Ichikawa, T Ito, H AF Hamano, M Kuramochi, H Nihei, N Kamiya, N Suzuki, H Igarashi, T Barrett, JC Ichikawa, T Ito, H TI Mechanisms of metastasis suppression by introduction of human chromosome 10 into rat prostate cancer SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE prostate cancer; human chromosome 10; invasion; neoplasm metastasis; suppression of metastasis ID RECONSTITUTED BASEMENT-MEMBRANE; ALLELIC LOSS; TUMOR-CELLS; PTEN/MMAC1 GENE; GROWTH-FACTOR; LONG ARM; PROGRESSION; EXPRESSION; CARCINOMA; INVASION AB Aim: The metastatic ability of a Dunning R-3327 rat prostate cancer subline (AT6.3) was suppressed by the introduction of human chromosome 10, when these hybrid cancer cells were injected subcutaneously into nude mice (Nihei et al., Genes Chromosomes Cancer 14:112-119, 1995). The present study was undertaken to clarify which step of metastasis was suppressed in the human chromosome 10-containing microcell hybrids (AT 6.3-10 clones). Methods: Gelatin zymography, an in vitro invasion assay using a Boyden chamber and an intravenous metastasis assay involving the injection of hybrid cells into nude mice were performed. Results: Gelatin zymography revealed that AT6.3-10 microcell hybrid clones expressed the 72 kD type IV collagenase (MMP-2) at an almost equal level as control microcell hybrid clones. Both the invasiveness as measured by the invasion assay and the number of lung metastases as measured by the intravenous metastasis assay of AT6.3-10 hybrid clones were significantly less than those of the AT6.3 parental clone. Conclusion: The human chromosome 10 suppresses both the local invasion and the metastatic process after entry into the blood circulation of rat prostate cancer. This decrease in local-invasive ability does not seem to require a decrease in MMP-2 activity. C1 Chiba Univ, Grad Sch Med, Dept Mol Oncol M7, Chuo Ku, Chiba 2608670, Japan. Chiba Univ, Grad Sch Med, Dept Urol, Chiba 2608670, Japan. NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ichikawa, T (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Oncol M7, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. NR 41 TC 3 Z9 3 U1 0 U2 0 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD JUN PY 2002 VL 4 IS 2 BP 123 EP 129 PG 7 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 569KE UT WOS:000176600900007 PM 12085103 ER PT J AU Hosoki, S Ota, S Ichikawa, Y Suzuki, H Ueda, T Naya, Y Akakura, K Igarashi, T Oshimura, M Nihei, N Barrett, JC Ichikawa, T Ito, H AF Hosoki, S Ota, S Ichikawa, Y Suzuki, H Ueda, T Naya, Y Akakura, K Igarashi, T Oshimura, M Nihei, N Barrett, JC Ichikawa, T Ito, H TI Suppression of metastasis of rat prostate cancer by introduction of human chromosome 13 SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE BRCA2; chromosome 13; metastasis; metastasis suppressor genes; prostate cancer; RB1 ID COMPARATIVE GENOMIC HYBRIDIZATION; SHORT ARM; SUSCEPTIBILITY GENE; DISTINCT REGIONS; MAMMARY-CANCER; ALLELIC LOSS; LONG ARM; IDENTIFICATION; LOCALIZATION; DELETION AB Aim: Chromosome 13 is one of the most frequently altered chromosomes in prostate cancer. The present study was undertaken to examine the role of human chromosome 13 in the progression of prostate cancer. Methods: Human chromosome 13 was introduced into highly metastatic rat prostate cancer cells via microcell-mediated chromosome transfer. Results: Microcell hybrid clones containing human chromosome 13 showed suppression of metastasis to the lung without any suppression of tumorigenicity, except for one clone, which contained the smallest sized human chromosome 13 and did not show any suppression on lung metastasis. Expression of two known tumor suppressor genes, BRCA2 and RB1, which map to chromosome 13, was examined by reverse transcription-polymerase chain reaction analysis. BRCA2 was expressed only in the metastasis-suppressed microcell-hybrid clones, whereas RB1 was expressed in all clones. Conclusion: Human chromosome 13 contains metastasis suppressor gene (s) for prostate cancer derived from rat. Furthermore, the RB1 gene is unlikely to be involved in the suppression of metastasis evident in this system. C1 Chiba Univ, Grad Sch Med, Dept Mol Oncol M7, Chuo Ku, Chiba 2608670, Japan. Chiba Univ, Grad Sch Med, Dept Urol, Chiba 2608670, Japan. NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Tottori Univ, Sch Med, Dept Mol & Cell Genet, Yonago, Tottori 6838503, Japan. Teikyo Univ, Sch Med, Ichihara Hosp, Dept Urol, Ichihara 2990111, Japan. RP Ichikawa, Y (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Oncol M7, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. NR 35 TC 6 Z9 7 U1 1 U2 1 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD JUN PY 2002 VL 4 IS 2 BP 131 EP 136 PG 6 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 569KE UT WOS:000176600900008 PM 12085104 ER PT J AU Bridle, N Pantelis, C Wood, SJ Coppola, R Velakoulis, D McStephen, M Tierney, P Le, TL Torrey, EF Weinberger, DR AF Bridle, N Pantelis, C Wood, SJ Coppola, R Velakoulis, D McStephen, M Tierney, P Le, TL Torrey, EF Weinberger, DR TI Thalamic and caudate volumes in monozygotic twins discordant for schizophrenia SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Article DE caudate nucleus; magnetic resonance imaging; schizophrenia; thalamus; twins ID NEVER-MEDICATED SCHIZOPHRENICS; POSITRON EMISSION TOMOGRAPHY; CEREBRAL GLUCOSE-METABOLISM; NEUROLEPTIC-NAIVE; FIRST-EPISODE; TREATED PATIENTS; NUCLEI VOLUMES; BASAL GANGLIA; BRAIN; ABNORMALITIES AB Objective: The thalamus and caudate nucleus are key subcortical structures in the fronto-striato-thalamic pathways that have been implicated in the pathogenesis of schizophrenia. Previous studies have been inconsistent in identifying structural and functional abnormalities in these structures. However, methodologies in these studies have been unreliable and some have not adequately matched patients and controls. Methods: Using algebraically-manipulated double-echo magnetic resonance (MR) images, we developed a reliable method to estimate caudate and thalamic volumes in a group of 13 monozygotic (MZ) twins; eight discordant for schizophrenia and five normal. Initially, volumes were measured on four image types: proton density (PD), T2-weighted, summed (PD + T2) and subtracted (PD-T2) to determine the most reliable method. Results: There was a significant method by region interaction, where caudate volumes measured on PD images were significantly larger than those measured on T2-weighted images, while the opposite was found for thalamic volumes. However, there was no interaction of method by diagnosis. Test-retest reliability was highest for the summed images. Using summed images to measure the volumes of the caudate and thalamus in each twin, we found significantly increased caudate volumes in affected twins compared to their unaffected cotwins, but no significant difference in thalamic volume. Conclusions: Our results in a small sample of MZ twins discordant for schizophrenia do not support the presence of structural abnormalities in the thalamus. The findings in the caudate are consistent with previously reported effects of antipsychotic medication. We also report a reliable method for assessing the volumes of subcortical structures. However, volumetric estimates of brain structures may be dependent on which method is used and the structure being assessed. Such interactions need to be considered in future studies investigating brain structural abnormalities in schizophrenia and other disorders. C1 Univ Melbourne, Cognit Neuropsychiat Res & Acad Unit, Parkville, Vic 3052, Australia. Mental Hlth Res Inst Victoria, Parkville, Vic, Australia. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Pantelis, C (reprint author), Univ Melbourne, Cognit Neuropsychiat Res & Acad Unit, Parkville, Vic 3052, Australia. RI Wood, Stephen/M-8652-2014; Pantelis, Christos/H-7722-2014 OI Wood, Stephen/0000-0003-4186-5919; Pantelis, Christos/0000-0002-9565-0238 FU NIMH NIH HHS [MH 41176] NR 40 TC 21 Z9 22 U1 1 U2 2 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0004-8674 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD JUN PY 2002 VL 36 IS 3 BP 347 EP 354 DI 10.1046/j.1440-1614.2001.01022.x PG 8 WC Psychiatry SC Psychiatry GA 561YB UT WOS:000176169700008 PM 12060183 ER PT J AU Al-Saleh, MF Zheng, G AF Al-Saleh, MF Zheng, G TI Estimation of bivariate characteristics using ranked set sampling SO AUSTRALIAN & NEW ZEALAND JOURNAL OF STATISTICS LA English DT Article DE bivariate ranked set sampling; regression estimator; relative efficiency; relative saving; simple random sampling ID EFFICIENCY AB The superiority of ranked set sampling (RSS) over simple random sampling (SRS) for estimating the mean of a population is well known. This paper introduces and investigates a bivariate version of RSS for estimating the means of two characteristics simultaneously. It turns out that this technique is always superior to SRS and the usual univariate RSS of the same size. The performance of this procedure for a specific distribution can be evaluated using simulation or numerical computation. For the bivariate normal distribution, the efficiency of the procedure with respect to that of SRS is evaluated exactly for set size m = 2 and 3. The paper shows that the proposed estimator is more efficient than the regression RSS estimators proposed by Yu & Lam (1997) and Chen (2001). Real data that consist of heights and diameters of 399 trees are used to illustrate the procedure. The procedure can be generalized to the case of multiple characteristics. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Sultan Qaboos Univ, Coll Sci, Dept Math & Stat, Muscat, Oman. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Rockledge 2,6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 22 TC 35 Z9 35 U1 0 U2 1 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1369-1473 J9 AUST NZ J STAT JI Aust. N. Z. J. Stat. PD JUN PY 2002 VL 44 IS 2 BP 221 EP 232 DI 10.1111/1467-842X.00224 PG 12 WC Statistics & Probability SC Mathematics GA 553BM UT WOS:000175655700009 ER PT J AU Hampton, RR Murray, EA AF Hampton, RR Murray, EA TI Learning of discriminations is impaired, but generalization to altered views is intact, in monkeys (Macaca mulatta) with perirhinal cortex removal SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; RHINAL CORTEX; RHESUS-MONKEYS; OBJECT-DISCRIMINATION; VISUAL-DISCRIMINATION; RECOGNITION MEMORY; INTERTRIAL INTERVALS; HIPPOCAMPAL-LESIONS; AREA TE; ABLATION AB Rhesus monkeys (Macaca mulatta) were taught a large number of visual discriminations and then either received bilateral removal of the perirhinal cortex or were retained as unoperated controls. Operated monkeys were impaired in retention of the preoperatively learned problems. To test for generalization to novel views, the monkeys were required to discriminate, in probe trials, familiar pairs of images that were rotated, enlarged, shrunken, presented with color deleted, or degraded by masks. Although these manipulations reduced accuracy in both groups, the operated group was not differentially affected. In contrast, the same operated monkeys were impaired in reversal of familiar discriminations and in acquisition of new single-pair discriminations. These results indicate an important role for perirhinal cortex in visual learning, memory, or both. and show that under a variety of conditions, perirhinal cortex is not critical for the identification of stimuli. C1 Natl Inst Mental Hlth, NIH, Lab Neuropsychol, Sect Neurobiol Learning & Memory, Bethesda, MD 20892 USA. RP Hampton, RR (reprint author), Natl Inst Mental Hlth, NIH, Lab Neuropsychol, Sect Neurobiol Learning & Memory, Bldg 49 Rm 1B-80, Bethesda, MD 20892 USA. OI Murray, Elisabeth/0000-0003-1450-1642 NR 38 TC 42 Z9 42 U1 1 U2 8 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD JUN PY 2002 VL 116 IS 3 BP 363 EP 377 DI 10.1037//0735-7044.116.3.363 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 553VP UT WOS:000175697100001 PM 12049317 ER PT J AU La Vecchia, C Brinton, LA McTiernan, A AF La Vecchia, C Brinton, LA McTiernan, A TI Cancer risk in menopausal women SO BEST PRACTICE & RESEARCH IN CLINICAL OBSTETRICS & GYNAECOLOGY LA English DT Article DE breast cancer; endometrial cancer; ovarian cancer; colorectal cancer; hormones ID HORMONE REPLACEMENT THERAPY; ESTROGEN-PROGESTIN-REPLACEMENT; EPITHELIAL OVARIAN-CANCER; STATES CASE-CONTROL; TERM FOLLOW-UP; BREAST-CANCER; ENDOMETRIAL CANCER; COLORECTAL-CANCER; POSTMENOPAUSAL WOMEN; UNITED-STATES AB The incidence for breast and other female-hormone-related neoplasms levels off after menopause. The relative risk (RR) of breast cancer is moderately elevated in current and recent users of hormone replacement therapy (HRT) and increases by about 2.3% per year with longer duration of use, but the effect drops after cessation. Unopposed oestrogen use is strongly related to endometrial cancer risk but cyclic combined oestrogen-progestin treatment appears to reduce this side-effect. However, combined HRT may be associated with higher risk of breast cancer as compared to unopposed oestrogens. Ovarian cancer may also be unfavourably influenced by the use of HRT. HRT has been related to decreased risk of colorectal cancer, the overall RR being about 0.8. Tamoxifen and other selective oestrogen receptor modulators (SERMs) may have a favourable effect on the risk of breast cancer but their risk-benefit profile requires further quantification. The potential effect of 'natural' SERMs (phytoestrogens) on cancer risk remains undefined. C1 Mario Negri Inst Pharmacol Res, I-20157 Milan, Italy. Univ Milan, Ist Stat Med & Biometria, I-20133 Milan, Italy. NCI, Environm Epidemiol Branch, Rockville, MD 20852 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98109 USA. RP La Vecchia, C (reprint author), Mario Negri Inst Pharmacol Res, Via Eritrea 62, I-20157 Milan, Italy. RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; La Vecchia, Carlo/0000-0003-1441-897X NR 100 TC 4 Z9 4 U1 0 U2 0 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6934 J9 BEST PRACT RES CL OB JI Best Pract. Res. Clin. Obstet. Gynaecol. PD JUN PY 2002 VL 16 IS 3 BP 293 EP 307 DI 10.1053/beog.2002.0283 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 575LP UT WOS:000176948000005 PM 12099664 ER PT J AU Hsiao, PW Deroo, BJ Archer, TK AF Hsiao, PW Deroo, BJ Archer, TK TI Chromatin remodeling and tissue-selective responses of nuclear hormone receptors SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Review DE chromatin; BRG1; SWI-SNF; nuclear receptor; glucorticoid receptor; transcription; MMTV ID HUMAN BREAST-CANCER; SWI-SNF COMPLEX; YEAST SWI/SNF COMPLEX; TUMOR VIRUS PROMOTER; GLUCOCORTICOID RECEPTOR; ESTROGEN-RECEPTOR; MMTV PROMOTER; HISTONE H1; SACCHAROMYCES-CEREVISIAE; PEPTIDE ANTAGONISTS AB Chromatin structure of eukaryotic genes regulates gene expression by controlling the accessibility of regulatory factors. To overcome the inhibitory nature of chromatin, protein complexes that modify higher order chromatin organization and histone-DNA contacts are critical players in regulating transcription. For example, nuclear hormone receptors regulate transcription by interacting with ATP-dependent chromatin-remodeling complexes and coactivators, which include histone acetyltransferases and histone methylases that modify the basic residues of histones. A growing number of tissue-specific nuclear hormone receptor ligands, termed "selective modulators", owe their specificity, at least in part, to the differential recruitment of these chromatin-modifying coactivators. The molecular mechanisms by which these compounds modulate the functions of nuclear hormone receptors are discussed here. C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. OI Hsiao, Pei-Wen/0000-0002-3589-6754 NR 88 TC 26 Z9 26 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD JUN PY 2002 VL 80 IS 3 BP 343 EP 351 DI 10.1139/O02-082 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 564KL UT WOS:000176313500007 PM 12123287 ER PT J AU Drotschmann, K Hall, MC Shcherbakova, PV Wang, H Erie, DA Brownewell, FR Kool, ET Kunkel, TA AF Drotschmann, K Hall, MC Shcherbakova, PV Wang, H Erie, DA Brownewell, FR Kool, ET Kunkel, TA TI DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers SO BIOLOGICAL CHEMISTRY LA English DT Review DE DNA binding; mismatch repair; Mlh1; Msh2; Msh6; Pms1 ID REPAIR PROTEIN MUTS; MISMATCH REPAIR; ESCHERICHIA-COLI; ATPASE ACTIVITY; CRYSTAL-STRUCTURE; HMUTS-ALPHA; RECOGNITION; PURIFICATION; MUTATION; SUBUNIT AB We describe here our recent studies of the DNA binding properties of Msh2-Msh6 and Mlh1-Pms1, two protein complexes required to repair mismatches generated during DNA replication. Mismatched DNA binding by Msh2-Msh6 was probed by mutagenesis based on the crystal structure of the homologous bacterial MutS homodimer bound to DNA. The results suggest that several amino acid side chains inferred to interact with the DNA backbone near the mismatch are critical for repair activity. These contacts, which are different in Msh2 and Msh6, likely facilitate stacking and hydrogen bonding interactions between side chains in Msh6 and the mismatched base, thus stabilizing a kinked DNA conformation that permits subsequent repair steps coordinated by the Mlh1-Pms1 heterodimer. Mlh1-Pms1 also binds to DNA, but independently of a mismatch. Mlh1-Pms1 binds short DNA substrates with low affinity and with a slight preference for singlestranded DNA. It also binds longer duplex DNA molecules, but with a higher affinity indicative of cooperative binding. Indeed, imaging by atomic force microscopy reveals cooperative DNA binding and simultaneous interaction with two DNA duplexes. The novel DNA binding properties of Mlh1- Pms1 may be relevant to signal transduction during DNA mismatch repair and to recombination, meiosis and cellular responses to DNA damage. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Stanford Univ, Dept Chem, Stanford, CA 94305 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RI Wang, Hong/F-3164-2014 OI Wang, Hong/0000-0003-0165-3559 NR 25 TC 28 Z9 31 U1 0 U2 16 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD JUN PY 2002 VL 383 IS 6 BP 969 EP 975 DI 10.1515/BC.2002.103 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568YE UT WOS:000176571900010 PM 12222686 ER PT J AU Grillon, C AF Grillon, C TI Associative learning deficits increase symptoms of anxiety in humans SO BIOLOGICAL PSYCHIATRY LA English DT Article DE classical conditioning; fear conditioning; context conditioning; startle; psychophysiology; anxiety ID FEAR-POTENTIATED STARTLE; PERSPECTIVE; DISORDERS; AWARENESS; AMYGDALA; NEUROSIS AB Background: Unpredictability has been postulated to be fundamental to anxiety and mood disorders. The origin of this unpredictability remains obscure. Because classical conditioning promotes predictability, this study investigated whether failure to learn conditioned stimulus (CS)unconditioned stimulus (US) relationship during fear conditioning increased anxiety and avoidance. Methods: Healthy subjects participated in two similar differential fear conditioning sessions separated by 1 week (n = 72) or a month (n = 61) in which one of two conditioned stimuli was associated with a shock/US. Following initial acquisition, subjects' awareness of CS-US relationship was assessed. Conditioned responses (CR) to the CS and to the experimental context were examined using the startle reflex and the skin conductance. Avoidance was operationally defined as failure to return for the second session. Results: Only aware subjects showed differential CR. In the unaware subjects, the deficit in differential conditioning was associated with increased signs of anxiety during the first and second sessions. In addition, there was greater avoidance in the unaware subjects. Conclusions: Deficits in explicit cue fear conditioning can enhance anxiety. These findings are consistent with theories that associate anxiety and mood disorders with perceived unpredictability. Contextual conditioning models may be relevant to study chronic forms of anxiety. Biol Psychiatry 2002;51:851-858 (C) 2002 Society of Biological Psychiatry. C1 NIMH, MAP, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, MAP, 15K N Dr,Bldg 15K,Room 113,MSC 2670, Bethesda, MD 20892 USA. FU NIMH NIH HHS [R01 MH53618-01] NR 34 TC 100 Z9 102 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2002 VL 51 IS 11 BP 851 EP 858 AR PII S0006-3223(01)01370-1 DI 10.1016/S0006-3223(01)01370-1 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 553AC UT WOS:000175651900001 PM 12022957 ER PT J AU Neumaier, JF Edwards, E Plotsky, PM AF Neumaier, JF Edwards, E Plotsky, PM TI 5-HT1B mRNA regulation in two animal models of altered stress reactivity SO BIOLOGICAL PSYCHIATRY LA English DT Article DE autoreceptor; depression; posttraumatic stress disorder; 5-HT1A receptor; 5-HT1B receptor ID DORSAL RAPHE NUCLEUS; RECEPTOR MESSENGER-RNA; LEARNED HELPLESSNESS; RAT-BRAIN; AUTORECEPTOR FUNCTION; SEROTONIN; EXPRESSION; RELEASE; SYSTEM; HIPPOCAMPUS AB Background: Acute stress has profound effects on serotonergic activity, but it is not known whether alterations in the serotonin system can predispose individuals to exaggerated stress responses. We examined the regulation of 5-HT1B and 5-HT1A mRNA in two rodent models of differential sensitivity to stress: congenital learned helplessness (cLH) and handling and maternal separation (HMS). Methods: 5-HT1B and 5-HT1A mRNAs in brain tissue sections were quantitated by in situ hybridization from control, stress-sensitive, and stress-resistant male rats in the HMS model and stress-sensitive and stress-resistant rats (both males and females) in the cLH model. Dorsal raphe nucleus, striatum, and hippocampus were examined. Results: The main result was that dorsal raphe 5-HT1B mRNA was substantially elevated (63-73%) in male rats in the stress-resistant group of both models compared with stress-sensitive animals. 5-HT1A mRNA in female rats did not differ between groups in the cLH model. There were no differences in 5-HT1A mRNA between HMS groups. Conclusions: These findings suggest that 5-HT1B autoreceptor regulation is altered in animals with diminished stress reactivity. These results suggest that 5-HT1B autoreceptors in unstressed and acutely stressed animals differ, indicating the importance of state versus trait changes in serotonin function in animal models of anxiety and depression. Biol Psychiatry 2002;51:902-908 (C) 2002 Society of Biological Psychiatry. C1 Univ Washington, Harborview Med Ctr, Dept Psychiat, Seattle, WA 98104 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. RP Neumaier, JF (reprint author), Univ Washington, Harborview Med Ctr, Dept Psychiat, Box 359911,325 9th Ave, Seattle, WA 98104 USA. FU NIMH NIH HHS [MH50113, MH57049] NR 43 TC 56 Z9 56 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2002 VL 51 IS 11 BP 902 EP 908 AR PII S0006-3223(01)01371-3 DI 10.1016/S0006-3223(01)01371-3 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 553AC UT WOS:000175651900008 PM 12022964 ER PT J AU Cupp, AS Tessarollo, L Skinner, MK AF Cupp, AS Tessarollo, L Skinner, MK TI Testis developmental phenotypes in neurotropin receptor trkA and trkC null mutations: Role in formation of seminiferous cords and germ cell survival SO BIOLOGY OF REPRODUCTION LA English DT Article DE developmental biology; gametogenesis; growth factors; Sertoli cells; testis ID NERVE GROWTH-FACTOR; RAT TESTIS; EXPRESSION; NGF; MORPHOGENESIS; LOCALIZATION; SPERMATIDS; ACTIVATION; NEURONS; FAMILY AB The objective of the present study was to determine if the neurotropin receptors trkC and trkA are involved in embryonic testis development. These receptors bind neurotropin 3 and nerve growth factor, respectively. The hypothesis tested was that the absence of trkC or trkA receptors will have detrimental effects on testis development and morphology. The trkA and trkC homozygote knockout (KO) mice generally die either at or shortly after birth. Therefore, heterozygote mice were mated to obtain homozygote gene KO mice at Embryonic Day (E) 13, E14, 1:17, and E19 of gestation, with EO being the plug date. Gonads from approximately 80 embryos were collected and fixed, and each embryo was genotyped. To determine gonadal characteristics for each genotype, the number of germ cells, number of seminiferous cords, serniniferous cord area, and interstitial area were calculated at each developmental age. Germ cell numbers varied in trkA gene KO mice from those of wild-type mice at each age evaluated. In trkC gene KO mice, differences were detected in germ cell numbers when compared to wild-type mice at E17 and E19. At E19, germ cell numbers were reduced in both trkA and trkC gene KO mice when compared to wildtype animals. Apoptosis was evaluated in testes of wild-type, trkC gene KO, and trkA gene KO mice to determine if the alteration in germ cell numbers at each developmental age was influenced by different patterns of germ cell survival or apoptosis. No differences were found in germ cell apoptosis during embryonic testis development. Interestingly, trkA gene KO mice that survived to Postnatal Day 19 had a 10-fold increase in germ cell apoptosis when compared to germ cells in wild-type mice. Evaluation of other morphological testis parameters demonstrated that trkC KID testes had reduced interstitial area at El 3, reduced number of seminiferous cords at E14, and reduced seminiferous cord area at E19. The trkA gene KO testes had a reduction in the number of serniniferous cords at E14. Histology of both trkA and trkC gene KO testes demonstrated that these gonads appear to be developmentally delayed when compared to their wild-type testis counterparts at E13 during testis development. The current study demonstrates that both trkA and trkC neurotropin receptors influence germ cell numbers during testis development and events such as seminiferous cord formation. C1 Washington State Univ, Sch Mol Biosci, Ctr Reprod Biol, Pullman, WA 99164 USA. NCI, Neural Dev Grp, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Skinner, MK (reprint author), Washington State Univ, Sch Mol Biosci, Ctr Reprod Biol, Pullman, WA 99164 USA. NR 27 TC 32 Z9 36 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUN PY 2002 VL 66 IS 6 BP 1838 EP 1845 DI 10.1095/biolreprod66.6.1838 PG 8 WC Reproductive Biology SC Reproductive Biology GA 554WP UT WOS:000175760400038 PM 12021070 ER PT J AU Ng, SSW Brown, M Figg, WD AF Ng, SSW Brown, M Figg, WD TI Thalidomide, an antiangiogenic agent with clinical activity in cancer SO BIOMEDICINE & PHARMACOTHERAPY LA English DT Review DE thalidomide; HIV-infection; bFGF; VEGF ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA PRODUCTION; PHASE-II TRIAL; MONONUCLEAR-CELLS; MULTIPLE-MYELOMA; PROSTATE-CANCER; NIGHT SWEATS; RENAL-CELL; ANGIOGENESIS; MECHANISM AB Despite the teratogenic past of thalidomide, there is recent evidence indicating the drug's efficacy in the management of various diseases from immune disorders to cancers. The history, pharmacodynamic and pharmacokinetic properties of thalidomide in the clinic are discussed in this review article. (C) 2002 Editions scientifiques et medicales Elsevier SAS. C1 Natl Canc Inst, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Natl Canc Inst, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bldg 10,Rm 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 45 TC 21 Z9 22 U1 1 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0753-3322 J9 BIOMED PHARMACOTHER JI Biomed. Pharmacother. PD JUN PY 2002 VL 56 IS 4 BP 194 EP 199 AR UNSP S0753332202001774/REV DI 10.1016/S0753-3322(02)00177-4 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 566HE UT WOS:000176420300005 PM 12109812 ER PT J AU Rieger, RH Weinberg, CR AF Rieger, RH Weinberg, CR TI Analysis of clustered binary outcomes using within-cluster paired resampling SO BIOMETRICS LA English DT Article DE clustered binary outcome data; conditional logistic regression; heterogeneity in response to exposure ID CASE-CROSSOVER; LONGITUDINAL DATA; MODELS; REGRESSION; ASSOCIATION; EXPOSURES; DESIGNS; BIAS AB Conditional logistic regression (CLR) is useful for analyzing clustered binary outcome data when interest lies in estimating a cluster-specific exposure parameter while treating the dependency arising from random cluster effects as a nuisance. CLR aggregates unmeasured clustor-specific factors into a cluster-specific baseline risk and is invalid in the presence of unmodeled heterogeneous covariate effects or within-cluster dependency. We propose an alternative, resampling-based method for analyzing clustered binary outcome data, within-cluster paired resampling (WCPR), which allows for within-cluster dependency not solely due to baseline heterogeneity. For example, dependency may be in part caused by heterogeneity in response to an exposure across clusters due to unmeasured cofactors. When both CLR and WCPR are valid, our simulations suggest that the two methods perform comparably. When CLR is invalid, WCPR continues to have good operating characteristics. For illustration, we apply both WCPR and CLR to a periodontal data set where there is heterogeneity in response to exposure across clusters. C1 W Chester Univ, Dept Math, W Chester, PA 19383 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Rieger, RH (reprint author), W Chester Univ, Dept Math, W Chester, PA 19383 USA. NR 28 TC 11 Z9 11 U1 1 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2002 VL 58 IS 2 BP 332 EP 341 DI 10.1111/j.0006-341X.2002.00332.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 561RT UT WOS:000176157000009 PM 12071406 ER PT J AU Zhou, HB Weaver, MA Qin, J Longnecker, MP Wang, MC AF Zhou, HB Weaver, MA Qin, J Longnecker, MP Wang, MC TI A semiparametric empirical likelihood method for data from an outcome-dependent sampling scheme with a continuous outcome SO BIOMETRICS LA English DT Article DE biased sampling; empirical likelihood; likelihood ratio statistics; missing data; semiparametric; supplemental sampling; validation sample ID LOGISTIC-REGRESSION; DISEASE; DESIGN; MODELS; BIAS AB Outcome-dependent sampling (ODS) schemes can be a cost effective way to enhance study efficiency. The case-control design has been widely used in epidemiologic studies. However, when the outcome is measured on a continuous scale, dichotomizing the outcome could lead to a loss of efficiency. Recent epidemiologic studies have used ODS sampling schemes where, in addition to an overall random sample, there are also a number of supplemental samples that are collected based on a continuous outcome variable. We consider a semiparametric empirical likelihood inference procedure in which the underlying distribution of covariates is treated as a nuisance parameter and is left unspecified. The proposed estimator has asymptotic normality properties. The likelihood ratio statistic using the semiparametric empirical likelihood function has Wilks-type properties in that, under the null, it follows a chi-square distribution asymptotically and is independent of the nuisance parameters. Our simulation results indicate that, for data obtained using an ODS design, the semiparametric empirical likelihood estimator is more efficient than conditional likelihood and probability weighted pseudolikelihood estimators and that ODS designs (along with the proposed estimator) can produce more efficient estimates than simple random sample designs of the same size. We apply the proposed method to analyze a data set from the Collaborative Perinatal Project (CPP), an ongoing environmental epidemiologic study, to assess the relationship between maternal polychlorinated biphenyl (PCB) level and children's IQ test performance. C1 Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. Family Hlth Int, Res Triangle Pk, NC 27599 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. RP Zhou, HB (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. OI Longnecker, Matthew/0000-0001-6073-5322 FU NCI NIH HHS [CA 79949] NR 25 TC 40 Z9 40 U1 0 U2 8 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2002 VL 58 IS 2 BP 413 EP 421 DI 10.1111/j.0006-341X.2002.00413.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 561RT UT WOS:000176157000018 PM 12071415 ER PT J AU Chanturiya, A Scaria, P Kuksenok, O Woodle, MC AF Chanturiya, A Scaria, P Kuksenok, O Woodle, MC TI Probing the mechanism of fusion in a two-dimensional computer simulation SO BIOPHYSICAL JOURNAL LA English DT Article ID MEMBRANE-FUSION; PHOSPHOLIPID-BILAYERS; INFLUENZA HEMAGGLUTININ; VESICLES; INTERMEDIATE; HEMIFUSION; STALK AB A two-dimensional (2D) model of lipid bilayers was developed and used to investigate a possible role of membrane lateral tension in membrane fusion. We found that an increase of lateral tension in contacting monolayers of 2D analogs of liposomes and planar membranes could cause not only hemifusion, but also complete fusion when internal pressure is introduced in the model. With a certain set of model parameters it was possible to induce hemifusion-like structural changes by a tension increase in only one of the two contacting bilayers. The effect of lysolipids was modeled as an insertion of a small number of extra molecules into the cis or trans side of the interacting bilayers at different stages of simulation. It was found that cis insertion arrests fusion and trans insertion has no inhibitory effect on fusion. The possibility of protein participation in tension-driven fusion was tested in simulation, with one of two model liposomes containing a number of structures capable of reducing the area occupied by them in the outer monolayer. It was found that condensation of these structures was sufficient to produce membrane reorganization similar to that observed in simulations with "protein-free" bilayers. These data support the hypothesis that changes in membrane lateral tension may be responsible for fusion in both model phospholipid membranes and in biological protein-mediated fusion. C1 Genet Therapy Inc, Gaithersburg, MD 20878 USA. Inst Biochem, Kiev, Ukraine. RP Chanturiya, A (reprint author), NICHHD, LCMB, NIH, Bldg 10,Rm 10D04,10 Ctr Dr,MSC, Bethesda, MD 20892 USA. NR 26 TC 16 Z9 16 U1 0 U2 1 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2002 VL 82 IS 6 BP 3072 EP 3080 PG 9 WC Biophysics SC Biophysics GA 555PP UT WOS:000175802700024 PM 12023230 ER PT J AU Hunsberger, S Albert, PS Follmann, DA Suh, E AF Hunsberger, S Albert, PS Follmann, DA Suh, E TI Parametric and semiparametric approaches to testing for seasonal trend in serial count data SO BIOSTATISTICS LA English DT Article DE harmonic models; incidence data; parametric bootstrap test; smoothing; time series count data ID TIME-SERIES; REGRESSION; MODELS AB We present two tests for seasonal trend in monthly incidence data. The first approach uses a penalized likelihood to choose the number of harmonic terms to include in a parametric harmonic model (which includes time trends and autogression as well as seasonal harmonic terms) and then tests for seasonality using a parametric bootstrap test. The second approach uses a semiparametric regression model to test for seasonal trend. In the semiparametric model, the seasonal pattern is modeled nonparametrically, parametric terms are included for autoregressive effects and a linear time trend, and a parametric bootstrap test is used to test for seasonality. For both procedures, a null distribution is generated under a null Poisson model with time trends and autoregression parameters. We apply the methods to skin melanoma incidence rates collected by the surveillance, epidemiology, and end results (SEER) program of the National Cancer Institute, and perform simulation studies to evaluate the type I error rate and power for the two procedures. These simulations suggest that both procedures are alpha-level procedures. In addition, the harmonic model/bootstrap test had similar or larger power than the serniparametric model/bootstrap, test for a wide range of alternatives, and the harmonic model/bootstrap test is much easier to implement. Thus, we recommend the harmonic model/bootstrap test for the analysis of seasonal incidence data. C1 NCI, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NHLBI, Rockledge Ctr 2, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Hunsberger, S (reprint author), NCI, 6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. NR 17 TC 18 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD JUN PY 2002 VL 3 IS 2 BP 289 EP 298 DI 10.1093/biostatistics/3.2.289 PG 10 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 696TG UT WOS:000183902900012 PM 12933619 ER PT J AU Fry, TJ Mackall, CL AF Fry, TJ Mackall, CL TI Interleukin-7: from bench to clinic SO BLOOD LA English DT Review ID T-CELL DEVELOPMENT; BONE-MARROW TRANSPLANTATION; RECEPTOR-DEFICIENT MICE; SEVERE COMBINED IMMUNODEFICIENCY; HUMAN PERIPHERAL-BLOOD; COMMON GAMMA-CHAIN; B-LINEAGE CELLS; RECOMBINANT HUMAN INTERLEUKIN-7; THYMIC STROMAL LYMPHOPOIETIN; ACTIVATED KILLER ACTIVITY C1 NCI, Immunol Sect, Pediat Branch, NIH, Bethesda, MD 20892 USA. RP Fry, TJ (reprint author), NCI, Immunol Sect, Pediat Branch, NIH, Bldg 10,Rm 13N240,MSC 1928,10 Ctr Dr, Bethesda, MD 20892 USA. NR 184 TC 285 Z9 293 U1 1 U2 6 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 JUN 1 PY 2002 VL 99 IS 11 BP 3892 EP 3904 DI 10.1182/blood.V99.11.3892 PG 13 WC Hematology SC Hematology GA 555QL UT WOS:000175804700003 PM 12010786 ER PT J AU Qiang, YW Kopantzev, E Rudikoff, S AF Qiang, YW Kopantzev, E Rudikoff, S TI Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk SO BLOOD LA English DT Article ID ACTIVATED PROTEIN-KINASE; GLYCOGEN-SYNTHASE KINASE-3; FORKHEAD TRANSCRIPTION FACTOR; CELL-SURVIVAL; FACTOR FKHRL1; TUMOR-GROWTH; P70S6 KINASE; S6 KINASE; PHOSPHORYLATION; INTERLEUKIN-6 AB In multiple myeloma cells, insulinlike growth factor-I (IGF-I) activates 2 distinct signaling pathways, mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K), leading to both proliferative and antiapoptotic effects. However, it is unclear through which of these cascades IGF-I regulates these different responses. The present studies identify a series of downstream targets in the PI-3K pathway, including glycogen synthase kinase-3beta, p70S6 kinase, and the 3 members of the Forkhead family of transcription factors. The contribution of the MAPK and PI-3K pathways and, where possible, individual elements to proliferation and apoptosis was evaluated by means of a series of specific kinase inhibitors. Both processes were regulated almost exclusively by the PI-3K pathway, with only minor contributions associated with the MAPK cascade. Within the PI-3K cascade, inhibition of p70S6 kinase led to significant decreases in proliferation and protection from apoptosis. Activation of p70S6 kinase could also be prevented by MAPK inhibitors, Indicating regulation by both pathways. The Forkhead transcription factor FKHRL1 was observed to provide a dual effect in that phosphorylation upon IGF-I treatment resulted In a loss of ability to Inhibit proliferation and Induce apoptosis. The PI-3K pathway was additionally shown to exhibit cross-talk and to regulate the MAPK cascade, as Inhibition of PI-3K prevented activation of Mek1/2 and other downstream MAPK elements. These results define Important elements In IGF-I regulation of myeloma cell growth and provide biological correlates critical to an understanding of growth-factor modulation of proliferation and apoptosis. (C) 2002 by The American Society of Hematology. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rudikoff, S (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 44 TC 104 Z9 106 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 JUN 1 PY 2002 VL 99 IS 11 BP 4138 EP 4146 DI 10.1182/blood.V99.11.4138 PG 9 WC Hematology SC Hematology GA 555QL UT WOS:000175804700037 PM 12010818 ER PT J AU Rabkin, CS Tess, BH Christianson, RE Wright, WE Waters, DJ Alter, HJ van den Berg, BJ AF Rabkin, CS Tess, BH Christianson, RE Wright, WE Waters, DJ Alter, HJ van den Berg, BJ TI Prospective study of hepatitis C viral infection as a risk factor for subsequent B-cell neoplasia SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; VIRUS-INFECTION; LYMPHOPROLIFERATIVE DISORDERS; T(14-18) TRANSLOCATION; LIVER-TRANSPLANTATION; HIGH PREVALENCE; ASSOCIATION AB Several case-control studies have found increased prevalence of hepatitis C virus (HCV) in patients with non-Hodgkin lymphoma (NHL) and other B-cell lympho-proliferative disorders. We examined whether HCV infection preceded the development of these neoplasms in a prospective cohort study of 48 420 individuals in northern California. Stored sera from 95 subjects with NHL (n = 57), multiple myeloma (n = 24), or Hodgkin disease (n = 14) diagnosed a mean of 21 years after phlebotomy were screened for antibodies to HCV as well as viral RNA, based on previous reports of antibody-negative viremia. Sera from 4 cases and one of 95 age-, sex-, and race-matched controls were repeatedly reactive by enzyme immunoassay, but none were confirmed by recombinant immunoblot assay; none of the case sera had HCV RNA by reverse transcription-polymerase chain reaction. Although acquisition In later life cannot be ruled out, these prospective data do not support a substantial role of chronic HCV Infection in the etiology of B-cell neoplasia. (C) 2002 by The American Society of Hematology. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Child Hlth & Dev Studies, Berkeley, CA USA. Calif Dept Hlth Serv, Canc Surveillance Sect, Sacramento, CA USA. Sci Applicat Int Corp, Frederick, MD USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD USA. RP Rabkin, CS (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-7026, Rockville, MD 20852 USA. NR 27 TC 48 Z9 49 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2002 VL 99 IS 11 BP 4240 EP 4242 DI 10.1182/blood-2002-01-0226 PG 3 WC Hematology SC Hematology GA 555QL UT WOS:000175804700055 PM 12010836 ER PT J AU Werhahn, KJ Mortensen, J Kaelin-Lang, A Boroojerdi, B Cohen, LG AF Werhahn, KJ Mortensen, J Kaelin-Lang, A Boroojerdi, B Cohen, LG TI Cortical excitability changes induced by deafferentation of the contralateral hemisphere SO BRAIN LA English DT Article DE amputation deafferentation; plasticity; motor cortex transcranial magnetic stimulation ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; CORPUS-CALLOSUM CONNECTIONS; ISCHEMIC NERVE BLOCK; SOMATOSENSORY CORTEX; ELECTRICAL-STIMULATION; CEREBRAL-CORTEX; INTERHEMISPHERIC INHIBITION; DEPENDENT PLASTICITY; ARCHITECTONIC FIELDS AB Short-term deprivation of sensory input by ischaemic nerve block (INB) leads to functional reorganization in the deafferented motor cortex. Here, we show that INB also elicits functional changes in homotopic regions of the cortex contralateral to the deafferented one. We measured motor evoked potential (MEP) amplitudes elicited by transcranial magnetic stimulation (TMS) in small hand and biceps brachii muscles before, during and after INB of the right hand. INB increased excitability of the cortical representation of (i) the intact hand and (ii) body parts proximal to the deafferented hand (upper arm), in the absence of excitability changes in other body part representations such as thorax or leg muscles. This effect persisted throughout the entire period of deafferentation and returned to baseline values afterward. Motor responses to brainstem electrical stimulation remained unchanged during INB, indicating that the effect is probably of cortical origin. Lorazepam, a GABA(A) receptor agonist, blocked this increased excitability. Interhemispheric inhibition between hand muscles decreased during INB. After chronic deafferentation in amputees, MEP amplitudes and motor output curves in small hand muscles were depressed and motor thresholds were elevated compared with aged-matched controls. These results indicate that acute hand deafferentation can elicit a focal increase in excitability in the hand motor representation contralateral to the deafferented cortex that is influenced by transcallosal interactions and GABAergic transmission, and is balanced in the setting of chronic deafferentation. C1 Natl Inst Neurol Disorders & Stroke, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Hosp Inselspital, Dept Neurol, Bern, Switzerland. Rhein Westfal TH Aachen, Dept Neurol, Aachen, Germany. RP Werhahn, KJ (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cortical Physiol Sect, NIH, Bldg 10,Room 5N2226,10 Ctr Dr,MSC-1430, Bethesda, MD 20892 USA. NR 72 TC 121 Z9 121 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2002 VL 125 BP 1402 EP 1413 DI 10.1093/brain/awf140 PN 6 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 563XG UT WOS:000176282700021 PM 12023328 ER PT J AU Brown, LM Williams, KJ Cowen, RL Melillo, G Sausville, E Stratford, IJ AF Brown, LM Williams, KJ Cowen, RL Melillo, G Sausville, E Stratford, IJ TI Evaluation of dominant negative and small molecular inhibitors of hypoxia mediated transcription for potential therapeutic application SO BRITISH JOURNAL OF CANCER LA English DT Meeting Abstract C1 Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England. NCI, Tumour Hypoxia Lab, DTP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN PY 2002 VL 86 SU 1 BP S97 EP S97 PG 1 WC Oncology SC Oncology GA 575KH UT WOS:000176945100307 ER PT J AU Manganiello, V AF Manganiello, V TI Short-term regulation of PDE4 activity SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Editorial Material ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; FAMILY; TARGETS; MODULE C1 NHLBI, PCCMB, NIH, Bethesda, MD 20892 USA. RP Manganiello, V (reprint author), NHLBI, PCCMB, NIH, Bldg 10,5N307,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 3 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUN PY 2002 VL 136 IS 3 BP 339 EP 340 DI 10.1038/sj.bjp.0704741 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 557HX UT WOS:000175904100001 PM 12023934 ER PT J AU Hadjokas, NE Dai, RK Friedman, FK Spence, MJ Cusack, BJ Vestal, RE Ma, YS AF Hadjokas, NE Dai, RK Friedman, FK Spence, MJ Cusack, BJ Vestal, RE Ma, YS TI Arginine to lysine 108 substitution in recombinant CYP1A2 abolishes methoxyresorufin metabolism in lymphoblastoid cells SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE oxidoreductases; CYP1A2; flavones; models; molecular; mutagenesis; site-directed ID HUMAN CYTOCHROME-P450 1A2; XENOBIOTIC METABOLISM; P450; INHIBITION; FLAVONOIDS; PROSPECTS; ENZYMES; LINE; CDNA; SITE AB 1 Cytochrome P4501A2 (CYP1A2) activates a large number of procarcinogens to carcinogens. Phytochemicals such as flavones can inhibit CYP1A2 activity competitively, and hydroxylated derivatives of flavone (galangin) may be potent, selective inhibitors of CYP1A2 activity relative to CYP1A1 activity. Molecular modelling of the CYP1A2 interaction with hydroxylated derivatives of flavone suggests that a number of hydrophobic residues of the substrate-binding domain engage in hydrogen bonding with such inhibitors. 