FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chesi, M Brents, LA Fly, SA Bais, C Robbiani, DF Mesri, E Kuehl, WM Bergsagel, PL AF Chesi, M Brents, LA Fly, SA Bais, C Robbiani, DF Mesri, E Kuehl, WM Bergsagel, PL TI Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma SO BLOOD LA English DT Article ID DYSPLASIA TYPE-II; PLASMA-CELL LINE; THANATOPHORIC DYSPLASIA; TRANSMEMBRANE DOMAIN; CHONDROCYTE PROLIFERATION; SKELETAL DISORDERS; GENE-MUTATIONS; FGF RECEPTORS; TRANSLOCATION; EXPRESSION AB The t(4;14) translocation occurs frequently in multiple myeloma (MM) and results in the simultaneous dysregulated expression of 2 potential oncogenes, FGFR3 (fibroblast growth factor receptor 3) from der(14) and multiple myeloma SET domain protein/Wolf-Hirschhorn syndrome candidate gene 1 from der(4), It is now shown that myeloma cells carrying a t(4;14) translocation express a functional FGFR3 that in some cases is constitutively activated by the same mutations that cause thanatophoric dysplasia, As with activating mutations of K-ras and N-ras, which are reported in approximately 40% of patients with MM, activating mutations of FGFR3 occur during tumor progression, However, the constitutive activation of ras and FGFR3 does not occur in the same myeloma cells, Thus the activated forms of these proteins appear to share an overlapping role in tumor progression, suggesting that they also share the signaling cascade, Consistent with this prediction, it is shown that activated FGFR3-when expressed at levels similar to those seen in t(4;14) myeloma-is an oncogene that acts through the MAP kinase pathway to transform NIH 3T3 cells, which can then generate tumors in nude mice, Thus, FGFR3,when overexpressed in MM, may be not only oncogenic when stimulated by FGF ligands in the bone marrow microenvironment, but is also a target for activating mutations that enable FGFR3 to play a ras-like role in tumor progression. (C) 2001 by The American Society of Hematology. C1 Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, Dept Med,Div Hematol Oncol, New York, NY 10021 USA. Cornell Univ, Weill Grad Sch Med Sci, Program Immunol, New York, NY 10021 USA. NCI, Dept Genet, Med Branch, Bethesda, MD 20892 USA. RP Bergsagel, PL (reprint author), Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, Dept Med,Div Hematol Oncol, Rm C-609,525 E 68th St, New York, NY 10021 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 FU NCI NIH HHS [CA74265] NR 49 TC 199 Z9 207 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2001 VL 97 IS 3 BP 729 EP 736 DI 10.1182/blood.V97.3.729 PG 8 WC Hematology SC Hematology GA 397LV UT WOS:000166697900019 PM 11157491 ER PT J AU Gubin, AN Miller, JL AF Gubin, AN Miller, JL TI Human erythroid porphobilinogen deaminase exists in 2 splice variants SO BLOOD LA English DT Article ID ASSISTED CELL PICKING; QUANTITATIVE RT-PCR; MESSENGER-RNA; GENE; EXPRESSION; SEQUENCE AB Human porphobilinogen deaminase (PBGD) is, reportedly, encoded by 2 distinct messenger RNAs (mRNAs) transcribing from a single gene. The ubiquitous form of the PBGD gene product is often used as an endogenous reference in gene expression studies because it is pseudo gene free and has minimal transcriptional variability among tissues. A distinct erythroid-specific gene product has also been described because of the alternate splicing of the gene. Here is reported the existence of an additional erythroid-specific isoform of PBGD mRNA in primary cells. (C) 2001 by The American Society of Hematology. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9B17, Bethesda, MD 20892 USA. NR 21 TC 10 Z9 12 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 FEB 1 PY 2001 VL 97 IS 3 BP 815 EP 817 DI 10.1182/blood.V97.3.815 PG 3 WC Hematology SC Hematology GA 397LV UT WOS:000166697900032 PM 11157504 ER PT J AU Gronthos, S Simmons, PJ Graves, SE Robey, PG AF Gronthos, S Simmons, PJ Graves, SE Robey, PG TI Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix SO BONE LA English DT Article DE integrins; marrow stromal precursor cells; CFU-F; extracellular matrix proteins; adhesion; monoclonal antibodies ID OSTEOBLAST-LIKE CELLS; SIGNAL-TRANSDUCTION; IN-VITRO; OSTEOGENIC PRECURSORS; ADHESION MOLECULES; CFU-F; EXPRESSION; DIFFERENTIATION; COLLAGEN; FIBROBLASTS AB To date, the precise interactions between bone marrow stromal cells and the extracellular matrix that govern stromal cell development remain unclear. The integrin super-family of cell-surface adhesion molecules represents a major pathway used by virtually all cell types to interact with different extracellular matrix components. In this study, purified populations of stromal precursor cells were isolated from the STRO-1-positive fraction of normal human marrow, by fluoresence-activated cell sorting, and then assayed for their ability to initiate clonogenic growth in the presence of various integrin ligands, Bone marrow-derived stromal progenitors displayed differential growth to fibronectin, vitronectin, and laminin, over collagen types I and III, but showed a similar affinity fur collagen type IV, The integrin heterodimers alpha (1)beta (1), alpha (2)beta (1), alpha (5)beta (1), alpha (6)beta (1), alpha (v)beta (3), and alpha (v)beta (5) were found to coexpress with the STRO-1 antigen on the cell surface of CFU-F, using dual-color analysis. Furthermore, only a proportion of stromal precursors expressed the integrin alpha (4)beta (1), while no measurable levels of the integrin alpha (3)beta (1) could be detected. Subsequent adhesion studies using functional blocking antibodies to different integrin alpha/beta heterodimers showed that stromal cell growth on collagen, laminin, and fibronectin was mediated by multiple beta (1) integrins, In contrast, cloning efficiency in the presence of vitronectin was mediated in part by alphav beta3, When human marrow stromal cells were cultured under osteoinductive conditions, their ability to form a mineralized matrix in vitro was significantly diminished in the presence of a functional blocking monoclonal antibody to the beta (1) integrin subunit, The results of this study indicate that beta (1) integrins appear to be the predominant adhesion receptor subfamily utilized by stromal precursor cells to adhere and proliferate utilizing matrix glycoproteins commonly found in the bone marrow microenvironment and bone surfaces. Furthermore, these data suggest a possible role for the beta (1) integrin subfamily during the development of stromal precursor tells into functional osteoblast-like cells. (Bone 28: 174-181; 2001) (C) 2001 by Elsevier Science Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Hanson Ctr Canc Res, Leukemia Res Unit, Matthew Roberts Lab, Adelaide, SA, Australia. Univ Adelaide, Royal Adelaide Hosp, Dept Orthopaed, Adelaide, SA, Australia. RP Gronthos, S (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & skeletal Dis Branch, NIH, Bldg 30, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011; Graves, Stephen/A-9463-2016 OI Robey, Pamela/0000-0002-5316-5576; Graves, Stephen/0000-0002-1629-319X NR 64 TC 203 Z9 218 U1 0 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD FEB PY 2001 VL 28 IS 2 BP 174 EP 181 DI 10.1016/S8756-3282(00)00424-5 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 403BE UT WOS:000167022000005 PM 11182375 ER PT J AU Tagamets, MA Horwitz, B AF Tagamets, MA Horwitz, B TI Interpreting PET and fMRI measures of functional neural activity: The effects of synaptic inhibition on cortical activation in human imaging studies SO BRAIN RESEARCH BULLETIN LA English DT Article DE human brain imaging; large-scale model; inhibition; local circuitry ID CEREBRAL GLUCOSE-UTILIZATION; ENERGY-METABOLISM; PREFRONTAL CORTEX; WORKING-MEMORY; HUMAN-BRAIN; BLOOD-FLOW; MECHANISMS; RAT; OBJECT AB Human brain imaging methods such as postiron emission tomography and functional magnetic resonance imaging have recently achieved widespread use in the study of both normal cognitive processes and neurological disorders, While many of these studies have begun to yield important insights into human brain function, the relationship between these measurements and the underlying neuronal activity is still not well understood. One open question is how neuronal inhibition is reflected in these imaging results. In this paper, we describe how large-scale modeling can be used to address this question. Specifically, we identify three factors that may play a role in how inhibition affects imaging results: (1) local connectivity; (2) context; and (3) type of inhibitory connection. Simulation results are presented that show how the interaction among these three factors can explain seemingly contradictory experimental results. The modeling suggests that neuronal inhibition can raise brain imaging measures if there is either low local excitatory recurrence or if the region is not otherwise being driven by excitation. Conversely, with high recurrence or actively driven excitation, inhibition can lower observed values. (C) 2001 Elsevier Science Inc. C1 Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. Natl Inst Deafness & Other Commun Disorders, Voice Speech & Language Branch, NIH, Bethesda, MD USA. RP Tagamets, MA (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. NR 31 TC 52 Z9 54 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB PY 2001 VL 54 IS 3 BP 267 EP 273 DI 10.1016/S0361-9230(00)00435-4 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 421CP UT WOS:000168044800003 PM 11287131 ER PT J AU Brinton, LA Persson, I Boice, JD McLaughlin, JK Fraumeni, JF AF Brinton, LA Persson, I Boice, JD McLaughlin, JK Fraumeni, JF TI Breast cancer risk in relation to amount of tissue removed during breast reduction operations in Sweden SO CANCER LA English DT Article DE breast cancer; breast reduction; risk ID PROPHYLACTIC MASTECTOMY; WOMEN; SIZE; AGE; TAMOXIFEN; SURGERY; TIME AB BACKGROUND. Women who undergo breast reduction operations have substantially lowered risks of breast cancer, and the reasons remain unclear. The current investigation attempted to assess whether the reduction in breast cancer risk was related directly to the amount of breast tissue removed. METHODS. Medical record retrieval was attempted for 161 breast cancer patients in a Swedish cohort of 31,910 women who had had breast reduction surgery and for 483 women who had not developed breast cancer. Information on amount of breast tissue removed was abstracted along with other factors that influence breast cancer risk. Odds ratios of developing breast cancer were calculated based on amount of breast tissue removed. RESULTS. The amount of tissue removed was a significant predictor of risk, as subjects in the highest quartile of tissue removal had a significantly lower risk than those in the lowest quartile. Considering the total amount of tissue removed (both breasts), subjects with greater than or equal to 1600 versus < 800 grams removed had an odds ratio (OR) of 0.24 [95% confidence interval (CI) 0.1-0.5]. This relation persisted after adjustment for other breast cancer risk factors and was apparent within every subgroup examined. CONCLUSIONS. The finding that breast cancer risk was reduced in proportion to the amount of tissue removed should be reassuring to women who are considering breast reduction procedures and to women who are electing to have bilateral total prophylactic mastectomies because of a strong genetic predisposition. Published 2001 by the American Cancer Society. C1 NCI, Bethesda, MD 20892 USA. Karolinska Inst, Stockholm, Sweden. Int Epidemiol Inst, Rockville, MD USA. RP Brinton, LA (reprint author), NCI, 6120 Execut Plaza S,Rm 7068, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 34 TC 46 Z9 47 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 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2001 VL 91 IS 3 BP 478 EP 483 DI 10.1002/1097-0142(20010201)91:3<478::AID-CNCR1025>3.0.CO;2-5 PG 6 WC Oncology SC Oncology GA 402GC UT WOS:000166976800004 PM 11169929 ER PT J AU Byrne, C Schairer, C Brinton, LA Wolfe, J Parekh, N Salane, M Carter, C Hoover, R AF Byrne, C Schairer, C Brinton, LA Wolfe, J Parekh, N Salane, M Carter, C Hoover, R TI Effects of mammographic density and benign breast disease on breast cancer risk (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE benign breast disease; breast cancer risk; mammographic density ID PARENCHYMAL PATTERNS; QUANTITATIVE-EVALUATION; FEMALE BREAST; FEATURES; WOMEN; CLASSIFICATION; TIME AB Background: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. Methods: This case-control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. Results: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3-3.6), and adjusting for benign breast histology, the OR for greater than or equal to 75% density was 3.8 (95% CI: 2.0-7.2). Women with nonproliferative benign breast disease and greater than or equal to 75% density had an OR of 5.8 (95% CI: 1.8-18.6), and women with < 50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1-8.0). Conclusions: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and greater than or equal to 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. Wolfe Radiol Associates, Detroit, MI USA. OncorMed, Gaithersburg, MD USA. RP Byrne, C (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. RI Brinton, Louise/G-7486-2015; Byrne, Celia/K-2964-2015 OI Brinton, Louise/0000-0003-3853-8562; Byrne, Celia/0000-0001-8289-4252 NR 25 TC 75 Z9 76 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2001 VL 12 IS 2 BP 103 EP 110 DI 10.1023/A:1008935821885 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 396LZ UT WOS:000166639000002 PM 11246838 ER PT J AU Brown, LM Gridley, G Pottern, LM Baris, D Swanson, CA Silverman, DT Hayes, RB Greenberg, RS Swanson, GM Schoenberg, JB Schwartz, AG Fraumeni, JF AF Brown, LM Gridley, G Pottern, LM Baris, D Swanson, CA Silverman, DT Hayes, RB Greenberg, RS Swanson, GM Schoenberg, JB Schwartz, AG Fraumeni, JF TI Diet and nutrition as risk factors for multiple myeloma among blacks and whites in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE case-control studies; diet; multiple myeloma; obesity; vitamin supplements ID FATTY-ACIDS; IMMUNE-SYSTEM; CANCER RISK; QUESTIONNAIRE; OBESITY AB Objectives: To explore whether dietary factors contribute to the risk of multiple myeloma and the two-fold higher incidence among blacks compared to whites in the United States. Methods: Data from a food-frequency questionnaire were analyzed for 346 white and 193 black subjects with multiple myeloma, and 1086 white and 903 black controls who participated in a population-based case-control study of multiple myeloma in three areas of the United States. Results: Elevated risks were associated with obese vs. normal weight (OR = 1.9, 95% confidence interval (CI) = 1.2-3.1 for whites and OR = 1.5, 95% CI = 0.9-2.4 for blacks), while the frequency of obesity was greater for black than white controls. Reduced risks were related to frequent intake of cruciferous vegetables (OR = 0.7, 95% CI = 0.6-0.99) and fish (OR = 0.7, 95% CI = 0.5-0.9) in both races combined, and to vitamin C supplements in whites (OR = 0.6, 95% CI = 0.5-0.9) and blacks (OR = 0.8, 95% CI = 0.5-1.4), with the frequency of vitamin supplement use being greater for white than black controls. However, frequent intake of vitamin C from food and supplements combined was associated with a protective effect in whites (OR = 0.6, 95% CI = 0.4-0.9), but not blacks (OR = 1.2, 95% CI = 0.8-2.1). Conclusions: The greater use of vitamin C supplements by whites and the higher frequency of obesity among blacks may explain part of the higher incidence of multiple myeloma among blacks compared to whites in the United States. In addition, the increasing prevalence of obesity may have contributed to the upward trend in the incidence of multiple myeloma during recent decades. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. Michigan Canc Fdn, Detroit, MI 48201 USA. New Jersey State Dept Hlth, Trenton, NJ 08625 USA. RP Brown, LM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 8026,6120 Execut Blvd,MSC 72, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-51089, N01-CP-51090, N01-CP51092] NR 35 TC 51 Z9 51 U1 2 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2001 VL 12 IS 2 BP 117 EP 125 DI 10.1023/A:1008937901586 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 396LZ UT WOS:000166639000004 PM 11246840 ER PT J AU Lacey, JV Frisch, M Brinton, LA Abbas, FM Barnes, WA Gravitt, PE Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Zaino, RJ Hildesheim, A AF Lacey, JV Frisch, M Brinton, LA Abbas, FM Barnes, WA Gravitt, PE Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Zaino, RJ Hildesheim, A TI Associations between smoking and adenocarcinomas and squamous cell carcinomas of the uterine cervix (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE cervical adenocarcinomas; confounding; human papillomaviruses; smoking; tobacco ID HUMAN-PAPILLOMAVIRUS INFECTION; RISK-FACTORS; CIGARETTE-SMOKING; INTRAEPITHELIAL NEOPLASIA; ORAL-CONTRACEPTIVES; ENDOMETRIAL CANCER; EPIDEMIOLOGY; NONSMOKERS; SMOKERS; WOMEN AB Objectives: Few studies of smoking and cervical carcinoma have addressed the rare cervical adenocarcinomas or used DNA-based tests to control for human papillomavirus (HPV) infection. Methods: This multicenter case-control study included 124 adenocarcinoma cases, 307 community controls (matched on age, race, and residence to adenocarcinoma cases), and 139 squamous carcinoma cases (matched on age, diagnosis date, clinic, and disease stage to adenocarcinoma cases). Participants completed risk-factor interviews and volunteered cervical samples for PCR-based HPV testing. Polychotomous logistic regression generated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for both histologic types. Results: Eighteen percent of adenocarcinoma cases, 43% of squamous carcinoma cases, and 22% of controls were current smokers. After control for HPV and other questionnaire data, adenocarcinomas were consistently inversely associated with smoking (e.g. current: OR = 0.6, 95% CI 0.3-1.1; greater than or equal to1 pack per day: OR = 0.7, 95% CI 0.4-1.3), while squamous carcinomas were positively associated with smoking (e.g. current: OR = 1.6, 95% CI 0.9-2.9; greater than or equal to1 pack per day: OR = 1.8, 95% CI 1.0-3.3). Results in analyses restricted to HPV-positive controls were similar. Conclusion: Smoking has opposite associations with cervical adenocarcinomas and squamous carcinomas. Although both histologic types are caused by HPV and arise in the cervix, etiologic co-factors for these tumors may differ. C1 NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, Hormonal Studies Sect, Rockville, MD 20852 USA. Statens Serum Inst, Dept Epidemiol Res, Danish Epidemiol Sci Ctr, DK-2300 Copenhagen, Denmark. Sinai Hosp, Baltimore, MD 21215 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. Roche Mol Syst Inc, Alameda, CA USA. Univ Penn, Grad Hosp, Philadelphia, PA 19104 USA. Westat Inc, Rockville, MD USA. Yale Univ, Sch Med, New Haven, CT USA. George Washington Univ, Div Gynecol Oncol, Washington, DC USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. RP Lacey, JV (reprint author), NCI, Div Canc Epidemiol & Genet, Environm Epidemiol Branch, Hormonal Studies Sect, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015; Frisch, Morten/E-9206-2016 OI Brinton, Louise/0000-0003-3853-8562; Frisch, Morten/0000-0002-3864-8860 NR 53 TC 44 Z9 45 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2001 VL 12 IS 2 BP 153 EP 161 DI 10.1023/A:1008918310055 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 396LZ UT WOS:000166639000008 PM 11246844 ER PT J AU Mellemkjaer, L Emborg, C Gridley, G Munk-Jorgensen, P Johansen, C Tjonneland, A Kjaer, SK Olsen, JH AF Mellemkjaer, L Emborg, C Gridley, G Munk-Jorgensen, P Johansen, C Tjonneland, A Kjaer, SK Olsen, JH TI Anorexia nervosa and cancer risk SO CANCER CAUSES & CONTROL LA English DT Article DE anorexia nervosa; epidemiology; neoplasms; record linkage ID EATING DISORDERS; BREAST-CANCER; CALORIC RESTRICTION; CELL-PROLIFERATION; FOOD RESTRICTION; MORTALITY; CARCINOGENESIS; COHORT; ADOLESCENCE; APOPTOSIS AB Objective: Energy restriction reduces the incidence of malignant tumors in experimental animals, but evidence for a similar effect in humans is lacking. To test the hypothesis in humans, we investigated cancer incidence among patients with anorexia nervosa, who have had an extremely low intake of calories for prolonged periods of their lives. Methods: Patients with anorexia nervosa (2151 women and 186 men) during 1970-1993 were identified in the population-based Danish Psychiatric Case Register and the National Registry of Patients. The cohort was linked to the Danish Cancer Registry, and cancer incidence among cohort members was compared with that of the general population. Results: The overall cancer incidence among women with anorexia nervosa was reduced by a factor of 0.80 (95% confidence interval 0.52-1.18) below that of the general population on the basis of 25 observed and 31.4 expected cases. Among men, two cases of cancer were observed, both confined to the brain, whereas 0.2 cases were expected. Conclusions: The finding of a slight reduction in cancer risk among women with anorexia nervosa may support the theory that a low-energy diet may decrease tumor development in humans. However, longer follow-up and control for confounding factors are needed to obtain more convincing evidence. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen O, Denmark. Hosp Psychiat, Inst Basic Psychiat Res, Dept Psychiat Demog, Aarhus, Denmark. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Mellemkjaer, L (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen O, Denmark. FU NCI NIH HHS [N01-CP-61111] NR 36 TC 23 Z9 23 U1 1 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2001 VL 12 IS 2 BP 173 EP 177 DI 10.1023/A:1008974414116 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 396LZ UT WOS:000166639000010 PM 11246846 ER PT J AU Grem, JL Quinn, M Ismail, AS Takimoto, CH Lush, R Liewehr, DJ Steinberg, SM Balis, FM Chen, AP Monahan, BP Harold, N Corse, W Pang, J Murphy, RF Allegra, CJ Hamilton, JM AF Grem, JL Quinn, M Ismail, AS Takimoto, CH Lush, R Liewehr, DJ Steinberg, SM Balis, FM Chen, AP Monahan, BP Harold, N Corse, W Pang, J Murphy, RF Allegra, CJ Hamilton, JM TI Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE 5-fluorouracil; infusion duration; pharmacology; biochemical modulation ID INTERFERON ALPHA-2A; RANDOMIZED TRIAL; GASTROINTESTINAL ADENOCARCINOMA; COLORECTAL-CARCINOMA; ADVANCED HEAD; NECK-CANCER; FLUOROURACIL; LEUCOVORIN; COMBINATION; SURVIVAL AB Purpose: Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion. Methods: A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon alpha -2a (5 MU/m(2) s.c., days 1-7), leucovorin (500 mg/m(2) i.v. over 30 min, days 2-6) and 5-FU (370 mg/m(2) i.v. over 1 h, days 2-6). The doses of 5-FU and interferon-a were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min. Results: The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m(2) per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min. Conclusion: Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUG. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity, These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered. C1 USN, Natl Med Ctr, Natl Canc Inst, Med Branch,Div Clin Sci, Bethesda, MD 20889 USA. NCI, Biostat & Data Management Sect, Off Director, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Pediat Branch, Bethesda, MD 20892 USA. USN, Natl Med Ctr, Dept Internal Med, Bethesda, MD 20889 USA. USN, Natl Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), USN, Natl Med Ctr, Natl Canc Inst, Med Branch,Div Clin Sci, 8901 Wisconsin Ave,Bldg 8,Rm 5101, Bethesda, MD 20889 USA. NR 32 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2001 VL 47 IS 2 BP 117 EP 125 DI 10.1007/s002800000189 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 412BX UT WOS:000167535100004 PM 11269737 ER PT J AU Nichols, KE Malkin, D Garber, JE Fraumeni, JF Li, FP AF Nichols, KE Malkin, D Garber, JE Fraumeni, JF Li, FP TI Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FRAUMENI-SYNDROME FAMILY; TUMOR-SUPPRESSOR GENE; ADRENAL-CORTICAL CARCINOMA; TP53 SPLICING MUTATION; CHOROID-PLEXUS TUMORS; BREAST-CANCER; PRONE FAMILY; ADRENOCORTICAL CARCINOMA; OLIGOMERIZATION DOMAIN; MALIGNANT-MELANOMA AB Germ-line p53 mutations are associated with dominantly inherited Li-Fraumeni syndrome (LFS), which features early-onset sarcomas of bone and soft tissues, carcinomas of the breast and adrenal cortex, brain tumors, and acute leukemias. However, carriers of germ-line p53 mutations may also be at increased risk of other cancers. To clarify the tumor spectrum associated with inherited p53 mutations, we examined cancer occurrences among our series of 45 families, plus 140 other affected cases and kindreds reported in the literature. The analyses included all cancers in patients with a germ-line p53 mutation and their first-degree relatives with nearly 50% likelihood of being a carrier. Data were abstracted on tumor types and ages at diagnosis in eligible family members, and duplicate reports were excluded. Among 738 evaluable cancers, 569 (77%) were the six tumor types (breast and adrenocortical carcinomas, sarcomas of the bone and soft tissues, brain tumors, and leukemias) associated with LFS, The remaining 169 (23%) cancers included diverse carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms that occurred at much earlier ages than expected in the general population. Unusually early ages at diagnosis are characteristic of hereditary cancers and suggest that carriers of germ-line p53 mutations are at increased risk of a wide range of neoplasms. Future studies addressing age-specific penetrance and site-specific cancer risks can increase the utility of LFS as a model for understanding the role of p53 alterations in carcinogenesis and for designing diagnostic and preventive interventions for the broad array of neoplasms in this syndrome. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, FP (reprint author), Dana Farber Canc Inst, Smith 201,44 Binney St, Boston, MA 02115 USA. NR 91 TC 181 Z9 186 U1 1 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 FEB PY 2001 VL 10 IS 2 BP 83 EP 87 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600001 PM 11219776 ER PT J AU Gravitt, PE Lacey, JV Brinton, LA Barnes, WA Kornegay, JR Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Zaino, R Hildesheim, A AF Gravitt, PE Lacey, JV Brinton, LA Barnes, WA Kornegay, JR Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Zaino, R Hildesheim, A TI Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; NATURAL-HISTORY; YOUNG-WOMEN; INFECTION; DNA; GENOTYPES; LESIONS; LAVAGE; RISK AB As human papillomavirus (HPV) becomes accepted as the central cause of cervical cancer, longitudinal studies are shifting focus away from causality to a more detailed investigation of the natural history of HPV infections. These studies commonly require repeated samples for HPV testing over several years, usually collected during a pelvic exam, which is inconvenient to the participants and costly to the study. To alleviate the inconvenience and cost of repeated clinic visits, it has been proposed that women collect cervicovaginal cells themselves, hopefully increasing participation in the natural history studies. We evaluated the technical feasibility of self-collection of cervicovaginal cells using a Dacron swab for HPV DNA detection. We compared the self-collected swab sample and two clinician-administered swab samples (one from the endocervix and another from the ectocervix) from a total of 268 women participating in a case-control study of adenocarcinoma and squamous cell carcinomas of the uterine cervix (111 cases and 157 controls). HPV DNA was detected and genotyped using an L1 consensus PCR assay. The overall agreement between the clinician- and self-collected swabs was excellent [88.1%; kappa = 0.73 (95% confidence interval (CI), 0.61-0.85)]. The correlation was highest between the two clinician-administered swabs [kappa = 0.81 (95% CI, 0.69-0.93)] but was still excellent when comparing either clinician-administered swab to the self-administered sample [kappa = 0.75 (95% CI, 0.63-0.87) and 0.67 (95% CI, 0.55-0.79) for ectocervix and endocervix, respectively], The type-specific agreement between samples was higher for high-risk, or cancer-associated, HPV genotypes than for low risk, noncancer-associated HPV genotypes when comparing the self-administered swab sample to the clinician-administered swab sample (kappa = 0.78 for high-risk versus 0.66 for low-risk HPV infections, t = -1.45, P = 0.15), The decrease in agreement for low risk types was largely attributable to an increased detection of these types in the self-administered sample (McNemar's chi (2) = 6.25, P = 0.01 for clinician- versus self-administered swab comparisons). The agreement did not vary significantly by age, menopausal status, case status, or clinic center, We have demonstrated that a self-collected Dacron swab sample of cervicovaginal cells is a technically feasible alternative to clinician-administered cervical cell collection in natural history studies of HPV and cervical cancer. C1 NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Roche Mol Syst, Dept Human Genet, Alameda, CA 94501 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. Grad Hosp Philadelphia, Philadelphia, PA 19146 USA. Westat Inc, Rockville, MD 20850 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. George Washington Univ, Washington, DC 20052 USA. Milton S Hershey Med Ctr, Hershey, PA 17033 USA. RP Gravitt, PE (reprint author), NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 24 TC 96 Z9 98 U1 1 U2 4 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 FEB PY 2001 VL 10 IS 2 BP 95 EP 100 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600003 PM 11219778 ER PT J AU Kjaer, SK Chackerian, B van den Brule, AJC Svare, EI Paull, G Walbomers, JMM Schiller, JT Bock, JE Sherman, ME Lowy, DR Meijer, CLM AF Kjaer, SK Chackerian, B van den Brule, AJC Svare, EI Paull, G Walbomers, JMM Schiller, JT Bock, JE Sherman, ME Lowy, DR Meijer, CLM TI High-risk human papillomavirus is sexually transmitted: Evidence from a follow-up study of virgins starting sexual activity (intercourse) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VIRUS-LIKE PARTICLES; YOUNG-WOMEN; SERUM ANTIBODIES; INFECTION; TYPE-16; DNA; TRANSMISSION; DETERMINANTS; GENOTYPES; ABSENCE AB Genital human papillomavirus (HPV) infection is generally considered to be sexually transmitted. However, nonsexual spread of the virus has also been suggested. The goal of this study was to assess: (a) the role of sexual intercourse in the transmission of HPV; (b) the determinants for seroconversion; and (c) the correlation between HPV DNA, abnormal cervical cytology, and serological response to HPV16, One hundred virgins and 105 monogamous women were randomly selected from a population-based cohort study in Copenhagen, Denmark, in which the women were examined twice with 2-year interval (interview, cervical swabs, Pap smear, blood samples), The presence of HPV DNA was determined by GP5+/6+ primers based HPV-PCR-EIA. HPV 16 virus-like particles (VLP) antibodies were detected by ELISA. All of the virgins were both HPV DNA negative and seronegative to VLP16, except for one woman who was weakly HPV 6 DNA positive. Only those virgins who initiated sexual activity became HPV DNA positive and/or VLP16 positive. The most important determinant of HPV DNA acquisition was the number of partners between the two examinations. The only significant risk factor for HPV 16 VLP seroconversion among women acquiring HPV DNA was HPV type, Our results show that sexual intercourse is important in the transmission of HPV, and that HPV 16 VLP seroconversion and the development of cervical lesions only occur after HPV transmission. Remarkably, no cervical lesions were found in HPV 16 DNA positive women who had seroconverted, Although based on small numbers, this may suggest that the development of antibodies had a protective effect. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen O, Denmark. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Univ Hosp, Dept Pathol, Sect Mol Pathol, Amsterdam, Netherlands. Gentofte Hosp, Dept Gynecol, Gentofte, Denmark. Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. Johns Hopkins Hosp, Dept Pathol, Baltimore, MD 21287 USA. RP Kjaer, SK (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen O, Denmark. FU NCI NIH HHS [R01 CA 47-812] NR 24 TC 142 Z9 151 U1 0 U2 7 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 FEB PY 2001 VL 10 IS 2 BP 101 EP 106 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600004 PM 11219765 ER PT J AU Ratnasinghe, D Yao, SX Tangrea, JA Qiao, YL Andersen, MR Barrett, MJ Giffen, CA Erozan, Y Tockman, MS Taylor, PR AF Ratnasinghe, D Yao, SX Tangrea, JA Qiao, YL Andersen, MR Barrett, MJ Giffen, CA Erozan, Y Tockman, MS Taylor, PR TI Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; TIN MINERS; DAMAGE; PROFICIENCY; SENSITIVITY; FREQUENCY; CARCINOMA; PROTEINS; EXPOSURE; YUNNAN AB We explored the association between polymorphisms of the DNA repair gene XRCC1 (codons 194, 280, and 399) and lung cancer risk in a case-control study nested within a cohort of tin miners. Cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased lung cancer risk (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) after adjustment for radon and tobacco exposure. In addition, individuals with the variant Arg280His allele who were alcohol drinkers seemed to be at higher risk for lung cancer compared with those with the homozygous wild-type genotype, Conversely, individuals with the variant Arg194Trp allele who were alcohol drinkers seemed to be at lower risk for lung cancer compared with those with the homozygous wild-type genotype, Polymorphisms of XRCC1 appear to influence risk of lung cancer and may modify risk attributable to environmental exposures. C1 NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Yunnan Tin Corp, Gejiu, Yunnan Province, Peoples R China. New Chem Ent Inc, Thetagen Div, Bothell, WA 98011 USA. Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. Informat Management Serv Inc, Silver Spring, MD 20904 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Ratnasinghe, D (reprint author), NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, 6006 Execut Blvd,Suite 321, Bethesda, MD 20892 USA. RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 20 TC 146 Z9 161 U1 0 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 FEB PY 2001 VL 10 IS 2 BP 119 EP 123 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600007 PM 11219768 ER PT J AU Stern, MC Umbach, DM van Gils, CH Lunn, RM Taylor, JA AF Stern, MC Umbach, DM van Gils, CH Lunn, RM Taylor, JA TI DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SISTER-CHROMATID EXCHANGE; BASE EXCISION-REPAIR; STRAND BREAK REPAIR; S-TRANSFERASE M1; LIGASE-III; POLY(ADP-RIBOSE) POLYMERASE; HUMAN CHROMOSOME-19; MOLECULAR-CLONING; PROTEIN XRCC1; FREE-RADICALS AB Bladder cancer is the sixth most common cancer in the United States. The main identified risk factor is cigarette smoking, which is estimated to contribute to up to 50% of new cases in men and 20% in women. Besides containing other carcinogens, cigarette smoke is a rich source of reactive oxygen species (ROS) that can induce a variety of DNA damage, some of which is repaired by the base excision repair (BER) pathway. The XRCC1 gene protein plays an important role in BER by serving as a scaffold for other repair enzymes and by recognizing single-strand DNA breaks. Three polymorphisms that induce amino acid changes have been found in codon 194 (exon 6), codon 280 (exon 9), and codon 399 (exon 10) of this gene. We tested whether polymorphisms in XRCC1 were associated with bladder cancer risk and whether this association was modified by cigarette smoking. Therefore, we genotyped for the three polymorphisms in 235 bladder cancer cases and 213 controls who had been frequency matched to cases on age, sex, and ethnicity. We found no evidence of an association between the codon 280 variant and bladder cancer risk [odds ratio (OR), 1.2; 95% confidence interval (CI), 0.6-2.6], We found some evidence of a protective effect for subjects that carried at least one copy of the codon 194 variant allele relative to those homozygous for the common allele (OR, 0.59; 95% CI, 0.3-1.0), The combined analysis with smoking history suggested a possible gene-exposure interaction; however, the results were not statistically significant. Similarly, for the codon 399 polymorphism, our data suggested a protective effect of the homozygous variant genotype relative to carriers of either one or two copies of the common allele (OR, 0.70; 95% CI, 0.4-1.3), and provided limited evidence, albeit not statistically significant, for a gene-smoking interaction. C1 NIEHS, Mol & Genet Epidemiol Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Computat Biol & Risk Anal, NIH, Res Triangle Pk, NC 27709 USA. RP Taylor, JA (reprint author), NIEHS, Mol & Genet Epidemiol Sect, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI taylor, jack/0000-0001-5303-6398 NR 52 TC 187 Z9 198 U1 0 U2 10 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 FEB PY 2001 VL 10 IS 2 BP 125 EP 131 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600008 PM 11219769 ER PT J AU Dorgan, JF Judd, JT Albert, P Brown, ED Corle, D Campbell, WS Baer, D Hartman, TJ Tejpar, A Clevidence, BA Giffen, CA Taylor, PR AF Dorgan, JF Judd, JT Albert, P Brown, ED Corle, D Campbell, WS Baer, D Hartman, TJ Tejpar, A Clevidence, BA Giffen, CA Taylor, PR TI Serum hormones potentially mediate the alcohol - Breast cancer association in postmenopausal women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Beltsville Human Nutr Res Ctr, Beltsville, MD USA. NCI, Bethesda, MD 20892 USA. Penn State Univ, University Pk, PA 16802 USA. NR 0 TC 0 Z9 0 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 FEB PY 2001 VL 10 IS 2 BP 155 EP 155 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600017 ER PT J AU Stolzenberg-Solomon, RZ Limburg, PJ Perez-Perez, G Blaser, MJ Virtamo, J Taylor, PR Albanes, D AF Stolzenberg-Solomon, RZ Limburg, PJ Perez-Perez, G Blaser, MJ Virtamo, J Taylor, PR Albanes, D TI Helicobacter pylori seropositivity and exocrine pancreatic cancer, a nested case-control study in male smokers. SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 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 FEB PY 2001 VL 10 IS 2 BP 155 EP 155 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600018 ER PT J AU Lee, BI Park, SH Kim, JW Sausville, EA Kim, HT Nakanishi, O Trepel, JB Kim, SJ AF Lee, BI Park, SH Kim, JW Sausville, EA Kim, HT Nakanishi, O Trepel, JB Kim, SJ TI MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells SO CANCER RESEARCH LA English DT Article ID HUMAN GASTRIC-CANCER; TGF-BETA; GENE PROMOTER; SP1; REPRESSION; ACTIVATION; SITES; LINE AB Transcriptional repression of the transforming growth factor (TGF)-beta type II receptor (T beta RII) gene appears to be a major mechanism to inactivate TGF-beta responsiveness in many human cancers. Because histone acetylation/deacetylation plays a role in transcriptional regulation, we have examined the effect of MS-275, a synthetic inhibitor of histone deacetylase, in human breast cancer cell lines. MS-275 showed antiproliferative activity against all human breast cancer cell lines examined and induced T beta RII mRNA, but not TGF-beta type I receptor mRNA. MS-275 caused an accumulation of acetylated histones H3 and H4 in total cellular chromatin, An increase in the accumulation of acetylated histones H3 and H4 was detected in the T beta RII promoter after treatment with MS-275, However, the level of histone acetylation did not change in chromatin associated with the TGF-beta type I receptor gene. MS-275 treatment enhanced TGF-beta1-induced plasminogen activator inhibitor 1 expression. Thus, antitumor activity of MS-275 may be mediated in part through the induction of T beta RII expression and consequent potentiation of TGF-beta signaling. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Med Branch, Bethesda, MD 20892 USA. Mitsui Pharmaceut, Chiba 2970017, Japan. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NR 27 TC 93 Z9 94 U1 0 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 FEB 1 PY 2001 VL 61 IS 3 BP 931 EP 934 PG 4 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100029 PM 11221885 ER PT J AU Lorenzo, PS Kung, JW Bottorff, DA Garfield, SH Stone, JC Blumberg, PM AF Lorenzo, PS Kung, JW Bottorff, DA Garfield, SH Stone, JC Blumberg, PM TI Phorbol esters modulate the ras exchange factor RasGRP3 SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; GOLGI-COMPLEX; BINDING; ACTIVATION; ASSOCIATION; MEMBRANE; SEQUENCE; PATHWAY; DOMAIN AB RasGRP represents the prototype of a new class of guanine nucleotide exchange factors that activate small GTPases, The guanyl nucleotide-releasing protein (GRP) family members contain catalytic domains related to CDC25, the Ras exchange factor of Saccharomyces cerevisiae, They also contain a motif resembling a pair of calcium-binding EF-hands and a C1 domain similar to the diacylglycerol interaction domain of protein kinase C, The sequence of KIAA0846, identified in a human brain cDNA library, encodes a member of the GRP family that we refer to as RasGRP3, We show here that RasGRP3 bound phorbol esters with high affinity. This binding depended on anionic phospholipids, which is characteristic of phorbol ester binding to C1 domain proteins. In addition, phorbol esters also caused activation of the RasGRP3 exchange activity in intact cells, as determined by an increase in Ras(GTP) and phosphorylation of the extracellular-regulated kinases, Finally, both phorbol 12-myristate Ij-acetate and the diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol induced redistribution of RasGRP3 to the plasma membrane and/or perinuclear area in HEK-293 cells, as demonstrated using a green fluorescent fusion protein. We conclude that RasGRP3 serves as a PKC-independent pathway to link the tumor-promoting phorbol esters with activation of pas GTPases. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. RP Blumberg, PM (reprint author), 37 Convent Dr MSC 4255,Bldg 37 Room 3A01, Bethesda, MD 20892 USA. NR 36 TC 86 Z9 88 U1 0 U2 4 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 FEB 1 PY 2001 VL 61 IS 3 BP 943 EP 949 PG 7 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100032 PM 11221888 ER PT J AU Fan, LJ Iyer, J Zhu, SX Frick, KK Wada, RK Eskenazi, AE Berg, PE Ikegaki, N Kennett, RH Frantz, CN AF Fan, LJ Iyer, J Zhu, SX Frick, KK Wada, RK Eskenazi, AE Berg, PE Ikegaki, N Kennett, RH Frantz, CN TI Inhibition of N-myc expression and induction of apoptosis by iron chelation in human neuroblastoma cells SO CANCER RESEARCH LA English DT Article ID HUMAN NEURO-BLASTOMA; TRANS-RETINOIC ACID; PROTEIN-KINASE-C; RIBONUCLEOTIDE REDUCTASE; DNA-SYNTHESIS; TRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; AMPLIFICATION; HYDROXYUREA; MECHANISM AB Neuroblastoma is the second most common solid malignancy of childhood. Enhanced expression of the amplified N-myc gene in the tumor tells may be associated with poor patient prognosis and may contribute to tumor development and progression. The use of deferoxamine mesylate (DFO), an iron chelator, to treat neuroblastoma is being investigated in national clinical studies. We show here by TUNEL assay and DNA laddering that DFO induces apoptosis in cultured human neuroblastoma cells, which is preceded by a decrease in the expression of N-myc and the altered expression of some other oncogenes (up-regulating c-fos and down-regulating c-myb) but not housekeeping genes. The decrease in N-myc expression is iron-specific but does not result from inhibition of ribonucleotide reductase, because specific inhibition of this iron-containing enzyme by hydroxyurea does not affect N-myc protein levels. Nuclear run-on and transient reporter gene expression experiments show that the decrease in N-myc expression occurs at the level of initiation of transcription and by inhibiting N-myc promoter activity. Comparison across neuroblastoma fell lines of the amount of residual cellular N-myc protein with the extent of apoptosis measured as pan-caspase activity after 48 h of iron chelation reveals no correlation, suggesting that the decrease in N-myc expression is unlikely to mediate apoptosis, In conclusion, chelation of cellular iron by DFO may alter the expression of multiple genes affecting the malignant phenotype by multiple pathways, Given the clinical importance of N-myc overexpression in neuroblastoma malignancy, decreasing N-myc expression by DFO might be useful as an adjunct to current therapy. C1 Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. NCI, Pediat Oncol Branch, NIH, Gaithersburg, MD 20877 USA. Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. Kapiolani Hlth Res Inst, Honolulu, HI 96813 USA. George Washington Univ, Dept Biochem & Mol Biol, Washington, DC 20037 USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. Wheaton Coll, Dept Biol, Wheaton, IL 60187 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Fan, LJ (reprint author), Univ Maryland, Sch Med, Dept Pediat, Room 10-044A,BRB,655 W Baltimore St, Baltimore, MD 21201 USA. FU NINDS NIH HHS [NS34432] NR 50 TC 49 Z9 52 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 FEB 1 PY 2001 VL 61 IS 3 BP 1073 EP 1079 PG 7 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100050 PM 11221835 ER PT J AU Harada, M Li, YF El-Gamil, M Rosenberg, SA Robbins, PF AF Harada, M Li, YF El-Gamil, M Rosenberg, SA Robbins, PF TI Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells SO CANCER RESEARCH LA English DT Article ID TYROSINASE-RELATED PROTEIN-2; IN-VIVO; INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; IDENTIFICATION; EXPRESSION; PEPTIDES; HLA-A2 AB An immunoselected melanoma cell line that had lost expression of the dominant melanoma antigens MART-1 and gp100 was generated in an attempt to identify previously unknown tumor antigens, After repeated stimulation with the autologous immunoselected tumor line, a number of HLA-A*0201-restricted T-cell clones were established from the peripheral blood of a single melanoma patient. One T-cell clone (C-22) recognized 14 of 16 HLA-A2(+) melanoma cell lines, as well as HLA-A2(+) melanocytes but recognized neither HLA-A2(+) fibroblasts nor autologous a cells. Screening of an autologous cDNA library resulted in the isolation of a transcript identical to an entry in the expressed sequence tag database. Northern blot analysis revealed that this gene was expressed in most melanoma cell lines and melanocytes but not in normal tissues. The peptide epitope (AMFGREFCYA) recognized by clone C-22 was identified based on studies of the recognition of truncated cDNAs and the use of the consensus HLA-A*0201 binding motif, A second T-cell clone (C-29) was found to recognize a new tyrosinase-related protein 2 epitope (455-363; YAIDLPVSV) in an HLA-A*0201-restricted manner. Together, these results provide additional targets that can be used for the development of immunotherapeutic protocols in HLA-A2(+) melanoma patients and demonstrate the utility of immunoselected tumor lines for the identification of new melanoma antigens. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Med Inst Bioregulat, Dept Virol, Fukuoka 8128582, Japan. RP Robbins, PF (reprint author), NCI, Surg Branch, NIH, Room 2B42, Bethesda, MD 20892 USA. NR 18 TC 42 Z9 44 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 FEB 1 PY 2001 VL 61 IS 3 BP 1089 EP 1094 PG 6 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100052 PM 11221837 ER PT J AU Pollock, PM Welch, J Hayward, NK AF Pollock, PM Welch, J Hayward, NK TI Evidence for three tumor suppressor loci on chromosome 9p involved in melanoma development SO CANCER RESEARCH LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; SPORADIC PRIMARY MELANOMAS; HOMOZYGOUS DELETIONS; CDKN2 GENE; MUTATIONAL ANALYSIS; GERMLINE MUTATIONS; BLADDER CANCERS; DELETED REGION; LUNG CANCERS; P16 GENE AB Cytogenetic and loss of heterozygosity (LOH) studies have long indicated the presence of a tumor suppressor gene (TSG) on 90 involved in the development of melanoma, Although LOH at 90 has been reported in approximately 60% of melanoma tumors, only 5-10% of these tumors have been shown to carry CDKN2A mutations, raising the possibility that another TSG involved in melanoma maps to chromosome 90. To investigate this possibility, a panel of 37 melanomas derived from 35 individuals was analyzed for CDKN2A mutations hy single-strand conformation polymorphism analysis and sequencing. The melanoma samples were then typed for 15 markers that map to 9p13-24 to investigate LOH trends in this region. In those tumors demonstrating retention of heterozygosity at markers flanking CDKN2A and LOH on one or both sides of the gene, multiplex microsatellite PCR was performed to rule out homozygous deletion of the region encompassing CDKN2A. CDKN2A mutations were found in tumors from 5 patients [5 (14%) of 35], 4 of which demonstrated LOH across the entire region examined. The remaining tumor with no observed LOH carried two point mutations, one on each allele, Although LOH was identified at one or more markers in 22 (59%) of 37 melanoma tumors corresponding to 20 (57%) of 35 individuals, only 11 tumors from 9 individuals [9 (26%) of 35] demonstrated LOH at D9S942 and D9S1748, the markers closest to CDKN2A. Of the remaining 11 tumors with LOH, 9 demonstrated LOH at two or more contiguous markers either centromeric and/or telomeric to CDKN2A while retaining heterozygosity at several markers adjacent to CDKN2A. Multiplex PCR revealed one tumor carried a homozygous deletion extending from D9S1748 to the IFN-alpha locus. In the remaining eight tumors, multiplex PCR demonstrated that the observed heterozygosity was not attributable to homozygous deletion and stromal contamination at D9S1748, D9S942, or D9S974, as measured by comparative amplification strengths, which indicates that retention of heterozygosity with flanking LOH does not always indicate a homozygous deletion, This report supports the conclusions of previous studies that at least two TSGs involved in melanoma development in addition to CDKN2A may reside on chromosome 9p. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Queensland, Queensland Inst Med Res, Joint Expt Oncol Program, Brisbane, Qld 4029, Australia. Queensland Canc Fund, Brisbane, Qld 4029, Australia. RP Hayward, NK (reprint author), Post Off Royal Brisbane Hosp, Queensland Inst Med Res, Canc Unit, Herston, Qld 4029, Australia. RI hayward, nicholas/C-1367-2015 OI hayward, nicholas/0000-0003-4760-1033 NR 42 TC 59 Z9 60 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 FEB 1 PY 2001 VL 61 IS 3 BP 1154 EP 1161 PG 8 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100061 PM 11221846 ER PT J AU Waidyanatha, S Rothman, N Fustinoni, S Smith, MT Hayes, RB Bechtold, W Dosemeci, M Guilan, L Yin, SN Rappaport, SM AF Waidyanatha, S Rothman, N Fustinoni, S Smith, MT Hayes, RB Bechtold, W Dosemeci, M Guilan, L Yin, SN Rappaport, SM TI Urinary benzene as a biomarker of exposure among occupationally exposed and unexposed subjects SO CARCINOGENESIS LA English DT Article ID S-PHENYLMERCAPTURIC ACID; TRANS,TRANS-MUCONIC ACID; MUCONIC ACID; CHINESE WORKERS; EXCRETION; METABOLISM; PHENOL; HYDROQUINONE; INDICATOR; RETENTION AB Urinary benzene (UB) was investigated as a biomarker of exposure among benzene-exposed workers and unexposed subjects in Shanghai, China, Measurements were performed via headspace solid phase microextraction of 0.5 mi of urine specimens followed by gas chromatography-mass spectrometry, This assay is simple and more sensitive than other methods (detection limit 0.016 mug benzene/l urine). The median daily benzene exposure was 31 p.p.m. (range 1.65-329 p.p.m.), When subjects were divided into controls (n = 41), those exposed to less than or equal to 31 p.p.m. benzene (n = 22) and >31 p.p.m. benzene (n = 20), the median UB levels were 0.069, 4.95 and 46.1 mug/l, respectively (Spearman r = 0.879, P < 0.0001), A linear relationship was observed between the logarithm of UB and the logarithm of benzene exposure in exposed subjects according to the following equation: In(UB, g/l) = 0.196 + 0.709 In (exposure, p.p.m.) (r = 0.717, P < 0.0001), Considering all subjects, linear relationships were also observed between the logarithm of UB and the corresponding logarithms of four urinary metabolites of benzene, namely t,t-muconic acid (r = 0.938, P < 0.0001), phenol (r = 0.826, P < 0.0001), catechol (r = 0.812, P < 0.0001) and hydroquinone (r = 0.898, P < 0.0001). Ratios of individual metabolite levels to total metabolites versus UB provide evidence of competitive inhibition of CYP450 enzymes leading to increased production of phenol and catechol at the expense of hydroquinone and muconic acid, Among control subjects UB was readily detected with a mean level of 0.145 g/l (range 0.027-2.06 mug/l), compared with 5.63 mug/l (range 0.837-26.38 mug/l) in workers exposed to benzene below 10 p.p.m. (P < 0.0001), This suggests that UB is a good biomarker for exposure to low levels of benzene. C1 Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. Chinese Acad Prevent Med, Inst Occupat Med, Beijing 100050, Peoples R China. Lovelace Resp Res Inst, Albuquerque, NM 87185 USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Ist Clin Perfezionamento, I-20122 Milan, Italy. NCI, Div Can Epidemiol & Genet, Bethesda, MD 20892 USA. RP Rappaport, SM (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. RI Fustinoni, Silvia/I-8773-2012 OI Fustinoni, Silvia/0000-0002-0287-7338 FU NIEHS NIH HHS [P42ES05948] NR 41 TC 71 Z9 77 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 FEB PY 2001 VL 22 IS 2 BP 279 EP 286 DI 10.1093/carcin/22.2.279 PG 8 WC Oncology SC Oncology GA 405LN UT WOS:000167161100010 PM 11181449 ER PT J AU Karabinis, ME Larson, D Barlow, C Wynshaw-Boris, A Moser, AR AF Karabinis, ME Larson, D Barlow, C Wynshaw-Boris, A Moser, AR TI Heterozygosity for a mutation in Brca1 or Atm does not increase susceptibility to ENU-induced mammary tumors in Apc(Min)/+ mice SO CARCINOGENESIS LA English DT Article ID ATAXIA-TELANGIECTASIA HETEROZYGOTES; MULTIPLE INTESTINAL NEOPLASIA; BREAST-CANCER; DEFICIENT MICE; GENE BRCA1; DNA-DAMAGE; APC GENE; MOUSE; MORPHOGENESIS; PREDISPOSES AB The proteins encoded by BRCA1 and ATM may be important in DNA repair and maintenance of genomic integrity. Women heterozygous for a mutation in BRCA1 have an increased incidence of breast cancer, Some evidence also suggests that female carriers of ATM mutations may be susceptible to breast cancer. However, mice carrying one mutant allele of Brca1 or Atm are not highly susceptible to breast cancer. We proposed that heterozygosity for a mutant allele of Brca1 or Atm may confer a decreased ability to repair DNA damage. Such a defect might lead to a heightened sensitivity to tumor development in susceptible animal models. Therefore, mice predispose to mammary tumor development might show an increased susceptibility if they also carry an Atm or Brca1 mutation. C57BL/6J (B6) Min/+ mice are predisposed to mammary and intestinal tumors and exposure to the point mutagen ethylnitrosourea (ENU) markedly increases mammary tumor multiplicity and incidence. To test our hypothesis, B6.Min/+ male mice were crossed with 129S6/SvEvTac females heterozygous for a mutant allele of either Brca1 or Atm, Female progeny from each cross were treated with ENU and followed for tumor development. Only Min/+ Fl females developed mammary tumors and heterozygosity for a mutant Brca1 or Atm allele had no effect on mammary or intestinal tumor incidence and multiplicity. These results suggest that heterozygosity for a mutation in Brca1 or Atm does not affect Min-induced tumorigenesis in mice under these conditions. Additionally, exposure to a somatic point mutagen does not increase tumor development in mice carrying Brca1 or Atm mutations. C1 Univ Wisconsin, Dept Human Oncol, Madison, WI 53792 USA. Univ Wisconsin, Genet Lab, Madison, WI 53792 USA. Univ Calif San Diego, Sch Med, Dept Pediat, San Diego, CA 92103 USA. Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92103 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Moser, AR (reprint author), Univ Wisconsin, Dept Human Oncol, K4-330 CSC 3864,600 Highland Ave, Madison, WI 53792 USA. NR 34 TC 8 Z9 8 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2001 VL 22 IS 2 BP 343 EP 346 DI 10.1093/carcin/22.2.343 PG 4 WC Oncology SC Oncology GA 405LN UT WOS:000167161100019 PM 11181458 ER PT J AU Laurent, P Wood, CM Wang, Y Perry, SF Gilmour, KM Part, P Chevalier, C West, M Walsh, PJ AF Laurent, P Wood, CM Wang, Y Perry, SF Gilmour, KM Part, P Chevalier, C West, M Walsh, PJ TI Intracellular vesicular trafficking in the gill epithelium of urea-excreting fish SO CELL AND TISSUE RESEARCH LA English DT Article DE gill epithelium; ultrastructure; pavement cell; lysosome vesicle trafficking; Opsanus beta; Opsanus tau; Porichthys notatus (Teleostei, Batrachoididae) ID TOADFISH OPSANUS-BETA; ACID-BASE REGULATION; FRESH-WATER FISHES; GULF TOADFISH; CHLORIDE CELLS; PAVEMENT CELLS; NITROGEN-EXCRETION; RAINBOW-TROUT; MORPHOLOGY; TRANSPORT AB Most teleost fish are ammoniotelic, and relatively few are ureotelic, in which the majority of nitrogenous waste is excreted as urea. This study aimed to determine whether the gill ultrastructure of ureotelic fish might have specific, unique characteristics compared with ammoniotelic fish. The gill morphology was studied in three closely related species of the family Batrachoididae: Opsanus beta, the gulf toadfish; Opsanus tau, the oyster toadfish; and Porichthys notatus, the plainfin midshipman, because prior studies have demonstrated that the two former species are ureotelic and excrete urea in unique, short daily pulses, whereas the latter is ammoniotelic. Ultrastructural studies demonstrated significant trafficking of dense-cored vesicles (50-200 nm) between the Golgi apparatus and the apical membrane of epithelial cells surrounding gill filaments and lamellae in these two Opsanus spp. The material constituting the core of these vesicles was intensely stained by lead salt and was unloaded externally when vesicles contacted the apical membrane. Another characteristic of these urea-secreting fish was the presence of numerous large, black-stained lysosomes, which contained cored vesicles, suggesting a second destination for the dense-cored vesicles. As a working hypothesis, the present data suggest that the urea-transporter protein, recently found in toadfish gills, is inserted in the vesicle. Subsequently, it could serve to either sequester cytosolic urea that ultimately is secreted into the water after contact of these vesicles with the pavement cell apical membrane, or it could allow facilitated diffusion of urea across the plasma membrane following insertion into the membrane. As further comparative evidence, the ammoniotelic P. notatus exhibited neither the vesicular trafficking nor the population of lysosomes both found in Opsanus spp. C1 CNRS, Ctr Ecol & Physiol Energet, F-67037 Strasbourg, France. Univ Waterloo, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Univ Ottawa, Dept Biol, Ottawa, ON K1N 6N5, Canada. Univ Ottawa, Dept Biol, Ottawa, ON K1S 5B5, Canada. Commiss European Communities, Joint Res Ctr, Inst Environm, CCR, I-21020 Ispra, VA, Italy. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS,Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Laurent, P (reprint author), CNRS, Ctr Ecol & Physiol Energet, 23 Rue Becquerel,BP 20 CR, F-67037 Strasbourg, France. NR 33 TC 16 Z9 16 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD FEB PY 2001 VL 303 IS 2 BP 197 EP 210 DI 10.1007/s004410000312 PG 14 WC Cell Biology SC Cell Biology GA 405VU UT WOS:000167181900006 PM 11291766 ER PT J AU Cuvillier, O Nava, VE Murthy, SK Edsall, LC Levade, T Milstien, S Spiegel, S AF Cuvillier, O Nava, VE Murthy, SK Edsall, LC Levade, T Milstien, S Spiegel, S TI Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; sphingosine; doxorubicin; cytochrome c; caspases ID PROTEIN-KINASE-C; DAUNORUBICIN-INDUCED APOPTOSIS; NEUTRAL SPHINGOMYELINASE ACTIVATION; NOVO SPHINGOLIPID BIOSYNTHESIS; INDUCED CERAMIDE GENERATION; FAS-INDUCED APOPTOSIS; NECROSIS-FACTOR-ALPHA; CANCER-CELLS; DNA FRAGMENTATION; GLUCOSYLCERAMIDE SYNTHASE AB Treatment of human breast carcinoma MCF7 cells with doxorubicin, one of the most active antineoplastic agents used in clinical oncology, induces apoptosis and leads to increases in sphingosine levels. The transient generation of this sphingolipid mediator preceded cytochrome c release from the mitochondria and activation of the executioner caspase-7 in MCF7 cells which do not express caspase-3. Bcl-x(L) overexpression did not affect sphingosine generation whereas it reduced apoptosis triggered by doxorubicin and completely blocked apoptosis triggered by sphingosine, Exogenous sphingosine-induced apoptosis was also accompanied by cytochrome c release and activation of caspase-7 in a Bcl-x(L)-sensitive manner. Furthermore, neither doxorubicin nor sphingosine treatment affected expression of Fas ligand or induced activation of the apical caspase-8, indicating a Fas/Fas ligand-independent mechanism. Our results suggest that a further metabolite of ceramide, sphingosine, may also be involved in mitochondria-mediated apoptotic signaling induced by doxorubicin in human breast cancer cells. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. CHU Rangueil, INSERM, Unite 466, F-31403 Toulouse, France. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. RI CUVILLIER, Olivier/B-2567-2009; Levade, Thierry/O-8948-2014 OI CUVILLIER, Olivier/0000-0003-3346-375X; FU NCI NIH HHS [CA61774] NR 66 TC 86 Z9 87 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2001 VL 8 IS 2 BP 162 EP 171 DI 10.1038/sj.cdd.4400793 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 406CV UT WOS:000167198100008 PM 11313718 ER PT J AU Brown, P AF Brown, P TI The pathogenesis of transmissible spongiform encephalopathy: routes to the brain and the erection of therapeutic barricades SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE transmissible spongiform encephalopathy; Creutzfeldt-Jakob disease; scrapie; variant Creutzfeldt-Jakob disease; prion disease; follicular dendritic cells; B lymphocyte ID FOLLICULAR DENDRITIC CELLS; CREUTZFELDT-JAKOB-DISEASE; SCRAPIE-INFECTED MICE; MOUSE SPLEEN; SCID MICE; INCUBATION PERIOD; AGENT REPLICATION; DEXTRAN SULFATE; PROTEIN; VIRUS AB Classical and modern studies of the pathogenesis of transmissible spongiform encephalopathy are reviewed with particular attention paid to recent investigations of the routes of neuroinvasion. In various experimental models, a heirarchy of paths to the brain includes direct neural transit from the site of infection, replication in the spleen and neural entry through the spinal cord, and hematogenous spread. Possible modes and sites of therapeutic intervention are suggested. C1 NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. RP Brown, P (reprint author), NINDS, Cent Nervous Syst Studies Lab, NIH, Bldg 36,Room 4A-05,MSC 4122, Bethesda, MD 20892 USA. NR 50 TC 18 Z9 19 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD FEB PY 2001 VL 58 IS 2 BP 259 EP 265 DI 10.1007/PL00000853 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 415DX UT WOS:000167706500010 PM 11289307 ER PT J AU Mongini, PKA Inman, JK AF Mongini, PKA Inman, JK TI Cytokine dependency of human B cell cycle progression elicited by ligands which coengage BCR and the CD21/CD19/CD81 costimulatory complex SO CELLULAR IMMUNOLOGY LA English DT Article DE human; B lymphocytes; cellular proliferation; costimulatory molecules; cytokines ID ANTIGEN RECEPTOR COMPLEX; EPSTEIN-BARR-VIRUS; MEMBRANE IGM; PHOSPHATIDYLINOSITOL 3-KINASE; LYMPHOCYTE RESPONSES; ACQUIRED-IMMUNITY; PROTEIN-KINASES; SELF-ANTIGENS; IL-4 RECEPTOR; CROSS-LINKING AB Coengagement of BCR and the CSdg binding CD21/CD19/CD81 costimulatory complex can profoundly reduce the BCR binding threshold for eliciting B cell S phase entry, provided cytokine is present. IL-4 is substantially better than IL-2, IL-13, and TNF-alpha at exhibiting synergy with BCR:CD21 coengaging ligand (anti-IgM:anti-CD21:dextran) in promoting B cell DNA synthesis. Synergy between IL-4 and anti-IgM:anti-CD21: dextran (a) is not explained by the viability-promoting function of IL-4, (b) occurs when the anti-CD21 moiety engages either C3dg binding or non-C3dg binding domains, (c) does not reflect reversal of Fc gamma RII-mediated negative regulation, and (d) involves differing temporal requirements for BCR and IL-4R signal transduction during the activation process. The IL-4R signaling pathway appears to synergize directly with the BCR:CD21 signaling pathway(s) in promoting the progression of resting B cells past an early G(1) checkpoint, as well as to promote independently the progression of activated B cells past a later G(1), to S checkpoint. (C) 2001 Academic Press. C1 Hosp Joint Dis, Dept Rheumatol, New York, NY 10003 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, Dept Pathol, New York, NY 10016 USA. NIH, Immunol Lab, Bethesda, MD 20892 USA. Vet Adm Med Ctr, New York, NY 10010 USA. RP Mongini, PKA (reprint author), Hosp Joint Dis, Dept Rheumatol, New York, NY 10003 USA. FU NIGMS NIH HHS [GM-35174] NR 78 TC 13 Z9 14 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD FEB 1 PY 2001 VL 207 IS 2 BP 127 EP 140 DI 10.1006/cimm.2000.1758 PG 14 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 413JP UT WOS:000167609500007 PM 11243702 ER PT J AU Wada, A Ogushi, K Kimura, T Hojo, H Mori, N Suzuki, S Kumatori, A Se, M Nakahara, Y Nakamura, M Moss, J Hirayama, T AF Wada, A Ogushi, K Kimura, T Hojo, H Mori, N Suzuki, S Kumatori, A Se, M Nakahara, Y Nakamura, M Moss, J Hirayama, T TI Helicobacter pylori-mediated transcriptional regulation of the human beta-defensin 2 gene requires NF-kappa B SO CELLULAR MICROBIOLOGY LA English DT Article ID CAG PATHOGENICITY ISLAND; GASTRIC EPITHELIAL-CELLS; ANTIMICROBIAL PEPTIDE GENE; VACUOLATING CYTOTOXIN; HUMAN BETA-DEFENSIN-2; VIRULENCE FACTORS; MESSENGER-RNA; PANETH CELLS; EXPRESSION; ACTIVATION AB Human beta -defensin 2 (hBD-2) is an antimicrobial peptide involved in host defence against bacterial infection in epithelial tissues. Its levels are dramatically increased after bacterial infection. The involvement of NF-kappaB in Helicobacter pylori-mediated induction of hBD-2 promoter activity was examined. A luciferase reporter plasmid containing the hBD-2 promoter extending from -2110 base pairs to -1 was transiently expressed in MKN45 cells, and promoter activity was determined after incubation with H. pylori for 6 h. Deletion or mutation of the NF-kappaB site at -208 abolished activation of the hBD-2 promoter. Only H. pylori strains carrying a cag pathogenicity island (PAI) induced activation of the NF-kappaB site of the hBD-2 promoter gene. By gel retardation analyses, H. pylori increased NF-kappaB binding to hBD-2 promoter gene sequences. Supershift analysis demonstrated that whereas H. pylori activated NF-kappaB p65-p65 and p50-p50 homodimers, and the p65-p50 heterodimer of NF-kappaB, only the p65-p65 homodimer bound to the NF-kappaB site of the hBD-2 promoter. Thus, specific NF-kappaB proteins are important cis-elements for induction of hBD-2 gene transcription by H. pylori. C1 Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. Tokai Univ, Dept Ind Chem, Hiratsuka, Kanagawa 2591292, Japan. Nagasaki Univ, Inst Trop Med, Dept Prevent Med & AIDS Res, Nagasaki 8528523, Japan. Nagasaki Univ, Inst Trop Med, Dept Biochem, Nagasaki 8528523, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. NR 44 TC 70 Z9 77 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD FEB PY 2001 VL 3 IS 2 BP 115 EP 123 DI 10.1046/j.1462-5822.2001.00096.x PG 9 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 405PF UT WOS:000167167700005 PM 11207625 ER PT J AU Weickert, CS Webster, MJ Hyde, TM Herman, MM Bachus, SE Bali, G Weinberger, DR Kleinman, JE AF Weickert, CS Webster, MJ Hyde, TM Herman, MM Bachus, SE Bali, G Weinberger, DR Kleinman, JE TI Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia SO CEREBRAL CORTEX LA English DT Article ID GROWTH-ASSOCIATED PROTEIN; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; HUMAN CEREBRAL-CORTEX; HUMAN-BRAIN; KINASE-C; DEVELOPMENTAL EXPRESSION; ANTI-GAP-43 ANTIBODIES; INTRINSIC CONNECTIONS; REGIONAL-DISTRIBUTION AB Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia. C1 NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. Stanley Fdn, Res Program, Bethesda, MD 20814 USA. Bangalore Univ, Dept Zool, Bangalore 560056, Karnataka, India. RP Weickert, CS (reprint author), NIMH, Clin Brain Disorders Branch, IRP, NIH, Bldg 10,Room 4N 308,MSC 1385, Bethesda, MD 20892 USA. EM shannowc@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011 NR 71 TC 38 Z9 39 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD FEB PY 2001 VL 11 IS 2 BP 136 EP 147 DI 10.1093/cercor/11.2.136 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 390NL UT WOS:000166302700005 PM 11208668 ER PT J AU Tomer, KB AF Tomer, KB TI Separations combined with mass spectrometry SO CHEMICAL REVIEWS LA English DT Review ID CAPILLARY-ZONE-ELECTROPHORESIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; MICELLAR ELECTROKINETIC CHROMATOGRAPHY; SUPERCRITICAL-FLUID CHROMATOGRAPHY; LASER-DESORPTION IONIZATION; SOLID-PHASE EXTRACTION; PRESSURE CHEMICAL-IONIZATION; SUPERSONIC MOLECULAR-BEAMS; SURFACE-PLASMON RESONANCE; OPEN-CHANNEL ELECTROCHROMATOGRAPHY C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Tomer, KB (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 316 TC 94 Z9 97 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD FEB PY 2001 VL 101 IS 2 BP 297 EP 328 DI 10.1021/cr990091m PG 32 WC Chemistry, Multidisciplinary SC Chemistry GA 405BM UT WOS:000167137400005 PM 11712249 ER PT J AU Anikster, Y Lacbawan, F Brantly, M Gochuico, BL Avila, NA Travis, W Gahl, WA AF Anikster, Y Lacbawan, F Brantly, M Gochuico, BL Avila, NA Travis, W Gahl, WA TI Pulmonary dysfunction in adults with nephropathic cystinosis SO CHEST LA English DT Article DE CT scan; myopathy; pulmonary function tests; restrictive lung disease ID CYSTEAMINE THERAPY; CTNS MUTATIONS; GENE; COMPLICATIONS; INSUFFICIENCY; DEPLETION; MYOPATHY; CHILDREN; PATIENT; STORAGE AB Objective: To characterize the pulmonary dysfunction in patients with nephropathic cystinosis after renal transplantation. Design: Cross-sectional analysis of consecutive adult patients. Patients: Twelve adult, nephropathic cystinosis patients and 3 adult, ocular, nonnephropathic cystinosis patients admitted to the National Institutes of Health Clinical Center. Results: The 12 nephropathic cystinosis patients (age range, 21 to 40 years) show ed an extraparenchymal pattern of restrictive lung disease, with inspiratory and expiratory dysfunction. Specifically the mean FVC was 58% of predicted, the mean FEV1 was 57% of predicted, and the mean total lung capacity was 66% of predicted, while the mean residual volume mas normal. Furthermore, the mean maximal inspiratory pressure for the eight patients tested was 40% of predicted, and the mean maximal expiratory pressure was 26% of predicted, Two patients died of respiratory insufficiency. All the patients had lived at least 17 years while lacking compliant cystine-depleting therapy with oral cysteamine. Seven patients had a conical chest, restricting excursion, and 10 of the 12 patients had evidence of the myopathy that typifies late cystinosis. In fact, the severity of pulmonary disease correlated directly with the severity of myopathy in our group of 12 patients. In contrast, the lung parenchyma was essentially normal as gauged by chest radiographs and CT scans of the lung. The three patients with nonnephropathic cystinosis displaced entirely normal pulmonary function. Conclusion: The distal myopathy characteristic of nephropathic cystinosis results in an extraparenchymal pattern of restrictive lung disease in adults who have not received long-term cystine depletion. Whether or not oral cysteamine therapy can prevent this complication remains to he determined. C1 NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm & Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Pulm Pathol, Washington, DC 20306 USA. RP Gahl, WA (reprint author), NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, 10 Ctr Dr,MSC 1830,Bldg 10,Room 9S-241, Bethesda, MD 20892 USA. NR 41 TC 27 Z9 27 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2001 VL 119 IS 2 BP 394 EP 401 DI 10.1378/chest.119.2.394 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 402GH UT WOS:000166977300015 PM 11171714 ER PT J AU Schindler, J Sausville, E Messmann, R Uhr, JW Vitetta, ES AF Schindler, J Sausville, E Messmann, R Uhr, JW Vitetta, ES TI The toxicity of deglycosylated ricin a chain-containing immunotoxins in patients with non-Hodgkin's lymphoma is exacerbated by prior radiotherapy: A retrospective analysis of patients in five clinical trials SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-18, 1999 CL ATLANTA, GEORGIA SP Amer Soc Clin Oncol ID B-CELL LYMPHOMA; A CHAIN; PHASE-I; ENDOTHELIAL-CELLS; CONTINUOUS-INFUSION; INVIVO THERAPY; ANTIBODIES; ANTIGENS AB A retrospective analysis of 102 patients with relapsed, non-Hodgkin's lymphoma treated with two different ricin A chain-containing immunotoxins (ITs) in five Phase I clinical trials indicates that the dose-limiting toxicity, vascular leak syndrome, was more frequent and more severe in patients who had undergone prior radiotherapy (RT). Excluding patients with prior RT from the calculations of the maximum tolerated dose indicates that the maximum tolerated doses of these ITs had not been reached in any trial and are clearly higher than reported previously. Excluding patients with prior RT from future clinical trials may increase the dose of ITs that can be given in the absence of severe vascular leak syndrome. C1 Univ Texas, SW Med Ctr, Ctr Canc Immunobiol, Dallas, TX 75390 USA. Natl Canc Inst, Dev Therapeut Program, Bethesda, MD USA. RP Vitetta, ES (reprint author), Univ Texas, SW Med Ctr, Ctr Canc Immunobiol, 6000 Harry Hines Blvd,NB9-210, Dallas, TX 75390 USA. FU NCI NIH HHS [CA-41081, CA-77701, CA-28149] NR 16 TC 38 Z9 38 U1 0 U2 0 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 FEB PY 2001 VL 7 IS 2 BP 255 EP 258 PG 4 WC Oncology SC Oncology GA 405LE UT WOS:000167160200006 PM 11234876 ER PT J AU Kahn, MES Senderowicz, A Sausville, EA Barrett, KE AF Kahn, MES Senderowicz, A Sausville, EA Barrett, KE TI Possible mechanisms of diarrheal side effects associated with the use of a novel chemotherapeutic agent, flavopiridol SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-18, 1999 CL ATLANTA, GEORGIA SP Amer Soc Clin Oncol ID EPIDERMAL GROWTH-FACTOR; EPITHELIAL-CELL LINE; CHLORIDE SECRETION; CL SECRETION; T84 CELLS; KINASE INHIBITOR; CYCLE CONTROL; CALCIUM; CAMP; CANCER AB The novel cyclin-dependent kinase inhibitor flavopiridol has recently completed Phase I trials for the treatment of refractory neoplasms. The dose-limiting toxicity observed with this agent was severe diarrhea, Because the compound otherwise showed promise, the present study sought to determine possible mechanisms underlying the diarrheal side effects. Flavopiridol was tested for its ability to modify chloride secretory responses of the human colonic epithelial cell line, T-84, Studies were conducted in vitro in modified Ussing chambers. High concentrations of flavopiridol (10(-4) M), above those likely to be clinically relevant, had a direct stimulatory effect on chloride secretion, probably ascribable to an increase in cyclic AMP. Lower, clinically relevant concentrations of flavopiridol (10(-6) M) had no effect on chloride secretion by themselves but potentiated responses to the calcium-dependent secretagogue, carbachol, The drug also potentiated responses to thapsigargin and taurodeoxycholate and reversed the inhibitory effects of carbachol and epidermal growth factor on calcium-dependent chloride secretion. Pretreatment with the cyclic AMP-dependent secretagogue, forskolin, potentiated responses to flavopiridol, but not vice versa, Thus, diarrheal side effects induced by flavopiridol are likely multifactorial in origin and may involve interactions with endogenous secretagogues such as acetylcholine and bile acids. A better understanding of the diarrhea induced by flavopiridol should allow optimization of therapy with this otherwise promising drug and/or the development of related agents with improved toxicity profiles. C1 Univ Calif San Diego, Sch Med, Dept Med, Div Gastroenterol, San Diego, CA 92103 USA. NCI, Med Branch, Dev Therapeut Program, Clin Trials Unit,Med Branch, Bethesda, MD 20892 USA. RP Barrett, KE (reprint author), Univ Calif San Diego, Med Ctr 8414, 200 W Arbor Dr, San Diego, CA 92103 USA. FU NIDDK NIH HHS [DK28305] NR 40 TC 25 Z9 27 U1 0 U2 0 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 FEB PY 2001 VL 7 IS 2 BP 343 EP 349 PG 7 WC Oncology SC Oncology GA 405LE UT WOS:000167160200019 PM 11234889 ER PT J AU Kokkinakis, DM Bocangel, DB Schold, SC Moschel, RC Pegg, AE AF Kokkinakis, DM Bocangel, DB Schold, SC Moschel, RC Pegg, AE TI Thresholds of O-6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide SO CLINICAL CANCER RESEARCH LA English DT Article ID DNA-REPAIR METHYLTRANSFERASE; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; BONE-MARROW; IN-VIVO; NUCLEAR TRANSLOCATION; ALKYLATING-AGENTS; GENE-TRANSFER; O-6-BENZYLGUANINE; CELLS; BCNU AB Bis-2-chloroethylnitrosourea (BCNU) or temozolomide (TMZ) were tested alone or in combination with the AGT inhibitors O-6-benzyl-2'-deoxyguanosine (dBG) or O-6-benzylguanine (BG) against human glial tumor xenografts growing s.c. in athymic mice. Four glioblastoma (SWB77, SWB40, SWB39, and D-54) and one anaplastic oligodendroglioma (SWB61) xenografts having O-6-alkylguanine-DNA alkyltransferase (AGT) activities of 75, 45, 10, < 10, and 16 fmol/mg protein, respectively, were used. BCNU at 35 mg/m(2) was ineffective against these tumors, although 70 mg/m(2) (LD10, 75 mg/m(2)) produced a marked tumor growth delay (T-C) in D54 but had no effect against SWB40 or SWB77. Coadministration of BG or dBG and BCNU necessitated reduction of the BCNU dose to a maximum of 30 and 35 mg/m(2), respectively, because of increased toxicity. Optimized treatment with dBG (250 mg/m(2)) and BCNU (35 mg/m(2)) resulted in T-Cs of 30, 29, 11, 16, and 14 days for SWB77, SWB40, SWB39, D-54 and SWB61, respectively. These delays mere more pronounced than those induced with optimized, isotoxic treatments with BG (180 mg/m(2)) and BCNU (30 mg/m(2)). In comparison to BCNU, TMZ was less toxic, with an LD10 of 400 mg/m(2). TMZ (300 mg/m(2)) was more effective than BCNU against SWB77, SWB40, and SWB61, inducing T-Cs of 23, 53, and 56 days, respectively. BG and dBG enhanced the toxicity of TMZ in athymic mice by decreasing the LD10 from 400 to 200 mg/m(2). TMZ (180 mg/m(2)) with either BG (180 mg/m(2)) or dBG (250 mg/m(2)) resulted in T-Cs of 31 and 49 days in SWB77, respectively, as compared with 16 days for TMZ (180 mg/m(2)) alone. In SWB40, the combination of TMZ with dBG, but not with BG, was significantly more effective than the maximum tolerated dose of TMZ (300 mg/m(2)) alone. The combination of TMZ,vith AGT inactivators had no benefit, as compared with TR/IZ alone, against xenografts with marginal AGT activity. In conclusion, at equimolar doses dBG was less toxic than BG in athymic mice when combined with either BCNU or TMZ. In this regard, BCNU or TMZ can be used at higher doses in combination with dBG than with BG. This study further demonstrates that there is a significant benefit of depleting AGT with nonspecific AGT inhibitors prior to treatment with either BCNU or TMZ in tumors having AGT activity >45 fmol/mg protein. C1 Univ Texas, SW Med Ctr, Dept Neurol Surg, Dallas, TX 75235 USA. Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA 15213 USA. RP Kokkinakis, DM (reprint author), Univ Texas, SW Med Ctr, Dept Neurol Surg, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. FU NCI NIH HHS [CA 57725, CA 78561] NR 34 TC 55 Z9 55 U1 0 U2 1 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 FEB PY 2001 VL 7 IS 2 BP 421 EP 428 PG 8 WC Oncology SC Oncology GA 405LE UT WOS:000167160200029 PM 11234899 ER PT J AU Bancroft, CC Chen, Z Dong, G Sunwoo, JB Yeh, N Park, C Van Waes, C AF Bancroft, CC Chen, Z Dong, G Sunwoo, JB Yeh, N Park, C Van Waes, C TI Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappa B signal pathways SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; TUMOR-NECROSIS-FACTOR; PROINFLAMMATORY CYTOKINE EXPRESSION; HUMAN INTERLEUKIN-8 GENE; FACTOR-ALPHA; IN-VIVO; FACTOR RECEPTOR; K-RAS; CANCER AB Interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) promote tumor angiogenesis, growth, and metastasis and are coexpressed by human head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers. The promoters of the IL-8 and VEGF genes contain different recognition sites for transcription factors nuclear factor (NF)-kappaB and activator protein-1 (AP-1), which we showed previously are coactivated in HNSCCs. NF-kappaB and AP-1 mag be modulated by the inhibitor kappaB kinase (IKK) and mitogen-activated protein kinase (MAPK) signal pathways, but the contribution of these pathways to expression of IL-8 and VEGF and as potential targets for antiangiogenesis therapy in HNSCC is not known, In this study, we examined the effects of modulation of the MAPK and IKK pathways on expression of IL-8 and VEGF by UM-SCC-9 and UM-SCC-11B cell lines. Interruption of IKK-mediated activation of NF-kappaB by expression of an inhibitor kappaB alpha mutant (I kappaB alphaM) in UM-SCC-9 cells resulted in partial inhibition of expression of IL-8 but not VEGF, Analysis of possible alternative pathways for induction of these genes revealed activation of the MAPK extracellular signal-regulated kinase (ER1/2) in cell lines UM-SCC-9 and UM-SCC-11B, Basal and tumor necrosis factor-alpha -inducible phosphorylation of ERK1/2 and secretion of IL-8 and VEGF could be specifically inhibited by a MEK inhibitor, U0126, Expression of IL-8 and VEGF in the cell lines was associated with coactivation of both NF-kappaB and AP-1, and U0126 inhibited both NF-kappaB and AP-1 reporter activity in UM-SCC-9 and UM-SCC-11B cells. The ERK pathway appears to contribute to expression of IL-8 and VEGF and transactivation of NF-kappaB as well as AP-1 in HNSCC, Combined inhibition of both MAPK and IKK pathways may be needed for suppression of the signal transduction mechanism(s) regulating VEGF and IL-8 secretion and angiogenesis by human HNSCC. C1 NIDOCD, Head & Neck Surg Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), NIDOCD, Head & Neck Surg Branch, Tumor Biol Sect, NIH, Bldg 10,Room SD55,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 50 TC 135 Z9 147 U1 0 U2 4 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 FEB PY 2001 VL 7 IS 2 BP 435 EP 442 PG 8 WC Oncology SC Oncology GA 405LE UT WOS:000167160200031 PM 11234901 ER PT J AU Tian, HJ Brody, LC Fan, SJ Huang, ZL Landers, JP AF Tian, HJ Brody, LC Fan, SJ Huang, ZL Landers, JP TI Capillary and microchip electrophoresis for rapid detection of known mutations by combining allele-specific DNA amplification with heteroduplex analysis SO CLINICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR; PCR AMPLIFICATION; BREAST-CANCER; BRCA1; GENE; POLYMORPHISMS; POLYMERASE; SPECTRA; PROTEIN; MMAC1 AB Background: Detection of mutations by gel electrophoresis and allele-specific amplification by PCR (ASPCR) is not easily scaled to accommodate a large number of samples. Alternative electrophoretic formats, such as capillary electrophoresis (CE) and microchip electrophoresis, may provide powerful platforms for simple, fast, automated, and high-throughput mutation detection after allele-specific amplification. Methods: DNA samples heterozygous for four mutations (185delAG, 5382insC, 3867G-->T, and 6174delT) in BRCA1 and BRCA2, and homozygous for one mutation (5382insC) in BRCA1 and two mutations (16delAA and 822delG) in PTEN were chosen as the model system to evaluate the capillary and microchip electrophoresis methods. To detect each mutation, three primers, of which one was labeled with the fluorescent dye 6-carboxyfluorescein and one was the allele-specific primer (mutation-specific primer), were used to amplify the DNA fragments in the range of 130-320 bp. AS-PCR was combined with heteroduplex (HD) analysis, where the DNA fragments obtained by AS-PCR were analyzed with the conditions developed for CE-based HD analysis (using a fluorocarbon-coated capillary and hydroxy-ethylcellulose). The CE conditions were transferred into the microchip electrophoresis format. Results: Three genotypes, homozygous wild type, homozygous mutant, and heterozygous mutant, could be identified by CE-based AS-PCR-HD analysis after 10-25 min of analysis time. Using the conditions optimized with CE, we translated the AS-PCR-HD analysis mutation detection method to the microchip electrophoresis format. The detection of three heterozygous mutations (insertion, deletion, and substitution) in BRCA1 could be accomplished in 180 s or less. Conclusions: It is possible to develop a CE-based method that exploits both AS-PCR and HD analysis for detecting specific mutations. Fast separation and the capacity for automated operation create the potential for developing a powerful electrophoresis-based mutation detection system. Fabrication of multichannel microchip platforms may enable mutation detection with high throughput (C) 2001 American Association for Clinical Chemistry. C1 Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. Univ Virginia, Med Ctr, Dept Pathol, Charlottesville, VA 22908 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Long Isl Jewish Med Ctr, Albert Einstein Coll Med, Dept Radiat Oncol, New Hyde Park, NY 11040 USA. RP Landers, JP (reprint author), Univ Virginia, Dept Chem, McCormick Rd, Charlottesville, VA 22901 USA. FU NCI NIH HHS [1R21CA78865-01]; PHS HHS [R-07591] NR 35 TC 42 Z9 44 U1 1 U2 4 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 FEB PY 2001 VL 47 IS 2 BP 173 EP 185 PG 13 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 399HN UT WOS:000166805700003 PM 11159764 ER PT J AU Hortin, GL Warshawsky, I Laude-Sharp, M AF Hortin, GL Warshawsky, I Laude-Sharp, M TI Macromolecular chromogenic substrates for measuring proteinase activity SO CLINICAL CHEMISTRY LA English DT Article ID THROMBIN; PROTEASES; ALPHA(2)-MACROGLOBULIN; ALPHA-2-MACROGLOBULIN; INHIBITORS; EXCLUSION; COMPLEXES; PEPTIDES; TRYPSIN; ASSAYS AB Background: Proteinase activities are often measured using chromogenic substrates that are much smaller than physiological substrates. Methods: The hydrodynamic size of macromolecular substrates (macrosubstrates) prepared by linking small chromogenic substrates to polyethylene glycol was determined by gel filtration. Efficiency of macrosubstrate cleavage by proteinases and alpha (2)-macroglobulin-proteinase complexes was monitored spectrophotometrically. Results: Macrosubstrates had hydrodynamic radii of similar to 20 Angstrom, similar to proteins with a molecular weight of 18 000. Different macrosubstrates served as efficient substrates for chymotrypsin, trypsin, and thrombin. Linking small substrates to a polymer variably affected substrate efficiency, with the impact on activity ranging from a 60-fold decrease to a 30-fold increase. Proteinases complexed with alpha (2)-macroglobulin had similar to 10-fold lower activity vs macrosubstrates than small substrates. Conclusions: Macrosubstrates are efficient substrates that allow decreased measurement of sterically hindered proteinase molecules such as alpha (2)-macroglobulin-proteinase complexes. Thus, macrosubstrates may provide more accurate functional assays of proteinases such as coagulation factors. (C) 2001 American Association for Clinical Chemistry. C1 NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. RP Hortin, GL (reprint author), NIH, Dept Clin Pathol, Bldg 10,Room 2C-407,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 21 Z9 21 U1 0 U2 4 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 FEB PY 2001 VL 47 IS 2 BP 215 EP 222 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 399HN UT WOS:000166805700008 PM 11159769 ER PT J AU Srivastava, S AF Srivastava, S TI Proteomic approaches within the National Cancer Institute's Early Detection Research Network for the discovery and identification of cancer biomarkers SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NCI, 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 FEB PY 2001 VL 47 IS 2 MA 6 BP 362 EP 362 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 399HN UT WOS:000166805700038 ER PT J AU Salkowitz, JR Purvis, SF Meyerson, H Zimmerman, P O'Brien, TR Aledort, L Eyster, ME Hilgartner, M Kessler, C Konkle, BA White, GC Goedert, JJ Lederman, MM AF Salkowitz, JR Purvis, SF Meyerson, H Zimmerman, P O'Brien, TR Aledort, L Eyster, ME Hilgartner, M Kessler, C Konkle, BA White, GC Goedert, JJ Lederman, MM TI Characterization of high-risk HIV-1 seronegative hemophiliacs SO CLINICAL IMMUNOLOGY LA English DT Article DE Multicenter Hemophilia Cohort Study; CCR5; beta-chemokines; HLA; HIV-1; alloreactive antibodies ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LYMPHOID-TISSUE; TYPE-1 INFECTION; CHEMOKINE RECEPTOR-5; RESISTANCE; GENE; ALLOIMMUNIZATION; SUSCEPTIBILITY; TRANSMISSION; LYMPHOCYTES AB Mechanisms that protect most high-risk HIV-1 seronegative (HRSN) persons are not well understood. Among hemophiliacs from the Multicenter Hemophilia Cohort Study who remained HIV-1 seronegative despite a high (94%) risk for acquisition of HIV-1 infection, only 7/43 were homozygous for the protective CCR5 Delta 32 polymorphism. Among the remainder, neither CCR5 density nor beta -chemokine production, nor in vitro susceptibility to infection with the HIV-1 isolate JR-FL could distinguish HRSN hemophiliacs from healthy controls. When compared to lymphocytes of healthy controls not at risk for HIV-1 infection, diminished spontaneous lymphocyte proliferation was seen in lymphocytes of HRSN hemophiliacs as well as in lymphocytes of hemophiliacs not at risk for HIV-1 infection. Surprisingly sera/plasmas obtained from highrisk HIV-1 seropositive hemophiliacs prior to seroconversion more often contained alloreactive antibodies than date-matched sera/plasmas obtained from HRSN hemophiliacs. Thus alloreactivity may predispose to acquisition of HIV-1 infection after parenteral exposure. (C) 2000 Academic Press. C1 Case Western Reserve Univ, Univ Hosp Cleveland, Dept Med, Div Infect Dis, Cleveland, OH 44106 USA. NCI, Viral Epidemiol Branch, Rockville, MD 20852 USA. CUNY, Mt Sinai Med Ctr, Hemophilia Ctr, New York, NY 10029 USA. Milton S Hershey Med Ctr, Hershey, PA 17033 USA. New York Presbyterian Hosp, Hemophilia Treatment Ctr, New York, NY 10021 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Univ Penn, Penn Comprehens Hemophilia Program, Philadelphia, PA 19104 USA. Univ N Carolina, Sch Med, Div Hematol Oncol, Chapel Hill, NC 27599 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Univ Hosp Cleveland, Dept Med, Div Infect Dis, Foley Bldg,2061 Cornell Rd, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI 36219] NR 48 TC 54 Z9 54 U1 0 U2 1 PU ACADEMIC PRESS INC 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 FEB PY 2001 VL 98 IS 2 BP 200 EP 211 DI 10.1006/clim.2000.4969 PG 12 WC Immunology SC Immunology GA 401WX UT WOS:000166952800007 PM 11161976 ER PT J AU Narita, M Hisada, M Thimmappa, B Stambaugh, JJ Ibrahim, E Hollender, ES Ashkin, D AF Narita, M Hisada, M Thimmappa, B Stambaugh, JJ Ibrahim, E Hollender, ES Ashkin, D TI Tuberculosis recurrence: Multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID INFECTED PATIENTS; RELAPSE AB We examined risk factors for tuberculosis recurrence in patients admitted to a tuberculosis hospital in Florida in 1996 and 1997. Recurrence of tuberculosis was not significantly associated with tuberculosis drug levels or HIV status, which indicates that routine drug monitoring may not be beneficial in general patient management. C1 AG Holley State TB Hosp, Lantana, FL 33462 USA. Florida Bur TB Control & Prevent, Florida Dept Hlth, Tallahassee, FL USA. Univ Miami, Sch Med, Div Pulm & Crit Care, Miami, FL 33152 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Ashkin, D (reprint author), AG Holley State TB Hosp, 1199 W Lantana Rd, Lantana, FL 33462 USA. NR 9 TC 34 Z9 37 U1 0 U2 1 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 FEB 1 PY 2001 VL 32 IS 3 BP 515 EP 517 DI 10.1086/318490 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 397BW UT WOS:000166674300026 PM 11170964 ER PT J AU Rex, JH Walsh, TJ Sobel, JD Filler, SG Pappas, PG Dismukes, WE Edwards, JE AF Rex, JH Walsh, TJ Sobel, JD Filler, SG Pappas, PG Dismukes, WE Edwards, JE TI Reply to Dr. Chandrasekar (Clin Infect Dis 2001; 32 : 320-1) and Drs. Marr and Boeckh (Clin Infect Dis 2001; 32 : 321) SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID NEUTROPENIC PATIENTS; AGENTS; FEVER C1 Univ Texas, Sch Med, Dept Internal Med,Div Infect Dis, Ctr Study Emerging & Reemerging Pathogens, Houston, TX USA. NCI, Infect Dis Sect, Pediat Branch, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Calif Los Angeles, Med Ctr, Torrance, CA 90509 USA. Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. RP Rex, JH (reprint author), Univ Texas Houston, Ctr Infect Dis, 6431 Fannin,1728 JFB, Houston, TX 77025 USA. NR 9 TC 0 Z9 0 U1 1 U2 1 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 FEB 1 PY 2001 VL 32 IS 3 BP 518 EP 519 DI 10.1086/318517 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 397BW UT WOS:000166674300027 PM 11170965 ER PT J AU Hagemann, D Naumann, E AF Hagemann, D Naumann, E TI The effects of ocular artifacts on (lateralized) broadband power in the EEG SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE electroencephalography; ocular artifacts; spectral analysis; alpha power density; hemispheric lateralization ID QUANTITATIVE-ANALYSIS; CEREBRAL ASYMMETRY; FREQUENCY-DOMAIN; EYE-MOVEMENTS; REMOVAL; EOG; GUIDELINES; BLINKS AB Objective: Empirical evidence suggests that blinks and eye movements do not generate substantial activity outside the delta and theta range, and that the propagation of ocular activity to the EEG is rather symmetrical. These observations suggest that an alteration of the alpha and beta asymmetry of the EEG due to ocular artifacts is not likely to occur. The aim of the present study is to examine the effects of ocular artifacts on broadband EEG parameters. Methods: EEG and EOG were recorded from 31 participants in a resting condition with eyes open and closed, allowing for spontaneous ocular activity. General effects: of ocular artifacts were examined with mean comparisons, and differential effects were examined with correlation analysis of data portions that were selected for a presence or absence of artifacts. Results: At single sites, blinks and eye movements exerted substantial general effects on the whole EEG spectrum, but there were no substantial differential effects of artifacts in the alpha and beta bands. except at the frontopolar sites. The distorting effects of ocular artifacts were smaller in magnitude for asymmetry than for single site measures. Conclusions: The control of ocular artifacts may be dispensable for correlation analyses of alpha or beta band parameters. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. Univ Trier, Fachbereich Psychol 1, D-5500 Trier, Germany. RP Hagemann, D (reprint author), NIA, Lab Personal & Cognit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM hagemann@lpc.grc.nia.nih.gov NR 61 TC 57 Z9 57 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2001 VL 112 IS 2 BP 215 EP 231 DI 10.1016/S1388-2457(00)00541-1 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 403TG UT WOS:000167058100001 PM 11165523 ER PT J AU Foltys, H Sparing, R Boroojerdi, B Krings, T Meister, IG Mottaghy, FM Topper, R AF Foltys, H Sparing, R Boroojerdi, B Krings, T Meister, IG Mottaghy, FM Topper, R TI Motor control in simple bimanual movements: a transcranial magnetic stimulation and reaction time study SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE transcranial magnetic stimulation; reaction time; mirror movements; bimanual movements ID CONGENITAL MIRROR MOVEMENTS; HUMAN PRIMARY SENSORIMOTOR; LINKED KALLMANNS-SYNDROME; FINGER MOVEMENTS; SOMATOSENSORY STIMULI; BRAIN-STIMULATION; CORTEX; COORDINATION; HANDEDNESS; RESPONSES AB Objective: Simple reaction rime (RT) can be influenced by transcranial magnetic stimulation (TMS) to the motor cortex. Since TMS differentially affects RT of ipsilateral and contralateral muscles a combined RT and TMS investigation sheds light on cortical motor control of bimanual movements. Methods: Ten normal subjects and one subject with congenital mirror movements (MM) were investigated with a RT paradigm in which they had to move one or both hands in response to a visual go-signal. Suprathreshold TMS was applied to the motor cortex ipsilateral or contralateral to the moving hand at various interstimulus intervals (ISIs) after presentation of the go-signal. EMG recordings from the thenar muscles of both hands were used to determine the RT. Results: TMS applied to the ipsilateral motor cortex shortened RT when TMS was delivered simultaneously with the go-signal. With increasing ISI between TMS and go-signal the RT was progressively delayed. This delay was more pronounced if TMS was applied contralateral to the moving hand. When normal subjects performed bimanual movements the TMS-induced changes in RT were essentially the same as if they had used the hand in an unimanual task. In the subject with MM, TMS given at the time of the go-signal facilitated both the voluntary and the MM. With increasing ISI, however, RT for voluntary movements and MM increased in parallel. Conclusions: Ipsilateral TMS affects the timing of hand movements to the same extent regardless of whether the hand is engaged in an unimanual or a bimanual movement. It can be concluded, therefore, that in normal subjects simple bimanual movements are controlled by each motor cortex independently. The results obtained in the subject with MM are consistent with the hypothesis that mirror movements originate from uncrossed corticospinal fibres. The alternative hypothesis that a deficit in transcallosal inhibition leads to MM in the contralateral motor cortex is not compatible with the presented data, because TMS applied to the motor cortex ipsilateral to a voluntary moved hand affected voluntary movements and MM to the same extent. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Hosp RWTH, Dept Neurol, D-52057 Aachen, Germany. Univ Hosp RWTH, Dept Neuroradiol, Aachen, Germany. Univ Dusseldorf, Forsch Zentrum Julich, D-4000 Dusseldorf, Germany. NINDS, Human Cort Physiol Sect, Bethesda, MD 20892 USA. RP Topper, R (reprint author), Univ Hosp RWTH, Dept Neurol, Pauwelsstr 30, D-52057 Aachen, Germany. RI Meister, Ingo/A-3642-2008 NR 44 TC 25 Z9 26 U1 1 U2 7 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 FEB PY 2001 VL 112 IS 2 BP 265 EP 274 DI 10.1016/S1388-2457(00)00539-3 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 403TG UT WOS:000167058100006 PM 11165528 ER PT J AU Alfaro, CL Wudarsky, M Nicolson, R Gochman, P Lenane, M Rapoport, JL AF Alfaro, CL Wudarsky, M Nicolson, R Gochman, P Lenane, M Rapoport, JL TI Correlation of antipsychotic (AP) and prolactin plasma concentrations (Cp) in children and adolescents treated with haloperidol (HL), clozapine (CL) or olanzapine (OL). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Nicolson, Robert/E-4797-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P16 EP P16 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500060 ER PT J AU Alfaro, CL Lam, YWF Miller, M Ereshefsky, L AF Alfaro, CL Lam, YWF Miller, M Ereshefsky, L TI Lack of correlation between oral midazolam (M) and dextromethorphan (DM) with administration of nefazodone (N) and ketoconazole (K). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol & Psychiat, San Antonio, TX USA. Univ Texas, Coll Pharm, Austin, TX 78712 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P17 EP P17 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500061 ER PT J AU DePetrillo, PB Wan, W AF DePetrillo, PB Wan, W TI Ritonavir is a competitive inhibitor of calcium-activated protease (calpain) activity in PC12 cells. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIH, NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P36 EP P36 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500138 ER PT J AU James, LP Farrar, HC Darville, TL Sullivan, JE Givens, TG Kearns, GL Wasserman, GS Simpson, PM Hinson, JA AF James, LP Farrar, HC Darville, TL Sullivan, JE Givens, TG Kearns, GL Wasserman, GS Simpson, PM Hinson, JA CA PPRU Network TI Elevation of interleukin-8 (IL-8) in acetaminophen (APAP) overdose (OD). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NICHHD, PPRU Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P13 EP P13 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500047 ER PT J AU Kearns, GL Andersson, T James, LP Li, BUK Gaedigk, A Kraynak, RA Kuczmanski, M Ramabadran, K AF Kearns, GL Andersson, T James, LP Li, BUK Gaedigk, A Kraynak, RA Kuczmanski, M Ramabadran, K CA Network Pediat Pharmacol Res Units TI Omeprazole (OMEP) disposition in children. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NICHHD, Bethesda, MD 20892 USA. AstraZeneca LP, Wayne, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P51 EP P51 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500199 ER PT J AU Kearns, GL Robinson, P Adcock, K Wilson-Costello, D Knight, G Zhou, HH Ward, R van den Anker, J AF Kearns, GL Robinson, P Adcock, K Wilson-Costello, D Knight, G Zhou, HH Ward, R van den Anker, J CA PPRU Network TI Cisapride (CIS) disposition in neonates and infants. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NICHHD, PPRU Network, Bethesda, MD 20892 USA. Jansseb Pharm Res Fdn, Titusville, NJ USA. Univ Utah, Salt Lake City, UT USA. Sophia Childrens Hosp, Rotterdam, Netherlands. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P31 EP P31 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500120 ER PT J AU Murphy, MG James, LP Wenning, L Blumer, JL Panebianco, D Yeh, K Kearns, GL AF Murphy, MG James, LP Wenning, L Blumer, JL Panebianco, D Yeh, K Kearns, GL TI Famotidine pharmacokinetics in infants. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Merck Res Labs, W Point, PA USA. Childrens Mercy Hosp, Kansas City, MO 64108 USA. Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. NICHHD, Network Pediat Pharmacol Res Units, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P80 EP P80 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500310 ER PT J AU Pieper, JA Johnson, ME Allen, TL Clarke, M Greenwood, R Goldstein, JA AF Pieper, JA Johnson, ME Allen, TL Clarke, M Greenwood, R Goldstein, JA TI Evaluation of losartan (L) as a CYP2C9 probe. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P69 EP P69 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500267 ER PT J AU Preston, KL Umbricht, A Huestis, MA Cone, EJ AF Preston, KL Umbricht, A Huestis, MA Cone, EJ TI Intravenous buprenorphine: Effects of 2 to 16 mg doses in nondependent opioid abusers. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P29 EP P29 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500112 ER PT J AU Rosenberg, LJ DeSantis, P Babaoglu, MO Abernethy, DR Freedman, J AF Rosenberg, LJ DeSantis, P Babaoglu, MO Abernethy, DR Freedman, J TI Polymorphic variant endothelial nitric oxide synthase impairs endothelium dependent vascular relaxation in both heterozygotes and homozygotes. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Natl Inst Hlth, Baltimore, MD USA. GRC, Baltimore, MD USA. Johns Hopkins Univ, Baltimore, MD USA. Georgetown Univ, Washington, DC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P89 EP P89 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500349 ER PT J AU Sokol, GH Knudsen, JK Murto, A Cantilena, LR AF Sokol, GH Knudsen, JK Murto, A Cantilena, LR TI Utilization of Troponin I as an index of chemo/radio therapy-induced cardiac toxicity. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Div Clin Pharmacol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P47 EP P47 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500180 ER PT J AU Tandon, V Rajagopalan, P Cherstniakova, SA Chiang, N Vocci, F Elkashef, A Mojsiak, J Haigney, M Cantilena, LR AF Tandon, V Rajagopalan, P Cherstniakova, SA Chiang, N Vocci, F Elkashef, A Mojsiak, J Haigney, M Cantilena, LR TI Pharmacokinetics of multiple escalating doses of GBR12909 in healthy volunteers. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Uniformed Serv Univ Hlth Sci, Natl Inst Drug Abuse, Bethesda, MD 20814 USA. US FDA, Bethesda, MD 20014 USA. US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2001 VL 69 IS 2 SU S BP P61 EP P61 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 408PA UT WOS:000167333500237 ER PT J AU Ballow, M Strober, W AF Ballow, M Strober, W TI Cellular immune deficiencies - Introduction SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Editorial Material C1 SUNY Buffalo, Childrens Hosp, Buffalo, NY 14260 USA. NIAID, Mucosal Immun Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Ballow, M (reprint author), SUNY Buffalo, Childrens Hosp, Buffalo, NY 14260 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD FEB PY 2001 VL 20 IS 1 BP 1 EP 2 DI 10.1385/CRIAI:20:1:1 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 407MN UT WOS:000167275500001 ER PT J AU Fleisher, TA Puck, JM Strober, W Dale, JK Lenardo, MJ Siegel, RM Straus, SE Bleesing, JJH AF Fleisher, TA Puck, JM Strober, W Dale, JK Lenardo, MJ Siegel, RM Straus, SE Bleesing, JJH TI The autoimmune lymphoproliferative syndrome - A disorder of human lymphocyte apoptosis SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review ID FAS GENE-MUTATIONS; DISEASE C1 NHGRI, Dept Lab Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Fleisher, TA (reprint author), NHGRI, Dept Lab Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 22 TC 10 Z9 10 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD FEB PY 2001 VL 20 IS 1 BP 109 EP 120 DI 10.1385/CRIAI:20:1:109 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 407MN UT WOS:000167275500007 PM 11269222 ER PT J AU Holland, SM AF Holland, SM TI Immune deficiency presenting as mycobacterial infection SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review ID INTERFERON-GAMMA-RECEPTOR; CALMETTE-GUERIN INFECTION; AVIUM COMPLEX INFECTION; CHRONIC GRANULOMATOUS-DISEASE; ERYTHEMA-NODOSUM LEPROSUM; COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; HUMAN MACROPHAGES; INTERLEUKIN-12 PRODUCTION; ABSCESSUS INFECTION C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,11N103,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. NR 69 TC 12 Z9 12 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD FEB PY 2001 VL 20 IS 1 BP 121 EP 137 DI 10.1385/CRIAI:20:1:121 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA 407MN UT WOS:000167275500008 PM 11269223 ER PT J AU Galperin, MY AF Galperin, MY TI Conserved 'hypothetical' proteins: new hints and new puzzles SO COMPARATIVE AND FUNCTIONAL GENOMICS LA English DT Article DE sequence analysis; orthologous proteins; database; phylogenetic pattern; GGDEF domain ID SEQUENCE-ANALYSIS; COG DATABASE; BIOSYNTHESIS; GENE; DOMAINS; GENOMICS; 4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL; IDENTIFICATION; TERPENOIDS; HISTIDINE AB Conserved hypothetical proteins, i.e. conserved proteins whose functions are still unknown, pose a challenge not just to functional genomics but also to general biology. For many conserved proteins, computational analysis provides only a general prediction of biochemical function; their exact biological functions have to be established through direct experimentation. In the few cases when this has been accomplished, the results were remarkable, revealing the deoxyxylulose, pathway and a new essential enzyme, the ITP pyrophosphatase. Comparative genome analysis is also instrumental in illuminating unsolved problems in biology, e.g. the mechanism of FtsZ-independent cell division, in Chlamydia, Ureaplasma and Aerapyrum or the role of uncharacterized conserved domains in, signal transduction. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 33 TC 33 Z9 33 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1531-6912 J9 COMPAR FUNCT GENOM JI Compar. Funct. Genom. PD FEB PY 2001 VL 2 IS 1 BP 14 EP 18 DI 10.1002/cfg.66 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 485RK UT WOS:000171771100004 PM 18628897 ER PT J AU Stevenson, MAMC Gates, L Murray, J Bloom, ME AF Stevenson, MAMC Gates, L Murray, J Bloom, ME TI Aleutian mink disease parvovirus: Implications for companion ferrets SO COMPENDIUM ON CONTINUING EDUCATION FOR THE PRACTICING VETERINARIAN LA English DT Article ID ACUTE INTERSTITIAL PNEUMONIA; INFECTED MINK; ADULT MINK; IN-VIVO; VIRUS; IDENTIFICATION; REPLICATION; PROTEIN; LESIONS; CELLS AB Aleutian mink disease parvovirus (ADV) causes disease in mink and ferrets and can infect such related animals as raccoons, weasels, fishers, martens, and striped skunks. Severe Aleutian disease (AD) in adult mink is characterized by viral persistence, high levels of antiviral antibody (which is ineffective at eliminating the virus), and immune-complex disease. Death results when virus-antibody immune complexes deposit in the kidneys, producing immune-mediated glomerulonephritis. Ferrets infected with ADV are usually asymptomatic and maintain a low antibody titer, but severe disease can occur. Ferrets with clinical signs of AD may have chronic wasting disease (similar to that seen in mink) or neurologic disease (most often manifested as posterior paresis or paralysis). C1 Univ Georgia, Dept Small Anim Med, Coll Vet Med, Universal City, TX 78148 USA. Univ Georgia, Dept Med Microbiol Parasitol, Coll Vet Med, Universal City, TX USA. Anim Clin Farmers Branch, Dallas, TX USA. NIAID, Rocky Mt Lab, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Universal City Anim Hosp, Universal City, TX USA. RP Stevenson, MAMC (reprint author), Univ Georgia, Dept Small Anim Med, Coll Vet Med, Universal City, TX 78148 USA. NR 55 TC 4 Z9 4 U1 1 U2 8 PU VETERINARY LEARNING SYSTEMS PI TRENTON PA 425 PHILLIPS BLVD #100, TRENTON, NJ 08618 USA SN 0193-1903 J9 COMP CONT EDUC PRACT JI Compend. Contin. Educ. Pract. Vet. PD FEB PY 2001 VL 23 IS 2 BP 178 EP 185 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 403TR UT WOS:000167059000007 ER PT J AU Pressel, SL Davis, BR Wright, JT Geraci, TS Kingry, C Ford, CE Piller, LB Bettencourt, J Kimmel, B Lusk, C Parks, H Simpson, LM Nwachuku, C Furberg, CD AF Pressel, SL Davis, BR Wright, JT Geraci, TS Kingry, C Ford, CE Piller, LB Bettencourt, J Kimmel, B Lusk, C Parks, H Simpson, LM Nwachuku, C Furberg, CD CA ALLHAT Collaborative Res Grp TI Operational aspects of terminating the doxazosin arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) SO CONTROLLED CLINICAL TRIALS LA English DT Article DE clinical trials; closeout; large simple trial; early termination ID TERM CLINICAL-TRIALS; DESIGN AB The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older (n = 42,448). In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized,open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. (C) Elsevier Science Inc. 2001. C1 Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Memphis VAMC, Memphis, TN USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. RP Pressel, SL (reprint author), ALLHAT Clin Trials Ctr, 1200 Herman Pressler St,Suite 801, Houston, TX 77030 USA. FU NHLBI NIH HHS [N01-HC-35130] NR 18 TC 11 Z9 11 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 2001 VL 22 IS 1 BP 29 EP 41 DI 10.1016/S0197-2456(00)00109-4 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 396EH UT WOS:000166623000004 PM 11165421 ER PT J AU Tavel, JA Fosdick, L AF Tavel, JA Fosdick, L CA ESPRIT Vanguard Grp ESPRIT Executive Comm TI Closeout of four phase II vanguard trials and patient rollover into a large international phase III HIV clinical endpoint trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE trial closeout; patient rollover; continued follow-up; feasibility; HIV clinical endpoint trial ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTRAVENOUS INTERLEUKIN-2; INFECTION; THERAPY AB Large phase III clinical trials typically require many years of planning and preparation. During this time, proposed study methods and overall trial feasibility can be assessed in smaller pilot studies. However, the patients enrolled in these pilot studies are not routinely included in the larger study. In preparation for a multinational randomized clinical end point trial of interleukin-2 in HIV-infected patients, four phase II "Vanguard" studies were initiated. These Vanguard trials served to increase safety and surrogate marker data in diverse patient cohorts, increase clinical experience with the study medication, and identify the optimal dose of medication for the phase III trial. These trials also served to assess patient recruitment potential and to develop international clinical trial coordination experience. The Vanguard trials were designed to allow continued follow-up of their patients as participants of the phase III trial once the feasibility of the phase III trial was confirmed. The purpose of this paper is to describe the steps taken in the closeout of these four phase II trials while reconsenting these patients to the phase III trial. Specifically, the reconsent process, the data collection transition plan, and the steps taken to minimize bias due to differential reconsent according to the assigned treatment arm in the phase II trial are described. The procedures employed are relevant to the reconsent of patients for long-term follow-up at the completion of clinical trials. (C) Elsevier Science Inc. 2001. C1 NIAID, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. RP Tavel, JA (reprint author), NIAID, NIH, 9000 Rockville Pike,Bldg 10,Room 11C-103, Bethesda, MD 20892 USA. NR 13 TC 10 Z9 10 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 2001 VL 22 IS 1 BP 42 EP 48 DI 10.1016/S0197-2456(00)00114-8 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 396EH UT WOS:000166623000005 PM 11165422 ER PT J AU Muth, K Yu, E Alston, B Ellenberg, JH AF Muth, K Yu, E Alston, B Ellenberg, JH TI The closeout process for a clinical trial terminated early for lagging enrollment and inadequate follow-up SO CONTROLLED CLINICAL TRIALS LA English DT Article DE closeout; administrative termination; failed accrual; inadequate follow-up AB Closeout of a clinical trial, whether carried out to its original completion of full accrual and attendant follow-up or stopped prematurely because of early indications of efficacy or adverse toxicity, presents challenges in many areas. Closing a clinical trial that fails to adequately accrue and/or successfully follow up patients may exacerbate these problems. The issues involved in the early termination of the Low-Dose Oral Alpha Interferon Trial are described. (C) Elsevier Science Inc. 2001. C1 WESTAT Corp, Rockville, MD 20850 USA. NIAID, Bethesda, MD 20892 USA. RP Muth, K (reprint author), WESTAT Corp, 1650 Res Blvd, Rockville, MD 20850 USA. FU PHS HHS [N01-A1-15123] NR 1 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 2001 VL 22 IS 1 BP 49 EP 55 DI 10.1016/S0197-2456(00)00111-2 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 396EH UT WOS:000166623000006 PM 11165423 ER PT J AU Silverman, H Hull, SC Sugarman, J AF Silverman, H Hull, SC Sugarman, J TI Variability among institutional review boards' decisions within the context of a multicenter trial SO CRITICAL CARE MEDICINE LA English DT Article DE respiratory distress syndrome; adult; informed consent; professional staff committees; bioethics; multicenter studies; human experimentation; clinical protocols; research; standards; research; legislation and jurisprudence ID INFORMED CONSENT; READABILITY AB Background: Institutional review boards (IRBs) are given discretion to interpret and apply the federal regulations governing the protection of human subjects in research. Objective: To determine the extent of the variability among different IRBs on their approved research practices and informed consent forms within the context of a multicenter trial that used a common protocol. Design: Descriptive analysis of survey information and informed consent forms. Setting and Participants: Sixteen IRBs from the institutions participating in a multicenter trial comparing lower vs, traditional tidal volume ventilation in patients with acute lung injury. Measurements: Analysis of survey information on IRBs' approved research practices. Analysis of informed consent forms for the presence and the adequacy of description of each basic element of informed consent specified in the federal regulations. Reading levels of informed consent forms. Main Results: Surveys and IRE-approved consent forms were obtained from all of the contacted IRBs (n = 16), Variability was observed among several of the research practices; one IRE waived the requirement for informed consent, five IRBs permitted telephone consent, and three IRBs allowed prisoners to be enrolled. Three consent forms contained all of the basic elements of informed consent outlined in the federal regulations, and 13 forms had varying numbers of these elements absent (six forms without one element, four without two, one without three, and two without four). Reading levels of the consent forms ranged from grades 8.2 to 13.4 (mean +/- SD was 11.6 +/- 1.2 grade level). Conclusions: Within a multicenter trial, IRBs reviewing a common protocol varied in several of their approved research practices and in the extent to which the basic elements of informed consent were included in their consent forms. C1 Univ Maryland, Sch Med, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21201 USA. NHGRI, Bioeth Sect, NIH, Bethesda, MD 20892 USA. Duke Univ, Ctr Study Med Eth & Human, Durham, NC USA. RP Silverman, H (reprint author), Univ Maryland, Sch Med, Div Pulm & Crit Care Med, Dept Med, 10 S Pine St, Baltimore, MD 21201 USA. FU Intramural NIH HHS [Z99 HG999999] NR 21 TC 112 Z9 112 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2001 VL 29 IS 2 BP 235 EP 241 DI 10.1097/00003246-200102000-00002 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 405UR UT WOS:000167179400002 PM 11246299 ER PT J AU Susla, GM AF Susla, GM TI Drug compatibility differences with propofol injectable emulsion products - Reply SO CRITICAL CARE MEDICINE LA English DT Letter C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Susla, GM (reprint author), NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2001 VL 29 IS 2 BP 467 EP 468 DI 10.1097/00003246-200102000-00068 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 405UR UT WOS:000167179400057 ER PT J AU Nelson, JE Danis, M AF Nelson, JE Danis, M TI End-of-life care in the intensive care unit: Where are we now? SO CRITICAL CARE MEDICINE LA English DT Review DE palliative care; end-of-life care; intensive care; critical care; critical illness; pain ID CRITICALLY ILL PATIENTS; MECHANICAL VENTILATION; PALLIATIVE CARE; SUSTAINING TREATMENTS; SUBSTITUTED JUDGMENT; SYMPTOM ASSESSMENT; DYING EXPERIENCE; DECISION-MAKING; FAMILY MEMBERS; SUPPORT AB A growing body of evidence and experience has effaced what were once thought to be clear distinctions between "critical illness" and "terminal illness" and has exposed the problems of postponing palliative care for intensive care patients until death is obviously imminent, Integration of palliative care as a component of comprehensive intensive care is now seen as more appropriate for all critically ill patients, including those pursuing aggressive treatments to prolong life. At present, however, data on which to base practice in this integrated model remain insufficient, and forces of the healthcare economy and other factors may constrain its application. The purpose of this article is to map where we are now in seeking to improve palliative care in the intensive care unit. We review existing evidence, which suggests that both symptom management and communication about preference's and goals of care warrant improvement and that prevailing practices for limitation of life-sustaining treatments are inconsistent and possibly irrational. We also address the need for assessment tools for research and quality improvement. We discuss recent initiatives and ongoing obstacles. Finally, we identify areas for further exploration and suggest guiding principles. C1 Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Med, Div Pulm & Crit Care Med,Med Intens Care Unit, New York, NY 10029 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Nelson, JE (reprint author), Mt Sinai Med Ctr, Mt Sinai Sch Med, Dept Med, Div Pulm & Crit Care Med,Med Intens Care Unit, Box 1232,1 Gustave Levy Pl, New York, NY 10029 USA. NR 81 TC 17 Z9 19 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2001 VL 29 IS 2 SU S BP N2 EP N9 DI 10.1097/00003246-200102001-00002 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 408NV UT WOS:000167333000002 PM 11228566 ER PT J AU Parshad, R Sanford, KK AF Parshad, R Sanford, KK TI Radiation-induced chromatid breaks and deficient DNA repair in cancer predisposition SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE chromatid breaks; DNA double-strand breaks; X-irradiation; DNA repair; cancer predisposition ID DOUBLE-STRAND BREAKS; ATAXIA-TELANGIECTASIA CELLS; LI-FRAUMENI-SYNDROME; PHASE X-IRRADIATION; G2 CHROMOSOMAL RADIOSENSITIVITY; PERIPHERAL-BLOOD LYMPHOCYTES; HUMAN-TUMOR-CELLS; XERODERMA-PIGMENTOSUM; SUSCEPTIBILITY GENE; FLUORESCENT LIGHT AB Deficient repair of DNA double-strand breaks, resulting in an abnormally high frequency of chromatid breaks after G(2) exposure of cells to radiation, appears to be associated with cancer predisposition. Unrepaired DNA strand breaks contribute to genomic instability. Unrepaired chromatid breaks representing DNA strand breaks can result in chromosome deletions, translocations and gene amplifications seen in human cancers. This cytogenetic response of cells to radiation may be useful as a marker of cancer susceptibility and in identifying individuals at risk of developing cancer in cancer families. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Howard Univ, Coll Med, Dept Pathol, Washington, DC 20059 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Parshad, R (reprint author), Howard Univ, Coll Med, Dept Pathol, 520 West St, Washington, DC 20059 USA. NR 88 TC 33 Z9 37 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1040-8428 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD FEB PY 2001 VL 37 IS 2 BP 87 EP 96 DI 10.1016/S1040-8428(00)00111-6 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 405KX UT WOS:000167159500001 PM 11166582 ER PT J AU Ramamurthy, NS Bain, S Liang, CT Barnes, J Llavaneras, A Liu, Y Puerner, D Strachan, MJ Golub, LM AF Ramamurthy, NS Bain, S Liang, CT Barnes, J Llavaneras, A Liu, Y Puerner, D Strachan, MJ Golub, LM TI A combination of subtherapeutic doses of chemically modified doxycycline (CMT-8) and a bisphosphonate (clodronate) inhibits bone loss in the ovariectomized rat: A dynamic histomorphometric and gene expression study SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID MODIFIED NONANTIMICROBIAL TETRACYCLINE; PERIODONTAL-DISEASES; PARATHYROID-HORMONE; INDUCED OSTEOPENIA; TRABECULAR BONE; CORTICAL BONE; GROWING RATS; AGED RATS; ESTROGEN; APOPTOSIS AB Recent studies have demonstrated that tetracyclines can reduce bone loss in the ovariectomized (OVX) rat model of osteoporosis. In the current study, a non-antimicrobial, chemically modified doxycycline (CMT-8), alone or in combination with a bisphosphonate (Clodronate), was evaluated in this model. Forty-two, 6month old. female rats were randomly assigned to the following groups, (6/ group): a) sham/vehicle, b) OVX/vehicle; c) OVX/1 mg/day CMT-8; d) OVX/2 mg/day CMT-8, e) OVX/1 mg/week Clodronate; and f) OVX/1 mg/day CMT-8 + 1 mg/week Clodronate, CMT-8 was administered by oral gavage, Clodronate injected S/C. Following sham surgery or OVX, the rats were treated for 90 days with CMT-8 or vehicle alone, injected at three different times with fluorochrome labels, the rats were sacrificed, and the tibiae excised for analysis by dynamic bone histomorphometry. Femurs were aseptically removed and analyzed for collagen, collagenase and osteopontin mRNAs by Northern and dot blot analysis. As expected, OVX decreased trabecular bone volume (BV/TV by 73.8% vs. sham p<.01), and also reduced trabecular thickness, numbers, and increased spacing. Done loss in the OVX animals was partially prevented with either 2 mg/day CMT-8 or 1 mg/wk Clodronate (p<.01), while the mg/day CMT-8 had no effect. Interestingly, the efficacy of the combination therapy of CMT-8 and Clodronate was significantly better than either treatment by itself; maintaining bone mass and structural indices at levels identical to sham values. OVX rats mRNA for collagen, collagenase and osteopontin were elevated indicating high-turnover bone loss. Only COMBO therapy significantly reduced the collagenase and osteopontin mRNA. In summary, CMT-8 mono-therapy (2 mg) alone partially inhibited bone loss in this animal model of osteoporosis. However, 1mgday (CMT-8) monotherapy had no effect on bone loss or bone mRNA levels and when combined with Clodronate, interacted to increase efficacy. Thus, a combination of a suboptimal dose of CMT-8 and a bisphosphonate appears to increase the amount of bone by suppressing resorption in a model of osteoporosis. C1 SUNY Stony Brook, Sch Dent Med, Stony Brook, NY 11794 USA. Skeletech Inc, Kirkland, WA USA. Cent Univ Venezuela, Caracas, Venezuela. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Natl Hlth Res Inst, Taipei, Taiwan. RP Ramamurthy, NS (reprint author), SUNY Stony Brook, Sch Dent Med, Stony Brook, NY 11794 USA. FU NIDCR NIH HHS [DE03987] NR 58 TC 13 Z9 14 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD FEB PY 2001 VL 8 IS 3 BP 295 EP 303 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 405UH UT WOS:000167178600009 PM 11172684 ER PT J AU Yewdell, JW Bennink, JR AF Yewdell, JW Bennink, JR TI Cut and trim: generating MHC class I peptide ligands SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID THIMET OLIGOPEPTIDASE; ANTIGEN PRESENTATION; PROTEASOME; PROTEIN; EPITOPE; CELLS; STABILITY AB Progress in understanding how peptide ligands are generated for MHC class I molecules took several interesting leaps and twists in the past year. Two independent lines of evidence suggest that most peptides are generated by proteasomal digestion of nascent proteins. The amino-terminally extended cytosolic precursors of an antigenic peptide were identified, bound to a mysterious carrier protein. Knowledge about the role of immunoproteasomes in antigen processing was fortified, cellular locales specialized for proteasomal degradation (and possibly antigenic-peptide production) were discovered and novel cytosolic proteases potentially involved in generating and trimming antigenic peptides were identified. The field is poised for quantitative analysis of the various pathways that contribute to the pool of peptides presented to the immune system by MHC class I molecules. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Room 211,4 Ctr Dr, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 33 TC 95 Z9 96 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 13 EP 18 DI 10.1016/S0952-7915(00)00175-8 PG 6 WC Immunology SC Immunology GA 395DW UT WOS:000166564300002 PM 11154911 ER PT J AU Gallucci, S Matzinger, P AF Gallucci, S Matzinger, P TI Danger signals: SOS to the immune system SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID DENDRITIC CELL MATURATION; ANTIGEN PRESENTATION; CYTOKINE PRODUCTION; CROSS-LINKING; IN-VITRO; B-CELLS; RECEPTOR; ACTIVATION; EXPRESSION; INTERFERON AB The activation of dendritic cells, necessary for the initiation of primary and secondary immune responses, can be induced by endogenous danger signals - released by tissues undergoing stress, damage or abnormal death - and also by exogenous danger signals elaborated by pathogens. Some endogenous danger signals that recently have been discovered are heat-shock proteins, nucleotides, reactive oxygen intermediates, extracellular-matrix breakdown products, neuromediators and cytokines like the IFNs. We propose that allergy may be initiated by the direct damage of dendritic or other cells by toxic chemicals and allergenic proteases, and suggest that the triggering of danger signal receptors by exogenous pathogen-derived molecules may be more to the advantage of the pathogen than to the host. C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Gallucci, S (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111, Bethesda, MD 20892 USA. NR 63 TC 753 Z9 783 U1 2 U2 39 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 114 EP 119 DI 10.1016/S0952-7915(00)00191-6 PG 6 WC Immunology SC Immunology GA 395DW UT WOS:000166564300018 PM 11154927 ER PT J AU Domenech, P Barry, CE Cole, ST AF Domenech, P Barry, CE Cole, ST TI Mycobacterium tuberculosis in the post-genomic age SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID TRANSPOSON MUTAGENESIS; SPECIES IDENTIFICATION; GENE-CLUSTER; BOVIS BCG; EXPRESSION; VIRULENCE; ARRAYS; SURVIVAL AB Since the publication of the complete genome sequence of Mycobacterium tuberculosis in 1998, there has been a marked intensification and diversification of activities in the field of tuberculosis research. Among the areas that have advanced spectacularly are comparative genomics, functional genomics - notably the study of the transcriptome and proteome - and cell envelope biogenesis, especially as it relates to the mechanism of action of antimycobacterial drugs. C1 Inst Pasteur, Unite Genet Mol Bacterienne, F-75724 Paris 15, France. NIAID, TB Res Sect, Host Def Lab, NIH, Rockville, MD 20852 USA. RP Cole, ST (reprint author), Inst Pasteur, Unite Genet Mol Bacterienne, 28 Rue Dr Roux, F-75724 Paris 15, France. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 42 TC 36 Z9 39 U1 1 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2001 VL 4 IS 1 BP 28 EP 34 DI 10.1016/S1369-5274(00)00160-0 PG 7 WC Microbiology SC Microbiology GA 399XU UT WOS:000166840200004 PM 11173030 ER PT J AU Graham, MR Smoot, LM Lei, BF Musser, JM AF Graham, MR Smoot, LM Lei, BF Musser, JM TI Toward a genome-scale understanding of group A Streptococcus pathogenesis SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID GROUP-A STREPTOCOCCI; PYROGENIC EXOTOXIN-B; EPITHELIAL-CELLS; HYALURONIC-ACID; NEGATIVE REGULATOR; SURFACE PROTEIN; SKIN INFECTION; PYOGENES; BINDING; VIRULENCE AB Recent significant contributions have been made to the understanding of Group A Streptococcus (GAS) pathogenesis. New regulatory pathways have been discovered, insight into the molecular basis of epidemics of serotype M1 disease has been obtained, the crystal structures of four toxins have been reported and a genome sequence of one GAS strain has been determined. Genome-scale approaches to the study of GAS pathogenesis are now rapidly emerging and will advance our fundamental understanding of the molecular basis of host-pathogen interactions. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 46 TC 9 Z9 10 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2001 VL 4 IS 1 BP 65 EP 70 DI 10.1016/S1369-5274(00)00166-1 PG 6 WC Microbiology SC Microbiology GA 399XU UT WOS:000166840200010 PM 11173036 ER PT J AU Howell, BW Herz, L AF Howell, BW Herz, L TI The LDL receptor gene family: signaling functions during development SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; NEURONAL MIGRATION; APOLIPOPROTEIN-E; CEREBRAL-CORTEX; MICE LACKING; TYROSINE PHOSPHORYLATION; LAMINAR ORGANIZATION; CYTOSOLIC ADAPTER; ALZHEIMER-DISEASE; VLDL RECEPTOR AB The traditional views regarding the biological functions of the low-density lipoprotein (LDL) receptor gene family have been revisited recently with new evidence that at least some of the members of this receptor family act as signal-transduction molecules. Known for their role in endocytosis, particularly of their namesake the LDLs, and for their role in the prevention of atherosclerosis, these receptors belong to an ancient family with numerous ligands, effector molecules and functions. Recent evidence implicates this family of receptors in diverse signaling pathways, long-term potentiation and neuronal degeneration. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Mol Genet, Dallas, TX 75390 USA. RP Howell, BW (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. OI Howell, Brian/0000-0002-0204-0773 FU NHLBI NIH HHS [R37 HL063762] NR 46 TC 53 Z9 53 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2001 VL 11 IS 1 BP 74 EP 81 DI 10.1016/S0959-4388(00)00176-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 408VP UT WOS:000167336800011 PM 11179875 ER PT J AU Gerber, MA Tanz, RR AF Gerber, MA Tanz, RR TI New approaches to the treatment of group A streptococcal pharyngitis SO CURRENT OPINION IN PEDIATRICS LA English DT Review ID PENICILLIN-V THERAPY; COMPARATIVE EFFICACY; PEDIATRIC-PATIENTS; CEFUROXIME AXETIL; CHILDREN; AZITHROMYCIN; TONSILLITIS; SAFETY; TONSILLOPHARYNGITIS; CEFDINIR AB An orally administered antimicrobial regimen for the treatment of pharyngitis caused by group A P-hemolytic streptococci that could be given once daily and for less than 10 days would be convenient and might improve compliance, decrease cost, and result in fewer side effects compared with a regimen given multiple times daily for 10 days. Previous attempts to administer oral penicillin once daily or for less than 10 days were not successful. Several cephalosporins and azithromycin have been reported to be effective when administered once daily or for less than 10 days. However, large, comprehensive studies have not been performed. In addition, the spectra of these cephalosporins and azithromycin are much broader than that of penicilin, and, even when they are administered for short courses, they are more expensive. Therefore, these novel regimens cannot be endorsed and should not supplant penicillin as the agent of choice. In contrast, once-daily amoxicillin therapy appears to be effective, is inexpensive, and has a narrower spectrum of antimicrobial activity; if these findings are confirmed by additional investigations, it could become an alternative regimen for the treatment of pharyngitis caused by group A P-hemolytic streptococci. (C) 2001 Lippincott Williams & Wilkins, Inc. C1 Univ Connecticut, Sch Med, NIAID, DMID,Dept Pediat, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Dept Pediat, Evanston, IL 60208 USA. RP Gerber, MA (reprint author), Univ Connecticut, Sch Med, NIAID, DMID,Dept Pediat, Room 3104,6700-B Rockledge Dr,MSC 7630, Bethesda, MD 20892 USA. NR 33 TC 13 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD FEB PY 2001 VL 13 IS 1 BP 51 EP 55 DI 10.1097/00008480-200102000-00009 PG 5 WC Pediatrics SC Pediatrics GA 397YB UT WOS:000166725300009 PM 11176244 ER PT J AU Telford, WG Cox, WG Singer, VL AF Telford, WG Cox, WG Singer, VL TI Detection of endogenous and. antibody-conjugated alkaline phosphatase with ELF-97 phosphate in multicolor flow cytometry applications SO CYTOMETRY LA English DT Article DE ELF-97; alkaline phosphatase; flow cytometry; multicolor analysis ID FAST RED; CELLS; SUBSTRATE; QUANTIFICATION; LOCALIZATION; ASSAY AB Background: The fluorogenic alkaline phosphatase (AP) substrate 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)quinazolinone (ELF(R)-97 phosphate, for Enzyme-Labeled Fluorescence) has been used primarily in microscope-based imaging applications to detect endogenous AP activity, antigens and various ligands in cells and tissues, and nucleic acid hybridization. In a previous study, we demonstrated the applicability of ELF-97 phosphate for detecting endogenous AP activity by flow cytometry. In this study, we show that the spectral characteristics and high signal-to-noise ratio provided by the ELF-97 phosphate make it a useful label for immunodetection via flow cytometry. It can be combined with a variety of other fluorochromes for multiparametric flow cytometry analysis of both endogenous AP activity and intracellular and extracellular immunolabeling with AP-conjugated antibodies. Methods: ELF-97 phosphate detection of endogenous AP activity in UMR-106 rat osteosarcoma cells was combined with intracellular antigen detection using Oregon Green 488 dye-conjugated secondary antibodies and DNA content analysis using propidium iodide (PT) or 7-aminoactinomycin D (7-AAD). ELF-97 phosphate detection of endogenous AP was also tested for spectral compatibility with a variety of other commonly used fluorochromes. ELF-97 phosphate was then used to directly label intracellular antigens via AP-conjugated antibodies, again combined with the analysis of DNA content using PI and 7-AAD. ELF-97 phosphate was also used to directly detect extracellular antigens. It was combined with Oregon Green 488 dye, phycoerythrin (PE), and PE-Cy5 dye-labeled antibodies for simultaneous four-color analysis. All samples were analyzed on a dual-beam flow cytometer, with UV excitation of the ELF-97 alcohol reaction product. Results: Application of the ELF-97 phosphate to detect AP was found to be compatible with immunodetection and DNA staining techniques. It was also spectrally compatible with a variety of other fluorochromes. Endogenous AP activity could be detected simultaneously with both intracellular antigens labeled using Oregon Green 488 dye, PE, Cy5 dye and Alexa Fluor 568 dye-conjugated antibodies, and DNA content analysis with PI or 7-AAD. This multiparametric assay accurately delineated the distribution of AP in cycling cells and was able to identify cell subsets with varying endogenous AP levels. The ELF-97 alcohol reaction product was found to be an effective label for intracellular antigen immunolabeling with AP-conjugated reagents, and could also be combined with PI and 7-AAD. ELF-97 phosphate was also found to be a useful label for extracellular antigen immunolabeling with AP conjugates, and was compatible with Oregon Green 488 dye, PE, and PE-Cy5 dye-labeled antibodies for four-color surface labeling with minimal spectral overlap and color compensation. Conclusions: ELF-97 phosphate was shown to be a useful label for both endogenous and antibody-conjugated AP activity as detected by flow cytometry. Its spectral characteristics allow it To be combined with a variety of fluorochromes for multiparametric analysis. Published 2001 Wiley-Liss, Inc. C1 NCI, Expt Transplantat & Immunol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Mol Probes Inc, Eugene, OR 97402 USA. RP Telford, WG (reprint author), NCI, Expt Transplantat & Immunol Sect, Med Branch, Div Clin Sci,NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 21 TC 17 Z9 19 U1 2 U2 6 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 FEB 1 PY 2001 VL 43 IS 2 BP 117 EP 125 DI 10.1002/1097-0320(20010201)43:2<117::AID-CYTO1026>3.3.CO;2-B PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 397MZ UT WOS:000166700600005 PM 11169576 ER PT J AU Pinnell, SR Yang, HS Omar, M Riviere, NM DeBuys, HV Walker, LC Wang, YH Levine, M AF Pinnell, SR Yang, HS Omar, M Riviere, NM DeBuys, HV Walker, LC Wang, YH Levine, M TI Topical L-ascorbic acid: Percutaneous absorption studies SO DERMATOLOGIC SURGERY LA English DT Article ID VITAMIN-C; HUMAN SKIN; ULTRAVIOLET-RADIATION; ALPHA-TOCOPHEROL; MOUSE SKIN; IN-VITRO; DEHYDROASCORBIC ACID; OXIDATIVE DAMAGE; INDUCED ERYTHEMA; HAIRLESS MOUSE AB BACKGROUND. Reactive oxygen species generated by ultraviolet light result in photocarcinogenic and photoaging changes in the skin. Antioxidants protect skin from these insults. OBJECTIVE. This study defines formulation characteristics for delivering L-ascorbic acid into the skin to supplement the skin's natural antioxidant reservoir. METHODS. L-ascorbic acid or its derivatives were applied to pig skin. Skin levels of L-ascorbic acid were measured to determine percutaneous delivery. RESULTS. L-ascorbic acid must be formulated at pH levels less than 3.5 to enter the skin. Maximal concentration for optimal percutaneous absorption was 20%. Tissue levels were saturated after three daily applications; the half-life of tissue disappearance was about 4 days. Derivatives of ascorbic acid including magnesium ascorbyl phosphate, ascorbyl-6-palmitate, and dehydroascorbic acid did not increase skin levels of L-ascorbic acid. CONCLUSIONS. Delivery of topical L-ascorbic acid into the skin is critically dependent on formulation characteristics. C1 Duke Univ, Med Ctr, Dept Med, Div Dermatol, Durham, NC 27707 USA. PhytoCeuticals, Elmwood Pk, NJ USA. N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Pinnell, SR (reprint author), Duke Univ, Med Ctr, Dept Med, Div Dermatol, POB 3135, Durham, NC 27707 USA. NR 68 TC 60 Z9 62 U1 0 U2 17 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD FEB PY 2001 VL 27 IS 2 BP 137 EP 142 DI 10.1046/j.1524-4725.2001.00264.x PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 405QF UT WOS:000167170000008 PM 11207686 ER PT J AU Koizumi, K Stivers, C Brody, T Zangeneh, S Mozer, B Odenwald, WF AF Koizumi, K Stivers, C Brody, T Zangeneh, S Mozer, B Odenwald, WF TI A search for Drosophila neural precursor genes identifies ran SO DEVELOPMENT GENES AND EVOLUTION LA English DT Article DE Drosophila; ran; embryogenesis; Ras superfamily ID NUCLEAR-PROTEIN IMPORT; EXPRESSION; RAN/TC4; TRANSPORT; GTP; LOCALIZATION; EMBRYOS; EMBRYOGENESIS; SPECIFICITY; INHIBITION AB The Drosophila ran gene has been isolated in a differential cDNA screen designed to identify genes that are dynamically expressed in embryonic neuroblasts. The guanine triphosphate (GTP)-binding Ran protein, a member of the Ras superfamily, has been shown to participate in a variety of transport related processes in other organisms. Drosophila ran codes for a 216 amino acid (aa) protein that shares 78% and 86% identity with the yeast and human Ran proteins, respectively. Database searches have identified a second Drosophila ran gene, ran-like. The predicted Ran-like protein shares 59% identity with its isoform. Embryo in situ mRNA localization of ran and ran-like expression reveals that both are maternally expressed; however zygotic ran expression is restricted to central nervous system (CNS) neuroblasts undergoing late lineage formation, while ran-like expression is detected in the developing trachea and salivary gland. To investigate the significance of ran-restricted CNS expression, we have targeted its misexpression to different temporal windows of CNS development. In addition, a dominant-negative mutant form of ran was targeted to the developing CNS and to the larval eye/antenna imaginal disc to assess the role of ran-dependent functions. Embryonic CNS misexpression of the mutant, but not wild-type, ran results in larval death. Neither wild-type nor mutant ran misexpression had any detectable effect on embryonic CNS lineage specification, nuclear transport of a number of CNS-specific transcription factors or axonal guidance. However, expression of the dominant-negative mutant ran in the developing eye/antenna disc did result in a severe adult eye phenotype marked by apoptosis of photoreceptor, cone and pigment cells. C1 NINDS, Neurogenet Unit, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Odenwald, WF (reprint author), NINDS, Neurogenet Unit, Neurochem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 7 Z9 9 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0949-944X J9 DEV GENES EVOL JI Dev. Genes Evol. PD FEB PY 2001 VL 211 IS 2 BP 67 EP 75 DI 10.1007/s004270000122 PG 9 WC Cell Biology; Evolutionary Biology; Developmental Biology SC Cell Biology; Evolutionary Biology; Developmental Biology GA 411WZ UT WOS:000167523800002 PM 11455416 ER PT J AU Flanders, KC Kim, ES Roberts, AB AF Flanders, KC Kim, ES Roberts, AB TI Immunohistochemical expression of Smads 1-6 in the 15-day gestation mouse embryo: Signaling by BMPs and TGF-beta s SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Smad proteins; immunohistochemistry; mouse embryo; transforming growth factor-beta; bone morphogenetic proteins; activin; organogenesis ID GROWTH-FACTOR-BETA; BONE MORPHOGENETIC PROTEIN-2; LUNG BRANCHING MORPHOGENESIS; TUMOR-SUPPRESSOR; MESODERM INDUCTION; TRANSFORMING GROWTH-FACTOR-BETA-1; TARGETED DISRUPTION; EPITHELIAL-CELLS; NERVOUS-SYSTEM; XENOPUS-LAEVIS AB The eight mammalian Smad proteins mediate cellular signaling from members of the transforming growth factor-beta (TGF-beta), bone morphogenetic protein (BMP), and activin families. Smads 1, 5, and 8 transmit signals from BMPs, while Smads 2 and 3 transmit signals from TGF-betas and activin, Smad 4 is a common mediator of both pathways, while Smads 6 and 7 inhibit signaling. Signal transduction involves translocation of Smad complexes to the nucleus and subsequent gene activation. Little is known about the expression of endogenous Smad proteins during development. We identified commercially available Smad antibodies that specifically recognize a unique Smad protein and are suitable for immunohistochemistry. Here we compare the localization of Smads 1, 2, 3, 4, 5, and 6 in tissues of the 15-day gestation mouse embryo. Immunoreactive Smad proteins are seen in many tissues with differences in the localization being dependent upon the cell type. All tissues express Smad 4 and at least one each of the BMP-specific and TGF-beta -specific Smads, while expression of Smad 6 is more restricted. Differences are observed in the nuclear versus cytoplasmic localization among the Smads in different cell types or tissues, suggesting selective activation of Smads during this stage of development. Published 2001 Wiley-Liss, Inc.(dagger). C1 NCI, LCRC, NIH, Bethesda, MD 20892 USA. RP Flanders, KC (reprint author), NCI, LCRC, NIH, Bldg 41,Rm C-629,41 Lib Dr MSC 5055, Bethesda, MD 20892 USA. NR 81 TC 67 Z9 72 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD FEB PY 2001 VL 220 IS 2 BP 141 EP 154 DI 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1096>3.0.CO;2-4 PG 14 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 397JR UT WOS:000166693000006 PM 11169847 ER PT J AU Pickens, RW Preston, KL Miles, DR Gupman, AE Johnson, EO Newlin, DB Soriano, J van den Bree, MBM Umbricht, A AF Pickens, RW Preston, KL Miles, DR Gupman, AE Johnson, EO Newlin, DB Soriano, J van den Bree, MBM Umbricht, A TI Family history influence on drug abuse severity and treatment outcome SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE heroin addiction; family history; genetics; treatment outcome; methadone; maintenance ID SUBSTANCE-ABUSE; METHADONE PATIENTS; OPIOID ABUSERS; OPIATE ADDICTS; FEMALE TWINS; ALCOHOLISM; COCAINE; PSYCHOPATHOLOGY; DIAGNOSIS; TRANSMISSION AB Influence of parental alcohol/substance abuse on methadone maintenance therapy (MMT) outcome was examined in 164 DSM-III-R opioid dependent adults with no other current DSM Axis I disorder. Family history positive patients had more DSM-III-R opioid dependence symptoms and were more likely to be classified as severely dependent. However, when placed on identical daily doses of methadone (50 mg), they had lower rates of illicit opioid use but higher rates of cocaine use than family history negative patients. Both effects remained significant after adjusting for gender and race. These results suggest that common genetic factors may underlie both susceptibility to heroin dependence and response to therapeutic methadone treatment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, Intramural Res Program, Clin Neurogenet Sect, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Treatment Res Branch, Baltimore, MD 21224 USA. RP Pickens, RW (reprint author), Sanger Hall,Room 1-018,1101 E Marshall St,POB 980, Richmond, VA 23298 USA. RI turton, miranda/F-4682-2011; Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 57 TC 11 Z9 11 U1 2 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2001 VL 61 IS 3 BP 261 EP 270 DI 10.1016/S0376-8716(00)00146-0 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 390ZG UT WOS:000166329200007 PM 11164690 ER PT J AU Chang, HT Yergey, AL Chrambach, A AF Chang, HT Yergey, AL Chrambach, A TI Electroelution of proteins from bands in gel electrophoresis without gel sectioning for the purpose of protein transfer into mass spectrometry: Elements of a new procedure SO ELECTROPHORESIS LA English DT Article DE direct electroelution; protein band transfer; mass ID AUTOMATED HPGE-1000 APPARATUS; POLYACRYLAMIDE-GEL; SDS-PROTEIN; RECOVERY; RESOLUTION; SYSTEM; STEP AB Electroelution of protein bands from a gel has advantages over the competitive common technique requiring gel sectioning with respect to yield, speed and the potential for computer-controlled application to multicomponent two-dimensional (2-D) gels. The electroelution design for the commercial high-performance gel electrophoresis (HPGE) apparatus represented the most advanced technique to date until the recent discontinuation of its production. The present report serves to summarize the necessary design elements for the purpose of renewing and further developing the electroelution technique. A rudimentary technique is presented by which the electroeluate is collected in a glass tube superimposed an a reversibly stained gel band and connected to an anolyte reservoir. Although the stain used is insufficiently sensitive, the technique allowed for the qualitative verification of its usefulness in the transfer of the electroeluate into mass spectrometry. C1 NICHD, Lab Cellular & Mol Biophys, Macromol Anal Sect, NIH, Bethesda, MD 20892 USA. NICHD, Lab Cellular & Mol Biophys, Sect Mass Spectrometry & Metab, NIH, Bethesda, MD 20892 USA. Natl Taiwan Univ, Dept Chem, Taipei 10764, Taiwan. RP Chrambach, A (reprint author), NICHD, Lab Cellular & Mol Biophys, Macromol Anal Sect, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. RI Chang, Huan-Tsung/C-1183-2011; OI Chang, Huan-Tsung/0000-0002-5393-1410 NR 15 TC 16 Z9 17 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 2001 VL 22 IS 3 BP 394 EP 398 DI 10.1002/1522-2683(200102)22:3<394::AID-ELPS394>3.0.CO;2-X PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 409AM UT WOS:000167362400003 PM 11258744 ER PT J AU Chiari, M Cretich, M Stastna, M Radko, SP Chrambach, A AF Chiari, M Cretich, M Stastna, M Radko, SP Chrambach, A TI Rapid capillary coating by epoxy-poly(dimethylacrylamide): Performance in capillary zone electrophoresis of protein and polystyrene carboxylate SO ELECTROPHORESIS LA English DT Article DE capillary coating; capillary zone electrophoresis ID FUSED-SILICA CAPILLARIES; SEPARATION; POLYMER; COLUMN AB A fast and simple method for the internal coating of capillaries in capillary zone electrophoresis (CZE) is that with epoxy-poly(dimethylacrylamide) (EPDMA), Duration of coating by that method is 30 min, compared with that of 24 h when using uncross-linked polyacrylamide (PA) under otherwise identical conditions. Under the conditions used for the CZE of proteins (pH 9.0, 2% polyethylene glycol), the capillary coating with EPDMA is stable for at least 50 consecutive runs as judged by the constancy of low electroosmotic flow, equalling the stability of coating achieved by PA. Protein mobilities and protein peak asymmetry (suggestive of reversible interaction with the capillary wall) are also found to be the same in EPDMA and PA coated capillaries, Differences between EPDMA and PA coating also exist: The former is unstable upon lowering the ionic strength of the buffer to 0.003, upon the addition of sodium dodecyl sulfate (SDS) to the buffer and in application to the hydrophobic analyte, polystyrene carboxylate. C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. CNR, Inst Biocatalysis & Mol Recognit, I-20133 Milan, Italy. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. RI Cretich, Marina/I-3631-2012; Stastna, Miroslava/G-9266-2014; OI Cretich, Marina/0000-0001-8251-5275; Chiari, Marcella/0000-0002-4670-1430 NR 12 TC 30 Z9 31 U1 0 U2 7 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 2001 VL 22 IS 4 BP 656 EP 659 DI 10.1002/1522-2683(200102)22:4<656::AID-ELPS656>3.0.CO;2-S PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 410DL UT WOS:000167424700006 PM 11296919 ER PT J AU Wong, C Xiong, LW Horiuchi, M Raymond, L Wehrly, K Chesebro, B Caughey, B AF Wong, C Xiong, LW Horiuchi, M Raymond, L Wehrly, K Chesebro, B Caughey, B TI Sulfated glycans and elevated temperature stimulate PrPSc-dependent cell-free formation of protease-resistant prion protein SO EMBO JOURNAL LA English DT Article DE heparan sulfate; pentosan polysulfate; prion; scrapie; transmissible spongiform encephalopathy ID CREUTZFELDT-JAKOB-DISEASE; SCRAPIE-ASSOCIATED FORM; MOUSE SCRAPIE; NEUROBLASTOMA-CELLS; AGENT REPLICATION; DEXTRAN SULFATE; AMYLOID PLAQUES; CULTURED-CELLS; CONVERSION; MICE AB A conformational conversion of the normal, protease-sensitive prion protein (PrP-sen or PrPC) to a protease-resistant form (PrP-res or PrPSc) is commonly thought to be required in transmissible spongiform encephalopathies (TSEs), Endogenous sulfated glycosaminoglycans are associated with PrP-res deposits in vivo, suggesting that they may facilitate PrP-res formation. On the other hand, certain exogenous sulfated glycans can profoundly inhibit PrP-res accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrP-res formation, we have assayed their direct effects on PrP conversion under physiologically compatible cell-free conditions. Heparan sulfate and pentosan polysulfate stimulated PrP-res formation. Conversion was stimulated further by increased temperature. Both elevated temperature and pentosan polysulfate promoted interspecies PrP conversion. Circular dichroism spectropolarimetry measurements showed that pentosan polysulfate induced a conformational change in PrP-sen that may potentiate its PrP-res-induced conversion. These results show that certain sulfated glycosaminoglycans can directly affect the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Obihiro Univ Agr & Vet Med, Dept Vet Publ Hlth, Obihiro, Hokkaido 0808555, Japan. Obihiro Univ Agr & Vet Med, Res Ctr Protozoan Dis, Obihiro, Hokkaido 0808555, Japan. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 56 TC 169 Z9 177 U1 0 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 FEB 1 PY 2001 VL 20 IS 3 BP 377 EP 386 DI 10.1093/emboj/20.3.377 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 400BH UT WOS:000166848400008 PM 11157745 ER PT J AU Nam, TW Cho, SH Shin, D Kim, JH Jeong, JY Lee, JH Roe, JH Peterkofsky, A Kang, SO Ryu, S Seok, YJ AF Nam, TW Cho, SH Shin, D Kim, JH Jeong, JY Lee, JH Roe, JH Peterkofsky, A Kang, SO Ryu, S Seok, YJ TI The Escherichia coli glucose transporter enzyme IICBGlc recruits the global repressor Mlc SO EMBO JOURNAL LA English DT Article DE enzyme IICBGlC; glucose induction; Mlc; protein-protein interaction; signal transduction ID SUGAR PHOSPHOTRANSFERASE SYSTEM; PTS OPERON; ALLOSTERIC REGULATION; TERMINAL DOMAIN; EXPRESSION; GENE; PHOSPHOENOLPYRUVATE; PROTEIN; PURIFICATION; TRANSCRIPTION AB In addition to effecting the catalysis of sugar uptake, the bacterial phosphoenolpyruvate :sugar phosphotransferase system regulates a variety of physiological processes. Exposure of cells to glucose can result in repression or induction of gene expression, While the mechanism for carbon catabolite repression by glucose was well documented, that for glucose induction was not clearly understood in Escherichia coli, Recently, glucose induction of several E.coli genes has been shown to be mediated by the global repressor Mlc, Here, we elucidate a general mechanism for glucose induction of gene expression in E.coli, revealing a novel type of regulatory circuit for gene expression mediated by the phosphorylation state-dependent interaction of a membrane-bound protein with a repressor. The dephospho-form of enzyme IICBGlc, but not its phospho-form, interacts directly with Mlc and induces transcription of Mlc-regulated genes by displacing Mlc from its target sequences. Therefore, the glucose induction of Mlc-regulated genes is caused by dephosphorylation of the membrane-bound transporter enzyme IICBGlc, which directly recruits Mlc to derepress its regulon. C1 Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. Seoul Natl Univ, Inst Microbiol, Seoul 151742, South Korea. Seoul Natl Univ, Sch Agr Biotechnol, Suwon 441744, South Korea. NHLBI, Lab Biochem Genet, Bethesda, MD 20892 USA. RP Seok, YJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. NR 39 TC 91 Z9 92 U1 2 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 FEB 1 PY 2001 VL 20 IS 3 BP 491 EP 498 DI 10.1093/emboj/20.3.491 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 400BH UT WOS:000166848400018 PM 11157755 ER PT J AU Marchler, G Wu, C AF Marchler, G Wu, C TI Modulation of Drosophila heat shock transcription factor activity by the molecular chaperone DROJ1 SO EMBO JOURNAL LA English DT Article DE Droj1; heat shock factor; HSP70; HSP83; transcription ID DNA-BINDING ACTIVITY; IN-VIVO; ACTIVATION DOMAIN; SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE-SEQUENCE; NEGATIVE REGULATION; SODIUM-SALICYLATE; XENOPUS OOCYTES; FACTOR CONTAINS; PROTEIN AB Heat shock transcription factors (HSFs) play important roles in the cellular response to physiological stress signals. To examine the control of HSF activity, we undertook a yeast two-hybrid screen for proteins interacting with Drosophila HSF, DROJ1, the fly counterpart of the human heat shock protein HSP40/HDJ1, was identified as the dominant interacting protein (15 independent isolates from 58 candidates). Overexpression of DROJ1 in Drosophila SL2 cells delays the onset of the heat shock response. Moreover, RNA interference involving transfection of SL2 cells with double-stranded droj1 RNA depletes the endogenous level of DROJ1 protein, leading to constitutive activation of endogenous heat shock genes. The induction level, modest when DROJ1 was depleted alone, reached maximal levels when DROJ1 and HSP70/HSC70, or DROJ1 and HSP90, were depleted concurrently, Chaperone co-depletion was also correlated with strong induction of the DNA binding activity of HSF, Our findings support a model in which synergistic interactions between DROJ1 and the HSP70/HSC70 and HSP90 chaperones modulate HSF activity by feedback repression. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, NIH, Bldg 37,Room 5E-26, Bethesda, MD 20892 USA. NR 78 TC 48 Z9 52 U1 0 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 FEB 1 PY 2001 VL 20 IS 3 BP 499 EP 509 DI 10.1093/emboj/20.3.499 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 400BH UT WOS:000166848400019 PM 11157756 ER PT J AU Donze, D Kamakaka, RT AF Donze, D Kamakaka, RT TI RNA polymerase III and RNA polymerase II promoter complexes are heterochromatin barriers in Saccharomyces cerevisiae SO EMBO JOURNAL LA English DT Article DE boundaries; HMR; promoters; tRNA; silencing ID YEAST TRANSFER-RNA; RESOLUTION STRUCTURAL-ANALYSIS; TRANSCRIPTION FACTOR-IIIB; CELL-CYCLE PROGRESSION; ZINC-FINGER PROTEIN; HEAT-SHOCK GENE; DROSOPHILA-MELANOGASTER; INVITRO TRANSCRIPTION; 5'-FLANKING SEQUENCES; INSULATOR ELEMENTS AB The chromosomes of eukaryotes are organized into structurally and functionally discrete domains. Several DNA elements have been identified that act to separate these chromatin domains. We report a detailed characterization of one of these elements, identifying it as a unique tRNA gene possessing the ability to block the spread of silent chromatin in Saccharomyces cerevisiae efficiently. Transcriptional potential of the tRNA gene is critical for barrier activity, as mutations in the tRNA promoter elements, or in extragenic loci that inhibit RNA polymerase III complex assembly, reduce barrier activity. Also, we have reconstituted the Drosophila gypsy element as a heterochromatin barrier in yeast, and have identified other yeast sequences, including the CHA1 upstream activating sequence, that function as barrier elements. Extragenic mutations in the acetyltransferase genes SAS2 and GCN5 also reduce tRNA barrier activity, and tethering of a GAL4/SAS2 fusion creates a robust barrier. We propose that silencing mediated by the Sir proteins competes with barrier element-associated chromatin remodeling activity. C1 NICHD, Unit Chromatin & Transcript, NIH, Bethesda, MD 20892 USA. RP Kamakaka, RT (reprint author), NICHD, Unit Chromatin & Transcript, NIH, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. NR 96 TC 188 Z9 193 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 1 PY 2001 VL 20 IS 3 BP 520 EP 531 DI 10.1093/emboj/20.3.520 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 400BH UT WOS:000166848400021 PM 11157758 ER PT J AU Le Roith, D Bondy, C Yakar, S Liu, JL Butler, A AF Le Roith, D Bondy, C Yakar, S Liu, JL Butler, A TI The somatomedin hypothesis: 2001 SO ENDOCRINE REVIEWS LA English DT Review ID GROWTH-FACTOR-I; MESSENGER-RIBONUCLEIC-ACID; HORMONE-BINDING-PROTEIN; INSULIN-RECEPTOR SUBSTRATE-1; LONGITUDINAL BONE-GROWTH; IMPROVES GLYCEMIC CONTROL; NEUROPEPTIDE-Y NEURONS; OSTEOBLAST-LIKE CELLS; GH-RELEASING HORMONE; IGF-I AB Since the original somatomedin hypothesis was conceived, a number of important discoveries have allowed investigators to modify the concept. Originally somatic growth was thought to be controlled by pituitary GH and mediated by circulating insulin-like growth factor-I (IGF-I, somatomedin C) expressed exclusively by the liver. With the discovery that IGF-I is produced by most, if not all, tissues, the role of autocrine/paracrine IGF-I vs. the circulating form has been hotly debated. Recent experiments using transgenic and gene-deletion technologies have attempted to answer these questions. In the liver-specific igf-l gene-deleted mouse model, postnatal growth and development are normal despite the marked reduction in circulating IGF-I and IGF-binding protein levels; free IGF-I levels are normal. Thus, the normal postnatal growth and development in these animals may be due to normal free IGF-I levels (from as yet unidentified sources), although the role of autocrine/paracrine IGF-I has yet to be determined. C1 NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA. RP Le Roith, D (reprint author), NIH, Clin Endocrinol Branch, Room 8D12,Bldg 10,MSC 1758, Bethesda, MD 20892 USA. NR 223 TC 739 Z9 757 U1 5 U2 31 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD FEB PY 2001 VL 22 IS 1 BP 53 EP 74 DI 10.1210/er.22.1.53 PG 22 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 405CK UT WOS:000167139500003 PM 11159816 ER PT J AU Bernard, C Sutter, A Vinson, C Ratineau, C Chayvialle, JA Cordier-Bussat, M AF Bernard, C Sutter, A Vinson, C Ratineau, C Chayvialle, JA Cordier-Bussat, M TI Peptones stimulate intestinal cholecystokinin gene transcription via cyclic adenosine monophosphate response element-binding factors SO ENDOCRINOLOGY LA English DT Article ID C-FOS; RAT CHOLECYSTOKININ; CELL-LINE; EXPRESSION; SECRETION; CCK; PROMOTER; CREB; PHOSPHORYLATION; ACTIVATION AB Cholecystokinin (CCK) is a potent intestinal hormone that regulates several digestive functions. Despite the physiological importance of CCK, the cellular and molecular mechanisms that govern its synthesis and secretion are not completely identified. Peptones, which are fair counterparts of the protein fraction in the intestinal lumen, are good stimulants of CCK secretion. We have previously shown that peptones activate CCK gene transcription in STC-1 enteroendocrine cells. The DNA element(s) necessary to induce the transcriptional stimulation was preliminary, localized in the first 800 bp of the CCK gene promoter. In the present study, we identify a DNA element [peptone-response element (PepRE)] essential to confer peptone-responsiveness to the CCK promoter, and we characterize the transcription factors implicated. Localization of the PepRE between -93 and -70 bp of the promoter was established using serial 5'-3' deletions. Systematic site-directed mutagenesis demonstrated that the core PepRE sequence, spanning from nucleotide -72 to -83, overlapped with the putative AP-1/CRE site. Mutations in the core sequence dramatically decreased peptone-responsiveness of CCK promoter fragments. The PepRE functioned as a low-aftinity CRE consensus site, binding only transcription factors of the CREB family. Overexpression, in STC-1 cells, of a dominant-negative protein (A-CREB), that prevented the binding of CREB factors to DNA, completely abolished the peptone-induced transcriptional stimulation. Peptone treatment did not modify the nature and the abundance of proteins bound to the PepRE but led to increased phosphorylation of the CREB factors. In conclusion, the present study first demonstrates that CCK gene expression is under the control of protein-derived nutrients in the STC-1 enteroendocrine cell line. C1 Hop Edouard Herriot, INSERM U45, F-69437 Lyon 03, France. NCI, Eleve Ecole Prat Hautes Etud, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Cordier-Bussat, M (reprint author), Hop Edouard Herriot, INSERM U45, Pavillon Hbis, F-69437 Lyon 03, France. NR 29 TC 18 Z9 20 U1 0 U2 0 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 FEB PY 2001 VL 142 IS 2 BP 721 EP 729 DI 10.1210/en.142.2.721 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398GC UT WOS:000166747700026 PM 11159844 ER PT J AU Jeffries, N Pfeiffer, R AF Jeffries, N Pfeiffer, R TI A mixture model for the probability distribution of rain rate SO ENVIRONMETRICS LA English DT Article DE mixtures; logistic regression; EM algorithm; rain rate ID EM ALGORITHM; LIKELIHOOD AB In this paper we present a logistic mixture model for rain rate, that is, a model where the regime probabilities are allowed to change over time and are modeled with a logistic regression structure. Such a model may be used as an alternative to simple mixture, threshold, or hidden Markov models. The maximum likelihood estimates for the model parameters are found using an EM algorithm and their asymptotic properties are stated. The model is fit to hourly measurements of rain rate that are part of the GATE dataset. The results are compared with results from a standard mixture model and from a single density model. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 NCI, Rockville, MD 20852 USA. NINDS, Bethesda, MD 20892 USA. RP Pfeiffer, R (reprint author), NCI, 6120 Execut Blvd EPS 8017, Rockville, MD 20852 USA. RI Pfeiffer, Ruth /F-4748-2011 NR 16 TC 5 Z9 5 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1180-4009 J9 ENVIRONMETRICS JI Environmetrics PD FEB PY 2001 VL 12 IS 1 BP 1 EP 10 DI 10.1002/1099-095X(200102)12:1<1::AID-ENV425>3.0.CO;2-N PG 10 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA 397YQ UT WOS:000166726800001 ER PT J AU Hill, MJ Davies, GJ Giacosa, A AF Hill, MJ Davies, GJ Giacosa, A TI Should we change our dietary advice on cancer prevention? SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Editorial Material ID COLORECTAL ADENOMAS; LARGE BOWEL; RECURRENCE; FIBER; VEGETABLES; ETIOLOGY; FRUIT; RISK C1 S Bank Univ, Nutr Res Ctr, London SE1 0AA, England. Natl Canc Inst, Gastroenterol & Nutr Unit, I-16132 Genoa, Italy. RP Hill, MJ (reprint author), S Bank Univ, Nutr Res Ctr, 103 Borough Rd, London SE1 0AA, England. NR 22 TC 18 Z9 19 U1 0 U2 1 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 FEB PY 2001 VL 10 IS 1 BP 1 EP 6 DI 10.1097/00008469-200102000-00001 PG 6 WC Oncology SC Oncology GA 410XD UT WOS:000167465600001 PM 11263581 ER PT J AU Kawamura, T Qualbani, M Thomas, EK Orenstein, JM Blauvelt, A AF Kawamura, T Qualbani, M Thomas, EK Orenstein, JM Blauvelt, A TI Low levels of productive HIV infection in Langerhans cell-like dendritic cells differentiated in the presence of TGF-beta 1 and increased viral replication with CD40 ligand-induced maturation SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Langerhans cell; dendritic cell; HIV; coreceptor; TGF-beta 1 ID IMMUNODEFICIENCY-VIRUS TYPE-1; HEMATOPOIETIC PROGENITOR CELLS; COLONY-STIMULATING FACTOR; HUMAN PERIPHERAL-BLOOD; IN-VITRO DEVELOPMENT; T-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; NULL MICE; TNF-ALPHA; GM-CSF AB Langerhans cells (LC) represent dendritic cells (DC) within mucosal epithelium that are purported initial targets for HIV following sexual exposure to virus. Here, morphologic, phenotypic, functional and HIV infection experiments were performed using monocyte-derived DC cultured in the presence of GM-CSF, IL-4 and TGF-beta1 (G4T-DC), GM-CSF and IL-4 (G4-DC), and G4T-DC incubated for an additional 3 days with CD40 ligand (CD40L-DC). G4T-DC, which demonstrated characteristics of immature LC, could be productively infected by either R5- or X4-HIV strains. Infection levels, however, were markedly lower than those observed in immature G4-DC. Surprisingly, CD40L-DC, which demonstrated features of mature LC, could be productively infected with HIV at higher levels than immature G4T-DC. Productive HIV infection in these three DC populations correlated positively with cell surface expression of CD4, CCR5 and CXCR4. We suggest that low levels of HIV infection in LC-like G4T-DC indicate an inefficient mechanism by which HIV can initially infect individuals, perhaps explaining the relative difficulty in becoming infected during sexual exposure to virus. In addition, enhanced HIV infection in LC-like G4T-DC following CD40L treatment suggests a mechanism by which inflammatory CD40L(+) T cells, if present in mucosal tissue, could lead to increased HIV transmission rates. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. Immunex Corp, Seattle, WA USA. George Washington Univ, Dept Pathol, Washington, DC USA. RP Blauvelt, A (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 49 TC 30 Z9 30 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2001 VL 31 IS 2 BP 360 EP 368 DI 10.1002/1521-4141(200102)31:2<360::AID-IMMU360>3.0.CO;2-X PG 9 WC Immunology SC Immunology GA 403EF UT WOS:000167029100005 PM 11180099 ER PT J AU Gabay, C Gigley, J Sipe, J Arend, WP Fantuzzi, G AF Gabay, C Gigley, J Sipe, J Arend, WP Fantuzzi, G TI Production of IL-1 receptor antagonist by hepatocytes is regulated as an acute-phase protein in vivo SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IL-1 receptor antagonist; acute-phase protein; hepatocyte; lipopolysaccharide; turpentine ID MICE; CLONING; ISOFORM; DISEASE; INFLAMMATION; EXPRESSION; INDUCTION AB IL-1 receptor antagonist (IL-1Ra) is produced by isolated human hepatocytes with characteristics of an acute-phase protein. There are multiple IL-1Ra peptides, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3). sIL-1Ra, but not icIL-1Ra1, mRNA is transcribed by cultured human hepatocytes. In this study, we examined in vivo production of IL-1Ra by the liver in mice in two experimental models of acute-phase response, systemic lipopolysaccharide (LPS) administration and local turpentine injection. Liver sIL-1Ra expression was up-regulated in response to both types of stimulation. After LPS injection, the hepatic production of sIL-1Ra correlated with the increase in plasma IL-1Ra levels. In addition, the total amount of IL-1Ra present in the liver after LPS injection was six- and tenfold higher than in the lung and spleen. As assessed by in situ hybridization, sIL-1Ra, but not icIL-1Ra, mRNA was produced by hepatocytes in vivo after LPS injection. Using IL-6(-/-) mice, we demonstrated that in turpentine-induced inflammation production of IL-1Ra mRNA by the liver is regulated by IL-6. In contrast, local production of IL-1Ra is independent of IL-6. Taken together, these results indicate that IL-1Ra is produced by the liver as an acute-phase protein in vivo. C1 Univ Hosp Geneva, Div Rheumatol, CH-1211 Geneva 14, Switzerland. Univ Colorado, Hlth Sci Ctr, Div Rheumatol, Denver, CO USA. NIH, Biochem Sci IRG, Ctr Sci Review, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Div Infect Dis, Denver, CO USA. RP Gabay, C (reprint author), Univ Hosp Geneva, Div Rheumatol, 26 Ave Beau Sejour, CH-1211 Geneva 14, Switzerland. RI Fantuzzi, Giamila/A-1758-2009 OI Fantuzzi, Giamila/0000-0001-5334-0082 FU NIAMS NIH HHS [AR40135] NR 31 TC 41 Z9 42 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2001 VL 31 IS 2 BP 490 EP 499 DI 10.1002/1521-4141(200102)31:2<490::AID-IMMU490>3.0.CO;2-H PG 10 WC Immunology SC Immunology GA 403EF UT WOS:000167029100020 PM 11180114 ER PT J AU Shirai, M Fujinaga, R Masaki, T Berzofsky, JA AF Shirai, M Fujinaga, R Masaki, T Berzofsky, JA TI Impaired development of HIV-1 gp160-specific CD8(+) cytotoxic T cells by a delayed switch from Th1 to Th2 cytokine phenotype in mice with Helicobacter pylori infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE helicobacter pylori; HIV; Th1; IL-12; urease; JNK ID RECOMBINANT VACCINIA VIRUS; IL-4-PRODUCING CELLS; LEISHMANIA-MAJOR; ENVELOPE PROTEIN; IMMUNE-RESPONSES; UREASE; DIFFERENTIATION; EXPRESSION; GASTRITIS; GAMMA AB Th1 and Th2 cells play a central role in immunoregulation during infection. We show that Helicobacter pylori induces Th1 cytokine responses early (2 weeks) but predominantly Th2 responses later (6 weeks) in infection. The switch is principally mediated by urease-specific CD4(+) T cells, and correlates with a loss of urease-specific high-avidity JNK(+) Th1 and gain of low-avidity JNK(-) (possibly Th2) cells at the later stage of infection, concomitant with a 100-fold higher colonization level of H. pylori at 6 weeks than at 2 weeks that might tolerize high-avidity Th1 cells. Furthermore, differentiation of HIV gp160-specific CD4(+) Th and CD8(+) cytotoxic T lymphocytes (CTL) into effector cells is impaired in g-week H. pylori-infected mice immunized with vaccinia expressing gp160, and serum IL-12 stimulated by vaccinia infection is barely detectable. Adoptive transfer of urease-specific Th2 cells to mice infected only with gp160-expressing vaccinia abrogates Th1 polarization of the gp120 response, downmodulates virus-specific CTL responses, and delays virus clearance. Therefore, the H. pylori urease-mediated immunoregulation in the switch from JNK(+) Th1 to JNK- Th2 phenotype, and the preceding low IL-12 response, are likely critical steps in the impairment of antiviral immunity. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. Yamaguchi Univ, Sch Med, Dept Microbiol, Yamaguchi, Japan. Kagawa Med Sch, Dept Internal Med 3, Kagawa 76107, Japan. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12, Bethesda, MD 20892 USA. NR 57 TC 2 Z9 2 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2001 VL 31 IS 2 BP 516 EP 526 DI 10.1002/1521-4141(200102)31:2<516::AID-IMMU516>3.0.CO;2-L PG 11 WC Immunology SC Immunology GA 403EF UT WOS:000167029100023 PM 11180117 ER PT J AU Kalbus, M Fleckenstein, BT Offenhausser, M Bluggel, M Melms, A Meyer, HE Rammensee, HG Martin, R Jung, G Sommer, N AF Kalbus, M Fleckenstein, BT Offenhausser, M Bluggel, M Melms, A Meyer, HE Rammensee, HG Martin, R Jung, G Sommer, N TI Ligand motif of the autoimmune disease-associated mouse MHC class II molecule H2-A(S) SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE MHC class II; H2-A(S); binding motif; SJL mouse strain; autoimmunity ID PEPTIDE BINDING MOTIF; MYELIN BASIC-PROTEIN; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NERVOUS-SYSTEM MYELIN; MULTIPLE-SCLEROSIS; LEWIS RAT; T-CELLS; HLA-DQ; CRYSTAL-STRUCTURE; SELF-PEPTIDES AB The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is the principle restriction element of autoreactive CD4(+) T cells mediating experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We deduced the H2-A(s) ligand motif from the analysis of naturally processed self peptides and from peptide binding studies. Major anchor residues were identified using various sets of substituted and truncated peptides, derived from natural peptide ligands and known H2-A(s) binders like myelin basic protein 81-99. The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9. The P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-aliphatic side chains. The P1 pocket contributes little to peptide binding. Primary anchors were identified in P4, P7, and in particular in P9. The preferred anchor residues are Lys (P4), His/Arg (P7), and Pro (P9), respectively. Ala-polysubstituted peptides containing only one of these dominant anchor residues still retain the capacity to bind to H2-AS. Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for high-affinity peptide binding, at least in the absence of negatively charged side chains nearby. The identified ligand motif facilitates the analysis of immunogenic peptides interacting with H2-AS and will allow a better prediction of pathogenetically relevant peptide antigens in the autoimmune mouse model. C1 Univ Tubingen, Dept Neurol, D-72076 Tubingen, Germany. Univ Tubingen, Inst Organ Chem, D-7400 Tubingen, Germany. Ruhr Univ Bochum, Inst Immunol, Med Proteom Ctr, D-4630 Bochum, Germany. Univ Tubingen, Interfac Inst Cell Biol, Dept Immunol, Tubingen, Germany. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. RP Kalbus, M (reprint author), Univ Tubingen, Dept Neurol, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. NR 36 TC 16 Z9 16 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2001 VL 31 IS 2 BP 551 EP 562 DI 10.1002/1521-4141(200102)31:2<551::AID-IMMU551>3.0.CO;2-P PG 12 WC Immunology SC Immunology GA 403EF UT WOS:000167029100026 PM 11180120 ER PT J AU Caplan, S Almogi-Hazan, O Ezernitchi, A Manaster, E Gazit, A Baniyash, M AF Caplan, S Almogi-Hazan, O Ezernitchi, A Manaster, E Gazit, A Baniyash, M TI The cytoskeleton-associated TCR zeta chain is constitutively phosphorylated in the absence of an active p56(lck) form SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE TCR; cytoskeleton; signaling; T cell ID T-CELL RECEPTOR; PROTEIN-TYROSINE KINASE; ANTIGEN-RECEPTOR; SIGNAL-TRANSDUCTION; ANCHORED PROTEINS; MEMBRANE DOMAINS; ACTIVATION; SURFACE; ZAP-70; REORGANIZATION AB The TCR recognizes peptide-MHC complexes and transmits activation signals leading to cellular responses. We have previously characterized two TCR populations expressed on the T cell surface; one is linked to the cytoskeleton via a detergent-insoluble cytoskeleton-associated zeta (cska-zeta) chain, while the other is detergent soluble and not linked to the cytoskeleton. The cska-zeta form displays unique properties: it is constitutively phosphorylated, does not undergo hyperphosphorylation upon TCR stimulation as opposed to its noncytoskeleton-associated counterpart (non-cska-zeta) and it maintains a molecular mass of 16 kDa. It is well established that p56(lck) and possibly p59(fyn) are responsible for the generation of the 21/23-kDa phosphorylated detergent-soluble zeta form. We now demonstrate that the phosphorylation of cska-zeta does not require the activity of p56(lc)k. We also show that although Lck does not phosphorylate cska-zeta in vivo, it retains the capacity to phosphorylate cska-zeta in vitro. Moreover, differences in zeta -associated kinase activity were detected for non-cska-zeta and cska-zeta. Our results indicating that different kinases phosphorylate the two zeta forms are consistent with a growing consensus that each TCR form may regulate distinct cellular functions. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Dept Organ Chem, Jerusalem, Israel. RP Baniyash, M (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, POB 12272, IL-91120 Jerusalem, Israel. NR 39 TC 1 Z9 1 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2001 VL 31 IS 2 BP 580 EP 589 DI 10.1002/1521-4141(200102)31:2<580::AID-IMMU580>3.0.CO;2-H PG 10 WC Immunology SC Immunology GA 403EF UT WOS:000167029100029 PM 11180123 ER PT J AU Gerber, LH Chaudhry, U DeBaun, M AF Gerber, LH Chaudhry, U DeBaun, M TI Joint laxity, scoliosis, and thoracic cage abnormalities in children with Beckwith-Wiedemann syndrome SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Article AB We report the frequency of joint laxity, scoliosis and thoracic cage asymmetry in 55 children with Beckwith-Wiedemann syndrome (BWS), findings not previously reported in the literature. C1 NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO 63110 USA. RP Gerber, LH (reprint author), NIH, Dept Rehabil Med, Bldg 10,Room 6S235,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6199 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD FEB PY 2001 VL 160 IS 2 BP 143 EP 144 DI 10.1007/s004310000650 PG 2 WC Pediatrics SC Pediatrics GA 398FT UT WOS:000166746800021 PM 11271391 ER PT J AU Muellbacher, W Ziemann, U Boroojerdi, B Cohen, L Hallett, M AF Muellbacher, W Ziemann, U Boroojerdi, B Cohen, L Hallett, M TI Role of the human motor cortex in rapid motor learning SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE motor learning; primary motor cortex; transcranial magnetic stimulation; motor evoked potentials; humans ID TRANSCRANIAL MAGNETIC STIMULATION; POSITRON EMISSION TOMOGRAPHY; MUSCLE; VOLUNTARY; STRENGTH; IMPLICIT; CONTRACTIONS; ACTIVATION; PLASTICITY; MODULATION AB Recent studies suggest that the human primary motor cortex (M1) is involved in motor learning, but the nature of that involvement is not clear. Here, learning-related changes in MI excitability were studied with transcranial magnetic stimulation (TMS) while na subjects practiced either a ballistic or a ramp pinch task to the 0.5-Hz beat of a metronome. Subjects rapidly learned to optimize ballistic contractions as indicated by a significant increase in peak pinch acceleration and peak force after the 60-min practice epoch. The increase in force and acceleration was associated with an increase in motor evoked potential (MEP) amplitude in a muscle involved in the training (flexor policis brevis) but not in a muscle unrelated to the task (abductor digiti minimi). MEPs returned to their baseline amplitude after subjects had acquired the new skill, whereas no practice-induced changes in MEP amplitude were observed after subjects had overlearned the task, or after practicing slow ramp pinches. Since the changes in MEP amplitude were observed only after TMS of M1 but not after direct stimulation of the corticospinal tract, these findings indicate task- and effector-specific involvement of human M1 in rapid motor learning. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC-1428, Bethesda, MD 20892 USA. NR 38 TC 227 Z9 231 U1 0 U2 12 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 2001 VL 136 IS 4 BP 431 EP 438 DI 10.1007/s002210000614 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 405WE UT WOS:000167182900002 PM 11291723 ER PT J AU Whittard, JD Akiyama, SK AF Whittard, JD Akiyama, SK TI Activation of beta(1) integrins induces cell-cell adhesion SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE integrin; cell-cell adhesion; F-actin; monoclonal antibody; activation ID KERATINOCYTE INTERCELLULAR-ADHESION; LIGAND-OCCUPIED CONFORMATION; BETA-1 INTEGRINS; E-CADHERIN; MONOCLONAL-ANTIBODY; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; DIVALENT-CATIONS; FIBRONECTIN; RECEPTOR AB Integrins are highly regulated receptors that can function in both cell-substrate and cell-cell adhesion. We have found that the activating anti-beta (1) mAb, 12G10, can specifically and rapidly induce both cell-substrate and cell-cell adhesion of HT-1080 human fibrosarcoma and other cell types. Binding of mAb 12G10 induced clustering of cell-surface integrins, and the preferential localization of beta (1) integrins expressing the 12G10 epitope at cell-cell adhesion sites, Fab fragments of mAb 12G10 induced HT-1080 cell-cell adhesion as effectively as did intact antibodies, suggesting that integrin clustering was not due to direct antibody crosslinking. Latrunculin B, an inhibitor of F-actin polymerization, inhibited cell-cell adhesion but not the clustering of integrins, Results from a novel, two-color cell-cell adhesion assay suggested that nonactivated cells can bind to activated cells and that integrin activation-induced MT-1080 cell-cell adhesion minimally requires the interaction of activated alpha (2)beta (1) with nonactivated alpha (3)beta (1). These findings suggest that MT-1080 cell-cell adhesion induced by integrin activation require a signaling process involving integrin clustering and the subsequent organization of the cytoskeleton, Integrin activation could therefore play a key role in cell-cell adhesion. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Akiyama, SK (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Mail Drop A2-09,POB 12233, Res Triangle Pk, NC 27709 USA. NR 50 TC 29 Z9 31 U1 1 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 1 PY 2001 VL 263 IS 1 BP 65 EP 76 DI 10.1006/excr.2000.5099 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 397PF UT WOS:000166703500007 PM 11161706 ER PT J AU Ringpfeil, F Raus, A DiGiovanna, JJ Korge, B Harth, W Mazzanti, C Uitto, J Bale, SJ Richard, G AF Ringpfeil, F Raus, A DiGiovanna, JJ Korge, B Harth, W Mazzanti, C Uitto, J Bale, SJ Richard, G TI Darier disease - novel mutations in ATP2A2 and genotype-phenotype correlation SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE keratosis follicularis; mutation; calcium ATPase; SERCA ID SARCOPLASMIC-RETICULUM CA2+-ATPASE; SITE-DIRECTED MUTAGENESIS; GENE; ATPASE; CA-2+-ATPASE; THAPSIGARGIN; PROTEINS; FEATURES; PRODUCTS; CELLS AB Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Inst Mol Med, Philadelphia, PA USA. Brown Univ, Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. Univ Cologne, Dept Dermatol, D-5000 Cologne, Germany. Hosp Erfurt, Dept Dermatol, Erfurt, Germany. Ist Dermopat Immacolata, Rome, Italy. NIAMSD, Genet Studies Sect, NIH, Bethesda, MD 20892 USA. RP Richard, G (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S 10th St,BLSB,Suite 409, Philadelphia, PA 19107 USA. FU NIAMS NIH HHS [P01-AR38923] NR 39 TC 64 Z9 68 U1 1 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD FEB PY 2001 VL 10 IS 1 BP 19 EP 27 DI 10.1034/j.1600-0625.2001.100103.x PG 9 WC Dermatology SC Dermatology GA 396UM UT WOS:000166654900003 PM 11168576 ER PT J AU Tumminia, SJ Clark, JI Richiert, DM Mitton, KP Duglas-Tabor, Y Kowalak, JA Garland, DL Russell, P AF Tumminia, SJ Clark, JI Richiert, DM Mitton, KP Duglas-Tabor, Y Kowalak, JA Garland, DL Russell, P TI Three distinct stages of lens opacification in transgenic mice expressing the HIV-1 protease SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE phase separation; 2D-electrophoresis; cataract; ion homeostasis; crystallins ID A-CRYSTALLIN PROMOTER; PHASE-SEPARATION INHIBITORS; SELENITE CATARACT; BETA-CRYSTALLIN; CYTOPLASM; CLEAVAGE; MOUSE AB Scanning electron microscopy of the lenses from transgenic mice (TG(72)) containing the HIV-1 protease linked to the lens alphaA-crystallin promoter showed structural changes around postnatal day 16. Frank opacification of the lens was observed at day 24. To relate the biochemical and biophysical changes that occur during the process of cataract development, high-resolution two-dimensional gel electrophoresis (2D), quantitative image analysis and ion measurements were carried out on lenses from postnatal day 10 and on days 15-24. The phase separation temperature (Tc), a measure of molecular interactions between proteins, was also determined for normal and transgenic lenses. A comparison of the transgenic and normal lenses on day 10 revealed no significant differences in any of the measured parameters. However, starting around day 16 or the first stage of observed structural changes, the TG(72) crystallin profiles of the alphaA- alphaB-, beta A3-, beta A4-, beta B3 and one gamma -crystallin began to deviate from the normal. By postnatal day 20, a second stage was initiated with an influx of calcium and sodium ions that was accompanied by modifications of beta B1- and beta B2-crystallin. In the third and final stage of the cataract process, a large increase in the proteolysis of crystallins was accompanied by the appearance of the frank cataract on day 24. The Tc initially increased in all of the mouse lenses until just prior to eyelid opening. After that time, the Tc decreased in all lenses. Although the Tc continued to decrease in the normal lenses with age, for the homozygous transgenic mice it exhibited a dramatic increase that began on day 20. Thus, in the TG(72) transgenic mouse, cataract formation occurs in a three-stage process. Tc and other biophysical parameters previously measured appeared to be insensitive to the modifications that occur during stage 1. However, during the second stage of cataract formation, there was a correspondence between abnormal Tc and the abnormal interactions between cellular constituents apparently resulting from lens hydration, the loss of ion homeostasis and continued proteolysis. The last stage of cataract formation results in a total loss of lens transparency and leakage of lens proteins. C1 Fdn Fighting Blindness, Hunt Valley, MD 21031 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Ophthalmol, Ann Arbor, MI USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Russell, P (reprint author), 6 Ctr Dr,MSC 2735,Bldg 6,Rm 228, Bethesda, MD 20892 USA. OI Mitton, Kenneth/0000-0002-4751-7440 FU NEI NIH HHS [R01 EY004542] NR 23 TC 7 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2001 VL 72 IS 2 BP 115 EP 121 DI 10.1006/exer.2000.0934 PG 7 WC Ophthalmology SC Ophthalmology GA 401EW UT WOS:000166915200002 PM 11161727 ER PT J AU Vazquez, N Lehrnbecher, T Chen, R Christensen, BL Gallin, JI Malech, H Holland, S Zhu, SX Chanock, SJ AF Vazquez, N Lehrnbecher, T Chen, R Christensen, BL Gallin, JI Malech, H Holland, S Zhu, SX Chanock, SJ TI Mutational analysis of patients with p47-phox-deficient chronic granulomatous disease: The significance of recombination events between the p47-phox gene (NCF1) and its highly homologous pseudogenes SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE phagocyte; nicotinamide adenine dinucleotide phosphate oxidase; allele; genetics; immunodeficiency ID RESPIRATORY-BURST OXIDASE; AUTOSOMAL RECESSIVE FORMS; NADPH OXIDASE; WILLIAMS-SYNDROME; CONVERSION; COMPONENT; MUTAGENESIS; ACTIVATION; MECHANISMS; SEQUENCES AB Objective. The aim of this study was to determine the molecular basis of p47-phox-deficient chronic granulomatous disease (CGD), the most common autosomal recessive form of the disease, CGD is an inherited condition characterized by defective oxygen radical production due to defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Mutational analysis of p47-phox-deficient CGD patients previously demonstrated that the majority of patients have a GT dinucleotide (Delta GT) deletion at the start of exon 2, a signature sequence also observed in the highly homologous pseudogenes of NCF1, Materials and Methods. We performed genetic analysis of NCF1 and its pseudogenes using genomic DNA in 29 p47-phox-deficient CGD patients from 2 2 separate families. First-strand cDNA analysis was performed in 17 of the 29 patients, Results, We confirmed the significance of the Delta GT mutation; in 27 of 29 patients, only the Delta GT sequence was detectable. All but one of the 27 had at least one additional signature sequence, specific to the pseudogene, in either intron 1 and/or intron 2, We extended our analysis to look at signature sequence differences in exons 6 and 9 and detected both the wild-type and pseudogene sequences in all patients tested. Conclusions. Although detection of only Delta GT sequence accounts for over 85% of affected patients, the molecular basis is most likely due to partial cross-over events between the wild-type and pseudogene(s) of p47-phox at different recombination sites, Our results suggest that complete gene conversion or deletion of the p47-phox gene (NCF1) occurs rarely, if it all. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Ctr Adv Technol, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 44 TC 21 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2001 VL 29 IS 2 BP 234 EP 243 DI 10.1016/S0301-472X(00)00646-9 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 401EG UT WOS:000166913900013 PM 11166463 ER PT J AU Gozar, MMG Muratova, O Keister, DB Kensil, CR Price, VL Kaslow, DC AF Gozar, MMG Muratova, O Keister, DB Kensil, CR Price, VL Kaslow, DC TI Plasmodium falciparum: Immunogenicity of alum-adsorbed clinical-grade TBV25-28, a yeast-secreted malaria transmission-blocking vaccine candidate SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Pfs25; Pfs28; transmission-blocking vaccine; Plasmodium falciparum; zygotes; ookinetes; Anopheles freeborni ID SEXUAL STAGES; ANTIBODIES; PROTEIN; PFS25; IMMUNITY; ELICITS; TARGET; IMMUNIZATION; EXPRESSION; ANTIGENS AB Plasmodium falciparum: Immunogenicity of alum-adsorbed clinical-grade TBV25-28, a yeast-secreted malaria transmission-blocking vaccine candidate. Experimental Parasitology 97, 61-69. The fusion of Pfs25 and Pfs28, two major surface antigens on zygotes and ookinetes of Plasmodium falciparum, as a single recombinant protein (TBV25-28) was previously shown to elicit potent transmission-blocking antibodies in mice. Clinical-grade TBV25-28 was subsequently manufactured and its potency was evaluated in rabbits. Rabbits received three doses of either clinical-grade TBV25H or clinical-grade TBV25-28 adsorbed to alum with or without QS-21. As measured in a standard membrane-feeding assay, addition of QS-21 to the formulations appeared to enhance transmission-blocking potency of rabbit sera after two vaccinations but not after three vaccinations. Surprisingly, TBV25H elicited more potent transmission blocking antibodies than did TBV25-28, a result strikingly different from those of previous mouse experiments using research-grade TBV25-28. The apparent decrease in potency of clinical-grade TBV25-28 in rabbits appears to reflect an enhancement in potency of clinical-grade TBV25H in a new formulation rather than simply a species difference in immunogenicity of TBV25-28. (C) 2001 Academic Press. C1 NIH, Parasit Dis Lab, Malaria Vaccines Sect, Bethesda, MD USA. Aquila Biopharmaceut, Worcester, MA USA. Immunex Corp, Seattle, WA USA. RP Kaslow, DC (reprint author), Merck Res Labs, 770 Sumneytown Pike, W Point, PA 19486 USA. NR 16 TC 22 Z9 25 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD FEB PY 2001 VL 97 IS 2 BP 61 EP 69 DI 10.1006/expr.2000.4580 PG 9 WC Parasitology SC Parasitology GA 417QT UT WOS:000167846200001 PM 11281702 ER PT J AU Carlton, JMR Yowell, CA Sturrock, KA Dame, JB AF Carlton, JMR Yowell, CA Sturrock, KA Dame, JB TI Biomagnetic separation of contaminating host leukocytes from Plasmodium-infected erythrocytes SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE malaria; host contamination; biomagnetic bead separation; cDNA library; EST (expressed sequence tag) ID BLOOD; VIVAX; PARASITE; REMOVAL; CELLS C1 Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32601 USA. RP Carlton, JMR (reprint author), Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 45,6AN36, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-65315] NR 8 TC 15 Z9 15 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD FEB PY 2001 VL 97 IS 2 BP 111 EP 114 DI 10.1006/expr.2001.4594 PG 4 WC Parasitology SC Parasitology GA 417QT UT WOS:000167846200007 PM 11281708 ER PT J AU Lavigne, MC Malech, HL Holland, SM Leto, TL AF Lavigne, MC Malech, HL Holland, SM Leto, TL TI Genetic requirement of p47phox for superoxide production by murine microglia SO FASEB JOURNAL LA English DT Article C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Leto, TL (reprint author), NIH, Bldg 10,Room 11N106, Bethesda, MD 20982 USA. NR 0 TC 41 Z9 43 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 FEB PY 2001 VL 15 IS 2 BP 285 EP 287 PG 3 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 400LK UT WOS:000166872900004 PM 11156938 ER PT J AU Segars, JH Hearns-Stokes, RM AF Segars, JH Hearns-Stokes, RM TI Role of providers in ART success - Reply SO FERTILITY AND STERILITY LA English DT Letter C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2001 VL 75 IS 2 BP 450 EP 450 DI 10.1016/S0015-0282(00)01730-1 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 400LB UT WOS:000166872100041 ER PT J AU Khan, S Jabbar, A Hasan, CM Rashid, MA AF Khan, S Jabbar, A Hasan, CM Rashid, MA TI Antibacterial activity of Barringtonia racemosa SO FITOTERAPIA LA English DT Article DE Barringtonia racemosa; antibacterial activity; diterpenenoids AB The antibacterial activity of the ethanol extract of Barringtonia racemosa roots, its chloroform soluble fraction and, a there from isolated clerodane diterpenoid is reported. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Dhaka, Fac Pharm, Phytochem Res Lab, Dhaka 1000, Bangladesh. RP Rashid, MA (reprint author), NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Bldg 560,Rm 32-63B,POB B, Frederick, MD 21702 USA. NR 6 TC 15 Z9 18 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0367-326X J9 FITOTERAPIA JI Fitoterapia PD FEB PY 2001 VL 72 IS 2 BP 162 EP 164 DI 10.1016/S0367-326X(00)00264-1 PG 3 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 410BY UT WOS:000167421200009 PM 11223225 ER PT J AU Ogawa, R Pacelli, R Espey, MG Miranda, KM Friedman, N Kim, SM Cox, G Mitchell, JB Wink, DA Russo, A AF Ogawa, R Pacelli, R Espey, MG Miranda, KM Friedman, N Kim, SM Cox, G Mitchell, JB Wink, DA Russo, A TI Comparison of control of Listeria by nitric oxide redox chemistry from murine macrophages and no donors: Insights into listeriocidal activity of oxidative and nitrosative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE free radicals; nitrosation stress; Listeria; NO ID REACTIVE NITROGEN; INTRACELLULAR BACTERIA; ANTIMICROBIAL ACTIVITY; MONOCYTOGENES; MICE; MECHANISMS; RESISTANCE; INFECTION; IMMUNITY; RELEASE AB The physiological function of nitric oxide (NO) in the defense against pathogens is multifaceted. The exact chemistry by which NO combats intracellular pathogens such as Listeria monocytogenes is yet unresolved. We examined the effects of NO exposure, either delivered by NO donors ol generated in situ within ANA-1 murine macrophages. on L. monocytogenes growth. Production of NO by the two NONOate compounds PAPA/NO (NH2(C3H6)(N[N(O)NO]C3H7)) and DEA/NO (Na(C2H5)(2)N[N(O)NO]) resulted in L. monocytogenes cytostasis with minimal cytotoxicity. Reactive oxygen species generated from xanthine oxidase/hypoxanthine were neither bactericidal nor cytostatic and did not alter the action of NO. L. monocytogenes growth was also suppressed upon internalization into ANA-1 murine macrophages primed with interferon-gamma (INF-gamma) + tumor necrosis factor-alpha TNF-alpha or INF-gamma + lipid polysaccharide (LPS). Growth suppression correlated with nitrite formation and nitrosation of 2,3-diaminonaphthalene elicited by stimulated murine macrophages. This: nitrosative chemistry was not dependent upon nor mediated by interaction with reactive oxygen species (ROS), but resulted solely from NO and intermediates related to nitrosative stress. The role of nitrosation in controlling L. monocytogenes was further examined by monitoring the effects of exposure to NO on an important virulence factor, Listeriolysin O, which was inhibited under nitrosative conditions. These results suggest that nitrosative stress mediated by macrophages is an important component of the immunological arsenal in controlling L. monocytogenes infections. (C) 2001 Elsevier Science Inc. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Immunol, Bethesda, MD 20814 USA. RP Russo, A (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 41 TC 24 Z9 24 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 1 PY 2001 VL 30 IS 3 BP 268 EP 276 DI 10.1016/S0891-5849(00)00470-6 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 396ZB UT WOS:000166667300006 PM 11165873 ER PT J AU Chandler, J Hohenstein, P Swing, DA Tessarollo, L Sharan, SK AF Chandler, J Hohenstein, P Swing, DA Tessarollo, L Sharan, SK TI Human BRCA1 gene rescues the embryonic lethality of Brca1 mutant mice SO GENESIS LA English DT Article DE BRCA1; humanized mice; bacterial artificial chromosome; transgenic mice; functional complementation ID OVARIAN-CANCER; BREAST; ACTIVATION; EXPRESSION; FAMILIES; MUTATION AB Half of all familial breast cancers are due to mutation in the BRCA1 gene. However, despite its importance, attempts to model BRCA1-induced disease in the mouse have been disappointing. Heterozygous Brca1 knockout mice do not develop mammary tumors and homozygous knockout mice die during embryogenesis from ill-defined causes. Sequence analysis has shown that the coding region, genomic organization, and regulatory sequences of the human and mouse genes are not well conserved. This has raised the question of whether the mouse can serve as an effective model for functional analysis of the human BRCA1 gene. To address this question we have introduced a bacterial artificial chromosome containing the human BRCA1 gene into the germline of Brca1 knockout mice. Surprisingly, we have found that the embryonic lethality of Brca1 knockout mice is rescued by the human transgene. We also show that expression of human BRCA1 transgene mirrors the endogenous murine gene. Our "humanized" transgenic mice can serve as a model system for functional analyses of the human BRCA1 gene. genesis 29:72-77, 2001. Published 2001 Wiley-Liss, Inc.(dagger). C1 NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Leiden Univ, Med Ctr, Dept Pathol, Pathophysiol Growth & Differentiat, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Human & Clin Genet, Ctr Med Genet, Leiden, Netherlands. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. OI Hohenstein, Peter/0000-0001-8548-4734 NR 16 TC 28 Z9 28 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 FEB PY 2001 VL 29 IS 2 BP 72 EP 77 DI 10.1002/1526-968X(200102)29:2<72::AID-GENE1007>3.0.CO;2-B PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 407ET UT WOS:000167259800004 PM 11170347 ER PT J AU Rieger, RH Kaplan, NL Weinberg, CR AF Rieger, RH Kaplan, NL Weinberg, CR TI Efficient use of siblings in testing for linkage and association SO GENETIC EPIDEMIOLOGY LA English DT Article DE sibship studies; logistic regression; sib TDT; sibship equilibrium test (SDT) ID SIBSHIP TEST; DISEQUILIBRIUM; MARKERS AB Tests of linkage and association between a disease and either a candidate gene or marker allele can be based on sibships with at least one affected and one unaffected sibling. However, specialized techniques are required to account for within-sibship correlation if some sibships contain more than one affected or more than one unaffected sib. In this paper, we propose Within Sibship Paired Resampling (WSPR), a technique that is designed to test the null hypothesis of no linkage or no association, even when sibships contain variable numbers of sibs. One repeatedly generates data subsets based on randomly sampling one affected and one unaffected sibling from each sibship, and each subset is analyzed individually. Then, evidence is combined by averaging results across these resampled data sets, applying a variance expression that implicitly accounts for the correlation among siblings. While the general WSPR procedure allows for numerous testing strategies, we describe two in detail. Simulation results for scenarios with varying degrees of population stratification demonstrate good power for the WSPR testing methods compared to the sib TDT (S-TDT) and the sibship disequilibrium test (SDT). (C) 2001 Wiley-Liss, Inc. C1 W Chester Univ, Dept Math, Chester, PA 19383 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. RP Rieger, RH (reprint author), W Chester Univ, Dept Math, Chester, PA 19383 USA. NR 13 TC 7 Z9 9 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2001 VL 20 IS 2 BP 175 EP 191 DI 10.1002/1098-2272(200102)20:2<175::AID-GEPI2>3.0.CO;2-2 PG 17 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 396KA UT WOS:000166634300002 PM 11180445 ER PT J AU Moore, DF Chatterjee, N Pee, D Gail, MH AF Moore, DF Chatterjee, N Pee, D Gail, MH TI Pseudo-likelihood estimates of the cumulative risk of an autosomal dominant disease from a kin-cohort study SO GENETIC EPIDEMIOLOGY LA English DT Article DE age of onset; breast cancer; BRCA; penetrance; proband; survival analysis ID PENETRANCE; CANCER AB Wacholder et al. [1998: Am J Epidemiol 148:623-629] and Struewing et al. [1997: N Engl J Med 336:1401-1408] have recently proposed a design called the kin-cohort design to estimate the probability of developing disease (penetrance) associated with an autosomal dominant gene. In this design, volunteers (probands) agree to be genotyped and one also determines the disease history (phenotype) of first-degree relatives of the proband. They used this design to estimate that the chance of developing breast cancer by age 70 in Ashkenazi Jewish women who carried mutations of the genes BRCA1 or BRCA2 was 0.56, a figure that was lower than previously estimated from highly affected families. The method that they used to estimate the cumulative risk of breast cancer, while asymptotically correct, does not necessarily produce monotone estimates in small samples. To obtain monotone, weakly parametric estimates, we consider separate piece-wise exponential models for carriers and non-carriers. As the number of intervals on which constant hazards are assumed increases, however, the maximum likelihood score equations become unstable and difficult to solve. We, therefore, developed alternative pseudo-likelihood procedures that are readily solvable for piecewise exponential models with many intervals. We study these techniques through simulations and a re-analysis of a portion of the data used by Struewing et al. [1997] and discuss possible extensions. (C) 2001 Wiley-Liss, Inc. C1 Temple Univ, Dept Stat, Philadelphia, PA 19122 USA. Natl Canc Inst, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Informat Management Serv, Rockville, MD USA. RP Moore, DF (reprint author), Temple Univ, Dept Stat, Speakman Hall 006-00, Philadelphia, PA 19122 USA. NR 12 TC 11 Z9 11 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2001 VL 20 IS 2 BP 210 EP 227 DI 10.1002/1098-2272(200102)20:2<210::AID-GEPI4>3.0.CO;2-I PG 18 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 396KA UT WOS:000166634300004 PM 11180447 ER PT J AU Koonin, EV Wolf, YI Aravind, L AF Koonin, EV Wolf, YI Aravind, L TI Prediction of the archaeal exosome and its connections with the proteasome and the translation and transcription machineries by a comparative-genomic approach SO GENOME RESEARCH LA English DT Article ID POLYADENYLATION SPECIFICITY FACTOR; PROTEIN FAMILIES; GENE CLUSTERS; PSI-BLAST; EVOLUTION; RNA; SEQUENCE; POLYMERASE; CHAPERONIN; HOMOLOGS AB By comparing the gene order in the completely sequenced archaeal genomes complemented by sequence profile analysis, we predict the existence and protein composition of the archaeal counterpart of the eukaryotic exosome, a complex of RNAses, RNA-binding proteins, and helicases that mediates processing and 3'->5' degradation of a variety of RNA species. The majority of the predicted archaeal exosome subunits are encoded in what appears to be a previously undetected superoperon. In Methanobacterium thermoautotrophicum, this predicted superoperon consists of 15 genes; in the Crenarchaea, Sulfolobus solfataricus and Aeropyrum pernix, one and two of the genes From the superoperon, respectively, are relocated ill the genome, whereas in other Euryarchaeota, the superoperon is split into a variable number of predicted operons and solitary genes. Methanococcus jannaschii partially retains the superoperon, but lacks the three core exosome subunits, and in Halobacterium sp., the superoperon is divided into two predicted operons, with the same three exosome subunits missing. This suggests concerted gene loss and an alteration of the structure and function of the predicted exosome in the Methanococcus and Halobacterium lineages. Additional potential components of the exosome are encoded by partially conserved predicted small operons. Along with the orthologs of eukaryotic exosome subunits, namely an RNase PH and two RNA-binding proteins, the predicted archaeal exosomal superoperon also encodes orthologs of two protein subunits of RNase P. This suggests a functional and possibly a physical interaction between RNase P and the postulated archaeal exosome, a connection that has not been reported in eukaryotes. In a pattern of apparent gene loss complementary to that seen in Methanococcus and Halobacterium, Thermoplasma acidophilum lacks the RNase P subunits. Unexpectedly, the identified exosomal superoperon, in addition to the predicted exosome components, encodes the catalytic subunits of the archaeal proteasome, two ribosomal proteins and a DNA-directed RNA polymerase subunit. These observations suggest that in archaea, a tight Functional coupling exists between translation, RNA processing and degradation, (apparently mediated by the predicted exosome) and protein degradation (mediated by the proteasome], and may have implications for cross-talk between these processes in eukaryotes. 