2 We have tested this model using site-directed mutagenesis of these residues in expression plasmids transfected into the human B-lymphoblastoid cell line, AHH-1 TK +/-. 3 Consistent with the molecular model's predicted placement in the active site, amino acid substitutions at the predicted residues abolished CYP1A2 enzymatic activity. 4 Transfected cell lines contained equal amounts of immunoreactive CYP1A2. 5 Our results support the molecular model's prediction of the critical amino acid residues present in the hydrophobic active site, residues that can hydrogen bond with CYP1A2 inhibitors and modify substrate binding and/or turnover. C1 Dept Vet Affairs Med Ctr, Res Serv 151, Boise, ID 83702 USA. Mt States Med Res Inst, Boise, ID 83712 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Dept Vet Affairs Med Ctr, Med Serv, Boise, ID 83702 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Ma, YS (reprint author), Dept Vet Affairs Med Ctr, Res Serv 151, 500 W Ft St, Boise, ID 83702 USA. RI Friedman, Fred/D-4208-2016 NR 25 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUN PY 2002 VL 136 IS 3 BP 347 EP 352 DI 10.1038/sj.bjp.0704711 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 557HX UT WOS:000175904100003 PM 12023936 ER PT J AU Samuels, J Eaton, WW Bienvenu, OJ Brown, CH Costa, PT Nestadt, G AF Samuels, J Eaton, WW Bienvenu, OJ Brown, CH Costa, PT Nestadt, G TI Prevalence and correlates of personality disorders in a community sample SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID DIAGNOSTIC-INTERVIEW-SCHEDULE; MENTAL-HEALTH; DEPRESSION; BALTIMORE AB Background Knowledge of the prevalence and correlates of personality disorders in the community is important for identifying treatment needs and for provision of psychiatric services. Aims To estimate the prevalence of personality disorders in a community sample and to identify demographic subgroups with especially high prevalence. Method Clinical psychologists used the International Personality Disorder Examination to assess DSM-IV and ICD-10 personality disorders in a sample of 742 subjects, ages 34-94 years, residing in Baltimore, Maryland. Logistic regression was used to evaluate the association between demographic characteristics and DSM-IV personality disorder clusters. Results The estimated overall prevalence of DSM-IV personality disorders was 9%. Cluster A disorders were most prevalent in men who had never married. Cluster B disorders were most prevalent in young men without a high school degree, and cluster C disorders in high school graduates who had never married. Conclusions Approximately 9% of this community sample has a DSM-IV personality disorder. Personality disorders are over-represented in certain demographic subgroups of the community. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Samuels, J (reprint author), Johns Hopkins Univ Hosp, Dept Psychiat & Behav Sci, Meyer 4-181,600 N Wolfe St, Baltimore, MD 21287 USA. OI Samuels, Jack/0000-0002-6715-7905; Costa, Paul/0000-0003-4375-1712 FU NIMH NIH HHS [MH47447, MH50616] NR 32 TC 217 Z9 220 U1 5 U2 11 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD JUN PY 2002 VL 180 BP 536 EP 542 DI 10.1192/bjp.180.6.536 PG 7 WC Psychiatry SC Psychiatry GA 560AF UT WOS:000176058500013 PM 12042233 ER PT J AU Petridou, E Zavras, AI Lefatzis, D Dessypris, N Laskaris, G Dokianakis, G Segas, J Douglas, CW Diehl, SR Trichopoulos, D AF Petridou, E Zavras, AI Lefatzis, D Dessypris, N Laskaris, G Dokianakis, G Segas, J Douglas, CW Diehl, SR Trichopoulos, D TI The role of diet and specific micronutrients in the etiology of oral carcinoma SO CANCER LA English DT Article DE iron; macronutrients; magnesium; micronutrients; oral carcinoma; riboflavin ID PHARYNGEAL CANCER; FOOD GROUPS; GREECE; RISK AB BACKGROUND. Carcinoma of the oral cavity is one of the most common cancers worldwide. Tobacco smoking and the consumption of alcoholic beverages are significant risk factors but to the authors' knowledge the role of nutrition is not adequately understood. The authors undertook an epidemiologic study of oral carcinoma occurring in Greece, where tobacco smoking and alcohol consumption are common but the incidence of the disease is among the lowest reported in Europe. METHODS. One hundred six patients with histologically confirmed incident oral carcinoma and an equal number of control subjects matched for age and gender were studied. Dietary information was assessed through a validated extensive food frequency questionnaire and the data were analyzed using conditional logistic regression. RESULTS. After adjustment for energy intake, tobacco smoking, and alcohol consumption, there was evidence that the consumption of cereals, fruits, dairy products, and added lipids (which in Greece are represented mostly by olive oil) was found to be associated inversely with the risk of oral carcinoma. Only with respect to meat and meat products was there adequate evidence of a positive association with the risk of oral carcinoma. Among the micronutrients studied, riboflavin, magnesium, and iron appeared to be correlated inversely with the disease. CONCLUSIONS. Fruits, cereals, dairy products, and olive oil appear to convey protection against oral carcinoma and their effects may be mediated through higher intakes of riboflavin, iron, and magnesium. The low incidence of oral carcinoma reported in Greece may be explained in part by the higher consumption of the food groups and micronutrients that appear to protect against the disease. Cancer 2002;94:2981- 8. (C) 2002 American Cancer Society. C1 Univ Athens, Sch Med, Dept Hyg & Epidemiol, TK, Athens 11527, Greece. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Hlth Policy & Epidemiol, Boston, MA 02115 USA. Red Cross Hosp, Ear Nose & Throat Clin, Athens, Greece. Univ Athens, Sch Med, Dept Dermatol, GR-11527 Athens, Greece. Syngrou Hosp, Athens, Greece. Univ Athens, Dept Ear Nose & Throat, Sch Med, Athens, Greece. Hippokratio Gen Hosp, Athens, Greece. NIDCR, Mol Epidemiol & Dis Indicators Branch, NIH, Bethesda, MD USA. RP Petridou, E (reprint author), Univ Athens, Sch Med, Dept Hyg & Epidemiol, TK, 75 M Asias Str, Athens 11527, Greece. FU NIDCR NIH HHS [K23DE00420, T32DE0751, Z01 DE-00659] NR 24 TC 36 Z9 37 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 1 PY 2002 VL 94 IS 11 BP 2981 EP 2988 DI 10.1002/cncr.10560 PG 8 WC Oncology SC Oncology GA 555JA UT WOS:000175789900022 PM 12115387 ER PT J AU Baris, D Gridley, G Ron, E Weiderpass, E Mellemkjaer, L Ekbom, A Olsen, JH Baron, JA Fraumeni, JF AF Baris, D Gridley, G Ron, E Weiderpass, E Mellemkjaer, L Ekbom, A Olsen, JH Baron, JA Fraumeni, JF TI Acromegaly and cancer risk: a cohort study in Sweden and Denmark SO CANCER CAUSES & CONTROL LA English DT Article DE acromegaly; cancer; cohort ID GROWTH-FACTOR-I; INSULIN-LIKE; PITUITARY-ADENOMA; PROSTATE-CANCER; BINDING PROTEIN-3; COLORECTAL-CANCER; COLONIC POLYPS; THYROID-CANCER; CARCINOMA; NEOPLASIA AB Objective: Several studies have suggested that patients with acromegaly have an increased risk of benign and malignant neoplasms, especially of the colon. To further investigate this relationship we evaluated cancer risk in population-based cohorts of acromegaly patients in Sweden and Denmark. Methods: Nationwide registry-based cohorts of patients hospitalized for acromegaly (Denmark 1977-1993; Sweden 1965-1993) were linked to tumor registry data for up to 15-28 years of follow-up, respectively. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated to estimate cancer risk among 1634 patients with acromegaly. Results: The patterns of cancer risk in Sweden and Denmark were similar. After excluding the first year of follow-up, 177 patients with acromegaly had a diagnosis of cancer compared with an expected number of 116.5 (SIR=1.5, 95% CI=1.3-1.8). Increased risks were found for digestive system cancers (SIR=2.1, 95% CI=1.6-2.7), notably of the small intestine (SIR=6.0, 95% CI=1.2-17.4), colon (SIR=2.6, 95% CI=1.6-3.8), and rectum (SIR=2.5, 95% CI=1.3-4.2). Risks were also elevated for cancers of the brain (SIR=2.7, 95% CI=1.2-5.0), thyroid (SIR=3.7, 95% CI=1.8-10.9), kidney (SIR=3.2, 95% CI=1.6-5.5), and bone (SIR=13.8, 95% CI=1.7-50.0). Conclusions: The increased risk for several cancer sites among acromegaly patients may be due to the elevated proliferative and anti-apoptotic activity associated with increased circulating levels of insulin-like growth factor-1 (IGF-1). Pituitary irradiation given to some patients may have contributed to the excess risks of brain tumors and thyroid cancer. Our findings indicate the need for close medical surveillance of patients with acromegaly, and further studies of the IGF-1 system in the etiology of various cancers. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Stockholm, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Danish Canc Soc, Copenhagen, Denmark. Dartmouth Coll, Sch Med, Hanover, NH 03755 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8122, Bethesda, MD 20892 USA. RI Weiderpass, Elisabete/M-4029-2016 OI Weiderpass, Elisabete/0000-0003-2237-0128 NR 50 TC 84 Z9 88 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2002 VL 13 IS 5 BP 395 EP 400 DI 10.1023/A:1015713732717 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 558CP UT WOS:000175947900001 PM 12146843 ER PT J AU Daniels, JL Olshan, AF Pollock, BH Shah, NR Stram, DO AF Daniels, JL Olshan, AF Pollock, BH Shah, NR Stram, DO TI Breast-feeding and neuroblastoma, USA and Canada SO CANCER CAUSES & CONTROL LA English DT Article DE breast-feeding; childhood neoplasms; neuroblastoma ID GROWTH-FACTOR SYSTEM; HUMAN-MILK; IMMUNE-SYSTEM; PERSPECTIVES; INFECTION; RISK AB Objective: Researchers have suggested an inverse association between breast-feeding and risk of childhood cancer. We investigated the association between breast-feeding and neuroblastoma in a large case-control study in the United States and Canada. Methods: Maternal reports of breast-feeding were compared among 393 children six months or older who had neuroblastoma and were identified through the Children's Cancer Group and the Pediatric Oncology Group and 376 age-matched controls identified by random-digit telephone dialing in a telephone interview case-control study. Results: Children with neuroblastoma were less likely to have breast-fed than control children (odds ratio (OR) = 0.6; 95% confidence interval (CI) = 0.5-0.9). The association between breast-feeding and neuroblastoma increased with breast-feeding duration (0-3 months OR = 0.7, CI = 0.4-1.0; 13+ months OR = 0.5, CI = 0.3-0.9). Conclusion: Breast-feeding was inversely associated with neuroblastoma and should be encouraged among healthy mothers. Additional research on possible mechanisms of this association may be warranted. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ Texas, Hlth Sci Ctr, Childrens Oncol Grp, San Antonio, TX USA. Geisinger Med Ctr, Dept Pediat Hematol Oncol, Danville, PA 17822 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. RP Daniels, JL (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA 57004] NR 26 TC 19 Z9 20 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2002 VL 13 IS 5 BP 401 EP 405 DI 10.1023/A:1015746701922 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 558CP UT WOS:000175947900002 PM 12146844 ER PT J AU Stolzenberg-Solomon, RZ Pietinen, P Taylor, PR Virtamo, J Albanes, D AF Stolzenberg-Solomon, RZ Pietinen, P Taylor, PR Virtamo, J Albanes, D TI A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland) SO CANCER CAUSES & CONTROL LA English DT Article DE anthropometry; medical conditions; metabolic syndrome; pancreatic cancer; physical activity; smokers ID UNITED-STATES ADULTS; DIABETES-MELLITUS; CIGARETTE-SMOKING; RISK-FACTORS; GLUCOSE-METABOLISM; INSULIN-RESISTANCE; BLOOD-PRESSURE; ENERGY-EXPENDITURE; COHORT; HYPERTENSION AB Objective: To examine the association between several medical conditions, anthropometric measurements, occupational and leisure physical activity, and pancreatic cancer in a cohort of male Finnish smokers. Methods: We performed a cohort analysis of the 172 subjects who developed pancreatic cancer between 1985 and 1997 (median 10.2 years follow-up) among the 29,048 male smokers, 50-69 years old, who had complete baseline data and participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: We observed positive associations between pancreatic cancer risk and self-reported history of diabetes mellitus (HR = 2.02, 95% CI 1.17-3.50) and bronchial asthma (HR = 2.16, 95% CI 1.17-3.98). Men having combined occupational and leisure activity greater than at sedentary levels had reduced risk for the cancer; for example those with moderate/heavy activity in both settings showed a HR of 0.42 (95% CI 0.22-0.83). There were no significant associations with other self-reported illnesses, total or HDL (high-density lipoprotein) cholesterol, height, weight, or body mass index. Conclusions: Our data suggest that diabetes mellitus and bronchial asthma predict the subsequent risk of developing pancreatic cancer in male smokers, and that greater physical activity may reduce the risk. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Rockville, MD USA. Natl Publ Hlth Inst, Helsinki, Finland. NCI, Canc Prevent Studies Branch, Clin Res Ctr, Rockville, MD USA. RP Stolzenberg-Solomon, RZ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7026, Rockville, MD 20852 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01CN45035, N01CN45165] NR 56 TC 85 Z9 87 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2002 VL 13 IS 5 BP 417 EP 426 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 558CP UT WOS:000175947900004 PM 12146846 ER PT J AU Colbert, LH Lanza, E Ballard-Barbash, R Slattery, ML Tangrea, JA Caan, B Paskett, ED Iber, F Kikendall, W Lance, P Shike, M Schoen, RE Daston, C Schatzkin, A AF Colbert, LH Lanza, E Ballard-Barbash, R Slattery, ML Tangrea, JA Caan, B Paskett, ED Iber, F Kikendall, W Lance, P Shike, M Schoen, RE Daston, C Schatzkin, A CA Polyp Prevention Trial Study Grp TI Adenomatous polyp recurrence and physical activity in the Polyp Prevention Trial (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE colorectal adenomas; physical activity; Polyp Prevention Trial ID COLORECTAL ADENOMAS; COLON-CANCER; RISK; EXERCISE; OBESITY; PROGRAM; HABITS; DIET; MEN; FAT AB Objective: To examine prospectively the association between physical activity and adenomatous polyp recurrence. Methods: Information on past year total physical activity was collected annually through an interview-administered questionnaire from the 1905 men and women enrolled in a randomized dietary intervention study, the Polyp Prevention Trial. Multiple logistic regression analysis was used to examine the association between physical activity and polyp recurrence in up to three years of follow-up from baseline colonoscopy. Results: There were no significant associations between moderate, vigorous, or total physical activity at the start of the trial and overall polyp recurrence in either men or women. Participants who reported consistent vigorous activity throughout the trial period had no significantly reduced risk of polyp recurrence compared to those who reported consistent sedentary activity (OR = 0.8, CI = 0.5-1.1). Consistent vigorous activity was also not significantly associated with either advanced or multiple polyps, nor with polyp recurrence at any specific anatomical location in the large bowel. Conclusions: These prospective data suggest that recent physical activity is not associated with polyp recurrence in a three-year period. C1 NIA, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT USA. Kaiser Fdn Res Inst, Oakland, CA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Vet Affairs Med Ctr, Edward Hines Jr Hosp, Hines, IL USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Pittsburgh, PA USA. Westat Corp, Rockville, MD USA. RP Colbert, LH (reprint author), Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave,MSC, Bethesda, MD 20892 USA. RI Lance, Peter/I-2196-2014 OI Lance, Peter/0000-0003-2944-1881 NR 27 TC 15 Z9 15 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2002 VL 13 IS 5 BP 445 EP 453 DI 10.1023/A:1015736524447 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 558CP UT WOS:000175947900007 PM 12146849 ER PT J AU Wacholder, S Rothman, N Caporaso, N AF Wacholder, S Rothman, N Caporaso, N TI Counterpoint: Bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID GENETIC ASSOCIATION; RISK; FAMILY; TESTS C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20854 USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8046, Rockville, MD 20854 USA. NR 29 TC 187 Z9 192 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2002 VL 11 IS 6 BP 513 EP 520 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 561LR UT WOS:000176142600002 PM 12050091 ER PT J AU McBride, CM Bepler, G Lipkus, IM Lyna, P Samsa, G Albright, J Datta, S Rimer, BK AF McBride, CM Bepler, G Lipkus, IM Lyna, P Samsa, G Albright, J Datta, S Rimer, BK TI Incorporating genetic susceptibility feedback into a smoking cessation program for African-American smokers with low income SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SELF-HELP MATERIALS; LUNG-CANCER RISK; FAMILY HISTORY; BREAST-CANCER; WOMEN; BEHAVIOR; INTERVENTION; PERCEPTIONS; SENSITIVITY; POPULATION AB Purpose: Markers of genetic susceptibility to tobacco-related cancers could personalize harms of smoking and motivate cessation. Our objective was to assess whether a multicomponent intervention that included feedback about genetic susceptibility to lung cancer increased risk perceptions and rates of smoking cessation compared with a standard cessation intervention. Experimental Design: Our design was a two-arm trial with eligible smokers randomized in a 1:2 ratio to Enhanced Usual Care or Biomarker Feedback (BF). Surveys were conducted at baseline, 6, and 12 months later. The setting was an inner city community health clinic. African-American patients who were current smokers (n = 557) were identified by chart abstraction and provider referral. All smokers received a self-help manual and, if appropriate, nicotine patches. Smokers in the BF arm also were offered a blood test for genotyping the GST(3) gene (GSTM1), sent a test result booklet, and called up to four times by a health educator. Prevalent abstinence was assessed by self-report of having smoked no cigarettes in the prior 7 days at the 6- and 12-month follow-ups and sustained abstinence, i.e., not smoking at either follow-up or in-between. Results: Smoking cessation was greater for the BF arm than the Enhanced Usual Care arm (19% versus 10%, respectively; P < 0.006) at 6 months but not at 12 months. Conclusions: Smokers agreed to genetic feedback as part of a multicomponent cessation program. Although the program increased short-term cessation rates compared with standard intervention, genetic feedback of susceptibility may not benefit smokers with high baseline risk perceptions. C1 Univ N Carolina, Duke Comprehens Canc Ctr, Chapel Hill, NC USA. Univ N Carolina, Duke Dept Community & Family Med, Chapel Hill, NC USA. Univ N Carolina, HP Lee Moffit Canc Ctr & Res Inst, Chapel Hill, NC USA. Univ N Carolina, Ctr Clin Hlth Policy Res, Duke Univ Med Ctr, Chapel Hill, NC USA. Univ N Carolina, Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP McBride, CM (reprint author), Duke Canc Control Res Program, DUMC Box 2949, Durham, NC 27710 USA. FU NCI NIH HHS [R01-CA-74000-02, R01-CA-63782, R01-CA-70317, R01-CA-80262] NR 38 TC 129 Z9 130 U1 3 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2002 VL 11 IS 6 BP 521 EP 528 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 561LR UT WOS:000176142600003 PM 12050092 ER PT J AU Bauer, AJ Cavalli, LR Rone, JD Francis, GL Burch, HB Tuttle, RM Ringel, MD Stratakis, CA Haddad, BR AF Bauer, AJ Cavalli, LR Rone, JD Francis, GL Burch, HB Tuttle, RM Ringel, MD Stratakis, CA Haddad, BR TI Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID NUCLEAR-DNA CONTENT; COLORECTAL-CANCER; TUMOR PROGRESSION; LESIONS; REVEAL AB To clarity the mechanism Of tumorigenesis in papillary thyroid carcinoma (PTC) and ascertain whether genomic changes correlate with histologic features, we conducted a comprehensive molecular evaluation of PTC using comparative genomic hybridization (CGH) and microsatellite instability (MSI) analysis in a set of 17 histologically well-characterized PTC specimens. To our knowledge, this is the first study that evaluates chromosomal Bind nucleotide instability in the same PTC tumor specimens. Four of 15 samples (27%) had aberrations detected by CGH. All four had a partial or complete gain of chromosome 20. and 3 of 4 had a partial or complete loss of chromosome 13. No MSI was detected in any, of the PTC samples (n = 16). and all samples examined by immunohistochemistry (n = 9) expressed the DNA repair enzymes hmlh1 and hmsh2. All PTC samples with abnormal CGH had vascular invasion or invasion of the thyroid capsule, and there was a significant correlation between the presence of chromosomal aberrations and capsular/vascular invasion (P=0.026). We conclude that although chromosomal and microsatellite instability are uncommon in PTC. tumors With chromosomal aberrations are more likely to be associated with invasion. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Dept Obstet & Gynecol, Washington, DC 20007 USA. Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Dept Clin Invest, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Dept Internal Med, Washington, DC 20307 USA. Mem Sloan Kettering Canc Ctr, Dept Endocrinol, New York, NY 10021 USA. Washington Hosp Ctr, Dept Endocrinol, Washington, DC 20010 USA. NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Haddad, BR (reprint author), Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Dept Oncol, Washington, DC 20007 USA. RI Cavalli, Luciane/J-6100-2012 NR 32 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JUN PY 2002 VL 135 IS 2 BP 182 EP 186 AR PII S0165-4608(01)00656-2 DI 10.1016/S0165-4608(01)00656-2 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 575UW UT WOS:000176967700011 PM 12127404 ER PT J AU Middleton, L Dimond, E Calzone, K Davis, J Jenkins, J AF Middleton, L Dimond, E Calzone, K Davis, J Jenkins, J TI The role of the nurse in cancer genetics SO CANCER NURSING LA English DT Article DE oncology; inherited; advanced practice; resources ID COLORECTAL-CANCER; DISCRIMINATION; PERSPECTIVES; GENES AB Knowledge gained from the Human Genome Project and related genetic research is already impacting clinical oncology nursing practice. Because cancer is now understood to be a genetic disease, changes in the traditional approaches to prevention, diagnosis, and therapeutic management of cancer are becoming increasingly genetically based. Therefore, to ensure competency in oncology nursing practice at all levels, nurses must incorporate an understanding of the underlying biology of carcinogenesis and the molecular rationale underlying strategies to prevent, diagnose, and treat cancer. C1 HIH, UOB, NCI, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Natl Canc Inst, NIH, Bethesda, MD USA. Univ Penn, Breast Canc Risk Evaluat Program, Philadelphia, PA USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. RP Middleton, L (reprint author), HIH, UOB, NCI, Bldg 10 Rm 10S251 10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD JUN PY 2002 VL 25 IS 3 BP 196 EP 206 DI 10.1097/00002820-200206000-00005 PG 11 WC Oncology; Nursing SC Oncology; Nursing GA 557FT UT WOS:000175898500005 PM 12040228 ER PT J AU Bindra, RS Vasselli, JR Stearman, R Linehan, WM Klausner, RD AF Bindra, RS Vasselli, JR Stearman, R Linehan, WM Klausner, RD TI VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; DOWN-REGULATION; GENE; GROWTH; HETEROZYGOSITY; PROTEOLYSIS; HOMEOSTASIS; BINDING; CANCER; ALPHA AB Renal cell carcinoma is associated with mutation of the von Hippel-Lindau (VHL) tumor suppressor gene. Cell lines derived from these tumors cannot exit the cell cycle when deprived of growth factors, and the ability to exit the cell cycle can be restored by the reintroduction of wild-type protein VHL (pVHL). Here, we report that cyclin D1 is over-expressed and remains inappropriately high in during contact inhibition in pVHL-deficient cell lines. In addition, hypoxia increased the expression of cyclin D1 specifically in pVHL-negative cell lines into which pVHL expression was restored. Hypoxic-induction of cyclin D1 was not observed in other pVHL-positive cell lines. This suggests a model whereby in some kidney cell types, pVHL may regulate a proliferative response to hypoxia, whereas the loss of pVHL leads to constitutively elevated cyclin D1 and abnormal proliferation under normal growth conditions. C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Klausner, RD (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 25 TC 85 Z9 87 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3014 EP 3019 PG 6 WC Oncology SC Oncology GA 559RE UT WOS:000176038500005 PM 12036906 ER PT J AU Khong, HT Rosenberg, SA AF Khong, HT Rosenberg, SA TI The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR; EXPRESSION; MELANOMA; CELLS; MOUSE; PAX3; MITF AB In this study, we have identified, for the first time, the presence of de novo cellular immune reactivity against the transcription factor SOX10, using tumor-infiltrating lymphocytes obtained from a patient who experienced a dramatic clinical response to immunotherapy. SOX10 acts as a critical transactivator of tyrosinase-related protein-2 during melanoblast development and a potent transactivator of micropthalmia-associated transcription factor, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. Mutations in SOX10 result in Waardenburg syndrome type 4. The overlapping epitopes AWISKPPGV and SAWISKPPGV, designated SOX10: 332-340 and SOX10: 331-340, respectively, were recognized by tumor-infiltrating lymphocyte clone M37 in an HLA-A2-restricted fashion. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-33] NR 20 TC 22 Z9 23 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3020 EP 3023 PG 4 WC Oncology SC Oncology GA 559RE UT WOS:000176038500006 PM 12036907 ER PT J AU Zhang, ZQ Li, J Lantry, LE Wang, Y Wiseman, RW Lubet, RA You, M AF Zhang, ZQ Li, J Lantry, LE Wang, Y Wiseman, RW Lubet, RA You, M TI p53 transgenic mice are highly susceptible to 1,2-dimethylhydrazine-induced uterine sarcomas SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUG; LI-FRAUMENI-SYNDROME; K-RAS MUTATIONS; WILD-TYPE P53; CELL-CYCLE; MUTANT P53; COLON CARCINOGENESIS; CALORIE RESTRICTION; SPONTANEOUS TUMORIGENESIS; CHEMOPREVENTIVE AGENTS AB p53 Transgenic mice were crossed with C57BL/6J mice to investigate whether a germ-line mutation in the p 53 gene predisposes for tumorigenesis in mice. (C57BL/6j x UL53-3) F-1 mice were treated with 1,2-dimethylhydrazine (DMH), a colon carcinogen. The presence of a mutant p53 led to an increased incidence or multiplicity of uterine sarcomas, colon carcinomas, lung adenomas, and hepatomas in DMH-treated mice. The most significant effect of mutant p53 was the increased incidence of uterine sarcomas, which were found in similar to90% of p53(val135/wt) mice but only seen in similar to10% of p53(wt/wt) mice. After examination of 15 known p53 downstream target genes in uterine sarcomas and normal uteri, we found that expression of the Reprimo gone was significantly increased in normal uteri of p53(wt/wt) mice but not in either normal uterus or uterine sarcomas of p53(val135/wt) mice. In DMH-treated animals, long-term treatment with this chemopreventive agent, piroxicam, reduced colon carcinoma incidence and multiplicity in both p53(val135/wt) or p53(wt/wt) mice but did not affect the formation of uterine sarcomas, lung adenomas, or hepatomas. These results demonstrate a tissue-specific enhancement of tumorigenesis in multiple organs by the mutant p53 transgene and additionally support the utility of (C57BL/6J x UL53-31) F-1 mice for chemoprevention studies. C1 Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Sch Publ Hlth, Columbus, OH 43210 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. NIEHS, Lab Womens Hlth, Res Triangle Pk, NC 27709 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, 420 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CA 58554, CN 05122, CA 78797, CA 16058] NR 52 TC 21 Z9 22 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3024 EP 3029 PG 6 WC Oncology SC Oncology GA 559RE UT WOS:000176038500007 PM 12036908 ER PT J AU Long, DJ Gaikwad, A Multani, A Pathak, S Montgomery, CA Gonzalez, FJ Jaiswal, AK AF Long, DJ Gaikwad, A Multani, A Pathak, S Montgomery, CA Gonzalez, FJ Jaiswal, AK TI Disruption of the NAD(P)H : quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia SO CANCER RESEARCH LA English DT Article ID BENZENE METABOLITES; DT-DIAPHORASE; MYELOID-LEUKEMIA; TOXICITY; CARCINOGENESIS; SUSCEPTIBILITY; POLYMORPHISM; APOPTOSIS; MECHANISM; EXPOSURE AB NAD(P)H:quinone oxidoreductasel (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myclogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity. C1 Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. Lexicon Genet, The Woodlands, TX 77381 USA. NCI, Bethesda, MD 20892 USA. RP Jaiswal, AK (reprint author), Baylor Coll Med, Dept Pharmacol, 1 Baylor Plaza, Houston, TX 77030 USA. FU NIEHS NIH HHS [R01 ES 07943] NR 31 TC 99 Z9 102 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3030 EP 3036 PG 7 WC Oncology SC Oncology GA 559RE UT WOS:000176038500008 PM 12036909 ER PT J AU Thompson, EJ MacGowan, J Young, MR Colburn, N Bowden, GT AF Thompson, EJ MacGowan, J Young, MR Colburn, N Bowden, GT TI A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion SO CANCER RESEARCH LA English DT Article ID MOUSE EPIDERMAL-CELLS; NF-KAPPA-B; INDUCED TRANSFORMATION; DELETION MUTANT; AP-1 ACTIVITY; DNA-BINDING; FOS JUN; EXPRESSION; KERATINOCYTES; ACTIVATION AB Okadaic acid (OA) is a prototypical non-phorbol ester skin tumor-promoting agent that works by inhibiting protein phosphatases, leading to an increase in protein phosphorylation. Increased protein phosphorylation can lead to stimulated signaling through various signal transduction pathways. One or more of the pathways affected by OA leads to increased signaling via the activator protein 1 (AP-1) transcription factor. Because AP-1 signaling has been shown to be required for skin tumor promotion by phorbol ester, studies were undertaken to determine whether AP-1 signaling is also required for 7,12-dimethylbenz(a)anthracene (DMBA)initiated/OA-promoted skin tumorigenesis. Transgenic mice expressing a dominant negative c-jun (TAM-67) controlled by the keratin 14 promoter in ICR mice were used to determine the effects of OA on AP-1 signaling. By crossing the TAM-67 mice with mice expressing an AP-1-responsive luciferase, it was shown that TAM-67 decreases AP-1 activation in response to OA treatment by 95%. After 7,12-dimethylbenz(a)anthracene initiation, the TAM-67 mice and nontransgenic littermates were promoted with twice weekly applications of OA. These experiments showed that TAM-67 expression decreased tumor multiplicity by 90%. Additional experiments with TAM-67 mice showed that the hyperplastic response to OA is not impaired in these mice, nor were there differences in OA-induced transcription of various genes known to be AM responsive under other conditions. This result suggests that-only a subset of AP-1-regulated genes is targeted by TAM-67 when it prevents tumor promotion by OA. A determination of the mechanism by which TAM-67 can block tumor promotion without affecting hyperplasia will be important. C1 Univ Arizona, Arizona Canc Ctr, Dept Radiat Oncol, Tucson, AZ 85724 USA. Univ Arizona, Dept Pharmacol & Toxicol, Tucson, AZ 85724 USA. NCI, Basic Res Lab, Frederick, MD 21701 USA. RP Bowden, GT (reprint author), Univ Arizona, Arizona Canc Ctr, Dept Radiat Oncol, Room 4999,1515 N Campbell Ave, Tucson, AZ 85724 USA. FU NCI NIH HHS [P30 CA 23074, R01 CA 40584]; NIEHS NIH HHS [P30 ES 06694, T32 ES 07091] NR 27 TC 43 Z9 44 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3044 EP 3047 PG 4 WC Oncology SC Oncology GA 559RE UT WOS:000176038500010 PM 12036911 ER PT J AU Miura, K Bowman, ED Simon, R Peng, AC Robles, AI Jones, RT Katagiri, T He, P Mizukami, H Charboneau, L Kikuchi, T Liotta, LA Nakamura, Y Harris, CC AF Miura, K Bowman, ED Simon, R Peng, AC Robles, AI Jones, RT Katagiri, T He, P Mizukami, H Charboneau, L Kikuchi, T Liotta, LA Nakamura, Y Harris, CC TI Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GENE-EXPRESSION; CHROMOSOMAL IMBALANCES; ALLELIC LOSSES; BUDDING YEAST; CANCER; REGION; HETEROZYGOSITY; IDENTIFICATION; BUB3 AB Recent expression profile analyses revealed that lung adenocarcinomas can be divided into several subgroups with diverse pathological features. Because cellular heterogeneity of tumors can confound these analyses, we used laser capture microdissection and microarray expression analysis to characterize the molecular profiles of lung adeno carcinomas. We found 45 genes delineating smokers and nonsmokers that were located at chromosomal loci frequently altered in non-small cell lung cancers, and 27 genes, which were differentially expressed between survivors and nonsurvivors 5 years after surgery. These results are consistent with the hypothesis that the abnormal expression of genes involved in maintaining the mitotic spindle checkpoint and genomic stability, e.g., hBUB3, hZW10, and APC2, contribute to the molecular pathogenesis and tumor progression of tobacco smoke-induced adenocarcinoma of the lung. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NIDDKD, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD 20850 USA. Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Program Oncol, Baltimore, MD 21201 USA. Univ Tokyo, Mol Med Lab, Ctr Human Genome, Inst Med Sci, Tokyo 1088639, Japan. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37, Bethesda, MD 20892 USA. OI Miura, Koh/0000-0001-7303-9430 NR 48 TC 123 Z9 135 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3244 EP 3250 PG 7 WC Oncology SC Oncology GA 559RE UT WOS:000176038500039 PM 12036940 ER PT J AU Thompson, TE Rogan, PK Risinger, JI Taylor, JA AF Thompson, TE Rogan, PK Risinger, JI Taylor, JA TI Splice variants but not mutations of DNA polymerase beta are common in bladder cancer SO CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; MESSENGER-RNA; COLORECTAL-CARCINOMA; INFORMATION-CONTENT; SITE MUTATIONS; SHORT ARM; GENE; HETEROZYGOSITY; IDENTIFICATION; POLYMORPHISMS AB DNA polymerase beta (POLbeta) is a highly conserved protein that functions in base excision repair. Loss of the POLbeta locus on chromosome 8p is a frequent event in bladder cancer, and loss of POLbeta function could hinder DNA repair leading to a mutator phenotype. Both point mutations and large intragenic deletions of POLbeta have been reported from analysis of various tumor cDNAs but not from genomic DNA. We noticed that the breakpoints of the presumed rearrangements were delineated by exon-exon junctions, which could instead be consistent with alternative splicing of POLbeta mRNA. We tested the hypothesis that the reported intragenic deletion were splice variants by screening genomic DNA of human bladder tumors, bladder cancer cell lines, and normal bladder tissues for mutations or deletions in exons 1-14, exon alpha, and the promoter region of POLbeta. We found no evidence of somatic mutations or deletions in our sample set, although two polymorphisms were identified. Examination of cDNA from a subset of the original sample set revealed that truncated forms of POLbeta were surprisingly common. Forty-eight of 89 (54%) sequenced cDNA clones had large deletions, each beginning and/or ending exactly at exon-exon junctions. Because these deletions occur at exon-exon junctions and are seen in cDNA but not genomic DNA, they are consistent with alternative mRNA splicing. We describe 12 different splicing events occurring in 18 different combinations. Loss of exon 2 was the most frequent, being found in 42 of 49 (86%) of the variant sequenced clones. The splice variants appear to be somewhat more common and variable in bladder cancer cell lines and tumor tissues but occur at a high frequency in normal bladder tissues as well. We examine alternative splicing in terms of the information content of splice donor and acceptor site sequences, and discuss possible explanations for the predominant splicing event, the loss of exon 2. C1 NIEHS, NIH, Mol Genet Epidemiol Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Canc & Aging Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ Missouri, Sch Med, Childrens Mercy Hosp & Clin, Sect Med Genet & Mol Med, Kansas City, MO 64108 USA. RP Taylor, JA (reprint author), NIEHS, NIH, Mol Genet Epidemiol Grp, POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. RI Rogan, Peter/B-9845-2017; OI Rogan, Peter/0000-0003-2070-5254; taylor, jack/0000-0001-5303-6398 NR 46 TC 37 Z9 38 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3251 EP 3256 PG 6 WC Oncology SC Oncology GA 559RE UT WOS:000176038500040 PM 12036941 ER PT J AU Potapova, O Anisimov, SV Gorospe, M Dougherty, RH Gaarde, WA Boheler, KR Holbrook, NJ AF Potapova, O Anisimov, SV Gorospe, M Dougherty, RH Gaarde, WA Boheler, KR Holbrook, NJ TI Targets of c-Jun NH2-terminal kinase 2-mediated tumor growth regulation revealed by serial analysis of gene expression SO CANCER RESEARCH LA English DT Article ID N-TERMINAL KINASE; MESSENGER-RNA; SIGNAL-TRANSDUCTION; MAP KINASES; PROTEIN-KINASE; JNK GROUP; CELLS; APOPTOSIS; DIFFERENTIATION; ACTIVATION AB Although the c-Jun NH2-terminal kinase (JNK) pathway has been implicated in mediating cell growth and transformation, its downstream effectors remain to be identified. Using JNK2 antisense oligonucleotides (JNK2AS), we uncovered previously a role for JNK2 in regulating cell cycle progression and survival of human PC3 prostate carcinoma cells. Here, to identify genes involved in implementing JNK2-mediated effects, we have analyzed global gene expression changes in JNK2-deprived PC3 cells using Serial Analysis of Gene Expression. More than 40,000 tags each were generated from control and PC3-JNK2AS libraries, corresponding to 15,999 and 20,698 unique transcripts, respectively. Transcripts corresponding to transcription factors, stress-induced genes, and apoptosis-related genes were up-regulated in the PC3-JNK2AS library, revealing a significant stress response after the inhibition of JNK2 expression. Genes involved in DNA repair, mRNA turnover, and drug resistance were found to be down-regulated by inhibition of JNK2 expression, further highlighting the importance of JNK2 signaling in regulating cell homeostasis and tumor cell growth. C1 NIA, IRP, Cell Stress & Aging Sect, Cellular & Mol Biol Lab,Gerontol Res Ctr, Baltimore, MD 21224 USA. NIA, IRP, Mol Cardiol Unit, Cardiovasc Sci Lab,Gerontol Res Ctr, Baltimore, MD 21224 USA. ISIS Pharmaceut Inc, Carlsbad, CA 92008 USA. RP Holbrook, NJ (reprint author), Yale Sch Med, 300 George St,8th Floor, New Haven, CT 06510 USA. NR 50 TC 41 Z9 42 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3257 EP + PG 8 WC Oncology SC Oncology GA 559RE UT WOS:000176038500041 PM 12036942 ER PT J AU Simmons, PT Portier, CJ AF Simmons, PT Portier, CJ TI Toxicogenomics: the new frontier in risk analysis SO CARCINOGENESIS LA English DT Editorial Material ID MOLECULAR EPIDEMIOLOGY; GENE-THERAPY; CANCER; TOXICOLOGY; TOXICITY AB Risk assessment involves the identification of potential human health hazards, the assessment of the level of exposure by humans to these hazards and the evaluation of the relationship between exposure and response in humans. Research is currently underway to improve the scientific basis of risk assessment through the incorporation of new technologies such as transgenic animals, molecular epidemiology, toxicogenomics, alternative models to animals and mechanism-based mathematical modeling into the estimation of risk in a quantitative manner. This paper briefly discusses these technologies and how each is being employed for more scientifically sound risk assessments. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Simmons, PT (reprint author), NIEHS, Lab Computat Biol & Risk Anal, MD A3-06, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 20 TC 36 Z9 40 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUN PY 2002 VL 23 IS 6 BP 903 EP 905 DI 10.1093/carcin/23.6.903 PG 3 WC Oncology SC Oncology GA 569NH UT WOS:000176608100001 PM 12082011 ER PT J AU Suarez, C Tornadu, IG Cristina, C Vela, J Iglesias, AG Libertun, C Diaz-Torga, G Becu-Villalobos, D AF Suarez, C Tornadu, IG Cristina, C Vela, J Iglesias, AG Libertun, C Diaz-Torga, G Becu-Villalobos, D TI Angiotensin and calcium signaling in the pituitary and hypothalamus SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Review DE angiotensin; pituitary; hypothalamus; hyperplasia; calcium; prolactin; desensitization ID PROTEIN-KINASE-C; THYROTROPIN-RELEASING-HORMONE; TRUNCATED AT(1A) RECEPTOR; RAT ANTERIOR-PITUITARY; SMOOTH-MUSCLE-CELLS; II RECEPTOR; PROLACTIN SECRETION; MESSENGER-RNA; FEMALE RAT; COUPLED RECEPTORS AB 1) In the rat pituitary, angiotensin type 1B receptors (AT(1B)) are located in lactotrophs and corticotrophs. 2) Activation of AT(1B) receptors are coupled to G(q/11) (Guanine protein coupled receptor, or GPCR); they increase phospholipase beta C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP(3)) and diacylglycerol (DAG) formation. A biphasic increase in [Ca(2+)](i) triggered by InsP(3) and DAG ensues. 3) As many GPCRs, AT(1B) pituitary receptors rapidly desensitize. 4) This was observed in the generation of InsP3, the mobilization of intracellular Ca(2+), and in prolactin release. Both homologous and heterologous desensitization was evidenced. 5) Desensitization of the angiotensin II type 1 (AT1) receptor in the pituitary shares similarities and differences with endogenously expressed or transfected AT1 receptors in different cell types. 6) In the pituitary hyperplasia generated by chronic estrogen treatment there was desensitization or alteration in angiotensin II (Ang II) evoked intracellular Ca(2+) increase, InsP3 generation, and prolactin release. This correlates with a downregulation of AT1 receptors. 7) In particular, in hyperplastic cells Ang II failed to evoke a transient acute peak in [Ca(2+)](i), which was replaced by a persistent plateau phase of [Ca(2+)](i) increase. 8) Different calcium channels participate in Ang II induced [Ca(2+)](i) increase in control and hyperplastic cells. While spike phase in control cells is dependent on intracellular stores sensitive to thapsigargin, in hyperplastic cells plateau increase is dependent on extracellular calcium influx. 9) Signal transduction of the AT1 pituitary receptor is greatly modified by hyperplasia, and it may be an important mechanism in the control of the hyperplastic process. 10) In the hypothalamus and brain stem there is a predominant expression of AT(1A) and AT(2) mRNA. 11) Ang II acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. 12) Calcium channels play important roles in the Ang II induced behavioral and endocrine responses. 13) Ang II, in physiological concentrations, can activate AT1 receptors to stimulate both Ca(2+) release from intracellular stores and Ca(2+) influx from the extracellular space to increase [Ca(2+)](i) in polygonal and stellate astroglia of the hypothalamus and brain stem. 14) In primary cell culture of neurons from newborn rat hypothalamus and brain stem, it has also been determined that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+) current and a stimulation of Ca(2+) current. 15) In primary cell cultures derived from the subfornical organ or the organum vasculosum laminae terminalis of newborn rat pups, Ang II produced a pronounced desensitization of the [Ca(2+)](i) response. 16) Hypothalamic and pituitary Ang II systems are involved in different functions, some of which are related. At both levels Ang II signals through [Ca(2+)](i) in a characteristic C1 Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, RA-1428 Buenos Aires, DF, Argentina. NICHD, Endocrinol & Reprod Res Branch, Bethesda, MD USA. RP Becu-Villalobos, D (reprint author), Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, V Obligado 2490, RA-1428 Buenos Aires, DF, Argentina. EM dbecu@dna.uba.ar NR 106 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUN PY 2002 VL 22 IS 3 BP 315 EP 333 DI 10.1023/A:1020772018703 PG 19 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 605GU UT WOS:000178670100009 PM 12469873 ER PT J AU Blumenthal, R Gallo, SA Viard, M Raviv, Y Puri, A AF Blumenthal, R Gallo, SA Viard, M Raviv, Y Puri, A TI Fluorescent lipid probes in the study of viral membrane fusion SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Review DE membrane fusion; HIV; influenza hemagglutinin; octadecyl rhodamine; photolabeling; fluorescence ID VESICULAR STOMATITIS-VIRUS; PH-DEPENDENT FUSION; INFLUENZA HEMAGGLUTININ; CELL-FUSION; IMMUNODEFICIENCY-VIRUS; BIOLOGICAL-MEMBRANES; ENVELOPE GLYCOPROTEIN; PLASMA-MEMBRANE; ENERGY-TRANSFER; LATERAL MOBILITY AB Fluorescent lipid probes are widely used in the observation of viral membrane fusion, providing a sensitive method to study fusion mechanism(s), Due to the wealth of data concerning liposome fusion, a variety of fusion assays has been designed including fluorescent probe redistribution, fluorescence dequenching, fluorescence resonance energy transfer and photosensitized labeling. These methods can be tailored for different virus fusion assays. For instance, virions can be loaded with membrane dye which dequenches at the moment of membrane merger. This allows for continuous observation of fusion and therefore kinetic information can be acquired, In the case of cells expressing viral envelope proteins, dye redistribution studies of lipidic and water-soluble fluorophores yield information about fusion intermediates. Lipid probes can be metabolically incorporated into cell membranes, allowing observation of membrane fusion in vitro with minimal chance of flip flop, non-specific transfer and formation of microcrystals. Fluorescent lipid probes have been incorporated into liposomes and;;or reconstituted viral envelopes, which provide a well-defined membrane environment for fusion to occur. Interactions of the viral fusion machinery with the membrane can be observed through the photosensitized labeling of the interacting segments of envelope proteins with a hydrophobic probe. Thus, fluorescent lipid probes provide a broad repertoire of fusion assays and powerful tools to produce precise, quantitative data in real time required for the elucidation of the complex process of viral fusion. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, SAIC, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC, Frederick, MD 21701 USA. RP NCI, Lab Expt & Computat Biol, Ctr Canc Res, SAIC, POB B,Bldg 469,Rm 216A,Miller Dr, Frederick, MD 21702 USA. EM blumen@helix.nih.gov OI Gallo, Stephen/0000-0001-6043-2153 FU PHS HHS [N01-C0-56000] NR 73 TC 38 Z9 39 U1 5 U2 33 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 EI 1873-2941 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD JUN PY 2002 VL 116 IS 1-2 SI SI BP 39 EP 55 AR PII S0009-3084(02)00019-1 DI 10.1016/S0009-3084(02)00019-1 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 576GH UT WOS:000176994500004 PM 12093534 ER PT J AU Gawrisch, K Eldho, NV Polozov, IV AF Gawrisch, K Eldho, NV Polozov, IV TI Novel NMR tools to study structure and dynamics of biomembranes SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Review DE nuclear magnetic resonance; NMR; magic angle spinning; MAS; nuclear Overhauser enhancement spectroscopy; NOESY ID NUCLEAR-MAGNETIC-RESONANCE; OVERHAUSER ENHANCEMENT SPECTROSCOPY; CROSS-RELAXATION SPECTROSCOPY; HIGH-RESOLUTION PROTON; MAS-NOESY SPECTRA; SOLID-STATE NMR; MODEL MEMBRANES; LIPID-BILAYERS; H-2 NMR; MACROSCOPIC ORIENTATION AB Nuclear magnetic resonance (NMR) Studies on biomembranes have benefited greatly from introduction of magic angle spinning (MAS) NMR techniques, Improvements in MAS probe technology. combined with the higher magnetic field strength of modern instruments. enables almost liquid-like resolution of lipid resonances. The cross-relaxation rates measured by nuclear Overhauser enhancement spectroscopy (NOESY) provide new insights into conformation and dynamics of lipids with atomic-scale resolution, The data reflect the tremendous motional disorder in the lipid matrix. Transfer of magnetization by spin diffusion along the proton network of lipids is of secondary relevance, even at a long NOESY mixing time of 300 ins. MAS experiments with re-coupling of anisotropic interactions, like the (13)C-(1)H dipolar Couplings. benefit from the excellent resolution of (13)C shifts that enables assignment of the couplings to specific carbon atoms. The traditional (2)H NMR experiments on deuterated lipids have higher sensitivity when conducted on oriented samples at higher magnetic field strength. A very large number of NMR parameters from lipid bilayers is now accessible, providing information about Conformation and dynamics for every lipid segment. The NMR methods have the sensitivity and resolution to study lipid-protein interaction. lateral lipid organization. and the location of solvents and drugs in the lipid matrix. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Room 150, Rockville, MD 20852 USA. EM gawrisch@helix.nih.gov NR 57 TC 53 Z9 53 U1 2 U2 36 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD JUN PY 2002 VL 116 IS 1-2 SI SI BP 135 EP 151 AR PII S0009-3084(02)00024-5 DI 10.1016/S0009-3084(02)00024-5 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 576GH UT WOS:000176994500009 PM 12093539 ER PT J AU Doolittle, ND Abrey, LE Ferrari, N Hall, WA Laws, ER McLendon, RE Muldoon, LL Peereboom, D Peterson, DR Reynolds, CP Senter, P Neuwelt, EA AF Doolittle, ND Abrey, LE Ferrari, N Hall, WA Laws, ER McLendon, RE Muldoon, LL Peereboom, D Peterson, DR Reynolds, CP Senter, P Neuwelt, EA TI Targeted delivery in primary and metastatic brain tumors: Summary report of the Seventh Annual Meeting of the Blood-Brain Barrier Disruption Consortium SO CLINICAL CANCER RESEARCH LA English DT Article ID NEUROBLASTOMA CELL-LINES; NERVOUS-SYSTEM LYMPHOMA; HIGH-DOSE CHEMOTHERAPY; INDUCED HEARING-LOSS; BUTHIONINE SULFOXIMINE; SODIUM THIOSULFATE; MULTIDRUG-RESISTANCE; DENDRITIC CELLS; CANCER; RADIOTHERAPY AB The November 2000 NIH report of the Brain Tumor Progress Review Group identified delivering and targeting therapeutic agents as a priority in the treatment of malignant brain tumors. For this reason, the seventh annual Blood-Brain Barrier Disruption Consortium meeting, partially funded by an NIH R13 Grant, focused on recent advances in targeted delivery to the central nervous system, clinical trials for primary and metastatic brain tumors using enhanced chemotherapy delivery, and strategies to lessen the toxicities associated with dose intensive treatments, using thiols. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Neurosurg, Minneapolis, MN 55455 USA. Univ Virginia, Dept Neurosurg, Charlottesville, VA 22903 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Finch Univ Hlth Sci Chicago Med Sch, Dept Physiol & Biophys, N Chicago, IL 60064 USA. Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. Seattle Genet Inc, Bothell, WA 98021 USA. RP Neuwelt, EA (reprint author), Oregon Hlth Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd L603, Portland, OR 97201 USA. FU NCI NIH HHS [1R13 CA 86959-02] NR 64 TC 14 Z9 14 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2002 VL 8 IS 6 BP 1702 EP 1709 PG 8 WC Oncology SC Oncology GA 561LJ UT WOS:000176141900004 PM 12060607 ER PT J AU Joshi, BH Kawakami, K Leland, P Puri, RK AF Joshi, BH Kawakami, K Leland, P Puri, RK TI Heterogeneity in interleukin-13 receptor expression and subunit structure in squamous cell carcinoma of head and neck: Differential sensitivity to chimeric fusion proteins comprised of interleukin-13 and a mutated form of Pseudomonas exotoxin SO CLINICAL CANCER RESEARCH LA English DT Article ID KAPOSIS-SARCOMA CELLS; COMMON GAMMA-CHAIN; HUMAN GLIOMA-CELLS; SIGNAL-TRANSDUCTION; CANCER-CELLS; ALPHA CHAIN; (IL)-13 BINDING; IL-4 RECEPTORS; GENE-THERAPY; B-CELLS AB Squamous cell carcinoma of the head and neck (SCCHN) is characterized by a high proliferation index and marked propensity for local invasion resulting in poor prognosis for these patients. To develop tumor-targeted novel therapeutic agents, here we demonstrate that SCCHN cell lines express receptors for an immune regulatory cytokine, interleukin (IL) 13. By reverse transcription-PCR (RT-PCR), we found that 16 SCCHN cell lines express equally strong RT-PCR positive bands for mRNA of IL-13Ralpha1 and IL-4Ralpha chains. However, only three cell lines, HN12, YCUM911, and KCCT873, expressed a strong band for transcripts for IL-13Ralpha2 chain and five cell lines, YCUL891, KCCTC871, KCCL871, KCCTCM901, and RPMI 2650 expressed faint bands. Transcripts for IL-2Rgammac. chain were absent in all of the cell lines tested. Indirect immunofluorescence analysis for four different receptor chains confirmed RT-PCR results and showed pronounced expression of IL-13Ralpha2 protein in three high IL-13R expressing cell lines. All of the cell lines were equally positive for IL-13Ralpha1 and IL-4Ralpha chains. Receptor-binding studies demonstrated that IL-13Ralpha2-positive cell lines expressed a high density of IL-13 receptors. Using two chimeric proteins composed of IL-13 and mutated forms of Pseudomonas exotoxin (IL-13-PE38 or IL-13-PE38QQR), we found that these two fusion toxins were highly and equally cytotoxic to IL-13Ralpha2-positive SCCHN, whereas IL-13Ralpha2-negative cell lines showed low or no sensitivity to IL-13 toxins. To additionally substantiate the critical role of the IL-13Ralpha2 chain in IL-13R-mediated cytotoxicity, two head and neck tumor cell lines (YCUMS861 and KB), devoid of the transcripts of this chain, were transfected with IL-13Ralpha2 cDNA and then tested for cytotoxicity. Transient transfection of the IL-13Ralpha2 chain highly sensitized these cells to IL-13 toxin as compared with mock-transfected control cells. Thus, our results indicate that IL-13Ralpha2 is present in 50% SCCHN tumor cell lines; of these, 19% are high expresser for this chain and respond to IL-13 cytotoxin. Thus, IL-13 cytotoxin may be a useful agent for high IL-13R-expressing SCCHN. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), NIH, Bldg 29 B,Room 2NN10,29 Lincoln Dr, Bethesda, MD 20892 USA. NR 51 TC 65 Z9 65 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2002 VL 8 IS 6 BP 1948 EP 1956 PG 9 WC Oncology SC Oncology GA 561LJ UT WOS:000176141900037 PM 12060640 ER PT J AU Ando, Y Fuse, E Figg, WD AF Ando, Y Fuse, E Figg, WD TI Thalidomide metabolism by the CYP2C subfamily SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN LIVER-MICROSOMES; S-MEPHENYTOIN 4'-HYDROXYLATION; SEX-SPECIFIC FORMS; CYTOCHROME-P450 ENZYMES; TERATOGEN METABOLISM; DRUG-METABOLISM; IN-VITRO; RATS; ANGIOGENESIS; INHIBITION AB Purpose: This research investigated the biotransformation of thalidomide by cytochrome P-450 (CYP). Experimental Design: We used liver microsomes from humans and/or animals and the recombinant specific CYP isozymes to investigate CYP-mediated metabolism of thalidomide. Results: Thalidomide was biotransformed into 5-hydroxythalidomide (5-OH) and diastereomeric 5'-hydroxythalidomide (5'-OH) by liver microsomes. The human liver microsomes with higher CYP2C19 activity formed more metabolites than those with lower CYP2C19 activity and had less activity in metabolite formations than those from rats. Recombinant human CYP2C19 and rat CYP2C6 isozymes were primarily responsible for forming these metabolites, and the male rat-specific CYP2C11 formed only 5'-OH. 5-OH was subsequently hydroxylated to 5,6dihydroxythalidomide by CYP2CI9, CYP2C9, and CYP1A1 in humans and by CYP2C11, CYP1A1, CYP2C6, and CYP2C12 in rats. Incubations with S-mephenytoin and omeprazole, substrates of CYP2C19, inhibited metabolism by human liver microsomes, supporting the involvement of CYP2C19. alpha-Naphthoflavone, an inhibitor of CYP1A, simultaneously stimulated the 5-OH formation and inhibited cis-5'-OH formation catalyzed by human liver microsomes. The contribution of the CYP2C subfamily was supported by the immunoinhibition study using human liver microsomes. When we used the microsomes from treated rats, the metabolite formations did not increase by inducers for CYP1A, CYP213, CYP2E, CYP3A, or CYP4A, suggesting that these could not be involved in the main metabolic pathway in rats. Conclusions: We discovered that the polymorphic enzyme CYP2C19 is responsible for 5- and 5'-hydroxylation of thalidomide in humans. In rats, thalidomide was hydroxylated extensively by CYP2C6 as well as the sex-specific enzyme CYP2C11. C1 NCI, Mol Pharmacol Sect, NIH, Canc Therapeut Branch,Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, NIH, Canc Therapeut Branch,Ctr Canc Res, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 54 TC 104 Z9 111 U1 2 U2 11 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2002 VL 8 IS 6 BP 1964 EP 1973 PG 10 WC Oncology SC Oncology GA 561LJ UT WOS:000176141900039 PM 12060642 ER PT J AU Chan, YW Lu, XI Sullivan, P Csako, G Remaley, AT AF Chan, YW Lu, XI Sullivan, P Csako, G Remaley, AT TI Evaluation of an automated immunoassay for 25-OH Vitamin D. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D40 BP A125 EP A125 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000404 ER PT J AU Costello, R Delgado, R Kirk, A Arioglu, E Csako, G AF Costello, R Delgado, R Kirk, A Arioglu, E Csako, G TI Erroneous LDL-C and VLDL-C results due to fast-migrating LDL in an electrophoretic lipoprotein-cholesterol method. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NIDDK Navy, Bethesda, MD USA. NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA C122 BP A111 EP A111 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000358 ER PT J AU Delgado, R Costello, R Sunderland, T Csako, G AF Delgado, R Costello, R Sunderland, T Csako, G TI Semi-automated PCR-single-strand conformation polymorphism (PCR-SSCP) methods for detection of a novel polymorphism in exon 2 of the human cathepsin D gene (CATD). SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA F29 BP A181 EP A181 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000589 ER PT J AU Ruddel, ME Remaley, AT Sampson, ML AF Ruddel, ME Remaley, AT Sampson, ML TI A two-step competitive binding assay modification for enhancing the functional sensitivity of a C-peptide assay. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D46 BP A127 EP A127 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000410 ER PT J AU Sampson, ML Ray, R Fitch, J Remaley, AT AF Sampson, ML Ray, R Fitch, J Remaley, AT TI Development of total cholesterol screening test with a patient specimen collection device. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Flexsite Diagnost Inc, Miami, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA C120 BP A110 EP A110 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000356 ER PT J AU Xu, M Chan, YW Fischer, SH Remaley, AT AF Xu, M Chan, YW Fischer, SH Remaley, AT TI Two new procedures for improving the RNA isolation step for the HIV viral load test. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA B81 BP A64 EP A64 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000205 ER PT J AU Azimi, N Nagai, M Mariner, J Jacobson, S Waldmann, T AF Azimi, N Nagai, M Mariner, J Jacobson, S Waldmann, T TI IL-15 plays an important role in the pathogenesis of HTLV-I associated neurological disease HAM/TSP through activation of the T cells and persistence of antigen specific CD8 cells. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NINDS, Viral Immunol Sect, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 226 BP S74 EP S75 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600227 ER PT J AU Bagenstose, LM Silver, P Hoffman, SC Kampen, RL Chan, CC Wiggert, B Harlan, DM Caspi, R AF Bagenstose, LM Silver, P Hoffman, SC Kampen, RL Chan, CC Wiggert, B Harlan, DM Caspi, R TI CD40/CD40 interactions required for EAU. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, LI, NIH, Bethesda, MD 20892 USA. USN, Med Res Inst, Transplantat Biol Lab, Bethesda, MD 20889 USA. NEI, LRCMB, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 160 BP S53 EP S53 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600161 ER PT J AU Bielekova, B Reichert-Scrivner, SA Ohayon, J McCartin, J Richert, N Waldmann, T McFarland, HF Martin, R AF Bielekova, B Reichert-Scrivner, SA Ohayon, J McCartin, J Richert, N Waldmann, T McFarland, HF Martin, R TI Combination therapy of multiple sclerosis patients failing interferon-beta with a humanized antibody against the interleukin-2 receptor alpha chain. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, CC, Bethesda, MD USA. NCI, NIH, Metab 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 320 BP S105 EP S105 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600319 ER PT J AU Bosticardo, M Witte, I Casanova, JL Candotti, F AF Bosticardo, M Witte, I Casanova, JL Candotti, F TI Retroviral-mediated correction of IL-12 receptor beta 1 deficiency. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Hop Necker Enfants Malad, Clin Unit Pediat Immunol & Hematol, Paris, France. 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 262 BP S85 EP S86 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600263 ER PT J AU Candotti, F Podsakoff, G Schurman, SH Muul, LM Engel, BC Carbonaro, DA Jagadeesh, GJ Tuschong, LM Carter, CS Ramsey, WJ Bauert, G Guo, G Smogorzweska, M Choi, C Hess, RA Hershfield, MS Read, EJ Tisdale, JF Dunbar, CE Kohn, DB AF Candotti, F Podsakoff, G Schurman, SH Muul, LM Engel, BC Carbonaro, DA Jagadeesh, GJ Tuschong, LM Carter, CS Ramsey, WJ Bauert, G Guo, G Smogorzweska, M Choi, C Hess, RA Hershfield, MS Read, EJ Tisdale, JF Dunbar, CE Kohn, DB TI Clinical evaluation of retroviral vectors for gene therapy of adenosine deaminase (ADA) deficiency. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. CHLA, Los Angeles, CA USA. Duke Univ, Med Ctr, Durham, NC 27710 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 128 BP S42 EP S42 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600129 ER PT J AU Hay, BN Malech, HL Davis, J Linton, G Uzel, G Woltz, P Puck, JM AF Hay, BN Malech, HL Davis, J Linton, G Uzel, G Woltz, P Puck, JM TI Incomplete immune reconstitution after bone marrow transplant (BMT) for X-linked severe combined immune deficiency (XSCID): A role for gene therapy?. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Bio 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 435 BP S142 EP S143 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600434 ER PT J AU Karabekian, Z Lytton, S Schneck, JP Caspi, R AF Karabekian, Z Lytton, S Schneck, JP Caspi, R TI Peptide/class II/Ig dimers for detection and study of T cells bearing antigen receptors specific to a major pathogenic epitope of a uveitogenic protein. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21218 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 203 BP S67 EP S68 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600204 ER PT J AU Koh, CY Bennett, M Murphy, WJ AF Koh, CY Bennett, M Murphy, WJ TI Allogeneic NK cells mediate more potent anti-tumor effects than syngeneic NK cells during ex vivo purging of C1498 murine leukemia. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NCI Frederick, LMI, Transplantat Biol Lab, Frederick, MD USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX USA. NCI, SAIC, IRSP, Frederick, MD 21701 USA. RI Koh, Crystal/D-9986-2013 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 180 BP S60 EP S60 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600181 ER PT J AU Marciano, BE Malech, HL Anderson, VL Gallin, JI Holland, SM AF Marciano, BE Malech, HL Anderson, VL Gallin, JI Holland, SM TI Inflammatory bowel disease in chronic granulomatous disease: a common manifestation of an uncommon disease SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIAID, NIH, Lab Host Defenses, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 307 BP S101 EP S101 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600306 ER PT J AU Mattapallil, MJ Pennesi, G Avichezer, D Sun, S David, CS Hargrave, P McDowell, JH Wiggert, B Chan, C Caspi, R Smith, WC AF Mattapallil, MJ Pennesi, G Avichezer, D Sun, S David, CS Hargrave, P McDowell, JH Wiggert, B Chan, C Caspi, R Smith, WC TI A humanised model of experimental autoimmune uveitis in HLA class II - Transgenic mice. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, NIH, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. Mayo Clin, Dept Immunol, Rochester, MN 55905 USA. NEI, Immunol Lab, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 428 BP S140 EP S140 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600427 ER PT J AU McDyer, JF Li, ZQ John, S Yu, X Wu, CY Ragheb, JA AF McDyer, JF Li, ZQ John, S Yu, X Wu, CY Ragheb, JA TI Production of both Thl and Th2 cytokines is inhibited by IL-2R blockade. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Guys Hosp, London SE1 9RT, England. 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 236 BP S77 EP S77 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600237 ER PT J AU Melchionda, F Fry, T McKirdy, M Mackall, C AF Melchionda, F Fry, T McKirdy, M Mackall, C TI A weak tumor antigen induces immune priming and not tolerance during progressive tumor growth. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NCI, Pediat Oncol 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 329 BP S108 EP S109 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600328 ER PT J AU Melchionda, F Sinha, M Khanna, C Merchant, M Fry, T Mackall, C AF Melchionda, F Sinha, M Khanna, C Merchant, M Fry, T Mackall, C TI Naturally acquired T cell responses prevent metastatic disease in murine osteosarcoma. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NCI, Pediat Oncol 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 281 BP S92 EP S92 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600282 ER PT J AU Monsurro, V Rosenberg, S Marincola, F AF Monsurro, V Rosenberg, S Marincola, F TI Functional heterogeneity of vaccine-induced CD8+T cell subsets. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 296 BP S97 EP S98 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600297 ER PT J AU Munson-Voskuil, S Ettinger, R Sanna, M Michie, S Vadeboncoeur, M Toma, J McDevitt, H AF Munson-Voskuil, S Ettinger, R Sanna, M Michie, S Vadeboncoeur, M Toma, J McDevitt, H TI Engagement of the lymphotoxin-beta receptor is required for development of diabetes in non-obese diabetic mice. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. Dept Microbiol & Immunol, Stanford, CA USA. NIAMS, Autoimmun Branch, NIH, Bethesda, MD USA. Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 191 BP S64 EP S64 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600192 ER PT J AU Nussenblatt, RB Buggage, R Thompson, D Li, ZQ Ragheb, J Waldmann, T AF Nussenblatt, RB Buggage, R Thompson, D Li, ZQ Ragheb, J Waldmann, T TI 4 year daclizumab therapy for sight threatening uveitis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD 20854 USA. NCI, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 319 BP S105 EP S105 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600318 ER PT J AU Renner, ED Puck, JM Holland, SM Schmitt, M Weiss, M Frosch, M Bergmann, M Davis, J Belohradsky, BH AF Renner, ED Puck, JM Holland, SM Schmitt, M Weiss, M Frosch, M Bergmann, M Davis, J Belohradsky, BH TI The autosomal recessive hyper-IgE syndrome in six consanguineous kindreds, presents a distinct disease entity. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NHGRI, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Ctr Med, Dept Rheumatol & Clin Immunol, Freiburg, Germany. Univ Childrens Hosp, Dr V Haunersches Kinderspital, Dept Infect Dis & Clin Immunol, Munich, Germany. Univ Childrens Hosp, Charite, Berlin, Germany. Univ Munster, Childrens Hosp, D-4400 Munster, Germany. Zentralkrankenhaus Bremen Ost, Inst Clin Neuropathol, Bremen, Germany. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 349 BP S115 EP S115 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600348 ER PT J AU Rosenzweig, SD Schaffer, AA Ding, L Roccia, R Holland, SM AF Rosenzweig, SD Schaffer, AA Ding, L Roccia, R Holland, SM TI Interferon-gamma receptor 1 promoter polymorphisms and susceptibility to nontuberculous mycobacterial infections. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Hosp Pediat JP Garrahan, Buenos Aires, DF, Argentina. RI Schaffer, Alejandro/F-2902-2012 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 431 BP S141 EP S142 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600430 ER PT J AU Sospedra, M Zhao, YD Blevins, G Mora, C Simon, R Pinilla, C Martin, R AF Sospedra, M Zhao, YD Blevins, G Mora, C Simon, R Pinilla, C Martin, R TI Unbiased identification of antigen specificities of cerebrospinal fluid-infiltrating T cells in multiple sclerosis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Stat & Bioinformat Sect, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies & Mixture Sci, San Diego, CA 92121 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 197 BP S65 EP S66 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600198 ER PT J AU Stoll, S Delon, J Brotz, T Schwartz, O Germain, R AF Stoll, S Delon, J Brotz, T Schwartz, O Germain, R TI High resolution, real-time, live cell imaging of T-cell: antigen presenting cell interactions in intact lymphoid tissue. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIAID, Lymphocyte Biol Sect, Immunol Lab, Bethesda, MD USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NIAID, Confocal Imaging Facil, RTB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 372 BP S122 EP S122 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600371 ER PT J AU Su, SB Silver, PB Wang, P Chan, CC Caspi, RR AF Su, SB Silver, PB Wang, P Chan, CC Caspi, RR TI Dissociating the enhancing and inhibitory effects of pertussis toxin on experimental autoimmune uveitis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, Immunol Lab, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 109 BP S35 EP S36 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600110 ER PT J AU Uzel, G Rosenzweig, SD Shaw, JM Tng, E Horwitz, ME Linton, GF Anderson, SM Kirby, MR Gallin, JI Fleisher, TA Law, SKA Holland, SM AF Uzel, G Rosenzweig, SD Shaw, JM Tng, E Horwitz, ME Linton, GF Anderson, SM Kirby, MR Gallin, JI Fleisher, TA Law, SKA Holland, SM TI Reversion mutations in 3 patients with leukocyte adhesion deficiency Type I leading to CD18 expression on CD3+/CD8+/CD57+T cells. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NHGRI, NIH, Bethesda, MD 20892 USA. Univ Oxford, Dept Biochem, MRC, Immunohistochem Unit, Oxford OX1 3QU, England. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, DLM, Serv Immunol, Bethesda, MD 20892 USA. RI Law, Alex/A-2212-2011 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 437 BP S143 EP S144 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600436 ER PT J AU Viley, AM Agarwal, RK Silver, PB Kronenberg, M Chan, CC Caspi, RR AF Viley, AM Agarwal, RK Silver, PB Kronenberg, M Chan, CC Caspi, RR TI T cell derived IL-10 reduces tissue damage and inhibits Th1 responses in the model of Experimental Autoimmune Uveitis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Microbiol & Immunol, Div Digest Dis, Inst Mol Biol, Los Angeles, CA 90095 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 111 BP S36 EP S36 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600112 ER PT J AU Wigginton, J Edgerly, M Bates, S Choyke, P Tomaszewski, J Wiltrout, R Janik, J AF Wigginton, J Edgerly, M Bates, S Choyke, P Tomaszewski, J Wiltrout, R Janik, J TI IL-12/pulse IL-2 combination cytokine therapy for solid tumors: Translation from bench to bedside. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NCI, 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 309 BP S102 EP S102 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600309 ER PT J AU Marti, GE AF Marti, GE TI The role of splenectomy in splenic marginal zone B-cell lymphoma SO CLINICAL LYMPHOMA LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; VILLOUS LYMPHOCYTES C1 NIH, Ctr Biol Evaluat & Res, US FDA, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), NIH, Ctr Biol Evaluat & Res, US FDA, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU CANCER INFORMATION GROUP, LP PI DALLAS PA 3535 WORTH ST, SAMMONS TOWER, STE 4802, DALLAS, TX 75246 USA SN 1526-9655 J9 CLIN LYMPHOMA JI Clin. Lymphoma PD JUN PY 2002 VL 3 IS 1 BP 48 EP 48 PG 1 WC Oncology SC Oncology GA 581CY UT WOS:000177274600006 PM 12141955 ER PT J AU Barbato, G Barker, C Bender, C Wehr, TA AF Barbato, G Barker, C Bender, C Wehr, TA TI Spontaneous sleep interruptions during extended nights. Relationships with NREM and REM sleep phases and effects on REM sleep regulation SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE non-rapid eye movement sleep; rapid eye movement sleep; awakening; circadian rhythm ID EYE-MOVEMENT DENSITY; HOMEOSTASIS; PROPENSITY; AWAKENINGS; HUMANS; CYCLE; EEG; AGE; ACCUMULATION; WAKEFULNESS AB Objectives: There is no agreement in the literature as to whether sleep interruption causes rapid eye movement (REM) pressure to increase, and if so, whether this increase is expressed as shortened REM latency, increased REM density, or increased duration of REM sleep. The purpose of the present study was to examine the effect of different durations of spontaneous steep interruptions on the regulation of REM sleep that occurs after return to sleep. Methods: The occurrence of spontaneous periods of wakefulness and their effects on subsequent REM sleep periods were analysed in a total sample of 1189 sleep interruptions which Occurred across 364 extended nights in 13 normal subjects. Results: Compared with sleep interruptions that last less than 10 min, sleep interruptions that last longer than 10 min occur preferentially out of REM sleep. In both the short and long types of sleep interruptions, the duration of REM periods that ended in wakefulness were shorter than the duration of those that were not interrupted by wakefulness. REM densities of the REM periods that terminated in periods of wakefulness were hi.-her than those of uninterrupted REM periods. The proportion of episodes of wakefulness following REM sleep that were long-lasting progressively increased over the course of the extended night period. The sleep episodes that followed the periods of wakefulness were characterised by a short REM latency. REM duration was increased in episodes that followed Ion, steep interruptions compared to those that followed short sleep interruptions. REM density did not appear to change significantly in the episodes that followed sleep interruption. Conclusions: REM sleep mechanisms appear to be the main force controlling sleep after a spontaneous sleep interruption. presumably because during the second half of the night, where more sleep interruptions occur, the pressure for non-rapid eye movement sleep is reduced and the circadian rhythm in REM sleep propensity reaches its peak. Processes promoting REM sleep at the end of the night are consistent with the Pittendrigh and Daan dual oscillator model of the circadian pacemaker. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Sect Biol Rhythm, Bethesda, MD 20892 USA. RP Barbato, G (reprint author), Univ Naples 2, Dept Psychol, Via Vivaldi 43, I-81100 Caserta, Italy. RI Barbato, Giuseppe/Q-9774-2016 OI Barbato, Giuseppe/0000-0001-6523-5327 NR 49 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2002 VL 113 IS 6 BP 892 EP 900 AR PII S1388-2457(02)00081-0 DI 10.1016/S1388-2457(02)00081-0 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 567UD UT WOS:000176503000012 PM 12048048 ER PT J AU Gonzales, JJ Ringeisen, HL Chambers, DA AF Gonzales, JJ Ringeisen, HL Chambers, DA TI The tangled and thorny path of science to practice: Tensions in interpreting and applying "evidence" SO CLINICAL PSYCHOLOGY-SCIENCE AND PRACTICE LA English DT Article DE mental health; children; evidence-based practice ID INTERVENTIONS; FAMILY; TRIALS AB As Chorpita et al. discuss, implementing scientific evidence into practice is a complex process. This commentary addresses additional issues to those mentioned in their article, issues related to the nature of evidence and its interpretation. Since the evidence base is inherently subjective and ever-changing, it is critically important to describe the decision-making processes involved in the interpretation and application of evidence. Increasing efforts should also be made to consider the context at the provider, patient, system and community levels in decision-making processes about scientific evidence as well as during the implementation of evidence in practice settings. This will enable the assessment of the fit between the evidence and local populations and settings. Attention to process factors and context should ideally occur during the creation, adaptation, and implementation of evidence. Attention to the complexities of scientific evidence and the process of its systematic review and implementation into real world practice settings will improve the translation of evidence into community practice. C1 NIMH, Div Serv & Intervent Res, Serv Res & Clin Epidemiol Branch, Bethesda, MD USA. RP Gonzales, JJ (reprint author), 6001 Execut Blvd,Rm 7146 MSC 9631, Bethesda, MD 20892 USA. NR 18 TC 33 Z9 35 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0969-5893 J9 CLIN PSYCHOL-SCI PR JI Clin. Psychol.-Sci. Pract. PD SUM PY 2002 VL 9 IS 2 BP 204 EP 209 DI 10.1093/clipsy/9.2.204 PG 6 WC Psychology, Clinical SC Psychology GA 552PN UT WOS:000175628900009 ER PT J AU Hoagwood, K AF Hoagwood, K TI Making the translation from research to its application: The je ne sais pas of evidence-based practices SO CLINICAL PSYCHOLOGY-SCIENCE AND PRACTICE LA English DT Article DE evidence-based treatments; children's mental health ID MANAGEMENT; CHILDREN; BEHAVIOR AB Moving evidence-based treatments into practice settings is an important new direction for the field of children's mental health., but is fraught with many unknowns. This commentary discusses scientific conundrums that surround that transportability of research-based interventions, including issues of definition (e.g., differences among treatments, preventive interventions, services); diagnostic reification and the absence of markers; the value and status of combination treatments (including pharmacologic) for conceptualizing the evidence base; and differences between evidence-based practices and evidence-based treatments. Suggestions are made for a disciplined approach to advancing a yoked research and policy agenda for children's mental health. C1 NIMH, Bethesda, MD 20892 USA. RP Hoagwood, K (reprint author), NYPSI, 1051 Riverside Dr,78, New York, NY 10032 USA. NR 22 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0969-5893 J9 CLIN PSYCHOL-SCI PR JI Clin. Psychol.-Sci. Pract. PD SUM PY 2002 VL 9 IS 2 BP 210 EP 213 DI 10.1093/clipsy/9.2.210 PG 4 WC Psychology, Clinical SC Psychology GA 552PN UT WOS:000175628900010 ER PT J AU Grieder, FB AF Grieder, FB TI Untitled SO COMPARATIVE MEDICINE LA English DT Letter C1 NCRR, Div Comparat Med, NIH, Bethesda, MD 20892 USA. RP Grieder, FB (reprint author), NCRR, Div Comparat Med, NIH, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 6 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2002 VL 52 IS 3 BP 203 EP 203 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 569DW UT WOS:000176586200002 PM 12102564 ER PT J AU Myles, MH Foltz, CJ Shinpock, SG Olszewski, RE Franklin, CL AF Myles, MH Foltz, CJ Shinpock, SG Olszewski, RE Franklin, CL TI Infertility in CFW/R1 mice associated with cystic dilatation of the bulbourethral gland SO COMPARATIVE MEDICINE LA English DT Article ID COWPERS SYRINGOCELE; GROWTH; CASTRATION AB A third of male inbred CFW/R1 mice in a breeding colony developed subcutaneous, bilateral, perineal masses determined to be cystic bulbourethral glands. The masses developed in mice between 4 and 15 months of age. After development of these perineal masses, diseased males were unable to produce offspring. Gross examination revealed the masses impinging on the scrotum and displacing the testes into the inguinal. canal. The perineal. masses were paired, membranous, translucent cysts, 6 to 10 MM3, attached to the bulbocavernosus muscle and connected to the pelvic urethra by way of a non-patent duct. The cysts contained a clear to tan, minimally cellular, viscous fluid with high mucus content, as documented by examination of Wright Giemsa-stained cytologic preparations. Histologic examination of hematoxylin and eosin-stained sections revealed cystic tubuloalveolar glands surrounded by striated muscle and lined by a single layer of pyramidal cuboidal to columnar epithelial cells with pale, basophilic, lacy cytoplasm and round, basal, condensed nuclei. These gross and histopathologic findings were consistent with cystic dilatation of the bulbourethral gland. C1 Univ Missouri, Dept Vet Pathobiol, Res Anim Diagnost Lab, Columbia, MO 65212 USA. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NIH, Vet Med Branch, Vet Resources Program, Bethesda, MD 20892 USA. RP Myles, MH (reprint author), Univ Missouri, Dept Vet Pathobiol, Res Anim Diagnost Lab, Columbia, MO 65212 USA. NR 26 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2002 VL 52 IS 3 BP 273 EP 276 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 569DW UT WOS:000176586200013 PM 12102575 ER PT J AU Lavori, PW Krause-Steinrauf, H Brophy, M Buxbaum, J Cockroft, J Cox, DR Fiore, L Greely, HT Greenberg, H Holmes, EW Nelson, LM Sugarman, J AF Lavori, PW Krause-Steinrauf, H Brophy, M Buxbaum, J Cockroft, J Cox, DR Fiore, L Greely, HT Greenberg, H Holmes, EW Nelson, LM Sugarman, J TI Principles, organization, and operation of a DNA bank for clinical trials: a Department of Veterans Affairs cooperative study SO CONTROLLED CLINICAL TRIALS LA English DT Article DE DNA banking; ethics; genes; pharmacogenomics ID GENETIC EPIDEMIOLOGY; DISCRIMINATION; MEDICINE; GENOMICS; ISSUES AB The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Palo Alto VA Hlth Care Syst, Palo Alto, CA USA. Stanford Univ, Sch Law, Stanford, CA 94305 USA. NHLBI, Bethesda, MD 20892 USA. Boston VA Hlth Care Syst, Boston, MA USA. Scripps Res Inst, La Jolla, CA USA. Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. Duke Univ, Sch Med, Durham, NC USA. RP Lavori, PW (reprint author), VA Cooperat Studies Program Coordinating Ctr, 795 Willow Rd,Bldg 205,Basement 151K, Menlo Pk, CA 94025 USA. NR 24 TC 30 Z9 30 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2002 VL 23 IS 3 BP 222 EP 239 AR PII S0197-2456(02)00193-9 DI 10.1016/S0197-2456(02)00193-9 PG 18 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 558JU UT WOS:000175963200001 PM 12057876 ER PT J AU DeRouen, TA Leroux, BG Martin, MD Townes, BD Woods, JS Leitao, J Castro-Caldas, A Braveman, N AF DeRouen, TA Leroux, BG Martin, MD Townes, BD Woods, JS Leitao, J Castro-Caldas, A Braveman, N TI Issues in design and analysis of a randomized clinical trial to assess the safety of dental amalgam restorations in children SO CONTROLLED CLINICAL TRIALS LA English DT Article DE safety; dental amalgam; mercury; multiple endpoints; interim analyses; children; neurobehavioral test ID LOW-LEVEL EXPOSURE; MERCURY EXPOSURE; URINE SAMPLES; SEYCHELLES; EXCRETION; VAPOR; BLOOD AB The Casa Pia Study of the Health Effects of Dental Amalgams-in Children is a randomized clinical trial designed to assess the safety of low-level mercury exposure from dental amalgam restorations in children. It is being carried out in 507 students (8 to 12 years of age at enrollment) of the Casa Pia school system in Lisbon, Portugal, by an interdisciplinary collaborative research team from the University of Washington (Seattle) and the University of Lisbon, with funding from the National Institute of Dental and Craniofacial Research. Since the goal of the trial-is to assess the safety of a treatment currently in use, rather than the efficacy of an experimental treatment, unique design issues come into play. The requirements to identify as participants children who have extensive unmet dental treatment needs and wh can be followed for 7 years after initial treatment are somewhat in conflict, since those with the most treatment needs are usually in lower socioeconomic categories and more difficult to track. The identification of a primary study outcome measure around which to design the trial is problematic, since there is little evidence to indicate how health effects from such low-level exposure would be manifested. The solution involves the use of multiple outcomes. Since there are concerns about safety, multiple interim comparisons over time between treatment groups are called for which, in conjunction with the use of multiple outcomes, require an extension of statistical methodology to meet this requirement. Ethical questions that have to be addressed include whether assent of the children participating is required or appropriate, and whether the director of the school system, who is the legal guardian for approximately 20% of the students who are wards of the state and live in school residences, should provide consent for such a large number of children. Approaches taken to address these and other design issues are described. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Washington, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Oral Med, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. Battelle Ctr Publ Hlth, Seattle, WA USA. Battelle Ctr Evaluat, Seattle, WA USA. Univ Lisbon, Fac Med Dent, P-1699 Lisbon, Portugal. Univ Lisbon, Fac Med, P-1699 Lisbon, Portugal. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP DeRouen, TA (reprint author), Univ Washington, Dept Dent Publ Hlth Sci, Box 357475, Seattle, WA 98195 USA. RI Castro-Caldas, Alexandre/M-4156-2013; Leroux, Brian/H-2254-2015 OI Castro-Caldas, Alexandre/0000-0002-9148-3719; FU NIDCR NIH HHS [U01 DE11894] NR 34 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2002 VL 23 IS 3 BP 301 EP 320 AR PII S0197-2456(01)00206-9 DI 10.1016/S0197-2456(01)00206-9 PG 20 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 558JU UT WOS:000175963200006 PM 12057882 ER PT J AU Ohta, K Yamagami, S Wiggert, B Dana, MR Streilein, JW AF Ohta, K Yamagami, S Wiggert, B Dana, MR Streilein, JW TI Chemokine gene expression in iris-ciliary body during experimental autoimmune uveoretinitis SO CURRENT EYE RESEARCH LA English DT Article DE anterior uveal tract; chemokine; experimental autoimmune uveoretinitis; iris-ciliary body; neutrophil ID RETINOID-BINDING PROTEIN; CENTRAL-NERVOUS-SYSTEM; ANTERIOR UVEITIS; HYPERSENSITIVITY REACTION; CHEMOTACTIC CYTOKINES; RECEPTOR EXPRESSION; IMMUNE PRIVILEGE; LYMPHOCYTES-T; AQUEOUS-HUMOR; MICE AB Purpose. To evaluate, through differential gene expression of chemokines in iris-ciliary body (I/CB), the extent to which leukocyte recruitment to the ocular anterior segment participates in the pathogenesis of experimental autoimmune uveoretinitis (EAU) in mice. Methods. B10.A mice were immunized with 50 mug of interphotoreceptor retinoid binding protein (IRBP) mixed with complete Freund's adjuvant. Aqueous humor (AqH) was collected at 0, 11, 17, and 28 days and assayed for leukocyte content and protein levels. Enucleated eyes were subjected to histologic analysis. Chemokine gene expression in I/CB was determined at these same time points by a multiprobe ribonuclease protection assay (RPA) system. Results. Inflammation was detected in the anterior chamber (AC) at 11 days and leukocyte recruitment continued thereafter. Polymorphonuclear neutrophils (PMN) were the predominant cell type in the AC, whereas macrophages/monocytes and lymphocytes were predominant in the retina/subretinal space at 17 days. Peak gene expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and MIP-2 and interferon-gamma-inducible protein of 10kd (IP-10) was detected in I/CB on day 11, whereas peak expression of RANTES and eotaxin was observed at 17 days. Conclusions. Early I/CB peak expression of mRNA for MIP-2 followed by PMN recruitment into the AC, suggests that PMN may play an important role in EAU pathogenesis. C1 Shinshu Univ, Dept Ophthalmol, Sch Med, Matsumoto, Nagano 3908621, Japan. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. Jichi Med Sch, Dept Ophthalmol, Kawachi, Tochigi, Japan. NIH, Lab Retinal & Mol Biol, Bethesda, MD 20892 USA. RP Ohta, K (reprint author), Shinshu Univ, Dept Ophthalmol, Sch Med, Matsumoto, Nagano 3908621, Japan. EM kohta@hsp.md.shinshu-u.ac.jp FU NEI NIH HHS [EY12963, EY05678] NR 41 TC 11 Z9 13 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD JUN PY 2002 VL 24 IS 6 BP 451 EP 457 PG 7 WC Ophthalmology SC Ophthalmology GA 625NQ UT WOS:000179822900005 PM 12525972 ER PT J AU Eisenhofer, G Lenders, JWM Pacak, K AF Eisenhofer, G Lenders, JWM Pacak, K TI Choice of biochemical test for diagnosis of pheochromocytoma: Validation of plasma metanephrines SO CURRENT HYPERTENSION REPORTS LA English DT Article ID CATECHOLAMINES; URINARY; LOCALIZATION AB Pheochromocytomas, although a rare cause of hypertension, are dangerous tumours that require consideration among large numbers of patients. The subsequent low prevalence of the tumour among those tested and inadequacies of commonly used biochemical tests make excluding or confirming the tumour an often difficult and time-consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumour cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Measurements of plasma concentrations of free metanephrines thereby promise more reliable and efficient diagnosis of pheochromocytoma than offered by conventional biochemical tests. C1 NIH, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. NR 23 TC 19 Z9 21 U1 0 U2 2 PU CURRENT SCIENCE INC PI PHILADELPHIA PA 400 MARKET STREET, STE 750, PHILADELPHIA, PA 19106 USA SN 1522-6417 J9 CURR HYPERTENS REP JI Curr. Hypertens. Rep. PD JUN PY 2002 VL 4 IS 3 BP 250 EP 255 DI 10.1007/s11906-002-0015-4 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 616TQ UT WOS:000179319400013 PM 12003709 ER PT J AU Oki, M Kamakaka, RT AF Oki, M Kamakaka, RT TI Blockers and barriers to transcription: competing activities? SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; BETA-GLOBIN LOCUS; SACCHAROMYCES-CEREVISIAE; CHROMATIN INSULATORS; GENE; CTCF; METHYLATION; BOUNDARIES; DROSOPHILA; EXPRESSION AB In the eukaryotic cell active and inactive genes reside adjacent to one another and are modulated by numerous regulatory elements. Insulator elements prevent the misregulation of adjacent genes by restricting the effects of the regulatory elements to specific domains. Enhancer blockers prevent enhancers from inadvertently activating neighboring genes, and recent results suggest that they might function by a conserved mechanism across species. These elements appear to disrupt enhancer-promoter 'communications' by interacting with the regulatory elements and sequestering these elements into specific regions of the nucleus thus rendering them non-functional, Barrier elements insulate active genes from neighboring heterochromatin and recent results suggest that they function by specific localized recruitment of acetyltransferases that antagonize the spread of heterochromatin-associated deacetylases, thus preventing the propagation of heterochromatin. C1 NICHHD, Unit Chromatin & Transcript, Bethesda, MD 20892 USA. RP Kamakaka, RT (reprint author), NICHHD, Unit Chromatin & Transcript, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. NR 40 TC 47 Z9 49 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2002 VL 14 IS 3 BP 299 EP 304 DI 10.1016/S0955-0674(02)00327-7 PG 6 WC Cell Biology SC Cell Biology GA 548HH UT WOS:000175382200006 PM 12067651 ER PT J AU Contreas, MA Rapoport, SI AF Contreas, MA Rapoport, SI TI Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review ID ALPHA-LINOLENIC ACID; DISEASE RISK-FACTORS; DOCOSAHEXAENOIC ACID; ARACHIDONIC-ACID; RAT-BRAIN; NUTRITIONAL DEPRIVATION; ALZHEIMERS-DISEASE; NEURONAL APOPTOSIS; NERVOUS-SYSTEM; DEFICIENCY AB Recent literature provides a basis for understanding the behavioral, functional, and structural consequences of nutritional deprivation or disease-related abnormalities of n-3 polyunsaturated fatty acids. The literature suggests that these effects are mediated through competition between n-3 and n-6 polyunsaturated fatty acids at certain enzymatic steps, particularly those involving polyunsaturated fatty acid elongation and desaturation. One critical enzymatic site is a Delta(6)-desaturase. On the other hand, an in-vivo method in rats, applied following chronic n-3 nutritional deprivation or chronic administration of lithium, indicates that the cycles of de-esterification/re-esterification of docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) within brain phospholipids operate independently of each other, and thus that the enzymes regulating each of these cycles are not likely sites of n-3/n-6 competition. Curr Opin Lipidol 13:267-272. (C) 2002 Lippincott Williams Wilkins. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,6N-202,90000 Rockville Pike, Bethesda, MD 20892 USA. NR 53 TC 49 Z9 49 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD JUN PY 2002 VL 13 IS 3 BP 267 EP 272 DI 10.1097/00041433-200206000-00006 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 557VH UT WOS:000175928700006 PM 12045396 ER PT J AU Kroetz, DL Zeldin, DC AF Kroetz, DL Zeldin, DC TI Cytochrome P450 pathways of arachidonic acid metabolism SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review ID MUSCLE RESISTANCE ARTERIES; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; PHOSPHOLIPASE-D ACTIVATION; CEREBRAL BLOOD-FLOW; EPOXYEICOSATRIENOIC ACIDS; ANGIOTENSIN-II; HYPERPOLARIZING FACTOR; CORONARY-ARTERIES; 20-HYDROXYEICOSATETRAENOIC ACID; SMOOTH-MUSCLE AB Cytochrome P450s metabolize arachidonic acid to hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. These eicosanoids are formed in a tissue and cell-specific manner and have numerous biological functions. Of major interest are the opposing actions of hydroxyeicosatetraenoic and epoxyeicosatrienoic acids within the vasculature. Regio- and stereoisomeric epoxyeicosatrienoic acids have potent vasodilatory proper-ties while 20-hydroxyeicosatetraenoic acid is a potent vasoconstrictor. Both effects are mediated through actions on large-conductance Ca2+-activated K+ channels. Cytochrome P450-derived eicosanoids are also important in the regulation of ion transport, and have recently been shown to influence a number of fundamental biological processes including cellular proliferation, apoptosis, inflammation, and hemostasis. The formation of these functionally relevant eicosanoids is tightly controlled by the expression and activity of the cytochrome P450 epoxygenases and hydroxylases. In addition, soluble epoxide hydrolase catalyzes the hydrolysis of epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids, and the activity of this enzyme is a critical determinant of tissue epoxyeicosatrienoic and dihydroxyeicosatrienoic acid levels. The intracellular balance between epoxyeicosatrienoic, dihydroxyeicosatrienoic and hydroxyeicosatetraenoic acids influences the biological response to these eicosanoids and alterations in their levels have recently been associated with certain pathological conditions. The involvement of the cytochrome P450-derived ecosanoids in a wide array of biological functions and the observation that levels are altered in pathological conditions suggest that the enzymes involved in the formation and degradation of these fatty acids may be novel therapeutic targets. Curr Opin Lipidol 13:273-283. (C) 2002 Lippincott Williams Wilkins. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, Sch Pharm, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101,Room D236, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01 HL53994] NR 120 TC 111 Z9 114 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD JUN PY 2002 VL 13 IS 3 BP 273 EP 283 DI 10.1097/00041433-200206000-00007 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 557VH UT WOS:000175928700007 PM 12045397 ER PT J AU Aravind, L Mazumder, R Vasudevan, S Koonin, EV AF Aravind, L Mazumder, R Vasudevan, S Koonin, EV TI Trends in protein evolution inferred from sequence and structure analysis SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID ESCHERICHIA-COLI PRIMASE; CRYSTAL-STRUCTURE; DNA-POLYMERASE; PHOSPHOSERINE PHOSPHATASE; PSEUDOURIDINE SYNTHASE; COMPARATIVE GENOMICS; ERROR-PRONE; DOMAIN; FAMILY; DATABASE AB Complementary developments in comparative genomics, protein structure determination and in-depth comparison of protein sequences and structures have provided a better understanding of the prevailing trends in the emergence and diversification of protein domains. The investigation of deep relationships among different classes of proteins involved in key cellular functions, such as nucleic acid polymerases and other nucleotide-dependent enzymes, indicates that a substantial set of diverse protein domains evolved within the primordial, ribozyme-dominated RNA world. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 55 TC 89 Z9 91 U1 0 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2002 VL 12 IS 3 BP 392 EP 399 DI 10.1016/S0959-440X(02)00334-2 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 562CG UT WOS:000176179400017 PM 12127460 ER PT J AU Minderman, H Suvannasankha, A O'Loughlin, KL Scheffer, GL Scheper, RJ Robey, RW Baer, MR AF Minderman, H Suvannasankha, A O'Loughlin, KL Scheffer, GL Scheper, RJ Robey, RW Baer, MR TI Flow cytometric analysis of breast cancer resistance protein expression and function SO CYTOMETRY LA English DT Article DE breast cancer resistance protein; multidrug resistance; mitoxantrone ID CARCINOMA CELL-LINE; MULTIDRUG-RESISTANCE; MITOXANTRONE-RESISTANT; DRUG-RESISTANCE; FUMITREMORGIN-C; TRANSPORTER; GENE; MECHANISMS; LEUKEMIA; ABC AB Background: The breast cancer resistance protein (BCRP) is an ATP-binding cassette (ABC) half-transporter that mediates energy-dependent drug efflux. Assessing the clinical relevance of the BCRP will require sensitive and specific methods for detecting its expression and function that allow high-volume specimen throughput and employ widely available instrumentation. Methods: The BXP-34 and BXP-21 monoclonal antibodies were evaluated for flow cytometric detection of BCRP expression, The modulation of efflux of rhodamine-123, 3,3'-diethyloxacarbocyanine iodide, doxorubicin, and mitoxantrone by fumitremorgin C was studied as an assay for BCRP function in BCRP-overexpressing cell lines and controls. Results: BXP-34 and BXP-21 allowed detection of BCRP expression by flow cytometry in all BCRP-expressing cell lines. Mitoxantrone was the only substrate transported by BCRP in all Lines, and with mitoxantrone at a 3-muM concentration, light emission (>670 nm) caused by excitation at 488 nm was sufficiently intense to allow detection of differences in retention associated with low levels of BCRP expression. Conclusions: Immunophenotyping with BXP-21 or BXP-34 and fumitremorgin C modulation of mitoxantrone retention allow detection of BCRP expression and function by flow cytometry with standard instrumentation. These assays will facilitate determination of the role of BCRP in clinical drug resistance. C1 Roswell Pk Canc Inst, Dept Med, Leukemia Sect, Buffalo, NY 14263 USA. Free Univ Amsterdam, Dept Pathol, Amsterdam, Netherlands. NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Minderman, H (reprint author), Roswell Pk Canc Inst, Dept Med, Leukemia Sect, Sci Bldg 616,Elm & Carlton St, Buffalo, NY 14263 USA. FU NCI NIH HHS [P30 CA 16056, 1R21 CA 89938-01] NR 27 TC 66 Z9 69 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOMETRY JI Cytometry PD JUN 1 PY 2002 VL 48 IS 2 BP 59 EP 65 DI 10.1002/cyto.10111 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 557QP UT WOS:000175919500001 PM 12116365 ER PT J AU Corsi, AK Brodigan, TM Jorgensen, EM Krause, M AF Corsi, AK Brodigan, TM Jorgensen, EM Krause, M TI Characterization of a dominant negative C-elegans Twist mutant protein with implications for human Saethre-Chotzen syndrome SO DEVELOPMENT LA English DT Article DE CeTwist; C. elegans; mesoderm; hlh-8; Saethre-Chotzen syndrome; sex myoblasts; bHLH ID STRIATED-MUSCLE DEVELOPMENT; LOOP-HELIX PROTEINS; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTOR; BHLH PROTEIN; DNA-BINDING; DROSOPHILA EMBRYOS; CRYSTAL-STRUCTURE; MUTATIONS; GENE AB Twist is a transcription factor that is required for mesodermal cell fates in all animals studied to date. Mutations of this locus in humans have been identified as the cause of the craniofacial disorder Saethre-Chotzen syndrome. The Caenorhabditis elegans Twist homolog is required for the development of a subset of the mesoderm. A semidominant allele of the gene that codes for CeTwist, hlh-8, has defects that occur earlier in the mesodermal lineage than a previously studied null allele of the gene. The semidominant allele has a charge change (E29K) in the basic DNA-binding domain of CeTwist. Surprisingly, the mutant protein retains DNA-binding activity as both a homodimer and a heterodimer with its partner E/Daughterless (CeE/DA). However, the mutant protein blocks the activation of the promoter of a target gene. Therefore, the mutant CeTwist may cause cellular defects as a dominant negative protein by binding to target promoters as a homo- or heterodimer and then blocking transcription. Similar phenotypes as those caused by the E29K mutation were observed when amino acid substitutions in the DNA-binding domain that are associated with the human Saethre-Chotzen syndrome were engineered into the C. elegans protein. These data suggest that Saethre-Chotzen syndrome may be caused, in some cases, by dominant negative proteins, rather than by haploinsufficiency of the locus. C1 Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. RP Corsi, AK (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. OI Krause, Michael/0000-0001-6127-3940 NR 46 TC 16 Z9 18 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2002 VL 129 IS 11 BP 2761 EP 2772 PG 12 WC Developmental Biology SC Developmental Biology GA 567EC UT WOS:000176471600018 PM 12015302 ER PT J AU Roman, BL Pham, V Lawson, ND Kulik, M Childs, S Lekven, AC Garrity, DM Moon, RT Fishman, MC Lechleider, RJ Weinstein, BM AF Roman, BL Pham, V Lawson, ND Kulik, M Childs, S Lekven, AC Garrity, DM Moon, RT Fishman, MC Lechleider, RJ Weinstein, BM TI Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels SO DEVELOPMENT LA English DT Article DE Acvrl1; hereditary hemorrhagic telangiectasia; endothelium; angiogenesis; zebrafish; violet beauregard ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; SERINE/THREONINE KINASE RECEPTOR; DORSOVENTRAL PATTERN-FORMATION; TGF-BETA; I RECEPTOR; ARTERIOVENOUS-MALFORMATIONS; SIGNAL-TRANSDUCTION; DEFICIENT MICE; GENE; ANGIOGENESIS AB The zebrafish mutant violet beauregarde (vbg) can be identified at two days post-fertilization by an abnormal circulation pattern in which most blood cells flow through a limited number of dilated cranial vessels and fail to perfuse the trunk and tail. This phenotype cannot be explained by caudal vessel abnormalities or by a defect in cranial vessel patterning, but instead stems from an increase in endothelial cell number in specific cranial vessels. We show that vbg encodes activin receptor-like kinase 1 (Acvr11; also known as Alk1), a TGFbeta type I receptor that is expressed predominantly in the endothelium of the vessels that become dilated in vbg mutants. Thus, vbg provides a model for the human autosomal dominant disorder, hereditary hemorrhagic telangiectasia type 2, in which disruption of ACVRL1 causes vessel malformations that may result in hemorrhage or stroke. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. Massachusetts Gen Hosp East, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98185 USA. Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98185 USA. RP Weinstein, BM (reprint author), NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RI Moon, Randall/B-1743-2014 OI Moon, Randall/0000-0002-9352-1408 FU NHLBI NIH HHS [HL65681]; NICHD NIH HHS [Z01-HD-01011] NR 59 TC 186 Z9 191 U1 1 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2002 VL 129 IS 12 BP 3009 EP 3019 AR UNSP DEV14536 PG 11 WC Developmental Biology SC Developmental Biology GA 572JB UT WOS:000176769800019 PM 12050147 ER PT J AU Kopnisky, KL Cowan, WM Hyman, SE AF Kopnisky, KL Cowan, WM Hyman, SE TI Levels of analysis in psychiatric research SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Review ID AMYLOID PRECURSOR PROTEIN; FRAGILE-X-SYNDROME; ONSET ALZHEIMERS-DISEASE; CROSS-FOSTERING ANALYSIS; CHILDHOOD SEXUAL ABUSE; INBRED MOUSE STRAINS; TRANSGENIC MICE; PARKINSONS-DISEASE; GENE-EXPRESSION; RAT STRIATUM AB Most of the major psychiatric disorders have been analyzed at each of several different levels. For example, at the broadest level, epidemiological studies have served to establish the incidence of disorders like schizophrenia and major depression in a number of different populations. Family and twin studies have been important in determining the heritability of certain mental illnesses, and chromosomal and linkage analyses have identified a number of discrete loci that appear to be implicated in disease susceptibility or, even directly, in the pathogenesis of some disorders. In a few cases, specific genes have been found to be mutated or polymorphic and proteins they encode are currently being analyzed. This article reviews how these different levels contribute to our understanding of a number of psychiatric disorders, including drug addiction, which has been the focus of much of our own work. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Kopnisky, KL (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 6216,MSC 9619, Bethesda, MD 20892 USA. NR 129 TC 3 Z9 4 U1 4 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2002 VL 14 IS 3 BP 437 EP 461 DI 10.1017/S0954579402003033 PG 25 WC Psychology, Developmental SC Psychology GA 597GV UT WOS:000178214600003 PM 12349868 ER PT J AU Nelson, CA Bloom, FE Cameron, JL Amaral, D Dahl, RE Pine, D AF Nelson, CA Bloom, FE Cameron, JL Amaral, D Dahl, RE Pine, D TI An integrative, multidisciplinary approach to the study of brain-behavior relations in the context of typical and atypical development SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID FACE RECOGNITION; PREFRONTAL CORTEX; EARLY ADOLESCENCE; HUMAN AMYGDALA; DEPRESSION; CHILDREN; MEMORY; GIRLS; AGE; NEUROSCIENCE AB The study of brain development and that of behavioral development have historically proceeded independently of one another. This is an unfortunate set of circumstances, given that the disciplines concerned with development-for example, developmental psychology, pediatrics, psychiatry, clinical psychology, and the neurosciences-have much to learn from each other. Drawing on recent advances in the developmental brain and behavioral sciences, we illustrate the transdisciplinary approach our group has adopted in the service of uniting the research on brain and behavior in the context of development. We specifically report on our nonhuman primate and human studies that collectively illustrate our "genes to behavior" approach to the study of development. Our goal in summarizing our research in this fashion is to promote discussion about promising templates for how research on brain, behavior, and development might proceed into the 21st century. C1 Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. Scripps Res Inst, La Jolla, CA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif Davis, Davis, CA 95616 USA. NIH, Bethesda, MD 20892 USA. RP Nelson, CA (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. RI Cameron, Judy/J-6682-2013 NR 56 TC 82 Z9 82 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2002 VL 14 IS 3 BP 499 EP 520 DI 10.1017/S0954579402003069 PG 22 WC Psychology, Developmental SC Psychology GA 597GV UT WOS:000178214600006 PM 12349871 ER PT J AU Post, RM Weiss, SB AF Post, RM Weiss, SB TI Psychological complexity: Barriers to its integration into the neurobiology of major psychiatric disorders SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID AMYGDALA-KINDLED SEIZURES; THYROTROPIN-RELEASING-HORMONE; SUBGENUAL PREFRONTAL CORTEX; CEREBRAL GLUCOSE-METABOLISM; LONG-TERM POTENTIATION; SERUM GROWTH-HORMONE; MOOD DISORDERS; MATERNAL-DEPRIVATION; DEPRESSED-PATIENTS; AFFECTIVE-ILLNESS AB In the authors' experience interactions between clinical and laboratory research have been greatly mutually facilitatory in the understanding and development of new treatments for the major mental illnesses. Examples in the literature are also highlighted to show how cross-disciplinary studies are important in understanding the subtle interactions of genetic and environmental mechanisms in psychiatric illness. Yet, the results of some current science policies encouraging project focus and superspecialization can lead to the separation of clinical and basic investigators, which threatens the integration of psychological complexity into the neurobiology of psychiatry at both a molecular and behavioral level. This paper endorses renewed effort toward the multidisciplinary team approach under the leadership of a physician-scientist in order to better integrate many fields of study critical to ameliorating the effects of psychiatric illness. C1 NIMH, BPB, Bethesda, MD 20892 USA. Natl Mental Hlth Assoc, Alexandria, VA 22314 USA. RP Post, RM (reprint author), NIMH, BPB, 10 Ctr Dr MSC 1272,Bldg 10,Room 3S239, Bethesda, MD 20892 USA. NR 99 TC 0 Z9 0 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2002 VL 14 IS 3 BP 635 EP 651 DI 10.1017/S0954579402003127 PG 17 WC Psychology, Developmental SC Psychology GA 597GV UT WOS:000178214600012 PM 12349877 ER PT J AU Tsai, RYL Kittappa, R McKay, RDG AF Tsai, RYL Kittappa, R McKay, RDG TI Plasticity, niches, and the use of stem cells SO DEVELOPMENTAL CELL LA English DT Editorial Material ID BONE-MARROW CELLS; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; LIMB REGENERATION; DROSOPHILA OVARY; BRAIN; TRANSPLANTATION; MUSCLE; PRECURSOR; MYOTUBES C1 NINCDS, LMB, NIH, Bethesda, MD 20892 USA. RP McKay, RDG (reprint author), NINCDS, LMB, NIH, Bldg 36,Room 5A29, Bethesda, MD 20892 USA. NR 56 TC 67 Z9 80 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JUN PY 2002 VL 2 IS 6 BP 707 EP 712 DI 10.1016/S1534-5807(02)00195-8 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 561VP UT WOS:000176164000007 PM 12062083 ER PT J AU Martinez, A Ozbun, LL Angdisen, J Jakowlew, SB AF Martinez, A Ozbun, LL Angdisen, J Jakowlew, SB TI Expression of differentially expressed nucleolar transforming growth factor-beta 1 target (DENTT) in adult mouse tissues SO DEVELOPMENTAL DYNAMICS LA English DT Article DE DENTT; TGF-beta; mouse; pituitary; gonads ID NUCLEOSOME-ASSEMBLY PROTEIN; FACTOR-BETA ISOFORMS; TGF-BETA; ANTERIOR-PITUITARY; CELL-PROLIFERATION; NERVOUS-SYSTEM; MESSENGER-RNA; II RECEPTORS; ACTIVIN; RAT AB Differentially expressed nucleolar TGF-beta1 target (DENTT) is a novel member of the TSPY/TSPY-L/SET/NAP-1 (TTSN) superfamily that we have previously identified in human lung cancer cells. Here, we have investigated the expression of this protein in the adult mouse. By Western analysis, DENTT is highly expressed in the pituitary gland and moderately in the adrenals, brain, testis, and ovary. Immunohistochemical staining analysis for DENTT showed differential cytoplasmic and nuclear staining patterns in several cell types. The pituitary gland showed the highest level of immunostaining for DENTT, with strong cytoplasmic immunoreactivity in the anterior lobe, moderate levels in the posterior lobe, and a few cells showing nuclear staining in the intermediate lobe. In contrast, the intermediate lobe of the pituitary showed intense cytoplasmic staining for TGF-beta1. Nuclear and cytoplasmic staining for DENTT was present in the islets of Langerhans in the pancreas. Cytoplasmic staining for DENTT was particularly intense in the cortex of the adrenal gland, whereas the medulla showed weak nuclear staining. In the nervous system, the choroid plexus showed the highest immunoreactivity, with cortical motoneurons and Purkinje cells having relatively high levels of staining for DENTT as well. DENTT immunoreactivity was found in Leydig interstitial cells, Sertoli cells, and primary spermatocytes in the testis. In the female reproductive system, DENTT immunoreactivity was present in oocytes, thecal cells, and corpora lutea. The bronchial epithelium of the lung showed moderate levels of staining for DENTT localized to the cell nucleus. Additionally, three rodent pituitary cell lines (AtT20, GH3, and alphaT3-1, representing corticotropes, lactotropes, and gonadotropes, respectively) showed expression of DENTT. Addition of TGF-beta1 or serum to AtT20 cells increased DENTT protein production by 4 hr and, after reaching maximal levels at 2.4-fold above basal level by 8 hr, decreased, whereas no more than a 1.5-fold increase in DENTT protein occurred in GH3 or alphaT3-1 cells. Transient transfection studies showed that ectopic DENTT expression significantly increased the level of p3TP-Lux reporter transcription in AtT20 cells, but not in GH3 or alphaT3-1 cells. Interestingly, addition of TGF-beta1 had no significant effect on the ability of DENTT expression to influence p3TP-Lux reporter transcription in AtT20 cells. This report is the first detailed immunohistochemical examination of a member of the TTSN superfamily in the adult mouse. Expression of DENTT in endocrine tissues, nervous system, lung, oocytes, and thecal cells, in addition to the testis, suggests new roles for the TTSN superfamily. The differential patterns of expression of DENTT and TGF-beta1 in some tissues, including the pituitary, suggest that other factors are likely to be regulators of DENTT besides TGF-beta1. Published 2002 Wiley-Liss, Inc.(dagger). C1 NCI, Cell & Canc Biol Branch, Rockville, MD 20850 USA. RP Jakowlew, SB (reprint author), NCI, Cell & Canc Biol Branch, 9610 Med Ctr Drive,Suite 300, Rockville, MD 20850 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 49 TC 9 Z9 12 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUN PY 2002 VL 224 IS 2 BP 186 EP 199 DI 10.1002/dvdy.10096 PG 14 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 558KC UT WOS:000175964000006 PM 12112471 ER PT J AU Saeki, K Zhu, M Kubosaki, A Xie, JP Lan, MS Notkins, AL AF Saeki, K Zhu, M Kubosaki, A Xie, JP Lan, MS Notkins, AL TI Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion SO DIABETES LA English DT Article ID DEPENDENT DIABETES-MELLITUS; PANCREATIC BETA-CELLS; TRANSMEMBRANE PROTEIN; GENOMIC STRUCTURE; MEMBRANE-PROTEIN; AUTOANTIGEN; AUTOANTIBODIES; PREDICTION; ICA512; PHOSPHORYLATION AB IA-2 is a major autoantigen in type 1 diabetes. Autoantibodies to IA-2 appear years before the development of clinical disease and are being widely used as predictive markers to identify individuals at risk for developing type 1 diabetes. IA-2 is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is an integral component of secretory granules in neuroendocrine cells. To study its function, we generated IA-2-deficient mice. Northern and Western blot analysis showed that neither IA-2 mRNA nor protein was expressed. Physical examination of the IA-2 'animals and histological examination of tissues failed to reveal any abnormalities. Nonfasting blood glucose levels, measured over 6 months, were slightly elevated in male IA-2(-/-) as compared to I-A-2(+/+) littermates, but remained within the nondiabetic range. Glucose tolerance tests, however, revealed statistically significant elevation of glucose in both male and female IA-2(-/-) mice and depressed insulin release. In vitro glucose stimulation of isolated islets showed that male and female mice carrying the disrupted gene released 48% (P < 0.001) and 42% (P < 0.01) less insulin, respectively, than mice carrying the wild-type gene. We concluded that IA-2 is involved in glucose-stimulated insulin secretion. C1 Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Res Inst Children, New Orleans, LA USA. Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA USA. Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bldg 30,Room 121,30 Convent Dr,MSC 4322, Bethesda, MD 20892 USA. NR 33 TC 81 Z9 85 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2002 VL 51 IS 6 BP 1842 EP 1850 DI 10.2337/diabetes.51.6.1842 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557YM UT WOS:000175936700023 PM 12031972 ER PT J AU Stefan, N Vozarova, B Funahashi, T Matsuzawa, Y Weyer, C Lindsay, RS Youngren, JF Havel, PJ Pratley, RE Bogardus, C Tataranni, PA AF Stefan, N Vozarova, B Funahashi, T Matsuzawa, Y Weyer, C Lindsay, RS Youngren, JF Havel, PJ Pratley, RE Bogardus, C Tataranni, PA TI Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans SO DIABETES LA English DT Article ID DEPENDENT DIABETES-MELLITUS; ADIPOSE-SPECIFIC PROTEIN; X-RAY ABSORPTIOMETRY; PIMA-INDIANS; RESISTANCE; OBESITY; KINASE; HYPERINSULINEMIA; ALPHA AB Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Osaka, Japan. Univ Calif San Francisco, Mt Zion Med Ctr, Dept Med, Div Diabet & Endocrine Res, San Francisco, CA 94120 USA. Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. RP Stefan, N (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Rm 5-41, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 30 TC 352 Z9 374 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2002 VL 51 IS 6 BP 1884 EP 1888 DI 10.2337/diabetes.51.6.1884 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557YM UT WOS:000175936700028 PM 12031977 ER PT J AU Vozarova, B Stefan, N Lindsay, RS Saremi, A Pratley, RE Bogardus, C Tataranni, PA AF Vozarova, B Stefan, N Lindsay, RS Saremi, A Pratley, RE Bogardus, C Tataranni, PA TI High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes SO DIABETES LA English DT Article ID FATTY LIVER-DISEASE; C VIRUS-INFECTION; PIMA-INDIANS; RISK-FACTORS; MELLITUS; RESISTANCE; POPULATION; NIDDM; OBESE; MICE AB It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. The aim of the present study was to examine whether elevated hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma-glutamyltranspeptidase [GGT]) are associated with prospective changes in liver or whole-body insulin sensitivity and/or insulin secretion and whether these elevated enzymes predict the development of type 2 diabetes in Pima Indians. We measured ALT, AST, and GGT in 451 nondiabetic (75-g oral glucose tolerance test) Pima Indians (aged 30 +/- 6 years, body fat 33 +/- 8%, ALT 45 +/- 29 units/l, AST 34 +/- 18 units/l, and GGT 56 +/- 40 units/l [mean +/- SD]) who were characterized for body composition (hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (H), and hepatic insulin sensitivity (hepatic glucose output [HGO] during the low-dose insulin infusion of a hyperinsulinemic clamp) and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 +/- 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r = 0.16, 0.17, and 0.11, respectively), M (r = -0.32, -0.28, and -0.24), and HGO (r = 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P = 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r = 0.21, P = 0.001) but not with changes in M or AIR (both P = 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Vozarova, B (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Rm 5-41, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 28 TC 322 Z9 337 U1 1 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2002 VL 51 IS 6 BP 1889 EP 1895 DI 10.2337/diabetes.51.6.1889 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557YM UT WOS:000175936700029 PM 12031978 ER PT J AU Schaefer, EJ McNamara, JR Shah, PK Nakajima, K Cupples, LA Ordovas, JM Wilson, PWF AF Schaefer, EJ McNamara, JR Shah, PK Nakajima, K Cupples, LA Ordovas, JM Wilson, PWF TI Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study SO DIABETES CARE LA English DT Article ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; HEART-DISEASE; RISK-FACTOR; EVENTS; PLASMA; TRIAL; DYSLIPIDEMIA; GEMFIBROZIL; PREVENTION AB OBJECTIVE - Remnants of triglyceride-rich lipoproteins are thought to be atherogenic. A new antibody-based assay allows for the isolation of remnant-like particles (RLPs) from plasma or serum, and the subsequent measurement of RLP cholesterol (RLPC) and triglycerides (RLPTGs). We hypothesized that diabetic patients would have higher remnant levels than nondiabetic patients. DESIGN AND METHODS - We compared RLPC and RLPTG levels of diabetic subjects (68 women, 121 men) participating in the Framingham Heart Study with those of nondiabetic subjects (1,499 women, 1,357 men). RESULTS - Mean RLPC values for diabetic women were 106% higher than those for nondiabetic women (0.367 +/- 0.546 mmol/l [14.2 +/- 21.1 mg/dl] vs. 0.179 +/- 0.1.09 mmol/l 16.9 +/- 14.2 mg/dl]; P < 0.0001), and RLPTG values for diabetic women were 385% higher than those for nondiabetic women (1.089 +/- 2.775 mmol/l [93.1 +/- 245.6 mg/dl] vs. 0.217 +/- 0.235 mmol/l [19.2 +/- 20.8 mg/dl]; P < 0.0001). Similar but less striking differences were observed in diabetic men, who had mean RLPC values 28% higher than those seen in nondiabetic men (0.285 +/- 0.261 mmol/l [11.0 +/- 10.1 mg/dl] vs. 0.223 +/- 0.163 mmol/l [8.6 +/- 6.3 mg/dl]; P < 0.001) and mean RLPTG values 70% higher than those seen in nondiabetic men (0.606 +/- 1.019 mmol/l [53.6 +/- 90.2 mg/dl] vs. 0.357 +/- 0.546 mmol/l [31.6 +/- 48.3 mg/dl] P < 0.001). Moreover, diabetic men and women had significantly higher total triglycerides and lower HDL cholesterol levels than nondiabetic subjects. CONCLUSIONS - The data indicate that RLP particles are elevated in diabetic subjects. To achieve optimal reduction of risk for cardiovascular disease, treatment of elevated RLP values, along with the control of LDL cholesterol levels, should be considered. C1 Tufts Univ New England Med Ctr, Lipid Res Lab, Div Endocrinol Diabet Metab & Mol Med, Boston, MA 02111 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. Otsuka Amer Pharmaceut Inc, Rockville, MD USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. RP Schaefer, EJ (reprint author), Tufts Univ New England Med Ctr, Lipid Res Lab, Div Endocrinol Diabet Metab & Mol Med, 750 Washington St,Box 216, Boston, MA 02111 USA. OI Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [N01-HC-38038] NR 25 TC 68 Z9 72 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2002 VL 25 IS 6 BP 989 EP 994 DI 10.2337/diacare.25.6.989 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 724TY UT WOS:000185503800008 PM 12032104 ER PT J AU Sambamurti, K Hardy, J Refolo, LM Lahiri, DK AF Sambamurti, K Hardy, J Refolo, LM Lahiri, DK TI Targeting APP metabolism for the treatment of Alzheimer's disease SO DRUG DEVELOPMENT RESEARCH LA English DT Review DE Alzheimer's disease; amyloid peptide; amyloid protein precursor; beta secretase; BACE; site APP cleaving enzyme; statins; NSAIDS; CTF gamma; CTF epsilon; AICD; NICD ID AMYLOID PRECURSOR PROTEIN; ALPHA-SECRETASE CLEAVAGE; A-BETA PEPTIDE; INSULIN-DEGRADING ENZYME; TERMINAL FRAGMENT-GAMMA; TRANSGENIC MOUSE MODEL; NECROSIS-FACTOR-ALPHA; CONVERTING-ENZYME; INHIBITOR WORTMANNIN; EXTRACELLULAR LEVELS AB Senile plaques consisting largely of extracellular deposits of a 38-42 residue peptide, amyloid (3 protein (A(3) and intraneuronal deposits of the microtubule-associated protein, tau, as neurofibrillary tangles (NFT) are defining features of Alzheimer's disease (AD). Abeta is produced after cleavage of a larger A(3 protein precursor (APP) by beta-secretase to the secreted sAPP(3 and cell-associated CTFbeta followed by cleavage of CTFbeta by gamma-secretase to secreted Abeta and the cognate cytoplasmic fragment, CTFgamma. Most Abeta is 40 residues long, but a small fraction is 42-43 residues in length. A currently favored hypothesis is that Abeta42 forms toxic aggregates that induce NFT formation and ultimately the neuronal dysfunction characteristic of AD. Based on this hypothesis, the popular targets for drug development are the enzymes that generate or degrade Abeta42, block Abeta aggregation or toxicity and other factors that regulate these pathways in the brain. This article examines the evidence supporting the amyloid hypothesis and alternative hypotheses based on APP metabolism. In addition, the current drug targets for modifying APP metabolism to reduce Abeta42 are discussed. We further discuss evidence that suggests that other APP fragments such as CTFgamma are altered by tested familial AD mutations and their role in AD pathogenesis needs to be carefully examined. We conclude that it is important to develop drugs based on alternative APP fragments (i.e., CTFgamma) as well as the other identified pathways (i.e., oxidative stress) to provide alternatives if antiamyloid drugs fail to treat AD. (C) 2002 Wiley-Liss, inc. C1 Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. NIA, NIH, Bethesda, MD 20892 USA. Inst Study Aging, New York, NY USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46204 USA. RP Sambamurti, K (reprint author), Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. RI Hardy, John/C-2451-2009 NR 172 TC 12 Z9 13 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 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD JUN PY 2002 VL 56 IS 2 BP 211 EP 227 DI 10.1002/ddr.10077 PG 17 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 590QH UT WOS:000177833200018 ER PT J AU Kohn, MC Melnick, RL Ye, F Portier, CJ AF Kohn, MC Melnick, RL Ye, F Portier, CJ TI Pharmacokinetics of sodium nitrite-induced methemoglobinemia in the rat SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID OXYHEMOGLOBIN; OXIDATION; MODEL AB A biologically based mathematical model was created to characterize time and dose-dependent relationships between exposure to nitrite and induction of methemoglobinemia. The model includes mass action equations for processes known to occur: oral absorption of nitrite, elimination from the plasma, partitioning between plasma and erythrocytes, binding of nitrite to hemoglobin and methemoglobin, and the free radical chain reaction for hemoglobin oxidation. The model also includes Michaelis-Menten kinetics for methemoglobin reductase-catalyzed regeneration of hemoglobin. Body weight-scaled rate constants for absorption (k(a)) and elimination (k(e)), the effective erythrocyte/plasma partition coefficient (P), and the apparent K-m for methemoglobin reductase were the only parameters estimated by formal optimization to reproduce the observed time course data. Time courses of plasma nitrite concentrations and blood levels of hemoglobin and methemoglobin in male and female rats that had received single intravenous or oral doses of sodium nitrite were measured. Peak plasma levels of nitrite were achieved in both sexes approximately 30 min after oral exposure, and peak methemoglobin levels were achieved after 100 min. The model predicts that 10% of the hemoglobin is oxidized to the ferric form after oral doses of 15.9 mg/kg in male rats and 11.0 mg/kg in female rats and after intravenous doses of 8.9 and 7.1 mg/kg in male and female rats, respectively. The t(1/2) for recovery from methemoglobinemia was 60 to 120 min depending on dose and route of administration. A sensitivity analysis of the model was performed to identify to which parameters the predictions of the model were most sensitive and guide attempts to simplify the model. Replacement of the V-max of methemoglobin reductase with a value representative of humans predicted a 10% methemoglobinemia following an intravenous dose of 5.8 mg/kg, in close agreement with an observed value of 5.7 mg/kg for humans. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Kohn, MC (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233,MD A3-06, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 27 TC 46 Z9 50 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUN PY 2002 VL 30 IS 6 BP 676 EP 683 AR UNSP 639/984787 DI 10.1124/dmd.30.6.676 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 554LQ UT WOS:000175737400012 PM 12019195 ER PT J AU Yu, LR Johnson, MD Conrads, TP Smith, RD Morrison, RS Veenstra, TD AF Yu, LR Johnson, MD Conrads, TP Smith, RD Morrison, RS Veenstra, TD TI Proteome analysis of camptothecin-treated cortical neurons using isotope-coded affinity tags SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 12th Annual Frederick Conference on Capillary Electrophoresis CY OCT 15-16, 2001 CL NATL CANC INST FREDERICK CTR, FREDERICK, MARYLAND HO NATL CANC INST FREDERICK CTR DE camptothecin; cortical neurons; isotope-coded affinity tag; proteomics ID LIQUID-CHROMATOGRAPHY; GEL-ELECTROPHORESIS; MASS-SPECTROMETRY; YEAST PROTEOME; IDENTIFICATION; MODULATION; EXPRESSION; TECHNOLOGY; PROTEINS; GENOMES AB Isotope-coded affinity tags (ICATs) were employed to identify and quantitate changes in protein expression between control and camptothecin-treated mouse cortical neurons. Proteins extracted from control cortical neurons and those treated with camptothecin were labeled with the light and heavy isotopic versions of the ICAT reagents, respectively. ICAT-labeled samples were combined, proteolytically digested, and the derivatized peptides isolated using immobilized avidin chromatography. The peptides thus isolated were analyzed by reversed-phase liquid chromatography coupled directly to either a conventional ion-trap mass spectrometer (IT-MS) or a Fourier transform ion cyclotron resonance mass spectrometer (FTICR). While a majority of the peptide identifications were accomplished using IT-MS, FTICR was used to quantitate the relative abundances of the ICAT-labeled peptides taking advantage of its high resolution, sensitivity, and duty cycle. By using this combination of MS technologies we have thus far identified and quantified the expression of greater than 125 proteins from control and camptothecin-treated mouse cortical neurons. While proteins from most functional classes of proteins were identified, a particularly large percentage of the enzymes involved in glycolysis and the tricarboxylic acid cycle were observed. C1 NCI, SAIC Frederick, Frederick, MD 21702 USA. Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. Pacific NW Natl Lab, Richland, WA USA. RP Veenstra, TD (reprint author), NCI, SAIC Frederick, POB B, Frederick, MD 21702 USA. RI Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU NCI NIH HHS [N01-CO-12400] NR 25 TC 34 Z9 36 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2002 VL 23 IS 11 BP 1591 EP 1598 AR UNSP EL 4921 DI 10.1002/1522-2683(200206)23:11<1591::AID-ELPS1591>3.0.CO;2-# PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 566LM UT WOS:000176429600006 PM 12179976 ER PT J AU Janini, G Saptharishi, N Waselus, M Soman, G AF Janini, G Saptharishi, N Waselus, M Soman, G TI Element of a validation method for MU-B3 monoclonal antibody using an imaging capillary isoelectric focusing system SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 12th Annual Frederick Conference on Capillary Electrophoresis CY OCT 15-16, 2001 CL NATL CANC INST FREDERICK CTR, FREDERICK, MARYLAND HO NATL CANC INST FREDERICK CTR DE imaging capillary isoelectric focusing; monoclonal antibodies; MU-B3; proteins; validation ID B3 AB This paper presents an imaging capillary isoelectric focusing (CIEF) assay for the determination of the identity, stability, and isoform distribution of a murine monoclonal antibody (MU-B3). The experiments were conducted using a Convergent Bioscience iCE280 instrument. The optimum carrier ampholyte composition that gave the best peak separation was found to be 25% Pharmalyte pH 3-10 and 75% Pharmalyte pH 5-8. The antibody gave a highly reproducible CIEF profile with three major peaks having average isoelectric point (pl) values of 6.83, 6.99, and 7.11. Intraday and interday reproducibility of pl values was found to be within RSD of 0.5%. The CIEF profile was also the same, with an alternate column cartridge and alternate batches of methyl cellulose. A plot of peak areas versus MU-B3 concentration was linear (R-2 = 0.995) up to a concentration of 0.5 mg/mL in the sample solution. Peak area measurements were reproducible to within 7% RSD. The CIEF profiles of two other antibodies were distinctly different from the profile of MU-B3, showing that the assay is specific. After a sample of MU-B3 was subjected to heat stress by exposure to heat at 55degreesC for 4 h, its CIEF profile was altered with extra peaks appearing at lower pl values, indicating that the assay could be used to monitor stability. The result of the heat stress experiment was also confirmed with a parallel slab-gel IEF analysis of the antibody sample before,and after application of the heat stress. The results of this work suggest that imaging CIEF can be used for product testing under a quality control environment. The assay can be used for pl profiling of proteins and for monitoring structural changes (deamidation, glycosylation, etc.) during the manufacturing process and upon storage. C1 NCI, SAIC Frederick Inc, Analyt Chem Lab, Ft Detrick, MD 21702 USA. NCI, SAIC Frederick Inc, Biopharmaceut Dev Program, Ft Detrick, MD 21702 USA. RP Janini, G (reprint author), NCI, SAIC Frederick Inc, Analyt Chem Lab, POB B,Bldg 469,Room 155, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 19 TC 30 Z9 31 U1 1 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2002 VL 23 IS 11 BP 1605 EP 1611 AR UNSP EL 4922 DI 10.1002/1522-2683(200206)23:11<1605::AID-ELPS1605>3.0.CO;2-O PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 566LM UT WOS:000176429600008 PM 12179978 ER PT J AU Viard, M Blumenthal, R Raviv, Y AF Viard, M Blumenthal, R Raviv, Y TI Improved separation of integral membrane proteins by continuous elution electrophoresis with simultaneous detergent exchange: Application to the purification of the fusion protein of the human immunodeficiency virus type 1 SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 12th Annual Frederick Conference on Capillary Electrophoresis CY OCT 15-16, 2001 CL NATL CANC INST FREDERICK CTR, FREDERICK, MARYLAND HO NATL CANC INST FREDERICK CTR DE continuous elution; electrophoresis; gp4l; human immunodeficiency virus; membrane proteins ID POLYACRYLAMIDE GEL-ELECTROPHORESIS; IMMOBILIZED PH GRADIENTS; DODECYL-SULFATE; ENVELOPE GLYCOPROTEIN; 2-DIMENSIONAL ELECTROPHORESIS; NONIONIC SURFACTANT; ATOMIC-STRUCTURE; HIV-1 GP41; SOLUBILIZATION; ECTODOMAIN AB We describe a protocol for preparative-scale purification of the fusion protein of the human immunodeficiency virus type 1 (HIV-1), gp41, from cells overexpressing the viral envelope proteins and from HIV-1 isolates. In the first step, the proteins were extracted from the membrane in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SIDS-PAGE) sample buffer. The extract was then subjected to separation by continuous elution electrophoresis using a nonionic or zwitterionic detergent in the mobile elution buffer, which results in the simultaneous exchange of SIDS with that detergent. The separated proteins were obtained in an SIDS-free buffer containing either Brij, 3-[(3-chloramidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) or Triton X-100 and could then be subjected to subsequent purification steps like isoelectric focusing in the second dimension or immunoaffinity chromatography. The dilute protein fraction was concentrated and applied on a 10 mL immunoaffinity column packed with anti-gp41 monoclonal antibody immobilized on protein-G sepharose. The protein was eluted from the column at pH 2.7 and obtained in pure form in amounts of 30-50 mug that constituted a yield of 1%. The pure gp4l could not be sustained in solution in the absence of detergent and was not susceptible to proteolytic digestion by trypsin. The identification of the protein and the degree of purity was confirmed indirectly using surface enhanced laser desorption ionization-time of flight-mass spectrometry (SELDI-TOF-MS). The possible application of this approach for the isolation of integral membrane proteins with the propensity to undergo spontaneous folding and aggregation is being discussed. C1 NCI, Ctr Canc Res, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Intramural Res Support, Program SAIC, Frederick, MD USA. RP Raviv, Y (reprint author), NCI, Ctr Canc Res, Lab Expt & Computat Biol, Frederick Bldg 469,Rm 213,Miller Dr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 32 TC 8 Z9 9 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2002 VL 23 IS 11 BP 1659 EP 1666 DI 10.1002/1522-2683(200206)23:11<1659::AID-ELPS1659>3.0.CO;2-R PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 566LM UT WOS:000176429600015 PM 12179985 ER PT J AU Afshari, CA AF Afshari, CA TI Perspective: Microarray technology, seeing more than spots SO ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION PATTERNS; COMPLEMENTARY-DNA MICROARRAY; CDNA MICROARRAY; SACCHAROMYCES-CEREVISIAE; CANCER; HYBRIDIZATION; PROFILES; GENOME; IDENTIFICATION; CELLS C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Afshari, CA (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,MD2-04,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 87 TC 32 Z9 34 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2002 VL 143 IS 6 BP 1983 EP 1989 DI 10.1210/en.143.6.1983 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 553AR UT WOS:000175653800002 PM 12021158 ER PT J AU Hu, ZZ Zhuang, L Meng, J Tsai-Morris, CH Dufau, ML AF Hu, ZZ Zhuang, L Meng, J Tsai-Morris, CH Dufau, ML TI Complex 5 ' genomic structure of the human prolactin receptor: Multiple alternative exons 1 and promoter utilization SO ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION AB Transcription of the prolactin receptor (PRLR) is under the control of multiple promoters. Following the recent demonstration of the human non-coding exon 1, hE1(N) (hE1(N1)) and the generic exon 1 hE1(3), we have identified their promoters and characterized four other novel human exons 1 (hE1(N2-5)) that are alternatively spliced to a common non-coding exon 2 in human tissues and breast cancer cells. Genomic regions containing these exons, and F-flanking and intronic sequences, were determined and their order was established in chromosome 5p14-13. Promoters utilized in the transcription of previously characterized PRLR exons 1 species hE1(3) (hPIII) and hE1(N1) (hP(N1)) were found to employ distinct mechanisms for controlling hPRLR transcription. hPIII requires C/EBPbeta and Sp1/Sp3 for basal transcriptional activity, while hP(N1) activity is conferred by domains containing an Ets element and an NR half-site. The complex promoter control system that governs transcription of the hPRLR in multiple tissues is of relevance for studies on the regulation of PRLR expression in physiological and pathological states. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 17 TC 37 Z9 37 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2002 VL 143 IS 6 BP 2139 EP 2142 DI 10.1210/en.143.6.2139 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 553AR UT WOS:000175653800021 PM 12021177 ER PT J AU Naranjo, WM Yakar, S Sanchez-Gomez, M Perez, AU Setser, J LeRoith, D AF Naranjo, WM Yakar, S Sanchez-Gomez, M Perez, AU Setser, J LeRoith, D TI Protein calorie restriction affects nonhepatic IGF-1 production and the lymphoid system: Studies using the liver-specific IGF-1 gene-deleted mouse model SO ENDOCRINOLOGY LA English DT Article ID GROWTH-FACTOR-I; MESSENGER RIBONUCLEIC-ACIDS; HORMONE-RELEASING FACTOR; FACTOR-BINDING PROTEINS; INSULIN-LIKE ACTIONS; NUTRITIONAL REGULATION; DIFFERENTIAL REGULATION; FOOD-DEPRIVATION; GH SECRETION; AMINO-ACID AB Nutritional status is a critical factor that modulates the responsiveness of the liver to GH and the resulting production of endocrine (mostly liver-derived) IGF-I. Using a conditional Cre/lox P system, we have established a liver-specific IGF-I-deficient mouse model. Despite the reduction in the circulating IGF-I (75%), the growth parameters are normal, except for the reduced spleen size, providing a unique model to study the effect of protein restriction on the autocrine/paracrine GH IGF-I axis. To determine the effects of protein calorie malnutrition on the spleen, liver-specific IGF-I-deficient mice were assigned to one of four isocaloric diets, differing in the protein content (20,12, 4, and 0%), for a period of 10 d. A low protein intake decreased the nonhepatic IGF-I secretion into the circulation, whereas it caused an increase in the level of circulating GH. This supports the view that nonhepatic IGF-I production contributes to circulating IGF-I levels. The lack of dietary protein led to an up-regulation of GH and IGF-l receptors expression in the spleen, whereas the IGF-I mRNA remained unchanged, as was demonstrated by flow cytometry and ribonuclease protection assay. B lymphocytes seem to be responsible for the up-regulated GH/IGF-I receptor expression. Northern blot analysis showed an up-regulation of IGF-binding protein-3 mRNA levels, which suggests that the protein deprivation may lead to an increased sequestration of circulating or locally synthesized IGF-I. These results support the hypothesis that the splenic GH/IGF-I axis responds to the nutritional stress caused by a low protein intake, to maintain the tissue homeostasis. C1 Natl Inst Diabetes & Digest & Kidney Dis, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Nacl Colombia, Dept Chem, Bogota, Colombia. RP Natl Inst Diabetes & Digest & Kidney Dis, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM derek@helix.nih.gov NR 48 TC 19 Z9 21 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2002 VL 143 IS 6 BP 2233 EP 2241 DI 10.1210/en.143.6.2233 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 553AR UT WOS:000175653800031 PM 12021187 ER PT J AU Mueller, SO Clark, JA Myers, PH Korach, KS AF Mueller, SO Clark, JA Myers, PH Korach, KS TI Mammary gland development in adult mice requires epithelial and stromal estrogen receptor alpha SO ENDOCRINOLOGY LA English DT Article ID WILD-TYPE MICE; MOUSE UTERUS; KNOCK-OUT; IN-VITRO; ER-ALPHA; FAT PAD; GROWTH; BETA; DISRUPTION; ONTOGENY AB Complete mammary gland development takes place following puberty and depends on the estrogen receptor (ER)alpha and the progesterone receptor (PR) and is tightly regulated by the interaction of the mammary epithelium with the stromal compartment. Studies using mammary tissues of immature mice have indicated that stromal but not epithelial ERalpha is required for mammary gland growth. This study investigates whether these same tissue growth requirements of neonate tissue are necessary for mammary development and response in adult mice. Mammary epithelial cells were isolated from adult mice with a targeted disruption of the ERalpha gene (alphaERKO) or from wild-type counterparts and injected into epithelial-free mammary fat pads of 3-wk-old female aERKO or wild-type mice. Ten weeks after cell injection, analysis of mammary gland whole mounts showed that both stromal and epithelial ERalpha were required for complete mammary gland development in adult mice. However, when the mice were treated with high doses of estradiol (E2) and progesterone, stromal ERalpha was sufficient to generate full mammary gland growth. Surprisingly, ERalpha-deficient epithelial cells were able to proliferate and develop into a rudimentary mammary ductal structure in an ERalpha-negative stroma, indicating that neither stromal nor epithelial ERalpha are required for the mammary rudiment to form in the adult mouse, as confirmed by the phenotype of the alphaERKO mammary gland. Use of this in vivo model system has demonstrated that neonatal and adult mammary tissues use a different tissue-specific role for ERalpha in mammary response. Immunostaining for ERalpha and PR in the mammary outgrowths supported the view that both stromal and epithelial ERalpha, in cooperation with epithelial PR, govern mammary gland development in adult mice. C1 Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Comparat Med Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, MD B3-02,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 35 TC 115 Z9 120 U1 0 U2 4 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2002 VL 143 IS 6 BP 2357 EP 2365 DI 10.1210/en.143.6.2357 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 553AR UT WOS:000175653800045 PM 12021201 ER PT J AU Suk, WA AF Suk, WA TI Beyond The Bangkok Statement: Research needs to address environmental threats to children's health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID CHILDHOOD ASTHMA; SINGAPORE; PREVALENCE; POLLUTION; HUMANS; TAIWAN; WATER C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Suk, WA (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 26 TC 6 Z9 8 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2002 VL 110 IS 6 BP A284 EP A286 DI 10.1289/ehp.110-a284 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 561HV UT WOS:000176134900001 PM 12055055 ER PT J AU Schmidt, D Rogawski, MA AF Schmidt, D Rogawski, MA TI New strategies for the identification of drugs to prevent the development or progression of epilepsy SO EPILEPSY RESEARCH LA English DT Article; Proceedings Paper CT Workshop on New Horizons in the Development of Antiepileptic Drugs CY NOV 28-29, 2001 CL PHILADELPHIA, PENNSYLVANIA DE epilepsy; antiepileptic drug; antiepileptogenic; progression; prevention; drug-resistance; kindling; drug development; maximal electroshock; pentylenetetrazole ID ANTIEPILEPTIC DRUGS; SEIZURE; DISCONTINUATION; METAANALYSIS AB During the last decade, several new antiepileptic drugs (AEDs) have been introduced in Europe, the United States, or other parts of the world. Although the antiepileptic efficacy of these drugs is not superior to that of older AEDs, some of the new drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential with other drugs. However, the new AEDs have only a modest impact on patients with refractory epilepsies, so that about one third of patients with epilepsy continue to have seizures with current pharmacotherapies. Thus, there is a continuing need for new medical therapies in epilepsy. During the Workshop on "New Horizons in the Development of Antiepileptic Drugs" (November 28-29, 2001, Philadelphia, PA), one topic dealt with the critical re-evaluation of previous preclinical strategies for the discovery and the development of new AEDs. The discussion of this session, which was chaired by the authors, is summarized in this article. Main issues of the discussion were whether epilepsy is a progressive disease and whether refractory epilepsy is preventable, the use of acute versus chronic animal models in the discovery and development of new AEDs, models for drug-resistant epilepsy, mechanisms of drug resistance, alterations in adverse effect potential of AEDs by epilepsy, and advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy. Overall, it was felt that the current preclinical strategies for the discovery and development of new AEDs have to be redefined in order to identify agents that are clearly superior to current medications. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Epilepsy Res Grp, D-14163 Berlin, Germany. NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Schmidt, D (reprint author), Epilepsy Res Grp, Goethestr 5, D-14163 Berlin, Germany. NR 18 TC 52 Z9 53 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD JUN PY 2002 VL 50 IS 1-2 BP 71 EP 78 AR PII S0920-1211(02)00070-0 DI 10.1016/S0920-1211(02)00070-0 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 592LU UT WOS:000177939800009 PM 12151119 ER PT J AU da Silva, FL Post, RM AF da Silva, FL Post, RM TI Evaluation and prediction of effects of antiepileptic drugs in a variety of other CNS disorders SO EPILEPSY RESEARCH LA English DT Article; Proceedings Paper CT Workshop on New Horizons in the Development of Antiepileptic Drugs CY NOV 28-29, 2001 CL PHILADELPHIA, PENNSYLVANIA DE antiepileptic drugs; bipolar disorders; kindling; pain; depression AB The putative value of antiepileptic drugs for the treatment of neurological and psychiatric disorders besides epilepsy was discussed at the Workshop, with special emphasis on the following conditions: painful peripheral neuropathies (e.g. carbamazepine, oxcarbazepine, gabapentin, lamotrigine); bipolar disorders (e.g. valproate, carbazepine, lamotrigine), strategies for developing new drugs based on pathophysiological mechanisms that may be similar in epilepsy and in recurrent mood disorders were analysed. The precise mechanisms of antiepileptic drug actions linked to differential efficacy in specific epilepsy syndromes were discussed in the light of molecular processes involved in different forms of epileptogenesis. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Amsterdam, Inst Neurobiol, NL-1098 Amsterdam, Netherlands. NIMH, Bethesda, MD 20892 USA. RP da Silva, FL (reprint author), Univ Amsterdam, Inst Neurobiol, Kruislaan 320, NL-1098 Amsterdam, Netherlands. NR 2 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD JUN PY 2002 VL 50 IS 1-2 BP 191 EP 193 AR PII S0920-1211(02)00079-7 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 592LU UT WOS:000177939800018 ER PT J AU Post, RM AF Post, RM TI Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms? SO EPILEPSY RESEARCH LA English DT Article; Proceedings Paper CT Workshop on New Horizons in the Development of Antiepileptic Drugs CY NOV 28-29, 2001 CL PHILADELPHIA, PENNSYLVANIA DE depression; mania; bipolar illness; seizures; anticonvulsants; gene expression ID THYROTROPIN-RELEASING-HORMONE; STRESSFUL LIFE EVENTS; FOS MESSENGER-RNA; CONTINGENT TOLERANCE; BIPOLAR DISORDER; AFFECTIVE-ILLNESS; ELECTRICAL STIMULATION; SPONTANEOUS SEIZURES; WITHDRAWAL SEIZURES; PREVIOUS EPISODES AB Kindling, in the classical sense, involves progressively increasing responsivity to the intermittent repetition of the same 1-s subthreshold electrical stimulation over time, with the amygdala being the area most frequently Studied. Such repeated subthreshold stimulation is associated with: lowering of the after-discharge (AD) threshold; lengthening and spread of the AD; marked seizure stage progression culminating in full-blown tonic-clonic forelimb convulsions with rearing and failing; and evolution from triggered to spontaneous seizures. This evolving process concomitantly involves changes in the spatio-temporal expression of immediate early genes (IEGs), neurotrophic factors, and late effector genes (LEGs), and an associated changing pattern of effectiveness of different pharmacological interventions. Since seizures are the paradigmatic behavioral manifestation of kindling, some types of pharmacological seizures, such as those induced by the local anesthetics cocaine and lidocaine, and some epileptic syndromes, are most likely homologously modeled by kindling. However, since non-epileptiform syndromes, such as recurrent episodes of affective illness and some pain syndromes possess non-homogenous elements of kindling-like evolution, some of the principles involved in kindling progression may, nonetheless, be pertinent to the understanding and treatment of these syndromes. For example, one could attempt to distinguish between the genes involved in the primary pathological processes of syndrome evolution versus those that are secondary and adaptive; such a differentiation could have important implications for the development of therapeutic approaches targeted to suppressing or enhancing these alterations, respectively. In these instances, inferences drawn from the kindling model are necessarily indirect and circumscribed because different neuroanatomical and biochemical processes are likely involved in the evolution of each neuropsychiatric syndrome. Given these recognized limitations of non-homologous models, kindling may still provide insights into the longitudinal course, progression, and treatment of some neuropsychiatric syndromes that can then be directly tested in the clinic. Published by Elsevier Science B.V. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH Bldg 10,Room 3S239,10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. NR 66 TC 36 Z9 36 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD JUN PY 2002 VL 50 IS 1-2 BP 203 EP 219 AR PII S0920-1211(02)00081-5 DI 10.1016/S0920-1211(02)00081-5 PG 17 WC Clinical Neurology SC Neurosciences & Neurology GA 592LU UT WOS:000177939800020 PM 12151130 ER PT J AU Chung, SY Karos, M Chang, YC Lukszo, J Wickes, BL Kwon-Chung, KJ AF Chung, SY Karos, M Chang, YC Lukszo, J Wickes, BL Kwon-Chung, KJ TI Molecular analysis of CPR alpha, a MAT alpha-specific pheromone receptor gene of Cryptococcus neoformans SO EUKARYOTIC CELL LA English DT Article ID CAPSULE-ASSOCIATED GENE; SACCHAROMYCES-CEREVISIAE; FILAMENTOUS GROWTH; PEPTIDE PHEROMONE; USTILAGO-MAYDIS; TUBE FORMATION; STE12 HOMOLOG; VIRULENCE; LOCUS; YEAST AB The putative Cryptococcus neoformans pheromone receptor gene CPRalpha was isolated and studied for its role in mating and filamentation. CPRalpha is MATalpha specific and located adjacent to STE12alpha at the MATalpha locus. It encodes a protein which possesses high sequence similarity to the seven-transmembrane class of G-protein-coupled pheromone receptors reported for other basidiomycetous fungi. Strains containing a deletion of the CPRalpha gene exhibited drastic reductions in mating efficiency but were not completely sterile. Deltacpralpha cells displayed wild-type mating efficiency when reconstituted with the wild-type CPRalpha gene. Hyphal production on filament agar was not affected in the Deltacpralpha strain, indicating no significant role for CPRa in sensing environmental cues during haploid fruiting. The wild-type MATalpha CPRalpha strain produced abundant hyphae in response to synthetic MATa pheromone; however, the hyphal response to pheromone by Deltacpralpha cells was significantly reduced. Exposure of wild-type cells to synthetic MATa pheromone for 2 h induced MFalpha pheromone expression, whereas unexposed cells showed only basal levels of the MFalpha transcript. The Deltacpralpha cells, however, exhibited only basal levels of MFalpha message with or without pheromone exposure, suggesting that CPRalpha and MFalpha are components of the same signaling pathway. C1 NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. Univ Texas, Ctr Hlth, Dept Microbiol, San Antonio, TX 78284 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bldg 10,11C304, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R29AI43522, R29 AI043522] NR 45 TC 35 Z9 35 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD JUN PY 2002 VL 1 IS 3 BP 432 EP 439 DI 10.1128/EC.1.3.432-439.2002 PG 8 WC Microbiology; Mycology SC Microbiology; Mycology GA 606HV UT WOS:000178729300011 PM 12455991 ER PT J AU Ji, BT Dai, Q Gao, YT Hsing, AW McLaughlin, JK Fraumeni, JF Chow, WH AF Ji, BT Dai, Q Gao, YT Hsing, AW McLaughlin, JK Fraumeni, JF Chow, WH TI Cigarette and alcohol consumption and the risk of colorectal cancer in Shanghai, China SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE colorectal cancer; tobacco smoking and alcohol; case-control study; Shanghai ID COLON-CANCER; UNITED-STATES; TOBACCO SMOKING; ADENOMA; MEN; COHORT; RECTUM; MORTALITY; HEALTH; WOMEN AB The relation of cigarette smoking and alcohol drinking to colorectal cancer risk has been inconsistent in the epidemiological literature. In a population-based case-control study of colorectal cancer in Shanghai, China, where the incidence rates are rising sharply, we examined the association with tobacco and alcohol use. Cases were aged 30-74 years and newly diagnosed with cancers of the colon (N = 931) or rectum (N = 874) between 1990 and 1992. Controls (N = 1552) were randomly selected among Shanghai residents, frequency-matched to cases by gender and age. Information on lifetime consumption of tobacco and alcohol, as well as demographic and other risk factors, was obtained through in-person interviews. Associations with cigarette smoking and alcohol use were estimated by odds ratios (ORs) and 95% confidence intervals (CIs). Among women, the prevalence of smoking and alcohol drinking was low, and no significant association with colon or rectal cancer was observed. Although cigarette smoking among men was not related overall to colon or rectal cancer risk, there was a 50% excess risk of rectal cancer (OR 1.5, 95% CI 0.9-2.5) among those who smoked 55 or more pack-years. Among men, former alcohol drinkers had an increased risk of colon cancer (OR 2.3, 95% CI 1.4-3.7) but not rectal cancer, while current drinkers had a 30-50% excess risk of colon cancer only among those with long-term (30+ years) and heavy (>560 g ethanol/week) consumption. The excess risks were mainly associated with hard liquor consumption, with no material difference in risk between proximal and distal colon cancer. Although cigarette smoking and alcohol drinking in general were not risk factors for colorectal cancers in Shanghai, there were small excess risks for rectal cancer among heavy smokers and colon cancer among heavy drinkers. (C) 2002 Lippincott Williams Wilkins. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Int Epidemiol Inst, Rockville, MD USA. RP Ji, BT (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8120, Bethesda, MD 20852 USA. NR 45 TC 27 Z9 27 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUN PY 2002 VL 11 IS 3 BP 237 EP 244 DI 10.1097/00008469-200206000-00007 PG 8 WC Oncology SC Oncology GA 578PW UT WOS:000177127800007 PM 12131657 ER PT J AU Bhandoola, A Bosselut, R Yu, Q Cowan, ML Feigenbaum, L Love, PE Singer, A AF Bhandoola, A Bosselut, R Yu, Q Cowan, ML Feigenbaum, L Love, PE Singer, A TI CD5-mediated inhibition of TCR signaling during intrathymic selection and development does not require the CD5 extracellular domain SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD5; CD5 ligand; negative regulation; transgenic mouse; TCR signaling ID T-CELL DEVELOPMENT; ALPHA-BETA-TCR; POSITIVE SELECTION; TRANSGENIC MICE; SURFACE LIGAND; RECEPTOR; ANTIBODIES; RESPONSES; IDENTIFICATION; TRANSDUCTION AB CD5 functions as a negative regulator of TCR signaling during intrathymic T cell development, but it is not known if this negative regulatory function requires CD5 engagement of an extracellular ligand. The present study has specifically examined the role of the CD5 extracellular domain in T cell development by introducing into CD5(-/-) mice a chimeric CD5 molecule in which the extracellular domain of CD5 is replaced with the extracellular domain of human IL-2R p55 (Tac) for which no ligand exists in the mouse. We now report that CD5 mediated down-regulation of TCR signaling during thymocyte development does not require the CD5 extracellular domain and, consequently, does not involve CD5 binding of an extracellular ligand in the thymus. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 30 TC 28 Z9 28 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2002 VL 32 IS 6 BP 1811 EP 1817 DI 10.1002/1521-4141(200206)32:6<1811::AID-IMMU1811>3.0.CO;2-G PG 7 WC Immunology SC Immunology GA 563RH UT WOS:000176269000033 PM 12115665 ER PT J AU Kashkin, VA Bagrov, AY Fedorova, OV Bagrov, YY Agalakova, NI Patkina, NA Zvartau, EE AF Kashkin, VA Bagrov, AY Fedorova, OV Bagrov, YY Agalakova, NI Patkina, NA Zvartau, EE TI Marinobufagenin (MBG) suppression of ethanol-seeking behavior is associated with inhibition of brain cortex Na/K-ATPase in mice SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE ethanol; self-administration; Na/K-ATPase; marinobufagenin; ouabain ID DIGITALIS-LIKE-FACTOR; IMMUNOREACTIVE FACTOR; DRUG-DEPENDENCE; OUABAIN; DEPRESSION; RATS; NA+,K+-ATPASE; HYPOTHALAMUS; HYPOTHESIS; COMPOUND AB In the present study the hypothesis was tested that sodium pump ligands (SPL) can modulate alcohol-seeking behavior and that this effect is related to changes in Na/K-ATPase activity in the central nervous system. Mice were tested for initiation of ethanol intravenous self-administration (IVSA) following i.p. pretreatment with vehicle or the endogenous SPL, marinobufagenin (MBG). Drug- and experimentally-naive mice acquired IVSA of 2% ethanol during a single 30-min session. MBG was found to dose-dependently attenuate (1.25-15 mug/kg) initiation of ethanol IVSA producing a decrease in the ratio and in the difference between operant responses of response-dependent and yoked animals as well as a decrease in percentage of mice demonstrating ethanol-seeking behavior. Attenuation of the reinforcing effect of ethanol resulting from MBG was associated with brain levels of this steroid capable of concurrently inhibiting Na/K-ATPase in the brain cortex. We hypothesize that endogenous digitalis-like factors could modulate the reinforcing effect of ethanol. (C) 2002 Elsevier Science B.V. All rights reserved. C1 IM Sechenov Evolutionary Physiol & Biochem Inst, Labs Membrane Barrier Funct & Pharmacol, St Petersburg 194223, Russia. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Zvartau, EE (reprint author), Pavlov Med Univ, Dept Psychopharmacol, Valdman Inst Pharmacol, 6-8 Lev Tolstoy St, St Petersburg 197089, Russia. OI Kashkin, Vladimir/0000-0002-7202-0233 NR 36 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD JUN PY 2002 VL 12 IS 3 BP 217 EP 223 AR PII S0924-977X(02)00026-3 DI 10.1016/S0924-977X(02)00026-3 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 558VK UT WOS:000175987300006 PM 12007673 ER PT J AU Chen, J Tekippe, M Astle, C Harrison, D AF Chen, J Tekippe, M Astle, C Harrison, D TI Trp53 null allele selectively expands hematopoietic progenitor and stem cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 8 BP 38 EP 38 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000008 ER PT J AU Purohit, S Klug, C Herrin, B Leonard, W AF Purohit, S Klug, C Herrin, B Leonard, W TI Graded levels of IL-7R expression in hematopoietic stem cells influence myeloid versus B cell developmental potential in vivo SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Univ Alabama, Birmingham, AL USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 16 BP 40 EP 40 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000016 ER PT J AU Orlic, D Cline, A Clevenger, R Chimenti, S Hoyt, R Anversa, P Bodine, D AF Orlic, D Cline, A Clevenger, R Chimenti, S Hoyt, R Anversa, P Bodine, D TI Hematopoietic stem cells regenerate myocardium in ischemia-induced heart disease: An experimental model SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD USA. New York Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 39 BP 46 EP 46 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000039 ER PT J AU Gurevich, R Pineault, N Antonchuk, J Aplan, P AF Gurevich, R Pineault, N Antonchuk, J Aplan, P TI The nucleoporin NUP98-topoisomerase I (NUP98-TOP1) fusion gene induces marked myelomonocytic proliferative abnormalities in murine hematopoietic cells in vitro and in vivo SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Terry Fox Lab, Toronto, ON, Canada. BC Canc Agcy Canada, Vancouver, BC, Canada. NCI, Bethesda, MD 20892 USA. RI Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 144 BP 72 EP 72 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000142 ER PT J AU Hoang, T Herblot, S Aplan, P AF Hoang, T Herblot, S Aplan, P TI Genetic interaction between SCL and E2A in lymphocyte development and in acute lymphoblastic leukemias SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RI Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 176 BP 80 EP 80 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000174 ER PT J AU Herblot, S Aplan, R Hoang, T AF Herblot, S Aplan, R Hoang, T TI Gradient of E2A activity in B cell development SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 252 BP 99 EP 99 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000250 ER PT J AU Chen, L Zhang, J Tang, D Fibach, E Shi, Y Rodgers, G AF Chen, L Zhang, J Tang, D Fibach, E Shi, Y Rodgers, G TI Comparison of gene expression patterns of erythroid and myeloid differentiation from human multipotential progenitor cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 324 BP 117 EP 117 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000320 ER PT J AU Chute, J Park, J Tanavde, V Harlan, D Civin, C AF Chute, J Park, J Tanavde, V Harlan, D Civin, C TI Co-culture with human brain endothelial cells differentially maintains human bone marrow SCID repopulating cells in vitro in the absence of exogenous cytokines SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NIDDK, Naval Med Res Ctr, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 383 BP 132 EP 132 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000379 ER PT J AU Liu, P Ortiz, M Tessarollo, L Nakamura, T Jenkins, N Copeland, N Keller, J AF Liu, P Ortiz, M Tessarollo, L Nakamura, T Jenkins, N Copeland, N Keller, J TI Evi9 is a zinc finger protein that is required for normal B and T cell development and may function as a T-Cell tumor suppressor SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, MCGP, Frederick, MD 21701 USA. NCI, IRSP, SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 426 BP 143 EP 143 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000421 ER PT J AU Suzuki, T Shen, H Akagi, K Liu, P Hisa, T Spence, S Du, D Morse, H Jenkins, N Copeland, N AF Suzuki, T Shen, H Akagi, K Liu, P Hisa, T Spence, S Du, D Morse, H Jenkins, N Copeland, N TI Leukemia disease genes: Prospects for high throughput gene function discovery in the post genome era SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, Mouse Canc Genet Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 431 BP 144 EP 144 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000426 ER PT J AU Koo, JS Kim, YD Jetten, AM Belloni, P Nettesheim, P AF Koo, JS Kim, YD Jetten, AM Belloni, P Nettesheim, P TI Overexpression of mucin genes induced by interleukin-1 beta, tumor necrosis factor-alpha, lipopolysaccharide, and neutrophil elastase is inhibited by a retinoic acid receptor alpha antagonist SO EXPERIMENTAL LUNG RESEARCH LA English DT Article DE bronchial epithelium; mucin; mucous hypersecretion; cytokine; interleukin-1 beta; retinoic acid receptor antagonist ID TRACHEOBRONCHIAL EPITHELIAL-CELLS; MESSENGER-RNA; EXPRESSION; IDENTIFICATION; CULTURES; AIRWAYS; REGION; GLYCOPROTEINS; ORGANIZATION; ACTIVATION AB Proinflammatory cytokines, lipopolysaccharide (LPS), and neutrophil elastase (NE) have been implicated in the induction of hypersecretion of respiratory mucus. In this study, we demonstrated that interleukin-1beta (IL-1beta) increased MUC2 and MUC5AC mRNA levels 2- to 3 fold in a time- and dose-dependent manner in NCI-H292 cells. In contrast, MUC5B mRNA was not significantly changed. A transcription inhibitor blocked the stimulation of MUC2 and MUC5AC gene expression by IL-1beta. A translation inhibitor did not interfere with the induction of MUC2 mRNA expression, whereas stimulation of MUC5AC mRNA was blocked, suggesting de novo protein synthesis is required for the stimulation of MUC5AC mRNA, We previously reported that induction of MUC2, MUC5AC, and MUC5B gene expressions by retinoic acid is mediated by the retinoic and receptor (RARalpha), and inhibited by the specific RARalpha antagonist Ro 41-5253. Here, we demonstrate that the RARalpha antagonist can effectively inhibit IL-1beta-induced MUC2 and MUC5AC gene expression and reduce intracellular MUC5AC protein. Further investigation showed that the RARalpha antagonist also inhibited the stimulation of MUC2 and MUC5AC mRNA expression by tumor necrosis factor-alpha, LPS, and NE. C1 Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. Roche Biosci, Resp Dis, Palo Alto, CA USA. RP Koo, JS (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd,Box 432, Houston, TX 77030 USA. OI Jetten, Anton/0000-0003-0954-4445 FU NIEHS NIH HHS [K22 ES003662-01] NR 40 TC 51 Z9 56 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0190-2148 J9 EXP LUNG RES JI Exp. Lung Res. PD JUN PY 2002 VL 28 IS 4 BP 315 EP 332 DI 10.1080/01902140252964393 PG 18 WC Respiratory System SC Respiratory System GA 556PK UT WOS:000175858000005 PM 12042033 ER PT J AU Truckenmiller, ME Vawter, MP Zhang, PS Conejero-Goldberg, C Dillon-Carter, O Morales, N Cheadle, C Becker, KG Freed, WJ AF Truckenmiller, ME Vawter, MP Zhang, PS Conejero-Goldberg, C Dillon-Carter, O Morales, N Cheadle, C Becker, KG Freed, WJ TI AF5, a CNS cell line immortalized with an N-terminal fragment of SV40 large T: Growth, differentiation, genetic stability and gene expression SO EXPERIMENTAL NEUROLOGY LA English DT Article DE SV40 large T; cell lines; immortalization; differentiation; microarray ID CENTRAL-NERVOUS-SYSTEM; NEURAL PRECURSOR CELLS; EMBRYONAL CARCINOMA-CELLS; SIMIAN-VIRUS-40 LARGE-T; LARGE TUMOR-ANTIGEN; STEM-CELLS; IN-VITRO; SV40-TRANSFORMED CELLS; REPLICATIVE SENESCENCE; NEUROBLASTOMA-CELLS AB Central nervous system progenitor cells that are self-renewing in culture and also differentiate under controlled conditions are potentially useful for developmental studies and for cell-based therapies. We characterized growth and plasticity properties and gene expression in a rat mesencephalic cell line, AF5, that was immortalized with an N-terminal fragment of SV40 large T (T155g). For over 150 population doublings in culture, the growth rate of AF5 cells remained steady, the cells remained responsive the bFGF, and telomerase activity and telomere lengths were unchanged. While karyotype analyses revealed some chromosomal abnormalities, these were also unchanged over time; additionally, no mutations in p53 gene sequences were found, and wild-type p53 activation was normal. AF5 cells produced PDGF, TGFbeta1, TFGbeta2, and bFGF. Similar to primary progenitor cells, AF5 cells retained in an undifferentiated state as "neurospheres" in serum-free media or as adherent cultures in serum-containing media, and they differentiated when allowed to become confluent. Adherent subconfluent actively growing cultures expressed a marker for immature neurons, nestin, while few cells expressed the mature neuron cell marker betaIII-tubulin. Confluent cultures ceased growing, developed differentiated morphologies, contained few or no nestin-expressing cells, and acquired was examined using a 15,000 gene microarray, comparing exponential growth with and without bFGF stimulation, and the differentiated state. The AF5 cell line exhibited stable genetic and growth properties over extended periods of time, while retaining the ability to differentiate in vitro. These data suggest that the AF5 cell line may be useful as an in vitro model system for studies of neural differentiation. (C) 2002 Elsevier Science (USA). C1 NIDA, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. NIA, DNA Array Unit, Res Resources Branch, Baltimore, MD 21224 USA. RP Truckenmiller, ME (reprint author), NIDA, Cellular Neurobiol Res Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 63 TC 23 Z9 24 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 318 EP 337 DI 10.1006/exnr.2002.7898 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600002 PM 12061863 ER PT J AU Cheng, GJ Yu, YF Zhou, DH Mattson, MP AF Cheng, GJ Yu, YF Zhou, DH Mattson, MP TI Phosphatidylinositol-3-kinase-Akt kinase and p42/p44 mitogen-activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Akt kinase; Alzheimer's disease; apoptosis; glutamate; GSK-3 beta; hippocampus; neurotrophic factor ID NF-KAPPA-B; MANGANESE SUPEROXIDE-DISMUTASE; NERVE GROWTH-FACTOR; CELL-LINE SH-SY5Y; HIPPOCAMPAL-NEURONS; SIGNALING PATHWAY; SYNAPTIC PLASTICITY; SYMPATHETIC NEURONS; ALZHEIMERS-DISEASE; INDUCED APOPTOSIS AB The alpha-secretase-derived form of the amyloid precursor protein (sAPPalpha), which is released from neurons in an activity-dependent manner, has been shown to promote long-term survival of hippocampal and cortical neurons in culture and can protect those neurons against excitotoxic and ischemic injury in culture and in vivo. The signal transduction pathway(s) activated by sAPPalpha has not been established. We now report that sAPPalpha activates the phosphatidylinositol-3-kinase (PI3K)-Akt kinase signaling pathway in cultured hippocampal neurons. sAPPalpha also stimulates phosphorylation of p42 (ERK1) and p44 (ERK2) mitogen-activated protein (MAP) kinases by a PI3K-independent pathway. Treatment of neurons with sAPPalpha protects them death induced by trophic factor deprivation and exposure to glutamate, and these survival-promoting effects of sAPPalpha are abolished or attenuated when either PI3K or p42/p44 MAP kinases are selectively blocked. Exposure of neurons to sAPPalpha resulted in a decrease in NF-kappaB and an increase in NF-kappaB DNA binding activity, both of which were blocked by wortmannin, suggesting that the transcription factor NF-kappaB may be a downstream target of the PI3K-Akt pathway that may play a role in the cell survival-promoting action of sAPPalpha. These findings suggest that the PI3K-Akt pathway and p42/p44 MAP kinases mediate responses of neurons to sAPPalpha in physiological and pathological settings, with implications for synaptic plasticity and the pathogenesis of Alzheimer's disease. (C) 2002 Elsevier Science (USA). C1 NIA, Ctr Gerontol Res, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Dept Internal Med, Lexington, KY 40536 USA. Univ Kentucky, Div Allergy Immunol & Rheumatol, Lexington, KY 40536 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Cheng, GJ (reprint author), NIA, Ctr Gerontol Res, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 54 TC 52 Z9 52 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 407 EP 414 DI 10.1006/exnr.2002.7920 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600009 PM 12061870 ER PT J AU Borlongan, CV Sumaya, I Moss, D Kumazaki, M Sakurai, T Hida, H Nishino, H AF Borlongan, CV Sumaya, I Moss, D Kumazaki, M Sakurai, T Hida, H Nishino, H TI Intracerebral transplantation of melatonin-secreting pineal gland protects against stroke-induced deficits in rats. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. Univ Texas, Dept Psychol, El Paso, TX 79968 USA. Nagoya City Univ, Sch Med, Dept Physiol, Nagoya, Aichi 467, Japan. 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 420 EP 421 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600031 ER PT J AU Hoffer, BJ Wang, Y Morales, M AF Hoffer, BJ Wang, Y Morales, M TI Chairman's introduction. Trophic factors and ischemic brain injury. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Natl Inst Drug Abuse, IRP, NIH, Baltimore, MD 21224 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 420 EP 420 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600030 ER PT J AU Chen, YI Sanchez-Pernaute, R Bjorklund, L Isacson, O Jenkins, BG AF Chen, YI Sanchez-Pernaute, R Bjorklund, L Isacson, O Jenkins, BG TI In vivo assessment of ES cells restoration of dopamine function using amphetamine and fMRL. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, McLean Hosp, Sch Med,Neuroregenerat Labs, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Dept Radiol, NMR Ctr, Charlestown, MA 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 422 EP 423 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600039 ER PT J AU Backman, C Hoffman, A Perlmann, T Hoffer, B AF Backman, C Hoffman, A Perlmann, T Hoffer, B TI Evaluation of nigrostriatal dopaminergic function in aged wild-type and heterozygous Nurr1 mutant mice after acute exposure to methamphetamine. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Karolinska Inst, Ludwig Inst Canc Res, S-17177 Stockholm, Sweden. NIDA, Cellular Neurobiol Dept, NIH, Baltimore, MD 21224 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 423 EP 424 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600043 ER PT J AU Bjorklund, LM Sonntag, KC Kim, KS Isacson, O AF Bjorklund, LM Sonntag, KC Kim, KS Isacson, O TI Time course of dopaminergic neuronal development from embryonic stem cells. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Neurogenet Lab, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 431 EP 431 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600066 ER PT J AU Freed, WJ Zhang, P Dillon-Carter, O Lehrmann, E Errico, S Truckenmiller, ME AF Freed, WJ Zhang, P Dillon-Carter, O Lehrmann, E Errico, S Truckenmiller, ME TI Basic FGF dependence of cell lines generated from the rat brain using the T155c oncogene. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 NIDA, Intramural Res Program, Baltimore, MD 21224 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 435 EP 435 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600079 ER PT J AU Zaman, V Granholm, AC Hoffer, B Tomac, A Gerhardt, G Middaugh, L Li, J AF Zaman, V Granholm, AC Hoffer, B Tomac, A Gerhardt, G Middaugh, L Li, J TI Morphology of substantia nigra of glial-cell-line-derived neurotrophic factor heterozygous mice: Age-related loss of dopamine neurons. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Univ Kentucky, Albert B Chandler Med Ctr, Dept Anat & Neurobiol, Lexington, KY 40536 USA. NIDA, Baltimore, MD 21224 USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 436 EP 436 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600082 ER PT J AU Chang, CF Wang, Y Chou, J Bickford, PC AF Chang, CF Wang, Y Chou, J Bickford, PC TI Diets rich in antioxidant phytochemicals reduce ischemic brain damage. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Univ S Florida, Ctr Aging & Brain Repair, Tampa, FL USA. NIDA, NIH, Baltimore, MD USA. RI Bickford, Paula/J-5970-2012 OI Bickford, Paula/0000-0001-9657-7725 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 437 EP 437 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600089 ER PT J AU Sanchez-Pernaute, R Bjorklund, LM Isacson, O AF Sanchez-Pernaute, R Bjorklund, LM Isacson, O TI Transplantation into 6-OHDA-lesioned rats: Rate of recovery of motor asymmetry corresponds to developmental rate of DA neurons of donor species SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, McLean Hosp, Sch Med,Udall Parkinsons Dis Res Ctr Excellence, Neuroregenerat Labs, Belmont, MA 02478 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 448 EP 448 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600134 ER PT J AU Chiang, YH Chen, SY Wang, JY Hoffer, BJ Wang, Y AF Chiang, YH Chen, SY Wang, JY Hoffer, BJ Wang, Y TI Interactions of BMP7 and MAPK in rat primary citrical culture. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 TriServ Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. NIDA, NIH, Baltimore, MD 21224 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 450 EP 450 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600141 ER PT J AU Camphausen, K Menard, C AF Camphausen, K Menard, C TI Angiogenesis inhibitors and radiotherapy of primary tumours SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE angiogenesis; angiostatin; endostatin; radiotherapy ID CYTOTOXIC CANCER THERAPIES; LEWIS-LUNG-CARCINOMA; IONIZING-RADIATION; MATRIX METALLOPROTEINASE-2; IN-VIVO; ANGIOSTATIN; ENDOSTATIN; POTENTIATION; CONCOMITANT; GENERATION AB The modern approach to cancer therapy involves combinations of surgery, radiation and drugs targeted against malignant tumour cells. However, expanding knowledge in the fields of angiogenesis and vascular biology over the last several years has led to the investigation of therapeutic strategies targeted to the vasculature (proliferating and non-proliferating endothelial cells) in combination with standard therapy. It is the objective of this review to describe the potential use of antiangiogenic therapy, targeted to the proliferating endothelium, from the point of view of the radiation oncologist. This review will describe the concept of a two-cell compartment model for tumours, with both the endothelial cells as well as the tumour cells being potential targets for radiotherapy. This review will then explore the promising evidence and rationale for combining antiangiogenic drugs and radiotherapy to enhance local control. C1 NCI, Imaging & Mol Therapeut Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Clin Canc Ctr,NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Imaging & Mol Therapeut Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Clin Canc Ctr,NIH, Bldg 10 B3B69, Bethesda, MD 20892 USA. NR 32 TC 15 Z9 16 U1 0 U2 2 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUN PY 2002 VL 2 IS 5 BP 477 EP 481 PG 5 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 566VV UT WOS:000176449700003 PM 12079484 ER PT J AU Wigginton, JM Wiltrout, RH AF Wigginton, JM Wiltrout, RH TI IL-12/IL-2 combination cytokine therapy for solid tumours: translation from bench to bedside SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE angiogenesis; apoptosis; cytokine; immunotherapy; tumour microenvironment ID CELL STIMULATORY FACTOR; NATURAL-KILLER-CELLS; RECOMBINANT HUMAN INTERLEUKIN-12; LYMPHOCYTE MATURATION FACTOR; INTERFERON-GAMMA PRODUCTION; PERIPHERAL-BLOOD LYMPHOCYTES; ACTIVATED PROTEIN-KINASE; CENTRAL-NERVOUS-SYSTEM; ANGIOGENESIS IN-VIVO; LUNG-CANCER PATIENTS AB A broad range of approaches are under active investigation for the biological therapy of cancer, in particular, strategies directed at host immune response potentiation. These efforts have been fuelled by studies demonstrating the presence of an endogenous, but ineffective, host antitumour immune response and a greater understanding of the key factors which regulate this response. These mechanisms involve complex interactions between various effector cell populations, soluble factors and the tumour itself and are determined by the timing and relative intensity of positive and negative autoregulatory pathways, as well as a variety of immunosuppressive effects capable of mediating tumour self-defence. Based on these observations, immunotherapeutic regimens have been developed to potentiate antigen-specific sensitisation of effector cells with tumour vaccines/adjuvants, expand and amplify the number and function of effector cells, and to counteract suppressive pathways engaged by tumour cells themselves. Significant effort has focused on evaluating the use of exogenous cytokines, administered either systemically or locally into the tumour site via gene therapy. Several cytokines have demonstrated unique activity in the preclinical setting, including IL-2 and IFN-gamma-inducing cytokines such as IL-12 and IL-18. Most notably, later studies have now attempted to build on the clinical efficacy of IL-2 alone, to define combinations of agents with synergistic immunoregulatory and/or antitumour efficacy. Several lines of evidence suggest that IL-12 and IL-2 provide complementary immunoregulatory signals and have now shown that in combination, these two cytokines mediate synergistic antitumour activity in preclinical tumour models. This paper will review existing data regarding mechanisms of interaction between IL-2 and IL-12 in vitro and in preclinial models and describe future opportunities for the investigation of these potentially promising cytokines; in the treatment of cancer. C1 NCI, Invest Biol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Wigginton, JM (reprint author), NCI, Invest Biol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-12400] NR 105 TC 33 Z9 40 U1 0 U2 4 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUN PY 2002 VL 2 IS 5 BP 513 EP 524 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 566VV UT WOS:000176449700006 PM 12079487 ER PT J AU Costouros, NG Libutti, SK AF Costouros, NG Libutti, SK TI Microarray technology and gene expression analysis for the study of angiogenesis SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE angiogenesis; gene expression profiling; microarray ID LASER-CAPTURE MICRODISSECTION; ENDOTHELIAL-CELLS; DNA MICROARRAY; INTERPRETING PATTERNS; OVARIAN-CANCER; BREAST-CANCER; PROFILES; CDNA; DIFFERENTIATION; AMPLIFICATION AB Angiogenesis plays a major role in multiple disease processes including cancer, and new agents that modulate angiogenesis are rapidly entering clinical trials. The understanding of the biological mechanisms and downstream effects for many of these agents is poorly understood. It is therefore important that methods evolve to understand how an agent regulates angiogenesis, in order to promote a higher percentage of successful drug candidates. With the emergence of microarray technology for the evaluation of gene expression, researchers have a powerful tool for dissecting the biological mechanisms of angiogenesis. However, huge data sets and complex statistics pose a hurdle for the investigator to obtain useful and meaningful data. To eliminate problems in data analysis, proper design and planning prior to performing a microarray experiment is crucial to making valid conclusions. This review will discuss the critical factors in designing, performing and analysing microarray experiments, and the utility of various models of angiogenesis for microarray analysis. C1 NIH, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), NIH, Bldg 10,Room 3C428, Bethesda, MD 20892 USA. NR 64 TC 5 Z9 5 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUN PY 2002 VL 2 IS 5 BP 545 EP 556 DI 10.1517/14712598.2.5.545 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 566VV UT WOS:000176449700009 PM 12079491 ER PT J AU Panelli, MC Wang, E Monsurro, V Marincola, FM AF Panelli, MC Wang, E Monsurro, V Marincola, FM TI The role of quantitative PCR for the immune monitoring of cancer patients SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE beta-actin; CD8; cytomegalovirus; Epstein-Barr virus; granulocyte-macrophage colony stimulating factor (GM-CSF); hepatitis B virus load; house-keeping gene; IFN-gamma; mRNA expression; quantitative real time PCR (qRT-PCR); systemic response; tumour antigen; tumour microenvironment ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; MESSENGER-RNA EXPRESSION; PULSED DENDRITIC CELLS; RT-PCR; METASTATIC MELANOMA; GENE-EXPRESSION; CYTOKINE EXPRESSION; FUNCTIONAL-ANALYSIS; T-LYMPHOCYTES AB Human tumour immunology is at a standstill whereas implemented cancer vaccines have shown effectiveness in inducing immune responses detectable in circulating lymphocytes. In most circumstances, however, such immune responses are not sufficient to induce cancer regression. This paradoxical observation could be explained in several ways depending upon the immunological endpoint used for immune monitoring. For instance, analysis of immune responses in circulating lymphocytes that address the presence of T cells bearing T-cell receptors specific for the epitope used for vaccination, can accurately enumerate the number of T cells elicited by the vaccines but does not yield information about their functional status. Other monitoring strategies may yield general information about the reactivity of various T cells in response to a relevant stimulus and, therefore, may provide information more relevant to the purpose of the immunisation. Furthermore, the material used to monitor immune responses may, in itself, determine the significance of the findings obtained. In the assessment of the therapeutic efficacy of specific cancer treatment, analysis of immune responses in circulating lymphocytes (systemic response) may not be as relevant as the analysis of the same effector populations within the tumour microenvironment (peripheral response). This review will describe a novel approach that allows extreme flexibility in the analysis of systemic and peripheral responses by accurately measuring the level of expression of relevant genes using quantitative real-time reverse transcriptase polymerase chain reaction. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Room 1C-711,Bldg 10, Bethesda, MD 20892 USA. NR 46 TC 8 Z9 12 U1 0 U2 1 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUN PY 2002 VL 2 IS 5 BP 557 EP 564 PG 8 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 566VV UT WOS:000176449700010 PM 12079490 ER PT J AU Wilting, J Papoutsi, M Christ, B Nicolaides, KH von Kaisenberg, CS Borges, J Stark, GB Alitalo, K Tomarev, SI Niemeyer, C Rossler, J AF Wilting, J Papoutsi, M Christ, B Nicolaides, KH von Kaisenberg, CS Borges, J Stark, GB Alitalo, K Tomarev, SI Niemeyer, C Rossler, J TI The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues SO FASEB JOURNAL LA English DT Article DE human fetus; lymphedema; lymphangioma; hemangioma; lymphangiogenesis ID GROWTH-FACTOR RECEPTOR-3; VASCULAR TUMORS; VEGF-C; EXPRESSION; BLOOD; GENE; LYMPHANGIOGENESIS; PROMOTES; ANTIGEN; SYSTEM AB Detection of lymphatic endothelal cells (LECs) has been problematic because of the lack of specific markers. The homeobox transcription factor Prox1 is expressed in LECs of murine and avian embryos. We have studied expression of Prox1 in human tissues with immunofluorescence. In 19-wk-old human fetuses, Prox1 and vascular endothelial growth factor receptor-3 (VEGFR-3) are coexpressed in LECs of lymphatic trunks and lymphatic capillaries. Prox1 is located in the nucleus, and its expression is mutually exclusive with that of the blood vascular marker PAL-E. Prox1 is a constitutive marker of LECs and is found in tissues of healthy adults and lymphedema patients. Blood vascular endothelial cells (BECs) of hemangiomas express CD31 and CD34, but not Prox1. A subset of these cells is positive for VEGFR-3. Lymphatics in the periphery of hemangiomas express Prox1 and CD31, but not CD34. In lymphangiomas, LECs express Prox1, CD31, and VEGFR-3, but rarely CD34. In the stroma, spindle-shaped CD34-positive cells are present. We show that Prox1 is a reliable marker for LECs in normal and pathologic human tissues, coexpressed with VEGFR-3 and CD31. VEGFR-3 and CD34 are less reliable markers for LECs and BECs, respectively, because exceptions from their normal expression patterns are found in pathologic tissues. C1 Univ Freiburg, Inst Anat, D-79104 Freiburg, Germany. Kings Coll Hosp London, Harris Birthright Res Ctr Fetal Med, London, England. Univ Kiel, Frauenklin, D-24105 Kiel, Germany. Univ Freiburg, Abt Plast & Handchirurg, D-79104 Freiburg, Germany. Univ Helsinki, Mol & Canc Biol Lab, FIN-00014 Helsinki, Finland. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Zentrum Kinderheilkunde & Jugendmed, D-79104 Freiburg, Germany. RP Wilting, J (reprint author), Univ Freiburg, Inst Anat, Albertstr 17, D-79104 Freiburg, Germany. EM Joerg.Wilting@anat.uni-freiburg.de RI Alitalo, Kari/J-5013-2014 OI Alitalo, Kari/0000-0002-7331-0902 NR 44 TC 99 Z9 107 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2002 VL 16 IS 8 BP 1271 EP + DI 10.1096/fj.01-1010fje PG 16 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 570WR UT WOS:000176683900038 PM 12060670 ER PT J AU Huang, STJ Cidlowski, JA AF Huang, STJ Cidlowski, JA TI Phosphorylation status modulates Bcl-2 function during glucocorticoid-induced apoptosis in T lymphocytes SO FASEB JOURNAL LA English DT Article DE Bcl-2 expression; glucocorticoids; cell shrinkage ID PERMEABILITY TRANSITION PORE; MITOTIC CHROMOSOMAL BCL-2; PROTEIN-KINASE; CELL-DEATH; DEPENDENT DEGRADATION; SIGNALING PATHWAY; FAMILY PROTEINS; CYTOCHROME-C; BAX; SUPPRESSION AB Glucocorticoids are known to induce apoptosis in lymphoid cells, and Bcl-2 overexpression can block the apoptosis-inducing action of glucocorticoids. Since phosphorylation of Bcl-2 is implicated in regulating Bcl-2 function, we considered the role of Bcl-2 phosphorylation in protecting lymphoid cells from glucocorticoid-induced cell death. Five stably transfected cell lines of WEHI 7.1 cells expressing either wild-type Bcl-2 or alanine mutants of Bcl-2 at amino acids threonine 56, serine 70, threonine 74, or serine 87 were created. Expression of the mutant Bcl-2 proteins was documented by flow cytometry and Western blot analysis. Mutation of Bcl-2 on T56 and S87 eliminated the ability of Bcl-2 to inhibit glucocorticoid-induced cell shrinkage, mitochondrial depolarization, DNA fragmentation, and cell death. Mutation of T74 only partially impaired the ability of Bcl-2 to block glucocorticoid-induced apoptosis whereas mutation of S70 in Bcl-2 did not alter its ability to block glucocorticoid-induced apoptosis. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), 111 TW Alexander Dr,Bldg 101,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov RI Huang, Se-Te/F-6881-2013 NR 46 TC 26 Z9 28 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2002 VL 16 IS 8 AR UNSP 0892-6638/02/0016-0825 DI 10.1096/fj.01-0852com PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 570WR UT WOS:000176683900008 PM 12039864 ER PT J AU Brandes, RP Miller, FJ Beer, S Haendeler, J Hoffmann, J Ha, T Holland, SM Gorlach, A Busse, R AF Brandes, RP Miller, FJ Beer, S Haendeler, J Hoffmann, J Ha, T Holland, SM Gorlach, A Busse, R TI The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE oxidative stress; NADPH oxidase; thrombin; superoxide anion; free radicals ID SMOOTH-MUSCLE CELLS; SUPEROXIDE ANION PRODUCTION; MESSENGER-RNA EXPRESSION; ANGIOTENSIN-II; NAD(P)H OXIDASE; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; CORONARY-ARTERIES; XANTHINE-OXIDASE; TISSUE FACTOR AB An NADPH oxidase is thought to be a main source of vascular superoxide (O-2(-)) production. The functional role of this oxidase, however, and the contribution of the different subunits of the enzyme to cellular signaling are still incompletely understood. We determined the role of the p47phox subunit of the oxidase in O-2(-) generation and signaling in aortic rings and cultured smooth muscle cells (SMC) from wild-type (WT) and p47phox-deficient (p47phox -/-) mice. Basal O-2(-) levels in aortae of p47phox -/- mice were lower than those in WT aortae. Infusion of [val(5)]-angiotensin 11 increased O-2(-) levels in aortae from WT more than in aortae from p47phox -/- mice. O-2(-) generation was similar in quiescent SMC from WT and p47phox -/- mice, However, exposure to thrombin selectively increased O-2(-) generation in VSMC from WT, but not from p47phox -/- mice. Thrombin-activated redox-mediated signal transduction and gene expression was attenuated in VSMC from p47phox -/- compared to cells from WT mice as determined by p39 MAP kinase activation and VEGF gene expression. We conclude that p47phox is important for vascular ROS production and redox-modulated signaling and gene expression in VSMC. (C) 2002 Elsevier Science Inc. C1 Univ Frankfurt Klinikum, Inst Kardiovaskulare Physiol, D-60590 Frankfurt, Germany. Univ Frankfurt Klinikum, Dept Cardiol, D-60590 Frankfurt, Germany. Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Brandes, RP (reprint author), Univ Frankfurt Klinikum, Inst Kardiovaskulare Physiol, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. RI Gorlach, Agnes/B-3494-2013; Miller Jr, Francis/N-7312-2015; Miller, Francis/F-3801-2017 OI Miller Jr, Francis/0000-0001-5822-0549; Miller, Francis/0000-0001-5822-0549 FU NHLBI NIH HHS [K08 HL003669-03, K08 HL003669, K08 HL003669-04, K08 HL003669-05] NR 40 TC 84 Z9 87 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 JUN 1 PY 2002 VL 32 IS 11 BP 1116 EP 1122 AR PII S0891-5849(02)00789-X DI 10.1016/S0891-5849(02)00789-X PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 555ZH UT WOS:000175822600009 PM 12031896 ER PT J AU Lee, SM Koh, HJ Park, DC Song, BJ Huh, TL Park, JW AF Lee, SM Koh, HJ Park, DC Song, BJ Huh, TL Park, JW TI Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE isocitrate dehydrogenase; NADPH; reactive oxygen species; cellular redox state; free radicals ID SACCHAROMYCES-CEREVISIAE; GLUTATHIONE DISULFIDE; SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; SENSITIVITY; EXPRESSION; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; STRESS; NADPH; CDNA AB NADPH is an important cofactor in many biosynthesis pathways and the regeneration of reduced glutathione, critically important in cellular defense against oxidative damage. It is mainly produced by glucose 6-phosphate dehydrogenase (GOD), malic enzyme, and the cytosolic form of NADP(+)-dependent isocitrate dehydrogenase (IDPc). Little information is available about the role of IDPc in antioxidant defense. In this study we investigated the role of IDPc against cytotoxicity induced by oxidative stress by comparing the relative degree of cellular responses in three different NIH3T3 cells with stable transfection with the cDNA for mouse IDPc in sense and antisense orientations, where IDPc activities were 3-4-fold hither and 35% lower, respectively, than that in the parental cells carrying the vector alone. Although the activities of other antioxidant enzymes, such as superoxide dismutase, catalase, glutathione reductase, glutathione poroxidase, and GOD, were comparable in all transformed cells, the ratio of GSSG to total glutathione was significantly higher in the cells expressing the lower level of IDPc. This finding indicates that IDPc is essential for the efficient glutathione recycling, Upon transient exposure to increasing concentrations of H2O2 or menadione, an intracellular source of free radicals and reactive oxygen species, the cells with low levels of IDPc became more sensitive to oxidative damage by H2O2 or menadione. Lipid peroxidation, oxidative DNA damage, and intracellular peroxide generation were higher in the cell-line expressing the lower level of IDPc. However, the cells with the highly over-expressed IDPc exhibited enhanced resistance against oxidative stress, compared to the control cells. This study provides direct evidence correlating the activities of IDPc and the maintenance of the cellular redox state, suggesting that IDPc plays an important role in cellular defense against oxidative stress. (C) 2002 Elsevier Science Inc. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Biochem, Taegu 702701, South Korea. Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. Kyungpook Natl Univ, TG Biotech Co Ltd, Taegu 702701, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Park, DC (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Biochem, Taegu 702701, South Korea. NR 53 TC 229 Z9 239 U1 4 U2 24 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 JUN 1 PY 2002 VL 32 IS 11 BP 1185 EP 1196 AR PII S0891-5849(02)00815-8 DI 10.1016/S0891-5849(02)00815-8 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 555ZH UT WOS:000175822600015 PM 12031902 ER PT J AU Bautista, AP AF Bautista, AP TI Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis SO FRONTIERS IN BIOSCIENCE LA English DT Article DE inflammation; gene expression; hepatitis; MCP-1; RANTES; MIP-1 alpha ID MACROPHAGE INFLAMMATORY PROTEIN-2; FACTOR-KAPPA-B; LIVER-DISEASE; EXPRESSION; HEPATITIS; INJURY; RAT; CHEMOATTRACTANT; HEPATOCYTES; ACTIVATION AB Chemokines are involved in the pathogenesis of alcoholic hepatitis and are considered to contribute to the migration of leukocytes into the liver during chronic ethanol intoxication. This work tests the hypothesis that chronic ethanol consumption selectively enhances chemokine release by Kupffer cells and hepatic sinusoidal endothelial cells and migration of inflammatory cells into the liver. Furthermore, enhanced hepatic chemokine secretion may induce an autocrine effect on the ability of Kupffer cells and endothelial cells to chemotax and ingest microbial particles. Male Wistar rats were fed with ethanol in agar block and water for 32 weeks, and were allowed free access to solid food. Results show that after 32 weeks of feeding, leukocyte infiltration and steatosis were observed in the livers of ethanol-fed rats. The majority of the infiltrated cells were CD8+ cells. Serum ALT, endotoxin, MIP-1, MCP-1 and RANTES, (but not CINC and MIP-2) were also increased in the ethanol-fed rats than in the pair-fed group. Isolated Kupffer cells from ethanol-fed rats were primed for enhanced MIP-1, MCP-1, and RANTES production in vitro, while the endothelial cells were primed for enhanced MIP-1 release only. Chronic alcohol intoxication was also associated with increased basal H2O2 formation, enhanced nuclear translocation and binding of NF-kappaB, AP-1 and MNP-1 in Kupffer Cells. Chronic ethanol feeding significantly enhanced MNP-1 binding, but not those of NF-kappaB and AP-1 in endothelial cells. Concomitantly, chemokine-induced chemotaxis, E. coli phagocytosis and f-met-leu-phe-induced superoxide anion production by Kupffer cells were downregulated in the ethanol-fed group. Taken together these data demonstrate that prolonged alcohol consumption may compromise the host to hepatitis as a result of increased chemokine production and at the same time may suppress the innate immune function of hepatic non-parenchymal cells. C1 Louisiana State Univ, Hlth Sci Ctr, NIAAA, Alcohol Res Ctr,Dept Physiol, New Orleans, LA USA. RP Bautista, AP (reprint author), NIH, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA. FU NIAAA NIH HHS [R01 AA08846, P50 AA09803] NR 27 TC 23 Z9 24 U1 0 U2 1 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD JUN PY 2002 VL 7 BP A117 EP A125 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569BE UT WOS:000176578800001 PM 12045006 ER PT J AU El-Serag, HB Everhart, JE AF El-Serag, HB Everhart, JE TI Diabetes increases the risk of acute hepatic failure SO GASTROENTEROLOGY LA English DT Article ID FATTY LIVER-DISEASE; OF-VETERANS-AFFAIRS; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; MELLITUS; TROGLITAZONE; MITOCHONDRIA; CIRRHOSIS; ETIOLOGY AB Background & Aims: It Is unclear whether patients with diabetes are at an Increased risk of developing acute liver failure (ALF). We performed a large cohort study to examine the occurrence of ALF by using the databases of the Department of Veterans Affairs. Methods: We identified all patients with a hospital discharge diagnosis of diabetes (ICD-9 codes: 250 [1-9][0-4]) from 1985 to :1990 and randomly assigned patients without diabetes for comparison (3:1 ratio). We excluded patients with concomitant liver disease as far back as 1980. After excluding the first year of follow-up, the remaining patients were observed through 2000 for the occurrence of ALF (ICD-9 570). The cumulative risk and the relative risk of ALF were determined by Kaplan-Meier and Cox Proportional Hazard survival analysis, respectively. Results: We included :173,643 patients with diabetes and 650,620 patients without diabetes. Patients with diabetes were significantly older (62 vs. 54 years) and were less likely to be white (28% vs. 24%). The cumulative risk of ALF was significantly higher among patients with diabetes (incidence rate, 2.31 per 10,000 vs. 1.44 per 10,000 person-years; P < 0.0001). In the Cox proportional hazard model, diabetes was associated with a relative risk of :1.44 (95% Cl, 1.26-1.63; P < 0.0001) for ALF while controlling for comorbidity index, age, sex, ethnicity, and period of service. This risk remained significantly Increased after excluding patients with liver disease or viral hepatitis recorded during follow-up or those with ALF recorded after the introduction of troglitazone (relative risk = 1.40; P < 0.0001). Conclusions: Diabetes Increases the risk of ALF. The Increase In ALF is Independent of recognized underlying chronic liver disease or viral hepatitis. C1 Houston Dept Vet Affairs Med Ctr, Serv Gastroenterol, Houston, TX USA. Houston Dept Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. NIDDKD, Bethesda, MD 20892 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 28 TC 81 Z9 87 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2002 VL 122 IS 7 BP 1822 EP 1828 DI 10.1053/gast.2002.33650 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563WQ UT WOS:000176280300017 PM 12055590 ER PT J AU Lok, AS Heathcote, EJ Hoofnagle, JH AF Lok, AS Heathcote, EJ Hoofnagle, JH TI Serum HBV-DNA levels in inactive hepatitis B virus carriers - Reply SO GASTROENTEROLOGY LA English DT Letter C1 Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. Univ Toronto, Toronto Western Hosp, Div Gastroenterol, Toronto, ON, Canada. NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Lok, AS (reprint author), Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. RI Lok, Anna /B-8292-2009 NR 1 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2002 VL 122 IS 7 BP 2093 EP 2093 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563WQ UT WOS:000176280300045 ER PT J AU Huang, Q Yu, GP McCormick, SA Mo, J Datta, B Mahimkar, M Lazarus, P Schaffer, AA Desper, R Schantz, SP AF Huang, Q Yu, GP McCormick, SA Mo, J Datta, B Mahimkar, M Lazarus, P Schaffer, AA Desper, R Schantz, SP TI Genetic differences detected by comparative genomic hybridization in head and neck squamous cell carcinomas from different tumor sites: Construction of oncogenetic trees for tumor progression SO GENES CHROMOSOMES & CANCER LA English DT Article ID OLIGONUCLEOTIDE-PRIMED PCR; COPY NUMBER CHANGES; CHROMOSOMAL-ABERRATIONS; BREAST-CANCER; SOLID TUMORS; DNA; IMBALANCES; GAINS; AMPLIFICATION; FREQUENT AB For a better understanding of genetic alterations in head and neck squamous cell carcinoma (HNSCC), we applied comparative genomic hybridization (CGH) in the analysis of 75 HNSCCs, comprised of 18 pharyngeal squamous cell carcinomas (PSCCs), 23 laryngeal squamous cell carcinomas (LSCCs), and 34 oral squamous cell carcinomas (OSCCs). The three subgroups of HNSCC showed significant differences in genetic alteration patterns. Overall, PSCC and LSCC had more copy number aberrations (CNAs) per tumor than did OSCC. Apparent differing patterns of high-level amplification were also observed. The smallest recurrent chromosomal regions of high-level amplification (greater than or equal to15% of cases) were 7q22, 8q24.1, and 11q12-13 in PSCC and 3q26.1-29 in OSCC. According to single frequency and combined frequencies of CNAs, we concluded that the most important chromosomal events for progression of head and neck cancer were +3q, +5p, +8q, and -3p for all subgroups of HNSCC; additionally, +7q, +17q, -9p, and -13q for PSCC; +7p, +9q, + 11q12-13, + 14q, and + 17q for LSCC; and +1p and +11q12-13 for OSCC. To identify further important genetic alterations and the relationships among the alterations, we constructed oncogenetic tree models for tumor progression of HNSCC from CGH data using branching and distance-based tree models. The tree models predicted that: (1) +3q21-29 was the most important early chromosomal event, and -3p, which occurred after +3q21-29, was also an important chromosomal event for all subsites of HNSCC; (2) +8q is the second most important early chromosomal event; (3) there may be at least three subgroups of HNSCC: one characterized by -3p, -9p, +7p, and -13q; another by +5p, + 9qter, and +17p; and the other by + 8q and + 18p. These results suggest that different chromosomal aberrations may play a role in the initiation and/or progression of different subgroups of HNSCC. (C) 2002 Wiley-Liss, Inc. C1 New York Med Coll, New York Eye & Ear Infirm, Dept Otolaryngol, New York, NY 10003 USA. New York Med Coll, New York Eye & Ear Infirm, Serv Epidemiol, New York, NY 10003 USA. New York Med Coll, New York Eye & Ear Infirm, Dept Pathol, New York, NY 10003 USA. NYU, Coll Dent, Div Basic Sci, New York, NY USA. Univ S Florida, H Lee Moffitt Canc Ctr, Interdisciplinary Oncol Program, Dept Biochem & Pharm, Tampa, FL 33682 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Interdisciplinary Oncol Program, Dept Therapeut, Tampa, FL 33682 USA. NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Strang Canc Prevent Ctr, New York, NY USA. RP Schantz, SP (reprint author), New York Med Coll, New York Eye & Ear Infirm, Dept Otolaryngol, 310 E 14th ST, New York, NY 10003 USA. RI Schaffer, Alejandro/F-2902-2012 NR 41 TC 122 Z9 124 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 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUN PY 2002 VL 34 IS 2 BP 224 EP 233 DI 10.1002/gcc.10062 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 543KU UT WOS:000175101800009 PM 11979556 ER PT J AU Agarwal, R Cohen-Fix, O AF Agarwal, R Cohen-Fix, O TI Phosphorylation of the mitotic regulator Pds1/securin by Cdc28 is required for efficient nuclear localization of Esp1/separase SO GENES & DEVELOPMENT LA English DT Article DE cell cycle regulation; Pds1p; Esp1p; Cdc28p; mitosis ID SISTER-CHROMATID SEPARATION; CYCLIN-DEPENDENT KINASE; DNA-DAMAGE CHECKPOINT; ANAPHASE-PROMOTING COMPLEX; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; PHOSPHATASE CDC14; PROTEIN-KINASE; INHIBITOR; PDS1P AB Sister chromatid separation at the metaphase-to-anaphase transition is induced by the proteolytic cleavage of one of the cohesin complex subunits. This process is mediated by a conserved protease called separase. Separase is associated with its inhibitor, securin, until the time of anaphase initiation, when securin is degraded in an anaphase-promoting complex/cyclosome (APC/C)-dependent manner. in budding yeast securin/Pds1 not only inhibits separase/Esp1, but also promotes its nuclear localization. The molecular mechanism and regulation of this nuclear targeting are presently unknown. Here we show that Pds1 is a substrate of the cyclin-dependent kinase Cdc28. Phosphorylation of Pds1 by Cdc28 is important for efficient binding of Pds1 to Esp1 and for promoting the nuclear localization of Esp1. Our results uncover a previously unknown mechanism for regulating the Pds1-Esp1 interaction and shed light on a novel role for Cdc28 in promoting the metaphase-to-anaphase transition in budding yeast. C1 NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. NR 40 TC 55 Z9 57 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2002 VL 16 IS 11 BP 1371 EP 1382 DI 10.1101/gad.971402 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 561BZ UT WOS:000176117800007 PM 12050115 ER PT J AU Rachel, RA Wellington, SJ Warburton, D Mason, CA Beermann, F AF Rachel, RA Wellington, SJ Warburton, D Mason, CA Beermann, F TI A new allele of Gli3 and a new mutation, circletail (Crc), resulting from a single transgenic experiment SO GENESIS LA English DT Article DE insertional mutant; transgene; tyrosinase; skeletal malformation; polydactyly ID GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; NEURAL-TUBE DEFECTS; EXTRA-TOES XT; MOUSE MUTANT; HOMEOBOX GENE; SPINAL-CORD; EXPRESSION; DELETION; MIDLINE; MICE AB While generating transgenic lines, transgene-linked mutations can occur, which are caused by an insertional mutation at a given locus. More rarely, mutations unlinked to the transgene insertion site are observed. In the process of generating a mouse overexpressing the enzyme tyrosinase, we have obtained one transgenic line that appears to carry a semidominant insertional mutation at the Gli3 (extra toes) locus, characterized by polydactyly and skeletal malformations. Additionally, the transgenic line contained a second mutation, Crc (circletail), which appears to be unlinked to the transgene insertion site. Heterozygous Crc mice are incompletely penetrant for a circled-tail phenotype, while all homozygous Crc/Crc mice die at birth of a severe neural tube defect (craniorachischisis). Anatomical evidence from a Crc/Crc; Gli3/+ fetus indicates that these two genes may interact. C1 Columbia Univ, Coll Phys & Surg, Ctr Neurobiol & Behav, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Anat & Cell Biol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY USA. Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland. RP Rachel, RA (reprint author), NCI, Mouse Canc Genet Program, POB B,Bldg 539,Room 234, Frederick, MD 21702 USA. NR 20 TC 11 Z9 11 U1 2 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD JUN PY 2002 VL 33 IS 2 BP 55 EP 61 DI 10.1002/gene.10088 PG 7 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 563WP UT WOS:000176280100001 PM 12112872 ER PT J AU Veraksa, A Kennison, J McGinnis, W AF Veraksa, A Kennison, J McGinnis, W TI DEAF-1 function is essential for the early embryonic development of Drosophila SO GENESIS LA English DT Article DE Drosophila; DEAF-1; Deformed; Hox; segmentation ID GLUCOCORTICOID MODULATORY ELEMENT; ACUTE MYELOID-LEUKEMIA; BINDING-PROTEIN; HISTONE DEACETYLASE; SAND DOMAIN; KDWK FAMILY; N-COR; TRANSCRIPTION; MELANOGASTER; CLONING AB The Drosophila protein DEAF-1 is a sequence-specific DNA binding protein that was isolated as a putative cofactor of the Hox protein Deformed (Dfd). In this study, we analyze the effects of loss or gain of DEAF-1 function on Drosophila development. Maternal/zygotic mutations of DEAF-1 largely result in early embryonic arrest prior to the expression of zygotic segmentation genes, although a few embryos develop into larvae with segmentation defects of variable severity. Overexpression of DEAF-1 protein in embryos can induce defects in migration/closure of the dorsal epidermis, and overexpression in adult primordia can strongly disrupt the development of eye or wing. The DEAF-1 protein associates with many discrete sites on polytene chromosomes, suggesting that DEAF-1 is a rather general regulator of gene expression. C1 Univ Calif San Diego, Div Biol, La Jolla, CA 92093 USA. NIH, Genet Mol Lab, Bethesda, MD 20892 USA. RP McGinnis, W (reprint author), Univ Calif San Diego, Div Biol, 0349,9500 Gilman Dr, La Jolla, CA 92093 USA. NR 38 TC 25 Z9 27 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD JUN PY 2002 VL 33 IS 2 BP 67 EP 76 DI 10.1002/gene.10090 PG 10 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 563WP UT WOS:000176280100003 PM 12112874 ER PT J AU Simon, R Radmacher, MD Dobbin, K AF Simon, R Radmacher, MD Dobbin, K TI Design of studies using DNA microarrays SO GENETIC EPIDEMIOLOGY LA English DT Article DE gene expression; bioinformatics; biomarkers; computational biology ID MOLECULAR CLASSIFICATION; EXPRESSION PATTERNS; CLUSTER-ANALYSIS; HYBRIDIZATION; GENOTYPE; CANCER AB DNA microarrays are assays that simultaneously provide information about expression levels of thousands of genes and are consequently finding wide use in biomedical research. In order to control the many sources of variation and the many opportunities for misanalysis, DNA microarray studies require careful planning. Different studies have different objectives, and important aspects of design and analysis strategy differ for different types of studies. We review several types of objectives of studies using DNA microarrays and address issues such as selection of samples, levels of replication needed, allocation of samples to dyes and arrays, sample size considerations, and analysis strategies. (C) 2002 Wiley-Liss, Inc. C1 NCI, Biomet Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biomet Res Branch, MSC 7434,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 116 Z9 121 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUN PY 2002 VL 23 IS 1 BP 21 EP 36 DI 10.1002/gepi.0202 PG 16 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 571CT UT WOS:000176697800003 PM 12112246 ER PT J AU Southworth, JW Kennison, JA AF Southworth, JW Kennison, JA TI Transvection and silencing of the Scr homeotic gene of Drosophila melanogaster SO GENETICS LA English DT Article ID BITHORAX COMPLEX; MOLECULAR-ORGANIZATION; EXPRESSION PATTERNS; ANTENNAPEDIA LOCUS; GROUP PROTEINS; POLYCOMB; CHROMATIN; TRANS; MUTATIONS; REGION AB The Sex combs reduced (Ser) gene specifies the identities of the labial and first thoracic segments in Drosophila melanogaster. In imaginal cells, some Ser mutations allow cis-regulatory elements oil one chromosome to stimulate expression of the promoter on the homolog, a phenomenon that was named transvection by Ed Lewis in 1954. Transvection at the Scr gene is blocked by rearrangements that disrupt pairing. lint IS zeste independent. Silencing of the Scr gene in the second and third thoracic segments, which requires the Polycomb group proteins, is disrupted by most chromosomal aberrations within the Scr gene. Some chromosomal aberrations completely derepress Scr even in the presence of normal levels of-all Polycomb group proteins. On the ha is of the pattern of chromosomal aberrations that disrupt Scr gene silencing, we propose a model in which two cis-regulatory elements interact to stabilize silencing of am, promoter Or cis-regulatory element physically between them. This model also explains the anomalous behavior of the Scx allele of the flanking homeotic gene, Antennapedia. This allele, which is associated with an insertion near the Anennapedia P1 promoter, inactivates the Antennapedia P1 and P2 promoters in cis and derepresses the Scr promoters both in cis and on the homologous chromosome. C1 NICHHD, Sect Drosophila Gene Regulat, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Kennison, JA (reprint author), NICHHD, Sect Drosophila Gene Regulat, Mol Genet Lab, NIH, Bldg 6B,Rm 3B-331, Bethesda, MD 20892 USA. NR 47 TC 16 Z9 16 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2002 VL 161 IS 2 BP 733 EP 746 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 565MT UT WOS:000176374600023 PM 12072469 ER PT J AU Foster, MW Sharp, RR AF Foster, MW Sharp, RR TI Race, ethnicity, and genomics: Social classifications as proxies of biological heterogeneity SO GENOME RESEARCH LA English DT Editorial Material ID TYPE-2 DIABETES-MELLITUS; HUMAN GENETIC-VARIATION; LINKAGE DISEQUILIBRIUM; POPULATION-GENETICS; DIVERSITY; PROJECT; DISEASE; SEARCH; POLYMORPHISMS; CHROMOSOME AB Over the past century, genetics has experienced a tension between the view that racial and ethnic categories are biologically meaningful and the view that these social classifications have little or no biological significance. That tension continues to inform genomics and is evident in the assembly of biological collections and sequence databases that seek to approximate the genetic variation found in human populations. Although social identities can be useful and convenient proxies of some biological features, for example, in ensuring that genomic resources capture a range of genetic variants found in most human populations, the ways in which geneticists Conceptualize the relationship between racial and ethnic identities and genetic variation can be problematic. Inclusion of racial and ethnic identifiers in genomic resources can create risks for all members of those identified Populations and influence lay perceptions of the nature of racial and ethnic groups. Thus, the burden of showing the Scientific utility Of racial and ethic identities in the construction and analysis of genomic resources falls oil researchers. This requires that genetic researchers pay as Much attention to the social constitution of human populations as presently is paid to their genetic composition. C1 Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Foster, MW (reprint author), Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. FU NIAID NIH HHS [AI 24717-S2]; NIEHS NIH HHS [ES 11174] NR 58 TC 84 Z9 87 U1 1 U2 9 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2002 VL 12 IS 6 BP 844 EP 850 DI 10.1101/gr.99202 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 566NC UT WOS:000176433700002 PM 12045138 ER PT J AU Zeeberg, B AF Zeeberg, B TI Shannon information theoretic computation of synonymous codon usage biases in coding regions of human and mouse genomes SO GENOME RESEARCH LA English DT Article ID HUMAN GENES; G+C-CONTENT; TRANSLATIONAL SELECTION; NUCLEOTIDE-SEQUENCES; VERTEBRATE GENES; ESCHERICHIA-COLI; DNA; EVOLUTION; DIVERSITY; DROSOPHILA AB Exonic GC of human mRNA reference sequences (RefSeqs), as well as A, C, G, and T in codon position 3 are linearly correlated with genomic GC. These observations utilize information from the completed human genome sequence and a large, high-quality set of human and mouse coding sequences, and are in accord with similar determinations published by others. A Shannon Information Theoretic measure of bias in synonymous codon usage was developed. When applied to either human or mouse RefSeqs, this measure is nonlinearly correlated with genomic, exonic, and third codon position A, C, G, and T. Information values between orthologous mouse and human RefSeqs are linearly correlated: mouse = 0.092 + 0.55 human. Mouse genes were consistently placed in genomic regions whose GC content was closer to 50% than was the GC content of the human ortholog, Since the (nonlinear) information versus percent GC curve has a minimum at 50% GC and monotonically increases with increasing distance from 50% GC, this phenomenon directly results in the low slope of 0.55. This appears to be a manifestation of an evolutionary strategy for placement of genes in regions of the genome with a GC content that relates synonymous codon bias and protein folding. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Zeeberg, B (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 42 TC 34 Z9 36 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2002 VL 12 IS 6 BP 944 EP 955 DI 10.1101/gr.213402 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 566NC UT WOS:000176433700011 PM 12045147 ER PT J AU Jordan, IK Rogozin, IB Wolf, YI Koonin, EV AF Jordan, IK Rogozin, IB Wolf, YI Koonin, EV TI Essential genes are more evolutionarily conserved than are nonessential genes in bacteria SO GENOME RESEARCH LA English DT Article ID COMPLETE GENOME SEQUENCE; PATHOGEN HELICOBACTER-PYLORI; AMINO-ACID SUBSTITUTIONS; COG DATABASE; RATE VARIES; NUMBER; ALIGNMENT; MUTATIONS; STRAIN; SITES AB The "knockout-rate" prediction holds that essential genes should be more evolutionarily conserved than are nonessential genes. This is because negative (purifying) selection acting on essential genes is expected to be more stringent than that for nonessential genes, which are more functionally dispensable and/or redundant. However, a recent survey of evolutionary distances between Saccharomyces cerevisiae and Caenorhabditis elegans proteins did not reveal any difference between the rates of evolution for essential and nonessential genes. An analysis of mouse and rat orthologous genes also found that essential and nonessential genes evolved at similar rates when genes thought to evolve under directional selection were excluded from the analysis. In the present study, we combine genomic Sequence data with experimental knockout data to compare the rates of evolution and the levels of selection for essential versus nonessential bacterial genes. In contrast to the results obtained for eukaryotic genes, essential bacterial genes appear to be more conserved than are nonessential genes over both relatively short (microevolutionary) and longer (macroevolutionary) time scales. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 30 TC 286 Z9 295 U1 2 U2 29 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2002 VL 12 IS 6 BP 962 EP 968 DI 10.1101/gr.87702 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 566NC UT WOS:000176433700013 PM 12045149 ER PT J AU Cozma, D Lukes, L Rouse, J Qiu, TH Liu, ET Hunter, KW AF Cozma, D Lukes, L Rouse, J Qiu, TH Liu, ET Hunter, KW TI A bioinformatics-based strategy identifies c-Myc and Cdc25A as candidates for the Apmt mammary tumor latency modifiers SO GENOME RESEARCH LA English DT Article ID BREAST-CANCER; OVARIAN-CANCER; BRCA1 MUTATIONS; LOCUS; GENE; RISK; DETERMINANTS; PHOSPHATASE; EXPRESSION; ONCOGENES AB The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. Oil the basis Of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding, polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorph isms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NCI, Mol Signalling & Oncogenesis Sect, Med Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. RI Liu, Edison/C-4141-2008 NR 33 TC 26 Z9 26 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2002 VL 12 IS 6 BP 969 EP 975 DI 10.1101/gr.210502 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 566NC UT WOS:000176433700014 PM 12045150 ER PT J AU Kehrl, JH Srikumar, D Harrison, K Wilson, GL Shi, CS AF Kehrl, JH Srikumar, D Harrison, K Wilson, GL Shi, CS TI Additional 5 ' exons in the RGS3 locus generate multiple mRNA transcripts, one of which accounts for the origin of human PDZ-RGS3 SO GENOMICS LA English DT Article DE RGS; RNA splicing; G-protein; genomic ID G-PROTEINS; CHEMOTAXIS; RECEPTORS; REGULATOR; ACTIVATION; FAMILY; ROLES AB Regulators of G-protein signaling (RGS) proteins can be broadly divided into those that consist predominantly of an RGS domain and those that possess an RGS domain along with additional domains. RGS3 fits into both categories, as both short and longer forms exist. Recently, a novel form of mouse RGS3 that possesses a PDZ domain was identified. Here we show that the human PDZ-RGS3 isoform arises from 10 upstream exons along with 6 exons from the previously characterized RGS3. We found that 47,000 nucleotides span the last of the 10 upstream exons and the first exon used from the original cluster of RGS3 exons. These 10 upstream exons encode 398 amino acids, which show strong conservation with those from mouse PDZ-RGS3. In addition, another isoform exists that uses 17 upstream exons, 9 of which overlap with those in PDZ-RGS3, along with the same 6 downstream exons used in PDZ-RGS3. Finally, a short form of human RGS3 arises from an unrecognized RGS3 exon that encodes an amino-terminal 140 amino acids. For each RGS3 isoform, RT-PCR detected specific mRNA transcripts and immunoblot analysis identified specific bands for RGS3 and PDZ-RGS3. RGS3 provides an example of the complex origins of the coding regions of mammalian proteins. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. OI Kehrl, John/0000-0002-6526-159X NR 22 TC 28 Z9 29 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 0888-7543 J9 GENOMICS JI Genomics PD JUN PY 2002 VL 79 IS 6 BP 860 EP 868 DI 10.1006/geno.2002.6773 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 558JY UT WOS:000175963600017 PM 12036301 ER PT J AU Yu, P Chen, YW Tagle, DA Cai, T AF Yu, P Chen, YW Tagle, DA Cai, T TI PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain SO GENOMICS LA English DT Article DE RING-H2 finger gene; ubiquitin ligase; chromosome Xq12; X-linked mental retardation; ubiquitination; brain ID LINKED MENTAL-RETARDATION; PROTEIN LIGASE; PERICENTROMERIC REGION; CONJUGATING ENZYME; ANGELMAN SYNDROME; MUTATIONS; FAMILY; LOCALIZATION; LINKAGE; MOTIF AB RING-finger proteins contain cysteine-rich, zinc-binding domains and are involved in the formation of macromolecular scaffolds important for transcriptional repression and ubiquitination. In this study, we have identified a RING-H2 finger gene, PJA1 (for praja-1), from a human brain cDNA library and mapped it to human chromosome Xq12 between markers DXS983 and DXS1216, a region implicated in X-linked mental retardation (MRX). Northern blot analysis indicated a 2.7-kb transcript that was abundantly expressed in the brain, including regions of the cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe, and putamen. Amino acid sequence analysis of the 71-kDa protein PJA1 showed 52.3% identity to human PJA2 (for praja-2, also known as NEURODAP1/KIAA0438) and also a significant identity to its homologs in rat, mouse, and zebrafish. In vitro binding and immunoprecipitation assays demonstrated that both PJA1 and PJA2 are able to bind the ubiquitin-conjugating enzyme UbcH5B. Moreover, the ubiquitination assay indicated that PJA1 and PJA2 have an E2-dependent E3 ubiquitin ligase activity. Thus our findings demonstrate that PJA1 can be involved in protein ubiquitination in the brain and is a suitable candidate gene for MRX. C1 NCI Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. NINCDS, Ctr Neurosci, NIH, Fujian 350001, Peoples R China. NIDCR, Expt Med Sect, NIH, Bethesda, MD 20892 USA. RP Cai, T (reprint author), NCI Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. NR 37 TC 24 Z9 30 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 0888-7543 J9 GENOMICS JI Genomics PD JUN PY 2002 VL 79 IS 6 BP 869 EP 874 DI 10.1006/geno.2002.6770 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 558JY UT WOS:000175963600018 PM 12036302 ER PT J AU Phillips, RKS Wallace, MH Lynch, PM Hawk, E Gordon, GB Saunders, BP Wakabayashi, N Shen, Y Zimmerman, S Godio, L Rodrigues-Bigas, M Su, LK Sherman, J Kelloff, G Levin, B Steinbach, G AF Phillips, RKS Wallace, MH Lynch, PM Hawk, E Gordon, GB Saunders, BP Wakabayashi, N Shen, Y Zimmerman, S Godio, L Rodrigues-Bigas, M Su, LK Sherman, J Kelloff, G Levin, B Steinbach, G CA FAP Study Grp TI A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis SO GUT LA English DT Article ID RHEUMATOID-ARTHRITIS; SULINDAC; COX-2; CARCINOGENESIS; EXPRESSION; CANCER AB Background: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. Patients and methods: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n= 17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. Results: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). Conclusions: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition. C1 St Marks Hosp, Harrow HA1 3UJ, Middx, England. Imperial Canc Res Fund, Colorectal Canc Unit, London WC2A 3PX, England. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Chemoprevent, Skokie, IL 60077 USA. Roswell Pk Canc Inst, Lower Gastrointestinal Dept, Div Surg Oncol, Buffalo, NY 14263 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Phillips, RKS (reprint author), St Marks Hosp, Northwick Pk,Watford Rd, Harrow HA1 3UJ, Middx, England. FU NCI NIH HHS [CA16672, N01 CN-65118, P30 CA016672] NR 22 TC 241 Z9 252 U1 1 U2 6 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD JUN PY 2002 VL 50 IS 6 BP 857 EP 860 DI 10.1136/gut.50.6.857 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 555UT UT WOS:000175812200022 PM 12010890 ER PT J AU Harris, Y Clauser, SB AF Harris, Y Clauser, SB TI Achieving improvement through nursing home quality measurement SO HEALTH CARE FINANCING REVIEW LA English DT Article ID RESIDENT ASSESSMENT INSTRUMENT AB CMS has initiated the Nursing Home Quality Initiative (NHQI) to improve the quality of nursing home care. Central to the NHQI is the public reporting of nursing home quality measures that serve as the basis for the Initiative's communication and quality improvement program. This article provides an overview of the NHQI, focusing on the role of nursing home quality measures in achieving improvements in nursing home care. We also describe the evolution of quality measurement in nursing homes, a recent CMS project to improve measures through risk adjustment and other refinements, the use of these measures in a pilot of the NHQI, and the lessons learned for future work in this area. C1 Ctr Medicare & Medicaid Serv, Baltimore, MD 21244 USA. NCI, Bethesda, MD 20892 USA. RP Harris, Y (reprint author), Ctr Medicare & Medicaid Serv, 7500 Secur Blvd,S3-02-01, Baltimore, MD 21244 USA. EM yharris@cms.hhs.gov NR 16 TC 29 Z9 29 U1 0 U2 1 PU CENTERS FOR MEDICARE & MEDICAID SERVICES PI BALTIMORE PA 7500 SECURITY BOULEVARD, BALTIMORE, MD 21244-1850 USA SN 0195-8631 J9 HEALTH CARE FINANC R JI Health Care Finan. Rev. PD SUM PY 2002 VL 23 IS 4 BP 5 EP 18 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 953OX UT WOS:000231088900002 PM 12500467 ER PT J AU Frederick, PR Maxey, NL Clauser, SB Sugarman, JR AF Frederick, PR Maxey, NL Clauser, SB Sugarman, JR TI Developing dialysis facility-specific performance measures for public reporting SO HEALTH CARE FINANCING REVIEW LA English DT Article ID STANDARDIZED MORTALITY RATIO; LIMITATIONS; CARE AB The Balanced Budget Act (BBA) of 1997 directed CMS to implement a system to measure and report the quality of dialysis services under Medicare by 2000. Because of this tight timeframe, a rapid-cycle measurement development process was initiated to develop dialysis facility-specific measures that could be released to the public. The result was "Dialysis Facility Compare" which has served as a template for the development of public reporting initiatives for other providers in the Medicare Program. This article describes the process used for developing and reporting these performance measures and the lessons learned for future work in this area. C1 Ctr Medicare & Medicaid Serv, Baltimore, MD 21244 USA. NCI, Bethesda, MD 20892 USA. RP Frederick, PR (reprint author), Ctr Medicare & Medicaid Serv, 7500 Secur Blvd,S3-02-01, Baltimore, MD 21244 USA. EM pfrederick@cms.hhs.gov NR 18 TC 12 Z9 12 U1 1 U2 1 PU CENTERS FOR MEDICARE & MEDICAID SERVICES PI BALTIMORE PA 7500 SECURITY BOULEVARD, BALTIMORE, MD 21244-1850 USA SN 0195-8631 J9 HEALTH CARE FINANC R JI Health Care Finan. Rev. PD SUM PY 2002 VL 23 IS 4 BP 37 EP 50 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 953OX UT WOS:000231088900004 PM 12500469 ER PT J AU Simon, SL Luckyanov, N Bouville, A VanMiddlesworth, L Weinstock, RM AF Simon, SL Luckyanov, N Bouville, A VanMiddlesworth, L Weinstock, RM TI Transfer of I-131 into human breast milk and transfer coefficients for radiological dose assessments SO HEALTH PHYSICS LA English DT Review DE milk; I-131; transfer coefficient; dose assessment ID IODIDE TRANSPORTER; MAMMARY-GLAND; EXCRETION; RADIOIODINE; CANCER; RADIOACTIVITY; PREGNANCY; RADIATION; SECRETION; CLONING AB Data on transfer of radioiodine into human milk are rare in the literature. Data from sixteen publications were reviewed and analyzed to estimate the transfer coefficient (f(hm)* having units of d L-1). The data on the radioiodine concentration in breast milk were analyzed by two methods: direct numerical integration and integration of a fitted exponential model. In general, the integrated fitted functions were greater. The fitted functions likely better describe the transfer into milk since few data sets sampled mothers' milk near the time of maximum excretion. The derived transfer coefficient values seem to represent two populations. The first group was those individuals who had very low excretions, including those where thyroid and mammary uptake was impaired by the administration of stable iodine or iodinated compounds. The second group included those with much higher excretions. The second group, termed the "normal-excretion" group, had transfers of iodine to milk that were more than ten-fold higher than in the "low-excretion" group. The derived milk transfer coefficient data for the low- and normal-excretion groups fitted to lognormal distributions gave geometric means, (geometric standard deviations), of 0.043 d L-1 (2.1, n = 14) and 0.37 d L-1 (1.5, n = 12), respectively. Estimates of the effective half-time (time from maximum concentration to half the value) were determined for the low- and normal-excretion groups separately. There was evidence that the effective half-time was longer for the normal- than for the low-excretion group; the geometric mean (and geometric standard deviation) were 12 (1.7) and 8.5 (2.6) h, respectively, though the difference was not statistically significant. The geometric mean times to maximum milk concentration in the low- and normal-excretion groups were nearly identical, 9.4 (3.1) and 9.0 (1.6) h, respectively. The data show that administration of large doses of stable iodine (commonly used to block uptake of iodine into the thyroid) is also an effective means to block radioiodine transfer into milk. Thus, protecting the mother's thyroid also protects the nursing infant. Despite inadequacies of available data describing the transfer of radioiodine to human milk within a healthy population of women, the values of f(hm)* provided here are believed to be the best available for use in radiological assessments. These values are particularly applicable to lactating women having normal diets and availability to stable iodine, as in the United States. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Coll Med, Memphis, TN 38163 USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov NR 55 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 BP 796 EP 806 AR UNSP 0017-9078/02/0 DI 10.1097/00004032-200206000-00007 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 554LZ UT WOS:000175738300007 PM 12046751 ER PT J AU Apostoaei, AI Hoffman, FO Thomas, B Land, C Gilbert, E AF Apostoaei, AI Hoffman, FO Thomas, B Land, C Gilbert, E TI Transfer of risk between populations applied to estimating probability of cancer causation. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 SENES Oak Ridge Inc, Oak Ridge, TN 37830 USA. NCI, Rockville, MD 20852 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S188 EP S189 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000215 ER PT J AU Austin, K Coronado, L Googins, S AF Austin, K Coronado, L Googins, S TI Informing research subjects about radiation. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S173 EP S173 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000169 ER PT J AU Coronado, L Googins, S AF Coronado, L Googins, S TI Research radiation studies: Improving informed consent. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S173 EP S173 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000168 ER PT J AU Googins, S Coronado, L AF Googins, S Coronado, L TI Challenges of calculating effective dose. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S173 EP S174 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000170 ER PT J AU Hoffman, FO Apostoaei, AI Thomas, B Land, C Gilbert, E AF Hoffman, FO Apostoaei, AI Thomas, B Land, C Gilbert, E TI The role of uncertainty analysis in estimating the probability of causation of radiogenic cancer. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 SENES Oak Ridge Inc, Oak Ridge, TN 37830 USA. NCI, Rockville, MD 20852 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S188 EP S188 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000213 ER PT J AU Land, C Gilbert, E Smith, J Hoffman, O Apostoaei, I Thomas, I AF Land, C Gilbert, E Smith, J Hoffman, O Apostoaei, I Thomas, I TI Report of the NCI-CDC Working Group to revise the 1985 NIH radioepidemiological tables: Overview. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Radiat Studies Branch, Atlanta, GA 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S187 EP S188 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000212 ER PT J AU Reed, SE Austin, K Ribaudo, C Zoon, R AF Reed, SE Austin, K Ribaudo, C Zoon, R TI Who you gonna call? SO HEALTH PHYSICS LA English DT Meeting Abstract C1 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S147 EP S147 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000098 ER PT J AU Simon, S Gordeev, K Bouville, A Luckyanov, N Land, C Carr, C AF Simon, S Gordeev, K Bouville, A Luckyanov, N Land, C Carr, C TI Estimates of radiation doses to members of a cohort residing in villages near the Semipalatinsk nuclear test site. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Minist Publ Hlth Russia, Inst Biophys, Moscow, Russia. 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2002 VL 82 IS 6 SU S BP S168 EP S169 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 558NC UT WOS:000175947000157 ER PT J AU Park, HJ Kim, BC Kim, SJ Choi, KS AF Park, HJ Kim, BC Kim, SJ Choi, KS TI Role of MAP kinases and their cross-talk in TGF-beta 1-induced apoptosis in FaO rat hepatoma cell line SO HEPATOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CYTOCHROME-C RELEASE; TRANSFORMING GROWTH FACTOR-BETA-1; SIGNAL-TRANSDUCTION PATHWAY; NECROSIS-FACTOR-ALPHA; N-TERMINAL KINASE; FACTOR-BETA; P38 KINASE; DEATH; GROWTH-FACTOR-BETA-1 AB Transforming growth factor (TGF) beta1 is a potent inducer of apoptosis in the liver. During TGF-beta1-induced apoptosis, 3 mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase [ERK], c-jun N-terminal kinase [JNK], and p38 kinase) showed simultaneonsly sustained activation in FaO rat hepatoma cells. TGF-beta1-induced apoptosis was markedly enhanced when ERK activation was selectively inhibited by the mitogen-activated protein kinase/extracellular signal-regalated kinase kinase inhibitor PD98059. In contrast, both interfering with p38 activity by overexpression of the dominant negative (DN) MKK6 mutant and inhibition of the JNK pathway by overexpression of the DN SEK1 mutant resulted in suppression of mitochondrial cytochrome c release, abrogating TGF-beta1-induced apoptosis. In addition, antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release, suppressing TGF-beta1-induced activation of JNK and p38. Inhibition of ERK activity enhanced TGF-beta1-induced p38 and JNK activation. However, inhibition of the JNK pathway suppressed p38 but induced transient ERK activation. Similarly, interfering with the p38 pathway also attenuated JNK activation but generated transient ERK activation in response to TGF-beta1. These results indicate that disrupting one MAP kinase pathway affects the TGF-beta1-induced activation of other MAP kinases, suggesting cross-talk among MAP kinase pathways. In conclusion, we propose that the balance and integration of MAP kinase signaling may regulate commitment to TGF-beta1-induced apoptosis modulating the release of cytochrome e from mitochondria. C1 Ajou Univ, Sch Med, Inst Med Sci, Lab Endocrinol, Suwon 441749, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Choi, KS (reprint author), Ajou Univ, Sch Med, Ajou Univ Hosp Genomic Res Ctr Gastroenterol, Inst Med Sci,Lab Endocrinol, 5 Wonchon Dong,Paldal Gu, Suwon 442749, South Korea. NR 49 TC 50 Z9 53 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2002 VL 35 IS 6 BP 1360 EP 1371 DI 10.1053/jhep.2002.33205 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 556XL UT WOS:000175874200008 PM 12029621 ER PT J AU Everhart, JE Yeh, F Lee, ET Hill, MC Fabsitz, R Howard, BV Welty, TK AF Everhart, JE Yeh, F Lee, ET Hill, MC Fabsitz, R Howard, BV Welty, TK TI Prevalence of gallbladder disease in American Indian populations: Findings from the Strong Heart Study SO HEPATOLOGY LA English DT Article ID GALLSTONE FORMATION; UNITED-STATES; PIMA-INDIANS; RISK-FACTORS; CHOLELITHIASIS; ADMIXTURE AB American Indians are believed to be at high risk of gallbladder disease (GBD), but there has been no systematic evaluation of its prevalence among diverse groups of American Indians. Therefore, we determined the prevalence of GBD and associated risk factors among specified American Indian populations using ultrasonography of the gallbladder and standardized diagnostic criteria. Enrolled members, aged 47 years and older, of 13 American Indian tribes or communities in Arizona, Oklahoma, and South and North Dakota who participated in the Strong Heart Study were analyzed. GBD was the sum of gallstones (determined by ultrasound examination) and cholecystectomy (determined by ultrasound and self-report). The proportion of American Indian heritage was based on the heritage of the grandparents of participants. GBD prevalence was determined among 3,296 participants at the 3 sites. Among women, 17.8% had gallstones, and 46.3% had evidence of a cholecystectomy, for a total of 64.1 % with GBD. Among men, 17.4% had gallstones, and 12.1% had evidence of a cholecystectomy, for a total of 29.5% with GBD. When figures were adjusted for age and Indian heritage, there was no significant difference in GBD prevalence across the 3 geographical areas. In multivariate logistic regression analysis, age, American Indian heritage, and waist circumference were associated with GBD among men, and age, American Indian heritage, diabetes, and parity were associated with GBD among women. Body mass index was not independently associated with GBD in either sex. In conclusion, GBD was found in epidemic proportions in diverse American Indian populations. C1 NIDDKD, Epidemiol & Clin Trials Branch, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Univ Oklahoma, Oklahoma City, OK USA. George Washington Univ, Washington, DC USA. NHLBI, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. RP Everhart, JE (reprint author), NIDDKD, Epidemiol & Clin Trials Branch, Div Digest Dis & Nutr, 2 Democracy Plaza,Room 655,6707 Democracy Blvd,MS, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [U01-HL41654, U01-HL41642, U01-HL41652] NR 30 TC 71 Z9 73 U1 0 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2002 VL 35 IS 6 BP 1507 EP 1512 DI 10.1053/jhep.2002.33336 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 556XL UT WOS:000175874200024 PM 12029637 ER PT J AU Wolkersdorfer, GW Bornstein, SR Higginbotham, JN Hiroi, N Vaquero, JJ Green, MV Blaese, RM Aguilera, G Chrousos, GP Ramsey, WJ AF Wolkersdorfer, GW Bornstein, SR Higginbotham, JN Hiroi, N Vaquero, JJ Green, MV Blaese, RM Aguilera, G Chrousos, GP Ramsey, WJ TI A novel approach using transcomplementing adenoviral vectors for gene therapy of adrenocortical cancer SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE adrenal gland; cancer; gene therapy; adenovirus; transcomplementing; bicistronic ID VIRUS THYMIDINE KINASE; ADRENAL-CORTICAL CARCINOMA; EARLY REGION-4; IN-VIVO; ANTITUMORAL EFFICACY; GAP-JUNCTIONS; PROTEIN; TUMORS; CELLS; TYPE-5 AB Current therapies for adrenocortical carcinomas do not improve the life expectancy of patients. In this study, we tested whether a gene-transfer therapy based upon a suicide gene/prodrug system would be effective in an animal model of the disease. We employed E4- and E1A/B-depleted, herpes simplex virus-thymidine kinase-expressing adenoviral mutants that transcomplement each other within tumor cells, hereby improving transgene delivery and efficacy by viral replication in situ. Transcomplementation of vectors increased the fraction of transduced of tumor cells. This increase was accompanied by greater tumor volume reduction compared to non-transcomplementing approaches. Survival time improved with non-replicating vectors plus GCV compared to controls. However, transcomplementation/replication of vectors led to a further significant increment in anti-tumor activity and survival time (p < 0.02). In treated animals, we observed a high number of apoptotic nuclei both adjacent to and distant from injection sites and sites of viral oncolysis. Ultrastructural analyses exhibited nuclear inclusion bodies characteristic of virus production in situ, and provided further evidence that this therapy induced apoptotic cell death within tumor cells. We conclude that the efficacy of suicide gene therapy is significantly amplified by viral replication and, in combination with GCV, significantly reduces tumor burden and increases survival time. C1 Tech Univ Dresden, Fac Med Carl Gustav Carus, Dept Med 1, D-01307 Dresden, Germany. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Univ Dusseldorf, Dept Endocrinol, D-4000 Dusseldorf, Germany. RP Wolkersdorfer, GW (reprint author), Tech Univ Dresden, Fac Med Carl Gustav Carus, Dept Med 1, Fetscherstr 74, D-01307 Dresden, Germany. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 56 TC 14 Z9 14 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN PY 2002 VL 34 IS 6 BP 279 EP 287 DI 10.1055/s-2002-33255 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 575FM UT WOS:000176936300001 PM 12173067 ER PT J AU Yanagihara, R Nerurkar, VR Scheirich, I Agostini, HT Mgone, CS Cui, XH Jobes, DV Cubitt, CL Ryschkewitsch, CF Hrdy, DB Friedlaender, JS Stoner, GL AF Yanagihara, R Nerurkar, VR Scheirich, I Agostini, HT Mgone, CS Cui, XH Jobes, DV Cubitt, CL Ryschkewitsch, CF Hrdy, DB Friedlaender, JS Stoner, GL TI JC virus genotypes in the Western Pacific suggest Asian mainland relationships and virus association with early population movements SO HUMAN BIOLOGY LA English DT Article DE polyomavirus; phylogenetics; genetics; Austronesian; Melanesian; Papua New Guinea; migration; population history ID HUMAN POLYOMAVIRUS JC; PAPUA-NEW-GUINEA; COMPLETE GENOMES; SEQUENCE-ANALYSIS; VIRAL EVOLUTION; HUMAN MIGRATION; DNA; AMERICANS; MELANESIA; AFRICANS AB Distinct genotypes of human polyomavirus JC (JCV) have remained population associated possibly from the time of dispersal of modern humans from Africa. Seven major genotypes with additional subtypes serve as plausible markers for following early and more recent human migrations in all parts of the world. Phylogenetic trees of JCV sequences from the major continental population groups show a trifurcation at the base indicating early division into European, African, and Asian branches. Here, we have explored JCV relationships in the island populations of the western Pacific. Since these islands were settled from the Asian mainland and islands of Southeast Asia, we expected that their virus genotypes might show an Asian connection. We found that Type 2E (Austronesian) and Type 8 (non-Austronesian) are widely distributed in western Pacific populations. A few south China strains were found (Type 7A). A subtype of Type 8, Type 8A, was confined to Papua New Guinea. In keeping with these assignments we find that phylogenetic analysis by neighbor-joining and maximum parsimony methods places Type 2E in a closer relationship to east Asian mainland strains such as Type 2A and Type 7. Our findings support the Asian origins of the western Pacific JCV strains, and suggest three broad movements: an ancient one characterized by Type 8A, and then Type 813, followed much later by migrations carrying Type 2E, which may correlate with the arrival of Austronesian-language speakers, the bearers of the "Lapita" cultural complex (similar to3,500 to 5,000 years ago), and relatively recent movements carrying largely Type 7A (south China) strains directly from the West. C1 Univ Hawaii Manoa, Retrovirol Res Lab, Pacific Biomed Res Ctr, Honolulu, HI 96822 USA. Univ Freiburg, Dept Ophthalmol, D-79106 Freiburg, Germany. Papua New Guinea Inst Med Res, Goroka, Papua N Guinea. NINDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Med Ctr, Div Infect & Immunol Dis, Sacramento, CA 95817 USA. Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. RP Yanagihara, R (reprint author), Univ Hawaii Manoa, Retrovirol Res Lab, Pacific Biomed Res Ctr, Honolulu, HI 96822 USA. FU NCRR NIH HHS [G12RR/AI-03061] NR 35 TC 29 Z9 29 U1 1 U2 2 PU WAYNE STATE UNIV PRESS PI DETROIT PA 4809 WOODWARD AVE, DETROIT, MI 48201-1309 USA SN 0018-7143 J9 HUM BIOL JI Hum. Biol. PD JUN PY 2002 VL 74 IS 3 BP 473 EP 488 DI 10.1353/hub.2002.0037 PG 16 WC Biology; Genetics & Heredity SC Life Sciences & Biomedicine - Other Topics; Genetics & Heredity GA 584RW UT WOS:000177483200009 PM 12180767 ER PT J AU Mautino, MR Morgan, RA AF Mautino, MR Morgan, RA TI Enhanced inhibition of human immunodeficiency virus type 1 replication by novel lentiviral vectors expressing human immunodeficiency virus type 1 envelope antisense RNA SO HUMAN GENE THERAPY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; DOUBLE-STRANDED-RNA; PKR CDNA CONSTRUCT; HIV-1 REPLICATION; RETROVIRAL VECTORS; GENE-TRANSFER; INTRACELLULAR EXPRESSION; VIRAL REPLICATION; TRANSDOMINANT REV; PACKAGING SIGNAL AB We have developed optimized versions of a conditionally replicating human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector for gene therapy of HIV-1 infection. These vectors target HIV-1 RNAs containing sequences of the envelope gene by expressing a 1-kb fragment of the HIV-1 Tat/Rev intron in the antisense orientation. Expression of the envelope antisense gene (envAS) was evaluated under the control of different internal promoters such as the human phosphoglycerate kinase (PGK) promoter, the human EF1-alpha promoter, and the U3 region of the SL3 murine leukemia virus. The U3-SL3 promoter transactivates transcription from the vector HIV-1 LTR and drives higher expression levels of envAS-containing RNAs than other promoters in T-cell lines. The effect of other vector structural features was also evaluated. We found that the central polypurine tract and central termination sequence (cPPT) produce a small increase in vector infectivity of 2-fold to 3-fold and results in a 10-fold higher inhibition of wild-type viral replication in challenge experiments. The woodchuck hepatitis posttranscriptional regulatory element (WPRE) does not increase the cytoplasmic levels of envAS mRNA in T-cell lines. We observed that SupT1 and primary CD4(+) T cells transduced with these vectors showed high inhibition of HIV-1 replication, suppression of syncitium formation, and increased cell viability when infected with several HIV-1 laboratory strains. Our results suggest that higher vector copy number and increased levels of envAS RNA expression contribute to block replication of divergent strains of HIV-1. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Mautino, MR (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 51 TC 9 Z9 12 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN PY 2002 VL 13 IS 9 BP 1027 EP 1037 DI 10.1089/104303402753812430 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 562BR UT WOS:000176178000003 PM 12067436 ER PT J AU Wada, T Jagadeesh, GJ Nelson, DL Candotti, F AF Wada, T Jagadeesh, GJ Nelson, DL Candotti, F TI Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction SO HUMAN GENE THERAPY LA English DT Article ID BONE-MARROW TRANSPLANTATION; X-LINKED THROMBOCYTOPENIA; SYNDROME PROTEIN; HEMATOPOIETIC-CELLS; MUTATIONS; LYMPHOCYTES; SELECTION; ANTIGEN; THERAPY; LINES AB The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema, and immunodeficiency. At present, the only definitive therapy for the disease is allogeneic bone marrow transplantation (BMT). Because of the frequent lack of suitable donors and the potential severe complications associated with BMT, the development of gene-based therapeutic strategies for WAS is highly desirable. To study whether corrective gene transfer into WAS T cells can lead to restoration of the immunologic defects of WAS, a retroviral vector expressing the WAS protein (WASP) gene was used to transduce human T-lymphotropic virus type 1-transformed T-cell lines and primary T lymphocytes from patients with WAS. After transduction, WAS T cells showed levels of WASP expression similar to those found in cells from normal individuals. In addition, the reconstituted WASP interacted in vitro with proteins containing SH3 domain such as Grb2, PLC-gamma1, and Fyn, each of which are connected to signaling pathways linked to the actin cytoskeleton. Furthermore, after CD3 cross-linking, transduced WAS T lines showed improvement of actin polymerization and T-cell receptor/CD3 down-regulation. More importantly, primary WAS T lymphocytes transduced with WASP acquired the ability to proliferate in response to anti-CD3 stimulation. These findings suggest that biologic defects of WAS T cells can be corrected in vitro by retrovirus-mediated gene transfer and pose the basis for future investigation of gene therapy as treatment for WAS. C1 NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Rockville, MD 20852 USA. NCI, Immunophysiol Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C103, Rockville, MD 20852 USA. NR 39 TC 36 Z9 38 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN PY 2002 VL 13 IS 9 BP 1039 EP 1046 DI 10.1089/104303402753812449 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 562BR UT WOS:000176178000004 PM 12067437 ER PT J AU Ahmed, ZM Smith, TN Riazuddin, S Makishima, T Ghosh, M Bokhari, S Menon, PSN Deshmukh, D Griffith, AJ Riazuddin, S Friedman, TB Wilcox, ER AF Ahmed, ZM Smith, TN Riazuddin, S Makishima, T Ghosh, M Bokhari, S Menon, PSN Deshmukh, D Griffith, AJ Riazuddin, S Friedman, TB Wilcox, ER TI Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC SO HUMAN GENETICS LA English DT Article ID SYNDROME TYPE 1F; SYNDROME TYPE 1C; MESSENGER-RNA; BETA-THALASSEMIA; GENE; DEFECTS; IDENTIFICATION; CDH23; 1D AB Human chromosome 11 harbors two Usher type I loci, USHIB and USHIC, which encode myosin VIIA and harmonin, respectively. The USHIC locus overlaps the reported critical interval for nonsyndromic deafness locus DFNB18. We found an IVS12+5G-->C mutation in the USHIC gene, which is associated with nonsyndromic recessive deafness (DFNB18) segregating in the original family, S-11/12. No other disease-associated mutation was found in the other 27 exons or in the intron-exon boundaries, and the IVS12+5G-->C mutation was not present in 200 representative unaffected individuals ascertained from the same area of India. An exon-trapping assay with a construct harboring IVS12+5G-->C generated wildtype spliced mRNA having exons 11 and 12 and mRNA that skipped exon 12. We conclude that mutations of USHIC can cause both Usher syndrome type IC and nonsyndromic recessive deafness DFNB18. C1 Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, Genet Mol Lab, NIH, Rockville, MD 20850 USA. All India Inst Med Sci, Genet Unit, Dept Pediat, New Delhi, India. Deshmukh Nursing Home, Ichalkaranji, Maharashtra, India. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. RP Wilcox, ER (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, 5 Res Court,2A-19, Rockville, MD 20850 USA. FU NIDCD NIH HHS [Z01DC00035] NR 27 TC 82 Z9 85 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2002 VL 110 IS 6 BP 527 EP 531 DI 10.1007/s00439-002-0732-4 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 572VZ UT WOS:000176796800001 PM 12107438 ER PT J AU Slavotinek, AM Searby, C Al-Gazali, L Hennekam, RCM Schrander-Stumpel, C Orcana-Losa, M Pardo-Reoyo, S Cantani, A Kumar, D Capellini, Q Neri, G Zackai, E Biesecker, LG AF Slavotinek, AM Searby, C Al-Gazali, L Hennekam, RCM Schrander-Stumpel, C Orcana-Losa, M Pardo-Reoyo, S Cantani, A Kumar, D Capellini, Q Neri, G Zackai, E Biesecker, LG TI Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients SO HUMAN GENETICS LA English DT Article ID CHROMOSOME 16Q; SYNDROME LOCUS; OBESITY; IDENTIFICATION; HETEROGENEITY; POPULATION AB McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome, comprising retinitis pigmentosa, polydactyly, obesity, mental retardation, and renal and genital anomalies. Bardet-Biedl syndrome is genetically heterogeneous with three cloned genes (BBS2, BBS4, and MKKS) and at least three other known loci (BBS1, BBS3, and BBS5). Both McKusick-Kaufman syndrome and Bardet-Biedl syndrome are inherited in an autosomal recessive pattern, and both syndromes are caused by mutations in the MKKS gene. However, mutations in MKKS are found in only 4%-11% of unselected Bardet-Biedl syndrome patients. We hypothesized that an analysis of patients with atypical Bardet-Biedl syndrome and McKusick-Kaufman syndrome (Group 1; 15 probands) and patients with Bardet-Biedl syndrome who had linkage results inconsistent with linkage to the other loci (Group II; 12 probands) could increase the MKKS mutation yield. Both mutant alleles were identified in only two families in Group II. Single (heterozygous) sequence variations were found in three Group I families and in two Group II families. Combining these results with previously published data showed that only one mutant allele was detected in nearly half of all patients screened to date, suggesting that unusual mutational mechanisms or patterns of inheritance may be involved. However, sequencing of the BBS2 gene in these patients did not provide any evidence of digenic or "triallelic" inheritance. The frequency of detected mutations in MKKS in Group II patients was 24%, i.e., six times higher than the published rate for unselected BBS patients, suggesting that small-scale linkage analyses may be useful in suitable families. C1 NHGRI, NIH, Bethesda, MD 20895 USA. Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52240 USA. United Arab Emirates Univ, Fac Med & Hlth Sci, Al Ain, U Arab Emirates. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. Afdeling Klin Genet, NL-6201 BL Maastricht, Netherlands. Hosp Univ Reina Sofia, Cordoba 14004, Spain. Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. Univ Roma La Sapienza, Rome, Italy. Sheffields Childrens Hosp, Sheffield S10 2TH, S Yorkshire, England. Osped Ninetto Melli, Brindisi, Italy. Univ Cattolica Sacro Cuore, I-00168 Rome, Italy. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Slavotinek, AM (reprint author), NHGRI, NIH, Bldg 49 Room 4B75,49 Convent Dr, Bethesda, MD 20895 USA. NR 28 TC 40 Z9 44 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2002 VL 110 IS 6 BP 561 EP 567 DI 10.1007/s00439-002-0733-3 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 572VZ UT WOS:000176796800005 PM 12107442 ER PT J AU Ren, ZX Lin, PY Klintworth, GK Iwata, F Munier, FL Schorderet, DF El Matri, L Theendakara, V Basti, S Reddy, M Hejtmancik, JF AF Ren, ZX Lin, PY Klintworth, GK Iwata, F Munier, FL Schorderet, DF El Matri, L Theendakara, V Basti, S Reddy, M Hejtmancik, JF TI Allelic and locus heterogeneity in autosomal recessive gelatinous drop-like corneal dystrophy SO HUMAN GENETICS LA English DT Article ID PRIMARY FAMILIAL AMYLOIDOSIS; CELL-SURFACE ANTIGENS; MONOCLONAL-ANTIBODIES; FINNISH TYPE; HUMAN CARCINOMAS; LINKAGE ANALYSIS; GENETIC-LINKAGE; GELSOLIN; MUTATION; BETA-IG-H3 AB Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disease characterized by the deposition of amyloid beneath the corneal epithelium and by severely impaired visual acuity leading to blindness. Although gelatinous corneal dystrophy has previously been mapped to chromosome 1p and seems to be associated with mutations in the M1S1 gene, molecular genetic studies have been limited to Japanese patients. To investigate the cause of GDLD in patients with diverse ethnic backgrounds, we performed linkage analyses in eight unrelated GDLD families from India, USA, Europe, and Tunisia. In seven of these families, the disease locus mapped to a 16-cM interval on the short arm of chromosome I between markers D1S519 and D1S2835, a region including the M1S1 gene. In addition, a 1.2-kb fragment containing the entire coding region of M1S1 gene was sequenced in affected individuals. Seven novel mutations (M1R, 8-bp ins., Q 118 E, V 194 E, C 119 S, 870delC, and 1117delA) were identified in six families and two unrelated individuals. No sequence abnormalities were detected in a single family in which the GDLD locus was also excluded from the M1S1 region by linkage analysis. These findings demonstrate allelic and locus heterogeneity for GDLD. C1 NEI, OGVFB, NIH, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD USA. Natl Yang Ming Univ, Dept Ophthalmol, Taipei Vet Gen Hosp, Taipei 112, Taiwan. Duke Univ, Dept Pathol, Durham, NC 27706 USA. Duke Univ, Dept Ophthalmol, Durham, NC 27706 USA. Univ Lausanne, Dept Ophthalmol, Lausanne, Switzerland. Univ Lausanne, Div Med Genet, Lausanne, Switzerland. Inst Hedi Rais Ophtalmol Tunis, Tunis, Tunisia. LV Prasad Eye Inst, Hyderabad 500034, Andhra Pradesh, India. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, Bldg 10,Room 10B10,10 Ctr Dr MSC 1860, Bethesda, MD 20892 USA. NR 39 TC 34 Z9 34 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2002 VL 110 IS 6 BP 568 EP 577 DI 10.1007/s00439-002-0729-z PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 572VZ UT WOS:000176796800006 PM 12107443 ER PT J AU Hayes, SM Love, PE AF Hayes, SM Love, PE TI Distinct structure and signaling potential of the gamma delta TCR complex SO IMMUNITY LA English DT Article ID T-CELL-RECEPTOR; EPSILON-RI-GAMMA; ALPHA-BETA; ANTIGEN RECEPTOR; POSITIVE SELECTION; MICE LACKING; ZETA-CHAIN; SURFACE EXPRESSION; LYMPHOCYTES-T; FC-RECEPTORS AB alphabeta and gammadelta T cells are distinguished by the clonotypic subunits contained within their TCRs. Although the alphabetaTCR has been well characterized, much less is known about the gammadeltaTCR. Here, we report that, unlike alphabetaTCRs, most gammadeltaTCRs expressed on ex vivo gammadelta T cells lack CD38. Despite this structural difference, signal transduction by the gammadeltaTCR is superior to that of the alphabetaTCR, as measured by its ability to induce calcium mobilization, ERK activation, and cellular proliferation. Additionally, the TCR complexes expressed on primary gammadelta T cells contain only homodimers; however, following activation and expansion, Fcis an element ofR1 7 is expressed and is included in the gammadeltaTCR complex. These results reveal fundamental differences in the primary structure and signaling potential of the alphabeta- and gammadeltaTCR complexes. C1 NICHHD, Lab Mammalian Genet & Dev, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genet & Dev, NIH, Bethesda, MD 20892 USA. NR 49 TC 77 Z9 81 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN PY 2002 VL 16 IS 6 BP 827 EP 838 DI 10.1016/S1074-7613(02)00320-5 PG 12 WC Immunology SC Immunology GA 568GL UT WOS:000176534000008 PM 12121664 ER PT J AU Arlotta, P Miyazaki, D Copeland, NG Gilbert, DJ Jenkins, NA Ono, SJ AF Arlotta, P Miyazaki, D Copeland, NG Gilbert, DJ Jenkins, NA Ono, SJ TI Murine NFX.1: isolation and characterization of its messenger RNA, mapping of its chromosomal location and assessment of its developmental expression SO IMMUNOLOGY LA English DT Article ID CLASS-II TRANSACTIVATOR; TRANSGENIC MICE; IN-VIVO; GENE; TRANSCRIPTION; COMPLEMENTATION; DEFICIENCY; MOLECULES; SEQUENCES; ABSENCE AB We have previously isolated (by expression cloning) a human cDNA, termed NFX.1, encoding a nucleic acid-binding protein that interacts with the conserved X1 box cis -element first discovered in class II major histocompatibility complex (MHC) genes. Functional studies involving expression of NFX.1 and assessment of expression from class II reporter constructs and endogenous class II MHC genes indicated that the factor could repress transcription of class II MHC genes. Subsequent studies have extended the biological significance of the factor, indicating that it plays an important role in neuronal development. Indeed, the reiterated RING finger motifs in the central domain of the polypeptide strongly suggest that NF-XI is a probable E3 ubiquitin protein ligase, indicating that the protein may have multiple activities. Here we report the cloning of the mouse homologue of the human NfX.1 cDNA: m-Nfx.1 . Comparison of the deduced primary sequence of mouse and human NFX.1 proteins shows very high homology and confirms that m-NFX.1 contains the conserved cysteine-rich DNA-binding motif first described in human NFX.1 (95% homology). Expression of MHC class II genes is substantially reduced following expression of m-NFX.1, which confirms that we have isolated the functional murine homologue of human NfX.1 cDNA. Further evidence comes from the mapping of m-Nfx.1 gene to the proximal region of mouse chromosome 4, a region syntenic to the location of human Nfx.1 (short arm of chromosome 9). Expression profiling shows that m-NFX.1 is expressed ubiquitously in both adult tissues and during development, supporting the hypothesis that it may have yet-undescribed roles in distinct biological processes. C1 UCL, Dept Immunol, Inst Ophthalmol, London EC1V 9EL, England. Univ London, Inst Child Hlth, London WC1N 1EH, England. Univ London, Inst Ophthalmol, London, England. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Ono, SJ (reprint author), UCL, Dept Immunol, Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England. EM santa.ono@ucl.ac.uk NR 25 TC 3 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD JUN PY 2002 VL 106 IS 2 BP 173 EP 181 DI 10.1046/j.1365-2567.2002.01416.x PG 9 WC Immunology SC Immunology GA 557AG UT WOS:000175884700005 PM 12047746 ER PT J AU Krause, RM AF Krause, RM TI A half-century of streptococcal research: Then & now SO INDIAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE acute rheumatic fever; GAS pharyngitis; Group A streptococcus; L forms; M-protein ID GROUP-A STREPTOCOCCUS; RHEUMATIC-FEVER; M PROTEIN; THROAT; INFECTIONS; SEQUENCE; DISEASE; SKIN AB Research on Group A streptococci (GAS) before 1950 paved the way for successful clinical trials to prevent acute rheumatic fever (ARF) by treating the prior streptococcal infection with penicillin. Prevention of ARF has led to almost complete disappearance of rheumatic heart disease in the industrialized world, but has yet to be accomplished in developing countries, where most of the world's populations reside. Twenty years of research beginning in. 1918 by Lancefield and others delineate the modern classification of haemolytic streptococci and led to the recognition that only Group A is responsible for the pharyngitis that causes ARE M-protein, identified as a major virulence factor, is a powerful inhibitor of phagocytosis, and antibodies to it promote type-specific phagocytosis and therefore type-specific immunity. Other virulent properties of GAS include a bulky capsule, as well as extracellular toxins such as streptolysins S and 0 and streptococcal proteinase. McCarty and others pursued the cell biology of GAS and identified the cellular localization of various antigenic components. The discovery of purified M-protein as a helical coiled-coiled fibrillar protein has sparked development of M-protein vaccine. US, UK, and Trinidad scientists described differences between streptococcal infections of the throat and skin and noted particularly that many of the GAS M-types that cause impetigo are less likely to cause pharyngitis. GAS impetigo may cause acute glomerulonephritis, but such infections do not result in ARF. The changing manifestations of disease over time and the evolution of microbes are common themes in medicine today. These themes are relevant to GAS pharyngitis and ARF, especially the decline in the incidence of severe ARF and the decrease in severity of GAS pharyngitis. Research on GAS bacteriophages led to the discovery of a relationship between lysogenic GAS and production of erythrogenic toxin and has broadened approaches to the molecular epidemiology of GAS virulence. The 21st century begins with determination of the complete genome sequence of M-1, M-18, and M-3 strains of GAS. These studies provide evidence for phage-encoded toxins, high-virulence phenotypes, and clone emergence. This research will reveal genetic processes at the molecular level that control the emergence and decline of streptococcai diseases in different, places and times and the shifting patterns in clinical manifestations. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Krause, RM (reprint author), NIAID, NIH, Bldg 16,Room 202,16 Ctr Dr, Bethesda, MD 20892 USA. NR 83 TC 10 Z9 10 U1 1 U2 2 PU INDIAN COUNCIL MEDICAL RES PI NEW DELHI PA PO BOX 4911 ANSARI NAGAR, NEW DELHI 110029, INDIA SN 0971-5916 J9 INDIAN J MED RES JI Indian J. Med. Res. PD JUN PY 2002 VL 115 BP 215 EP 241 PG 27 WC Immunology; Medicine, General & Internal; Medicine, Research & Experimental SC Immunology; General & Internal Medicine; Research & Experimental Medicine GA 611BM UT WOS:000178996600001 PM 12440194 ER PT J AU Morrison, RP Caldwell, HD AF Morrison, RP Caldwell, HD TI Immunity to murine chlamydial genital infection SO INFECTION AND IMMUNITY LA English DT Review ID OUTER-MEMBRANE PROTEIN; CD8(+) T-CELLS; MOUSE PNEUMONITIS BIOVAR; NITRIC-OXIDE SYNTHASE; GENE KNOCKOUT MICE; PROTECTIVE MONOCLONAL-ANTIBODIES; ANTI-BACTERIAL ACTIVITY; TRACT INFECTION; GAMMA-INTERFERON; TRACHOMATIS INFECTION C1 Montana State Univ, Dept Microbiol, Bozeman, MT 59717 USA. NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Morrison, RP (reprint author), Montana State Univ, Dept Microbiol, Lewis Hall,Room 109, Bozeman, MT 59717 USA. FU NIAID NIH HHS [AI-38991, R01 AI038991, R56 AI038991] NR 126 TC 273 Z9 286 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2002 VL 70 IS 6 BP 2741 EP 2751 DI 10.1128/IAI.70.6.2741-2751.2002 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 554XA UT WOS:000175761400001 PM 12010958 ER PT J AU Garraud, O Perraut, R Diouf, A Nambei, WS Tall, A Spiegel, A Longacre, S Kaslow, DC Jouin, H Mattei, D Engler, GM Nutman, TB Riley, EM Mercereau-Puijalon, O AF Garraud, O Perraut, R Diouf, A Nambei, WS Tall, A Spiegel, A Longacre, S Kaslow, DC Jouin, H Mattei, D Engler, GM Nutman, TB Riley, EM Mercereau-Puijalon, O TI Regulation of antigen-specific immunoglobulin G subclasses in response to conserved and polymorphic Plasmodium falciparum antigens in an in vitro model SO INFECTION AND IMMUNITY LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; MONKEY SAIMIRI-SCIUREUS; BLOOD B-LYMPHOCYTES; IN-VITRO; ANTIBODY-RESPONSES; IMMUNE-RESPONSES; T-CELL; PROTECTIVE IMMUNITY; MALARIA MORBIDITY; HOLOENDEMIC AREA AB Cytophilic antibodies (Abs) play a critical role in protection against Plasmodium falciparum blood stages, yet little is known about the parameters regulating production of these Abs. We used an in vitro culture system to study the subclass distribution of antigen (Ag)-specific immunoglobulin G (IgG) produced by peripheral blood mononuclear cells (PBMCs) from individuals exposed to P. falciparum or unexposed individuals. PBMCs, cultivated with or without cytokines and exogenous CD40/CD40L signals, were stimulated with a crude parasite extract, recombinant vaccine candidates derived from conserved Ags (19-kDa C terminus of merozoite surface protein 1 [MSP1(19)], R23, and PfEB200), or recombinant Ags derived from the polymorphic Ags MSP1 block 2 and MSP2. No P. falciparum -specific Ab production was detected in PBMCs from unexposed individuals. PBMCs from donors exposed frequently to P. falciparum infections produced multiple IgG subclasses when they were stimulated with the parasite extract but usually only one IgG subclass when they, Acre stimulated with a recombinant Ag. Optimal Ab production required addition of interleukin-2 (IL-2) and IL-10 for all antigenic preparations. The IgG subclass distribution was both donor and Ag dependent and was only minimally influenced by the exogenous cytokine environment. In vitro IgG production and subclass distribution correlated with plasma Abs to some Ags (MSP1, R23, and MSP2) but not others (PfEB200 and the three MSPI block 2-derived Ags). Data presented here suggest that intrinsic properties of the protein Ag itself play a major role in determining the subclass of the Ab response, which has important implications for rational design of vaccine delivery. C1 Inst Pasteur, Immunol Lab, Dakar, Senegal. Inst Pasteur, Lab Epidemiol Paludisme, Dakar, Senegal. Inst Pasteur, Unite Immunol Mol Parasites, Paris, France. Inst Pasteur, Unite Biol Interact Hote Parasite, Paris, France. NIAID, Malaria Vaccine Sect, NIH, Bethesda, MD 20892 USA. NIAID, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1, England. RP Univ St Etienne, GIMAP Immunol, Fac Med, 15 Rue Ambroise Pare, F-42023 St Etienne 2, France. EM Olivier.Garraud@univ-st-etienne.fr RI Riley, Eleanor/C-8960-2013; Mattei, Denise/B-1088-2014 OI Riley, Eleanor/0000-0003-3447-3570; NR 45 TC 37 Z9 37 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2002 VL 70 IS 6 BP 2820 EP 2827 DI 10.1128/IAI.70.6.2820-2827.2002 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 554XA UT WOS:000175761400011 PM 12010968 ER PT J AU Baranova, I Vishnyakova, T Bocharov, A Chen, ZG Remaley, AT Stonik, J Eggerman, TL Patterson, AP AF Baranova, I Vishnyakova, T Bocharov, A Chen, ZG Remaley, AT Stonik, J Eggerman, TL Patterson, AP TI Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells SO INFECTION AND IMMUNITY LA English DT Article ID CORONARY HEART-DISEASE; NF-KAPPA-B; HIGH-DENSITY-LIPOPROTEIN; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE CELLS; CHOLESTEROL EFFLUX; CHLAMYDIA-PNEUMONIAE; GENE-EXPRESSION; CELLULAR CHOLESTEROL; SIGNAL-TRANSDUCTION AB Lipopolysaccharide (LPS) has recently been shown to facilitate macrophage foam cell formation and has been suggested to be a proatherogenic factor. The mechanism of LPS induced cholesterol accumulation, however, is unclear. In this report, using the macrophage-like RAW 264.7 cell line, we provide experimental evidence that LPS's proatherogenic effects may at least in part reflect altered cholesterol metabolism. Data presented demonstrate that in a dose-dependent manner, LPS is able to down regulate the mRNA expression of the two primary high-density lipoprotein (HDL) receptors, scavenger receptor B1 (SR-B1) and ATP binding cassette A1 (ABCA1), with a 50% inhibitory concentration of less than 0.2 ng/ml, as well as to decrease SR-B1 protein expression by 80%. We also found that LPS treatment resulted in a significant decrease (to 20% of the control level) of the specific I-125-HDL binding as well as in 50% inhibition of the HDL-mediated cholesterol efflux compared to untreated cells. In addition, we compared the potencies of various modified LPS preparations and demonstrated that the phosphorylated lipid A portion of LPS, which is highly conserved among gram-negative microorganisms, including Chlamydia, is primarily responsible for the effects of LPS on SR-B1 and ABCA1 expression. Inhibitors of NF-kappaB activation were observed to efficiently block the suppressive effect of LPS on SR-B1 and ABCA1, suggesting a mechanism involving NF-kappaB. These data indicate that the LPS effects on cholesterol metabolism may contribute to the proatherogenic properties of LPS. C1 NHLBI, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. RP Patterson, AP (reprint author), NIH, Off Director, 6705 Rockledge Dr,Suite 750, Bethesda, MD 20892 USA. NR 60 TC 103 Z9 108 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2002 VL 70 IS 6 BP 2995 EP 3003 DI 10.1128/IAI.70.6.2995-3003.2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 554XA UT WOS:000175761400033 PM 12010990 ER PT J AU Feng, CG Woodside, KJ Vance, BA El-Khoury, D Canelles, M Lee, J Gress, R Fowlkes, BJ Shores, EW Love, PE AF Feng, CG Woodside, KJ Vance, BA El-Khoury, D Canelles, M Lee, J Gress, R Fowlkes, BJ Shores, EW Love, PE TI A potential role for CD69 in thymocyte emigration SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE CD69 antigen; development; lymphocyte activation; transgenes ID ACTIVATION ANTIGEN CD69; T-CELL ACTIVATION; RECENT THYMIC EMIGRANTS; POSITIVE SELECTION; TRANSGENIC MICE; RECEPTOR; EXPRESSION; DIFFERENTIATION; CHEMOKINES; MAJORITY AB The early activation marker, CD69, is transiently expressed on activated mature T cells and on thymocytes that are undergoing positive or negative selection in the thymus. CD69 is a member of the NK gene complex family of C-type lectin-like signaling receptors; however, its function is unknown. In this report, we describe the characterization of mice that constitutively express high levels of surface CD69 on immature and mature T cells throughout development. Constitutive surface expression of CD69 did not affect T cell maturation, signaling through the TCR or thymocyte selection. However, phenotypically and functionally mature thymocytes accumulated in the medulla of CD69 transgenic mice and failed to be exported from the thymus. The retention of mature thymocytes correlated with transgene dose and CD69 surface levels. These results identify a potential role for CD69 in controlling thymocyte export, and suggest that the transient expression of CD69 on thymocytes and T cells may function to regulate thymocyte and T cell trafficking. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Lab Mol & Cellular Immunol, NIH, Bethesda, MD 20892 USA. US FDA, Div Hematol Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. OI Woodside, Kenneth/0000-0002-7495-3758 NR 37 TC 89 Z9 92 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUN PY 2002 VL 14 IS 6 BP 535 EP 544 DI 10.1093/intimm/dxf020 PG 10 WC Immunology SC Immunology GA 557MJ UT WOS:000175912100001 PM 12039905 ER PT J AU Hendrick, RE Klabunde, C Grivegnee, A Pou, G Ballard-Barbash, R AF Hendrick, RE Klabunde, C Grivegnee, A Pou, G Ballard-Barbash, R TI Technical quality control practices in mammography screening programs in 22 countries SO INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE LA English DT Article DE mammography screening; quality assurance; quality control practices AB Objective. To assess current technical quality control (QC) practices within breast cancer screening or surveillance programs internationally. Materials and methods. The International Breast Cancer Screening Network (IBSN) conducted an extensive survey of quality assurance (QA) activities in developed countries known to have population-based breast cancer screening or surveillance programs in place. Twenty-three countries were sent questionnaires that included items about QA and QC requirements at screening sites, the minimum frequencies of QC test performance, and the personnel responsible for performing QC tests. Results. All 23 countries in the IBSN completed general information on their QA practices. Twenty-two countries responded with complete details on their technical QC practices. The responses indicated a pattern of consistently high-quality control practices among population-based breast cancer screening and surveillance programs. Most programs performed the great majority of QC tests. Variations were observed in the performance frequencies of QC tests and in the personnel responsible for performing QC tests. Conclusion. QC practices among population-based breast cancer screening and surveillance programs are highly evolved, with the great majority of responding countries following prescribed QC protocols. Further research is needed on appropriate performance frequencies for mammography QC tests. C1 Northwestern Univ, Sch Med, Lynn Sage Comprehens Breast Ctr, Chicago, IL 60611 USA. NCI, Appl Res Program, Bethesda, MD 20892 USA. Jules Bordet Canc Inst, Screening Epidemiol Clin, Brussels, Belgium. BCSP, Pro Qual Salute, Montevideo, Uruguay. RP Hendrick, RE (reprint author), Northwestern Univ, Sch Med, Lynn Sage Comprehens Breast Ctr, Galter Pavil,13th Floor,251 E Huron St, Chicago, IL 60611 USA. NR 9 TC 14 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1353-4505 J9 INT J QUAL HEALTH C JI Int. J. Qual. Health Care PD JUN PY 2002 VL 14 IS 3 BP 219 EP 226 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 563HA UT WOS:000176249200010 PM 12108532 ER PT J AU Bancroft, CC Chen, Z Yeh, J Sunwoo, JB Yeh, NT Jackson, S Jackson, C Van Waes, C AF Bancroft, CC Chen, Z Yeh, J Sunwoo, JB Yeh, NT Jackson, S Jackson, C Van Waes, C TI Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappa B and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE EGFR; NF-kappa B; AP-1; IL-8; VEGF; P13K; MEK; HNSCC ID PROINFLAMMATORY CYTOKINE EXPRESSION; HUMAN PANCREATIC ADENOCARCINOMA; CANCER-CELLS; TUMOR-GROWTH; FACTOR-ALPHA; CONSTITUTIVE ACTIVATION; BREAST-CANCER; IN-VIVO; PROANGIOGENIC CYTOKINES; INHIBITS ANGIOGENESIS AB We previously reported that expression of angiogenesis factors interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) is promoted by coactivation of transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) by interleukin-1alpha in human head and neck squamous cell carcinomas (HNSCC). However, expression of IL-1 receptor antagonist incompletely blocked reporter gene activity and cytokine expression, suggesting that other upstream signals may contribute to activation. Overexpression and autocrine activation of epidermal growth factor receptor (EGFR) is detected in 90% of HNSCC, and EGFR inhibitors have been reported to inhibit IL-8 and VEGF expression, but the intermediary signal pathways and transcription factors by which EGFR modulates proangiogenic factors is unknown. EGFR can activate the phosphotidylinositol-3 kinase (PI3K) and mitogen-activated/extracellular signal-regulated kinase (MEK) pathways, which can potentially modulate activation of NF-kappaB and AP-1, respectively. In our study, we examined the effect of EGF and antagonists of EGFR, P13K and MEK on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in HNSCC cell lines UM-SCC-9 and I I B in which EGFR is overexpressed and activated. Recombinant EGF induced EGFR phosphorylation, activation of NF-kappaB and AP-1 reporter genes and IL-8 and VEGF expression, indicating that EGFR can mediate coactivation of both transcription factors and cytokine genes in HNSCC. EGFR antagonist PD153035 and anti-EGFR antibody C225 completely inhibited EGF-induced reporter activity and cytokine expression, but only partially inhibited constitutive activity. MEK inhibitor U0126 preferentially blocked AP-1 activity and expression of both IL-8 and VEGF, while PI3K inhibitor LY-294002 or a dominant negative inhibitor-kappaB preferentially blocked NF-kappaB activation and expression of IL-8 but not VEGF. EGFR, PI3K and MEK antagonists inhibited growth of HNSCC. We conclude that antagonists of EGFR, PI3K and MEK signal pathways have inhibitory activity against EGFR-induced NF-kappaB and AP-1 activation, IL-8 and VEGF expression and growth by HNSCC. Published 2002 Wiley-Liss, Inc. C1 NIDOCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), NIDOCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bldg 10,Room 5D55,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD NIH HHS [Z01 DC 00016] NR 58 TC 175 Z9 182 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2002 VL 99 IS 4 BP 538 EP 548 DI 10.1002/ijc.10398 PG 11 WC Oncology SC Oncology GA 548DE UT WOS:000175372700007 PM 11992543 ER PT J AU Patel, V Aldridge, K Ensley, JF Odell, E Boyd, A Jones, J Gutkind, JS Yeudall, WA AF Patel, V Aldridge, K Ensley, JF Odell, E Boyd, A Jones, J Gutkind, JS Yeudall, WA TI Laminin-gamma 2 overexpression in head-and-neck squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE laminin; oral cancer; differential display; tumor progression; biomarker ID MALIGNANT-CELLS; ALPHA(6)BETA(4) INTEGRIN; ORAL KERATINOCYTES; BASEMENT-MEMBRANE; PROSTATE-CANCER; SARCOMA-CELLS; TUMOR-CELLS; LAMININ; EXPRESSION; LINES AB To identify molecular markers for the progression of head-and-neck squamous cell carcinoma (HNSCC), we used RNA arbitrarily primed (RAP) PCR to determine the qualitative and quantitative differences in gene expression between normal epithelial cells, those derived from dysplastic oral mucosa and invasive and metastatic HNSCC. Three differentially expressed DNA fragments (RAP20, RAP21, RAP26) that were upregulated in a tumor cell line (T45) were identified as being regions of the gamma2 subunit of human laminin-5. Northern blot analysis of total cellular RNA revealed overexpression of these transcripts in 6 of 7 HNSCC cell lines compared with normal epidermal keratinocytes. In contrast, no differences were observed in HeLa (cervical carcinoma) or HCT 116 (colon carcinoma) cells. Immunostaining of HNSCC cells derived from primary (HN4) and metastatic (HN12) tumors indicated elevated levels of endogenous laminin-gamma2 protein. Furthermore, HNSCC tissues demonstrated strong laminin-gamma2 staining, particularly in the peripheral basaloid cells of tumor islands at the invasion front. In contrast, only minimal staining of laminin-gamma2 was detected in basal cells of the normal epithelium. The data indicate that laminin-gamma2 is frequently overexpressed in HNSCCs and derivative cell lines and that its overexpression is likely to be useful as a marker of head-and-neck squamous malignancy. (C) 2002 Wiley-Liss, Inc. C1 Kings Coll London, GKT Dent Inst, Head & Neck Canc Program, London SE1 9RT, England. NIDCR, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. Wayne State Univ, Div Hematol Oncol, Detroit, MI USA. RP Yeudall, WA (reprint author), Kings Coll London, GKT Dent Inst, Head & Neck Canc Program, Floor 27,Guys Tower,St Thomas St, London SE1 9RT, England. EM andrew.yeudall@kcl.ac.uk RI Gutkind, J. Silvio/A-1053-2009; odell, edward/E-9920-2012 OI odell, edward/0000-0001-8435-0048 NR 44 TC 33 Z9 33 U1 1 U2 1 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 JUN 1 PY 2002 VL 99 IS 4 BP 583 EP 588 DI 10.1002/ijc.10403 PG 6 WC Oncology SC Oncology GA 548DE UT WOS:000175372700014 PM 11992550 ER PT J AU Singh, GK Siahpush, M AF Singh, GK Siahpush, M TI Increasing inequalities in all-cause and cardiovascular mortality among US adults aged 25-64 years by area socioeconomic status, 1969-1998 SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE mortality; cardiovascular; area socio-economic status; social inequality; time trend; Poisson regression ID HEART-DISEASE MORTALITY; COMMUNITY OCCUPATIONAL STRUCTURE; UNITED-STATES; SICK POPULATIONS; SOCIAL-CLASS; DEPRIVATION; DIFFERENTIALS; HEALTH; TRENDS; NEIGHBORHOODS AB Background This study examined the extent to which areal socio-economic gradients in all-cause and cardiovascular disease (CVD) mortality among US men and women aged 25-64 years increased between 1969 and 1998. Methods Using factor analysis 17 census tract variables were used to develop an areal index of socio-economic status that was used to stratify all US counties into five socio-economic categories. By linking the index to county-level mortality data from 1969 to 1998, we calculated annual age-adjusted mortality rates for each area socio-economic group. Poisson regression models were fitted to estimate areal socio-economic gradients in mortality over time. Results Areal socio-economic gradients in all-cause and cardiovascular mortality have increased substantially over the past three decades. Compared to men in the highest area socio-economic group, rates of all-cause and CVD mortality among men in the lowest area socio-economic group were 42% and 30% greater in 1969-1970 and 73% and 79% greater in 1997-1998, respectively. The gradients in mortality among women were steeper for CVD than for all causes. Compared to women in the highest area socio-economic group, rates of all-cause and CVD mortality among women in the lowest area socio-economic group were 29% and 49% greater in 1969-1970 and 53% and 94% greater in 1997-1998, respectively. Conclusions Although US all-cause and cardiovascular mortality declined for all area socio-economic groups during 1969-1998, the gradient increased because of significantly larger mortality declines in the higher socio-economic groups. Increasing areal inequalities in mortality shown here may be related to increasing temporal differences in the material and social living conditions between areas. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. VicHlth Ctr Tobacco Control, Canc Control Res Inst, Anticanc Council Victoria, Carlton, Vic 3053, Australia. RP Singh, GK (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Suite 504,MSC 8316, Bethesda, MD 20892 USA. NR 76 TC 98 Z9 101 U1 4 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2002 VL 31 IS 3 BP 600 EP 613 DI 10.1093/ije/31.3.600 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 562ZQ UT WOS:000176229200020 PM 12055162 ER PT J AU Brown, LM Thomas, TL Ma, JL Chang, YS You, WC Liu, WD Zhang, L Pee, D Gail, MH AF Brown, LM Thomas, TL Ma, JL Chang, YS You, WC Liu, WD Zhang, L Pee, D Gail, MH TI Helicobacter pylori infection in rural China: demographic, lifestyle and environmental factors SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Helicobacter pylori; risk factors; aetiology; transmission ID PRECANCEROUS GASTRIC-LESIONS; STOMACH-CANCER; HIGH-RISK; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; ALLIUM VEGETABLES; LIVING-CONDITIONS; ACTIVE INFECTION; LIFE-STYLE; PREVALENCE AB Background Although Helicobacter pylori is one of the most common human bacterial infections worldwide, its mode of transmission is unclear. Methods To investigate possible associations between H. pylori infection and demographic, lifestyle, and environmental factors in a rural Chinese population, a cross-sectional survey was administered to 3288 adults (1994 seropositive, 1019 seronegative, 275 indeterminate) from 13 villages in Linqu County, Shandong Province, China. Results Helicobacter pylori prevalence was elevated for: infrequent handwashing before meals (OR = 1.7, 95% CI: 1.0-3.0), crowding (i.e. sharing a bed with >2 people [OR = 2.3, 95% CI: 1.3-4.2]), washing/bathing in a pond or ditch (OR = 1.5, 95% CI: 1.0-2.4), and medium (OR = 1.6, 95% CI: 1.3-2.0) and low (OR = 2.3, 95% CI: 1.9-2.9) compared to high village education level, and reduced for never being married or divorced (OR = 0.4, 95% CI: 0.2-1.0). There was also a suggestion that source of drinking water, especially water from a shallow village well might be related to H. pylori seropositivity. There was no evidence of an association between H. pylori prevalence and alcohol or tobacco use, raw fruit and vegetable intake, or individual social class measures. Conclusions The results of this study suggest that person-to-person transmission is the most plausible route of H. pylori infection in this rural Chinese population, but waterborne exposures deserve further investigation. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Beijing Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Beijing Univ, Sch Oncol, Beijing 100034, Peoples R China. Linqu Publ Hlth Bur, Linqu 262600, Shandong Provin, Peoples R China. IMS Inc, Rockville, MD 20852 USA. RP Brown, LM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 8026,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-71103] NR 60 TC 45 Z9 52 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2002 VL 31 IS 3 BP 638 EP 646 DI 10.1093/ije/31.3.638 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 562ZQ UT WOS:000176229200025 PM 12055167 ER PT J AU Locke, JE Bradbury, CM Wei, SJ Shah, S Rene, LM Clemens, RA Roti, JR Horikoshi, N Gius, D AF Locke, JE Bradbury, CM Wei, SJ Shah, S Rene, LM Clemens, RA Roti, JR Horikoshi, N Gius, D TI Indomethacin lowers the threshold thermal exposure for hyperthermic radiosensitization and heat-shock inhibition of ionizing radiation-induced activation of NF-kappa B SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; MAP KINASE; CELL-LINES; ALPHA; SENSITIVITY; CISPLATIN; TARGETS; HELA AB Purpose: It is well established that salicylate and several other non-steroidal anti-inflammatory agents (NSAID), including indomethacin, can activate the heat-shock response, albeit at high concentrations. This is significant since heat shock significantly alters the cellular cytotoxic response to ionizing radiation (IR). It was previously shown that heat shock, as well as NSAIDs, inhibits IR-induced activation of NF-kappaB and that NF-kappaB protects against IR-induced cytotoxicity. Hence, it is hypothesized that pretreatment with indomethacin before heating will lower the temperature and heating times required to inhibit the activation of NF-kappaB and induce significant hyperthermic radiosensitization. Materials and methods: Experiments were performed in HeLa cell lines and the DNA-binding activity was determined by EMSA. Cellular radiosensitivity was determined by clonogenic assay. Results : HeLa cells pretreated with indomethacin showed a decrease in the temperature-time combination necessary to inhibit IR-induction of NF-kappaB DNA binding. In addition, clonogenic cell survival assays using identical conditions showed an indomethacin dose-dependent enhancement of hyperthermic radiosensitization. Thus, similar concentrations of indomethacin both lowered the threshold thermal exposure to inhibit activation of NF-kappaB DNA-binding and increased the sensitivity of tumour cells to hyperthermic radiosensitization-induced cytotoxicity. In HeLa cells treated with N-alpha-tosylphenylalanyl-chloromethyl ketone (TPCK), a serine protease inhibitor that blocks activation of NF-kappaB, an increase in radiosensitivity was observed. Interestingly, no additional cell killing was observed when heat shock was added to cells treated with TPCK before IR, suggesting a possible common cytotoxic pathway. Conclusions : The results demonstrate that indomethacin lowers the temperature-time conbination necessary to induce several physiological processes associated with the heat-shock response. Furthermore, NSAID may be potential adjuvants in improving the clinical effectiveness of hyperthermia in radiation therapy. C1 Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, Radiat Oncol Ctr,Sect Canc Biol, St Louis, MO 63110 USA. NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM giusd@mail.nih.gov FU NCI NIH HHS [P01 CA75556, 1 K08 CA72602-01, R01 CA43198] NR 32 TC 15 Z9 15 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0955-3002 EI 1362-3095 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD JUN PY 2002 VL 78 IS 6 BP 493 EP 502 DI 10.1080/09553000110120355 PG 10 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 561RF UT WOS:000176155800006 PM 12065054 ER PT J AU Sheets, NL Chauhan, BK Wawrousek, E Hejtmancik, JF Cvekl, A Kantorow, M AF Sheets, NL Chauhan, BK Wawrousek, E Hejtmancik, JF Cvekl, A Kantorow, M TI Cataract- and lens-specific Upregulation of ARK receptor tyrosine kinase in Emory mouse cataract SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALPHA-CRYSTALLIN; GROWTH ARREST; PROTEINS; EXPRESSION; CELLS; GENES; GLUTATHIONE; EVOLUTION; UFO/AXL; FAMILY AB PURPOSE. The Emory mouse is a well-characterized model for age-onset cataract. The purpose of the present study was to identify differentially expressed genes between pre- and post-cataract Emory mouse lenses. METHODS. Eyes were extracted from Emory mice at 3 weeks (precataract) and 7.5 months (postcataract) of age, and lenses were dissected. Lens RNA was compared for gene expression differences by RT-PCR differential display, and transcripts exhibiting altered levels of gene expression were cloned and identified by sequencing. The levels of two transcripts were further evaluated by RT-PCR in 3-week- and 7.5-month-old lenses and the remainder of the eye. The same transcripts were also measured in lenses front three non-Emory mouse strains (FVB/N, 129Sv, and CD1) ages 4 weeks to 11.5 months. RESULTS. Three transcripts were identified as exhibiting altered levels of gene expression between 3-week- and 7.5-month-old Emory mouse lenses. These encoded alphaA-crystallin (decreased), betaA3/A1-crystallin (decreased), and adhesion-related kinase (ARK) receptor tyrosine kinase (increased). Decreased alphaA-crystallin and increased ARK expression were not detected in lenses isolated from three non-Emory mouse strains of similar age. Increased expression of ARK was not detected between 3-week- and 7.5-month-old Emory mouse eye nonlens tissues. CONCLUSIONS. The present data confirm that expression of the alphaA-crystallin gene is decreased in cataract in the Emory mouse tens relative to age-matched control lenses and they provide evidence for cataract- and lens-specific upregulation of the ARK receptor tyrosine kinase in the Emory mouse. C1 W Virginia Univ, Dept Biol, Morgantown, WV 26506 USA. Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10467 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP W Virginia Univ, Dept Biol, 311 Brooks Hall, Morgantown, WV 26506 USA. EM mkantoro@wvu.edu RI Wawrousek, Eric/A-4547-2008; Cvekl, Ales/B-2427-2013 FU NEI NIH HHS [EY12200, EY13022, R01 EY012200, R01 EY013022, R01 EY013022-03] NR 25 TC 14 Z9 14 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2002 VL 43 IS 6 BP 1870 EP 1875 PG 6 WC Ophthalmology SC Ophthalmology GA 557VA UT WOS:000175927800027 PM 12036992 ER PT J AU Kador, PF Takahashi, Y Akagi, Y Neuenschwander, H Greentree, W Lackner, P Blessing, K Wyman, M AF Kador, PF Takahashi, Y Akagi, Y Neuenschwander, H Greentree, W Lackner, P Blessing, K Wyman, M TI Effect of galactose diet removal on the progression of retinal vessel changes in galactose-fed dogs SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALDOSE REDUCTASE INHIBITORS; DIABETIC-LIKE RETINOPATHY; PERICYTES; POLYOL; CAPILLARIES; PREVENTION; CELLS; RATS AB PURPOSE. Feeding dogs a diet containing 30% galactose induces experimental galactosemia and results in the formation of diabetes-like microvascular lesions of the retina. The appearance and progression of these retinal lesions can be arrested in a close-dependent manner by treating these dogs with aldose reductase inhibitors from the onset of galactosemia. To determine whether the elimination of galactosemia can also reduce the progression of retinal lesions, the galactose diet was removed from the galactosemic dogs after either the appearance of pericyte ghosts or formation of microaneurysms. METHODS. Ten control dogs were fed a normal diet, and 50 dogs were fed a diet containing 30% galactose. The galactose diet was removed from 15 dogs after 24 months, the time at which pericyte ghosts had previously been observed to develop, and from another 15 dogs after 31 months, when microaneurysms had previously been observed to develop. Eighteen dogs were continued on a galactose diet. Beginning at 24 months, eyes from each group were enucleated at approximately 6-month intervals. Changes in retinal lesions were quantified by computer image analyses. RESULTS. Significant (P < 0.05-0.01) increases in the endothelium-pericyte (E-P) ratio and decreases in pericyte density were observed with increased duration of galactose feeding. Although no reversal of retinal lesions occurred, differences in the progression of retinal lesions between the galactose-fed and galactose-deprived groups became evident after 12 to 24 months. CONCLUSIONS. Discontinuation of galactose in the diet at the initial stages of background retinopathy beneficially delays the progression of retinal lesions. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. Fukui Med Sch, Dept Ophthalmol, Fukui 91011, Japan. RP Kador, PF (reprint author), Dept Pharmaceut Sci, 986025 Nebraska Med Ctr, Omaha, NE 68198 USA. NR 35 TC 19 Z9 19 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2002 VL 43 IS 6 BP 1916 EP 1921 PG 6 WC Ophthalmology SC Ophthalmology GA 557VA UT WOS:000175927800034 PM 12036999 ER PT J AU Mofenson, LM Munderi, P AF Mofenson, LM Munderi, P TI Safety of antiretroviral prophylaxis of perinatal transmission for HIV-infected pregnant women and their infants SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE toxicity; antiretroviral therapy; perinatal HIV prevention ID IMMUNODEFICIENCY-VIRUS TYPE-1; TO-CHILD TRANSMISSION; EXPOSED IN-UTERO; NUCLEOSIDE ANALOGS; MITOCHONDRIAL-DNA; RANDOMIZED TRIAL; REVERSE-TRANSCRIPTASE; DISEASE PROGRESSION; ORAL ZIDOVUDINE; COTE-DIVOIRE AB Worldwide, more than 1600 infants become infected with HIV each day. Almost all infections are a result of rnother-to-child transmission of HIV, with most of these infections occurring in resource-poor countries. In developed Countries, antiret-roviral prophylaxis has dramatically reduced perinatal transmission to <2%. The potential now exists to extend this success to resource-poor countries using effective but shorter and less expensive antiretroviral regimens. With the potential widespread use of antiretroviral therapy for perinatal HIV prevention in resource-limited settings, there will be exposure of increasing numbers of infants to in utero and postpartum antiretroviral drugs for which long-term toxicity data is unknown. This article focuses on a review of what is known about safety of antiretroviral regimens used to interrupt mother-to-child transmission for women and their children. C1 NICHHD, Adolescent & Maternal AIDS Branch, NIH, Rockville, MD 20852 USA. WHO, CH-1211 Geneva, Switzerland. RP Mofenson, LM (reprint author), NICHHD, Adolescent & Maternal AIDS Branch, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 59 TC 66 Z9 69 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD JUN 1 PY 2002 VL 30 IS 2 BP 200 EP 215 DI 10.1097/01.QAI.0000018366.28828.86 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 574WV UT WOS:000176913400010 PM 12045684 ER PT J AU Nolan, M Fowler, MG Mofenson, LM AF Nolan, M Fowler, MG Mofenson, LM TI Antiretroviral prophylaxis of perinatal HIV-1 transmission and the potential impact of antiretroviral resistance SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Review DE resistance; perinatal HIV transmission; antiretroviral; treatment; prevention ID HUMAN-IMMUNODEFICIENCY-VIRUS; TO-CHILD TRANSMISSION; TYPE-1 REVERSE-TRANSCRIPTASE; SELECTIVE VERTICAL TRANSMISSION; MATERNAL-INFANT TRANSMISSION; RANDOMIZED CONTROLLED TRIAL; HIGH-LEVEL RESISTANCE; ZIDOVUDINE-RESISTANCE; DRUG-RESISTANCE; PROTEASE INHIBITORS AB Since 1994, trials of zidovudine, zidovudine and lamivudine. and nevirapine have demonstrated that these antiretroviral drugs can Substantially reduce the risk of perinatal HIV-1 transmission. With reductions in drug price. identification of simple, effective antiretroviral regiments to prevent perinatal HIV-1 transmission, and an increasing international commitment to support health care infrastructure, antiretrovirals for both perinatal HIV-1 prevention and HIV-1 treatment will likely become more widely available to HIV-1-infected persons in resource-limited countries. In the United States, widespread antiretroviral usage has been associated with increased antiretroviral drug resistance. This raises concern that drug resistance may reduce the effectiveness of perinatal antiretroviral prophylaxis as well as therapeutic intervention strategies. The purpose of this article is to review what is known about resistance and risk of perinatal HIV transmission, assess the interaction between antiretroviral resistance and the prevention of perinatal HIV-1 transmission, and discuss implications for Current global prevention and treatment strategies. C1 Ctr Dis Control & Prevent, NCHSTP, Div HIV AIDS, Epidemiol Branch,Project RETRO CI, Atlanta, GA 30333 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Rockville, MD USA. RP Nolan, M (reprint author), Ctr Dis Control & Prevent, NCHSTP, Div HIV AIDS, Epidemiol Branch,Project RETRO CI, MS E45, Atlanta, GA 30333 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 102 TC 31 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD JUN 1 PY 2002 VL 30 IS 2 BP 216 EP 229 DI 10.1097/01.QAI.0000018365.28828.5D PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 574WV UT WOS:000176913400011 PM 12045685 ER PT J AU Moolchan, ET Mermelstein, R AF Moolchan, ET Mermelstein, R TI Research on tobacco use among teenagers: Ethical challenges SO JOURNAL OF ADOLESCENT HEALTH LA English DT Review DE adolescents; ethics; research; substance abuse; tobacco ID SMOKING INITIATION; ADOLESCENTS; CHILDREN; CESSATION; ISSUES; AGE; PERMISSION; PATTERNS; CONSENT; SMOKERS AB Recent increases in adolescent smoking portend upcoming public health challenges as the majority of smokers initiate long-term addiction during youth, but experience major health consequences later in life. To effectively address this important teenage and adult health issue, critical research information and early interventions are needed, yet conducting tobacco research with teen smokers poses substantial challenges, including several ethical dilemmas. This paper reviews some of the ethical issues presented in etiologic and clinical treatment research addressing adolescent smoking. Common problems and possible solutions are presented. Issues of parent/guardian involvement, decision-making ability of teens, the need to maintain confidentiality are discussed, along with the specific problems of recruitment, compensation, and ethical challenges that arise in group treatment settings. Context-specific ethical adjustments and alternative perspectives are likely to be needed if we are to overcome procedural difficulties in conducting teen smoking studies. (C) Society for Adolescent Medicine, 2002. C1 NIDA, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, NIH, Baltimore, MD 21224 USA. Univ Illinois, Dept Psychol, Chicago, IL 60680 USA. Univ Illinois, Hlth Res Ctr, Chicago, IL 60680 USA. Univ Illinois, Policy Ctr, Chicago, IL 60680 USA. RP Moolchan, ET (reprint author), NIDA, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 42 Z9 42 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUN PY 2002 VL 30 IS 6 BP 409 EP 417 AR PII S1054-139X(02)00365-8 DI 10.1016/S1054-139X(02)00365-8 PG 9 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 557KZ UT WOS:000175908900002 PM 12039510 ER PT J AU Mechold, U Murphy, H Brown, L Cashel, M AF Mechold, U Murphy, H Brown, L Cashel, M TI Intramolecular regulation of the opposing (p)ppGpp catalytic activities of Rel(Seq), the Rel/Spo enzyme from Streptococcus equisimilis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID STREPTOMYCES-COELICOLOR A3(2); RELA/SPOT-HOMOLOGOUS GENE; ESCHERICHIA-COLI; GUANOSINE TETRAPHOSPHATE; SPOT GENE; MYCOBACTERIUM-TUBERCULOSIS; FUNCTIONAL-ANALYSIS; STRINGENT RESPONSE; MYXOCOCCUS-XANTHUS; PPGPP SYNTHESIS AB Catalytic and regulatory domains of the Rel/Spo homolog of Streptococcus equisimilis affecting (p)ppGpp synthesis and degradation activities have been defined, and opposing activities of the purified protein and its fragments have been compared. Two major domains of the 739-residue Rel(Seq) protein are defined by limited proteolytic digestion. In vitro assays of the purified N-terminal half-protein reveal synthesis of (p)ppGpp by an ATP-GTP 3'-pyrophosphotransferase as well as an ability to degrade (p)ppGpp by a Mn2+-dependent 3% pyrophosphohydrolase. Removal of the C-terminal half-protein has reciprocal regulatory effects on the activities of the N-terminal half-protein. Compared to the full-length protein, deletion activates (p)ppGpp synthesis specific activity about 12-fold and simultaneously inhibits (p)ppGpp degradation specific activity about 150-fold to shift the balance of the two activities in favor of synthesis. Cellular (p)ppGpp accumulation behavior is consistent with these changes. The bifunctional N-terminal half-protein can be further dissected into overlapping monofunctional subdomains, since purified peptides display either degradation activity (residues 1 to 224) or synthetic activity (residues 79 to 385) in vitro. These assignments can also apply to RelA and SpoT. The ability of Rel(Seq) to mediate (p)ppGpp accumulation during amino acid starvation in S. equisimilis is absent when the protein is expressed ectopically in Escherichia coli. Fusing the N-terminal half of RelSeq with the C-terminal domain of RelA creates a chimeric protein that restores the stringent response in E. coli by inhibiting unregulated degradation and restoring regulated synthetic activity. Reciprocal intramolecular regulation of the dual activities may be a general intrinsic feature of Rel/Spo homolog proteins. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Cashel, M (reprint author), NICHHD, Genet Mol Lab, NIH, Bldg 6B,Room 3B-314, Bethesda, MD 20892 USA. NR 51 TC 72 Z9 76 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2002 VL 184 IS 11 BP 2878 EP 2888 DI 10.1128/JB.184.11.2878-2888.2002 PG 11 WC Microbiology SC Microbiology GA 552AP UT WOS:000175596400005 PM 12003927 ER PT J AU Zhou, Y Filter, JJ Court, DL Gottesman, ME Friedman, DI AF Zhou, Y Filter, JJ Court, DL Gottesman, ME Friedman, DI TI Requirement for NusG for transcription antitermination in vivo by the lambda N protein SO JOURNAL OF BACTERIOLOGY LA English DT Article ID RHO-DEPENDENT TERMINATION; ESCHERICHIA-COLI; PHAGE-LAMBDA; BACTERIOPHAGE-LAMBDA; EXPRESSION; MUTATIONS; SIGNALS; COMPLEX; MUTANT AB Transcription antitermination by the bacteriophage lambda N protein is stimulated in vitro by the Escherichia coli NusG protein. Earlier work suggested that NusG was not required for N activity in vivo. Here we present evidence that NusG also stimulates N-mediated transcription antitermination in intact cells. C1 Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Frederick, MD 21702 USA. Columbia Univ Coll Phys & Surg, Inst Canc Res, New York, NY 10032 USA. RP Friedman, DI (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, 5641 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. FU NIGMS NIH HHS [GM37219, R01 GM037219, R56 GM037219]; PHS HHS [A111459-10] NR 28 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2002 VL 184 IS 12 BP 3416 EP 3418 DI 10.1128/JB.184.12.3416-3418.2002 PG 3 WC Microbiology SC Microbiology GA 557QG UT WOS:000175918800033 PM 12029062 ER PT J AU Bushel, PR Hamadeh, HK Bennett, L Green, J Ableson, A Misener, S Afshari, CA Paules, RS AF Bushel, PR Hamadeh, HK Bennett, L Green, J Ableson, A Misener, S Afshari, CA Paules, RS TI Computational selection of distinct class- and subclass-specific gene expression signatures SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE clustering; classification; microarray; ANOVA; LDA; gene expression; pattern recognition; bioinformatics ID MICROARRAY DATA; BREAST-CANCER; NORMAL COLON; PATTERNS; PROFILES; TOXICOGENOMICS; CLASSIFICATION; PREDICTION; MECHANISM; TOXICITY AB In this investigation we used statistical methods to select genes with expression profiles that partition classes and subclasses of biological samples. Gene expression data corresponding to liver samples from rats treated for 24 h with an enzyme inducer (phenobarbital) or a peroxisome proliferator (clofibrate, gemfibrozil or Wyeth 14,643) were subjected to a modified Z-score test to identify gene outliers and a binomial distribution to reduce the probability of detecting genes as differentially expressed by chance. Hierarchical clustering of 238 statistically valid differentially expressed genes partitioned class-specific gene expression signatures into groups that clustered samples exposed to the enzyme inducer or to peroxisome proliferators. Using analysis of variance (ANOVA) and linear discriminant analysis methods we identified single genes as well as coupled gene expression profiles that separated the phenobarbital from the peroxisome proliferator treated samples and discerned the fibrate (gemfibrozil and clofibrate) subclass of peroxisome proliferators. A comparison of genes ranked by ANOVA with genes assessed as significant by mixed linear models analysis [J. Comput. Biol. 8 (2001) 625] or ranked by information gain revealed good congruence with the top 10 genes from each statistical method in the contrast between phenobarbital and peroxisome proliferators expression profiles. We propose building upon a classification regimen comprised of analysis of replicate data, outlier diagnostics and gene selection procedures to utilize cDNA microarray data to categorize subclasses of samples exposed to pharmacologic agents. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Mol Min Corp, Kingston, ON K7L 2Y4, Canada. RP Bushel, PR (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 33 TC 27 Z9 32 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 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD JUN PY 2002 VL 35 IS 3 BP 160 EP 170 DI 10.1016/S1532-0464(02)00525-7 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 656ZX UT WOS:000181641900002 PM 12669979 ER PT J AU Zweckstetter, M Bax, A AF Zweckstetter, M Bax, A TI Evaluation of uncertainty in alignment tensors obtained from dipolar couplings SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE alignment tensor; backbone dynamics; dipolar coupling; error analysis; liquid crystal; order matrix; protein structure determination; ubiquitin ID LIQUID-CRYSTALLINE PHASE; PROTEIN-STRUCTURE DETERMINATION; RIGID-BODY MINIMIZATION; MAGNETIC-FIELD; DOMAIN ORIENTATION; HUMAN UBIQUITIN; SOLUTION NMR; DYNAMICS; MACROMOLECULES; VALIDATION AB Residual dipolar couplings and their corresponding alignment tensors are useful for structural analysis of macromolecules. The error in an alignment tensor, derived from residual dipolar couplings on the basis of a known structure, is determined not only by the accuracy of the measured couplings but also by the uncertainty in the structure (structural noise). This dependence is evaluated quantitatively on the basis of simulated structures using Monte-Carlo type analyses. When large numbers of dipolar couplings are available, structural noise is found to result in a systematic underestimate of the magnitude of the alignment tensor. Particularly in cases where only few dipolar couplings are available, structural noise can cause significant errors in best-fitted alignment tensor values, making determination of the relative orientation of small fragments and evaluation of local backbone mobility from dipolar couplings difficult. An example for the protein ubiquitin demonstrates the inherent limitations in characterizing motions on the basis of local alignment tensor magnitudes. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany. RP Zweckstetter, M (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 30 TC 95 Z9 95 U1 0 U2 7 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUN PY 2002 VL 23 IS 2 BP 127 EP 137 DI 10.1023/A:1016316415261 PG 11 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 573DE UT WOS:000176813400004 PM 12153038 ER EF