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 59 TC 174 Z9 175 U1 1 U2 8 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 FEB PY 2001 VL 11 IS 2 BP 240 EP 252 DI 10.1101/gr.162001 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 399TP UT WOS:000166828700008 PM 11157787 ER PT J AU Beck, TW Menninger, J Voigt, G Newman, K Nishigaki, Y Nash, WG Stephens, RM Wang, Y de Jong, PJ O'Brien, SJ Yuhki, N AF Beck, TW Menninger, J Voigt, G Newman, K Nishigaki, Y Nash, WG Stephens, RM Wang, Y de Jong, PJ O'Brien, SJ Yuhki, N TI Comparative feline genomics: A BAC/PAC contig map of the major histocompatibility complex class II region SO GENOMICS LA English DT Article ID CANINE-DISTEMPER VIRUS; RADIATION HYBRID PANEL; BOVINE LEUKEMIA-VIRUS; IMMUNODEFICIENCY VIRUS; DOMESTIC CAT; MHC GENES; DROSOPHILA-MELANOGASTER; LINKAGE DISEQUILIBRIUM; NATURAL-SELECTION; MAMMALIAN MHC AB The genome organization of the human major histocompatibility complex (MHC) will be best understood in a comparative evolutionary context. We describe here the construction of a physical map for the feline MHC. A large-insert domestic cat genomic DNA library was developed using a P1 artificial chromosome (PAC) with a genomic representation of 2.5 x and an average insert size of 80 kb. A sequence-ready 660-kb bacterial artificial chromosome/PAC contig map of the domestic cat MHC class II region was constructed with a gene order similar to, but distinct from, that of human and mice: DPB/DPA, Ring3, DMB, TAP1, DOB, DRB2, DRA3, DRB1, DRA2, and DRA1. Fluorescence in situ hybridization analyses of selected class II PAC clones confirmed that the class II region lies in the pericentromeric region of cat chromosome B2. However, apparently unlike the human and mouse MHCs, the domestic cat DRA and DRB genes have undergone multiple duplications and the DQ region has been deleted. (C) 2001 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Lab Gen Divers, Frederick, MD 21702 USA. H&W Cytogenet Serv Inc, Lovettsville, VA 22080 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. RP Beck, TW (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, POB B, Frederick, MD 21702 USA. NR 97 TC 24 Z9 24 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB 1 PY 2001 VL 71 IS 3 BP 282 EP 295 DI 10.1006/geno.2000.6414 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 404GG UT WOS:000167088600003 PM 11170745 ER PT J AU Simons-Morton, B Haynie, DL Crump, AD Eitel, P Saylor, KE AF Simons-Morton, B Haynie, DL Crump, AD Eitel, P Saylor, KE TI Peer and parent influences on smoking and drinking among early adolescents SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID ALCOHOL-USE; DRUG-USE; CIGARETTE-SMOKING; UNITED-STATES; SUBSTANCE USE; BEHAVIOR; FAMILY; SOCIALIZATION; PREVENTION; CONTEXT AB Social influences can promote or discourage adolescent substance use. The authors surveyed 4,263 sixth- to eighth-grade students to assess the effect of peer and parent influences on adolescent substance use. The authors conducted separate multiple logistic regression analyses for smoking and drinking, controlling for grade, sex, and race. Positive independent associations with smoking and drinking were found for direct peer pressure and associating with problem-behaving friends. Independent negative associations with smoking and drinking were also found for parent involvement, parent expectations, and parent regard. In an analysis of interactions, peer pressure was positively associated with drinking for girls but not for boys and problem-behaving friends was positively associated with drinking for both boys and girls. The findings are consistent with the hypothesis that associating with deviant peers promotes and that authoritative parenting protects against smoking and drinking. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Hlth Educ, College Pk, MD 20742 USA. Menninger Fdn, New York, NY USA. Neurosci Inc, Bethesda, MD USA. RP Simons-Morton, B (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 45 TC 160 Z9 160 U1 6 U2 45 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD FEB PY 2001 VL 28 IS 1 BP 95 EP 107 DI 10.1177/109019810102800109 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 393ZP UT WOS:000166499800008 PM 11213145 ER PT J AU Nagy, P Teramoto, T Factor, VM Sanchez, A Schnur, J Paku, S Thorgeirsson, SS AF Nagy, P Teramoto, T Factor, VM Sanchez, A Schnur, J Paku, S Thorgeirsson, SS TI Reconstitution of liver mass via cellular hypertrophy in the rat SO HEPATOLOGY LA English DT Article ID I-KAPPA-B; MITOCHONDRIAL PERMEABILITY TRANSITION; HEPATOCYTE PROLIFERATION; PARTIAL-HEPATECTOMY; TRANSGENIC MICE; DNA-BINDING; OVAL CELLS; GROWTH; REGENERATION; ALPHA AB The liver has an extremely effective regenerative capacity. When 70% of a rat liver is removed by surgery, the liver mass regrows in 7 to 10 days by the compensatory hyperplasia of the remnant part. In case of damage to the surviving hepatocytes, the facultative stem-cell compartment is activated and the liver regenerates by means of oval-cell proliferation/differentiation. In the present study, we demonstrate that when both hepatocyte proliferation and stem-cell activation were prevented by dexamethasone (Dex) administration, the liver mass was restored in the absence of DNA synthesis. The restoration of the liver was accomplished by the preferential enlargement/hypertrophy of the periportal hepatocytes. A similar response was observed when cell proliferation was arrested by S-fluorouracil (FU) following partial hepatectomy. Therefore, the hepatocytic hypertrophy appears to provide an alternative mechanism of liver-mass restoration. This hypertrophic condition of the liver is not stable, because following the withdrawal of Dex, the enlarged hepatocytes entered in the cell cycle and the normal liver structure and DNA content was re-established. C1 NCI, Expt Carcinogenesis Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Inst Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. Hungarian Acad Sci, Joint Res Org, Budapest, Hungary. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Div Basic Sci, NIH, Bldg 37,Room 3C28,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov RI Sanchez, Aranzazu/H-7810-2015 OI Sanchez, Aranzazu/0000-0001-9145-6633 NR 34 TC 44 Z9 46 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2001 VL 33 IS 2 BP 339 EP 345 DI 10.1053/jhep.2001.21326 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 397QF UT WOS:000166705800004 PM 11172335 ER PT J AU Seeff, LB Hollinger, FB Alter, HJ Wright, EC Cain, CMB Buskell, ZJ Ishak, KG Iber, FL Toro, D Samanta, A Koretz, RL Perrillo, RP Goodman, ZD Knodell, RG Gitnick, G Morgan, TR Schiff, ER Lasky, S Stevens, C Vlahcevic, RZ Weinshel, E Tanwandee, T Lin, HJ Barbosa, L AF Seeff, LB Hollinger, FB Alter, HJ Wright, EC Cain, CMB Buskell, ZJ Ishak, KG Iber, FL Toro, D Samanta, A Koretz, RL Perrillo, RP Goodman, ZD Knodell, RG Gitnick, G Morgan, TR Schiff, ER Lasky, S Stevens, C Vlahcevic, RZ Weinshel, E Tanwandee, T Lin, HJ Barbosa, L TI Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A national heart, lung, and blood institute collaborative study SO HEPATOLOGY LA English DT Article ID G VIRUS-INFECTION; LIVER-DISEASE; UNITED-STATES; POSTTRANSFUSION HEPATITIS; CLINICAL OUTCOMES; EPIDEMIOLOGY; EFFICACY; GLOBULIN; VIREMIA AB Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of followup, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P = .05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA. C1 Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Washington, DC USA. Baylor Coll Med, Houston, TX 77030 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Westat, Rockville, MD USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Olive View UCLA Med Ctr, Sylmar, CA 91342 USA. Alton Ochsner Med Fdn & Ochsner Clin, New Orleans, LA 70121 USA. RP Seeff, LB (reprint author), NIDDK, NIH, 31 Ctr Dr,Rm 9A-18, Bethesda, MD 20892 USA. RI Jepsen, Peter/A-2593-2010 OI Jepsen, Peter/0000-0002-6641-1430 FU NHLBI NIH HHS [N01-HB-37093, N01-HB-87047] NR 39 TC 237 Z9 245 U1 0 U2 5 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 FEB PY 2001 VL 33 IS 2 BP 455 EP 463 DI 10.1053/jhep.2001.21905 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 397QF UT WOS:000166705800018 PM 11172349 ER PT J AU Wan, YJY Cai, Y Li, J Yuan, QX French, B Gonzalez, FJ French, S AF Wan, YJY Cai, Y Li, J Yuan, QX French, B Gonzalez, FJ French, S TI Regulation of peroxisome proliferator activated receptor alpha-mediated pathways in alcohol fed cytochrome P450 2E1 deficient mice SO HEPATOLOGY RESEARCH LA English DT Article DE CYP2E1 knockout; ethanol; peroxisome proliferator; fatty acid; fatty liver ID FATTY-ACIDS; COMPLEMENTARY-DNA; LIPID-METABOLISM; BETA-OXIDATION; LIVER-DISEASE; ETHANOL; RAT; IDENTIFICATION; EXPRESSION; FAMILY AB Fatty acids are substrates and inducers for cytochrome P450 2E1 (CYP7E1) and peroxisome proliferator activated receptor alpha (PPAR alpha). Previously, we have shown that the ethanol-induced CYP2E1 expression in rat is accompanied by the inhibition of the expression of the PPAR alpha gene and the reduction in polyunsaturated fatty acid content. To further analyze the effect of CYP2E1 and ethanol in PPAR alpha -mediated fatty acid homeostasis, the expression of PPAR alpha and retinoid x receptor alpha (RXR alpha) and their target genes was examined in ethanol fed CYP2E1 deficient mice. Our data demonstrated that the expression of PPAR alpha and RXR alpha genes was activated in the livers of CYP2E1-null mice suggesting a compensatory effect for the absence of CYP2E1. In addition, the expression of PPAR alpha target genes, which included the liver fatty acid-binding protein, malic enzyme, and CYP4A1 genes, was induced indicating the activation of PPAR alpha -mediated pathways in CYP2E1 deficient mice. Ethanol inhibited the expression of some of the PPAR alpha target genes in wild-type mouse livers, and the inhibitory effect of ethanol was particularly prominent in the CYP2E1-null mice. Morphologically, centrilobular fat accumulation was detected in the ethanol fed CYP2E1-null mouse livers suggesting that inhibition of PPAR alpha -mediated pathways might be responsible for the ethanol-induced fatty liver in CYP2E1-null mice. In addition, the expression of CYP2E1 was not changed in the PPAR alpha -null mice. These data suggest that CYP2E1 and ethanol can regulate PPAR alpha -mediated fatty acid homeostasis. CYP2E1-induced lipid peroxidation might play a major role in lipid metabolism. PPAR I only becomes important when the CYP2E1 level is low and polyunsaturated fatty acids increase. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Harbor UCLA Med Ctr, Dept Pathol, Torrance, CA 90509 USA. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD USA. RP Wan, YJY (reprint author), Harbor UCLA Med Ctr, Dept Pathol, 1000 W Carson St, Torrance, CA 90509 USA. FU NCI NIH HHS [R01 CA053596] NR 38 TC 25 Z9 28 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1386-6346 J9 HEPATOL RES JI Hepatol. Res. PD FEB PY 2001 VL 19 IS 2 BP 117 EP 130 DI 10.1016/S1386-6346(00)00089-9 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 396HV UT WOS:000166631000003 PM 11164737 ER PT J AU Palmisano, GL Pistillo, MP Capanni, P Pera, C Nicolo, G Salvi, S Perdelli, L Pasciucco, G Ferrara, GB AF Palmisano, GL Pistillo, MP Capanni, P Pera, C Nicolo, G Salvi, S Perdelli, L Pasciucco, G Ferrara, GB TI Investigation of HLA class I downregulation in breast cancer by RT-PCR SO HUMAN IMMUNOLOGY LA English DT Article DE HLA class I downregulation; beta(2)-microglobulin; TAP genes; RT-PCR; breast cancer ID MHC CLASS-I; CERVICAL CARCINOMAS; DOWN-REGULATION; MELANOMA-CELLS; HIGH-FREQUENCY; EXPRESSION; ANTIGEN; GENE; PHENOTYPES; MOLECULES AB Downregulation of HLA class I antigen expression has been reported in a significant proportion of primary breast carcinomas suggesting an escape mechanism from CTL mediated lysis leading to tumor dissemination and metastasis. We have previously reported the biochemical and immunohistochemical analysis of HLA total class I (W6/32 mAb), alpha -chain (Q1/28,TP25.99 mAbs) and beta (2)-microglobulin (Namb-1 mAb) subunits expression in 25 primary breast carcinomas. This study at protein level resulted in the observation of three different HLA class I expression patterns by both techniques: high, low, and absent downregulation patterns To better characterize the HLA class I antigens downregulation we extended such analysis also at RNA level by RT-PCR using HLA-A, HLA-B, HLA-C, and beta (2)-microglobulin specific primers either in breast cancer or normal tissues derived from the same patient. None (100%) of the alpha -chain genes analyzed in patient tumor tissues showed significant reduction of expression. In 10 patients out of 25 (40%) the beta (2)-microglobulin gene showed complete loss of expression compared with the corresponding normal tissue counterpart, which showed a constitutive expression, whereas in 2 patients (12.5%) its expression was comparable with the normal counterpart. Sequence analysis at genomic level revealed no defects affecting beta (2)-microglobulin gene in whose patients showing lack of expression. Also TAP1 and TAP2 genes expression were investigated in order to confirm or exclude involvement of the MHC class I molecules assembling machinery. The RT-PCR approach mainly confirmed our beta (2)-microglobulin biochemical analysis indicating that in breast cancer specimens it is possible to address the HLA class I gene downregulation as a phenomenon occurring at post-transcriptional level mainly affecting the beta (2)-microglobulin gene expression. (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc. C1 Univ Genoa, Adv Biotechnol Ctr, Immunogenet Lab, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. Natl Canc Inst, Immunogenet Lab, Genoa, Italy. Natl Canc Inst, Pathol Lab, Genoa, Italy. RP Ferrara, GB (reprint author), Univ Genoa, Adv Biotechnol Ctr, Immunogenet Lab, Dept Oncol Biol & Genet, Lgo R Benzi 10, I-16132 Genoa, Italy. NR 25 TC 26 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD FEB PY 2001 VL 62 IS 2 BP 133 EP 139 DI 10.1016/S0198-8859(00)00241-X PG 7 WC Immunology SC Immunology GA 405CZ UT WOS:000167141200005 PM 11182222 ER PT J AU Grene, H Pinto, LA Landay, AL Kessler, HA Anderson, SA Dolan, MJ Shearer, GM AF Grene, H Pinto, LA Landay, AL Kessler, HA Anderson, SA Dolan, MJ Shearer, GM TI Anti-CCR5 antibodies in sera of HIV-positive individuals SO HUMAN IMMUNOLOGY LA English DT Article DE HIV infection; chemokines; CCR5 ID CHEMOKINE RECEPTOR; CCR5; INDUCTION; INFECTION AB One Of the proposed mechanisms for resistance to human immunodeficiency virus-1 (HIV-1) injection is the presence of antibodies against receptor for CC-chemokines (CCR5). These antibodies, detected in sera of uninfected individuals exposed to HIV, have been shown to downmodulate surface CCR5 in vivo and are able co neutralize thr infectivity of CCR5 strains in vitro. To address the potential rt,le of anti-CCR5 antibodies in HN infection, we analyzed anti-CCR5 antibody levels in plasma from HIV-infected patients who present a wide range of CD4(+) T-cell counts and viral load. Increased levels of anti-CCR5 antibodies were found in plasma from 13/46 HIV-positive donors compared with healthy controls (0/36). However, antibody levels were not associated with disease stage evaluated by CD4(+) T-cell counts and viral load. (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Dept Med, Chicago, IL 60612 USA. Henry M Jackson Fdn, San Antonio, TX USA. Wilford Hall USAF Med Ctr, Infect Dis Serv, San Antonio, TX 78236 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 8 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD FEB PY 2001 VL 62 IS 2 BP 143 EP 145 PG 3 WC Immunology SC Immunology GA 405CZ UT WOS:000167141200007 ER PT J AU Kumaki, F Kawai, T Hiroi, S Shinomiya, N Ozeki, Y Ferrans, VJ Torikata, C AF Kumaki, F Kawai, T Hiroi, S Shinomiya, N Ozeki, Y Ferrans, VJ Torikata, C TI Telomerase activity and expression of human telomerase RNA component and human telomerase reverse transcriptase in lung carcinomas SO HUMAN PATHOLOGY LA English DT Article DE telomerase; lung carcinoma; human telomerase RNA component and human telomerase reverse transcriptase; telomeric repeat amplification protocol assay; in situ hybridization; immunohistochemistry; clinicopathologic features ID CATALYTIC SUBUNIT GENE; HUMAN FIBROBLASTS; IMMORTAL CELLS; HUMAN CANCER; TUMOR; ASSOCIATION; TISSUES; HTRT; DNA AB The aim of this study was to evaluate the usefulness of determination of telomerase activity and expression of human telomerase RNA component (hTERC) and human telomerase reverse transcriptase (hTERT) for the diagnosis of lung carcinomas. The tissues studied consisted of 115 carcinomas and adjacent nonneoplastic lung, which were removed surgically without previous chemotherapy or radiotherapy. Telomerase activity was determined using a semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) assay. The results obtained were classified into high and low telomerase groups. Localization of expression was examined by using in situ hybridization and immunohistochemistry. The correlation between telomerase activity in lung carcinoma and clinicopathologic features, including prognosis, was investigated. Telomerase activity in lung carcinomas was detected in 107 of 115 (93%) lung carcinomas, but not in any adjacent noncancerous tissues, and was significantly higher in small cell carcinoma than in any other histologic type. This activity also was significantly higher in poorly differentiated than in well-differentiated squamous cell carcinomas and adenocarcinomas. The overall survival rate (P = .020) was significantly lower in the high telomerase group. Messenger RNAs for hTERC and hTERT were mainly detected in the cytoplasm of cancer cells by in situ hybridization, and TERT protein was localized in the nuclei of these cells by immunohistochemical staining. Determinations of telomerase activity by in situ hybridization, immunohistochemistry, and TRAP assay are useful for evaluating the diagnosis and prognosis of lung carcinomas. HUM PATHOL 32:188-195. Copyright (C) 2001 by W.B. Saunders Company. C1 NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. Natl Def Med Coll, Dept Pathol, Tokorozawa, Saitama 359, Japan. Natl Def Med Coll, Dept Microbiol, Tokorozawa, Saitama 359, Japan. Natl Def Med Coll, Dept Thorac Surg, Tokorozawa, Saitama 359, Japan. RP Kumaki, F (reprint author), NHLBI, Pathol Sect, NIH, Bldg 10,2N240,10 Ctr Dr,MSC-1518, Bethesda, MD 20892 USA. NR 49 TC 76 Z9 86 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2001 VL 32 IS 2 BP 188 EP 195 DI 10.1053/hupa.2001.21567 PG 8 WC Pathology SC Pathology GA 407LU UT WOS:000167273700007 PM 11230706 ER PT J AU Lei, JY Middleton, LP Guo, XD Duray, PH McWilliams, G Linehan, WM Merino, MJ AF Lei, JY Middleton, LP Guo, XD Duray, PH McWilliams, G Linehan, WM Merino, MJ TI Pigmented renal clear cell carcinoma with melanocytic differentiation SO HUMAN PATHOLOGY LA English DT Article DE renal cell carcinoma; pigment; melanin; metastasis ID VARIANTS AB Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney, and its incidence has been steadily rising. RCC consists of several subtypes, each of which has its own clinical features, and cytogenetic and molecular characteristics. Recognizing histologic patterns of RCC is important not only for correct diagnosis, but also for providing insight into the biological behavior of the tumor and subsequent appropriate medical care for the patient. Pigments other than hemosiderin has been observed in RCC, but none of them have been proved to be melanin. Melanotic tumors, either primary or metastatic, are rare in the kidney. We present an unusual case of melanin-pigmented clear cell RCC with melanocytic differentiation, an unusual variant that may lead to errors in diagnosis and treatment. HUM PATHOL 32:233-236. This is a US Government work. There are no restrictions on its use. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, 10-2N212,10 Ctr Dr, Bethesda, MD 20892 USA. NR 14 TC 16 Z9 17 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2001 VL 32 IS 2 BP 233 EP 236 DI 10.1053/hupa.2001.22009 PG 4 WC Pathology SC Pathology GA 407LU UT WOS:000167273700014 PM 11230713 ER PT J AU Block, G Mangels, AR Norkus, EP Patterson, BH Levander, OA Taylor, PR AF Block, G Mangels, AR Norkus, EP Patterson, BH Levander, OA Taylor, PR TI Ascorbic acid status and subsequent diastolic and systolic blood pressure SO HYPERTENSION LA English DT Article DE blood pressure; nutrition; diet; ascorbic acid; antioxidants ID VITAMIN-C; ENDOTHELIAL DYSFUNCTION; HYPERTENSION; DISEASE; HUMANS AB Free radicals and oxidation are involved in several aspects of blood pressure physiology. We investigated the relationship between blood pressure and antioxidants, including plasma ascorbic acid (AscA), in a 17-week controlled-diet study. Study subjects included 68 men aged 30 to 59 years who had a mean diastolic blood pressure of 73.4 mm Hg and a mean systolic blood pressure of 122.2 mm Hg. One month of vitamin C depletion was followed by 1-month repletion with 117 mg/d, repeated twice. All food and drink were provided in the study. Subjects did not smoke or drink alcohol, all consumed fruits and vegetables, and body weight was maintained. Plasma was assayed periodically for AscA, alpha -tocopherol, carotenoids, and lipids. Plasma AscA was inversely related to diastolic blood pressure 1 month later (correlation -0.48, P<0.0001). Persons in the bottom fourth of the plasma AscA distribution had >7 mm Hg higher diastolic blood pressure than did those in the top fourth of the plasma AscA distribution. Multivariate analysis with control for age, body mass index, other plasma antioxidants, and dietary energy, calcium, fiber, sodium, and potassium did not reduce the plasma AscA effect. One fourth of the Variance in diastolic blood pressure was accounted for by plasma AscA alone. Plasma AscA was also significantly associated with systolic blood pressure in logistic regression. Vitamin C may be an important component of the effectiveness of fruits and vegetables in the reduction in blood pressure, and tissue AscA levels may be important in the maintenance of low blood pressure. Long-term intervention studies are warranted. C1 NCI, Bethesda, MD 20892 USA. ARS, USDA, Beltsville, MD USA. Our Lady Mercy Med Ctr, Bronx, NY USA. RP Block, G (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 426 Warren Hall, Berkeley, CA 94720 USA. RI Block, Gladys/E-3304-2010 NR 28 TC 57 Z9 60 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2001 VL 37 IS 2 BP 261 EP 267 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412PL UT WOS:000167563500015 PM 11230282 ER PT J AU Fedorova, OV Kolodkin, NI Agalakova, NI Lakatta, EG Bagrov, AY AF Fedorova, OV Kolodkin, NI Agalakova, NI Lakatta, EG Bagrov, AY TI Marinobufagenin, an endogenous alpha-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats SO HYPERTENSION LA English DT Article; Proceedings Paper CT 54th Annual Fall Conference and Scientific Sessions of the American-Heart-Association Council for High Pressure Research CY OCT 24-27, 2000 CL WASHINGTON, D.C. SP Amer Heart Assoc DE NaCl; Dahl rats; Na+/K+-ATPase; kidney; bufadienolides; marinobufagenin ID VOLUME EXPANSION; NA,K-ATPASE; OUABAIN; INHIBITOR; PLASMA; BUFODIENOLIDE; ATPASE AB Dahl salt-sensitive rats (DS), which have a mutation in the alpha -1 subunit of Na+/K+-ATPase, exhibit impaired pressure natriuresis and on a high-salt diet, retain Na+ and exhibit increased blood pressure. Recently, we have shown that mammalian tissues contain a bufadienolide Na+/K+-ATPase inhibitory factor, marinobufagenin (MBG), that exhibits greater affinity for the alpha -1 than alpha -3 sodium pump isoform. The present study investigated the possible role of MBG in hypertension in DS on a high NaCl intake. Eight DS and 8 Dahl salt-resistant rats (DR) were placed on an 8% NaCl diet. Within 2 weeks, systolic blood pressure increased in DS (162+/-9 mm Hg at week 2 versus 110+/-2 mm Hg in baseline, P<0.01), and increased less in DR (124+/-3 mm Hg at week 2 versus 112+/-2 mm Hg in baseline). Renal excretion of MBG increased rt-fold (38.9+/-7.6 pmol versus 9.1+/-1.3 pmol in baseline, P<0.01) in DS, but by only 25% in DR (13.2+/-0.9 pmol versus 10.3+/-0.7 pmol in baseline). Excretion of endogenous ouabain did not change in either strain. MBG-immunoreactive material was purified from the urine of hypertensive DS by means of 2 steps of reverse-phase high performance liquid chromatography (HPLC) and compared with plant ouabain and amphibian MBG for its ability to inhibit the Na+/K+-ATPase from rat kidney (which expresses only alpha -1 Na+/K+-ATPase isoform). Unlike ouabain (IC50=248 mu mol/L), serially diluted, HPLC-purified MBG immunoreactivity from DS and authentic MBG potently inhibited rat kidney Na+/K+-ATPase (IC50=70 and 78 nmol/L, respectively). Our results suggest that an alpha -1 Na+/K+-ATPase ligand, MEG, is elaborated to promote natriuresis in hypertensive DS. MBG acts as a selective inhibitor of the ouabain-resistant alpha -1 Na+/K+-ATPase subunit, ie, the major sodium pump isoform of the kidneys, as would be expected of a putative natriuretic hormone. C1 NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Inst Highly Pure Biopreparat, St Petersburg, Russia. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 29 TC 64 Z9 65 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2001 VL 37 IS 2 SU S BP 462 EP 466 PN 2 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412PM UT WOS:000167563600024 PM 11230319 ER PT J AU Waldmann, TA Dubois, S Tagaya, Y AF Waldmann, TA Dubois, S Tagaya, Y TI Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: Implications for immunotherapy SO IMMUNITY LA English DT Review ID T-CELL LEUKEMIA; ACTIVATED KILLER-CELLS; RECEPTOR-BETA-CHAIN; HUMANIZED ANTI-TAC; ALPHA-CHAIN; IN-VIVO; INTERLEUKIN-2 RECEPTOR; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; PROLIFERATION C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 49 TC 336 Z9 350 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2001 VL 14 IS 2 BP 105 EP 110 DI 10.1016/S1074-7613(09)00091-0 PG 6 WC Immunology SC Immunology GA 404HZ UT WOS:000167092500001 PM 11239443 ER PT J AU Cherukuri, A Cheng, PC Sohn, HW Pierce, SK AF Cherukuri, A Cheng, PC Sohn, HW Pierce, SK TI The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts SO IMMUNITY LA English DT Article ID T-DEPENDENT ANTIGEN; PHOSPHOLIPASE-C; LYMPHOCYTES-B; TRANSDUCTION MOLECULE; ACQUIRED-IMMUNITY; KINASE ACTIVATION; DOWN-REGULATION; CD19; IMMUNOGLOBULIN; PROTEIN AB The CD19/CD21 complex functions to significantly enhance B cell antigen receptor (BCR) signaling in response to complement-tagged antigens. Recent studies showed that following antigen binding the BCR translocates into plasma membrane lipid rafts that serve as platforms for BCR signaling. Here, we show that the binding of complement-tagged antigens stimulates the translocation of both the BCR and the CD19/ CD21 complex into lipid rafts, resulting in prolonged residency in and signaling from the rafts, as compared to BCR cross-linking alone. When coligated to the BCR, the CD19/CD21 complex retards the internalization and degradation of the BCR. The colocalization and stabilization of the BCR and the CD19/CD21 complex in plasma membrane lipid rafts represents a novel mechanism by which a coreceptor enhances BCR signaling. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 37 TC 145 Z9 151 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2001 VL 14 IS 2 BP 169 EP 179 PG 11 WC Immunology SC Immunology GA 404HZ UT WOS:000167092500007 PM 11239449 ER PT J AU Chaussee, MS Watson, RO Smoot, JC Musser, JM AF Chaussee, MS Watson, RO Smoot, JC Musser, JM TI Identification of rgg-regulated exoproteins of Streptococcus pyogenes SO INFECTION AND IMMUNITY LA English DT Article ID EXTRACELLULAR CYSTEINE PROTEASE; SIGMA-FACTOR SIGMA(B); GROUP-A STREPTOCOCCUS; HYALURONIC-ACID CAPSULE; STAPHYLOCOCCUS-AUREUS; LACTOCOCCUS-LACTIS; BACILLUS-SUBTILIS; VIRULENCE GENES; GROWTH-PHASE; PROTEINS AB Streptococcus pyogenes secretes many proteins that influence host-pathogen interactions. Despite their importance, relatively little is known about the regulation of these proteins. The rgg gene (also known as ropB) is required for the expression of streptococcal erythrogenic toxin B (SPE B), an extracellular cysteine protease that contributes to virulence. Proteomics was used to determine if rgg regulates the expression of additional exoproteins. Exponential- and stationary-phase culture supernatant proteins made by S, pyogenes NZ131 rgg and NZ131 speB were separated by two-dimensional electrophoresis, Differences were identified in supernatant proteins from both exponential- and stationary-phase cultures, although considerably more differences cr ere detected among stationary-phase supernatant proteins, Forty-two proteins were identified by peptide fingerprinting with matrix-assisted laser desorption mass spectrometry. Mitogenic factor, DNA entry nuclease (open reading frame [ORF 226]), and ORF 953, which has no known function, were more abundant in the culture supernatants of the rgg mutant compared to the speB mutant. ClpB, lysozyme, and autolysin were detected in the culture supernatant of the speB mutant but not the rgg mutant. To determine if Rgg affected protein expression at the transcriptional level, real-time (TaqMan) reverse transcription (RT)-PCR was used to quantitate Rgg-regulated transcripts from NZ131 wild-type and speB and rgg mutant strains. The results obtained with RT-PCR correlated with the proteomic data. We conclude that Rgg regulates the transcription of several genes expressed primarily during the stationary phase of growth. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 46 TC 92 Z9 93 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2001 VL 69 IS 2 BP 822 EP 831 DI 10.1128/IAI.69.2.822-831.2001 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 394MW UT WOS:000166528700026 PM 11159974 ER PT J AU Moss, J Ehrmantraut, ME Banwart, BD Frank, DW Barbieri, JT AF Moss, J Ehrmantraut, ME Banwart, BD Frank, DW Barbieri, JT TI Sera from adult patients with cystic fibrosis contain antibodies to Pseudomonas aeruginosa type III apparatus SO INFECTION AND IMMUNITY LA English DT Article ID EXOENZYME-S; EXOTOXIN-A; IGG ANTIBODIES; EXPRESSION; INFECTION; RESPONSES; CYTOTOXICITY; PROTEINS; INJURY; CELLS AB Expression of type III proteins of Pseudomonas aeruginosa in patients with cystic fibrosis (CF) was investigated by measuring the immune response against components of the type III pathway. Twenty-three of the 33 sera contained antibodies against PcrV, a protein involved in translocation of type III cytotoxins into eukaryotic cells, and 11 of 33 had antibodies against ExoS, while most CF sera contained antibodies against PopB and PopD, components of the type III apparatus. These data indicate that P. aeruginosa commonly expresses components of the type III translocation apparatus in adult CF patients. C1 Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. RP Barbieri, JT (reprint author), Med Coll Wisconsin, Dept Microbiol & Mol Genet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NIAID NIH HHS [R01 AI030162, AI01289, AI30162] NR 29 TC 30 Z9 30 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2001 VL 69 IS 2 BP 1185 EP 1188 DI 10.1128/IAI.69.2.1185-1188.2001 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 394MW UT WOS:000166528700071 PM 11160019 ER PT J AU Henderson, DK AF Henderson, DK TI Raising the bar: The need for standardizing the use of "standard precautions" as a primary intervention to prevent occupational exposures to bloodborne pathogens SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material ID HEALTH-CARE WORKERS; HUMAN-IMMUNODEFICIENCY-VIRUS; UNIVERSAL PRECAUTIONS; IMPLEMENTATION; NEEDLESTICK; FREQUENCY; EMERGENCY; HIV C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Warren G Magnuson Clin Ctr, Bldg 10,Room 2C146,9000 Rockville Pk, Bethesda, MD 20892 USA. NR 26 TC 2 Z9 3 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2001 VL 22 IS 2 BP 70 EP 72 DI 10.1086/501866 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 401NQ UT WOS:000166934300004 PM 11232881 ER PT J AU Chen, X Oppenheim, J Howard, OMZ AF Chen, X Oppenheim, J Howard, OMZ TI Shikonin, a component of antiinflammatory Chinese herbal medicine, selectively blocks chemokine binding to CC chemokine receptor-1 SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE CCR1; receptor binding; shikonin; antagonist ID SMALL-MOLECULE ANTAGONIST; IDENTIFICATION; ACETYLSHIKONIN; NEUTROPHILS; INHIBITION; POTENT AB Shikonin is a chemically characterized component of traditional Chinese herbal medicine and has been shown to possess antiinflammatory activities. We ascertained that shikonin blocked radiolabelled Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) and macrophage inflammatory protein-1 (MIP-1 alpha) binding to human monocytes with IC50 values of 3.58 x 10(-6) and 2.57 X 10(-6) M, respectively. In contrast, up to 1.7 X 10(-5) M of shikonin failed to inhibit stromal cell-derived factor-1 (SDF-1 alpha )binding to the cells. Additionally, shikonin blocked RANTES and MIP-1 alpha binding to stable CC chemokine receptor-1 (CCR1) transfected human embryonic kidney (HEK)/293 cells with IC50 values of 2.63 x 10(-6) and 2.57 X 10-6 M, respectively. However, shikonin inhibited neither RANTES nor MIP-1 alpha binding to CCR5 transfected HEK/293 cells. Shikonin also did not inhibit monocyte chemoattractant protein-1 (MCP-1) binding to CCR2 cells, eotaxin binding to CCR3 cells, interferon-inducible T cell alpha -chemoattractant (1-TAC) binding to CXCR3 cells and SDF-1 alpha binding to CXCR4 cells. Additionally, shikonin inhibited RANTES-induced CCR1 cell migration, but did not inhibit CCR1 cell migration induced by epidermal growth factor (EGF). Our study suggests shikonin may be a target for the future design of more potent, highly selective therapeutics that could be useful antiinflammatory agents far selectively blocking the binding of CCR1 ligands. (C) 2001 Published by Elsevier Science B.V. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Mol Immunoregulat Lab, Frederick, MD 21701 USA. RP Howard, OMZ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Mol Immunoregulat Lab, Frederick, MD 21701 USA. RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU NCCIH NIH HHS [Y2-AT-9002] NR 24 TC 48 Z9 55 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD FEB PY 2001 VL 1 IS 2 BP 229 EP 236 DI 10.1016/S1567-5769(00)00033-3 PG 8 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 426BE UT WOS:000168328800006 PM 11360924 ER PT J AU Brams, P Black, A Padlan, EA Hariharan, K Leonard, J Chambers-Slater, K Noelle, RJ Newman, R AF Brams, P Black, A Padlan, EA Hariharan, K Leonard, J Chambers-Slater, K Noelle, RJ Newman, R TI A humanized anti-human CD154 monoclonal antibody blocks CD154-CD40 mediated human B cell activation SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE humanized; monoclonal antibody; human CD154; blockade of co-stimulation ID VIVO CD40-GP39 INTERACTIONS; DEPENDENT HUMORAL IMMUNITY; HYPER-IGM SYNDROME; CD40 LIGAND; T-CELLS; IN-VIVO; ENDOTHELIAL-CELLS; HUMAN SPLENOCYTES; SCID MICE; GP39 AB Humanized anti-CD154 antibodyl IDEC-131, had a slightly, but reproducibly, better binding affinity for CD154 (K-d = 5.6 nM), compared to the parent antibody 23-31 (K-d = 8.5 nM). Otherwise it was indistinguishable from the murine parent antibody in its ability to bind to CD154, block CD154 binding to CD40 and inhibit T cell-dependent B cell differentiation. The latter activity was independent of FcR binding as the Fab'1 fragment of IDEC-131 had an equivalent biological activity to that of the whole antibody, IDEC-131 blocked soluble CD154 from inducing proliferation of purified B cells, and blocked T cell dependent anti-tetanus toxoid specific antibody production by human B cells in vitro. IDEC-131, gammal, kappa, had strong Fc gamma RI, Fc gamma RII and Clq binding, but was unable to induce complement dependent (CDC) or antibody dependent cell-cytotoxicity (ADCC) of activated peripheral blood T cells, which express relatively low levels of CD154. IDEC-131 antibody inhibited both primary and secondary antibody responses to ovalbumin in cynomolgus monkeys at a dose of 5 mg/kg. In non-immunized animals, treatment with IDEC-131 at 50 mg/kg weekly for 13 weeks induced no change in any of the measured lymphocyte subsets, including B cells, CD4 + and CD8 + T cells. Similarly, a safety study in chimpanzees showed no discernible safety related issues at 20 mg/kg, including B and T cell subsets. These results show that the humanized anti-CD154 antibody, IDEC-131, has retained the affinity and functional activity of its murine parent antibody, is unlikely to deplete CD154 positive lymphocytes in humans, and is safe and effective in blocking antibody production in monkeys. Based on its safety and efficacy profile IDEC-131 is being developed for therapy of systemic lupus erythematosus. (C) 2001 Elsevier Science B.V. All rights reserved. C1 IDEC Pharmaceut Corp, San Diego, CA 92121 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Dartmouth Med Sch, Dept Microbiol, Lebanon, NH 03756 USA. RP Newman, R (reprint author), IDEC Pharmaceut Corp, 3010 Sci Pk Rd, San Diego, CA 92121 USA. NR 46 TC 45 Z9 45 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD FEB PY 2001 VL 1 IS 2 BP 277 EP 294 DI 10.1016/S1567-5769(00)00020-5 PG 18 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 426BE UT WOS:000168328800011 PM 11360929 ER PT J AU Naqvi, RU Tweedie, D MacLeod, KT AF Naqvi, RU Tweedie, D MacLeod, KT TI Evidence for the action potential mediating the changes to contraction observed in cardiac hypertrophy in the rabbit SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE cardiac hypertrophy; intracellular calcium homeostasis; cell contraction; relaxation; action potentials ID FELINE VENTRICULAR MYOCYTES; RENOVASCULAR HYPERTENSIVE RATS; ISOFORM-SPECIFIC REGULATION; CONGESTIVE-HEART-FAILURE; GUINEA-PIG HEARTS; SARCOPLASMIC-RETICULUM; PRESSURE-OVERLOAD; PROTEIN-LEVELS; GENE-EXPRESSION; CALCIUM CURRENT AB Background: We investigated the effects of cardiac hypertrophy on intracellular calcium (Ca2+) homeostasis, the amounts of proteins involved in calcium regulation and the influence of the action potential on such changes. Methods: Cardiac hypertrophy was induced in rabbits by constriction of the ascending aorta. They were kept for 6 weeks then the heart was removed and left ventricular myocytes isolated. A portion of these myocytes was immediately frozen and stored for subsequent protein analyses using Western blotting. Results After aortic banding, cardiac myocyte two-dimensional area and membrane capacitance were increased by 53% and 23%, respectively. Hypertrophy prolonged cell contraction and relaxation and the corresponding Indo-1 Ca2+ transients. Hypertrophied cells displayed longer action potentials but Ca2+ current densities were unchanged compared with myocytes from sham hearts. If Ca2+ was released from the sarcoplasmic reticulum using rapid cooling, so bypassing the normal mechanisms involved in excitation-contraction coupling, then no functional differences between hypertrophied and control cells could be observed. Western blot analysis showed that the amounts of sarcoplasmic reticulum Ca2+ ATPase, its regulatory protein phospholamban and the sodium/calcium exchanger were unchanged whereas the amount of calsequestrin was increased by 65% and the alpha (1) subunit of the sodium/potassium ATPase was reduced by 72%. These changes do not appear to evoke functional consequences under these conditions. Conclusion: In this model of cardiac hypertrophy, the increase in action potential duration is responsible for changes: in contraction and relaxation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England. NIA, NIH, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP MacLeod, KT (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dovehouse St, London SW3 6LY, England. NR 59 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB PY 2001 VL 77 IS 2-3 BP 189 EP 206 DI 10.1016/S0167-5273(00)00421-6 PG 18 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 409QU UT WOS:000167395000013 PM 11182183 ER PT J AU Brenner, AV Wang, ZY Kleinerman, RA Wang, LD Zhang, SZ Metayer, C Chen, K Lei, SW Cui, HX Lubin, JH AF Brenner, AV Wang, ZY Kleinerman, RA Wang, LD Zhang, SZ Metayer, C Chen, K Lei, SW Cui, HX Lubin, JH TI Previous pulmonary diseases and risk of lung cancer in Gansu Province, China SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; lung neoplasms; tuberculosis; pulmonary; bronchitis; pulmonary emphysema; asthma; pneumonia ID NONSMOKING WOMEN; FAMILY HISTORY; TUBERCULOSIS PATIENTS; RESPIRATORY-DISEASE; MORTALITY; SMOKING; COHORT; EXPOSURE; ASTHMA; MINERS AB Backgrounds Although active smoking is well established as the main cause of lung cancer, there is accumulating evidence that history of prior lung diseases may be an independent risk factor for lung cancer. Methods A population-based case-control study in Gansu Province, China identified 886 lung cancer cases (656 male, 230 female) diagnosed between January 1994 and April 1998. A standardized interview collected information on a variety of potential risk factors including a history of physician-diagnosed non-malignant lung diseases (pulmonary tuberculosis, chronic bronchitis/emphysema, asthma, pneumonia), age and year in which each condition was first diagnosed, and any therapy or hospitalization received. Results Pulmonary tuberculosis (odds ratio [OR] = 2.1, 95% CI:1.4-3.1) and chronic bronchitis/emphysema (OR = 1.4 95% CI : 1.1-1.8) were associated with increased risk of lung cancer, after adjustment for active smoking and socioeconomic status. The OR for asthma (OR = 1.4, 95% CI : 0.9-2.1) and pneumonia (OR = 1.5, 95% CI: 1.0-2.3) were also elevated. The risk of lung cancer remained significant for pulmonary tuberculosis and chronic bronchitis/emphysema when analysis was limited to the pathologically confirmed cases and self-responders. Conclusions This study provides additional evidence that previous pulmonary tuberculosis and chronic bronchitis/emphysema are causally related to lung cancer, although the precise mechanism is still unclear. The results for asthma and pneumonia, while suggestive of a positive association, did not reach the traditional level of statistical significance and should be interpreted with caution. C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Brenner, AV (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Execut Blvd,MSC 7362, Bethesda, MD 20892 USA. OI Kleinerman, Ruth/0000-0001-7415-2478 FU NCI NIH HHS [N01-CP-50509] NR 38 TC 89 Z9 96 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2001 VL 30 IS 1 BP 118 EP 124 DI 10.1093/ije/30.1.118 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 413AG UT WOS:000167587300032 PM 11171871 ER PT J AU Schaffer, AA Simon, R Desper, R Richter, J Sauter, G AF Schaffer, AA Simon, R Desper, R Richter, J Sauter, G TI Tree models for dependent copy number changes in bladder cancer SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE bladder cancer; comparative genomic hybridization; algorithms; phylogenetic trees; maximum branching; survival analysis ID COMPARATIVE GENOMIC HYBRIDIZATION; TRANSITIONAL-CELL CARCINOMA; CHROMOSOMAL IMBALANCES; STATISTICAL-ANALYSIS; GENETIC ALTERATIONS; PTA; ABERRATIONS AB We analyzed comparative genomic hybridization data on a collection of 237 bladder cancer tumors with the aim of identifying sets of copy number aberrations (CNAs) that tend to occur together. A test based on Fisher's exact test for pairs, but taking into account multiple testing, showed strong dependencies amongst several pairs of aberrations including (+1q, -11p), (+17q, +20q), (+10p, -17p), (-8p, -17p), (+5p, +10p). To determine whether co-occurrence of CNAs may characterize tumor subtypes, we used two recently proposed methods to construct tree models of tumor progression. We constructed tree models for all the tumors, the tumors of stage pT1, and the tumors of stages pT2-4. The tree models confirmed that most of the non-random events and the associations are the same for different stages. We conclude that the combination of large data sets and tree models provide a useful approach to systematically identifying tumor subgroups characterized by more than a single chromosomal aberration. C1 NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Deutsch Krebsforschungszentrum, Abt Theoret Bioinformat, D-6900 Heidelberg, Germany. RP Schaffer, AA (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bldg 38A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. RI Schaffer, Alejandro/F-2902-2012 NR 34 TC 15 Z9 16 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD FEB PY 2001 VL 18 IS 2 BP 349 EP 354 PG 6 WC Oncology SC Oncology GA 392YA UT WOS:000166439100019 PM 11172603 ER PT J AU Nicoletti, MI Myers, TG Fojo, T Blagosklonny, MV AF Nicoletti, MI Myers, TG Fojo, T Blagosklonny, MV TI Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE p53; MDR-1; drug resistance ID BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN GENE; ANTICANCER DRUG; P53-EXPRESSING ADENOVIRUS; CELLULAR-RESPONSE; TUMOR-SUPPRESSOR; MUTANT P53; NF-Y; EXPRESSION; MUTATIONS AB The notion that wt p53 downregulates MDR-1 links p53 mutations to multidrug resistant phenotype. Alternatively, it has been envisioned that wt p53 protects cells against DNA damaging drugs by inducing MDR-1. Opposing conclusions on the relationship between MDR-1 and p53 have been predominantly based on the effects of p53 on MDR-1 promoter-constructs. We found that introduction of wt p53 slightly induced MDR-1 mRNA in three cell lines having endogenous mt p53. Wt p53-mediated induction of endogenous MDR-1 may represent a rudiment of cellular protection against toxic compounds earlier in evolution. Marked induction of p21(WAF1/CIP1) (p21) mRNA was observed in all cell lines; and lower levels of wt p53 were required to induce p21 than MDR-1. Pgp was undetectable and wt p53 did not increase resistance to an MDR-1 substrate, suggesting the changes in MDR-1 mRNA may be functionally insignificant. Unlike endogenous MDR-1, the expression of an MDR-1 promoter (-434/+147 fragment) - luciferase construct was unchanged or even inhibited by wt p53 that may be secondary to wt p53-mediated cytotoxicity. Thus, partial promoter constructs may not accurately represent endogenous MDR-1. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. NR 49 TC 4 Z9 4 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD FEB PY 2001 VL 18 IS 2 BP 375 EP 381 PG 7 WC Oncology SC Oncology GA 392YA UT WOS:000166439100023 PM 11172607 ER PT J AU Deb, D Lanyi, A Scian, M Keiger, J Brown, DR Le Roith, D Deb, SP Deb, S AF Deb, D Lanyi, A Scian, M Keiger, J Brown, DR Le Roith, D Deb, SP Deb, S TI Differential modulation of cellular and viral promoters by p73 and p53 SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE p53; p73; transcriptional activation; repression; IGF-I-R ID WILD-TYPE P53; P53-MEDIATED TRANSCRIPTIONAL REPRESSION; TATA-BINDING PROTEIN; TUMOR-SUPPRESSOR P53; LARGE T-ANTIGEN; FACTOR RECEPTOR PROMOTER; KINASE C-ABL; P53-RELATED PROTEIN; HUMAN CANCERS; APOPTOTIC RESPONSE AB p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus once-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha, only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and eye A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Richmond, VA 23298 USA. NIDDKD, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Deb, S (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. FU NCI NIH HHS [CA70712, CA74172] NR 77 TC 14 Z9 14 U1 1 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD FEB PY 2001 VL 18 IS 2 BP 401 EP 409 PG 9 WC Oncology SC Oncology GA 392YA UT WOS:000166439100026 PM 11172610 ER PT J AU Coleman, CN AF Coleman, CN TI International Conference on Translational Research and Preclinical Strategies in Radio-Oncology (ICTR) - Conference summary SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 NCI, Radiat Oncol Sci Progra, Div Clin Sci, Div Canc Diagnosis & Treamtent,NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Oncol Sci Progra, Div Clin Sci, Div Canc Diagnosis & Treamtent,NIH, ROB,Bldg 10,B3B69, Bethesda, MD 20892 USA. NR 9 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2001 VL 49 IS 2 BP 301 EP 309 DI 10.1016/S0360-3016(00)01521-2 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 397QV UT WOS:000166707700002 PM 11173122 ER PT J AU Sedelnikova, OA Luu, AN Karamychev, VN Panyutin, IG Neumann, RD AF Sedelnikova, OA Luu, AN Karamychev, VN Panyutin, IG Neumann, RD TI Development of DNA-based radiopharmaceuticals carrying Auger-electron emitters for antigene radiotherapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 1st International Conference on Translational Research and Pre-Clinical Strategies in Clinical Radio-Oncology (ICTR 2000) CY MAR 05-08, 2000 CL LUGANO, SWITZERLAND SP NCI, Radiat Res Soc, Amer Coll Radiol, European ch Oncol, European Org Res & Treatment Canc, Swiss League Against Canc DE Iodine-125; tripler-forming oligonucleotides; MDR1 gene; antigene radiotherapy ID TRIPLEX-FORMING-OLIGONUCLEOTIDES; GENE-EXPRESSION; CELLS; SEQUENCE; I-125; DAMAGE; DECAY AB Purpose: Antigene radiotherapy (AR) is based on targeting localized radiodamage to specific sites in the genome by using sequence-specific tripler-forming oligonucleotides (TFO) to carry Auger-electron-emitters (A-Ettr) such as Iodine-125 (I-125) to the target gene sequence. The radiodecay of an A-Ettr produces a cascade of low-energy electrons and creates a highly positively-charged daughter atom; delivered by a TFO, it should produce double-strand breaks (dsb) localized to the specific DNA target sequence. The result should be a "knock-out" of the targeted gene, Methods and Materials: As a model, we used the MDR1 gene amplified nearly 100 times in the human KB-V1 carcinoma cen line, Chemically modified TFO complementary to the polypurine/polypyrimidine region of the MDR1 gene were synthesized and radiolabeled with I-125-dCTP by the primer extension method. Purified plasmid and genomic DNA and extracted nuclei were treated with I-125-TFO and analyzed for sequence specific cleavage by electrophoresis in agarose gel and Southern hybridization. Results: We created I-125-TFO that could effectively recognize, bind, and cleave the target sequence in plasmid and genomic DNA, We showed that these I-125-TFO in nanomolar concentrations were able to cleave the target MDR1 gene sequence in a natural environment, i.e., within the eucaryotic nucleus, Conclusion: I-125-TFO can effectively introduce sequence-specific dsb to a target within the MDR1 gene, both in purified DNA and inside intact nuclei. Chemically modified TFO conjugated with nuclear localization signal appear to be a promising delivery vehicle for future in vivo trials of AR. (C) 2001 Elsevier Science Inc. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bldg 10,Room 1C401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. NR 19 TC 21 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2001 VL 49 IS 2 BP 391 EP 396 DI 10.1016/S0360-3016(00)01486-3 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 397QV UT WOS:000166707700012 PM 11173132 ER PT J AU Giles, F Cortes, J Garcia-Manero, G Kornblau, S Estey, E Kwari, M Murgo, A Kantarjian, H AF Giles, F Cortes, J Garcia-Manero, G Kornblau, S Estey, E Kwari, M Murgo, A Kantarjian, H TI Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE irofulven; MGI 114; acute leukemia; Phase I; illudins; acylfulvene ID CHRONIC MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; TRADITIONAL ANTICANCER AGENTS; ACUTE MYELOGENOUS LEUKEMIA; REFRACTORY ACUTE-LEUKEMIA; LUNG-CARCINOMA XENOGRAFT; LONG-TERM SURVIVAL; MYELODYSPLASTIC SYNDROMES; LYMPHOBLASTIC-LEUKEMIA; PRECLINICAL EVALUATION AB Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic illudin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Irofulven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS). Irofulven was given as an intravenous infusion over five minutes daily for five days. The starting dose was 10 mg/m(2)/day (50 mg/m(2)/course). Courses were scheduled to be given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty patients {AML: 17 patients; MDS: one patient; ALL: one patient; mixed lineage acute leukemia: one patient} were treated. Nausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulmonary edema were dose limiting toxicities, occurring in two of five patients treated at 20 mg/m(2)/day and two of three patients treated at 12.5 mg/m(2)/day. The MTD was defined as 10 mg/m(2)/day for five days. One patient with primary resistant AML achieved complete remission. Proposed phase II studies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single agent and in combination regimens, particularly with topoisomerase 1 inhibitors. C1 Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Giles, F (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Box 61,1515 Holcombe Blvd, Houston, TX 77030 USA. NR 46 TC 9 Z9 9 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2001 VL 19 IS 1 BP 13 EP 20 DI 10.1023/A:1006432012394 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 401JM UT WOS:000166924500002 PM 11291829 ER PT J AU Kannan, R Ouyang, B Wawrousek, E Kaplowitz, N Andley, UP AF Kannan, R Ouyang, B Wawrousek, E Kaplowitz, N Andley, UP TI Regulation of GSH in alpha A-expressing human lens epithelial cell lines and in alpha A knockout mouse lenses SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 09-14, 1999 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol, Natl Hlth Public Serv Award, Childrens Hosp, Res Fdn ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; SUBUNIT GENE-EXPRESSION; SMALL STRESS PROTEINS; AMINO-ACID-SEQUENCE; B-CRYSTALLIN; HEAVY SUBUNIT; TRANSCRIPTIONAL REGULATION; GLUTATHIONE SYNTHESIS; IMMUNOREACTIVE ALPHA; MOLECULAR CHAPERONE AB PURPOSE. TO Study the mechanism of regulation of GSH in HLE-B3 cells expressing alphaA-crystallin (alphaA) and in alphaA knockout mouse; lenses. METHODS. GSH levels and maximal rates of GSH synthesis were measured in immortalized, alphaA-transfected HLE-B3 cells containing varying amounts of alphaA. The mRNA and protein for the rate-limiting enzyme for GSH synthesis, gamma -glutamylcysteine synthetase (GCS), were also determined in alphaA- and mock-transfected cells by Northern blot analysis and Western blot analysis of heavy (GCS-HS) and light (GCS-LS) subunits. The effect of absence of alphaA and alphaB on lens GSH concentrations was evaluated in whole lenses of alphaA knockout and alphaB knockout mice as a function of age. GCS-HS mRNA and protein were determined in young, precataractous and cataractous alphaA knockout lenses. RESULTS. GSH levels were significantly higher in HLE-B3 cells expressing alphaA- compared with mock-transfected cells and were correlated positively with alphaA content. Mean rate of GSH synthesis was also higher in alphaA-expressing cells than in mock controls (0.84, vs. 0.61 nmol . min(-1) per mg protein, respectively). GCS-HS mRNA and GCS-LS mRNA were approximately twofold higher in alphaA-expressing cells, whereas the heavy and light GCS subunit proteins increased by 80% to 100%. In alphaA(-/-) mouse lenses, GSH level was not different from that of wild type up to 2 months from birth, after which it dropped to similar to 50% of controls. On the other hand, GCS-HS and GCS-LS proteins showed a significant decrease before cataract formation as early as 15 days after birth. GSH level in cataract-free alphaB(-/-) lenses was similar to that of wild type for up to 14 months. CONCLUSIONS. Expression of alphaA caused an increase in cellular GSH, in part, because of an increase in mRNA and protein of both GCS subunits. GSH levels decreased with increasing age in cataractous alphaA(-/-) lenses but not in the noncataractous alphaB(-/-) lenses. It is suggested that neonatal precataractous lenses (with normal GSH and decreased GCS) map maintain their GSH level by other compensatory mechanisms such as increased GSH transport. C1 Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. NEI, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Kannan, R (reprint author), Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, 2011 Zonal Ave,HMR 803A, Los Angeles, CA 90033 USA. RI Wawrousek, Eric/A-4547-2008; OI Kannan, Ram/0000-0002-1583-3414 FU NEI NIH HHS [EY 02687, EY 05681, EY 11135] NR 54 TC 17 Z9 17 U1 0 U2 1 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 FEB PY 2001 VL 42 IS 2 BP 409 EP 416 PG 8 WC Ophthalmology SC Ophthalmology GA 401NG UT WOS:000166933300017 PM 11157875 ER PT J AU Barnes, KC Beck, LA Liu, MC Sanico, AM Jimenez, S Stockton, ML Brummet, ME Mantaring, M Freidhoff, LR Teichberg, D Becker, KG AF Barnes, KC Beck, LA Liu, MC Sanico, AM Jimenez, S Stockton, ML Brummet, ME Mantaring, M Freidhoff, LR Teichberg, D Becker, KG TI Analysis of gene expression in asthma, allergic rhinitis, and atopic dermatitis using cDNA microarray SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Cartagena, Cartagena, Colombia. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 770 BP S234 EP S235 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300766 ER PT J AU Brockow, K Akin, F Huber, MM Scott, LM Metcalfe, DD AF Brockow, K Akin, F Huber, MM Scott, LM Metcalfe, DD TI Determination of cytokine levels in the plasma and in suction skin blisters of patients with mastocytosis - Comparison to values obtained in patients with atopic eczema and in normal controls SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. Lab Allerg Dis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 949 BP S290 EP S290 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300945 ER PT J AU Chegini, SF AF Chegini, SF TI Experimental autoimmune gastritis induced by a Th2 cell line SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 902 BP S276 EP S276 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300898 ER PT J AU Chen, LC Lin, J Myers, AC Zhang, ZJ Huang, SK AF Chen, LC Lin, J Myers, AC Zhang, ZJ Huang, SK TI Regulatory role of clara cell secretory protein, CC10, in pulmonary allergic responses SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 582 BP S177 EP S177 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300580 ER PT J AU Hsieh, LS Moharram, RM Martin, BM Slater, JE AF Hsieh, LS Moharram, RM Martin, BM Slater, JE TI Latex allergen detection and epitope mapping using microarray technology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 US FDA, Rockville, MD 20857 USA. NIH, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 382 BP S115 EP S115 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300381 ER PT J AU Huang, SK Ober, C Blumenthal, MN Bleecker, E Banks-Schlegel, S Rich, S Beaty, TH AF Huang, SK Ober, C Blumenthal, MN Bleecker, E Banks-Schlegel, S Rich, S Beaty, TH CA CSGA TI Fine-mapping and positional candidate studies of asthma susceptibility gene SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Chicago, Chicago, IL 60637 USA. Univ Minnesota, Minneapolis, MN USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 768 BP S234 EP S234 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300764 ER PT J AU Johnson, EN Druey, KM AF Johnson, EN Druey, KM TI Characterization of regulator of G-protein signaling 13 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 485 BP S147 EP S147 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300484 ER PT J AU Kirshenbaum, AS Hettinger, B Day, YJ Gilfillan, AM Metcalfe, DD Kim, YC Linden, J Jacobson, KA AF Kirshenbaum, AS Hettinger, B Day, YJ Gilfillan, AM Metcalfe, DD Kim, YC Linden, J Jacobson, KA TI MRS 1754, a selective A2B adenosine receptor antagonist, inhibits degranulation of cultured human butnotmurine mast cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 5 Z9 5 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 922 BP S281 EP S281 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300918 ER PT J AU Luccioli, S Brody, DT Noben-Trauth, N Prussin, C Metcalfe, DD AF Luccioli, S Brody, DT Noben-Trauth, N Prussin, C Metcalfe, DD TI Early IL-4 production in a murine model of allergic pulmonary inflammation is IgE-dependent and is mediated by an Fc epsilon R1-bearing non-T, non-B cell SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 1050 BP S322 EP S322 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172301046 ER PT J AU Pawliczak, R Logun, C Danner, R Shelhamer, JH AF Pawliczak, R Logun, C Danner, R Shelhamer, JH TI Gene expression in human airway cells after dexamethasone treatment SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 1060 BP S325 EP S325 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172301056 ER PT J AU Taylor, ML Sehgal, D Mage, RG Raffeld, M Akin, C Metcalfe, DD AF Taylor, ML Sehgal, D Mage, RG Raffeld, M Akin, C Metcalfe, DD TI Detection of the activating Kit mutation D816V in laser capture microdissected mast cells and lymphoid cells from bone marrow biopsy tissues from patients with mastocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 1004 BP S307 EP S307 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172301000 ER PT J AU Tkaczyk, C Metcalfe, DD Gilfillan, AM AF Tkaczyk, C Metcalfe, DD Gilfillan, AM TI Are mouse bone marrow derived mast cells (BMMC's) more reflective of Fc epsilon RI-dependent tyrosine phosphorylation in human mast cells (HuMC's) than are RBL 2H3 cells? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 585 BP S178 EP S178 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300583 ER PT J AU Uzel, G Frucht, DF Fleisher, TH Holland, SM AF Uzel, G Frucht, DF Fleisher, TH Holland, SM TI Going with the flow: Simple, rapid diagnosis of TH1 T cell-monocyte defects SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NIH, NIAMS, Bethesda, MD USA. NIH, NIAID, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 995 BP S304 EP S304 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300991 ER PT J AU Woolhiser, M Okayama, Y Gilfillan, A Metcalfe, D AF Woolhiser, M Okayama, Y Gilfillan, A Metcalfe, D TI Degranulation of human mast cells following the crosslinking of monomeric IgG1 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 NIH, NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 929 BP S283 EP S283 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300925 ER PT J AU Zambelli-Weiner, A Casolaro, V Mathias, RA Stockton, ML Nutman, TB Barnes, KC AF Zambelli-Weiner, A Casolaro, V Mathias, RA Stockton, ML Nutman, TB Barnes, KC TI Cross-reactivity of T cell responses to major allergens of cockroach and antigens from extracellular parasites in individuals with cockroach sensitization SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NIH, Bethesda, MD 20892 USA. RI Casolaro, Vincenzo/E-9144-2010 OI Casolaro, Vincenzo/0000-0001-9810-0488 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 290 BP S86 EP S86 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300290 ER PT J AU Richardson, MA Russell, NC Sanders, T Barrett, R Salveson, C AF Richardson, MA Russell, NC Sanders, T Barrett, R Salveson, C TI Assessment of outcomes at alternative medicine cancer clinics: A feasibility study SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID COMPLEMENTARY/ALTERNATIVE MEDICINE; QUESTIONABLE METHODS; THERAPY USE; PREVALENCE; ONCOLOGY; CHILDREN AB Objective: This pilot study tested the feasibility of performing outcomes and more advanced research regarding cancer patients at two complementary and alternative (CAM) clinics. The primary objectives were to determine the feasibility of (1) obtaining and collecting data from medical records, (2) determining 5-year survival, and (3) comparing 5-year survival to that of conventional treatment. In addition, in this paper we present the barriers and recommend strategies to facilitate high-quality research. Settings/Location: The Bio-Medical Center in Tijuana, Mexico, and the Livingston Foundation Medical Center in San Diego, California. Subjects: New patients who were treated for cancer during 1992 at the Livingston Foundation Medical Center and during the first quarter of 1992 at the Bio-Medical Center. Results: Charts were available for 89.6% of the 307 new patients treated at the Bio-Medical Center; 149 (54%) patients were treated for cancer and 65 (43.6%) cases were confirmed by pathology reports. In contrast, all records were available for 193 new patients treated for cancer at the Livingston Clinic; 152 (78.8%) cases had pathology confirmation. At both clinics, patients were equally divided by gender and were predominantly Caucasian, were married, and were U.S. residents. On average, patients were 51-54 years old and within 1 year of diagnosis for breast, colorectal, lung, or male genital cancer. Most patients (61.1%-63.7%) arrived with distant or regional disease after conventional surgery and/or chemotherapy/radiotherapy. Survival at 5 years was determined for 57.0% at the Bio-Medical Center (11.4% were alive and 45.6% were deceased) and 94.8% at Livingston (14.5% were alive and 80.3% were deceased). The limited number of cases by cancer site prevented comparison to conventional treatment. Conclusions: Historical, widespread use of clinics such as these with anecdotal reports of extraordinary survival merit prospective, systematic monitoring of patient outcomes, For data to be meaningful, however, disease status must be pathologically confirmed and patient follow-up improved. C1 Univ Texas, Houston Hlth Sci Ctr, Sch Publ Hlth, Ctr Alternat Med Res, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Symptom Control & Palliat Care, Houston, TX 77030 USA. Univ Texas, Houston Hlth Sci Ctr, Sch Publ Hlth, Ctr Hlth Promot Res & Dev, Houston, TX USA. Livingston Fdn Med Ctr, San Diego, CA USA. Oregon Hlth Sci Univ, Sch Nursing, Portland, OR 97201 USA. RP Richardson, MA (reprint author), NIH, Ctr Alternat & Complementary Med, 6707 Democracy Blvd 106, Bethesda, MD 20892 USA. FU NCI NIH HHS [5 U24 CA66826-03] NR 48 TC 11 Z9 11 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD FEB PY 2001 VL 7 IS 1 BP 19 EP 32 DI 10.1089/107555301300004501 PG 14 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 404ZM UT WOS:000167132800006 PM 11246933 ER PT J AU Hochhut, B Beaber, JW Woodgate, R Waldor, MK AF Hochhut, B Beaber, JW Woodgate, R Waldor, MK TI Formation of chromosomal tandem arrays of the SXT element and R391, two conjugative chromosomally integrating elements that share an attachment site SO JOURNAL OF BACTERIOLOGY LA English DT Article ID VIBRIO-CHOLERAE O139; ESCHERICHIA-COLI; CTX-PHI; PLASMID; RESISTANCE; TRANSPOSON; DETERMINANTS; REPLICATION; PROTEIN; PMERPH AB The SXT element, a conjugative, self-transmissible, integrating element (a constin) originally derived from a Vibrio cholerae O139 isolate from India, and IncJ element R391, originally derived from a South African Providencia rettgeri isolate, were found to be genetically and functionally related. Both of these constins integrate site specifically into the Escherichia coli chromosome at an identical attachment site within the 5' end of prfC. They encode nearly identical integrases, which are required for chromosomal integration, excision, and extrachromosomal circularization of these elements, and they have similar tra genes, Therefore, these closely related constins have virtually identical mechanisms for chromosomal integration and dissemination. The presence of either element in a recipient cell did not significantly reduce its ability to acquire the other element, indicating that R391 and SXT do not encode surface exclusion determinants. In cells harboring both elements, SXT and R391 were integrated in tandem fashion on the chromosome, and homologous recombination appeared to play little or no role in the formation of these arrays. Interference between R391 and SXT was detected by measuring the frequency of loss of an unselected resident element upon introduction of a second selected element. In these assays, R391 was found to have a stronger effect on SXT stability than vice verse. The level of expression and/or activity of the donor and recipient integrases may play a role in the interference between these two related constins. C1 New England Med Ctr, Div Geog Med Infect Dis, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Howard Hughes Med Inst, Boston, MA 02111 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Waldor, MK (reprint author), New England Med Ctr, Div Geog Med Infect Dis, 750 Washington St,NEMC 041, Boston, MA 02111 USA. FU NIAID NIH HHS [AI42347, R01 AI042347, R37 AI042347]; NIDDK NIH HHS [P30 DK034928, P30DK-34928] NR 31 TC 60 Z9 66 U1 0 U2 2 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 FEB PY 2001 VL 183 IS 4 BP 1124 EP 1132 DI 10.1128/JB.183.4.1124-1132.2001 PG 9 WC Microbiology SC Microbiology GA 397LM UT WOS:000166697200002 PM 11157923 ER PT J AU Guichon, A Hersh, D Smith, MR Zychlinsky, A AF Guichon, A Hersh, D Smith, MR Zychlinsky, A TI Structure-function analysis of the Shigella virulence factor IpaB SO JOURNAL OF BACTERIOLOGY LA English DT Article ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; EPITHELIAL-CELLS; MACROPHAGE APOPTOSIS; YERSINIA-ENTEROCOLITICA; FLEXNERI; INVASION; SALMONELLA; ENTRY; PROTEINS; CASPASE-1 AB Infection by the gram-negative bacterium Shigella flexneri results in dysentery, an acute inflammatory disease of the colon. Essential events in the pathogenesis of Shigella infections include bacterial invasion of epithelial cells, escape from the phagosome, and induction of apoptosis in macrophages. The Shigella virulence factor invasion plasmid antigen B (IpaB) is required for all of these processes. Induction of apoptosis is dependent on IpaB binding to the cysteine protease caspase-1 (Casp-l). The activation of this enzyme triggers both apoptosis and release of the proinflammatory cytokine interleukin-1 beta. Several IpaB mutants were generated to correlate function with protein subdomains. We determined that the N terminal portion of IpaB is necessary for stable expression of IpaB. A putative amphipathic alpha -helical domain preserves the structure of IpaB, We found 10 consecutive residues within the amino terminus of the hydrophobic region that play a critical role in invasion, phagosomal escape, and cytotoxicity. An IpaB mutant carrying a mutation in this region binds to Casp-1 yet is not cytotoxic, even following direct delivery to the macrophage cytoplasm. These results indicate that the association between IpaB and Casp-1 is only a step in the activation of macrophage apoptosis. C1 NYU, Med Ctr, Skirball Inst, New York, NY 10016 USA. NYU, Med Ctr, Dept Microbiol, New York, NY 10016 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Zychlinsky, A (reprint author), NYU, Med Ctr, Skirball Inst, 540 1st Ave, New York, NY 10016 USA. FU NIAID NIH HHS [AI 42780-01] NR 41 TC 35 Z9 38 U1 0 U2 2 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 FEB PY 2001 VL 183 IS 4 BP 1269 EP 1276 DI 10.1128/JB.183.4.1269-1276.2001 PG 8 WC Microbiology SC Microbiology GA 397LM UT WOS:000166697200018 PM 11157939 ER PT J AU Cheung, JOP Hillarby, MC Ayad, S Hoyland, JA Jones, CJP Denton, J Thomas, JT Wallis, GA Grant, ME AF Cheung, JOP Hillarby, MC Ayad, S Hoyland, JA Jones, CJP Denton, J Thomas, JT Wallis, GA Grant, ME TI A novel cell culture model of chondrocyte differentiation during mammalian endochondral ossification SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE chondrocyte; endochondral ossification; azacytidine; cell culture; growth plate ID HORMONE-RELATED PEPTIDE; X COLLAGEN-SYNTHESIS; GROWTH-PLATE CHONDROCYTES; PARATHYROID-HORMONE; MESSENGER-RNA; BONE-FORMATION; EPIPHYSEAL CARTILAGE; SKELETAL DISORDERS; GENE-EXPRESSION; 5-AZACYTIDINE AB Endochondral ossification (EO) occurs in the growth plate where chondrocytes pass through discrete stages of proliferation, maturation, hypertrophy, and calcification. We have developed and characterized a novel bovine cell culture model of EO that mirrors these events and will facilitate in vitro studies on factors controlling chondrocyte differentiation. Chondrocytes derived from the epiphyses of long bones of fetal calves were treated with 5-azacytidine (aza-C) for 48 h. Cultures were maintained subsequently without aza-C and harvested at selected time points for analyses of growth and differentiation status. A chondrocytic phenotype associated with an extensive extracellular matrix rich in proteoglycans and collagen types II and VI was observed in aza-C-treated and -untreated cultures. aza-C-treated cultures were characterized by studying the expression of several markers of chondrocyte differentiation. Parathyroid hormone-related protein (PTHrP) and its receptor, both markers of maturation, were expressed at days 5-9. Type X collagen, which is restricted to the stage of hypertrophy, was expressed from day 11 onward. Hypertrophy was confirmed by a 14-fold increase in cell size by day 15 and an increased synthesis of alkaline phosphatase during the hypertrophic period (days 14-28). The addition of PTHrP to aza-C-treated cultures at day 14 led to the down-regulation of type X collagen by 6-fold, showing type X collagen expression is under the control of PTHrP as in vivo. These findings show that aza-C can induce fetal bovine epiphyseal chondrocytes to differentiate in culture in a manner consistent with that which occurs during the EO process in vivo. C1 Univ Manchester, Musculoskeletal Res Grp, Manchester M13 9PT, Lancs, England. Univ Manchester, Sch Biol Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. Univ Manchester, Sch Med Sci, Manchester M13 9PT, Lancs, England. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Hillarby, MC (reprint author), Univ Manchester, Musculoskeletal Res Grp, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. RI Hoyland, Judith/P-5168-2014 OI Hoyland, Judith/0000-0003-4876-5208 NR 44 TC 16 Z9 16 U1 0 U2 4 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD FEB PY 2001 VL 16 IS 2 BP 309 EP 318 DI 10.1359/jbmr.2001.16.2.309 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 393XD UT WOS:000166494200014 PM 11204431 ER PT J AU Martinez-Lacaci, I De Santis, M Kannan, S Bianco, C Kim, N Wallace-Jones, B Wechselberger, C Ebert, AD Salomon, DS AF Martinez-Lacaci, I De Santis, M Kannan, S Bianco, C Kim, N Wallace-Jones, B Wechselberger, C Ebert, AD Salomon, DS TI Regulation of heparin-binding EGF-like growth factor expression in Ha-ras transformed human mammary epithelial cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID DIPHTHERIA-TOXIN RECEPTOR; HUMAN-BREAST-CANCER; ACTIVATED PROTEIN-KINASE; HUMAN PANCREATIC-CANCER; TYROSINE KINASE; PHORBOL ESTER; MESSENGER-RNA; FACTOR-ALPHA; SIGNAL-TRANSDUCTION; HUMAN KERATINOCYTES AB Heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein expression is induced by EGF in MCF-10A nontransformed and Ha-ras transfected human mammary epithelial cells. The anti-EGF receptor (EGFR) blocking monoclonal antibody (MAb) 225 and the EGFR tyrosine kinase inhibitor PD153035 were able to inhibit the induction of HB-EGF mRNA levels in MCF-10A cells. However, the Ha-ras transformed MCF-10A cells were more refractory to inhibition by these agents and only a combination of the 225 MAb and PD153035 was able to significantly abrogate HB-EGF induction by EGF. The anti-erbB2 MAb L26 which interferes with heterodimer formation was able to block HB-EGF induction in response to EGF in MCF-10A cells and in the Ha-ras transformed cells only when used in combination with either the 225 MAb or PD153035. The MEK inhibitor PD90859 completely blocked EGF induction of HB-EGF mRNA levels in the nontransformed and Ha-ras transformed MCF-10A cells, which indicates that MAPK is involved in the signaling pathway of HB-EGF induction by EGF. An increase in the levels of HB-EGF may, therefore, be an important contributor to oncogenic transformation that is caused by Ha-ras overexpression in mammary epithelial cells. J. Cell. Physiol. 186:233-242, 2001. Published 2001 Wiley-Liss, Inc.dagger C1 NCI, Tumor Growth Factor Sect, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Mol Pathol, Washington, DC 20307 USA. McMaster Univ, Hamilton, ON, Canada. Free Univ Berlin, Benjamin Franklin Med Ctr, Dept Obstet & Gynecol, D-1000 Berlin, Germany. RP Salomon, DS (reprint author), NCI, Tumor Growth Factor Sect, Lab Tumor Immunol & Biol, NIH, Bldg 10,Rm 5B39, Bethesda, MD 20892 USA. NR 62 TC 7 Z9 7 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 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 2001 VL 186 IS 2 BP 233 EP 242 DI 10.1002/1097-4652(200002)186:2<233::AID-JCP1017>3.0.CO;2-L PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 388AD UT WOS:000166154500008 PM 11169460 ER PT J AU Bicout, DJ Berezhkovskii, AM Szabo, A AF Bicout, DJ Berezhkovskii, AM Szabo, A TI Irreversible bimolecular reactions of Langevin particles SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID KRAMERS PROBLEM AB The reaction A+B -->B is studied when the reactants diffuse in phase space, i.e., their dynamics is described by the Langevin equation. The steady-state rate constants are calculated for both the target (static A and mobile B's) and trapping (mobile A and static B's) problems when the reaction is assumed to occur at the first contact. For Brownian dynamics (i.e., ordinary diffusion), the rate constant for both problems is a monotonically decreasing function of the friction coefficient gamma. For Langevin dynamics, however, we find that the steady-state rate constant exhibits a turnover behavior as a function of gamma for the trapping problem but not for the target problem. This turnover is different from the familiar Kramers turnover of the rate constant for escape from a deep potential well because the reaction considered here is an activationless process. (C) 2001 American Institute of Physics. C1 Inst Max Von Laue Paul Langevin, Theory Grp, F-38042 Grenoble 9, France. INFM, Operat Grp Grneoble CRG IN13, F-38042 Grenoble 9, France. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Karpov Inst Phys Chem, Moscow 103064, Russia. RP Inst Max Von Laue Paul Langevin, Theory Grp, BP 156, F-38042 Grenoble 9, France. EM bicout@ill.fr RI Szabo, Attila/H-3867-2012 NR 18 TC 18 Z9 19 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 1 PY 2001 VL 114 IS 5 BP 2293 EP 2303 DI 10.1063/1.1332807 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 397CQ UT WOS:000166676100043 ER PT J AU Chrousos, GP AF Chrousos, GP TI Adrenal suppression versus clinical glucocorticoid deficiency in the premature infant: No simple answers SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CONTROLLED TRIAL; DEXAMETHASONE; AXIS C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9D42, Bethesda, MD 20892 USA. NR 12 TC 7 Z9 7 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 473 EP 474 DI 10.1210/jc.86.2.473 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900002 PM 11157992 ER PT J AU Hirshberg, B Skarulis, MC Pucino, F Csako, G Brennan, R Gorden, P AF Hirshberg, B Skarulis, MC Pucino, F Csako, G Brennan, R Gorden, P TI Repaglinide-induced factitious hypoglycemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INSULINOMA AB We report the first case of repaglinide-induced factitious hypoglycemia in a young male. This case posed a challenging diagnostic dilemma because commercial assays for repaglinide are not available. Furthermore, the patient had a series of positive diagnostic tests such as high proinsulin and localizing intra-arterial calcium stimulation suggestive of insulinoma. This case, again, demonstrates the importance of pure clinical judgment in the face of often-conflicting laboratory data in making a correct diagnosis and the requirement of definitive data for an appropriate therapeutic resolution. C1 NIDDKD, Div Intramural Res, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA. Laurel Endocrine Associates, Columbia, SC 29204 USA. RP Gorden, P (reprint author), NIDDKD, Div Intramural Res, NIH, Bldg 10,Room 8S235, Bethesda, MD 20892 USA. NR 15 TC 20 Z9 20 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 475 EP 477 DI 10.1210/jc.86.2.475 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900003 PM 11157993 ER PT J AU Vgontzas, AN Legro, RS Bixler, EO Grayev, A Kales, A Chrousos, GP AF Vgontzas, AN Legro, RS Bixler, EO Grayev, A Kales, A Chrousos, GP TI Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID WOMEN; PREVALENCE; TESTOSTERONE; GLUCOSE AB Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by chronic hyperandrogenism, oligoanovulation, and insulin resistance. Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) are strongly associated with insulin resistance and hypercytokinemia, independently of obesity. We hypothesized that women with PCOS are at risk for OSA and EDS. Fifty-three women with PCOS (age range, 16-45 yr) and 452 control premenopausal women (age range, 20-42), from a general randomized sample far the assessment of prevalence of OSA, were evaluated in the sleep laboratory for 1 night. In addition, women with PCOS were tested for plasma free and weakly bound testosterone, total testosterone, and fasting blood glucose and insulin concentrations. In this study, PCOS patients were 30 times more likely to suffer from sleep disordered breathing (SDB) than the controls [odds ratio = 30.6, 95% confidence interval (7.2-139.4)]. Nine of the PCOS patients (17.0%) were recommended treat-ment for SDB, in contrast with only 3 (0.6%) of the control group (P < 0.001). In addition, PCOS patients reported more frequent daytime sleepiness than the controls (80.4% vs. 27.0%, respectively; P < 0.001). PCOS patients who were recommended treatment for SDB, compared with those who were not, had significantly higher fasting plasma insulin levels (306.48 +/- 52.39 vs. 176.71 +/- 18.13 pmol/L, P < 0.01) and a lower glucose-to-insulin ratio (0.02 +/- 0.00 vs. 0.04 +/- 0.00, P < 0.05). Plasma free and total testosterone and fasting blood glucose concentrations were not different between the two groups of PCOS women. Our data indicate that SDB and EDS are markedly and significantly more frequent in PCOS women than in premenopausal controls. Also, insulin resistance is a stronger risk factor than is body mass index or testosterone for SDB in PCOS women. These data support our proposal that, independently of gender, sleep apnea might be a manifestation of an endocrine/metabolic abnormality in which insulin resistance plays a principal role. C1 Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Obstet & Gynecol, Hershey, PA 17033 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD USA. RP Vgontzas, AN (reprint author), Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, 500 univ Dr, Hershey, PA 17033 USA. EM axv3@psu.edu FU AHRQ HHS [HS K08-HD-0118]; NCRR NIH HHS [M01-RR-10732]; NICHD NIH HHS [U54-HD-34449] NR 24 TC 158 Z9 170 U1 2 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 517 EP 520 DI 10.1210/jc.86.2.517 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900012 PM 11158002 ER PT J AU Jorge, BH Agarwal, SK Lando, VS Salvatori, R Barbero, RR Abelin, N Levine, MA Marx, SJ Toledo, SPA AF Jorge, BH Agarwal, SK Lando, VS Salvatori, R Barbero, RR Abelin, N Levine, MA Marx, SJ Toledo, SPA TI Study of the multiple endocrine neoplasia type 1, growth hormone-releasing hormone receptor, Gs alpha, and Gi2 alpha genes in isolated familial acromegaly SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TUMOR-SUPPRESSOR GENE; STIMULATORY G-PROTEIN; LEYDIG-CELL TUMORS; ACTIVATING MUTATION; PITUITARY-TUMORS; MEN1 GENE; DISEASE; SUBUNIT AB Familial acromegaly may occur as an isolated pituitary disorder or as a feature of hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or the Carney complex. Herein, we characterized a newly identified kindred with isolated acromegaly and searched for germline mutation in genes that have been associated with endocrine tumors [i.e. MEN1, Gs alpha (GNAS1), and Gi2 alpha (GNAI2)], as well as the GHRH receptor (GHRH-R) gene. Genomic DNA was used to amplify exons 2-10 of MEN1, followed by dideoxy fingerprinting mutation analysis and direct sequencing. The GHRH-R gene was analyzed via direct sequencing of PCR-amplified fragments representing the coding exons and intron-exon junctions. To exclude mutation at hot spot areas of GNAS1 and GNAI2, exons 8 and 9 of GNAS1 and exons 5 and 6 of GNAI2 were amplified and screened for mutation via denaturing gradient gel electrophoresis. No mutations were detected in any of the four genes. The present data extend prior reports of the absence of mutation in MEN1, GHRH-R, and GNAS1 and describe the first family with isolated acromegaly in which germline mutation in GNAI2 has been searched. C1 Univ Sao Paulo, Sch Med, Endocrine Genet Unit, BR-01246903 Sao Paulo, Brazil. Univ Sao Paulo, Sch Med, Dept Med, Endocrinol Sect,Hormone & Mol Genet Lab, BR-01246903 Sao Paulo, Brazil. NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Endocrinol, Baltimore, MD 21287 USA. RP Jorge, BH (reprint author), Univ Sao Paulo, Sch Med, Endocrine Genet Unit, Ave Dr Arnaldo,455 5th Floor, BR-01246903 Sao Paulo, Brazil. EM beatrizjorge@hotmail.com RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU NCRR NIH HHS [3-M01-RR-000052] NR 26 TC 18 Z9 20 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 542 EP 544 DI 10.1210/jc.86.2.542 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900016 PM 11158006 ER PT J AU Harman, SM Metter, EJ Tobin, JD Pearson, J Blackman, MR AF Harman, SM Metter, EJ Tobin, JD Pearson, J Blackman, MR TI Longitudinal effects of aging on serum total and free testosterone levels in healthy men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BONE-MINERAL DENSITY; CORONARY-ARTERY DISEASE; SKELETAL-MUSCLE MASS; LEYDIG-CELL FUNCTION; LEAN BODY-MASS; PLASMA TESTOSTERONE; LUTEINIZING-HORMONE; SEX-HORMONES; ELDERLY MEN; GONADAL-FUNCTION AB Many studies have shown cross-sectional land two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG yr. T, but not free T index, also decreased with increasing body mass index. Use of beta -blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21224 USA. NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Harman, SM (reprint author), Kronos Res Fdn, 4455 E Camelback Rd,Suite B135, Phoenix, AZ 85018 USA. EM harman@kronofoundation.org RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 65 TC 1222 Z9 1278 U1 14 U2 68 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 724 EP 731 DI 10.1210/jc.86.2.724 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900047 PM 11158037 ER PT J AU Kitazono, M Chuman, Y Aikou, T Fojo, T AF Kitazono, M Chuman, Y Aikou, T Fojo, T TI Construction of gene therapy vectors targeting thyroid cells: Enhancement of activity and specificity with histone deacetylase inhibitors and agents modulating the cyclic adenosine 3 ',5 '-monophosphate pathway and demonstration of activity in follicular and anaplastic thyroid carcinoma cells SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DOXORUBICIN PLUS CISPLATIN; VIRUS THYMIDINE KINASE; IN-VITRO; CANCER; LINES; EXPRESSION; PROMOTER; PAPILLARY; RETINOIDS; TRIAL AB Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. Although effective therapies exist for well differentiated tumors, the treatment options for poorly differentiated and anaplastic tumors are much less effective. In the present study we demonstrate that the thyroglobulin (Tg) promoter can be used to direct specific expression of either luciferase or thymidine kinase in thyroid cancer cells. Furthermore, using a putative enhancer element for the Tg gene, the activity of the Tg promoter in and its specificity for thyroid cells were enhanced. In transient transfectants or in stably transfected thyroid carcinoma cells, treatment with the histone deacetylase inhibitors, depsipeptide (FR9012228) and sodium butyrate, alone or in combination with 8-bromo-cAMP, resulted in further enhancement. In experiments in which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the Tg promoter and the putative enhancer, HSV-TK expression and ganciclovir sensitivity were augmented. Similar results were obtained in two cell lines derived from a follicular thyroid carcinoma and in two anaplastic thyroid carcinoma cell lines. In summary, we report the construction of a suicide HSV-TK vector with preferential toxicity for thyroid cells. The results in anaplastic thyroid carcinoma cells suggest that it may be of use in the full spectrum of thyroid malignancies. C1 Kagoshima Univ, Fac Med, Dept Surg 1, Kagoshima 8908520, Japan. NCI, Med Branch, DCS, NIH, Bethesda, MD 20892 USA. RP Kitazono, M (reprint author), Kagoshima Univ, Fac Med, Dept Surg 1, Sakuragaoka 8-35-1, Kagoshima 8908520, Japan. EM kita@box-k.nih.gov NR 24 TC 21 Z9 22 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 834 EP 840 DI 10.1210/jc.86.2.834 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900064 PM 11158054 ER PT J AU Charmandari, E AF Charmandari, E TI Is hydrocortisone clearance 50% slower in the evening than in the morning? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Letter C1 UCL, London Ctr Paediat Endocrinol, London W1N 8AA, England. RP Charmandari, E (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Suite 9D42, Bethesda, MD 20892 USA. EM charmane@mail.nih.gov RI Charmandari, Evangelia/B-6701-2011 NR 5 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 948 EP 948 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900088 PM 11158078 ER PT J AU Mattson, MP Camandola, S AF Mattson, MP Camandola, S TI NF-kappa B in neuronal plasticity and neurodegenerative disorders SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BETA-AMYLOID PRECURSOR; NECROSIS-FACTOR-ALPHA; NERVE GROWTH-FACTOR; TRANSCRIPTION FACTOR; NUCLEAR TRANSLOCATION; CALCIUM HOMEOSTASIS; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; PROTECT NEURONS; BINDING FACTOR C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 4F02,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 36 TC 524 Z9 557 U1 0 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2001 VL 107 IS 3 BP 247 EP 254 DI 10.1172/JCI11916 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000002 PM 11160145 ER PT J AU Hodgin, JB Krege, JH Reddick, RL Korach, KS Smithies, O Maeda, N AF Hodgin, JB Krege, JH Reddick, RL Korach, KS Smithies, O Maeda, N TI Estrogen receptor alpha is a major mediator of 17 beta-estradiol's atheroprotective effects on lesion size in Apoe(-/-) mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SMOOTH-MUSCLE CELLS; MESSENGER-RNA EXPRESSION; CORONARY HEART-DISEASE; E-DEFICIENT MICE; APOLIPOPROTEIN-E; REPLACEMENT THERAPY; VASCULAR INJURY; POSTMENOPAUSAL WOMEN; BALLOON INJURY; CAROTID-ARTERY AB The inhibitory effects of estrogen (17 beta -estradiol) on atherosclerosis have been well documented in numerous animal models, and epidemiological evidence supports this protective effect in humans. The detailed mechanisms for this protection are not understood, but most are thought to be mediated through estrogen receptors (ERs), of which two are known (ER alpha and ERP). To investigate the role of ER alpha in the atheroprotective effect of 17 beta -estradiol(E2), we ovariectomized female mice that lack apoE (AAee) or lack both apoE and ER alpha (alpha alpha ee), and treated half of them with E2 for three months. E2 treatment of ovariectomized AAee females dramatically reduced the size of the lesions as well as their histological complexity. Plasma cholesterol was significantly reduced in this group, although the observed extent of protection by E2 was greater than could be explained solely by the change in lipid levels. In contrast, E2 treatment of ovariectomized alpha alpha ee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with alpha alpha ee mice without E2, demonstrating that ER alpha is a major mediator of the atheroprotective effect of E2. Nevertheless, E2 treatment significantly reduced the complexity of plaques in the alpha alpha ee females, although not to the same degree as in AAee females, suggesting the existence of ER alpha -independent atheroprotective effects of E2. C1 Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Guilford Med Associates, Greensboro, NC USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Maeda, N (reprint author), Univ N Carolina, Dept Pathol & Lab Med, 703 Brinkhous Bullitt Bldg, Chapel Hill, NC 27599 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NHLBI NIH HHS [HL42630, HL-03470, R01 HL042630, R37 HL042630]; NIGMS NIH HHS [F31 GM020069, GM-20069, R01 GM020069] NR 59 TC 136 Z9 139 U1 2 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2001 VL 107 IS 3 BP 333 EP 340 DI 10.1172/JCI11320 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000014 PM 11160157 ER PT J AU Blaser, MJ Musser, JM AF Blaser, MJ Musser, JM TI Bacterial polymorphisms and disease in humans SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID INFECTION; EVOLUTION C1 NYU, Sch Med, Dept Med, New York, NY 10016 USA. NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. Vet Affairs Med Ctr, New York, NY 10016 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Blaser, MJ (reprint author), NYU, Sch Med, Dept Med, 550 1st Ave, New York, NY 10016 USA. NR 9 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2001 VL 107 IS 4 BP 391 EP 392 DI 10.1172/JCI11993 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 403YY UT WOS:000167071700001 PM 11181636 ER PT J AU Reid, SD Hoe, NP Smoot, LM Musser, JM AF Reid, SD Hoe, NP Smoot, LM Musser, JM TI Group A Streptococcus: allelic variation, population genetics, and host-pathogen interactions SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROUP-A STREPTOCOCCUS; PYROGENIC-EXOTOXIN-A; COMPLEMENT-INHIBITING PROTEIN; SCARLET FEVER TOXIN; CYSTEINE PROTEASE; VIRULENCE FACTOR; PYOGENES; STRAINS; SUPERANTIGEN; VARIANTS C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, 903 S 4th St, Hamilton, MT 59840 USA. FU NIAID NIH HHS [AI-33119] NR 38 TC 32 Z9 32 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2001 VL 107 IS 4 BP 393 EP 399 DI 10.1172/JCI11972 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 403YY UT WOS:000167071700002 PM 11181637 ER PT J AU Dent, S Zee, B Dancey, J Hanauske, A Wanders, J Eisenhauer, E AF Dent, S Zee, B Dancey, J Hanauske, A Wanders, J Eisenhauer, E TI Application of a new multinomial phase II stopping rule using response and early progression SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICAL-TRIALS AB Purpose: A multinomial stopping rule had previously been developed that incorporated both objective response and early progression into decisions to stop or continue phase II trials of anticancer agents. The purpose of this study was to apply the multinomial rule to two independent sets of phase II data to assess its utility in appropriately recommending early trial closure as compared with other stopping rules. Materials and Methods: Data from completed phase II trials of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and European Organization for Research and Treatment of Cancer Early Clinical Studies Group (ECSG) formed the basis of the study. Based on observed results for each trial, the recommendation of the multinomial stopping rule was applied, as was the recommendation of the actual stopping rule used (Fleming or Gehan). The appropriateness of the recommendations was evaluated based on interpretation of final study results. Results: The standard and multinomial rules disagreed on early stopping in one of 16 NCIC CTG trials and in seven of 23 ECSG trials. In all cases, the standard rule advised continuing to the second stage whereas the multinomial rule advised stopping early because of excessive numbers of patients experiencing early disease progression. Final trial results indicated that the multinomial recommendation was appropriate, because in no study did final results lead to conclusions of activity. Conclusion: In this series of trials, the multinomial stopping rule performed more efficiently than the Fleming or Gehan rules in advising early stopping of trials. These results encourage continued exploration of this approach for phase II trials of cytotoxic and noncytotoxic anticancer agents. (C) 2001 by American Society of Clinical Oncology. C1 Queens Univ, Natl Canc Inst, Canada Clin Traials Grp, Kingston, ON K7L 3N6, Canada. Northwestern Ontario Reg Canc Ctr, Thunder Bay, ON, Canada. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. European Org Res Treatment Canc, Early Clin Studies Grp, Munich, Germany. New Drug Dev Off, Amsterdam, Netherlands. RP Eisenhauer, E (reprint author), Queens Univ, Natl Canc Inst, Canada Clin Traials Grp, 82-84 Barrie St, Kingston, ON K7L 3N6, Canada. OI Zee, Benny Chung-Ying/0000-0002-7238-845X NR 6 TC 58 Z9 62 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 785 EP 791 PG 7 WC Oncology SC Oncology GA 399GK UT WOS:000166803100025 PM 11157032 ER PT J AU Sunwoo, JB Herscher, LL Kroog, GS Thomas, GR Ondrey, FG Duffey, DC Solomon, BI Boss, C Albert, PS McCullugh, L Rudy, S Muir, C Zhai, S Figg, WD Cook, JA Mitchell, JB Van Waes, C AF Sunwoo, JB Herscher, LL Kroog, GS Thomas, GR Ondrey, FG Duffey, DC Solomon, BI Boss, C Albert, PS McCullugh, L Rudy, S Muir, C Zhai, S Figg, WD Cook, JA Mitchell, JB Van Waes, C TI Concurrent paclitaxel and radiation in the treatment of locally advanced head and neck cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; PHASE-I TRIAL; LUNG-CANCER; RANDOMIZED TRIAL; TUMOR RADIORESPONSE; 24-HOUR INFUSION; BREAST-CANCER; RADIOTHERAPY; TAXOL; CHEMOTHERAPY AB Purpose: To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study, paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m(2), and 17 patients received 120 mg/m2, Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy, Results: Three months alter therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival. Conclusion: paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC. (C) 2001 by American Society of Clinical Oncology. C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIDCD, Head & Neck Surg Branch, Speech & Language Pathol Sect, Rehabil Med Dept,Clin Ctr, Bethesda, MD 20892 USA. NCI, Branch Radiat Biol, NIH, Bethesda, MD 20892 USA. NCI, Branch Biometr Res, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Herscher, LL (reprint author), NCI, Radiat Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 56 TC 44 Z9 45 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 800 EP 811 PG 12 WC Oncology SC Oncology GA 399GK UT WOS:000166803100027 PM 11157034 ER PT J AU Chico, I Kang, MH Bergan, R Abraham, J Bakke, S Meadows, B Rutt, A Robey, R Choyke, P Merino, M Goldspiel, B Smith, T Steinberg, S Figg, WD Fojo, T Bates, S AF Chico, I Kang, MH Bergan, R Abraham, J Bakke, S Meadows, B Rutt, A Robey, R Choyke, P Merino, M Goldspiel, B Smith, T Steinberg, S Figg, WD Fojo, T Bates, S TI Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; MULTIDRUG-RESISTANCE; SDZ PSC-833; TISSUE DISTRIBUTION; 96-HOUR INFUSION; CYCLOSPORINE-A; BREAST-CANCER; PHARMACOKINETICS; MODULATOR; DEXAMETHASONE AB Purpose: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. Patients and Methods: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion, Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. Results: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C-pss) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received ct paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. Conclusion: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent, This in turn will facilitate dosing to achieve comparable CPss and AUCs. (C) 2001 by American Society of Clinical Oncology. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Pathol, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NIH, Clin Ctr Pharm, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Novartis Pharmaceut Corp, E Hanover, NJ USA. RP Bates, S (reprint author), NCI, Med Branch, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 32 TC 68 Z9 70 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 832 EP 842 PG 11 WC Oncology SC Oncology GA 399GK UT WOS:000166803100030 PM 11157037 ER PT J AU Haynie, DL Nansel, T Eitel, P Crump, AD Saylor, K Yu, K Simons-Morton, B AF Haynie, DL Nansel, T Eitel, P Crump, AD Saylor, K Yu, K Simons-Morton, B TI Bullies, victims, and bully/victims: Distinct groups of at-risk youth SO JOURNAL OF EARLY ADOLESCENCE LA English DT Article ID SCHOOL-CHILDREN; RELATIONAL AGGRESSION; INTERVENTION PROGRAM; PEER VICTIMIZATION; ADOLESCENT BOYS; BEHAVIOR; ADJUSTMENT; ADULTHOOD; ANXIETY; ALCOHOL AB Bullying and victimization are prevalent problems in the area of adolescent peer relationships. Middle school students (N = 4,263) in one Maryland school district completed surveys covering a range of problem behaviors and psychosocial variables. Overall, 30.9% of the students reported being victimized three or more limes in the past year and 7.4% reported bullying three or more rimes over the past year. More than one half of the bullies also reported being victimized. Those bully/victims were found to score less favorably than either bullies or victims on all the measured psychosocial and behavioral variables. Results of a discriminant function analysis demonstrated that a group of psychosocial and behavioral predictors-including problem behaviors, attitudes toward deviance, peer influences depressive symptoms, school-related functioning, and parenting-formed a linear separation between the comparison group (never bullied or victimized), the victim group, the bully group, and the bully/victim group. C1 NICHD, NIH, Rockville, MD 20852 USA. Univ Maryland, College Pk, MD 20742 USA. RP Haynie, DL (reprint author), NICHD, NIH, 6100 Execut Blvd,Room 4A01, Rockville, MD 20852 USA. OI Nansel, Tonja/0000-0002-8298-7595; Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 61 TC 306 Z9 309 U1 5 U2 66 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-4316 J9 J EARLY ADOLESCENCE JI J. Early Adolesc. PD FEB PY 2001 VL 21 IS 1 BP 29 EP 49 DI 10.1177/0272431601021001002 PG 21 WC Family Studies; Psychology, Developmental SC Family Studies; Psychology GA 391TR UT WOS:000166372000002 ER PT J AU Rodgers, BD Levine, MA Bernier, M Montrose-Rafizadeh, C AF Rodgers, BD Levine, MA Bernier, M Montrose-Rafizadeh, C TI Insulin regulation of a novel WD-40 repeat protein in adipocytes SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; CULTURED RAT HEPATOCYTES; MESSENGER-RNA STABILITY; 3T3-L1 ADIPOCYTES; PERTUSSIS-TOXIN; EXPRESSION; TRANSCRIPTION; GLUCAGON; RIBONUCLEASE; G(I-ALPHA-2) AB A 400 bp PCR product generated with degenerate primers derived from the gluagon-like peptide-1 receptor was used to screen a rat skeletal muscle cDNA library. The predicted amino acid sequence oft he 978 bp open reading frame has a predicted M-r of 35 804, an estimated isoelectric point (pI) of 5.31 and contains seven WD-40 repeats, which are common to G-protein beta subunits (G beta). Although chemically and structurally similar to G beta subunits, the predicted amino acid sequence, when compared with the previously cloned G beta isoforms, was found to be only 31-41% similar and thus was named G beta -like (G betaL, 'Gable'). Western blotting of whole-cell lysates and immunoprecipitates of membrane and cytosolic fractions of HEK 293 cells stably overexpressing a carboxy-terminal His-tagged G betaL indicates that the protein is cytosolic and that it migrates at 42 kDa. A 4 kb transcript was detected in all tissues surveyed by northern blotting; however, an additional 2 kb transcript was detected in testis. Expression of G betaL mRNA was highest in the brain and testis, followed by lung, heart, kidney, skeletal muscle, spleen and liver. In addition, reverse transcriptase/PCR showed that several other tissues and cell lines express G betaL. The ubiquitous nature of the tissue expression pattern of G betaL is similar to thar of the insulin receptor, which suggests that insulin may influence G betaL expression. Indeed, G betaL protein and mRNA levels, in fully differentiated 3T3-L1 adipocytes, were upregulated by insulin in a concentration-dependent fashion. These changes were highly sensitive to insulin stimulation, being minimally affected by doses as low as 0.1 nM and maximally elevated by 1 nM doses. These data suggest that insulin regulates G betaL production and imply that some of the actions of insulin may be mediated, in part, by this novel intracellular protein. C1 Johns Hopkins Univ, Sch Med, Div Pediat Endocrinol, Baltimore, MD 21287 USA. NIA, Diabet Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Rodgers, BD (reprint author), Johns Hopkins Univ, Sch Med, Div Pediat Endocrinol, 600 N Wolfe St,Park 211, Baltimore, MD 21287 USA. OI Bernier, Michel/0000-0002-5948-368X; Levine, Michael/0000-0003-0036-7809 NR 28 TC 8 Z9 10 U1 0 U2 2 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD FEB PY 2001 VL 168 IS 2 BP 325 EP 332 DI 10.1677/joe.0.1680325 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 406HX UT WOS:000167209800014 PM 11182770 ER PT J AU Weed, DL AF Weed, DL TI Methods in epidemiology and public health: does practice match theory? SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID BLOOD-PRESSURE; CALCIUM INTAKE; METAANALYSIS; FUTURE; PARADIGMS; INCOMMENSURABILITY; GUIDELINES; REVIEWS; QUALITY; SCIENCE C1 NCI, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Off Prevent Oncol, Div Canc Prevent, Execut Plaza S,Suite T-41,6130 Execut Blvd MSC 71, Bethesda, MD 20892 USA. NR 60 TC 7 Z9 7 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD FEB PY 2001 VL 55 IS 2 BP 104 EP 110 DI 10.1136/jech.55.2.104 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 393WX UT WOS:000166493600009 PM 11154249 ER PT J AU Shin, TY Jeong, HJ Kim, DK Kim, SH Lee, JK Kim, DK Chae, BS Kim, JH Kang, HW Lee, CM Lee, KC Park, ST Lee, EJ Lim, JP Kim, HM Lee, YM AF Shin, TY Jeong, HJ Kim, DK Kim, SH Lee, JK Kim, DK Chae, BS Kim, JH Kang, HW Lee, CM Lee, KC Park, ST Lee, EJ Lim, JP Kim, HM Lee, YM TI Inhibitory action of water soluble fraction of Terminalia chebula on systemic and local anaphylaxis SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Terminalia chebula Retz.; anaphylactic shock; passive cutaneous anaphylaxis; rat peritoneal mast cells; histamine; compound 48/80; anti-dinitrophenyl IgE; tumor necrosis factor-alpha ID PASSIVE CUTANEOUS ANAPHYLAXIS; MAST-CELLS; MEDIATED ACTIVATION; IMMUNOGLOBULIN-E; HIGH-AFFINITY; SUBSTANCE-P; IGE; HISTAMINE; RECEPTOR; RELEASE AB We investigated the effects of the water soluble fraction of Terminalia chebula (Combretaceae) (WFTC) on systemic and local anaphylaxis. WFTC administered Ih before compound 48/80 injection inhibited compound 48/80-induced anaphylactic shock 100% with doses of 0.01-1.0 g/kg. When WFTC was administered 5 or 10 min after compound 48/80 injection, the mortality also decreased in a dose-dependent manner. Passive cutaneous anaphylaxis was inhibited by 63.5 +/- 7.8% by oral administration of WFTC (1.0 g/kg). When WFTC was pretreated at concentrations ranging from 0.005 to 1.0 g/kg, the serum histamine levels were reduced in a dose-dependent manner. WFTC (0.01-1.0 mg/ml) also significantly inhibited histamine release from rat peritoneal mast cells (RPMC) by compound 48/80. However, WFTC (1.0 mg/ml) had a significant increasing effect on anti-dinitrophenyl IgE-induced tumor necrosis factor-oc production from RPMC. These results indicate that WFTC may possess a strong antianaphylactic action. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Wonkwang Univ, Ctr Oriental Med Sci, Coll Pharm, Iksan 570750, Chonbuk, South Korea. Woosuk Univ, Coll Pharm, Chonju 565701, Chonbuk, South Korea. NIAID, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. Woosuk Univ, Coll Sci & Engn, Chonju 565701, Chonbuk, South Korea. Wonkwang Univ, Coll Oriental Med, Iksan 570750, Chonbuk, South Korea. Wonkwang Univ, Sch Med, Iksan 570750, Chonbuk, South Korea. RP Lee, YM (reprint author), Wonkwang Univ, Ctr Oriental Med Sci, Coll Pharm, Iksan 570750, Chonbuk, South Korea. NR 33 TC 27 Z9 34 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD FEB PY 2001 VL 74 IS 2 BP 133 EP 140 DI 10.1016/S0378-8741(00)00360-3 PG 8 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 398TB UT WOS:000166771500004 PM 11167031 ER PT J AU Walsh, PJ Grosell, M Goss, GG Bergman, HL Bergman, AN Wilson, P Laurent, P Alper, SL Smith, CP Kamunde, C Wood, CM AF Walsh, PJ Grosell, M Goss, GG Bergman, HL Bergman, AN Wilson, P Laurent, P Alper, SL Smith, CP Kamunde, C Wood, CM TI Physiological and molecular characterization of urea transport by the gills of the Lake Magadi tilapia (Alcolapia grahami) SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE Alcolapia grahami; urea transporter gene; UT-A2; gills; nitrogen excretion; Lake Magadi tilapia ID TOADFISH OPSANUS-BETA; OREOCHROMIS-ALCALICUS-GRAHAMI; EXTREMELY ALKALINE ENVIRONMENT; FUNCTIONAL EXPRESSION; ACID-BASE; CLONING; FISH; WATER; EXCRETION; PERMEABILITY AB The Lake Magadi tilapia (Alcolapia grahami) is an unusual fish, excreting all its nitrogenous waste as urea because of its highly alkaline and buffered aquatic habitat. Here, using both physiological and molecular studies, we describe the mechanism of branchial urea excretion in this species. In vivo, repeated short-interval sampling revealed that urea excretion is continuous, The computed urea permeability of A. grahami gill is 4.74x10(-5)+/-0.38x10(-5) cm s(-1) (mean +/- S.E.M., N=11), some 10 times higher than passive permeability through a lipid bilayer and some five times higher than that of even the most urea-permeable teleosts studied to date (e.g. the gulf toadfish), Transport of urea was bidirectional, as demonstrated by experiments in which external [urea] was elevated, Furthermore, urea transport was inhibited by classic inhibitors of mammalian and piscine urea transporters in the order thiourea>N-methylureal>acetamide. A 1700 base pair cDNA for a putative Magadi tilapia urea transporter (mtUT) was cloned, sequenced and found to display high homology with urea transporters from mammals, amphibians and other fishes, When cRNA transcribed from mtUT cDNA was injected into Xenopus laevis oocytes, phloretin-inhibitable urea uptake was enhanced 3.4-fold relative to water-injected controls, Northern analysis of gill, red blood cells, liver, muscle and brain using a portion of mtUT as a probe revealed that gill is the only tissue in which mtUT RNA is expressed, Magadi tilapia gill pavement cells exhibited a trafficking of dense-cored vesicles between the well-developed Golgi cisternae and the apical membrane. The absence of this trafficking and the poor development of the Golgi system in a non-ureotelic relative (Oreochromis niloticus) suggest that vesicle trafficking could be related to urea excretion in Alcolapia grahami, Taken together, the above findings suggest that the gills of this alkaline-lake-adapted species excrete urea constitutively via the specific facilitated urea transporter mtUT. C1 Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, MBF,NIEHS Marine & Freshwater Biomed Sci Ctr, Div Marine Biol & Fisheries, Miami, FL 33149 USA. McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. Univ Wyoming, Dept Zool & Physiol, Laramie, WY 82071 USA. Trent Univ, Dept Chem, Wildlife Forens DNA Lab, Peterborough, ON K9J 7B8, Canada. CNRS, Ctr Ecol & Physiol Energet, F-67037 Strasbourg, France. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Mol Med Unit, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Renal Unit, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Cell Biol,Mol Med Unit, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Cell Biol,Renal Unit, Boston, MA 02215 USA. Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. Univ Nairobi, Dept Vet Anat, Nairobi, Kenya. RP Walsh, PJ (reprint author), Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, MBF,NIEHS Marine & Freshwater Biomed Sci Ctr, Div Marine Biol & Fisheries, 4600 Rickenbacker Causeway, Miami, FL 33149 USA. RI Goss, Greg/A-2646-2014; Goss, Greg/D-2723-2015 OI Goss, Greg/0000-0003-0786-8868 FU NIDDK NIH HHS [DK43495, DK34854] NR 39 TC 57 Z9 58 U1 1 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD FEB PY 2001 VL 204 IS 3 BP 509 EP 520 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 403NT UT WOS:000167049900010 PM 11171302 ER PT J AU D'Costa, J Brown, HM Kundra, P Davis-Warren, A Arya, SK AF D'Costa, J Brown, HM Kundra, P Davis-Warren, A Arya, SK TI Human immunodeficiency virus type 2 lentiviral vectors: packaging signal and splice donor in expression and encapsidation SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID CIS-ACTING SEQUENCES; VIVO GENE DELIVERY; CELL-CYCLE ARREST; IN-VIVO; REGULATORY ELEMENTS; MUTATIONAL ANALYSIS; FUNCTIONAL DOMAINS; NONDIVIDING CELLS; NUCLEAR IMPORT; HIV TYPE-1 AB Retroviral vectors provide the means for gene transfer with long-term expression. The lentivirus subgroup of retroviruses, such as human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), possesses a number of regulatory and accessory genes and other special elements. These features can be exploited to design vectors for transducing non-dividing as well as dividing cells with the potential for regulated transgene expression. Encapsidation of the transgene RNA in lentiviral vectors is determined by the leader sequence-based multipartite packaging signal. Embedded in the packaging signal is a major splice donor site that, this study shows, is not by itself essential for transgene expression or encapsidation. We designed HIV-2 vectors that contained all the sequence elements thought to be necessary and sufficient for vector RNA encapsidation. Unexpectedly, despite abundant expression, only a small fraction of the transgene RNA was encapsidated and the titre of the vector was low. Redesign of the vector with a mutant splice donor resulted in increased vector RNA encapsidation and yielded vectors with high titre, Inefficient encapsidation by the conventionally designed vector was not due to suboptimal Rev responsive element (RRE)-Rev function. Varying the length of RRE in the vector did not change vector RNA encapsidation, nor did the introduction of a synthetic intron into the mutant vector. The vector RNA with the intact splice donor may have been excessively spliced, decreasing the amount of packageable RNA. A titre of 10(5) transducing units (TU)/ml was readily obtained for vectors with the neo or GFP transgene, and the vector could be concentrated to a titre of 1-5 x 10(7) TU/ml. C1 NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Arya, SK (reprint author), NCI, Basic Res Lab, Div Basic Sci, NIH, Bldg 37,Room 5E10, Bethesda, MD 20892 USA. NR 48 TC 18 Z9 18 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 2001 VL 82 BP 425 EP 434 PN 2 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 397LR UT WOS:000166697600019 PM 11161282 ER PT J AU Glaser, VP Bodine, DM AF Glaser, VP Bodine, DM TI Investigator profile - David M. Bodine, Ph.D. SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Editorial Material C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD FEB PY 2001 VL 10 IS 1 BP 11 EP 15 PG 5 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 415UW UT WOS:000167742800003 PM 11276353 ER PT J AU Crow, M Taub, DD Cooper, S Broxmeyer, HE Sarris, AH AF Crow, M Taub, DD Cooper, S Broxmeyer, HE Sarris, AH TI Human recombinant interferon-inducible protein-10: Intact disulfide bridges are not required for inhibition of hematopoietic progenitors and chemotaxis of T lymphocytes and monocytes SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Article ID IN-VIVO; 3-DIMENSIONAL STRUCTURE; CHEMOKINE RECEPTORS; GEL ELECTROPHORESIS; SULFHYDRYL GROUPS; ESCHERICHIA-COLI; INTERLEUKIN-8; CELLS; IP-10; EXPRESSION AB Human recombinant interferon-inducible protein-10 (rIP-10), a C-X-C chemokine, inhibits proliferation of human hematopoietic progenitors responsive to co-stimulation by recombinant steel factor (rSLF), is chemotactic for human monocytes and T-lymphocytes, and promotes T-lymphocyte adhesion to endothelial cells. Because chemokines have four conserved cysteines forming two intramolecular disulfide bridges, we decided to investigate their contribution in the biological activity of rIP-10. Since amino acid residues 22-98 of the sequence predicted by the cDNA constitute the naturally occurring IP-10, they were cloned after an initiating methionine into expression vector pET-3d. Subsequently rIP-10 was purified by enzymatic cell lysis, solubilization of refractile bodies with guanidine hydrochloride, renaturation by dialysis against dilute acetic acid, and sequential ion-exchange and reverse-phase high-performance liquid chromatography. Purified rIP-10 was reduced with 20 mM dithiothreitol, and chemically modified with 100 mM iodoacetamide (IAA), or S-methyl-methanethiosulfonate (MMTS), or N-methylmaleimide (NMM). Radiolabeling experiments demonstrated that 95% of the rIP-10 thiols were modified, and this was confirmed with SDS-PAGE. The biological activity of modified rIP-10 was determined in vitro by inhibition of rSLF-responsive human bone marrow hematopoietic progenitor proliferation and by chemotaxis assays using human T-lymphocytes and monocytes. In both assay systems, the biological activity was evident at rIP-10 concentrations of 20-100 ng/ml. The activity was preserved after modification of rIP-10 by IAA or MMTS, but was abolished after modification by NMM. We conclude that disulfide bridges are not essential for the biological activity of rIP-10. C1 Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Immunol Microbiol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. RP Sarris, AH (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma Myeloma, 1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [R01 CA58655]; NHLBI NIH HHS [R01 HL56416] NR 41 TC 6 Z9 6 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD FEB PY 2001 VL 10 IS 1 BP 147 EP 156 DI 10.1089/152581601750098417 PG 10 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 415UW UT WOS:000167742800018 PM 11276368 ER PT J AU Jamur, MC Grodzki, ACG Moreno, AN de Mello, LD Pastor, MVD Berenstein, EH Siraganian, RP Oliver, C AF Jamur, MC Grodzki, ACG Moreno, AN de Mello, LD Pastor, MVD Berenstein, EH Siraganian, RP Oliver, C TI Identification and isolation of rat bone marrow-derived mast cells using the mast cell-specific monoclonal antibody AA4 SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE mast cells; gangliosides; maturation; bone marrow; immunochemistry; rat ID BASOPHILIC LEUKEMIA-CELLS; ALPHA-GALACTOSYL DERIVATIVES; DIFFERENTIATION; PERITONEAL; IGE; BINDING; PROGENITORS; MECHANISMS; MATURATION; RECEPTORS AB Previous studies of mast cell maturation, structure, and function have been hampered by the lack of mast cell-specific markers. In this study, using a well-characterized mast cell-specific monoclonal antibody, MAb AA4, mast cells from rat bone marrow in various stages of maturation were isolated and characterized. The very immature mast cells, which have not been previously described, contained few granules and would not be recognized as mast cells by standard cytological methods. Pure populations of mast cells were isolated from the bone marrow using MAb AA4-conjugated magnetic beads. The same stages of maturation were observed in the isolated mast cells as were seen in the unfractionated bone marrow. All of these cells were immunopositive for the alpha -subunit of Fc epsilon RI, IgE, and c-kit, confirming their identity as mast cells. By direct counting of immunolabled cells and by flow cytometry, approximately 2.4% of the cells in the bone marrow are mast cells. Staining with toluidine blue and berberine sulfate, as well as RT-PCR of the cells, indicates that these cells are connective tissue-type mast cells. The use of immunological methods for identification of mast cell precursors should facilitate the study of these cells. C1 Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Morfol, BR-14049900 Ribeirao Preto, SP, Brazil. Univ Fed Parana, Dept Biol Celular, BR-80060000 Curitiba, Parana, Brazil. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Oliver, C (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Morfol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. RI Jamur, Maria Celia/L-5520-2016 OI Jamur, Maria Celia/0000-0001-7065-8543 NR 47 TC 20 Z9 21 U1 0 U2 1 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD FEB PY 2001 VL 49 IS 2 BP 219 EP 228 PG 10 WC Cell Biology SC Cell Biology GA 397VF UT WOS:000166717900009 PM 11156690 ER PT J AU Segal, DM Weiner, GJ Weiner, LM AF Segal, DM Weiner, GJ Weiner, LM TI Introduction: bispecific antibodies SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Editorial Material ID CYTOTOXIC LYMPHOCYTES; ESCHERICHIA-COLI; DOMAINS; PROTEIN C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 16 TC 27 Z9 27 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 1 PY 2001 VL 248 IS 1-2 BP 1 EP 6 DI 10.1016/S0022-1759(00)00338-0 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 405ZA UT WOS:000167189400001 PM 11223064 ER PT J AU Wallace, PK Tsang, KY Goldstein, J Correale, P Jarry, TM Schlom, J Guyre, PM Ernstoff, MS Fanger, MW AF Wallace, PK Tsang, KY Goldstein, J Correale, P Jarry, TM Schlom, J Guyre, PM Ernstoff, MS Fanger, MW TI Exogenous antigen targeted to Fc gamma RI on myeloid cells is presented in association with MHC class I SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Fc receptor (CD64); prostate specific antigen; MHC class I; antigen presentation; cross-priming ID PROSTATE-SPECIFIC ANTIGEN; EPIDERMAL GROWTH-FACTOR; DENDRITIC CELLS; T-CELLS; MEDIATED ENDOCYTOSIS; CANCER; RECEPTOR; LYMPHOCYTES; EXPRESSION; TUMOR AB Vaccine therapy is attractive for prostate cancer patients because the tumor is slow growing (allowing time to augment host responses) and occurs in an older population less likely to tolerate more toxic treatments. We have constructed an expression vector based on a monoclonal antibody (mAb) that targets the high affinity receptor for IgG (Fc gamma RI, CD64) which is exclusively expressed on myeloid cells including dendritic cells (DC). The heavy chain of mAb H22 CH2 and CH3 domains were removed and replaced with the gene for prostate specific antigen (PSA). Using that vector, we have constructed and purified FPH22.PSA, a fusion protein that targets PSA to Fc gamma RI on antigen presenting cells (APC). This fusion protein has an apparent molecular mass of 80-83 kDa, binds to Fc gamma RI with high affinity and expresses PSA. We demonstrate that FPH22.PSA targeted PSA was internalized and processed by the human myeloid THP-I cell line resulting in presentation of MHC class I-associated PSA peptides and lysis of THP-1 by PSA-specific human CTL. Moreover, pretreatment of THP-I cells with antibodies to block either Fc gamma RI or MHC class I, blocked lysis indicating that targeting to Fc gamma RI results in presentation of exogenous antigen on MHC class I molecules. These data demonstrate that FPH22.PSA was processed in such a manner by the myeloid cell line to allow for presentation of immunodominant peptides in MHC class I molecules and suggests that uptake of antigen via Fc gamma RI results in cross-priming. (C) 2001 Elsevier Science BN. All rights reserved. C1 Dartmouth Med Sch, Dept Microbiol, Lebanon, NH 03756 USA. Medarex Inc, Annandale, NJ 08801 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20893 USA. Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03756 USA. Dartmouth Med Sch, Dept Med, Lebanon, NH 03756 USA. RP Wallace, PK (reprint author), Dartmouth Med Sch, Dept Microbiol, HB7556,1 Med Ctr Dr, Lebanon, NH 03756 USA. RI Correale, Pierpaolo/K-1640-2016 OI Correale, Pierpaolo/0000-0003-2154-6734 FU NCI NIH HHS [CA-23108]; NIAID NIH HHS [AI19053] NR 51 TC 44 Z9 46 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 1 PY 2001 VL 248 IS 1-2 BP 183 EP 194 DI 10.1016/S0022-1759(00)00351-3 PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 405ZA UT WOS:000167189400015 PM 11223078 ER PT J AU Le, YY Yazawa, H Gong, WH Yu, ZX Ferrans, VJ Murphy, PM Wang, JM AF Le, YY Yazawa, H Gong, WH Yu, ZX Ferrans, VJ Murphy, PM Wang, JM TI Cutting edge: The neurotoxic prion peptide fragment PrP106-126 is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MICROGLIAL CELLS; DISEASE; SCRAPIE; PRP; 7-TRANSMEMBRANE; IDENTIFICATION; ACTIVATION; PATHWAYS AB Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP106-126, was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes, The cell surface receptor(s) mediating the activity of PrP106-126 is unknown. In this study, we show that PrP106-126 is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP106-126, FPRL1 underwent a rapid internalization and, furthermore, PrP106-126 enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin, Thus, FPRL1 may act as a "pattern recognition" receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases. C1 NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, Bethesda, MD 20892 USA. RP Wang, JM (reprint author), NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 24 TC 98 Z9 107 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1448 EP 1451 PG 4 WC Immunology SC Immunology GA 396EE UT WOS:000166622700004 PM 11160182 ER PT J AU Derby, MA Alexander-Miller, MA Tse, R Berzofsky, JA AF Derby, MA Alexander-Miller, MA Tse, R Berzofsky, JA TI High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; RECOMBINANT VACCINIA VIRUS; ADOPTIVE-TRANSFER THERAPY; IN-VITRO; ENVELOPE GENE; TARGET-CELLS; CD8(+) CTL; IMMUNOTHERAPY; MELANOMA AB Previously, we observed that high-avidity CTL are much more effective in vivo than low-avidity CTL in elimination of infected cells, but the mechanisms behind their superior activity remained unclear. In this study, we identify two complementary mechanisms: 1) high-avidity CTL lyse infected cells earlier in the course of a viral infection by recognizing lower Ag densities than those distinguished by low-avidity CTL and 2) they initiate lysis of target cells more rapidly at any given Ag density. Alternative mechanisms were excluded, including: 1) the possibility that low-avidity CTL might control virus given more time (virus levels remained as high at 6 days following transfer as at 3 days) and 2) that differences in efficacy might be correlated with homing ability. Furthermore, adoptive transfer of high- and low-avidity CTL into SCID mice demonstrated that transfer of a 10-fold greater amount of low-avidity CTC could only partially compensate for their decreased ability to eliminate infected cells. Thus, we conclude that high-avidity CTL exploit two complementary mechanisms that combine to prevent the spread of virus within the animal: earlier recognition of infected cells when little viral protein has been made and more rapid lysis of infected cells. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 44 TC 154 Z9 158 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 FEB 1 PY 2001 VL 166 IS 3 BP 1690 EP 1697 PG 8 WC Immunology SC Immunology GA 396EE UT WOS:000166622700034 PM 11160212 ER PT J AU Melby, PC Chandrasekar, B Zhao, WG Coe, JE AF Melby, PC Chandrasekar, B Zhao, WG Coe, JE TI The hamster as a model of human visceral leishmaniasis: Progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; TRANSFORMING-GROWTH-FACTOR; ACUTE CHAGASIC CARDIOMYOPATHY; DEPENDENT KILLING MECHANISM; IFN-GAMMA; IMMUNE-RESPONSE; L-ARGININE; KALA-AZAR; IN-VIVO; ACTIVATED MACROPHAGES AB Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia. In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease. Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function. Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L. donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model. Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-gamma, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function. Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice. The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-beta. Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Dept Vet Affairs Med Ctr, Med Serv, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA. NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Melby, PC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 54 TC 150 Z9 153 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1912 EP 1920 PG 9 WC Immunology SC Immunology GA 396EE UT WOS:000166622700061 PM 11160239 ER PT J AU Khan, IA Murphy, PM Casciotti, L Schwartzman, JD Collins, J Gao, JL Yeaman, GR AF Khan, IA Murphy, PM Casciotti, L Schwartzman, JD Collins, J Gao, JL Yeaman, GR TI Mice lacking the chemokine receptor CCR1 show increased susceptibility to Toxoplasma gondii infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; PERIPHERAL-BLOOD NEUTROPHILS; CD8+ LYMPHOCYTES-T; NITRIC-OXIDE; INTERFERON-GAMMA; IFN-GAMMA; CHEMOTACTIC CYTOKINES; GENE-EXPRESSION; CELL RESPONSES; INTERLEUKIN-12 AB Chemokines are critical for the recruitment of effector immune cells to sites of infection. Mice lacking the chemokine receptor CCR1 have defects in neutrophil trafficking and proliferation. In the present study, we tested the susceptibility of CCR1 knockout mice to infection with the obligate intracellular protozoan parasite Toxoplasma gondii. In comparison with parental wild-type mice, CCR1(-/-) mice exhibited dramatically increased mortality to T. gondii in association with an increased tissue parasite load. No differences were observed in Ag-specific T cell proliferation or in cytokine responses between mutant and wild-type mice. However, the influx of PMNs to the peripheral blood and to the liver were reduced in CCR1(-/-) mice during early infection. Our results suggest that CCR1-dependent migration of neutrophils to the blood and tissues may have a significant impact in controlling parasite replication. C1 Dartmouth Coll, Sch Med, Dept Med, Lebanon, NH 03756 USA. Dartmouth Coll, Sch Med, Dept Microbiol, Lebanon, NH 03756 USA. Dartmouth Coll, Sch Med, Dept Pathol, Lebanon, NH 03756 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Khan, IA (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol, 1901 Perdido St, New Orleans, LA 70122 USA. FU NIAID NIH HHS [AI33325] NR 54 TC 56 Z9 62 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1930 EP 1937 PG 8 WC Immunology SC Immunology GA 396EE UT WOS:000166622700063 PM 11160241 ER PT J AU Zhou, P Freidag, BL Caldwell, CC Seder, RA AF Zhou, P Freidag, BL Caldwell, CC Seder, RA TI Perforin is required for primary immunity to Histoplasma capsulatum SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; IFN-GAMMA; LISTERIA-MONOCYTOGENES; PULMONARY HISTOPLASMOSIS; HOST-RESISTANCE; MICE LACKING; SCID MICE; TNF-ALPHA; INFECTION; CYTOTOXICITY AB Protective immunity against primary and secondary infection by the fungus Histoplasma capsulatum (HC) is multifactorial, requiring cells of the innate and adaptive immune response. Effector mechanisms that could mediate intracellular killing of HC include cytokines such as IFN-gamma and TNF-alpha and/or direct cytolytic activity by T and NK cells. In this regard, although previous work has clearly demonstrated a critical role for IFN-gamma and TNF-alpha in limiting fungal growth in primary HC infection, less is known regarding the role of cytolytic mechanisms. The studies reported here first address the role of perforin in mediating immunity to HC. Remarkably, perforin-deficient knockout (PfKO) mice were shown to have accelerated mortality and increased fungal burden following a lethal or sublethal primary challenge. These data established an essential role for perforin in primary immunity systemic HC infection. Interestingly, depletion of CD8(+) T cells in PfKO mice caused a further increase in fungal burden and accelerated mortality, suggesting a perforin-independent role for CD8(+) T cells. Moreover, adoptive transfer of CD8(+) T cells from PfKO mice into IFN-gamma (-/-) mice caused a reduction in fungal burden following infectious challenge compared with control IFN-gamma (-/-) mice. Together, these data suggest that CD8(+) T cells can mediate immunity to HC through both perforin-dependent and -independent mechanisms. C1 NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, 10 Ctr Dr,Room 10-11C215, Bethesda, MD 20892 USA. NR 25 TC 20 Z9 21 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1968 EP 1974 PG 7 WC Immunology SC Immunology GA 396EE UT WOS:000166622700067 PM 11160245 ER PT J AU Steinbrecher, A Reinhold, D Quigley, L Gado, A Tresser, N Izikson, L Born, I Faust, J Neubert, K Martin, R Ansorge, S Brocke, S AF Steinbrecher, A Reinhold, D Quigley, L Gado, A Tresser, N Izikson, L Born, I Faust, J Neubert, K Martin, R Ansorge, S Brocke, S TI Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; TRANSFORMING GROWTH FACTOR-BETA-1; T-CELL ACTIVATION; MULTIPLE-SCLEROSIS; IMMUNE-RESPONSES; ORAL TOLERANCE; FACTOR-BETA; DEMYELINATING DISEASES; CHEMOKINE REGULATION AB CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells, Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO2)]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE, I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-beta1 in spinal cord tissue and plasma during acute EAE, In vitro, while suppressing autoreactive T cell proliferation and TNF-alpha production, I40 consistently up-regulated TGF-beta1 secretion. A neutralizing anti-TGF-beta1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag, DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-beta1-mediated antiinflammatory effect at the site of pathology. C1 NINDS, Neurol Dis Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Magdeburg, Dept Internal Med, Inst Expt Internal Med, D-39106 Magdeburg, Germany. NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. Univ Halle Wittenberg, Dept Biochem & Biotechnol, Inst Biochem, Halle, Germany. RP Steinbrecher, A (reprint author), Univ Regensburg, Dept Neurol, Univ Str 84, D-93053 Regensburg, Germany. NR 58 TC 105 Z9 105 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 2041 EP 2048 PG 8 WC Immunology SC Immunology GA 396EE UT WOS:000166622700076 PM 11160254 ER PT J AU McFarland, HI Lobito, AA Johnson, MM Palardy, GR Yee, CSK Jordan, EK Frank, JA Tresser, N Genain, CP Mueller, JP Matis, LA Lenardo, MJ AF McFarland, HI Lobito, AA Johnson, MM Palardy, GR Yee, CSK Jordan, EK Frank, JA Tresser, N Genain, CP Mueller, JP Matis, LA Lenardo, MJ TI Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; PROTEOLIPID PROTEIN; T-CELLS; DEMYELINATING DISEASE; CEREBROSPINAL-FLUID; NONHUMAN PRIMATE; OLIGODENDROCYTE GLYCOPROTEIN; ALLERGIC ENCEPHALOMYELITIS; CALLITHRIX-JACCHUS AB Mature T cells initially respond to Ag by activation and expansion, but high and repeated doses of Ag cause programmed cell death and can suppress T cell-mediated diseases in rodents, We evaluated repeated systemic Ag administration In a marmoset model of experimental allergic encephalomyelitis that closely resembles the human disease multiple sclerosis, We found that treatment with MP4, a chimeric, recombinant polypeptide containing human myelin basic protein and human proteolipid protein epitopes, prevented clinical symptoms and did not exacerbate disease, CNS lesions were also reduced as assessed in vivo by magnetic resonance imaging, Thus, specific Ag-directed therapy can be effective and nontoxic in primates. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Diagnost Radiol Res, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Alexion Pharmaceut Inc, New Haven, CT 06511 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. RI McFarland, Hugh/K-1503-2016 OI McFarland, Hugh/0000-0002-3322-038X NR 43 TC 12 Z9 13 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 2116 EP 2121 PG 6 WC Immunology SC Immunology GA 396EE UT WOS:000166622700085 PM 11160263 ER PT J AU Tisch, R Wang, B Weaver, DJ Liu, S Bui, T Arthos, J Serreze, DV AF Tisch, R Wang, B Weaver, DJ Liu, S Bui, T Arthos, J Serreze, DV TI Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NONOBESE DIABETIC MICE; GLUTAMIC-ACID DECARBOXYLASE; NOD MICE; EXACERBATE DISEASE; GENE GUN; T-CELLS; MELLITUS; PREVENTS; IMMUNIZATION; INDUCTION AB In this study, we have investigated the use of plasmid DNA (pDNA) vaccination to elicit Th2 effector cell function in an Ag-specific manner and in turn prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. pDNA recombinants were engineered encoding a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4, Intramuscular injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented diabetes in NOD mice treated at early or late preclinical stages of IDDM, This protection was GAD65-specific since NOD mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop diabetes. Furthermore, disease prevention correlated with suppression of insulitis and induction of GAD65-specific regulatory Th2 cells. Importantly, GAD65-specific immune deviation was dependent on pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was significantly enhanced in animals immunized with pDNA encoding only GAD65-IgGFc, Finally, NOD.IL4(null) mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for disease prevention. These results demonstrate that pDNA vaccination is an effective strategy to elicit beta cell-specific Th2 regulatory cell function fur the purpose of preventing IDDM even at a late stage of disease development. C1 Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Tisch, R (reprint author), Univ N Carolina, Dept Microbiol & Immunol, Mary Ellen Jones Bldg,Room 804,Campus Box 7290, Chapel Hill, NC 27599 USA. FU NIAID NIH HHS [5P01 AI41580] NR 43 TC 88 Z9 91 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 2122 EP 2132 PG 11 WC Immunology SC Immunology GA 396EE UT WOS:000166622700086 PM 11160264 ER PT J AU Tanaka, Y Primi, D Wang, RYH Umemura, T Yeo, AET Mizokami, M Alter, HJ Shih, JWK AF Tanaka, Y Primi, D Wang, RYH Umemura, T Yeo, AET Mizokami, M Alter, HJ Shih, JWK TI Genomic and molecular evolutionary analysis of a newly identified infectious agent (SEN virus) and its relationship to the TT virus family SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID FEATHER DISEASE VIRUS; POSTTRANSFUSION HEPATITIS; NUCLEOTIDE-SEQUENCE; PORCINE CIRCOVIRUS; PLANT CIRCOVIRUSES; UNKNOWN ETIOLOGY; DNA; GENOTYPES; ISOLATE; REGIONS AB A new group of transmissible single-stranded (ss) DNA viruses (SENV) distantly related to the large TT virus (TTV) family was recently identified. Eight different SENV isolates have been found, some with an association with posttransfusion hepatitis. A phylogenetic analysis of near-complete open-reading frame 1, including conserved motifs and excluding recombinant regions, was performed. The analysis used TTV-like minivirus as an outgroup, to determine a root of the phylogenetic tree, and compared 8 SENV isolates, 6 prototype TTV isolates, and 7 TTV variants (including SANBAN, TUS01, PMV, and YONBAN). Four distinct clusters separated by a bootstrap value of 100% were observed. YONBAN isolates formed a distinct outer group, representing the earliest recognized phylogenetic divergence (group 1). Prototype TTV formed group 2, PMV formed group 3, and SENV, SANBAN, and TUS01 isolates formed group 4, the most recently evolved group. This taxonomic classification suggests that these circular ssDNA viruses probably evolved from a common ancestor virus. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Diasorin, Saluggia, Italy. Nagoya City Univ, Sch Med, Dept Med 2, Nagoya, Aichi 467, Japan. RP Shih, JWK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Rm 1C711, Bethesda, MD 20892 USA. NR 33 TC 130 Z9 160 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 359 EP 367 DI 10.1086/318091 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000001 PM 11133366 ER PT J AU Grene, E Pinto, LA Cohen, SS Trubey, CM Trivett, MT Simonis, TB Liewehr, DJ Steinberg, SM Shearer, GM AF Grene, E Pinto, LA Cohen, SS Trubey, CM Trivett, MT Simonis, TB Liewehr, DJ Steinberg, SM Shearer, GM TI Generation of alloantigen-stimulated anti-human immunodeficiency virus activity is associated with HLA-A*02 expression SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTION; HLA ANTIGENS; T-CELLS; AIDS; ALLOIMMUNIZATION; REPLICATION; TYPE-1; PROGRESSION; INHIBITION; CHEMOKINES AB Stimulation of peripheral blood mononuclear cells (PBMC) with allogeneic PBMC (ALLO) can result in activity that inhibits the replication of human immunodeficiency virus (HIV). The present study demonstrates that strong anti-HIV activity is dependent on expression of HLA-A*02 by the responding PBMC. Anti-HIV activity was equally effective against 2 primary isolates that use different coreceptors. Neither ALLO-stimulated cell proliferation nor cytokine and beta -chemokine production was associated with the expression of HLA-A*02. ALLO-stimulated production of strong anti-HIV activity required intact PBMC and was not inhibited by monoclonal antibodies directed against nonpolymorphic regions of human leukocyte antigens (HLAs). Anti-HIV activity was generated by ALLO-stimulated CD4(+) cells, CD8(+) T lymphocytes, and monocytes from HLA-A*02-positive patients. These findings provide the first evidence that the production of an HIV inhibitory factor or factors is associated with certain HLA genes and raise new possibilities concerning the role of the major histocompatibility complex in controlling viral infections via alloantigen stimulation. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Bethesda, MD 20892 USA. NCI, Dept Transfus Med, HLA Lab, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. FU PHS HHS [N01-C0-56000] NR 33 TC 12 Z9 12 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 409 EP 416 DI 10.1086/318085 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000007 PM 11133372 ER PT J AU El Sahly, HM Adams, GJ Soini, H Teeter, L Musser, JM Graviss, EA AF El Sahly, HM Adams, GJ Soini, H Teeter, L Musser, JM Graviss, EA TI Epidemiologic differences between United States- and foreign-born tuberculosis patients in Houston, Texas SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the Infectious-Diseases-Society-of-America CY NOV 18-21, 1999 CL PHILADELPHIA, PENNSYLVANIA SP Infect Dis Soc Amer ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEW-YORK-CITY; FRAGMENT-LENGTH-POLYMORPHISM; LABORATORY CROSS-CONTAMINATION; MYCOBACTERIUM-TUBERCULOSIS; SAN-FRANCISCO; STRAIN DIFFERENTIATION; MOLECULAR EPIDEMIOLOGY; COMPLEX STRAINS; TRANSMISSION AB The proportion of foreign-born tuberculosis patients in the United States is increasing. To analyze the epidemiology of tuberculosis in foreign-born people, culture-positive patients with tuberculosis in Houston, Texas, were interviewed from October 1995 through September 1998, and their isolates were molecularly characterized. Of the 1131 patients included in the study, 795 (70.3%) were US born and 336 (29.7%) were foreign born. The decrease in tuberculosis case rate among US-born people was 3.5 times that of foreign-born people. Significantly more US-born than foreign-born patients belonged to strain clusters (71.3% vs. 29.5%; P < .001). Risk factors associated with strain clustering were as follows: black ethnicity, low income, and homelessness in US-born patients and homelessness in foreign-born patients. Isolates from foreign-born patients were more likely to be resistant to 1 drug (15.4% vs. 8.4%;) P = .001 and to be multidrug resistant (2.4% vs. 0.7%; P = .027) than isolates from US-born patients. These observations warrant increased emphasis on this distinct subpopulation of tuberculosis patients. C1 Baylor Coll Med, Dept Pathol 209 E, Div Infect Dis, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Div Infect Dis, Houston, TX 77030 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Graviss, EA (reprint author), Baylor Coll Med, Dept Pathol 209 E, Div Infect Dis, 1 Baylor Plaza, Houston, TX 77030 USA. FU NIDA NIH HHS [DA-09238] NR 41 TC 36 Z9 36 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 461 EP 468 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000013 PM 11133378 ER PT J AU Henry, NL Law, M Nutman, TB Klion, AD AF Henry, NL Law, M Nutman, TB Klion, AD TI Onchocerciasis in a nonendemic population: Clinical and immunologic assessment before treatment and at the time of presumed cure SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY OCT, 2000 CL HOUSTON, TEXAS SP Amer Soc Trop Med & Hyg ID MEDIATED IMMUNE-RESPONSES; IVERMECTIN; PARASITE; VOLVULUS; RESPONSIVENESS; INFECTION AB Although suppressive therapy for onchocerciasis with intermittent ivermectin prevents the development of pathology in endemic populations, the clinical and immunologic effects of therapy in the absence of continued exposure are unknown. To address this question, 14 patients treated with ivermectin for onchocerciasis acquired >10 years ago during temporary residence in Africa were reevaluated. None had evidence of continued infection or pathology at follow-up. Although eosinophilia, serum IgE, and antifilarial antibody levels decreased after ivermectin therapy, none of these parameters was useful in predicting the resolution of symptoms in infected patients. Peripheral blood mononuclear cells isolated from patients at follow-up were more responsive to parasite antigen in vitro, which is as assessed by proliferation and production of interferon-gamma and interleukin (IL)-5. In contrast, antigen-induced levels of IL-10 were significantly decreased at follow-up, consistent with diminished down-regulatory factors rather than a switch from type 2 to type 1 immune responses. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIH, Parasit Dis Lab, Bldg 4,Rm 126, Bethesda, MD 20892 USA. OI Klion, Amy/0000-0002-4986-5326 NR 14 TC 21 Z9 21 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 512 EP 516 DI 10.1086/318088 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000021 PM 11133386 ER PT J AU Roilides, E Sein, T Roden, M Schaufele, RL Walsh, TJ AF Roilides, E Sein, T Roden, M Schaufele, RL Walsh, TJ TI Elevated serum concentrations of interleukin-10 in nonneutropenic patients with invasive aspergillosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID FUMIGATUS; CYTOKINE C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Dept Pediat 3, GR-54006 Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 10 TC 48 Z9 52 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 518 EP 520 DI 10.1086/318077 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000023 PM 11133388 ER PT J AU Aurelian, L Smith, CC Winchurch, R Kulka, M Gyotoku, T Zaccaro, L Chrest, FJ Burnett, JW AF Aurelian, L Smith, CC Winchurch, R Kulka, M Gyotoku, T Zaccaro, L Chrest, FJ Burnett, JW TI A novel gene expressed in human keratinocytes with long-term in vitro growth potential is required for cell growth SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE cell adhesion proteins; epidermis; HSV-2; RR1 PK; stem cells ID HERPES-SIMPLEX-VIRUS; RIBONUCLEOTIDE REDUCTASE ICP10; PROTEIN-KINASE ACTIVITY; HUMAN EPIDERMAL-KERATINOCYTES; TRANSIT AMPLIFYING CELLS; EARLY MESSENGER RNA-4; LARGE SUBUNIT; STEM-CELLS; IN-VITRO; ANTISENSE OLIGONUCLEOTIDES AB The herpes simplex virus large subunit of ribonucleotide reductase differs from its counterparts in eukaryotic and prokaryotic cells and in other viruses in that it contains a unique domain that codes for a distinct serine-threonine protein kinase that activates the Ras/MEK/MAPK mitogenic pathway and is required for virus growth. Previous studies suggested that ribonucleotide reductase protein kinase was co-opted from a cellular gene. Cellular genes similar to ribonucleotide reductase protein kinase were not cloned, however, and their function is unknown. Here we report that a novel gene (H11) that codes for a protein similar to herpes simplex virus 2 ribonucleotide reductase protein kinase, is expressed in skin tissues, cultured keratinocytes, and the keratinocyte cell line A431. The protein is phosphorylated and it associates with the plasma membrane. H11 is expressed in keratinocytes with long-term in vitro growth potential and is coexpressed with high levels of adhesion molecules involved in signal transduction, such as beta1 integrin. Antisense oligonucleotides that inhibit H11 expression inhibit DNA synthesis and keratinocyte proliferation, suggesting that H11 expression is required for cell growth. C1 Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Dermatol, Baltimore, MD 21201 USA. Johns Hopkins Med Inst, Dept Surg, Baltimore, MD 21205 USA. Univ Pisa, Dept Biomed, Retrovirus Ctr, Pisa, Italy. Univ Pisa, Dept Biomed, Virol Sect, Pisa, Italy. Univ Pisa, Dept Biomed, Pisa, Italy. NIA, Gerontol Res Ctr, Flow Cytometry Unit, Res Resources Branch, Baltimore, MD 21224 USA. RP Aurelian, L (reprint author), Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. FU NCI NIH HHS [CA75453] NR 75 TC 21 Z9 21 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2001 VL 116 IS 2 BP 286 EP 295 DI 10.1046/j.1523-1747.2001.00191.x PG 10 WC Dermatology SC Dermatology GA 405QN UT WOS:000167170700013 PM 11180006 ER PT J AU Egan, CA Reddy, ED Nie, ZX Taylor, TB Schmidt, LA Meyer, LJ Petersen, MJ Hashimoto, T Marinkovich, MP Zone, JJ AF Egan, CA Reddy, ED Nie, ZX Taylor, TB Schmidt, LA Meyer, LJ Petersen, MJ Hashimoto, T Marinkovich, MP Zone, JJ TI IgG anti-LABD97 antibodies in bullous pemphigoid patients' sera react with the mid-portion of the BPAg2 ectodomain SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID AFFINITY PURIFICATION; SKIN DISEASES; AUTOANTIBODIES; BP180; IDENTIFICATION; PROTEIN; ANTIGEN; DOMAIN; BLOTS C1 Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. Stanford Univ, Dept Dermatol, Stanford, CA 94305 USA. Kurume Univ, Sch Med, Dept Dermatol, Fukuoka, Japan. Salt Lake City Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Med Serv, Dermatol Sect, Salt Lake City, UT USA. RP Egan, CA (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [R01 DK50678-01A1] NR 15 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2001 VL 116 IS 2 BP 348 EP 350 DI 10.1046/j.1523-1747.2001.01246.x PG 3 WC Dermatology SC Dermatology GA 405QN UT WOS:000167170700021 PM 11180014 ER PT J AU Geiszt, M Kapus, A Ligeti, E AF Geiszt, M Kapus, A Ligeti, E TI Chronic granulomatous disease: more than the lack of superoxide? SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE neutrophils; NADPH oxidase; proton channel; calcium; membrane potential ID PHORBOL 12-MYRISTATE 13-ACETATE; CAPACITATIVE CALCIUM-ENTRY; NADPH OXIDASE; HUMAN-NEUTROPHILS; PLASMA-MEMBRANE; H+ CONDUCTANCE; ELECTRON CURRENTS; CA2+ INFLUX; ACTIVATION; PATHWAY AB Chronic granulomatous disease (CGD) is an inherited disease characterized by severe and recurrent bacterial and fungal infections manifested in most cases in early childhood, Phagocytic cells of CGD patients are unable to produce superoxide anions, and their efficiency in bacterial killing is significantly impaired, Recent work has shown alterations in the electrophysiological properties of CGD granulocytes, which might contribute to the pathogenesis of the disease, The new aspects that we discuss in this review concern the proton channel function of gp91(phox) (the electron-transporting subunit of the NADPH oxidase) and the electrogenic activity of the active enzyme complex, which can affect the transmembrane trafficking of several ions. Based on the reviewed data, we also propose a hypothesis that the absence of a functional NADPH oxidase in CGD neutrophils could result in altered ion compositions within intracellular and intraphagosomal spaces during the process of phagocytosis. C1 Semmelweis Univ, Dept Physiol, H-1444 Budapest, Hungary. RP Geiszt, M (reprint author), NIH, Bldg 10,Rm 11N106, Bethesda, MD 20892 USA. EM mgeiszt@nih.gov NR 49 TC 48 Z9 49 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2001 VL 69 IS 2 BP 191 EP 196 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 400UG UT WOS:000166889600002 PM 11272268 ER PT J AU Liang, TS Hartt, JK Lu, S Martins-Green, M Gao, JL Murphy, PM AF Liang, TS Hartt, JK Lu, S Martins-Green, M Gao, JL Murphy, PM TI Cloning, mRNA distribution, and functional expression of an avian counterpart of the chemokine receptor/HIV coreceptor CXCR4 SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE G protein-coupled receptor; SDF-1; inflammation; evolution; development; signal transduction ID TROUT ONCORHYNCHUS-MYKISS; GROWTH-STIMULATING FACTOR; MOLECULAR-CLONING; EMBRYONIC EXPRESSION; INNATE IMMUNITY; HIV-1 ENTRY; FACTOR-I; HEMATOPOIESIS; DISEASE; HOMOLOG AB The chemokine signaling system, which coordinates the basal and emergency trafficking of leukocytes, presumably coevolved with the hematopoietic system, To study its phylogenetic origins, we used the open reading frame (ORF) of the human chemokine receptor CXCR4 as a genomic probe, since in mammals it is the most highly conserved chemokine receptor known, CXCR4 cross-hybridized to genomic DNA from mouse and chicken, but not zebrafish, Drosophila, or Caenorhabditis elegans. Accordingly, we cloned the corresponding chicken cDNA. The ORF is 359 codons long versus 352 for human CXCR4, and encodes a protein 82% identical to human CXCR4. In a calcium flux assay of receptor function, CHO-K1 cells stably transfected with the chicken cDNA responded specifically to human SDF-1, the specific ligand for CXCR4, but not to a panel of other chemokines tested at 100 nM. SDF-1 activated the cells in a dose-dependent manner (EC50 similar to5 nM), whereas parental CHO-K1 cells did not respond, The CHO-K1 cell transfectants also bound I-125-SDF-1 specifically. Leukocytes from chicken peripheral blood expressed chCXCR4 mRNA and responded to human SDF-1 in a calcium flux assay with an EC50 similar to that for chCXCR4-transfected CHO cells, suggesting that this response is mediated by native chCXCR4. Analysis of chicken genomic DNA with the chicken cDNA as probe revealed a pattern consistent with a single copy gene, and the absence of any closely related genes. mRNA was detected in brain, bursa, liver, small and large intestine, embryonal fibroblasts, and blood leukocytes, but not in stomach or pancreas, These results, which identify the first functional non-viral, non-mammalian chemokine receptor, suggest that the origins of a functional chemokine system extend at least to birds and suggest that, as in mammals, CXCR4 functions in many avian tissues. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. RP Murphy, PM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 37 TC 12 Z9 12 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2001 VL 69 IS 2 BP 297 EP 305 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 400UG UT WOS:000166889600015 PM 11272281 ER PT J AU Lee, MH Hazard, S Carpten, JD Yi, S Cohen, Y Gerhardt, GT Salen, G Patel, SB AF Lee, MH Hazard, S Carpten, JD Yi, S Cohen, Y Gerhardt, GT Salen, G Patel, SB TI Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in US pedigrees SO JOURNAL OF LIPID RESEARCH LA English DT Article DE genetics; cholesterol; cholestanol; bile acids ID STEROL 27-HYDROXYLASE GENE; ACID BIOSYNTHETIC ENZYME; PREMATURE TERMINATION CODON; MOLECULAR-GENETICS; MITOCHONDRIAL CYTOCHROME-P-450; ADRENODOXIN BINDING; LIVER-MITOCHONDRIA; JAPANESE PATIENTS; CHRONIC DIARRHEA; BILE-ACIDS C1 Med Univ S Carolina, Div Endocrinol, Charleston, SC 29403 USA. Med Univ S Carolina, Coll Dent Med, Charleston, SC 29403 USA. NHGRI, Prostate Canc Invest Grp Lab Canc Genet, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75235 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Vet Affairs Med Ctr, New Jersey Healthcare Syst, Newark, NJ 07103 USA. RP Patel, SB (reprint author), Med Univ S Carolina, Div Endocrinol, Strom Thurmond Bldg,Room 541,114 Doughty St, Charleston, SC 29403 USA. OI Patel, Shailendra/0000-0003-0046-5513 FU NCRR NIH HHS [M01 RR001070, MO1 RR01070-25, S10 RR015928]; NHLBI NIH HHS [HL53917, HL60613, R01 HL060613] NR 56 TC 44 Z9 46 U1 0 U2 1 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2001 VL 42 IS 2 BP 159 EP 169 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 407FG UT WOS:000167261100001 PM 11181744 ER PT J AU Stratakis, CA Taymans, SE Schteingart, D Haddad, BR AF Stratakis, CA Taymans, SE Schteingart, D Haddad, BR TI Segmental uniparental isodisomy (UPD) for 2p16 without clinical symptoms: implications for UPD and other genetic studies of chromosome 2 SO JOURNAL OF MEDICAL GENETICS LA English DT Letter ID CONFINED PLACENTAL MOSAICISM; INTRAUTERINE GROWTH RESTRICTION; IN-SITU HYBRIDIZATION; MATERNAL ISODISOMY; CARNEY COMPLEX; SHORT ARM; PATERNAL ISODISOMY; DISOMY; DUPLICATION; PHENOTYPE C1 Natl Inst Child Hlth & Human Dev, Unite Genet & Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Dept Internal Med Endocrinol & Metab, Ann Arbor, MI 48109 USA. RP Stratakis, CA (reprint author), Natl Inst Child Hlth & Human Dev, Unite Genet & Endocrinol, Dev Endocrinol Branch, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 38 TC 12 Z9 12 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2001 VL 38 IS 2 BP 106 EP 109 DI 10.1136/jmg.38.2.106 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 401GC UT WOS:000166919000006 PM 11288708 ER PT J AU Zouboulis, CC Stratakis, CA Gollnick, HPM Orfanos, CE AF Zouboulis, CC Stratakis, CA Gollnick, HPM Orfanos, CE TI Keratosis pilaris/ulerythema ophryogenes and 18p deletion: is it possible that the LAMA1 gene is involved? SO JOURNAL OF MEDICAL GENETICS LA English DT Letter ID ULERYTHEMA-OPHRYOGENES; HUMAN LAMININ; TRANSLOCATION; EXPRESSION; PILARIS; GLAND; CHAIN C1 NICHHD, Dev Endocrinol Branch, Unit Genet & Endocrinol, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Dev Endocrinol Branch, Unit Genet & Endocrinol, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. RI Dr. Zouboulis, Christos/I-4493-2013 OI Dr. Zouboulis, Christos/0000-0003-1646-2608 NR 11 TC 15 Z9 16 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2001 VL 38 IS 2 BP 127 EP 128 DI 10.1136/jmg.38.2.127 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 401GC UT WOS:000166919000012 PM 11288714 ER PT J AU Kim, YC Brown, SG Harden, TK Boyer, JL Dubyak, G King, BF Burnstock, G Jacobson, KA AF Kim, YC Brown, SG Harden, TK Boyer, JL Dubyak, G King, BF Burnstock, G Jacobson, KA TI Structure-activity relationships of pyridoxal phosphate derivatives as potent and selective antagonists of P2X(1) receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE-C; FUNCTIONAL-CHARACTERIZATION; PHARMACOLOGICAL-PROPERTIES; NUCLEOTIDE RECEPTORS; MEDIATED RESPONSES; ADENYLYL-CYCLASE; VAS-DEFERENS; PPADS; ATP; CLONING AB Novel analogues of the P2 receptor antagonist pyridoxal-5'-phosphate 6-azophcnyl-2',5'-disulfonate (2) were synthesized and studied as antagonists in functional assays at recombinant rat P2X(1), P2X(2), and P2X(3) receptors expressed in Xenopus oocytes lion flux stimulation) and at turkey erythrocyte P2Y(1) receptors (phospholipase C activation). Selected compounds were also evaluated as antagonists of ion flux and the opening of a large pore at the recombinant human P2X(7) receptor. Modifications were made in the 4-aldehyde and 5'-phosphate groups of the pyridoxal moiety: i.e. a CH2OH group at the 4-position in pyridoxine was either condensed as a cyclic phosphate or phosphorylated separately to form a bisphosphate, which reduced potency at P2 receptors. 5-Methylphosphonate substitution, anticipated to increase stability to hydrolysis, preserved P2 receptor potency. At the g-position, halo, carboxylate, sulfonate, and phosphonate variations made on the phenylazo ring modulated potency at P2 receptors. The p-carboxyphenylazo analogue, 4, of phosphate 2 displayed an IC50 value of 9 nM at recombinant P2X(1) receptors and was 1300-, 16-, and >10000-fold selective for P2X(1) versus P2X(2), P2X(3), and P2Y(1) subtypes, respectively. The corresponding Ei-methylphosphonate was equipotent at P2X(1) receptors. The 5-methylphosphonate analogue containing a 6-[3,5-bis(methylphosphonate)]phenylazo moiety, 9, had IC50 values of 11 and 25 nM at recombinant P2X(1) and P2X(3) receptors, respectively. The analogue containing a phenylazo 4-phosphonate group, 11, was also very potent at both P2X(1) and P2X(3) receptors. However, the corresponding 2,5-disulfonate analogue, 10, was 28-fold selective for P2X(1) versus P2X(3) receptors. None of the analogues were more potent at P2X(7) and P2Y(1) receptors than 2, which acted in the micromolar range at these two subtypes. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. UCL Royal Free & Univ Col Med Sch, Autonom Neurosci Inst, London NW3 2PF, England. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. RP Jacobson, KA (reprint author), NIDDK, MRS, LBC, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [HL34322, HL54889]; NIGMS NIH HHS [GM38213] NR 43 TC 73 Z9 74 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 1 PY 2001 VL 44 IS 3 BP 340 EP 349 DI 10.1021/jm9904203 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 397MP UT WOS:000166699700007 PM 11462975 ER PT J AU Mu, FR Coffing, SL Riese, DJ Geahlen, RL Verdier-Pinard, P Hamel, E Johnson, J Cushman, M AF Mu, FR Coffing, SL Riese, DJ Geahlen, RL Verdier-Pinard, P Hamel, E Johnson, J Cushman, M TI Design, synthesis, and biological evaluation of a series of lavendustin A analogues that inhibit EGFR and Syk tyrosine kinases, as well as tubulin polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; DRUG DISCOVERY SCREEN; SOLID-PHASE SYNTHESIS; IN-VITRO; ANTIMITOTIC AGENTS; CELL-LINE; POTENT; IDENTIFICATION; CYTOTOXICITY; PICEATANNOL AB A series of N-alkylamide analogues of the lavendustin A pharmacophore were synthesized and tested for inhibition of the epidermal growth factor receptor (EGFR) protein tyrosine kinase and the nonreceptor protein tyrosine kinase Syk. Although several compounds in the series were effective inhibitors of both kinases, it seemed questionable whether their inhibitory effects on these kinases were responsible for the cytotoxic properties observed in a variety of human cancer cell cultures. Accordingly, a COMPARE analysis of the cytotoxicity profile of the most cytotoxic member of the series was performed, and the results indicated that its cytotoxicity profile was similar to that of antitubulin agents. This mechanism of action was supported by demonstrating that most compounds in the series were moderately effective as inhibitors of tubulin polymerization. This suggests that the lavendustin A analogues reported here, as well as some of the previously reported lavendustin A analogues, may be acting as cytotoxic agents by a mechanism involving the inhibition of tubulin polymerization. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Frederick Canc Res & Dev Ctr, Screening Technol Branch, Dev Therapeut Program,Div Canc Treatment & Diagno, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, NIH, Rockville, MD 20852 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. OI Geahlen, Robert/0000-0001-8400-2924; Verdier-Pinard, Pascal/0000-0002-6149-6578 FU NCI NIH HHS [CA37372, CA80770] NR 44 TC 40 Z9 42 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 1 PY 2001 VL 44 IS 3 BP 441 EP 452 DI 10.1021/jm000387g PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 397MP UT WOS:000166699700015 PM 11462983 ER PT J AU Duan, WZ Lee, JW Guo, ZH Mattson, MP AF Duan, WZ Lee, JW Guo, ZH Mattson, MP TI Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE apoptosis; BDNF; caloric restriction; cerebral cortex; epileptic seizures; glutamate ID FIBROBLAST-GROWTH-FACTOR; NT-3 MESSENGER-RNAS; NEUROTROPHIC FACTOR; HIPPOCAMPAL-NEURONS; FOOD RESTRICTION; OXIDATIVE STRESS; CALORIC RESTRICTION; RAT-BRAIN; PHOSPHATIDYLINOSITOL 3-KINASE; CEREBRAL-ISCHEMIA AB Dietary restriction (DR) increases the lifespan of rodents and increases their resistance to several different age-related diseases including cancer and diabetes. Beneficial effects of DR on brain plasticity and neuronal vulnerability to injury have recently been reported, but the underlying mechanisms are unknown. We report that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex, and striatum of rats maintained on a DR regimen compared to animals fed ad libitum (AL). Seizure-induced damage to hippocampal neurons was significantly reduced in rats maintained on DR, and this beneficial effect was attenuated by intraventricular administration of a BDNF-blocking antibody. These findings provide the first evidence that diet can effect expression of a neurotrophic factor, demonstrate that BDNF signaling plays a central role in the neuroprotective effect of DR, and proffer DR as an approach for reducing neuronal damage in neurodegenerative disorders. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Dept Anat & Neurobiol, 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 Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 NR 51 TC 109 Z9 109 U1 2 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB PY 2001 VL 16 IS 1 BP 1 EP 12 DI 10.1385/JMN:16:1:1 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429NW UT WOS:000168524700001 PM 11345515 ER PT J AU Bokesch, HR Pannell, LK Cochran, PK Sowder, RC McKee, TC Boyd, MR AF Bokesch, HR Pannell, LK Cochran, PK Sowder, RC McKee, TC Boyd, MR TI A novel anti-HIV macrocyclic peptide from Palicourea condensata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID CHASSALIA-PARVIFOLIA; POLYPEPTIDES AB A 37 amino acid cyclic polypeptide has been isolated from the organic extract of the tropical tree Palicourea condensata. Palicourein (1) is the largest of a growing family of plant peptides that contain a cyclized amino acid backbone cross-linked via three internal disulfide bridges. Palicourein inhibits the in vitro cytopathic effects of HIV-1(RF) infection of CEM-SS cells with an EC50 value of 0.1 muM and an IC50 value of 1.5 muM. C1 NCI, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick, MD 21702 USA. SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 16 TC 94 Z9 100 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2001 VL 64 IS 2 BP 249 EP 250 DI 10.1021/np000372l PG 2 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 407DR UT WOS:000167257100027 PM 11430013 ER PT J AU Yang, SS Cragg, GM Newman, DJ Bader, JP AF Yang, SS Cragg, GM Newman, DJ Bader, JP TI Natural product-based anti-HIV drug discovery and development facilitated by the NCI developmental therapeutics program SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; HIGH-LEVEL RESISTANCE; AIDS-RELATED COMPLEX; CALANOLIDE-A; OXATHIIN CARBOXANILIDE; CALOPHYLLUM-LANIGERUM; INACTIVATING PROTEIN; MACROCYCLIC PEPTIDES; ANTIVIRAL ACTIVITY AB During the decade 1987-1996, the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) provided infrastructure support for both intramural and extramural anti-HIV (human immunodeficiency virus) drug discovery research and development. This retrospective review describes some of the anti-HIV lead discovery and development that took place under DTP auspices or which was substantially facilitated by resources made available through the DTP. Examples highlighted include leads identified through the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts, and these are classified according to the mechanism of action targeting the critical steps within the replication cycle of HIV. C1 NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Yang, SS (reprint author), NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NR 102 TC 65 Z9 68 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2001 VL 64 IS 2 BP 265 EP 277 DI 10.1021/np0003995 PG 13 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 407DR UT WOS:000167257100033 PM 11430019 ER PT J AU Li, BS Daniels, MP Pant, HC AF Li, BS Daniels, MP Pant, HC TI Integrins stimulate phosphorylation of neurofilament NF-M subunit KSP repeats through activation of extracellular regulated-kinases (Erk1/Erk2) in cultured motoneurons and transfected NIH 3T3 cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE fibronectin; integrin; laminin; MAPK; motoneuron; neurofilament ID PROTEIN-KINASES; SIGNAL-TRANSDUCTION; NEURITE OUTGROWTH; PERIPHERAL-NERVE; SPINAL-CORD; MAMMALIAN NEUROFILAMENTS; ADHESION MOLECULES; AXONAL-TRANSPORT; GROWTH-FACTOR; TAIL DOMAIN AB Integrin-mediated interactions of cells with components of the extracellular matrix (ECM) regulate cell survival, cell proliferation, cell differentiation and cell migration through activation of multiple intracellular signal transduction pathways. In this study, we have demonstrated that integrin-matrix interactions promote KSP tail-domain phosphorylation of neurofilament medium molecular weight subunits (NF-M)in cultured rat spinal cord motoneurons and NF-M transfected NIH 3T3 cells. We found that laminin and fibronectin induce NF-M tail-domain phosphorylation in motoneurons and NIH 3T3 cells transfected with NF-M, respectively. This phosphorylation was selectively inhibited by PD98059, a specific MEK1 inhibitor. This suggests that laminin and fibronectin-induced MEK1 activation and the downstream targets Erk1 and Erk2 are involved in NF-M KSP tail-domain phosphorylation. This pathway appears to represent one of the mechanisms whereby integrin-extracellular matrix interactions are involved in phosphorylation of the NF-M KSP tail domain. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D20,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 59 TC 12 Z9 12 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 3 BP 703 EP 710 DI 10.1046/j.1471-4159.2001.00064.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 397UG UT WOS:000166715300007 PM 11158240 ER PT J AU Imam, SZ Newport, GD Itzhak, Y Cadet, JL Islam, F Slikker, W Ali, SF AF Imam, SZ Newport, GD Itzhak, Y Cadet, JL Islam, F Slikker, W Ali, SF TI Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE copper zinc superoxide dismutase; dopamine; methamphetamine; neurotoxicity; nitric oxide synthase; peroxynitrite ID TRANSGENIC MICE; 7-NITROINDAZOLE; INHIBITOR; PROTECTS; RELEASE; BRAIN; DRUGS AB The use of methamphetamine (METH) leads to neurotoxic effects in mammals. These neurotoxic effects appear to be related to the production of free radicals. To assess the role of peroxynitrite in METH-induced dopaminergic, we investigated the production of 3-nitrotyrosine (3-NT) in the mouse striatum. The revels of 3-NT increased in the striatum of wild-type mice treated with multiple doses of METH (4 x 10 mg/kg, 2 h interval) as compared with the controls. However, no significant production or 3-NT was observed either in the striata of neuronal nitric oxide synthase knockout mice (nNOS -/-) or copper-zinc superoxide dismutase overexpressed transgenic mice (SOD-Tg) treated with similar doses of METH. The dopaminergic damage induced by METH treatment was also attenuated in nNOS-/- or SOD-TS mice. These data further confirm that METH causes its neurotoxic effects via the production of peroxynitrite. C1 US FDA, Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, Jefferson, AR 72079 USA. Hamdard Univ, Neurotoxicol Lab, Dept Med Elementol & Toxicol, New Delhi, India. Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. NIDA, Mol Neurosci Sect, Intramural Res Program, Baltimore, MD USA. RP Ali, SF (reprint author), US FDA, Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. NR 20 TC 82 Z9 85 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 3 BP 745 EP 749 DI 10.1046/j.1471-4159.2001.00029.x PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 397UG UT WOS:000166715300012 PM 11158245 ER PT J AU Barger, SW Basile, AS AF Barger, SW Basile, AS TI Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; glutamate; microglia; nitric oxide; synapse; xc exchange ID NECROSIS-FACTOR-ALPHA; NEURONAL CELL-LINE; ALZHEIMERS-DISEASE; NITRIC-OXIDE; TRANSGENIC MICE; OXIDATIVE STRESS; SENILE PLAQUES; HIPPOCAMPAL-NEURONS; DECREASED LEVELS; FREE-RADICALS AB Microglial activation as part of a chronic inflammatory response is a prominent component of Alzheimer's disease. Secreted forms of the P-amyloid precursor protein (sAPP) previously were found to activate microglia, elevating their neurotoxic potential. To explore neurotoxic mechanisms, we analyzed microglia-conditioned medium for agents that could activate glutamate receptors. Conditioned medium from primary rat microglia activated by sAPP caused a calcium elevation in hippocampal neurons, whereas medium from untreated microglia did not. This response was sensitive to the NMDA receptor antagonist, aminophosphonovaleric acid. Analysis of microglia-conditioned by HPLC revealed dramatically higher concentrations of glutamate in cultures exposed to sAPP. Indeed, the glutamate levels in sAPP-treated cultures were substantially higher than those in cultures treated with amyloid p-peptide. This sAPP-evoked glutamate release was completely blocked by inhibition of the cystineglutamate antiporter by alpha -aminoadipate or use of cystine-free medium. Furthermore, a sublethal concentration of sAPP compromised synaptic density in microglia-neuron cocultures, as evidenced by neuronal connectivity assay. Finally, the neurotoxicity evoked by sAPP in microglia-neuron cocultures was attenuated by inhibitors of either the neuronal nitric oxide synthase (N-G-propyl-L-arginine)or inducible nitric oxide synthase (1400 W). Together, these data indicate a scenario by which microglia activated by sAPP release excitotoxic levels of glutamate, probably as a consequence of autoprotective antioxidant glutathione production within the microglia, ultimately causing synaptic degeneration and neuronal death. C1 Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Anat, Little Rock, AR 72205 USA. Cent Arkansas Vet Healthcare Syst, Ctr Geriatr Res Educ & Clin, Little Rock, AR USA. NIDDK, Neurosci Lab, Bethesda, MD 20892 USA. RP Barger, SW (reprint author), Univ Arkansas Med Sci, Dept Geriatr, Slot 807,629 S Elm St, Little Rock, AR 72205 USA. FU NIA NIH HHS [2P01AG12411-04A10003] NR 56 TC 155 Z9 162 U1 2 U2 9 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 3 BP 846 EP 854 DI 10.1046/j.1471-4159.2001.00075.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 397UG UT WOS:000166715300023 PM 11158256 ER PT J AU Jaffe, H Sharma, P Grant, P Pant, HC AF Jaffe, H Sharma, P Grant, P Pant, HC TI Characterization of the phosphorylation sites of the squid (Loligo pealei) high-molecular-weight neurofilament protein from giant axon axoplasm SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE kinases; mass spectrometry; neurofilament; phosphorylation; squid ID TANDEM MASS-SPECTROMETRY; CASEIN KINASE-I; STELLATE GANGLION; INTERMEDIATE-FILAMENTS; S-ETHYLCYSTEINE; SCIATIC-NERVE; FIBER SYSTEM; TAIL DOMAIN; NF-H; SUBUNIT AB Axonal caliber in vertebrates is attributed, in part, to the extensive phosphorylation of NFM and NFH C-terminal tail domain KSP repeats by proline-directed kinases. The squid giant axon, primarily involved in rapid impulse conduction during jet propulsion motility, is enriched in squid-specific neurofilaments, particularly the highly phosphorylated NF-220. Of the 228 serine-threonine candidate phosphate acceptor sites in the NF-220 tail domain (residues 401-1220), 82 are found in numerous repeats of three different motifs SAR/K, SEK/R, K/RSP, with 62 of these tightly clustered in the C-terminal repeat segment (residues 840-1160). Characterization of the in vivo NF-220 phosphorylated sites should provide clues as to the relevant kinases. To characterize these sites, proteolytic digests of NF-220 were analyzed by a combination of HPLC, electrospray tandem mass spectrometry and database searching. A total of 53 phosphorylation sites were characterized, with 47 clustered in the C-terminal repeat segment (residues 840-1160), representing 76% (47/62) of the total acceptor sites in the region. As in mammalian NFH, approximately 64% of the K/RSP sites (14/22) in this region were found to be phosphorylated implicating proline-directed kinases. Significantly, 78% of serines (31/40) in the KAES*EK and EKS*ARSP motifs were also phosphorylated suggesting that non proline-directed kinases such as CKI may also be involved. This is consistent with previous studies showing that CKI is the principal kinase associated with axoplasmic NF preparations. It also suggests that phosphorylation of large macromolecules with multiple phospho-sites requires sequential phosphorylation by several kinases. C1 NINDS, LNC, NIH, Bethesda, MD 20892 USA. NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP NINDS, LNC, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov NR 58 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 4 BP 1022 EP 1031 DI 10.1046/j.1471-4159.2001.00115.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 403NR UT WOS:000167049800008 PM 11181821 ER PT J AU Allen, DD Smith, QR AF Allen, DD Smith, QR TI Characterization of the blood-brain barrier choline transporter using the in situ rat brain perfusion technique SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE acetylcholine; blood-brain barrier; cerebrovascular; choline; hemicholinium; transporter ID CEREBROVASCULAR TRANSPORT; ENDOTHELIAL-CELLS; NERVOUS-SYSTEM; METABOLISM; HEMICHOLINIUM-3; INCREASES; MEMBRANE; KINETICS; DISEASE; ANALOGS AB Choline enters brain by saturable transport at the blood-brain barrier (BBB). In separate studies, both sodium-dependent and passive choline transport systems of differing affinity have been reported at brain capillary endothelial cells. In the present study, we re-examined brain choline uptake using the in situ rat brain perfusion technique. Saturable brain choline uptake from perfusion fluid was best described by a model with a single transporter (V(max) = 2.4-3.1 nmol/min/g; K(m) = 39-42 muM) With an apparent affinity (1/K(m)) for choline five to ten-fold greater than previously reported in vivo, but less than neuronal 'high-affinity' brain choline transport (K(m) = 1-5 muM) BBB choline uptake from a sodium-free perfusion fluid using sucrose for osmotic balance was 50% greater than in the presence of sodium suggesting that sodium is not required for transport. Hemicholinium-3 inhibited brain choline uptake with a K(i) (57 +/- 11 muM) greater than that at the neuronal choline system. In summary, BBB choline transport occurs with greater affinity than previously reported, but does not match the properties of the neuronal choline transporter. The V(max) of this system is appreciable and may provide a mechanism for delivering cationic drugs to brain. C1 Texas Tech Univ, Dept Pharmaceut Sci, Sch Pharm, HSC, Amarillo, TX 79106 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Allen, DD (reprint author), Texas Tech Univ, Dept Pharmaceut Sci, Sch Pharm, HSC, 1300 S Coulter Dr, Amarillo, TX 79106 USA. EM dallen@cortex.ama.ttuhsc.edu NR 44 TC 66 Z9 69 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 4 BP 1032 EP 1041 DI 10.1046/j.1471-4159.2001.00093.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 403NR UT WOS:000167049800009 PM 11181822 ER PT J AU Chang, RCC Chen, W Hudson, P Wilson, B Han, DSK Hong, JS AF Chang, RCC Chen, W Hudson, P Wilson, B Han, DSK Hong, JS TI Neurons reduce glial responses to lipopolysaccharide (LPS) and prevent injury of microglial cells from over-activation by LPS SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE glia; lipopolysaccharide; microglia; neuronal inhibition ID CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; IN-VITRO; INFLAMMATORY REACTION; OXIDATIVE STRESS; NITRIC-OXIDE; FAS LIGAND; TNF-ALPHA; EXPRESSION; APOPTOSIS AB The microenvironment of the CNS has been considered to tonically inhibit glial activities. It has been shown that glia become activated where neuronal death occurs in the aging brain. We have previously demonstrated that neurons tonically inhibit glial activities including their responses to the bacterial endotoxin lipopolysaccharide (LPS). It is not clear whether activation of glia, especially microglia in the aging brain, is the consequence of disinhibition due to neuronal death. This study was designed to determine if glia regain their responsiveness to LPS once the neurons have died in aged cultures. When cultured alone, glia from postnatal day one rat mesencephalons stimulated with LPS (0.1-1000 ng/mL) produced both nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha), yielding a sigmoid and a bell-shaped curve, respectively. When neuron-containing cultures were prepared from embryonic day 14/15 mesencephalons, the shape of the dose-response curve for NO was monotonic and the bell-shaped curve for TNFa production was shifted to the right. After 1 month of culture under conditions where neurons die, the production curves for NO and TNF alpha in LPS-stimulated glia shifted back to the left compared to mixed neuron-glia cultures. Immunostaining of rat microglia for the marker CR3 (the receptor for complement component C3) demonstrated that high concentrations of LPS (1 mug/mL) reduced the number of microglia in mixed-glial cultures. In contrast, reduction of CR3 immunostaining was not observed in LPS-stimulated mixed neuron-glia cultures. Taken together, the results demonstrate that disinhibition of the glial response to LPS occurs after neurons die in aged cultures. Once neurons have died, the responsiveness of glia to LPS is restored. Neurons prevented injury to microglia by reducing their responsiveness to LPS. This study broadens our understanding of the ways in which the CNS microenvironment affects cerebral inflammation. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Chang, RCC (reprint author), Univ Hong Kong, Dept Anat, Fac Med, 5-F Li Shu Fan Bldg,5 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. RI Chang, Raymond Chuen-Chung/C-1107-2009 OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993 NR 36 TC 38 Z9 41 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 4 BP 1042 EP 1049 DI 10.1046/j.1471-4159.2001.00111.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 403NR UT WOS:000167049800010 PM 11181823 ER PT J AU Hanes, DP Wurtz, RH AF Hanes, DP Wurtz, RH TI Interaction of the frontal eye field and superior colliculus for saccade generation SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID RHESUS-MONKEY; REVERSIBLE INACTIVATION; COLLIDING SACCADES; COMBINED LESIONS; MOVEMENTS; STIMULATION; NEURONS; DEFICITS; PARIETAL; CORTEX AB Both the frontal eye field (FEF) in the prefrontal cortex and the superior colliculus (SC) on the roof of the midbrain participate in the generation of rapid or saccadic eye movements and both have projections to the premotor circuits of the brain stem where saccades are ultimately generated. In the present experiments, we tested the contributions of the pathway from the FEF to the premotor circuitry in the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying information to the brain stem, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF-brain stem pathway. If the contributions of the direct pathway were substantial, removal of the SC should have minimal effect on the FEF stimulation, whereas if the FEF stimulation were dependent on the SC, removal of the SC should alter the effect of FEF stimulation. By acutely inactivating the SC, instead of ablating it, we were able to test the efficiency of the direct FEF-brain stem pathway before substantial compensatory mechanisms could mask the effect of removing the SC. We found two striking effects of SC inactivation. In the first, we stimulated the FEF at a site that evoked saccades with vectors that were very close to those evoked at the site of the SC inactivation, and with such optimal alignment, we found that SC inactivation eliminated the saccades evoked by FEF stimulation. The second effect was evident when the FEF evoked saccades were disparate from those evoked in the SC, and in this case we observed a shift in the direction of the evoked saccade that was consistent with the SC inactivation removing a component of a vector average. Together these observations lead to the conclusion that in the nonablated monkey the direct FEF-brain stem pathway is not functionally sufficient to generate accurate saccades in the absence of the indirect pathway that courses from the FEF through the SC to the brain stem circuitry. We suggest that the recovery of function following SC ablation that has been seen in previous studies must result not from the use of an already functioning parallel pathway but from neural plasticity within the saccadic system. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hanes, DP (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 48 TC 107 Z9 109 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2001 VL 85 IS 2 BP 804 EP 815 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 400DU UT WOS:000166857600028 PM 11160514 ER PT J AU Li, Y Holtzclaw, LA Russell, JT AF Li, Y Holtzclaw, LA Russell, JT TI Muller cell Ca2+ waves evoked by purinergic receptor agonists in slices of rat retina SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID ASTROCYTES IN-SITU; CALCIUM WAVES; GLIAL-CELLS; ENDOPLASMIC-RETICULUM; NEURONAL-ACTIVITY; AMPHIBIAN RETINA; ATP; RELEASE; MODULATION; OSCILLATIONS AB We have measured agonist evoked Ca2+ waves in Muller cells in situ within freshly isolated retinal slices. Using an eye cup dye loading procedure we were able to preferentially fill Muller glial cells in retinal slices with calcium green. Fluorescence microscopy revealed that bath perfusion of slices with purinergic agonists elicits Ca2+ waves in Muller cells, which propagate along their processes. These Ca2+ signals were insensitive to tetrodotoxin (TTX, 1.0 muM) pretreatment. Cells were readily identified as Muller cells by their unique morphology and by subsequent immunocytochemical labeling with glial fibrillary acidic protein antibodies. While cells never exhibited spontaneous Ca2+ oscillations, purinoreceptor agonists, ATP, 2 MeSATP, ADP, 2 MeSADP, and adenosine readily elicited Ca2+ waves. These waves persisted in the absence of [Ca2+](o) but were abolished by thapsigargin pretreatment, suggesting that the purinergic agonists tested act by releasing Ca2+ from intracellular Ca2+ stores. The rank order of potency of different purines and pyrimidines for inducing Ca2+ signals was 2 MeSATP = 2MeSADP > ADP > ATP >> alpha beta meATP = uridine triphosphate (UTP). uridine diphosphate (UDP). The Ca2+ signals evoked by ATP, ADP, and 2 MeSATP were inhibited by reactive blue (100 muM) and suramin (200 muM), and the adenosine induced signals were abolished only by 3,7-dimethyl-1-propargylxanthine (200 muM) and not by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine) or 8-cyclopentyl-1,3-dipropylxanthine at the same concentration. Based on these pharmacological characteristics and the dose-response relationships for ATP, 2 MeSATP, 2 MeSADP, ADP, and adenosine, we concluded that Muller cells express the P1A2 and P2Y(1) subtypes of purinoceptors. Analysis of Ca2+ responses showed that, similar to glial cells in culture, wave propagation occurred by regenerative amplification at specialized Ca2+ release sites (wave amplification sites), where the rate of Ca2+ release was significantly enhanced. These data suggest that Muller cells in the retina may participate in signaling, and this may serve as an extra-neuronal signaling pathway. C1 NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Russell, JT (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Rm 5A-78, Bethesda, MD 20892 USA. NR 42 TC 50 Z9 51 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2001 VL 85 IS 2 BP 986 EP 994 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 400DU UT WOS:000166857600042 PM 11160528 ER PT J AU Martini, S Silvotti, L Shirazi, A Ryba, NJP Tirindelli, R AF Martini, S Silvotti, L Shirazi, A Ryba, NJP Tirindelli, R TI Co-expression of putative pheromone receptors in the sensory neurons of the vomeronasal organ SO JOURNAL OF NEUROSCIENCE LA English DT Article DE vomeronasal organ; pheromone receptors; G-protein-coupled receptors; immunohistochemistry; coexpression; olfaction; pheromone; receptors and signal transduction; chemosensory receptors; sensory coding ID CA2+-SENSING RECEPTOR; MULTIGENE FAMILY; OLFACTORY-BULB; G-PROTEINS; MAMMALS; LOCALIZATION; SYSTEM; TRANSDUCTION; PROJECTIONS; CLONING AB Two large and divergent families of G-protein-coupled receptors (V1Rs and V2Rs) are expressed in subsets of neurons in the vomeronasal organ. These receptors are likely to mediate pheromone responses, but it appears that many V2R genes may encode expressed pseudogenes rather than functional proteins. Therefore we have raised antibodies to representative V2Rs and show labeling of vomeronasal neurons demonstrating that V2R genes encode expressed receptors. V2R immunoreactivity was detected at the sensory surface of the vomeronasal organ in dendritic terminals, indicating that these receptors are capable of directly interacting with pheromones and mediating physiological responses. Immunohistochemistry confirmed that three V2R receptors are expressed in small subsets of sensory neurons. However, surprisingly we found that a subfamily of V2R genes is broadly expressed in the Go alpha -layer of the vomeronasal organ and are coexpressed in the same cells as other V2Rs. This is in direct contrast to the main olfactory epithelium where sensory neurons express only a single receptor. Thus, our results suggest that different modes of the information processing may occur in the main and accessory olfactory systems. C1 Univ Parma, Ist Fisiol Umana, I-43100 Parma, Italy. NIDCR, NIH, Bethesda, MD 20892 USA. RP Tirindelli, R (reprint author), Univ Parma, Ist Fisiol Umana, Via Volturno 39, I-43100 Parma, Italy. NR 36 TC 99 Z9 100 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 FEB 1 PY 2001 VL 21 IS 3 BP 843 EP 848 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 398WF UT WOS:000166778900014 PM 11157070 ER PT J AU Ralston, E Ploug, T Kalhovde, J Lomo, T AF Ralston, E Ploug, T Kalhovde, J Lomo, T TI Golgi complex, endoplasmic reticulum exit sites, and microtubules in skeletal muscle fibers are organized by patterned activity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE muscle; Golgi complex; microtubules; plasticity; patterned activity; denervation ID REINNERVATED MOTOR UNITS; HEAVY-CHAIN ISOFORMS; ELECTRICAL-ACTIVITY; GENE-REGULATION; SOLEUS MUSCLE; CAT MUSCLE; RAT; SLOW; EXPRESSION; STIMULATION AB The Golgi complex of skeletal muscle fibers is made of thousands of dispersed elements. The distributions of these elements and of the microtubules they associate with differ in fast compared with slow and in innervated compared with denervated fibers. To investigate the role of muscle impulse activity, we denervated fast extensor digitorum longus (EDL) and slow soleus (SOL) muscles of adult rats and stimulated them directly with patterns that resemble the impulse patterns of normal fast EDL (25 pulses at 150 Hz every 15 min) and slow SOL (200 pulses at 20 Hz every 30 sec) motor units. After 2 weeks of denervation plus stimulation, peripheral and central regions of muscle fibers were examined by immunofluorescence microscopy with regard to density and distribution of Golgi complex, microtubules, glucose transporter GLUT4, centrosomes, and endoplasmic reticulum exit sites. In extrajunctional regions, fast pattern stimulation preserved normal fast characteristics of all markers in EDL type IIB/IIX fibers, although inducing changes toward the fast phenotype in originally slow type I SOL fibers, such as a 1.5-fold decrease of the density of Golgi elements at the fiber surface. Slow pattern stimulation had converse effects such as a 2.2-fold increase of the density of Golgi elements at the EDL fiber surface. In junctional regions, where fast and slow fibers are similar, both stimulation patterns prevented a denervation-induced accumulation of GLUT4. The results indicate that patterns of muscle impulse activity, as normally imposed by motor neurons, play a major role in regulating the organization of Golgi complex and related proteins in the extrajunctional region of muscle fibers. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Panum Inst, Dept Med Physiol, Copenhagen Muscle Res Ctr, DK-2200 Copenhagen, Denmark. Univ Oslo, Dept Physiol, N-0317 Oslo, Norway. RP Ralston, E (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Room 2A-21, Bethesda, MD 20892 USA. NR 43 TC 49 Z9 51 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2001 VL 21 IS 3 BP 875 EP 883 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 398WF UT WOS:000166778900018 PM 11157074 ER PT J AU Salichon, N Gaspar, P Upton, AL Picaud, S Hanoun, N Hamon, M De Maeyer, E Murphy, DL Mossner, R Lesch, KP Hen, R Seif, I AF Salichon, N Gaspar, P Upton, AL Picaud, S Hanoun, N Hamon, M De Maeyer, E Murphy, DL Mossner, R Lesch, KP Hen, R Seif, I TI Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-HT transporter knock-out mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE 5-HT1B receptor; monoamine oxidase; serotonin transporter; activity-dependent development; retinal projections; dorsal lateral geniculate nucleus; thalamocortical; barrel field ID RAT SOMATOSENSORY CORTEX; LESION-INDUCED REORGANIZATION; SPONTANEOUS RETINAL ACTIVITY; VIBRISSAE-RELATED PATTERNS; VISUAL-SYSTEM DEVELOPMENT; CENTRAL-NERVOUS-SYSTEM; POSTNATAL-DEVELOPMENT; CORTICAL ACTIVITY; SUBCELLULAR-LOCALIZATION; THALAMOCORTICAL AXONS AB Deficiency in the monoamine degradation enzyme monoamine oxidase A (MAOA) or prenatal exposure to the monoamine uptake inhibitor cocaine alters behavior in humans and rodents, but the mechanisms are unclear. In MAOA knock-out mice, inhibiting serotonin synthesis during development can prevent abnormal segregation of axons in the retinogeniculate and somatosensory thalamocortical systems. To investigate this effect, we crossed MAOA knock-outs with mice lacking the serotonin transporter 5-HTT or the 5-HT1B receptor, two molecules present in developing sensory projections. Segregation was abnormal in 5-HTT knock-outs and MAOA/5-HTT double knock-outs but was normalized in MAOA/5-HT1B double knock-outs and MAOA/5-HTT/5-HT1B triple knock-outs. This demonstrates that the 5-HT1B receptor is a key factor in abnormal segregation of sensory projections and suggests that serotonergic drugs represent a risk for the development of these projections. We also found that the 5-HT1B receptor has an adverse developmental impact on beam-walking behavior in MAOA knock-outs. Finally, because the 5-HT1B receptor inhibits glutamate release, our results suggest that visual and somatosensory projections must release glutamate for proper segregation. C1 Inst Curie, CNRS, Unite Mixte Rech 146, F-91405 Orsay, France. Hop La Pitie Salpetriere, INSERM, U106, F-75651 Paris, France. Hop La Pitie Salpetriere, INSERM, U288, F-75634 Paris, France. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97080 Wurzburg, Germany. Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. RP Seif, I (reprint author), Inst Curie, CNRS, Unite Mixte Rech 146, F-91405 Orsay, France. RI Gaspar, Patricia/G-8892-2011; hanoun, naima/M-6408-2014; Lesch, Klaus-Peter/J-4906-2013 OI Gaspar, Patricia/0000-0003-4217-5717; Lesch, Klaus-Peter/0000-0001-8348-153X NR 67 TC 183 Z9 185 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2001 VL 21 IS 3 BP 884 EP 896 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 398WF UT WOS:000166778900019 PM 11157075 ER PT J AU Hayes, WP Yangco, N Chin, HM Mill, JF Pu, LP Taira, M Dawid, IB Gallo, V AF Hayes, WP Yangco, N Chin, HM Mill, JF Pu, LP Taira, M Dawid, IB Gallo, V TI Expression and regulation of the LIM-class homeobox gene rlim-1 in neuronal progenitors of the rat cerebellum SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE granule cells; in situ hybridization histochemistry; homeobox genes; neurogenesis; neuronal migration ID POSTNATAL-DEVELOPMENT; HOMEODOMAIN GENE; GRANULE CELLS; CAENORHABDITIS-ELEGANS; MOLECULAR LAYER; DIFFERENTIATION; SPECIFICATION; BRAIN; PROTEINS; DOMAIN AB To investigate LIM gene function in the rat cerebellar system, we analyzed expression and regulation of the rat homologue of frog Xlim-1 (rlim-1) in vivo and in cultured cells. In developing cerebellum, peak levels of rlim-1 mRNA at postnatal day 8 (p8) are coincident with the peak period of granule cell proliferation. Analysis of rlim-1 protein with a specific antibody showed that expression was also maximal at p8, In situ hybridization showed that at p8 rlim-1 mRNA was expressed in Purkinje and granule cells. Both the proliferative and the premigratory granule cells in the external germinal zone displayed high levels of rlim-1 mRNA expression. Immunocytochemical staining demonstrated that at p8 rlim-1 protein was also present in proliferative and premigratory granule cells, In adult cerebellum (p30), rlim-1 mRNA and protein expression in granule cells was strongly attenuated. The down-regulation of rlim-1 mRNA occurred in granule cells just after the time of final division, coinciding with the onset of their migration. rlim-1 protein was detected in migratory granule neurons. The developmental decrease in rlim-1 mRNA and protein found in vivo was reproduced in pure cerebellar granule cell cultures. In these cultures, granule neurons were postmitotic I day after plating but still displayed high levels of rlim-1 protein expression up to 3 days in vitro. Our findings indicate that 1) rlim-1 is likely to act in concert with other genes to specify granule cell fate, 2) rlim-1 expression in granule neurons is regulated autonomously, and 3) rlim-1 protein may also play an important role in granule neuron differentiation and survival. Published 2001 Wiley-Liss, Inc.dagger C1 NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Room 5A78, Bethesda, MD 20892 USA. NR 46 TC 5 Z9 5 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 1 PY 2001 VL 63 IS 3 BP 237 EP 251 DI 10.1002/1097-4547(20010201)63:3<237::AID-JNR1017>3.3.CO;2-W PG 15 WC Neurosciences SC Neurosciences & Neurology GA 398VF UT WOS:000166776600002 PM 11170173 ER PT J AU Levin, MC Rosenblum, MK Fox, CH Jacobson, S AF Levin, MC Rosenblum, MK Fox, CH Jacobson, S TI Localization of retrovirus in the central nervous system of a patient co-infected with HTLV-1 and HIV with HAM/TSP and HIV-associated dementia SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE HIV; HTLV-1; HIV-associated dementia; HAM/TSP ID VIRUS TYPE-I; NEUROLOGIC DISEASE; SITU HYBRIDIZATION; MYELOPATHY; LYMPHOCYTES; EXPRESSION AB Persons co-infected with HTLV-1 and HIV are at increased risk for neurologic disease. These patients may develop HAM/TSP and/or HIV-associated dementia. In this study, we localized cells infected with retrovirus in the central nervous system (CNS) of a patient with both HAM/TSP and HIV associated dementia. HTLV-1 was localized to astrocytes and HIV to macrophage/microglia. There was no co-infection of a single cell phenotype in this patient. These data suggest that mechanisms other than co-infection of the same CNS cell may play a role in the development of neurologic disease in patients dual infected with HTLV-1 and HIV. C1 Univ Tennessee, Dept Neurol, Ctr Hlth Sci, Lab Virol & Demyelinating Dis, Memphis, TN 38163 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol Neuropathol, New York, NY 10021 USA. Univ Arkansas, Med Ctr, Little Rock, AR 72205 USA. Mol Histol Labs, Gaithersburg, MD 20879 USA. RP Levin, MC (reprint author), Univ Tennessee, Dept Neurol, Ctr Hlth Sci, Lab Virol & Demyelinating Dis, Link Bldg 415,855 Monroe Ave, Memphis, TN 38163 USA. NR 16 TC 4 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 2001 VL 7 IS 1 BP 61 EP 65 PG 5 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 472QZ UT WOS:000170997600009 PM 11519484 ER PT J AU Marques, AR Straus, SE Fahle, G Weir, S Csako, G Fischer, SH AF Marques, AR Straus, SE Fahle, G Weir, S Csako, G Fischer, SH TI Lack of association between HSV-1 DNA in the brain, Alzheimer's disease and apolipoprotein E4 SO JOURNAL OF NEUROVIROLOGY LA English DT Letter ID VIRUS C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Marques, AR (reprint author), NIAID, Clin Invest Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 6 TC 16 Z9 16 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 2001 VL 7 IS 1 BP 82 EP 83 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 472QZ UT WOS:000170997600012 PM 11519487 ER PT J AU Ballard-Barbash, R AF Ballard-Barbash, R TI Designing surveillance systems to address emerging issues in diet and health SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 3 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 437S EP 439S PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800001 PM 11160575 ER PT J AU Flegal, KM Troiano, RP Ballard-Barbash, R AF Flegal, KM Troiano, RP Ballard-Barbash, R TI Aim for a healthy weight: What is the target? SO JOURNAL OF NUTRITION LA English DT Article DE body weight; dietary guidelines; health and nutrition surveys; obesity; overweight ID UNITED-STATES; OBESITY; PREVALENCE; ADIPOSITY; TRENDS; WOMEN; MEN AB The first guideline statement of the Year 2000 edition of Nutrition and Your Health: Dietary Guidelines for Americans is "Aim for a healthy weight." The purpose of this paper is to describe the evolution of the weight guideline and discuss some issues related to it. We reviewed current and previous editions of the Dietary Guidelines and the corresponding advisory committee reports. The weight guideline has evolved over the years into one that is complex and touches on a wide range of issues. The 2000 edition emphasizes weight loss more than previous editions. Unlike the other guidelines in the Dietary Guidelines, the weight guideline has a health outcome, a "healthy" weight, rather than a behavioral outcome as its goal. Also unlike the other guidelines, the weight guideline has become more medically oriented over time. The concept of healthy weight in the guidelines includes aspects of body composition, fat distribution and weight-related health conditions, it may be difficult for the public and even for health care providers to interpret some of the concepts included in the weight guideline. Issues related to the appropriate management of weight can be complex and may require a health care provider as a resource for interpretation. Rather than try to incorporate further clinical decision-making and weight loss guidance within the weight guideline, it may be more appropriate to refer the reader to a health care provider for guidance, as was done in previous editions. C1 Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RI Flegal, Katherine/A-4608-2013 NR 37 TC 12 Z9 13 U1 0 U2 2 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 440S EP 450S PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800002 PM 11160576 ER PT J AU Troiano, RP Macera, CA Ballard-Barbash, R AF Troiano, RP Macera, CA Ballard-Barbash, R TI Be physically active each day. How can we know? SO JOURNAL OF NUTRITION LA English DT Article DE guideline; surveillance; health surveys; exercise; physical activity ID ENVIRONMENTAL-INFLUENCES; COLLEGE-STUDENTS; MINORITY WOMEN; UNITED-STATES; HEALTH; EXERCISE; FITNESS; PARTICIPATION; PREVALENCE; INACTIVITY AB For the first time in its five versions, Nutrition and Your Health: Dietary Guidelines for Americans contains an apparently nondietary guideline recommending physical activity. Although new as a separate guideline, physical activity has been included in the weight guideline of previous versions. The current version recognizes the importance of physical activity to health beyond its effect on weight maintenance. The purpose of this paper is to examine what data are available or required to evaluate the level of physical activity in the population, particularly in light of current recommendations. The physical activity sections of several national surveys that assess individual behavior or activity-related policies are described. Surveillance of physical activity as a risk factor for chronic disease is critical because physical inactivity is highly prevalent, strongly associated with increased morbidity and mortality, costly and preventable. Determinants of physical activity behavior are also considered. These determinants are potentially important factors for surveillance and are critical components for planning successful interventions. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Nutr & Phys Act, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. RP Troiano, RP (reprint author), NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NR 38 TC 25 Z9 27 U1 0 U2 6 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 451S EP 460S PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800003 PM 11160577 ER PT J AU Dixon, LB Cronin, FJ Krebs-Smith, SM AF Dixon, LB Cronin, FJ Krebs-Smith, SM TI Let the pyramid guide your food choices: Capturing the total diet concept SO JOURNAL OF NUTRITION LA English DT Article DE dietary guideline; dietary pattern; dietary quality; dietary variety; Food Guide Pyramid ID UNITED-STATES POPULATION; QUALITY INDEX; ENERGY-INTAKE; DIVERSITY; PATTERNS; RECOMMENDATIONS; VARIETY; CANCER AB This paper discusses how the guideline "Eat a variety of foods" became "Let the Pyramid guide your food choices," presents background information on the food guidance system upon which the Food Guide Pyramid is based and reviews methods that have been used to assess aspects of the total diet, i.e., the variety, moderation and proportionality, promoted by this guidance. The methods include measures of dietary variety, patterns based on Pyramid food group intakes and scoring methods comprised of multiple dietary components. Highlights of results from these methods include the following. Although approximately one third of the U.S. population eat at least some food from all Pyramid food groups, only similar to1-3% eat the recommended number of servings from all food groups on a given day. Fruits are the most commonly omitted food group. Vegetables and meat are the groups most commonly met by adults, and dairy the most commonly met by youth. Intakes of specific types of vegetables (i.e., dark green, deep yellow) and of grains (i.e., whole grains) are well below that recommended; intakes of total fat and added sugars exceed current recommendations. Scoring methods show those diets of the majority of the population require improvement, and that diets improve with increases in education and income. This paper also discusses the limitations and strengths of these approaches, and concludes with suggestions to improve current food guidance and methods to assess the total diet. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Dixon, LB (reprint author), NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NR 60 TC 38 Z9 41 U1 0 U2 4 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 461S EP 472S PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800004 PM 11160578 ER PT J AU Krebs-Smith, SM Kantor, LS AF Krebs-Smith, SM Kantor, LS TI Choose a variety of fruits and vegetables daily: Understanding the complexities SO JOURNAL OF NUTRITION LA English DT Article DE fruits; vegetables; diet surveys; dietary assessment; food supply ID BASE-LINE; ADULTS; STATES AB The 2000 edition of Nutrition and Your Health: Dietary Guidelines for Americans is the first to include a recommendation aimed specifically at fruits and vegetables, apart from grains. This paper discusses these changes in the Dietary Guidelines, summarizes the methods of assessment pertaining to fruit and vegetable intakes and their related factors, and reviews the data available on current levels and trends over time. Recent methodological advances in the measurement of both the aggregate U.S. food supply and foods consumed by individuals have allowed for better estimates with which recommendations can be compared. The data on individual intakes suggest the following: Americans are consuming fruits and vegetables at a level near the minimum recommendations; to be in concordance with energy-based recommendations, they would have to consume similar to2 more servings per day; and dark green and deep yellow vegetables are accounting for a disproportionately small share of the total. Fruit and vegetable consumption appears to be rising, but only slightly, and this increase might be only an artifact of shifts in the population demographics. A number of studies suggest that tow income households in poor central cities and sparsely populated rural areas often have less access to food stores and face higher prices for food, including fruits and vegetables, compared with other households. At the aggregate level, supplying enough fruits and vegetables to meet dietary recommendations for all U.S, consumers would require adjustments in U.S. agricultural production, trade, marketing practices and prices of these commodities. C1 NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. USDA, Econ Res Serv, Washington, DC USA. RP Krebs-Smith, SM (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. NR 57 TC 53 Z9 54 U1 2 U2 13 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 487S EP 501S PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800006 PM 11160580 ER PT J AU Dixon, LB Ernst, ND AF Dixon, LB Ernst, ND TI Choose a diet that is low in saturated fat and cholesterol and moderate in total fat: Subtle changes to a familiar message SO JOURNAL OF NUTRITION LA English DT Review DE cardiovascular; cholesterol; dietary fat; dietary guideline; saturated fat ID UNITED-STATES; NATIONAL-HEALTH; CHILDREN DISC; TRENDS; DISTRIBUTIONS; INTERVENTION; PROGRESS; DISEASE; ENERGY; TIME AB "Choose a diet that is low in saturated fat and cholesterol and moderate in total fat," issued in Nutrition and Your Health: Dietary Guidelines for Americans in the year 2000, has an interesting and lengthy history. The first guideline, for which there was extensive scientific data to show that dietary excess increased chronic disease risk, prompted much scientific discussion and debate when implemented as dietary guidance. Three major changes in the guideline are noted since it was issued in 1980, i.e., numerical goals for dietary fats; the applicability of recommended fat intakes for all individuals greater than or equal to2 y old; and rewording to emphasize reducing saturated fat and cholesterol intakes. The shift in emphasis includes the terminology moderate fat, which replaces the phrasing low fat. National data about the food supply, the population's dietary intake, knowledge, attitudes and behaviors, and nutritional status indicators (e.g., serum cholesterol levels) related to dietary fats help to monitor nutrition and health in the population. Experts consider that national data, although not without limitations, are sufficient to conclude that U.S. intakes of fats, as a proportion of energy, have decreased, The lower intakes of saturated fat and cholesterol are consistent with decreases in blood cholesterol levels and lower rates of coronary mortality over the past 30 years. Strategies are needed and some are suggested, to further encourage the population to achieve a dietary pattern that is low in saturated fat and cholesterol and moderate in total fat. Other suggestions are offered to improve national nutrition monitoring and surveillance related to the guideline. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NHLBI, Div Clin Applicat & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Dixon, LB (reprint author), NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NR 119 TC 19 Z9 19 U1 0 U2 2 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 510S EP 526S PG 17 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800008 PM 11160582 ER PT J AU Krebs-Smith, SM AF Krebs-Smith, SM TI Choose beverages and foods to moderate your intake of sugars: Measurement requires quantification SO JOURNAL OF NUTRITION LA English DT Article DE sugars; diet surveys; dietary behaviors; dietary assessment ID DIETARY SOURCES; US CHILDREN; RECOMMENDATIONS; NUTRIENTS AB The Dietary Guidelines for Americans, which form the basis of federal nutrition policy, have changed in subtle, but important ways with regard to sugars since they were first introduced in 1980; one might say they have become "sweeter" over time. Nonetheless, they have continued to maintain that there is a concern with overconsumption of sugars in the diets of Americans. Although the Dietary Guidelines themselves have never quantified how much constitutes overconsumption vs, moderation, the Food Guide Pyramid provides some guidance on that subject. The Pyramid's recommendations for added sugars, which vary by total energy level, are posed as a benchmark for gauging the appropriateness of the population's intakes. Data from the Food Supply series and from the Continuing Surveys of Food intakes by Individuals are used to assess recent intakes. The population is consuming added sugars at levels far in excess of recommendations; this is generally true for all population subgroups examined, but especially for adolescents. Soft drinks are the major source of added sugars in the diet. Suggestions are given to facilitate correction of these dietary imbalances. C1 NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. RP Krebs-Smith, SM (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. NR 42 TC 58 Z9 59 U1 0 U2 4 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 527S EP 535S PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800009 PM 11160583 ER PT J AU Loria, CM Obarzanek, E Ernst, ND AF Loria, CM Obarzanek, E Ernst, ND TI Choose and prepare foods with less salt: Dietary advice for all Americans SO JOURNAL OF NUTRITION LA English DT Review DE dietary sodium; dietary sodium chloride; blood pressure; nutrition policy ID NUTRITION EXAMINATION SURVEY; OVERNIGHT URINE COLLECTIONS; 3RD NATIONAL-HEALTH; SODIUM-INTAKE; BLOOD-PRESSURE; ENERGY-INTAKE; POTASSIUM INTAKE; US POPULATION; HYPERTENSION; REDUCTION AB The Nutrition and Your Health: Dietary Guidelines for Americans have included dietary guidance on salt and sodium since they were first released in 1980. This paper briefly reviews the impetus for including sodium guidelines, changes in them over time and factors influencing these changes. Although guidance appears to have changed little over the five editions, differences in wording reflect changes in knowledge of the link between sodium and blood pressure, a shift in public health policy toward prevention and increased consumption of processed and prepared foods. We examine methods to monitor sodium intake and assess whether Americans are following these guidelines. Available data indicate that American adolescents and adults are consuming more sodium than recommended and are unable to judge whether the amount of sodium in their diet is appropriate. Although Americans avoid adding salt to food at the table, their efforts may have little effect given that the majority of salt consumed is added during commercial processing and preparation. Thus, changes to the Dietary Guidelines that emphasize the major sources of sodium in U.S, diets and advice to "choose and prepare foods with less salt" may help all Americans meet recommended sodium intake levels in the future. C1 NHLBI, Bethesda, MD 20892 USA. RP Loria, CM (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 120 TC 28 Z9 30 U1 0 U2 7 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 536S EP 551S PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800010 PM 11160584 ER PT J AU Dufour, MC AF Dufour, MC TI If you drink alcoholic beverages do so in moderation: What does this mean? SO JOURNAL OF NUTRITION LA English DT Article DE alcohol; moderate drinking; alcohol epidemiology; alcohol consumption; self-report; survey measurement ID FOOD FREQUENCY QUESTIONNAIRE; HIGH-RISK; CONSUMPTION; VALIDITY; REPRODUCIBILITY; US; PREVALENCE; MORTALITY; VOLUME AB The changes in content of the alcohol guideline of the various editions of the Dietary Guidelines for Americans from 1980 to 2000 are discussed. This is followed by a capsule summary of the history and evolution of the discipline of alcohol epidemiology compared with that of nutrition epidemiology. Methods of assessment are discussed, and issues surrounding the validity and reliability of self-report of alcohol consumption are then outlined. Relevant objectives from Healthy People 2010 are discussed. Surveillance of the alcohol guideline discloses that, at present, very few American drinkers follow the recommendations of the alcohol guideline. Indications for future research needs to address this issue conclude the discussion. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Dufour, MC (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 16 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2001 VL 131 IS 2 SU 1 BP 552S EP 561S PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401PQ UT WOS:000166936800011 PM 11160585 ER PT J AU Sternberg, WF Bokat, C Kass, L Alboyadjian, A Gracely, RH AF Sternberg, WF Bokat, C Kass, L Alboyadjian, A Gracely, RH TI Sex-dependent components of the analgesia produced by athletic competition SO JOURNAL OF PAIN LA English DT Article DE sex differences; athletic competition-induced analgesia; exercise; cold pressor pain ID STRESS-INDUCED ANALGESIA; PAIN SENSITIVITY; GENDER; EXERCISE; RESPONSES; HUMANS; SUPPRESSION; PERCEPTION; INTENSITY; NALOXONE AB Competing in various athletic events (track meet, basketball game, or fencing match) can produce analgesia to cold presser stimuli in male and female college athletes compared with baseline assessments. This competition-induced analgesia has been attributed to the stress associated with competition, which has components related to both physical exercise and the cognitive aspects of competing. This study evaluated the analgesic effect of exercise-related stress, and that caused by the cognitively stressful components of competing independent of exercise. Cold presser pain ratings were assessed after competition in a track meet and after treadmill exercise or sedentary video game competition in both athletes and nonathletes. As expected, competing in athletics resulted in a decrease in cold presser ratings in both male and female athletes. Independent of athletic status, treadmill running induced analgesia in women, but not in males, whereas sedentary video game competition produced analgesia in men, but not in women. These findings suggest that different components of the competitive athletic experience might be responsible for the analgesic effects in a sex-dependent manner. C1 Haverford Coll, Dept Psychol, Haverford, PA 19041 USA. NIDCR, Clin Measurement & Mechanisms Unit, NIH, Bethesda, MD USA. RP Sternberg, WF (reprint author), Haverford Coll, Dept Psychol, 370 Lancaster Ave, Haverford, PA 19041 USA. NR 32 TC 34 Z9 35 U1 1 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD FEB PY 2001 VL 2 IS 1 BP 65 EP 74 DI 10.1054/jpai.2001.18236 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 401HN UT WOS:000166922300007 PM 14622787 ER PT J AU Feuillan, P Peters, KF Cutler, GB Biesecker, LG AF Feuillan, P Peters, KF Cutler, GB Biesecker, LG TI Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE growth hormone; somatotropin; hypothalamic hamartoma; Pallister-Hall syndrome ID PRECOCIOUS PUBERTY; NORMAL GIRLS; SECRETION; HYPOPITUITARISM; BOYS AB Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly, Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr), We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h, At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH, We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I, Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Feuillan, P (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Rm 10N262, Bethesda, MD 20892 USA. NR 26 TC 5 Z9 5 U1 0 U2 0 PU FREUND PUBLISHING HOUSE LTD PI LONDON PA STE 500, CHESHAM HOUSE, 150 REGENT ST, LONDON W1R 5FA, ENGLAND SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD FEB PY 2001 VL 14 IS 2 BP 141 EP 149 PG 9 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 411EJ UT WOS:000167484900002 PM 11305791 ER PT J AU Wierzba, TF Abu El-Yazeed, R Savarino, SJ Mourad, AS Rao, M Baddour, M El-Deen, AN Naficy, AB Clemens, JD AF Wierzba, TF Abu El-Yazeed, R Savarino, SJ Mourad, AS Rao, M Baddour, M El-Deen, AN Naficy, AB Clemens, JD TI The interrelationship of malnutrition and diarrhea in a periurban area outside Alexandria, Egypt SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE children; diarrhea; growth; malnutrition ID INTERNATIONAL GROWTH REFERENCE; RURAL BANGLADESH; LONGITUDINAL DATA; CHILDREN; INFECTION; IMPACT AB Background: In the developing world, children are often observed to have both diarrhea and malnutrition. This observation has led many researchers to speculate that diarrhea may produce malnutrition and that malnutrition may predispose to diarrhea. In this study, the interrelationship between diarrhea and malnutrition was investigated among 143 Egyptian children less than 3 years of age. Methods: For 22 months, children were followed for diarrhea at twice weekly home visits and measured for nutritional status at approximately 3-month intervals. Nutritional measurements were converted to z-scores based on the National Center for Health Statistics/World Health Organization (NCHS/WHO) reference population. Results: Three hundred fifty-eight diarrheal episodes were reported with only 1% of episodes lasting 14 days or mon. Stunting, wasting, and low weight-for-age were found in 19%, 3%, and 7%, of these children, respectively. When testing whether malnutrition predisposes to diarrhea, a weight-for-age z-score of <-2 standard deviations was associated with increased incidence of diarrhea (RR = 1.7, P < 0.01) but not height-for-age or weight-for-height. Diarrhea itself was associated with a subsequent attack of diarrhea (RR = 2.1, P < 0.001). During short intervals of follow-up (approximately 3 months), an association was detected between diarrhea episodes and growth faltering for height-for-age z-score (-0.16, P < 0.05). This association was reduced, however, when analyzed during 6-month intervals, if no diarrhea was reported in either the first or second half of this interval. Conclusions: In a population with moderate malnutrition, both low weight-for-age and diarrhea itself are associated with increased diarrhea risk. Diarrhea alone does not appear to contribute substantially to malnutrition when children have diarrhea-free time for catch-up growth. C1 Int Vaccine Inst, Seoul, South Korea. NICHHD, Bethesda, MD 20892 USA. Univ Alexandria, Fac Med, Dept Microbiol, Alexandria, Egypt. USN, Med Res Unit 3, Appl Field Sci Div, Cairo, Egypt. USN, Enter Dis Res Program, Med Res Unit 3, Cairo, Egypt. RP Wierzba, TF (reprint author), NAMRU3,PSC 452,Box 5000, FPO, AE 09385 USA. FU NICHD NIH HHS [Y1-HD-0026-01] NR 32 TC 15 Z9 18 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD FEB PY 2001 VL 32 IS 2 BP 189 EP 196 DI 10.1097/00005176-200102000-00018 PG 8 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 418EZ UT WOS:000167879100017 PM 11321391 ER PT J AU Takasaki, I Andoh, T Nojima, H Shiraki, K Kuraishi, Y AF Takasaki, I Andoh, T Nojima, H Shiraki, K Kuraishi, Y TI Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEUROPATHIC PAIN; INTRATHECAL GABAPENTIN; CALCIUM CHANNELS; N-TYPE; P-TYPE; RAT; INJECTION; ALLODYNIA; NEURALGIA; BLOCKADE AB The effects of systemic and local injections of gabapentin, a novel anticonvulsant agent, were tested on nociceptive behaviors in mice with acute herpetic pain. Transdermal infection with herpes simplex virus type-1 (HSV-1) produced nociceptive hypersensitivity of the infected hind paw to innocuous (allodynia) and noxious mechanical stimulation (hyperalgesia) with von Frey filaments. Systemic administration of gabapentin (10-100 mg/kg, peroral) produced a dose-dependent inhibition of both allodynia and hyperalgesia; gabapentin (30-300 mg/kg) did not affect locomotor activity. Intrathecal injection of gabapentin (10-100 mug/animal) also attenuated dose dependently both nociceptive hypersensitivities. In contrast, intraplantar, intracisternal, and intracerebroventricular administration of gabapentin (10-100 mug/animal) had no effect on the HSV-1-induced nociceptive hypersensitivities. Pretreatment with naltrexone (1 mg/kg) inhibited antinociceptive effect of morphine (5 mg/kg), but not gabapentin (100 mg/kg). Repeated administration of morphine (5 mg/kg, four times) led to tolerance of antinociceptive action, whereas gabapentin (100 mg/kg, four times) had antinociceptive effect even after the forth administration. The present results suggest that gabapentin is effective in the treatment of acute herpetic pain without apparent adverse effects, and analgesic action of gabapentin is mainly mediated by actions on the spinal cord. C1 Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Appl Pharmacol, Toyama 9300194, Japan. Toyama Med & Pharmaceut Univ, Fac Med, Dept Virol, Toyama, Japan. NHLBI, NIH, Bethesda, MD 20892 USA. RP Kuraishi, Y (reprint author), Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Dept Appl Pharmacol, 2630 Sugitani, Toyama 9300194, Japan. NR 28 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2001 VL 296 IS 2 BP 270 EP 275 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 393HG UT WOS:000166462700006 PM 11160607 ER PT J AU Schetz, JA Sibley, DR AF Schetz, JA Sibley, DR TI The binding-site crevice of the D-4 dopamine receptor is coupled to three distinct sites of allosteric modulation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID AMILORIDE ANALOGS; SODIUM; INHIBITION AB Most biogenic amine G protein-coupled receptors contain a conserved aspartic acid residue positioned near the intracellular side of the second transmembrane-spanning (TMS) domain that is the primary site of allosteric modulation by sodium ions and pH. Recently, zinc ions and amiloride derivatives were found to allosterically modulate antagonist binding to dopamine receptors. In the current study, the wild-type D-4 dopamine receptor showed an 8-fold decrease in zinc affinity in the presence of 120 mM NaCl, but the binding of zinc to the neutral TMS2 D-4-D77N mutant was completely sodium-insensitive. In contrast to zinc, methylisobutylamiloride (MIA) binding to the wild-type D-4 receptor was virtually unaffected by sodium. In addition, the binding affinity for MIA was essentially unchanged in the presence of an IC50 concentration of zinc and vice versa. Furthermore, MIA binding affinity was decreased 4-fold for the D-4-D77N mutant and increased 30-fold for the TMS3 mutant D-4-M107V, even though the binding affinity for zinc was similar to the wild-type D-4 background for both mutants. These findings demonstrate for the first time the existence of three distinct sites of allosteric modulation within a G protein-coupled receptor. C1 Univ Mississippi, Dept Pharmacol, University, MS 38677 USA. NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Schetz, JA (reprint author), Univ Mississippi, Dept Pharmacol, POB 1848, University, MS 38677 USA. NR 16 TC 37 Z9 37 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2001 VL 296 IS 2 BP 359 EP 363 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 393HG UT WOS:000166462700017 PM 11160618 ER PT J AU Han, YH Sweet, DH Hu, DN Pritchard, JB AF Han, YH Sweet, DH Hu, DN Pritchard, JB TI Characterization of a novel cationic drug transporter in human retinal pigment epithelial cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PH-DEPENDENT TRANSPORT; TOPICAL VERAPAMIL; FUNCTIONAL-CHARACTERISTICS; INTRAOCULAR-PRESSURE; EXPRESSION; CLONING; RABBITS; LOCALIZATION; MECHANISMS; OCTN2 AB Retinal pigment epithelial (RPE) cells transport a variety of solutes, but the capacity of human RPE cells to transport drugs and xenobiotics is not well understood. As an initial step to address this issue, we have examined human RPE transport of verapamil. Transport of [H-3] verapamil was measured in two human RPE cell lines (RPE/Hu and ARPE-19) grown to confluence on 12-well culture plates. Verapamil uptake by RPE/Hu cells was highly concentrative, reaching cell-to-medium ratios as high as 42 by 1 h. Uptake was saturable, with an apparent K-m of 7.2 muM. Verapamil uptake decreased in the presence of metabolic inhibitors, low temperature, and organic cations, including quinidine, pyrilamine, quinacrine, and diphenhydramine. However, other organic cations, including tetraethylammonium and cimetidine failed to inhibit. Verapamil uptake was also inhibited by the cationic antiglaucoma drugs diltiazem, timolol, and propranolol. Verapamil uptake was insensitive to changes in membrane potential. However, transport was markedly altered by changes in pH. Decreasing external pH inhibited uptake, whereas efflux was stimulated. Intracellular acidification via NH4Cl prepulse also stimulated uptake. Identical findings were obtained using the commercially available cell line ARPE-19. In view of its unique specificity, the RPE cell verapamil transporter described above is a novel, heretofore undescribed, organic cation transporter, distinct from the known members of the OCT family of organic cation transporters. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. New York Med Coll, New York Eye & Ear Infirm, New York, NY USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Sweet, Douglas/H-7914-2013 OI Sweet, Douglas/0000-0002-8911-9184 NR 41 TC 52 Z9 54 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2001 VL 296 IS 2 BP 450 EP 457 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 393HG UT WOS:000166462700029 PM 11160630 ER PT J AU Rochat, B Morsman, JM Murray, GI Figg, WD Mcleod, HL AF Rochat, B Morsman, JM Murray, GI Figg, WD Mcleod, HL TI Human CYP1B1 and anticancer agent metabolism: Mechanism for tumor-specific drug inactivation? SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HUMAN CYTOCHROME-P450 1B1; XENOBIOTICS; EXPRESSION; CANCER AB The cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of procarcinogens and xenobiotics. Human CYP1B1 protein has been detected in a variety of tumors but is not detected in adjacent normal tissues or in liver. This suggests that CYP1B1 could biotransform anticancer agents specifically in the target cells. The interaction between CYP1B1 and 12 commonly used anticancer drugs was screened using an ethoxyresorufin deethylase assay. Four agents were competitive inhibitors of CYP1B1 activity: flutamide (K-i = 1.0 muM), paclitaxel (K-i = 31.6 muM), mitoxantrone (K-i = 11.6 muM), and docetaxel (K-i = 28.0 muM). Doxorubicin (K-i = 2.6 muM) and daunomycin (K-i = 2.1 muM) were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor (K-i = 5.0 muM). Vinblastine, vincristine, 5-fluorouracil, etoposide, and cyclophosphamide did not inhibit CYP1B1 activity. In vitro incubations with flutamide and CYP1B1 produced a metabolite consistent with 2-hydroxyflutamide. Comparison of kinetic parameters (K-m, K-i, V-max) for flutamide 2-hydroxylation by CYP1B1, CYP1A1, and CYP1A2 indicate that CYP1B1 could play a major role for flutamide biotransformation in tumors. The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy. C1 Univ Aberdeen, Dept Med & Therapeut, Aberdeen, Scotland. Univ Aberdeen, Dept Pathol, Aberdeen, Scotland. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Mcleod, HL (reprint author), Washington Univ, Sch Med, Dept Med, Room 1021 CSRB NT,660 S Euclid Ave,Campus Box 806, St Louis, MO 63110 USA. RI Figg Sr, William/M-2411-2016 NR 16 TC 115 Z9 120 U1 3 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2001 VL 296 IS 2 BP 537 EP 541 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 393HG UT WOS:000166462700040 PM 11160641 ER PT J AU Cui, XM Kawashima, H Barclay, TB Peters, JM Gonzalez, FJ Morgan, ET Strobel, HW AF Cui, XM Kawashima, H Barclay, TB Peters, JM Gonzalez, FJ Morgan, ET Strobel, HW TI Molecular cloning and regulation of expression of two novel mouse CYP4F genes: Expression in peroxisome proliferator-activated receptor alpha-deficient mice upon lipopolysaccharide and clofibrate challenges SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID B-4 OMEGA-HYDROXYLASE; POLYMORPHONUCLEAR LEUKOCYTES; PPAR-GAMMA; KAPPA-B; NUCLEAR RECEPTORS; CDNA CLONING; FATTY-ACIDS; RAT-BRAIN; CYTOCHROME-P450; SUBFAMILY AB Cytochrome P450 4F isoforms catalyze the hydroxylation of eicosanoids such as leukotriene B-4, prostaglandins, and lipoxins as well as hydroxyeicosatetraenoic acids. In the present study, we report the molecular cloning of two novel mouse CYP4F isoforms, CYP4F15 and CYP4F16. Sequence comparison showed that CYP4F15 has 93.5% homology to CYP4F4 and CYP4F16 has 90.8% homology to CYP4F5, therefore they are the orthologs for rat CYP4F4 and CYP4F5, respectively. Both isoforms are expressed in liver and also in extrahepatic tissues but the patterns of expression are slightly different. To elucidate further the regulation and regulatory mechanism of the two isoforms, renal and hepatic CYP4F15 and CYP4F16 expression were analyzed using wild-type (SV/129) mice and peroxisome proliferator-activated receptor (PPAR) alpha null mice with or without challenge by bacterial endotoxin (LPS) or clofibrate. Renal expression of CYP4F15 was induced by LPS and clofibrate in (+/+) mice, and these effects were absent in the (-/-) mice. Renal expression of CYP4F16 was not affected by LPS or clofibrate in (+/+) or (-/-) mice. In contrast, hepatic expression of CYP4F15 and CYP4F16 was significantly reduced by LPS-treatment in (+/+) mice. A lesser reduction was also seen in the (-/-) mice, suggesting that PPAR alpha is partially responsible for this down-regulation. Clofibrate treatment caused the reduction of hepatic CYP4F16 expression and this effect was not dependent on PPAR alpha. Clofibrate treatment had no effect on hepatic CYP4F15 expression. Together, our data indicate that CYP4Fs are regulated in an isoform-specific, tissue-specific, and species-specific manner. C1 Univ Texas, Sch Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. Osaka City Univ, Sch Med, Dept Urol, Osaka 545, Japan. Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. NCI, Metab Lab, NIH, Bethesda, MD 20892 USA. RP Strobel, HW (reprint author), Univ Texas, Sch Med, Dept Biochem & Mol Biol, POB 20708, Houston, TX 77030 USA. RI Peters, Jeffrey/D-8847-2011 FU NIGMS NIH HHS [GM46897]; NIMH NIH HHS [MH58297] NR 36 TC 35 Z9 36 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2001 VL 296 IS 2 BP 542 EP 550 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 393HG UT WOS:000166462700041 PM 11160642 ER PT J AU Brooks, HL Sorensen, AM Terris, J Schultheis, PJ Lorenz, JN Shull, GE Knepper, MA AF Brooks, HL Sorensen, AM Terris, J Schultheis, PJ Lorenz, JN Shull, GE Knepper, MA TI Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CL COTRANSPORTER; RAT; EXPRESSION; EXCHANGER; LACKING AB 1. The Na+-H+ exchanger NHE3 and the thiazide-sensitive Na+-C1(-) cotransporter NCC are the major apical sodium transporters in the proximal convoluted tubule and the distal convoluted tubule of the kidney, respectively. We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice. 2. We used a so-called 'targeted proteomics' approach, which profiles the entire renal tubule with regard to changes in Na+ transporter and aquaporin abundance in response to the gene deletions, Specific antibodies to the Na+ transporters and aquaporins expressed along the nephron were utilized to determine the relative abundance of each transporter. Semiquantitative immunoblotting was used which gives an estimate of the percentage change in abundance of each transporter in knockout compared with wild-type mice. 3. In NHE3 knockout mice three changes were identified which could compensate for the loss of NHE3-mediated sodium absorption. (a) The proximal sodium-phosphate cotransporter NaPi-2 was markedly upregulated. (b) In the collecting duct, the 70 kDa form of the gamma -subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. This is thought to be an aldosterone-stimulated form of gamma -ENaC. (c) Glomerular filtration was significantly reduced. 4. In the NCC knockout mice, amongst all the sodium transporters expressed along the renal tubule, only the 70 kDa form of the gamma -subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. 5. In conclusion, both mouse knockout models, demonstrated successful compensation for loss of the deleted transporter. More extensive adaptation occurred in the case of the NHE3 knockout, presumably because NHE3 is responsible for much more sodium absorption in normal mice than in NCC knockout mice. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Sch Med, Dept Cellular & Mol Physiol, Cincinnati, OH 45267 USA. Univ Cincinnati, Sch Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr MSC 1603, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [Z01-HL-01282-KE]; NIDDK NIH HHS [DK50594, R01-DK57552, R37 DK050594, R01 DK050594, R01 DK057552] NR 25 TC 73 Z9 73 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB 1 PY 2001 VL 530 IS 3 BP 359 EP 366 DI 10.1111/j.1469-7793.2001.0359k.x PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 402NJ UT WOS:000166994800003 PM 11158268 ER PT J AU Heymann, JB AF Heymann, JB TI Bsoft: Image and molecular processing in electron microscopy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE STAR format; image file format; mmIFL; Unix; VMS; AFM ID PACKAGE; SYSTEM; RECONSTRUCTION; VISUALIZATION; INFORMATION; SOFTWARE; PROGRAM; MAPS AB Software for the processing of electron micrographs in structural biology suffers from incompatibility between different packages, poor definition and choice of conventions, and a lack of coherence in software development. The solution lies in adopting a common philosophy of interaction and conventions between the packages. To understand the choices required to have such common interfaces, I am developing a package called "Bsoft." Its foundations lie in the variety of different image file formats used in electron microscopy-a continually frustrating experience to the user and programmer alike. In Bsoft, this problem is greatly diminished by support for many different formats (including MRC, SPIDER, MAGIC, SUPRIM, and PIF) and by separating algorithmic issues from image format-specific issues. In addition, I implemented a generalized functionality for reading the tag-base STAR (self-defining text archiving and retrieval) parameter file format as a mechanism to exchanging parameters between different packages. Bsoft is written in highly portable code (tested on several Unix systems and under VMS) and offers a continually growing range of image processing functionality, such as Fourier transformation, cross-correlation, and interpolation. Finally, prerequisites for software collaboration are explored, which include agreements on information exchange and conventions, and tests to evaluate compatibility between packages. (C) 2001 Academic Press. C1 NIAMSD, LSBR, NIH, Bethesda, MD 20892 USA. RP Heymann, JB (reprint author), NIAMS, LSBR, NIH, Bldg 6,Room B2-34,MSC 2717, Bethesda, MD 20892 USA. RI Heymann, Bernard/F-6825-2011; OI Heymann, Bernard/0000-0002-8872-5326 NR 25 TC 152 Z9 152 U1 1 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB-MAR PY 2001 VL 133 IS 2-3 BP 156 EP 169 DI 10.1006/jsbi.2001.4339 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 457MU UT WOS:000170142000008 PM 11472087 ER PT J AU Vitiello, B Severe, JB Greenhill, LL Arnold, LE Abikoff, HB Bukstein, OG Elliott, GR Hechtman, L Jensen, PS Hinshaw, SP March, JS Newcorn, JH Swanson, JM Cantwell, DP AF Vitiello, B Severe, JB Greenhill, LL Arnold, LE Abikoff, HB Bukstein, OG Elliott, GR Hechtman, L Jensen, PS Hinshaw, SP March, JS Newcorn, JH Swanson, JM Cantwell, DP TI Methylphenidate dosage for children with ADHD over time under controlled conditions: Lessons from the MTA SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder; attention deficit; hyperactivity; methylphenidate ID DEFICIT HYPERACTIVITY DISORDER; PHARMACOTHERAPY AB To examine the trajectory of methylphenidate (MPH) dosage over time. following a controlled titration, and to ascertain how accurately the titration was able to predict effective long-term treatment in children with attention-deficit/hyperactivity disorder (ADHD). Method: Using the 14-month-treatment database of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), the outcome of the initial placebo-controlled, double-blind, randomized daily switch titration of MPH was compared with the subsequent maintenance pharmacotherapy. Children received monthly monitoring visits and, when needed, medication adjustments. Results: Of the 198 children for whom MPH was the optimal treatment at titration (mean +/- SD dose: 30.5 +/- 14.2 mg/day), 88% were still taking MPH at the end of maintenance (mean dose 34.4 +/- 13.3 mg/day). Titration-determined dose and end-of-maintenance dose were significantly correlated (r = 0.52-0.68). Children receiving combined pharmacotherapy and behavioral treatment ended maintenance on a lower dose (31.1 +/- 11.7 mg/day) than did children receiving pharmacotherapy only (38.1 +/- 14.2 mg/day). Of the 230 children for whom titration identified an optimal treatment. 17% continued both the assigned medication and dosage throughout maintenance. The mean number of pharmacological changes per child was 2.8 +/- 1.8 (SD), and time to first change was 4.7 months +/- 0.3 (SE). Conclusions: Far most children, initial titration found a dose of MPH in the general range of the effective maintenance dose, but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed. C1 NIMH, Child & Adolescent Treatment & Prevent Res Branch, Div Serv & Intervent Res, Bethesda, MD 20982 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Montreal Childrens Hosp, Long Isl Jewish Med Ctr, Montreal, PQ H3H 1P3, Canada. Columbia Univ, New York State Psychiat Inst, Mt Sinai Med Ctr, New York, NY 10027 USA. Stanford Univ, Stanford, CA 94305 USA. RP Vitiello, B (reprint author), NIMH, Child & Adolescent Treatment & Prevent Res Branch, Div Serv & Intervent Res, Room 7147,6001 Execut Blvd,MSC 9633, Bethesda, MD 20982 USA. OI Jensen, Peter/0000-0003-2387-0650; Newcorn, Jeffrey /0000-0001-8993-9337 FU NIMH NIH HHS [U01 MH064868, UO1 MH50447, UO1 MH50453, U01 MH064869, UO1 MH50454, U01 MH064911, UO1 MH50467, UO1 MH50440, UO1 MH50461] NR 19 TC 78 Z9 80 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2001 VL 40 IS 2 BP 188 EP 196 DI 10.1097/00004583-200102000-00013 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 397KL UT WOS:000166694800013 PM 11211367 ER PT J AU Egan, CA Stratakis, CA Turner, ML AF Egan, CA Stratakis, CA Turner, ML TI Multiple lentigines associated with cutaneous myxomas SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID CARNEY-COMPLEX; ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; SCHWANNOMAS C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NICHHD, Sect Pediat Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Egan, CA (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2001 VL 44 IS 2 BP 282 EP 284 DI 10.1067/mjd.2001.112387 PG 3 WC Dermatology SC Dermatology GA 398EX UT WOS:000166744900016 PM 11174387 ER PT J AU Lang, CCE Mohiddin, SA Flapan, AD Fananapazir, L AF Lang, CCE Mohiddin, SA Flapan, AD Fananapazir, L TI Abnormal repolarization dynamics in patients with hypertrophic cardiomyopathy: A new risk factor for sudden death? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Univ Edinburgh, Edinburgh, Midlothian, Scotland. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 133A EP 134A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400615 ER PT J AU Lloyd-Jones, DM Larson, MG Beiser, A D'Agostino, RB Vasan, RS Benjamin, EJ Levy, D AF Lloyd-Jones, DM Larson, MG Beiser, A D'Agostino, RB Vasan, RS Benjamin, EJ Levy, D TI Increasing pulse pressure contributes to lifetime risk of congestive heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 157A EP 157A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400717 ER PT J AU Mohiddin, SA Winkler, J MClam, E Begley, DA Fananapazir, L AF Mohiddin, SA Winkler, J MClam, E Begley, DA Fananapazir, L TI Genetic screening in hypertrophic cardiomyopathy: Most beta-myosin mutations that are identified are novel with undefined clinical outcomes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 174A EP 174A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400792 ER PT J AU Bristow, MR Zelis, R AF Bristow, MR Zelis, R TI Baseline and three month change in systemic venous norepinephrine as predictors of clinical outcomes in the BEST Trial investigators. SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 VA Cooperat Clin Trials Ctr, Palo Alto, CA USA. NHLBI, Bethesda, MD 20892 USA. RI bristow, michael/G-7850-2011 NR 0 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 183A EP 183A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400836 ER PT J AU Morshedi-Meibodi, A Larson, MG Levy, D O'Donnell, CJ Vasan, RS AF Morshedi-Meibodi, A Larson, MG Levy, D O'Donnell, CJ Vasan, RS TI Heart rate recovery after exercise testing and risk of coronary disease in the Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 184A EP 184A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400843 ER PT J AU Begley, DA Mohiddin, S Fananapazir, L AF Begley, DA Mohiddin, S Fananapazir, L TI Left atrial dimension predicts impaired exercise performance in non obstructive hypertrophic cardiomyopathy: Relation to impaired left ventricular systolic and diastolic function but not to severity of left ventricular hypertrophy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 203A EP 203A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400929 ER PT J AU Begley, DA Mohiddin, S Fananapazir, L AF Begley, DA Mohiddin, S Fananapazir, L TI Angiotensin-1 converting enzyme gene deletion polymorphism is associated with impaired left ventricular systolic function and exercise performance in non-obstructive hypertrophic cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 214A EP 214A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400979 ER PT J AU Mohiddin, SA Winkler, J Clam, EM Begley, DA Fananapazir, L AF Mohiddin, SA Winkler, J Clam, EM Begley, DA Fananapazir, L TI Prevalence and clinical characteristics of hypertrophic cardiomyopathy caused by actin mutations SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, NHLBI, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 214A EP 214A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400977 ER PT J AU Voltchikhina, SA Yacono, BC Lakatta, EG Talan, MI AF Voltchikhina, SA Yacono, BC Lakatta, EG Talan, MI TI Two distinct chronic heart failure phenotypes following myocardial infarction in mice SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 215A EP 215A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400982 ER PT J AU Halcox, JPJ Zalos, G Mincemoyer, R Schenke, WH Waclwiw, MA Nour, KRA Prasad, A Quyyumi, AA AF Halcox, JPJ Zalos, G Mincemoyer, R Schenke, WH Waclwiw, MA Nour, KRA Prasad, A Quyyumi, AA TI Coronary microvascular endothelial dysfunction is associated with an increased risk of acute cardiovascular events during long-term follow-up SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 242A EP 242A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401111 ER PT J AU Paniagua, OA Bryant, MB Panza, JA AF Paniagua, OA Bryant, MB Panza, JA TI Reduced shear stress-induced, nitric oxide-mediated, dilation of the microvasculature in hypertensive patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 242A EP 242A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401110 ER PT J AU Zuzak, KJ Schaeberle, MD Gladwin, MT Cannon, RO Levin, IW AF Zuzak, KJ Schaeberle, MD Gladwin, MT Cannon, RO Levin, IW TI Noninvasive measurement of hemoglobin saturation by visible reflectance hyperspectral imaging during nitric oxide inhibition and inhalation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 250A EP 251A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401149 ER PT J AU Zhu, JH Quyyumi, AA Rott, D Wu, HS Halcox, JPJ Epstein, SE AF Zhu, JH Quyyumi, AA Rott, D Wu, HS Halcox, JPJ Epstein, SE TI Antibodies to human heat shock protein 60 are associated with presence and severity of coronary artery disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington, DC 20010 USA. NIH, NHLBI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 265A EP 265A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401215 ER PT J AU Bristow, MR Zelis, R Nuzzo, R Lindenfeld, J Lowes, BD Domanski, MJ Eichhorn, EJ Krause-Steinrauf, HJ AF Bristow, MR Zelis, R Nuzzo, R Lindenfeld, J Lowes, BD Domanski, MJ Eichhorn, EJ Krause-Steinrauf, HJ CA BEST Trial Investigators Na TI Baseline and three month change in systemic venous norepinephrine as predictors of clinical outcomes in the BEST trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 VA Cooperat Clin Trials Ctr, Palo Alto, CA USA. NHLBI, Bethesda, MD 20892 USA. RI bristow, michael/G-7850-2011 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 281A EP 281A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401288 ER PT J AU Cannon, RO Gladwin, MT Bryant, MB Schechter, AN Panza, JA AF Cannon, RO Gladwin, MT Bryant, MB Schechter, AN Panza, JA TI Nitric oxide inhalation enhances systemic vasodilator tone during regional inhibition of nitric oxide synthesis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 284A EP 284A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401304 ER PT J AU Campia, U Choucair, WK Bryant, MB Cardillo, C Panza, JA AF Campia, U Choucair, WK Bryant, MB Cardillo, C Panza, JA TI Racial differences in endothelium-dependent and -independent dilation of large arteries SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 293A EP 293A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401350 ER PT J AU Halcox, JPJ McDermott, DH Merrell, MN Epstein, N Murphy, PM Quyyumi, AA AF Halcox, JPJ McDermott, DH Merrell, MN Epstein, N Murphy, PM Quyyumi, AA TI Association between polymorphisms in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 302A EP 302A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401394 ER PT J AU Nour, KRA Halcox, JPJ Fuchs, S Sachdev, V Panza, JA Dilsizian, V Mincemoyer, R Kornowski, R Quyyumi, AA AF Nour, KRA Halcox, JPJ Fuchs, S Sachdev, V Panza, JA Dilsizian, V Mincemoyer, R Kornowski, R Quyyumi, AA TI Electromechanical left ventricular mapping with dobutamine stress for detection of myocardial viability SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. Washington Hosp Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 348A EP 348A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401598 ER PT J AU Chuang, ML Salton, CJ Kissinger, KV Levy, D O'Donnell, CJ Manning, WJ AF Chuang, ML Salton, CJ Kissinger, KV Levy, D O'Donnell, CJ Manning, WJ TI Relation between left ventricular sphericity and errors in M-mode mass: Insights from magnetic resonance imaging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 388A EP 388A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401778 ER PT J AU Kim, YJ Jones, M Shiota, T Bauer, F Qin, JX Sitges, M Tsujino, H Travaglini, A Cardon, LA Zetts, AD Panza, JA Thomas, JD AF Kim, YJ Jones, M Shiota, T Bauer, F Qin, JX Sitges, M Tsujino, H Travaglini, A Cardon, LA Zetts, AD Panza, JA Thomas, JD TI Is ejection fraction a reliable marker of left ventricular contractility? Comparison with Emax in chronic animal models with load alterations SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 388A EP 388A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401776 ER PT J AU Chuang, ML Salton, CJ Kissinger, KV Levy, D O'Donnell, CJ Manning, WJ AF Chuang, ML Salton, CJ Kissinger, KV Levy, D O'Donnell, CJ Manning, WJ TI M-mode errors in determination of left ventricular mass are greater with increasing cavity size and wall thickness: An MRI study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 392A EP 392A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401794 ER PT J AU Vasan, RS Larson, MG Levy, D Galderisi, M Wolf, PA Benjamin, EJ AF Vasan, RS Larson, MG Levy, D Galderisi, M Wolf, PA Benjamin, EJ TI Doppler indices of left ventricular filling and risk of atrial fibrillation: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 397A EP 397A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401814 ER PT J AU Plehn, JF O'Meara, E Newman, AB Polak, J Manolio, TA Gottdiener, JS AF Plehn, JF O'Meara, E Newman, AB Polak, J Manolio, TA Gottdiener, JS TI Echocardiographic predictors of abdominal aortic aneurysm: The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 St Francis Hosp, Roslyn, NY USA. NHLBI, Bethesda, MD 20892 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 404A EP 404A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401846 ER PT J AU Bauer, F Jones, M Shiota, T Firstenberg, M Qin, JX Tsujino, H Kim, YJ Sitges, M Cardon, L Zetts, AD Thomas, JD AF Bauer, F Jones, M Shiota, T Firstenberg, M Qin, JX Tsujino, H Kim, YJ Sitges, M Cardon, L Zetts, AD Thomas, JD TI Left ventricular outflow tract mean systolic acceleration as a surrogate of the slope of the left ventricular end-systolic pressure-volume relationship SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 417A EP 417A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401903 ER PT J AU Watanabe, J Johns, M Shiota, T Tsujino, H Zetts, AD Qin, JX Cardon, LA Sitges, M Bauer, F Kim, YJ Garcia, MJ Thomas, JD AF Watanabe, J Johns, M Shiota, T Tsujino, H Zetts, AD Qin, JX Cardon, LA Sitges, M Bauer, F Kim, YJ Garcia, MJ Thomas, JD TI Characteristics of left ventricular aneurysm by color M-mode echocardiography: A chronic animal study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 418A EP 418A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401907 ER PT J AU Khin, MM Kitsiou, AN Carson, J Bacharach, SL Dilsizian, V AF Khin, MM Kitsiou, AN Carson, J Bacharach, SL Dilsizian, V TI Increased right ventricular thallium uptake in chronic ischemic left ventricular dysfunction: Evidence for improvement after coronary artery revascularization SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 420A EP 420A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401914 ER PT J AU Sitges, M Jones, M Shiota, T Caden, DM Qin, JX Tsujino, H Bauer, F Kim, YJ Cardon, LA Martin, MG Zetts, AD Panza, JA McCarthy, PM Thomas, JD AF Sitges, M Jones, M Shiota, T Caden, DM Qin, JX Tsujino, H Bauer, F Kim, YJ Cardon, LA Martin, MG Zetts, AD Panza, JA McCarthy, PM Thomas, JD TI Real-time three-dimensional echocardiography and cine-ventriculography for determining left ventricular volumes in the presence of left ventricular aneurysms SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 425A EP 426A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401940 ER PT J AU Nour, KA Fuchs, S Halcox, JPJ Kornowski, R Mincemoyer, R Miller-Davis, C Dilsizian, V Quyyumi, AA AF Nour, KA Fuchs, S Halcox, JPJ Kornowski, R Mincemoyer, R Miller-Davis, C Dilsizian, V Quyyumi, AA TI Characteristics of ischemic myocardium detected by positron emission tomography during left ventricular electromechanical mapping SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 435A EP 435A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401982 ER PT J AU Watanabe, J Jones, M Shiota, T Bauer, F Tsujino, H Kim, YJ Garcia, MJ Qin, JX Sitges, M Travaglini, A Thomas, JD AF Watanabe, J Jones, M Shiota, T Bauer, F Tsujino, H Kim, YJ Garcia, MJ Qin, JX Sitges, M Travaglini, A Thomas, JD TI Color M-mode Doppler flow propagation of late diastolic velocity caused by left atrial-left ventricular pressure gradient: An animal study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 435A EP 435A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401984 ER PT J AU Daugherty, DW Jones, M Shiota, T Teien, D Bauer, F Sitges, M Qin, JX Tsujino, H Zetts, AD Panza, JA Thomas, JD AF Daugherty, DW Jones, M Shiota, T Teien, D Bauer, F Sitges, M Qin, JX Tsujino, H Zetts, AD Panza, JA Thomas, JD TI Relationship between the left atrial and left ventricular pressures and pulmonary venous flow velocities in animals with and without mitral regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 439A EP 439A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401998 ER PT J AU Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Hang, XY Greenberg, NL Panza, JA Thomas, JD AF Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Hang, XY Greenberg, NL Panza, JA Thomas, JD TI Combination of real-time 3-D color Doppler flow rate estimation and pulsed-wave Doppler echocardiography for quantifying stroke volume through the left ventricular outflow tract SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 442A EP 442A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402014 ER PT J AU Tamura, K Ishizaki, M Sugisaki, Y Saku, Y Yu, ZX Ferrans, VJ AF Tamura, K Ishizaki, M Sugisaki, Y Saku, Y Yu, ZX Ferrans, VJ TI Histopathological study of congenital bicuspid aortic valves SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, NHLBI, Bethesda, MD 20892 USA. Nippon Med Sch, Tokyo 113, Japan. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 475A EP 476A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402158 ER PT J AU Deserranno, D Sitges, M Greenberg, NL Shiota, T Jones, M Thomas, JD Garcia, MJ AF Deserranno, D Sitges, M Greenberg, NL Shiota, T Jones, M Thomas, JD Garcia, MJ TI Geometrical correction improves accuracy of the interaliasing distance method for quantifying mitral regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 481A EP 481A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402186 ER PT J AU Li, XK Li, J Jones, M Davies, CH Sahn, DJ AF Li, XK Li, J Jones, M Davies, CH Sahn, DJ TI Real-time 3-D echo methods for quantification of aortic regurgitation in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, LAMS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 481A EP 481A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402184 ER PT J AU Tsujino, H Jones, M Shiota, T Kim, Y Bauer, F Qin, JX Sitges, M Cardon, LA Zetts, AD Thomas, JD AF Tsujino, H Jones, M Shiota, T Kim, Y Bauer, F Qin, JX Sitges, M Cardon, LA Zetts, AD Thomas, JD TI Influence of loading conditions on physical determinants of aortic regurgitant flow volume and severity: A chronic animal experiment SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 485A EP 485A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402206 ER PT J AU Freed, LA Benjamin, EJ Levy, D Larson, MG Evans, JC Fuller, DL Lehman, B Levine, RA AF Freed, LA Benjamin, EJ Levy, D Larson, MG Evans, JC Fuller, DL Lehman, B Levine, RA TI The progression of mitral valve prolapse: A follow-up investigation in the Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 490A EP 490A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402226 ER PT J AU Andrews, NP Husain, M Dakak, N Quyyumi, AA AF Andrews, NP Husain, M Dakak, N Quyyumi, AA TI Platelet inhibitory effect of nitric oxide in the human coronary circulation: Impact of endothelial dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID RELAXING FACTOR; SMOOTH-MUSCLE; SODIUM-NITROPRUSSIDE; DEPENDENT RELAXATION; RISK-FACTORS; WHOLE-BLOOD; CYCLIC-GMP; VASCULAR ENDOTHELIUM; S-NITROSOHEMOGLOBIN; THROMBUS FORMATION AB OBJECTIVES We sought to determine whether coronary vascular nitric oxide (NO) release in vivo modulates platelet activation. BACKGROUND Nitric oxide modulates vasodilator tone and platelet activity via the cyclic guanosine monophosphate (cGMP) pathway, but whether coronary endothelial dysfunction influences platelet cGMP content during intracoronary infusion of acetylcholine (ACH), L-N-G monomethyl arginine (L-NMMA) and sodium nitroprusside. RESULTS Acety;choline increased platelet cGMP content (p = 0.013), but its magnitude was lower in patients with endothelial dysfunction; thus, patients with epicardial constriction with ACH had a 7 +/- 6%, p = ns change compared with a 32 +/- 13%, p = 0.05 increase in platelet cGMP in those with epicardial dilation. Similarly, patients with atherosclerosis or its risk factors had a smaller increase (9 +/- 6%) compared with those having normal coronary arteries without risk factors (51 +/- 22%, p = 0.019). L-N-G monomethyl arginine decreased platelet cGMP content to a greater extent in patients with epicardial dilation with ACH (-15 +/- 7%, p = 0.06) compared to those with constriction (+5 +/- 6% change, p = 0.5). Sodium nitroprusside produced a similar increase in platelet cGMP content in patients with and without endothelial dysfunction (p = 0.56). The effect of sodium nitroprusside, but not ACH or L-NMMA, were reproduced in vitro. CONCLUSIONS Platelet cGMP levels can be modulated by basal and stimulated release of NO. The platelet inhibitory effect of NO is reduced in patients with endothelial dysfunction, which may explain their increased risk from thrombotic events and the improved survival associated with strategies designed to improve vascular function. (C) 2001 by the American College of Cardiology. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B-15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 51 TC 24 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 BP 510 EP 516 DI 10.1016/S0735-1097(00)01114-1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 400AV UT WOS:000166847200023 PM 11216971 ER PT J AU Mori, Y Irvine, T Jones, M Rusk, RA Pham, Q Kenny, A Sahn, DJ AF Mori, Y Irvine, T Jones, M Rusk, RA Pham, Q Kenny, A Sahn, DJ TI Validation of a digital color Doppler flow measurement method for pulmonary regurgitant volumes and regurgitant fractions in an in vitro model and in a chronic animal model of postoperative repaired tetralogy of Fallot SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CARDIAC-OUTPUT; BLOOD-FLOW; IN-VITRO; ECHOCARDIOGRAPHY; QUANTIFICATION; AREA AB OBJECTIVES The purpose of this study was to validate a digital color Doppler (DCD) automated cardiac flow measurement method for quantifying pulmonary regurgitation (PR) in an in vitro and a chronic animal model of the right ventricular outflow tract of postoperative tetralogy of Fallot (TOF). BACKGROUND There has been no reliable ultrasound method that can accurately quantitate PR. METHODS We developed an in vitro model of mild pulmonary stensosis and wide-open PR that mimics the patterns of flow seen in patients with postoperative TOF. Thirteen different forward and regurgitant stroke volumes (RSVs) across the noncircular shaped cross-sectional outflow tract flow area were estimated using the DCD method in two orthogonal planes. In six sheep with surgically created PR, 24 different hemodynamic states with PR fstrictly quantitified by electromagnetic probes were also studied. RESULTS The RSVs and regurgitant fractions (RFs) obtained by the DCD method using average values from two orthogonal planes correlated well with reference values (RSV:r = 0.99, mean difference = 0.02 +/- 0.39 ml/beat for in vitro model; r = 0.97, mean differences = 1.79 +/- 1.84 ml/beat for animal model, RF:r = 0.98, mean difference = -1.10 +/- 4.34% for in vitro model; r = 0.94, mean difference = 2.73 +/- 6.75% for animal model). However, the DCD method using a single plane had limited accuracy for estimating pulmonary RFs and RSVs. CONCLUSIONS The DCD method using average values from two orthogonal planes provides accurate estimation of RSVs and RFs and should have clinical importance for serially quantifying PR in patients with postoperative TOF. (C) 2001 by the American College of Cardiology. C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Lab Anim Med & Surg, Bethesda, MD 20892 USA. Freeman Rd Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England. RP Jones, M (reprint author), Oregon Hlth Sci Univ, Portland, OR 97201 USA. NR 14 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 BP 632 EP 640 DI 10.1016/S0735-1097(00)01106-2 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 400AV UT WOS:000166847200042 PM 11216990 ER PT J AU Costello, RB Coates, P AF Costello, RB Coates, P TI In the midst of confusion lies opportunity: Fostering quality science in dietary supplement research SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Review DE dietary supplements; government programs; evidence-based medicine; botanicals AB The Office of Dietary Supplements (ODS) was established at the National Institutes of Health (NIH) by Congress through the Dietary Supplement Health and Education Act (DSHEA) of 1994. The mission of the ODS is to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, stimulating and supporting research, disseminating research results and educating the public, all in an effort to foster an enhanced quality of life and health for the U.S. population. In pursuit of this mission, ODS takes into account an array of dietary supplement ingredients and products. This includes vitamin and mineral supplements and botanicals, as well as non-nutrient supplements. Toward that end, ODS has taken a number of steps. In collaboration with other Institutes and Centers at NIH, ODS has established a network of Dietary Supplement Research Centers around the country that provide the focus for multidisciplinary research efforts; it supports research activities and scientific conferences, it supports evidence-based reviews of supplements, and it maintains a public database of scientific literature on dietary supplements. The lack of credible information from well-controlled studies of many dietary supplements raises issues of caution and concern. The ODS is committed to providing and disseminating accurate and reliable scientific information on dietary supplements. C1 NIH, ODS, Off Director, Bethesda, MD 20892 USA. RP Costello, RB (reprint author), NIH, ODS, Off Director, 31 Ctr Dr,1B29, Bethesda, MD 20892 USA. NR 22 TC 6 Z9 6 U1 0 U2 0 PU AMER COLL NUTRITION PI NEW YORK PA C/O HOSP. JOINT DIS. 301 E. 17TH ST., NEW YORK, NY 10003 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD FEB PY 2001 VL 20 IS 1 BP 21 EP 25 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 415UQ UT WOS:000167742300004 PM 11293464 ER PT J AU Shenkin, JD Baum, BJ AF Shenkin, JD Baum, BJ TI Oral health and the role of the geriatrician SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID ADULTS 30 YEARS; PERIODONTAL-DISEASE; UNITED-STATES; CEREBROVASCULAR ISCHEMIA; CORONARY HEART; OLDER; CARE; RISK; ASSOCIATION; BACTERIAL C1 Natl Inst Dent & Craniofacial Res, Off Sci Policy & Anal, NIH, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Shenkin, JD (reprint author), Natl Inst Dent & Craniofacial Res, Off Sci Policy & Anal, NIH, Bethesda, MD USA. NR 18 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2001 VL 49 IS 2 BP 229 EP 230 DI 10.1046/j.1532-5415.2001.49044.x PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 403TA UT WOS:000167057500018 PM 11207880 ER PT J AU Kim, W Wilbur, WJ AF Kim, W Wilbur, WJ TI Corpus-based statistical screening for content-bearing terms SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID RETRIEVAL; WORDS AB An important problem in the indexing of natural language text is how to identify those words and phrases that reflect the content of the text. In general, automatic indexing has dealt with this problem by removing instances of a few hundred common words known as stop words, and treating the remaining words as though they were content bearing. This approach is acceptable for some applications such as statistical estimates of the similarity of queries and documents for the purpose of document retrieval. However, when the indexing terms are to be examined by a human as a means of accessing the literature, it greatly improves efficiency if most of the noncontent-bearing words and phrases can be eliminated from the indexing, Here we present three statistical techniques for identifying content-bearing phrases within a natural language database. We demonstrate the effectiveness of the methods on test data, and show how all three methods can be combined to produce a single improved method. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,Rm 8S806,8600 Rockville Pike, Bethesda, MD 20894 USA. EM wonkim@ncbi.nlm.nih.gov NR 33 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1532-2882 EI 1532-2890 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD FEB 1 PY 2001 VL 52 IS 3 BP 247 EP 259 DI 10.1002/1097-4571(2000)9999:9999<::AID-ASI1588>3.0.CO;2-7 PG 13 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 406CU UT WOS:000167198000006 ER PT J AU Ecelbarger, CA Knepper, MA Verbalis, JG AF Ecelbarger, CA Knepper, MA Verbalis, JG TI Increased abundance of distal sodium transporters in rat kidney during vasopressin escape SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MOLECULAR-CLONING; CL COTRANSPORTER; BLOOD-PRESSURE; WATER CHANNEL; SALT; DESENSITIZATION; ANTIDIURESIS; EXPRESSION; ADAPTATION; RECEPTOR AB Hyponatremia is associated with inappropriately elevated vasopressin levels. A brisk natriuresis precedes the escape from this antidiuresis. Thus, the hypothesis was that the abundance of one or more of the sodium transporters of the distal tubule (a site for fine tuning of sodium balance) would be altered during vasopressin escape. Semiquantitative immunoblotting was used to examine the regulation of abundance of several sodium transporters/channels of the thick ascending limb through the collecting duct in the rat model. Osmotic minipumps to infuse dDAVP, the V2-selective vasopressin agonist (5 ng/h) for the entire experiment, were implanted in Male Sprague-Dawley rats. After 4 d, rats were divided into a control (dry AIN-76 diet/ad libitum water) or a water-loaded (gelled-agar-AIN-76 diet/ad libitum water) group. Rats were killed after 1, 2, 3, or 7 additional days. The water-loaded rats were hyponatremic (plasma Na+, 98 to 122 mmol/L) and manifested the expected early natriuresis and diuresis of vasopressin escape. Water loading (with dDAVP infusion) resulted in increased whole-kidney abundances of the thiazide-sensitive Na-Cl co-transporter, the alpha -subunit of the epithelial sodium channel (ENaC), and the 70-kD dimer of the gamma -subunit of ENaC. No changes were observed for the beta -subunit of ENaC. Similar protein changes have recently been associated with elevated aldosterone levels in rats. However, plasma aldosterone levels were significantly suppressed in this model. These data suggest that several distal sodium reabsorptive mechanisms are upregulated during vasopressin escape; this may help to attenuate the developing hyponatremia resulting from water loading when vasopressin levels are inappropriately elevated. C1 Georgetown Univ, Dept Med, Div Endocrinol & Metab, Washington, DC 20052 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Ecelbarger, CA (reprint author), Georgetown Univ, Dept Med, Div Endocrinol & Metab, Bldg D,Room 232,4000 Reservoir Rd NW, Washington, DC 20052 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NIDDK NIH HHS [DK38094, K01 DK002672, K01 DK02672-01] NR 52 TC 49 Z9 49 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2001 VL 12 IS 2 BP 207 EP 217 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 397UR UT WOS:000166716200001 PM 11158210 ER PT J AU Choyke, PL Pavlovich, CP Daryanani, KD Hewitt, SM Linehan, WM Walther, MM AF Choyke, PL Pavlovich, CP Daryanani, KD Hewitt, SM Linehan, WM Walther, MM TI Intraoperative ultrasound during renal parenchymal sparing surgery for hereditary renal cancers: A 10-year experience SO JOURNAL OF UROLOGY LA English DT Article DE ultrasonography; kidney neoplasms; neoplastic syndromes; hereditary; intraoperative care ID CELL CARCINOMA; IMAGING FEATURES; LINDAU DISEASE; SONOGRAPHY; ULTRASONOGRAPHY; FAMILIES; TUMORS AB Purpose: We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers. Materials and Methods: Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but I of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map. Results: A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm, to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat. Conclusions: Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery. C1 NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Pathol Lab, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 14 TC 31 Z9 32 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2001 VL 165 IS 2 BP 397 EP 400 DI 10.1097/00005392-200102000-00010 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 391QP UT WOS:000166366900010 PM 11176381 ER PT J AU Chang, R Cannon, RO Chen, CC Doppman, JL Shawker, TH Mayo, DJ Wood, B Horne, MK AF Chang, R Cannon, RO Chen, CC Doppman, JL Shawker, TH Mayo, DJ Wood, B Horne, MK TI Daily catheter-directed single dosing of t-PA in treatment of acute deep venous thrombosis of the lower extremity SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE thrombolysis; thrombosis, venous; tissue-type plasminogen activator ID THROMBOLYTIC THERAPY AB The strong fibrin affinity of recombinant tissue plasminogen activator (rt-PA) theoretically obviates continuous infusion or replacement of t-PA after direct intrathrombic injection. This hypothesis led the authors to evaluate single daily catheter-directed injection of rt-PA as a thrombolytic treatment for acute deep vein thrombosis of the lower extremity. Once-daily injection of rt-PA was performed in large thrombosed veins (popliteal or larger) with use of pulse-spray catheters and in small thrombosed veins in patients' calves with use of 3-4-F coaxial catheters. Patients received only full systemic anticoagulation on his/her patient care unit. This dosing regimen has been tested in 10 patients (12 legs) with a maximum dose of 50 mg per leg per day. Extensive thrombolysis was achieved in nine patients and partial thrombolysis was achieved in one patient, at an average total dose of 106 mg of rt-PA per leg. Minor bleeding was seen in three patients and no transfusions were needed. Our technique and the rationale for this pilot study is the focus of this article. C1 NHLBI, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Imaging Sci, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Clin Pathol, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Chang, R (reprint author), NIH, Dept Radiol, Bldg 10,Room 1C-660, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 22 TC 31 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2001 VL 12 IS 2 BP 247 EP 252 DI 10.1016/S1051-0443(07)61832-6 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 402QE UT WOS:000166999000015 PM 11265890 ER PT J AU Wood, BJ Bates, S AF Wood, BJ Bates, S TI Radiofrequency thermal ablation of a splenic metastasis SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE radiofrequency (RF) ablation; spleen, neoplasms ID SPLEEN; CARCINOMA; BIOPSY AB Effective local ablation of large tumors with radiofrequency has been made possible by recent advancements. Tumor ablation with radiofrequency has been described mainly in the liver, but also recently in the kidney, adrenal gland, lung, and breast. A rapidly growing splenic metastasis from renal cell carcinoma was effectively treated percutaneously, with US guidance. Focal splenic disease may not be a common indication for ablation; however, further work is necessary to evaluate the safety and efficacy of this procedure in this setting. C1 NIH, Ctr Clin, Special Procedures Diagnost Radiol Dept, Bethesda, MD 20892 USA. NCI, Med Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Clin, Special Procedures Diagnost Radiol Dept, Bldg 10,Room 1C-660, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 14 TC 38 Z9 52 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2001 VL 12 IS 2 BP 261 EP 263 DI 10.1016/S1051-0443(07)61835-1 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 402QE UT WOS:000166999000018 PM 11265893 ER PT J AU Yuan, CC Miley, W Waters, D AF Yuan, CC Miley, W Waters, D TI A quantification of human cells using an ERV-3 real time PCR assay SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE cell marker; quantification; ERV-3; real-lime PCR ID POLYMERASE-CHAIN-REACTION; DETECTION SYSTEM; ENDOGENOUS RETROVIRUSES; INFECTED INDIVIDUALS; QUANTITATIVE PCR; PROVIRUS; GENE AB A novel approach to quantifying human cells using a real time PCR assay was developed. The target sequence used in the assay is a 135 bp segment within the unique 1.7 kb Hind III; Pst I fragment of the ERV-3 envelope gene. ERV-3 is a full-length human endogenous retrovirus present in known copy number in all human cells. The detection range of ERV-3 by real time PCR is from 10(6) to 10(1). The precision described, sensitivity and specificity of the assay indicate that the ERV-3 sequence is an accurate cell quantitation marker. The quantitative ERV-3 assay enables simple. fast, and reproducible detection and quantitation of the cell number. The assay can be used to determine the sample DNA conditions and also it can be used to adjust the quantitative DNA measurements of other target gene assays relative to the number of cell equivelants, (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Viral Epidemiol Sect, Frederick, MD 21702 USA. RP Yuan, CC (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Viral Epidemiol Sect, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 18 TC 87 Z9 87 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD FEB PY 2001 VL 91 IS 2 BP 109 EP 117 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 396RG UT WOS:000166649900002 PM 11164492 ER PT J AU Esser, MT Bess, JW Suryanarayana, K Chertova, E Marti, D Carrington, M Arthur, LO Lifson, JD AF Esser, MT Bess, JW Suryanarayana, K Chertova, E Marti, D Carrington, M Arthur, LO Lifson, JD TI Partial activation and induction of apoptosis in CD4(+) and CD8(+) T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID BLOOD MONONUCLEAR-CELLS; FAS-LIGAND EXPRESSION; HIV-INFECTED PERSONS; DISEASE PROGRESSION; IN-VITRO; CLASS-II; GLYCOPROTEIN GP120; MEMBRANE-PROTEINS; CD4+ LYMPHOCYTES; BYSTANDER CELLS AB Increased levels of apoptosis are seen in human immunodeficiency virus (HIV) infection, and this has been proposed as an important mechanism contributing to HIV pathogenesis. However, interpretation of in vitro studies aimed at understanding HIV-related apoptosis has been complicated by the use of high concentrations of recombinant proteins or by direct cytopathic effects of replicating virus. We have developed an Inactivation procedure that destroys retroviral infectivity while preserving the structural and functional integrity of the HIV surface proteins, These noninfectious virions interact authentically dth target cells, providing a powerful tool to dissect mechanisms of HIV pathogenesis that do or do not require viral replication, Noninfectious CXCR4-tropic HIV-1 virions, but not microvesicles, partially activated freshly isolated CD4(+) and CD8(+) peripheral blood mononuclear cell T lymphocytes to express FasL and Fas, but not CD69 or CD25 (interleukin-2 receptor alpha) and eventually die via apoptosis starting 1 to 6 days postexposure. These effects required conformationally. intact virions, as heat-denatured virions or equivalent amounts of recombinant gp120 did not induce apoptosis, The maximal apoptotic effect was dependent on major histocompatibility complex (MHC) class II proteins being present on the virion, but was not MHC restricted. The results suggest that the immunopathogenesis of HIV infection may not depend solely on direct cytopathic effects of HIV replication, but that effects due to noninfectious HIV-1 virions may also contribute importantly. C1 NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, SAIC Frederick,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Lifson, JD (reprint author), NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, SAIC Frederick,Frederick Canc Res & Dev Ctr, Bldg 535,Room 509, Frederick, MD 21702 USA. RI Bess, Jr., Julian/B-5343-2012 FU NCI NIH HHS [N01-CO-560000] NR 75 TC 67 Z9 67 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1152 EP 1164 DI 10.1128/JVI.75.3.1152-1164.2001 PG 13 WC Virology SC Virology GA 391WF UT WOS:000166378700007 PM 11152488 ER PT J AU Wei, L Huhn, JS Mory, A Pathak, HB Sosnovtsev, S Green, KY Cameron, CE AF Wei, L Huhn, JS Mory, A Pathak, HB Sosnovtsev, S Green, KY Cameron, CE TI Proteinase-polymerase precursor as the active form of feline calicivirus RNA-dependent RNA polymerase SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-DISEASE VIRUS; ESCHERICHIA-COLI; CLEAVAGE SITES; 3C-LIKE PROTEASE; IN-VITRO; IDENTIFICATION; POLYPROTEIN; POLIOVIRUS; EXPRESSION; POLYPEPTIDE AB The objective of this study was to identify the active form of the feline calicivirus (FCV) RNA dependent RNA polymerase (RdRP). Multiple active forms of the FCV RdRP were identified. The most active enzyme was the full-length proteinase-polymerase (Pro Pol) precursor protein, corresponding to amino acids 1072 to 1763 of the FCV polyprotein encoded by open reading frame 1 of the genome. Deletion of 163 amino acids from the amino terminus of Pro-Pol (the Val-1235 amino terminus) caused a threefold reduction in polymerase activity, Deletion of an additional one (the Thr-1236 amino terminus) or two (the Ala-1237 amino terminus) amino acids produced derivatives that were 7- and 175-fold, respectively, less active than Pro-Pol. FCV proteinase-dependent processing of Pro-Pol in the interdomain region preceding Val-1235 was not observed in the presence of a catalytically active proteinase; however, processing within the polymerase domain was observed. Inactivation of proteinase activity by changing the catalytic cysteine-1193 to glycine permitted the production and purification of intact Pro-Pol. Biochemical analysis of Pro-Pol showed that this enzyme has properties expected of a replicative polymerase, suggesting that Pro-Pol is an active form of the FCV RdRP. C1 Penn State Univ, Dept Biochem & Mol Biol, Althouse Lab 201, University Pk, PA 16802 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cameron, CE (reprint author), Penn State Univ, Dept Biochem & Mol Biol, Althouse Lab 201, University Pk, PA 16802 USA. FU NCI NIH HHS [CA75118] NR 27 TC 41 Z9 43 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1211 EP 1219 DI 10.1128/JVI.75.3.1211-1219.2001 PG 9 WC Virology SC Virology GA 391WF UT WOS:000166378700013 PM 11152494 ER PT J AU Taylor, DR Tian, B Romano, PR Hinnebusch, AG Lai, MMC Mathews, MB AF Taylor, DR Tian, B Romano, PR Hinnebusch, AG Lai, MMC Mathews, MB TI Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; NF-KAPPA-B; POLYACRYLAMIDE-GEL ELECTROPHORESIS; KINASE PKR; INTERFERON ACTION; HUMAN-CELLS; IN-VIVO; ACTIVATION; PHOSPHORYLATION; DAI AB Double-stranded-RNA (dsRNA)-dependent protein kinase PKR is induced by interferon and activated upon autophosphorylation. We previously identified four autophosphorylated amino acids and elucidated their participation in PKR activation. Three of these sites are in the central region of the protein, and one is in the kinase domain, Here we describe the identification of four additional autophosphorylated amino acids in the spacer region that separates the two dsRNA-binding motifs in the RNA-binding domain. Eight amino acids, including these autophosphorylation sites, are duplicated in hepatitis C virus (HCV) envelope protein E2. This region of E2 is required for its inhibition of PKR although the mechanism of inhibition is not known. Replacement of all four of these residues in PKR with alanines did not dramatically affect kinase activity in vitro or in yeast Saccharomyces cerevisiae, However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased PKR protein expression in mammalian cells, consistent with diminished kinase activity. A synthetic peptide corresponding to this region of PKR was phosphorylated in vitro by PKR, but phosphorylation was strongly inhibited after PKR was preincubated with HCV E2. Another synthetic peptide, corresponding to the central region of PKR and containing serine 242, was also phosphorylated by active PKR, but E2 did not inhibit this peptide as efficiently. Neither of the PKR peptides was able to disrupt the HCV E2-PKR interaction. Taken together, these results show that PKR is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of PKR by HCV E2 is not solely due to duplication of and competition with these autophosphorylation sites. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. SUNY Stony Brook, Genet Program, Stony Brook, NY 11794 USA. Univ So Calif, Sch Med, Howard Hughes Med Inst, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. NICHHD, Lab Eukaryot Gene Regulat, Bethesda, MD 20892 USA. RP Mathews, MB (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. RI Lai, Michael Ming-Chao/I-7001-2012; OI Tian, Bin/0000-0001-8903-8256 FU NCI NIH HHS [CA 13106, P01 CA013106]; NIAID NIH HHS [AI 34552, R01 AI034552] NR 60 TC 44 Z9 47 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1265 EP 1273 DI 10.1128/JVI.75.3.1265-1273.2001 PG 9 WC Virology SC Virology GA 391WF UT WOS:000166378700018 PM 11152499 ER PT J AU Ishii, K Moss, B AF Ishii, K Moss, B TI Role of vaccinia virus A20R protein in DNA replication: Construction and characterization of temperature-sensitive mutants SO JOURNAL OF VIROLOGY LA English DT Article ID MESSENGER-RNA; GENE; GLYCOSYLASE; POLYMERASE; MUTATIONS; VIABILITY; RESIDUES; SEQUENCE; ALANINE; KINASE AB Previous analyses of randomly generated, temperature-sensitive vaccinia virus mutants led to the mapping of DNA synthesis negative complementation groups to the B1R, D4R, D5R, and E9L genes. Evidence from the yeast two-hybrid system that the D4R and D5R proteins can interact with the A20R protein suggested that A20R was also involved in DNA replication. We found that the A20R gene was transcribed early after infection, consistent with such a role. To investigate the function of the A20R protein, targeted mutations were made by substituting alanines for charged amino acids occurring in 11 different clusters. Pour mutants were not isolated, suggesting that they were lethal, two mutants exhibited no temperature sensitivity, two mutants exhibited partial temperature sensitivity, and two mutants formed no plaques or infectious virus at 39 degreesC, The two mutants with stringent phenotypes were further characterized. Temperature shift-up experiments indicated that the crucial period was between 6 and 12 h after infection, making it unlikely that the defect was in virus entry, early gene expression, or a late stage of virus assembly. Similar patterns of metabolically labeled viral early proteins were detected at permissive and nonpermissive temperatures, but one mutant showed an absence of late proteins under the latter conditions. Moreover, no viral DNA synthesis was detected when cells were infected with either stringent mutant at 39 degreesC. The previous yeast two-hybrid analysis together with the present characterization of A20R temperature-sensitive mutants suggested that the A20R, D4R, and D5R proteins are components of a multiprotein DNA replication complex. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 27 TC 39 Z9 40 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 4 BP 1656 EP 1663 DI 10.1128/JVI.75.4.1656-1663.2001 PG 8 WC Virology SC Virology GA 397LK UT WOS:000166697000008 PM 11160663 ER PT J AU Mahieux, R Lambert, PF Agbottah, E Halanski, MA Deng, L Kashanchi, F Brady, JN AF Mahieux, R Lambert, PF Agbottah, E Halanski, MA Deng, L Kashanchi, F Brady, JN TI Cell cycle regulation of human interleukin-8 gene expression by the human immunodeficiency virus type 1 Tat protein SO JOURNAL OF VIROLOGY LA English DT Article ID NF-KAPPA-B; CREB-BINDING-PROTEIN; HIV-1 TAT; TRANSCRIPTIONAL ACTIVATION; I TAX; P300; COACTIVATORS; REQUIRES; PROMOTER; IL-8 AB The human immunodeficiency virus type 1 (HIV-1) Tat protein has been reported to transactivate several cellular genes, including the potent chemotactic factor interleukin-8 (IL-8). Consistent with these in vitro assays, elevated levels of IL-8 protein are found in the serum of HIV-infected individuals. We now extend these observations by demonstrating that Tat induction of IL-8 is linked to the cell cycle. Cells that constitutively express the Tat(1-86) protein (eTat) and control cells (pCEP) were reversibly blocked at the G(1)/S border,vith hydroxyurea or thymidine. The cells were subsequently released, and IL-8 expression was monitored by RNase protection assays and enzyme-linked immunosorbent assay (ELISA). RNase protection assays demonstrated that in 8 mRNA expression is transiently induced, approximately fourfold, as the Tat-expressing cells enter S phase. Consistent with the RNase protection assay, an increase in IL-8 protein was observed in the cell supernatant using an IL-8 ELISA. Similar experiments were performed following a reversible block at the G(2)/M border with nocodazole and release into G,. Using the RNase protection assay and ELISA, little or no increase in IL-8 expression was observed during G,. Using gel shift as well as an immobilized DNA binding assay, we demonstrate that the increase in IL-8 gene expression correlates with a specific increase in p65 NF-kappaB binding activity only in the nucleus of the Tat-expressing cells. Moreover, the CREB-binding protein coactivator is present in the complex in the Tat cell line. Finally, we demonstrate that the presence of the proteasome inhibitor MG-132 inhibits the induction of NF-kappaB binding, as well as IL-8 expression, supporting the role of NF-kappaB. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. RP Brady, JN (reprint author), NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NR 30 TC 22 Z9 23 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 4 BP 1736 EP 1743 DI 10.1128/JVI.75.4.1736-1743.2001 PG 8 WC Virology SC Virology GA 397LK UT WOS:000166697000016 PM 11160671 ER PT J AU Schech, JM AF Schech, JM TI An ounce of cooperation SO LAB ANIMAL LA English DT Editorial Material C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Schech, JM (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD FEB PY 2001 VL 30 IS 2 BP 20 EP 20 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 397PN UT WOS:000166704200003 ER PT J AU Calzone, T Montijo, KS St Claire, MB Lamoreaux, E AF Calzone, T Montijo, KS St Claire, MB Lamoreaux, E TI An integrated database for managing animal study proposals and animal inventory for the small animal facility SO LAB ANIMAL LA English DT Article AB The authors describe how they created a user-friendly, multifunctional database for use by a variety of vivarium staff. C1 NIAAA, NIH, Bethesda, MD 20892 USA. Pathol Associates Int, Frederick, MD USA. RP Calzone, T (reprint author), NIAAA, NIH, 31 Ctr Dr,MSC 2088, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD FEB PY 2001 VL 30 IS 2 BP 28 EP 31 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 397PN UT WOS:000166704200006 PM 11385750 ER PT J AU Morse, HC Kearney, JF Isaacson, PG Carroll, M Fredrickson, TN Jaffe, ES AF Morse, HC Kearney, JF Isaacson, PG Carroll, M Fredrickson, TN Jaffe, ES TI Cells of the marginal zone - origins, function and neoplasia SO LEUKEMIA RESEARCH LA English DT Article DE marginal zone lymphomas; marginal zone B cells; hepatitis C virus; API/ML; BCL10; FAS ID NON-HODGKIN-LYMPHOMA; B-CELL; HELICOBACTER-PYLORI; GASTRIC LYMPHOMA; REGION GENES; MUCOSA; TISSUE; INFECTION; MICE; ERADICATION AB Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIAAA, Immunopathol Lab, Bethesda, MD 20892 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Univ Coll & Middlesex Sch Med, Dept Pathol, London, England. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Morse, HC (reprint author), NIAAA, Immunopathol Lab, Bldg 7,Room 304,7 Ctr Dr,MSC 0760, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 FU NIAID NIH HHS [R01 AI014782] NR 38 TC 46 Z9 47 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2001 VL 25 IS 2 BP 169 EP 178 DI 10.1016/S0145-2126(00)00107-7 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 403DC UT WOS:000167026400010 PM 11166833 ER PT J AU Casibang, M Purdom, S Jakowlew, S Neckers, L Zia, F Ben-Av, P Hla, T You, L Jablons, DM Moody, TW AF Casibang, M Purdom, S Jakowlew, S Neckers, L Zia, F Ben-Av, P Hla, T You, L Jablons, DM Moody, TW TI Prostaglandin E-2 and vasoactive intestinal peptide increase vascular endothelial cell growth factor mRNAs in lung cancer cells SO LUNG CANCER LA English DT Article DE VEGF mRNA; PGE(2); VIP; somatostatin; cyclic AMP ID BOMBESIN-LIKE PEPTIDES; FACTOR EXPRESSION; FUNCTIONAL EXPRESSION; TYROSINE KINASE; GENE-EXPRESSION; EP(2) SUBTYPE; MESSENGER-RNA; RECEPTOR; ANGIOGENESIS; INDUCTION AB The effects of prostaglandin E-2 (PGE(2)) and vasoactive intestinal peptide (VIP) on vascular endothelial cell growth factor (VEGF) mRNAs were investigated using lung cancer cells. By RT-PCR, VEGF(121), VEGF(165), and VEGF(189), but not VEGF(206) isoforms were detected in all lung cancer cell lines and biopsy specimens examined. By Northern blot. VEGF mRNA was detected in all small cell lung cancer (SCLC) and non-SCLC (NSCLC) cell lines examined. PGE,. VIP and forskolin caused increased VEGF expression in a time- and concentration-dependent manner using NSCLC cell line NCI-H157. Approximately 1 muM PGE(2). 0.1 muM VIP and 50 muM forskolin caused cAMP elevation. 64-, 33- and 128-fold, respectively, using NCI-H157 cells after 5 min. The increase in cAMP caused by PGE(2) and VIP was reversed by somatostatin (SST). Also 1 muM PGE(2). 0.1 muM VIP and 50 muM forskolin increased the VEGF mRNA 2.0-. 1.5- and 2.3-fold, respectively. after 4 h. The increase in VEGF mRNA caused by PGE(2), VIP and forskolin was inhibited by H-89. a protein kinase A inhibitor. A VIP receptor antagonist. VlPhybrid. inhibited the increase in cAMP and VEGF mRNA caused by VIP. By ELISA, VEGF was detected in the conditioned media exposed to the lung cancer cell lines. These results suggest that VEGF synthesis ill and secretion from lune cancer cells can be regulated by agents, which cause adenylyl cyclase activation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, CCBD, Med Branch, Rockville, MD 20850 USA. George Washington Univ, Med Ctr, Dept Microbiol, Washington, DC 20037 USA. Amer Red Cross, Holland Lab, Dept Mol Biol, Rockville, MD 20855 USA. Univ Calif San Francisco, Mt Zion Canc Ctr, San Francisco, CA 94115 USA. RP Moody, TW (reprint author), NCI, CCBD, Med Branch, Bldg KWC,Rm 300,9610 Med Ctr Dr, Rockville, MD 20850 USA. RI Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 NR 41 TC 48 Z9 48 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD FEB-MAR PY 2001 VL 31 IS 2-3 BP 203 EP 212 DI 10.1016/S0169-5002(00)00168-9 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 401AQ UT WOS:000166905100012 PM 11165399 ER PT J AU Bulchand, S Grove, EA Porter, FD Tole, S AF Bulchand, S Grove, EA Porter, FD Tole, S TI LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem SO MECHANISMS OF DEVELOPMENT LA English DT Article DE cortical hem; patterning; Lhx2; Wnt; Bmp; shh; dorsoventral ID CEREBRAL-CORTEX; HOMEOBOX GENE; DORSOVENTRAL COMPARTMENTALIZATION; DEVELOPING FOREBRAIN; EARLY SPECIFICATION; WING DEVELOPMENT; VERTEBRATE LIMB; SONIC HEDGEHOG; RAT-BRAIN; EXPRESSION AB We are interested in the early mechanisms that initiate regional patterning in the dorsal telencephalon, which gives rise to cerebral cortex. Members of the LIM-homeodomain (LIM-HD) family of transcription factors are implicated in patterning and cell fate specification in several systems including the mammalian forebrain. Mice in which Lhx2 is disrupted were reported to have reduced telencephalic development, and the hippocampal primordium appeared to be missing, by morphological observation. We hypothesized that this may be due to a defect in the cortical hem, a Wnt- and Bmp-rich putative signaling center in the medial telencephalon, a source of regulatory signals for hippocampal development. We asked if the expression of any known hem-specific signaling molecule is deficient in Lhx2 -/- mice. Our results reveal, unexpectedly, that at embryonic day (E)12.5, what appears to be some spared 'lateral' cortex is instead an expanded cortical hem. Normally restricted to the extreme medial edge of the telencephalon, the hem covers almost the entire dorsal telencephalon in the Lhx2-/- mice. This indicates a role for Lhx2 in the regulation of the extent of the cortical hem. In spite of an expanded, mislocated hem in the Lhx2 -/- telencephalon, a potential source of ectopic dorsalizing cues, no hippocampal differentiation is detected in tissue adjacent to the mutant hem, nor does the overall dorsoventral patterning appear perturbed. We propose that Lhx2 is involved at a crucial early step in patterning the telencephalon, where the neuroepithelium is first divided into presumptive cortical tissue, and the cortical hem. The defect in the Lhx2 -/- telencephalon appears to be at this step. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Tata Inst Fundamental Res, Dept Biol Sci, Mumbai 400005, India. Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA. NIH, Bethesda, MD 20892 USA. RP Tole, S (reprint author), Tata Inst Fundamental Res, Dept Biol Sci, Mumbai 400005, India. FU NIMH NIH HHS [R01 MH59962-01] NR 55 TC 116 Z9 119 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2001 VL 100 IS 2 BP 165 EP 175 DI 10.1016/S0925-4773(00)00515-3 PG 11 WC Developmental Biology SC Developmental Biology GA 399WQ UT WOS:000166837600002 PM 11165475 ER PT J AU Wei, XR Ellis, HM AF Wei, XR Ellis, HM TI Localization of the Drosophila MAGUK protein Polychaetoid is controlled by alternative splicing SO MECHANISMS OF DEVELOPMENT LA English DT Article DE adherens junction; dorsal closure; Drosophila; membrane-associated guanylate kinase; PDZ domain; polychaetoid; sensory organs; septate junction; Zonula Occludens 1 ID JUNCTION-ASSOCIATED PROTEIN; TIGHT JUNCTION; EPITHELIAL-CELLS; PRONEURAL CLUSTERS; DIRECT BINDING; K+ CHANNELS; WING DISK; ZO-1; EXPRESSION; EXTRAMACROCHAETAE AB The Drosophila membrane-associated guanylate kinase (MAGUK) protein Polychaetoid (Pyd) is required for dorsal closure of the embryo, sensory organ patterning, and cell fate specification in the developing eye. We demonstrate that pyd is alternatively spliced resulting in two isoforms that differ by the presence or absence of exon 6. To determine the role of alternative splicing in Pyd function, we generated antibodies specific for each isoform. We find that the exon 6(+) form of Pyd is localized at adherens junctions of embryonic and imaginal epithelia, while the exon 6(-) form is distributed broadly along the lateral membrane. These results suggest that localization of Pyd is controlled by alternative splicing and raise the possibility that exon 6 represents a distinct protein-protein interaction domain. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Emory Univ, Dept Biol, Atlanta, GA 30322 USA. Emory Univ, Grad Program Biochem Cell & Dev Biol, Atlanta, GA 30322 USA. RP Ellis, HM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Control & Genet Sect, Bldg 539,Room 243,POB B, Frederick, MD 21702 USA. NR 46 TC 26 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2001 VL 100 IS 2 BP 217 EP 231 DI 10.1016/S0925-4773(00)00550-5 PG 15 WC Developmental Biology SC Developmental Biology GA 399WQ UT WOS:000166837600006 PM 11165479 ER PT J AU Cope, JU Tsokos, M Miller, RW AF Cope, JU Tsokos, M Miller, RW TI Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE Ewing sarcoma; retinoblastoma; olfactory neuroblastoma; sinonasal neuroectodermal tumors; second malignant neoplasms; RB-1 gene ID 2ND NONOCULAR TUMORS; OLFACTORY NEUROBLASTOMA; HEREDITARY RETINOBLASTOMA; BILATERAL RETINOBLASTOMA; HODGKINS-DISEASE; CHILDHOOD-CANCER; SURVIVORS; GENE; CHILDREN; BONE AB Background. Excesses of various childhood cancers have been reported after retinoblastoma, including a trickle of Ewing sarcoma (ES) and perhaps histologically similar olfactory neuroblastoma, both of which are neural tumors. To update and advance this information, case reports were sought by an extensive review of the literature. Procedure. The search was made through the use of PubMed, and the Web of Science (Citation Index Expanded), keying on primary references. Three sinonasal cancers diagnosed as ES were immunohistochemically stained for MIC-2 protein (positive in ES). Results. Retinoblastoma occurred before ES in ten cases (seven bilateral). In four others, retinoblastoma (three bilateral) developed before sinonasal neural tumors (poorly differentiated). ES also occurred after 14 cancers other than retinoblastoma (five lymphomas, four leukemias, and one each of five miscellaneous cancers). The predominance of retinoblastoma prior to ES differs markedly from the low-frequency of retinoblastoma among childhood cancers in the general population. On the contrary, cancers other than retinoblastoma were proportionate to those in the general population. Previously, retinoblastoma followed by excesses of osteosarcoma and soft tissue sarcomas has been attributed to the action of the inherited RB-1 gene. The sinonasal tumors stained negative for MIC-2 protein. Conclusions, Heritable retinoblastoma may predispose to ES and perhaps to a subset of poorly differentiated neuroectodermal tumors in the sinonasal region that may be related to olfactory neuroblastoma. Med. Pediatr. Oncol. 36:290-294, 2001. (C) 2001 Wiley-Liss, Inc. C1 NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Clin Genet Branch, Bethesda, MD 20892 USA. RP Cope, JU (reprint author), NCI, Genet Epidemiol Branch, 6120 Execut Blvd,EPS Room 7007, Bethesda, MD 20892 USA. NR 50 TC 5 Z9 8 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 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD FEB PY 2001 VL 36 IS 2 BP 290 EP 294 DI 10.1002/1096-911X(20010201)36:2<290::AID-MPO1067>3.0.CO;2-5 PG 5 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 398UU UT WOS:000166775500005 PM 11452937 ER PT J AU Weyer, C Salbe, AD Lindsay, RS Pratley, RE Bogardus, C Tataranni, PA AF Weyer, C Salbe, AD Lindsay, RS Pratley, RE Bogardus, C Tataranni, PA TI Exaggerated pancreatic polypeptide secretion in Pima Indians: Can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans? SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID VENTROMEDIAL HYPOTHALAMIC-LESIONS; X-RAY ABSORPTIOMETRY; THRIFTY PHENOTYPE; GLUCOSE-TOLERANCE; INSULIN-RESPONSE; NERVOUS-SYSTEM; VAGAL CONTROL; RATS; VAGOTOMY; STIMULATION AB Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity that have a high propensity for type 2 diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, obesity, and type 2 diabetes also have an increased parasympathetic drive to the pancreas. To test this, we measured plasma concentrations of insulin and pancreatic polypeptide (PP), a surrogate marker of pancreatic vagal tone, in lean and obese Pima Indian and Caucasian children (n = 43, 26P/17C, 7 +/- 1 y) and adults (n = 92, 61P/31C, 31 +/- 5 y). Pima Indian children had similar to2-fold higher fasting insulin and 57% higher fasting PP concentrations than age- and sex-matched Caucasian children (P < .05). Although there was no difference in fasting PP concentration between Pima Indian and Caucasian adults, in response to a mixed meal, Pima Indians had a 51% higher early (30 minutes) PP concentration and 2-fold higher early insulin concentration than Caucasians (P < .05). PP concentrations at 60 minutes and 120 minutes after the meal were also markedly higher in both lean and obese Pima Indians compared with lean and obese Caucasians. These results suggest that Pima Indians may have an increased parasympathetic drive to the pancreas, which could lead to a primary hypersecretion of insulin and contribute to their high propensity for obesity and diabetes, as is the case in various rodent models of obesity. Copyright (C) 2001 by W.B. Saunders Company. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St,Rm 5-41, Phoenix, AZ 85016 USA. NR 57 TC 31 Z9 31 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2001 VL 50 IS 2 BP 223 EP 230 DI 10.1053/meta.2001.20170 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 399WV UT WOS:000166838000016 PM 11229433 ER PT J AU Braun, MC Kelsall, BL AF Braun, MC Kelsall, BL TI Regulation of interleukin-12 production by G-protein-coupled receptors SO MICROBES AND INFECTION LA English DT Article DE G protein; interleukin-12; tumor necrosis factor alpha; antigen-presenting cells; dendritic cells; monocytes; cholera toxin; pertussis toxin ID COLLAGEN-INDUCED ARTHRITIS; IL-12 PRODUCTION; ORAL TOLERANCE; GRANULOMA-FORMATION; CYTOKINE RESPONSES; ADENYLATE-CYCLASE; DENDRITIC CELLS; HUMAN MONOCYTES; C5A RECEPTOR; U-937 CELLS AB G-protein-coupled receptors have long been known to play a critical role in the recruitment and migration of leukocytes to areas of inflammation. This review will focus, however, on emerging data that G-protein-coupled receptors can modulate cytokine production by antigen-presenting cells including interleukin-12 and tumor necrosis factor-alpha and may therefore play a significant role in the regulation of innate and acquired immunity. (C) 2001 Editions scientifiques et medicales Elsevier SAS. C1 NIAID, Immune Cell Interact Unit, Mucosal Immun Sect, Clin Invest Lab,NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Immune Cell Interact Unit, Mucosal Immun Sect, Clin Invest Lab,NIH, Bldg 10,11-N-238,10 Ctr Dr, Bethesda, MD 20892 USA. NR 46 TC 59 Z9 59 U1 0 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2001 VL 3 IS 2 BP 99 EP 107 DI 10.1016/S1286-4579(00)01357-5 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 409LV UT WOS:000167385900002 PM 11251296 ER PT J AU Yao, X Teruya-Feldstein, J Raffeld, M Sorbara, L Jaffe, ES AF Yao, X Teruya-Feldstein, J Raffeld, M Sorbara, L Jaffe, ES TI Peripheral T-cell lymphoma with aberrant expression of CD79a and CD20: A diagnostic pitfall SO MODERN PATHOLOGY LA English DT Article DE CD20; CD79a; cytotoxic T-cells; immunophenotyping; monoclonal antibodies; S-100 protein; T-cell lymphoma ID EPSTEIN-BARR-VIRUS; HODGKINS-DISEASE; B-CELLS; SUBSET; MARKER; MB-1; NEOPLASMS; DISORDER; ENTITY AB Immunohistochemical studies are increasingly used for the routine diagnosis of lymphomas as it is widely accepted that lymphomas of different cell lineages vary in their prognosis and response to therapy. A case of peripheral T-cell lymphoma with aberrant expression of B-cell-associated antigens L-26 (CD20) and mb-1 (CD 79a) is described. The disease pursued al aggressive clinical course, and the patient died of disease 6 weeks after presentation. Immunohistochemical studies demonstrated expression of both T- and B-cell-associated antigens, including CD3, CD8, CD43, TIA-1, CD20, and CD79a. Other markers expressed by the tumor cells included CD56 and S-100. Of interest, betaF-1 staining for the beta chain of T-cell receptor (TCR) complex was positive in the small admired T lymphocytes but was negative in the tumor cells, raising the possibility of a gamma/delta T-cell lymphoma Molecular studies by polymerase chain reaction (PCR) demonstrated clonal TCR-gamma chain gene rearrangement without evidence for a clonal rearrangement of the immunoglobulin heavy chain gene. PCR for HHV-8 related sequences was negative. Mh-1 is an IgM-associated protein that was thought to be restricted to normal and neoplastic B cells. Although its coexpression has been reported in up to 10% cases of precursor T-cell lymphoblastic lymphoma the coexpression of both CD20 and CD79a has not been described in mature T-cell malignancies. Biphenotypic lymphomas associated with HHV-8 have been reported in immunodeficiency, but no evidence of immune deficiency was identified, and studies for EBV and HHV-8 were negative. This case illustrates that no marker has absolute lineage specificity and that immunophenotypic studies should always be performed with panels of monoclonal antibodies. Moreover, cases with ambiguous phenotypes may require genotypic studies for precise lineage assignment. C1 NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), Bldg 10,Room 2N202,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. NR 27 TC 75 Z9 77 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2001 VL 14 IS 2 BP 105 EP 110 DI 10.1038/modpathol.3880265 PG 6 WC Pathology SC Pathology GA 408AW UT WOS:000167305200008 PM 11235901 ER PT J AU Kadekoppala, M Cheresh, P Catron, D Ji, DD Deitsch, K Wellems, TE Seifert, HS Haldar, K AF Kadekoppala, M Cheresh, P Catron, D Ji, DD Deitsch, K Wellems, TE Seifert, HS Haldar, K TI Rapid recombination among transfected plasmids, chimeric episome formation and trans gene expression in Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE malaria; co-transfection; recombination; GFP; transformation; selectable marker ID GREEN FLUORESCENT PROTEIN; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; MALARIA PARASITES; STABLE TRANSFECTION; MAMMALIAN-CELLS; TRANSCRIPTION; RESISTANCE; LOCUS; DISRUPTION AB Although recombination is known to be important to generating diversity in the human malaria parasite P. falciparum. the low efficiencies of transfection and the fact that integration of transfected DNA into chromosomes is observed only after long periods (typically 12 weeks or more) have made it difficult to genetically manipulate the blood stages of this major human pathogen. Here we show that co-transfection of a P. falciparum line with two plasmids. one expressing a green fluorescent protein (gfp) reporter and the other expressing a drug resistance marker (Tgdhfr-ts M23). allowed selection of a population in which about similar to 30% of the parasites product GFP. In these GFP-producing parasites, the transfected plasmids had recombined into chimeric episomes as large as 30 kb and could be maintained under drug pressure for at least 16 weeks. Our data suggest that chimera formation occurs early (detected by 7-14 days) and that it involves homologous recombination Favored by presence of the same P. falciparum 5'hrp3 UTR promoting transcription from each plasmid. This indicates the presence of high levels of homologous recombination activity in blood stage parasites that can be used to drive rapid recombination of newly introduced DNA, study mechanisms of recombination, and introduce genes for trans expression in P. falciparum, (C) 2001 Elsevier Science B.V. All rights reserved. C1 Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Microbiol Immunol, Chicago, IL 60611 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Haldar, K (reprint author), Northwestern Univ, Sch Med, Dept Pathol, 303 E Chicago, Chicago, IL 60611 USA. RI Haldar, Kasturi/C-6685-2014 FU NIAID NIH HHS [AI 39071, AI26670] NR 35 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD FEB PY 2001 VL 112 IS 2 BP 211 EP 218 DI 10.1016/S0166-6851(00)00368-6 PG 8 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 411UE UT WOS:000167517000006 PM 11223128 ER PT J AU Alper, O Bergmann-Leitner, ES Abrams, S Cho-Chung, YS AF Alper, O Bergmann-Leitner, ES Abrams, S Cho-Chung, YS TI Apoptosis, growth arrest and suppression of invasiveness by CRE-decoy oligonucleotide in ovarian cancer cells: Protein kinase A downregulation and cytoplasmic export of CRE-binding proteins SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE cAMP-response element (CRE); protein kinase A; apoptosis; invasion; ovarian cancer; transcription factor decoy oligonucleotide ID TRANSCRIPTION FACTOR DECOY; AMP RESPONSE ELEMENT; CYCLIC-AMP; TUMOR-GROWTH; METALLOPROTEINASE EXPRESSION; MATRIX-METALLOPROTEINASE; REGULATORY SUBUNIT; CYTOCHROME-C; GENE; PHOSPHORYLATION AB The CRE (cyclic AMP response element)-transcription factor complex plays a critical role in response to hormonal signals for cell proliferation, differentiation, and apoptosis. We have reported previously that the CRE-transcription factor decoy oligonucleotide specifically slows tumor cell proliferation and inhibits CRE- and Ap-1-directed transcription in vivo (Park et al., 1999 [12]). We have investigated the effect of inhibiting CRE-directed transcription on ovarian cancer cell growth. Here, we report that CRE-decoy oligonucleotide treatment results in the inhibition of cell growth and a marked reduction in the expression of the regulatory and catalytic subunits of protein kinase A and the type I and type II protein kinase A holoenzymes. Growth inhibition was accompanied by changes in cell morphology, appearance of apoptotic nuclei, and DNA fragmentation. In addition, MMP-9 (matrix methalloproteinase-9) activity was markedly reduced in CRE-decoy treated cells. Indirect immunofluorescence revealed that CRE-decoy oligonucleotide treatment promoted export of the CRE-binding protein, CREB, from the nucleus to the cytoplasm, while importing the catalytic subunit of protein kinase A from the cytoplasm to the nucleus. The results indicate that the decoy oligonucleotide, by binding specifically to CRE-transcription factors, interferes with CRE-directed transcription in vivo. These results show a critical role for CRE-directed transcription in ovarian cancer cell growth. Thus, the CRE-decoy oligonucleotide may provide a powerful means to combat ovarian cancer. C1 NCI, Cellular Biochem Sect, Bethesda, MD 20892 USA. NCI, Expt Oncol Sect, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Bldg 10,Room 5B05, Bethesda, MD 20892 USA. RI Bergmann-Leitner, Elke/B-3548-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956 NR 33 TC 25 Z9 25 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD FEB PY 2001 VL 218 IS 1-2 BP 55 EP 63 DI 10.1023/A:1007205205131 PG 9 WC Cell Biology SC Cell Biology GA 409RK UT WOS:000167397700008 PM 11330838 ER PT J AU Foster, JS Henley, DC Bukovsky, A Seth, P Wimalasena, J AF Foster, JS Henley, DC Bukovsky, A Seth, P Wimalasena, J TI Multifaceted regulation of cell cycle progression by estrogen: Regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID BREAST-CANCER-CELLS; MYC ONCOGENE EXPRESSION; RETINOBLASTOMA PROTEIN-PHOSPHORYLATION; UBIQUITIN-PROTEASOME PATHWAY; DEPENDENT KINASE-ACTIVITY; MAMMARY EPITHELIAL-CELLS; GROWTH-FACTOR-BETA; C-MYC; S-PHASE; G(1)/S TRANSITION AB Estrogens induce proliferation of estrogen receptor (ER)-positive MCF-7 breast cancer cells by stimulating G(1)/S transition associated with increased cyclin D1 expression, activation of cyclin-dependent kinases (Cdks), and phosphorylation of the retinoblastoma protein (pRb). We have utilized blockade of cyclin D1-Cdk4 complex formation through adenovirus-mediated expression of p16(INK4a) to demonstrate that estrogen regulates Cdk inhibitor expression and expression of the Cdk-activating phosphatase Cdc25A independent of cyclin D1-Cdk4 function and cell cycle progression. Expression of p16(INK4a) inhibited G(1)/S transition induced in MCF-7 cells by 17-beta -estradiol (E-2) with associated inhibition of both Cdk4- and Cdk2-associated kinase activities. Inhibition of Cdk2 activity was associated with delayed removal of Cdk-inhibitory activity in early G(1) and decreased cyclin A expression. Cdk-inhibitory activity and expression of both p21(Cip1) and p27(Kip1) was decreased, however, in both control and p16(INK4a)-expressing cells 20 h after estrogen treatment. Expression of Cdc25A mRNA and protein was induced by E-2 in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity and was reversed in vivo and in vitro by active Cdk2. Transfection of MCF-7 cells with a dominant-negative Cdk2 construct inhibited the E-2-dependent activation of ectopic Cdc25A. Supporting a role for Cdc25A in estrogen action, antisense CDC25A oligonucleotides inhibited estrogen-induced Cdk2 activation and DNA synthesis. In addition, inactive cyclin E-Cdk2 complexes from p16(INK4a)-expressing, estrogen-treated cells were activated in vitro by treatment with recombinant Cdc25A and in vivo in cells overexpressing Cdc25A. The results demonstrate that functional association of cyclin D1-Cdk4 complexes is required for Cdk2 activation in MCF-7 cells and that Cdk2 activity is, in turn, required for the in vivo activation of Cdc25A. These studies establish Cdc25A as a growth-promoting target of estrogen action and further indicate that estrogens independently regulate multiple components of the cell cycle machinery, including expression of p21(Cip1) and p27(Kip1). C1 Univ Tennessee, Med Ctr, Dept Obstet & Gynecol, Grad Sch Med, Knoxville, TN 37920 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Wimalasena, J (reprint author), Univ Tennessee, Med Ctr, Dept Obstet & Gynecol, Grad Sch Med, 1924 Alcoa Highway, Knoxville, TN 37920 USA. FU NCI NIH HHS [CA-68538, CA-84048, R01 CA084048] NR 105 TC 113 Z9 114 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 3 BP 794 EP 810 DI 10.1128/MCB.21.3.794-810.2001 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 391JW UT WOS:000166353700011 PM 11154267 ER PT J AU Shcherbakova, PV Hall, MC Lewis, MS Bennett, SE Martin, KJ Bushel, PR Afshari, CA Kunkel, TA AF Shcherbakova, PV Hall, MC Lewis, MS Bennett, SE Martin, KJ Bushel, PR Afshari, CA Kunkel, TA TI Inactivation of DNA mismatch repair by increased expression of yeast MLH1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NONPOLYPOSIS COLON-CANCER; HUMAN MUTL HOMOLOGS; SACCHAROMYCES-CEREVISIAE; MICROSATELLITE INSTABILITY; PROMOTER HYPERMETHYLATION; REPLICATION FIDELITY; MUTATOR PHENOTYPES; HMLH1; GENE; MUTATIONS AB Inactivation of DNA mismatch repair by mutation or by transcriptional silencing of the MLH1 gene results in genome instability and cancer predisposition. We recently found (P. V. Shcherbakova and T. A. Kunkel, Mel. Cell. Biol. 19:3177-3183, 1999) that an elevated spontaneous mutation rate can also result from increased expression of yeast MLH1. Here we investigate the mechanism of this mutator effect. Hybridization of poly(A)(+) mRNA to DNA microarrays containing 96.4% of yeast open reading frames revealed that MLH1 overexpression did not induce changes in expression of other genes involved in DNA replication or repair. MLH1 overexpression strongly enhanced spontaneous mutagenesis in yeast strains with defects in the 3'-->5' exonuclease activity of replicative DNA polymerases delta and epsilon but did not enhance the mutation rate in strains with deletions of MSH2, MLH1, or PMS1. This suggests that overexpression of MLH1 inactivates mismatch repair of replication errors. Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression. The mutator effect was also reduced by a missense mutation in the MLH1 gene that disrupted Mlh1p-Pms1p interaction. Analytical ultracentrifugation experiments showed that purified Mlh1p forms a homodimer in solution, albeit with a K-d of 3.14 muM, 36-fold higher than that for Mlh1p-Pms1p heterodimerization. These observations suggest that the mismatch repair defect in cells overexpressing MLH1 results from an imbalance in the levels of Mlh1p and Pms1p and that this imbalance might lead to formation of nonfunctional mismatch repair complexes containing Mlh1p homodimers. C1 NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Kunkel, TA (reprint author), NIEHS, Genet Mol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 47 TC 33 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 3 BP 940 EP 951 DI 10.1128/MCB.21.3.940-951.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 391JW UT WOS:000166353700024 PM 11154280 ER PT J AU Swanson, DA Liu, ML Baker, PJ Garrett, L Stitzel, M Wu, JM Harris, M Banerjee, R Shane, B Brody, LC AF Swanson, DA Liu, ML Baker, PJ Garrett, L Stitzel, M Wu, JM Harris, M Banerjee, R Shane, B Brody, LC TI Targeted disruption of the methionine synthase gene in mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NEURAL-TUBE DEFECTS; VITAMIN SUPPLEMENTATION; FOLATE-DEFICIENCY; CDNA CLONING; FOLIC-ACID; HOMOCYSTEINE; PERFORMANCE; PREVENTION; COBALAMIN; MUTATIONS AB Alterations in homocysteine, methionine, folate, and/or B-12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B-12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia, They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice, On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients, with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice. C1 NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Brody, LC (reprint author), NHGRI, Genet & Mol Biol Branch, 49 Convent Dr,Rm 3A14, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [R01 HL058984, HL58991, HL58984]; NIDDK NIH HHS [DK42033, R01 DK042033] NR 30 TC 87 Z9 93 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1058 EP 1065 DI 10.1128/MCB.21.4.1058-1065.2001 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800008 PM 11158293 ER PT J AU Gui, CY Dean, A AF Gui, CY Dean, A TI Acetylation of a specific promoter nucleosome accompanies activation of the epsilon-globin gene by beta-globin locus control region HS2 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; CHROMATIN STRUCTURE; HISTONE ACETYLATION; IN-VIVO; MAMMALIAN-CELLS; MMTV PROMOTER; CROSS-TALK; HYPERACETYLATION; BINDING; REPRESSION AB On stably replicating episomes, transcriptional activation of the epsilon -globin promoter by the beta -globin locus control region HS2 enhancer is correlated with an increase in nuclease sensitivity which is limited to the TATA-proximal nucleosome (N1). To elucidate what underlies this increase in nuclease sensitivity and the link between chromatin modification and gene expression, we examined the nucleoprotein composition and histone acetylation status of transcriptionally active and inactive promoters. Micrococcal nuclease digestion of active promoters in nuclei released few nucleosome-like nucleoprotein complexes containing N1 sequences in comparison to results with inactive promoters, We also observed that NI DNA fragments from active promoters are of a subnucleosomal length. Nevertheless, chromatin immunoprecipitation experiments indicate that histones H3 and H4 are present on N1 sequences from active promoters, with H3 being dramatically hyperacetylated compared with that from inactive promoters and vector sequences. Strikingly, H3 in the adjacent upstream nucleosome (N2) does not appear to be differentially acetylated in active and inactive promoters, indicating that the nucleosome modification of the promoter that accompanies transactivation by HS2 is highly directed and specific, However, global acetylation of histones in vivo by trichostatin A did not activate transcription in the absence of HS2, suggesting that HS2 contributes additional activities necessary for transactivation, N1 sequences from active promoters also contain reduced levels of linker histone H1. The detection of a protected subnucleosomal sized N1 DNA fragment and the recovery of N1 DNA sequences in immunoprecipitations using anti-acetylated H3 and H4 antibodies argue that N1 is present, but in an altered conformation, in the active promoters. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 6,Room B1-08,6 Ctr Dr,MSC 2715, Bethesda, MD 20892 USA. NR 48 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1155 EP 1163 DI 10.1128/MCB.21.4.1155-1163.2001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800017 PM 11158302 ER PT J AU McCullough, KD Martindale, JL Klotz, LO Aw, TY Holbrook, NJ AF McCullough, KD Martindale, JL Klotz, LO Aw, TY Holbrook, NJ TI Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bc12 and perturbing the cellular redox state SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HEPATIC GLUTATHIONE SYNTHESIS; C-MYC; OXIDATIVE STRESS; INDUCED APOPTOSIS; GSH EXTRUSION; GENE GADD153; DNA DAMAGE; PROTEIN; EXPRESSION; INDUCTION AB gadd153, also known as chop, is a highly stress-inducible gene that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). Although all reported types of ER stress induce expression of Gadd153, its role in the stress response has remained largely undefined. Several studies have correlated Gadd153 expression with cell death, but a mechanistic link between Gadd153 and apoptosis has never been demonstrated. To address this issue we employed a cell model system in which Gadd153 is constitutively overexpressed, as well as two cell lines in which Gadd153 expression is conditional. In all cell lines, overexpression of Gadd153 sensitized cells to ER stress. Investigation of the mechanisms contributing to this effect revealed that elevated Gadd153 expression results in the down-regulation of Bc12 expression, depletion of cellular glutathione, and exaggerated production of reactive oxygen species. Restoration of Bc12 expression in Gadd153-overexpressing cells led to replenishment of glutathione and a reduction in levels of reactive oxygen species, and it protected cells from ER stress-induced cell death. We conclude that Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bc12 and enhanced oxidant injury. C1 NIA, Cell Stress & Aging Sect, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. RP Holbrook, NJ (reprint author), NIA, Cell Stress & Aging Sect, Biol Chem Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDDK NIH HHS [R01 DK044510, R01 DK044510-08] NR 45 TC 1057 Z9 1123 U1 6 U2 28 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1249 EP 1259 DI 10.1128/MCB.21.4.1249-1259.2001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800026 PM 11158311 ER PT J AU Hayhurst, GP Lee, YH Lambert, G Ward, JM Gonzalez, FJ AF Hayhurst, GP Lee, YH Lambert, G Ward, JM Gonzalez, FJ TI Hepatocyte nuclear factor 4 alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; APOLIPOPROTEIN A-II; TRIGLYCERIDE TRANSFER PROTEIN; DENSITY-LIPOPROTEIN RECEPTOR; TRANSCRIPTION FACTOR HNF-4; TISSUE-SPECIFIC KNOCKOUT; FACTOR-IV; TARGETED DISRUPTION; REGULATORY ELEMENT; RESPONSE ELEMENT AB The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1 alpha [HNF1 alpha], -1 beta, -3 alpha, -3 beta, -3 gamma, 4 alpha, and -6 and members of the c/ebp family). Of these, only HNF4 alpha (nuclear receptor 2A1) and HNF1 alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1 alpha -null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4 alpha -null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4 alpha is indispensable for hepatocyte differentiation, However, the function of HNF4 alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4 alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4 alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4 alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis. C1 NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NHLBI, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Off Lab Anim Resources, NIH, Frederick, MD 21702 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Div Basic Sci, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. NR 69 TC 614 Z9 629 U1 0 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1393 EP 1403 DI 10.1128/MCB.21.4.1393-1403.2001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800039 PM 11158324 ER PT J AU Schulze, S Sinclair, DAR Silva, E Fitzpatrick, KA Singh, M Lloyd, VK Morin, KA Kim, J Holm, DG Kennison, JA Honda, BM AF Schulze, S Sinclair, DAR Silva, E Fitzpatrick, KA Singh, M Lloyd, VK Morin, KA Kim, J Holm, DG Kennison, JA Honda, BM TI Essential genes in proximal 3L heterochromatin of Drosophila melanogaster SO MOLECULAR AND GENERAL GENETICS LA English DT Article DE essential heterochromatic genes; position-effect variegation; Drosophila melanogaster ID POSITION-EFFECT VARIEGATION; X-CHROMOSOME; INSERTIONAL MUTAGENESIS; CHROMATIN STRUCTURE; ROLLED LOCUS; LIGHT GENE; ENCODES; EXPRESSION; REGION; SEQUENCE AB We have further characterized essential loci within the centric heterochromatin of the left arm of chromosome 3 (3L) of Drosophila melanogaster, using EMS, radiation and P element mutagenesis. We failed to find any new essential genes, a result that suggests a lower-than-average gene density in this region. Mutations affecting expression of the most proximal gene [lethal 1, l1 or l(3)80Fj] act as dominant suppressors of Polycomb (Pc), behavior which is consistent with a putative trithorax group (trx-G) gene. The third gene to the left of the centromere [lethal 3, l3 or l(3)80Fh] is likely to correspond to verthandi (vtd), a known trx-G gene that plays a role in the regulation of hedgehog (hh) expression and signalling. The intervening gene [lethal 2, l2 or l(3)80Fi] is required throughout development, and mutant alleles have interesting phenotypes; in Various allelic combinations that survive, we observe fertility, bristle, wing, eye and cuticle defects. C1 Simon Fraser Univ, Dept Biochem & Mol Biol, Burnaby, BC V5A 1S6, Canada. Univ British Columbia, Dept Zool, Vancouver, BC V6T 1Z4, Canada. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Honda, BM (reprint author), Simon Fraser Univ, Dept Biochem & Mol Biol, Burnaby, BC V5A 1S6, Canada. RI Silva, Elizabeth/C-1495-2008 NR 45 TC 20 Z9 20 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0026-8925 J9 MOL GEN GENET JI Mol. Gen. Genet. PD FEB PY 2001 VL 264 IS 6 BP 782 EP 789 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 408RH UT WOS:000167341100006 PM 11254125 ER PT J AU Chen, H Liu, J Merrick, BA Waalkes, MP AF Chen, H Liu, J Merrick, BA Waalkes, MP TI Genetic events associated with arsenic-induced malignant transformation: Applications of cDNA microarray technology SO MOLECULAR CARCINOGENESIS LA English DT Article DE arsenic; chronic arsenic-transformed cells; aberrant gene expression; cDNA microarray ID GROWTH-FACTOR-II; HEPATOCELLULAR-CARCINOMA; RAT-LIVER; C-MYC; ENZYMATIC METHYLATION; DNA METHYLATION; SODIUM ARSENATE; H19 GENES; EXPRESSION; CELLS AB Arsenic is a human carcinogen. Our recent work showed that chronic (> 18 wk), low-level (125-500 nM) arsenite exposure induces malignant transformation in normal rat liver cell line TRL1215. In these arsenic-transformed cells, the cellular S-adenosylmethionine pool was depleted from arsenic metabolism, resulting in global DNA hypomethylation. DNA methylation status in turn may affect the expression of a variety of genes. This study examined the aberrant gene expression associated with arsenic-induced transformation with the use of Atlas Rat cDNA Expression microarrays. Poly(A(+)) RNA was prepared from arsenic-transformed cells and passage-matched control cells, and P-32-labeled cDNA probes were synthesized with Clontech Rat cDNA Synthesis primers and moloney murine leukemia virus reverse transcriptase. The hybrid intensity was analyzed with AtlasImage software and normalized with the sum of the four housekeeping genes. Four hybridizations from separate cell preparations were performed, and mean and SEM for the expression of each gene were calculated for statistical analysis. Among the 588 genes, approximately 80 genes (similar to 13%) were aberrantly expressed. These included genes involved in cell-cycle regulation, signal transduction, stress response, apoptosis, cytokine production and growth-factor and hormone-receptor production and various oncogenes. These initial gene expression analyses for the first time showed potentially important aberrant gene expression patterns associated with arsenic-induced malignant transformation and set the stage for numerous further studies. Published 2001 Wiley-Liss. Inc.(dagger). C1 NIEHS, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Comparat Carcinogenesis Lab, Mail Drop FO-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Saran, Anna/0000-0002-5587-064X NR 45 TC 96 Z9 98 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2001 VL 30 IS 2 BP 79 EP 87 DI 10.1002/1098-2744(200102)30:2<79::AID-MC1016>3.0.CO;2-F PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 407PR UT WOS:000167280400001 PM 11241755 ER PT J AU Giannoukos, G Szapary, D Smith, CL Meeker, JEW Simons, SS AF Giannoukos, G Szapary, D Smith, CL Meeker, JEW Simons, SS TI New antiprogestins with partial agonist activity: Potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID CELL GLUCOCORTICOID RECEPTORS; NUCLEAR HORMONE RECEPTORS; COREPRESSOR N-COR; DEXAMETHASONE 21-MESYLATE; STEROID-RECEPTORS; TRANSCRIPTIONAL COACTIVATOR; FUNCTIONAL-GROUP; GENE-EXPRESSION; IN-VIVO; COMPLEXES AB A pharmacologically relevant property of steroid hormone-regulated gene induction is the partial agonist activity of antisteroid complexes. We now report that dexamethasone-mesylate (Dex-Mes) and dexamethasone-oxetanone (Dex-Ox), each a derivative of the glucocorticoid-selective steroid dexamethasone (Dex), are two new antiprogestins with significant amounts of agonist activity with both the A and B isoforms of progesterone receptor (PR), for different progesterone-responsive elements, and in several cell lines. These compounds continue to display activity under conditions where another partial antiprogestin (RTI-020) is inactive. These new antiprogestins were used to determine whether the partial agonist activity of PR complexes can be modified by changing concentrations of receptor or coregulator, as we have recently demonstrated for glucocorticoid receptors (GRs). Because GR and coregulator concentrations simultaneously altered the position of the physiologically relevant dose-response curve, and associated EC50 of GR-agonist complexes, we also examined this phenomenon with PR. We find that elevated PR or transcriptional intermediary factor 2 (TIF2) concentrations increase the partial agonist activity of Dex-Mes and Dex-Ox, and the EC50 of agonists, independently of changes in total gene transactivation. Furthermore, the corepressors SMRT (silencing mediator for retinoid and thyroid receptors) and NCoR (nuclear receptor corepressor) each suppresses gene induction but NCoR acts opposite to SMRT and, like the coactivator TIF2, reduces the EC50 and increases the partial agonist activity of antiprogestins. These comparable responses of GR and PR suggest that variations in receptor and coregulator concentrations may be a general mechanism for altering the induction properties of other steroid receptors. Finally, the magnitude of coregulator effects on PR induction properties are often not identical for agonists and the new antagonists, suggesting subtle mechanistic differences. These properties of Dex-Mes and Dex-Ox, plus the sensitivity of their activity to cellular differences in PR and coregulator concentrations, make these steroids potential new SPRMs (selective progesterone receptor modulators) that should prove useful as probes of PR induction properties. C1 NIDDK, LMCB, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LMCB, Steroid Hormones Sect, NIH, Bldg 8,Room B2A-07, Bethesda, MD 20892 USA. NR 66 TC 46 Z9 47 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2001 VL 15 IS 2 BP 255 EP 270 DI 10.1210/me.15.2.255 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398NH UT WOS:000166762200005 PM 11158332 ER PT J AU Carmel-Harel, O Stearman, R Gasch, AP Botstein, D Brown, PO Storz, G AF Carmel-Harel, O Stearman, R Gasch, AP Botstein, D Brown, PO Storz, G TI Role of thioredoxin reductase in the Yap1p-dependent response to oxidative stress in Saccharomyces cerevisiae SO MOLECULAR MICROBIOLOGY LA English DT Article ID YAP-1 TRANSCRIPTIONAL REGULATION; GENE DISRUPTIONS; NUCLEAR EXPORT; TARGET GENE; YEAST; ACTIVATION; EXPRESSION; PROTEIN; DNA; STRAINS AB The Saccharomyces cerevisiae Yap1p transcription factor is required for the H2O2-dependent activation of many antioxidant genes including the TRX2 gene encoding thioredoxin 2. To identify factors that regulate Yap1p activity, we carried out a genetic screen for mutants that show elevated expression of a TRX2-HIS3 fusion in the absence of H2O2. Two independent mutants isolated in this screen carried mutations in the TRR1 gene encoding thioredoxin reductase. Northern blot and whole-genome expression analysis revealed that the basal expression of most Yap1p targets and many other H2O2-inducible genes is elevated in Delta trr1 mutants in the absence of external stress. In Delta trr1 mutants treated with H2O2, the Yap1p targets, as well as genes comprising a general environmental stress response and genes encoding protein-folding chaperones, are hyperinduced. However, despite the elevated expression of genes encoding antioxidant enzymes, Delta trr1 mutants are extremely sensitive to H2O2. The results suggest that cells lacking thioredoxin reductase have diminished capacity to detoxify oxidants and/or to repair oxidative stress-induced damage and that the thioredoxin system is involved in the redox regulation of Yap1p transcriptional activity. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 NR 39 TC 68 Z9 71 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2001 VL 39 IS 3 BP 595 EP 605 DI 10.1046/j.1365-2958.2001.02255.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 403PR UT WOS:000167052100006 PM 11169101 ER PT J AU Stewart, PE Thalken, R Bono, JL Rosa, P AF Stewart, PE Thalken, R Bono, JL Rosa, P TI Isolation of a circular plasmid region sufficient for autonomous replication and transformation of infectious Borrelia burgdorferi SO MOLECULAR MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; OPEN READING FRAMES; ANTIGENIC VARIATION; OSPC GENE; DECORIN; FAMILY; DNA; B31; ORGANIZATION; HOMOLOGY AB Borrelia burgdorferi contains abundant circular and linear plasmids, but the mechanism of replication of these extrachromosomal elements is unknown. A S. burgdorferi 9 kb circular plasmid (cp9) was amplified in its entirety by the polymerase chain reaction and used to construct a shuttle vector that replicates in Escherichia coli and B. burgdorferi. A 3.3 kb region of cp9 containing three open reading frames was used to construct a smaller shuttle vector, designated pBSV2. This vector was stably maintained in B. burgdorferi, indicating that all elements necessary for autonomous replication are probably located on this 3.3 kb fragment. a noninfectious B. Burgdorferi strain was efficiently transformed by pBSV2. Additionally, infectious B. burgdorferi was also successfully transformed by pBSV2, indicating that infectious strains of this important human pathogen can now be genetically manipulated. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Stewart, PE (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 41 TC 140 Z9 147 U1 0 U2 5 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2001 VL 39 IS 3 BP 714 EP 721 DI 10.1046/j.1365-2958.2001.02256.x PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 403PR UT WOS:000167052100016 PM 11169111 ER PT J AU Gaborik, Z Szaszak, M Szidonya, L Balla, B Paku, S Catt, KJ Clark, AJL Hunyady, L AF Gaborik, Z Szaszak, M Szidonya, L Balla, B Paku, S Catt, KJ Clark, AJL Hunyady, L TI beta-arrestin- and dynamin-dependent endocytosis of the AT(1) angiotensin receptor SO MOLECULAR PHARMACOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-for-Cell-Biology CY DEC 11-15, 1999 CL WASHINGTON, D.C. SP Amer Soc Cell Biol ID PLECKSTRIN HOMOLOGY DOMAIN; PROTEIN-COUPLED RECEPTORS; MEDIATED ENDOCYTOSIS; BETA(2)-ADRENERGIC RECEPTOR; MUSCARINIC ACETYLCHOLINE; CLATHRIN ADAPTER; INTERNALIZATION; MECHANISMS; CAVEOLAE; SYSTEM AB The major mechanism of agonist-induced internalization of G protein-coupled receptors (GPCRs) is beta -arrestin- and dynamin-dependent endocytosis via clathrin-coated vesicles. However, recent reports have suggested that some GPCRs, exemplified by the AT(1) angiotensin receptor expressed in human embryonic kidney (HEK) 293 cells, are internalized by a beta -arrestin- and dynamin-independent mechanism, and possibly via a clathrin-independent pathway. In this study, agonist-induced endocytosis of the rat AT(1A) receptor expressed in Chinese hamster ovary (CHO) cells was abolished by clathrin depletion during treatment with hyperosmotic sucrose and was unaffected by inhibition of endocytosis via caveolae with filipin. In addition, internalized fluorescein-conjugated angiotensin II appeared in endosomes, as demonstrated by colocalization with transferrin. Overexpression of beta -arrestin1( V53D) and beta -arrestin1(1-349) exerted dominant negative inhibitory effects on the endocytosis of radioiodinated angiotensin II in CHO cells. GTPase-deficient (K44A) mutant forms of dynamin-1 and dynamin-2, and a pleckstrin homology domain-mutant (K535A) dynamin-2 with impaired phosphoinositide binding, also inhibited the endocytosis of AT(1) receptors in CHO cells. Similar results were obtained in COS-7 and HEK 293 cells. Confocal microscopy using fluorescein-conjugated angiotensin II showed that overexpression of dynamin-1( K44A) and dynamin-2( K44A) isoforms likewise inhibited agonist-induced AT(1) receptor endocytosis in CHO cells. Studies on the angiotensin II concentration-dependence of AT(1) receptor endocytosis showed that at higher agonist concentrations its rate constant was reduced and the inhibitory effects of dominant negative dynamin constructs were abolished. These data demonstrate the importance of beta -arrestin- and dynamin-dependent endocytosis of the AT(1) receptor via clathrin-coated vesicles at physiological angiotensin II concentrations. C1 Semmelweis Univ, Sch Med, Dept Physiol, H-1444 Budapest, Hungary. Semmelweis Univ, Joint Res Org, Dept Mol Pathol, H-1085 Budapest, Hungary. Hungarian Acad Sci, Joint Res Org, Budapest, Hungary. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. St Bartholomews & Royal London Sch Med & Dent, Dept Endocrinol, London, England. RP Hunyady, L (reprint author), Semmelweis Univ, Sch Med, Dept Physiol, POB 259, H-1444 Budapest, Hungary. EM hunyady@puskin.sote.hu RI Szidonya, Laszlo/A-2271-2010; Szaszak, Marta/G-7957-2011 NR 40 TC 81 Z9 82 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2001 VL 59 IS 2 BP 239 EP 247 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394XG UT WOS:000166549200011 PM 11160859 ER PT J AU Lee, M Jeon, YJ AF Lee, M Jeon, YJ TI Paclitaxel-induced immune suppression is associated with NF-kappa B activation via conventional PKC isotypes in lipopolysaccharide-stimulated 70Z/3 pre-B-lymphocyte tumor cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-KINASE-C; MURINE MACROPHAGES; T-LYMPHOCYTES; ALPHA; BETA; PHOSPHORYLATION; TAXOL; RAF-1; TRANSLOCATION; TRANSCRIPTION AB Paclitaxel, a potent antitumor agent, has been shown to be lipopolysaccharide (LPS) mimetic in mice, stimulating signaling pathways and gene expression indistinguishably from LPS. In the present study, we showed the intracellular signaling pathway of paclitaxel-induced nuclear factor-kappaB (NF-kappaB) activation and its suppressive effect on LPS-induced signaling in murine 70Z/3 pre-B cells. Stimulation of 70Z/3 cells with LPS for 30 min caused activation of NF-kappaB in the nuclei by detection of DNA-protein binding specific to NF-kappaB. Similarly, paclitaxel also produced a marked and dose-related NF-kappaB activation. However, pretreatment of cells with 10 muM paclitaxel for 18 h resulted in complete inhibition of LPS-mediated NF-kappaB activation. Interestingly, the activity of I kappaB kinase (IKK-beta), which plays an essential role in NF-kappaB activation through I kappaB phosphorylation, was largely enhanced in paclitaxel-treated cells, detected as I kappaB alpha phosphorylation. Because protein kinase C (PKC) is implicated in the activation of NF-kappaB via IKK-beta, the effect of paclitaxel on PKC activation was also measured. It was shown that NF-kappaB nuclear translocation and DNA binding in response to paclitaxel was completely blocked by the conventional PKC inhibitor, Go 6976. Moreover, immunoblotting analysis with paclitaxel-treated cell extract demonstrated that the conventional PKC isotype PKC-alpha was found to be involved in the regulation of paclitaxel-induced NF-kappaB activation, as determined by electrophoretic mobility shift of PKC. Therefore, these data suggest that paclitaxel may activate IKK-beta via conventional PKC isotypes, resulting in NF-kappaB activation and, finally, desensitization of LPS-inducible signaling pathway in 70Z/3 pre-B cells. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. Korea Res Inst Biosci & Biotechnol, Biopotency Evaluat Lab, Taejon, South Korea. RP Lee, M (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Room 3E-08,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2001 VL 59 IS 2 BP 248 EP 253 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394XG UT WOS:000166549200012 PM 11160860 ER PT J AU Yoshinari, K Sueyoshi, T Moore, R Negishi, M AF Yoshinari, K Sueyoshi, T Moore, R Negishi, M TI Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYP2B1 gene by phenobarbital in rat livers SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; RESPONSIVE ENHANCER MODULE; DNA-BINDING ACTIVITY; HEAT-SHOCK PROTEIN; GLUCOCORTICOID RECEPTOR; SIGNALING PATHWAY; CYTOCHROMES P450; DIOXIN RECEPTOR; MOUSE-LIVER; EXPRESSION AB The nuclear receptor constitutive active receptor (CAR) translocates into liver nuclei after phenobarbital (PB) treatment, and activates the conserved enhancer called the PB-response element module (PBREM) found in CYP2B genes. We have examined whether CAR regulates the dimorphic induction by PB of the CYP2B1 gene in Wistar Kyoto (WKY) rats. Northern blot analysis showed that PB induced CYP2B1 mRNA in male WKY rats but not female rats. An in situ injected PBREM-luciferase reporter gene was activated by PB only in the male livers. Western blot analysis revealed extremely low levels of CAR in the cytosols of female livers compared with male counterparts. CAR was accumulated in the liver nucleus of male rats in response to PB treatment, whereas the receptor was barely detectable in the liver nuclei of PB-induced females. These sexually dimorphic responses of PBREM and CAR to PB treatment were not observed with Fisher 344 rats, in which CYP2B1 mRNA was induced in both sexes. Thus, these results indicate that CAR is a regulatory factor that leads to the sexual dimorphic induction of CYP2B1 gene in WKY rats. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 69 Z9 75 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2001 VL 59 IS 2 BP 278 EP 284 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394XG UT WOS:000166549200016 PM 11160864 ER PT J AU Gardner, B Liu, ZF Jiang, D Sibley, DR AF Gardner, B Liu, ZF Jiang, D Sibley, DR TI The role of phosphorylation/dephosphorylation in agonist-induced desensitization of D-1 dopamine receptor function: Evidence for a novel pathway for receptor dephosphorylation SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ADENYLYL-CYCLASE; BETA(2)-ADRENERGIC RECEPTOR; CHOLECYSTOKININ RECEPTOR; DIFFERENTIAL REGULATION; MEDIATED ENDOCYTOSIS; BETA-ARRESTINS; PHOSPHORYLATION; RESENSITIZATION; INTERNALIZATION AB Exposure of D-1 dopamine receptors to agonists results in rapid desensitization of the receptor-stimulated accumulation of cAMP. It is believed that agonist-induced phosphorylation of the receptor plays a critical role in the processes that underlie this phenomenon. To investigate the role of agonist-induced receptor phosphorylation, a FLAG epitope was added to the amino terminus of the rat D-1 dopamine receptor and this construct was stably expressed in C6 glioma cells. It was found that the D-1 receptor was stoichiometrically phosphorylated under basal conditions and that its phosphorylation state was increased by 2- to 3-fold upon exposure of the cells to dopamine for 10 min. The dopamine-induced receptor phosphorylation could be blocked by D-1-selective antagonists but was unaffected by inhibitors of either protein kinase A or protein kinase C. The incorporation of phosphate into the receptor was rapid but transient, despite the continued presence of dopamine. A comparison of the rates of receptor phosphorylation (t(1/2), < 1 min) and dopamine-induced desensitization (t(1/2) 7 min) revealed that receptor phosphorylation was not the rate limiting step for receptor desensitization. Upon removal of dopamine, the receptor was rapidly dephosphorylated (t(1/2) similar to 10 min) and this was not blocked by agents (i.e., concanavalin A or hypertonic sucrose) that inhibit D-1 receptor internalization. Using specific inhibitors, the phosphatase involved in D-1 receptor dephosphorylation was shown not to correlate with the recently identified "G protein-coupled receptor phosphatase" (Proc Natl Acad Sci USA 92:8343-8347, 1995). These results suggest that the phosphorylated D-1 receptor is processed through a novel recovery pathway and that internalization is not required for receptor dephosphorylation. C1 NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bldg 10,Room 5C108,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 36 TC 68 Z9 70 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2001 VL 59 IS 2 BP 310 EP 321 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394XG UT WOS:000166549200020 PM 11160868 ER PT J AU Hribal, ML D'Alfonso, R Giovannone, B Lauro, D Liu, YY Borboni, P Federici, M Lauro, R Sesti, G AF Hribal, ML D'Alfonso, R Giovannone, B Lauro, D Liu, YY Borboni, P Federici, M Lauro, R Sesti, G TI The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms SO MOLECULAR PHARMACOLOGY LA English DT Article ID STIMULATED GLUCOSE-TRANSPORT; II DIABETIC SUBJECTS; RAT HEPATOCYTES; HEPATOMA-CELLS; NIDDM PATIENTS; INTERNALIZATION; ADIPOCYTES; DISSOCIATION; DEGRADATION; PHOSPHORYLATION AB Sulfonylureas may stimulate glucose metabolism by protein kinase C (PKC) activation. Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. Association of PKC-beta II and -epsilon with insulin receptors was increased in glimepiride-treated cells. Selective depletion of cellular PKC-beta II and -epsilon by exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) or treatment of cells with PKC-beta II inhibitor G06976 reversed the effect of glimepiride on intracellular insulin-receptor processing. Glimepiride increased the effects of insulin on glucose incorporation into glycogen by enhancing both sensitivity and maximal efficacy of insulin. Exposing cells to TPA or G06976 inhibitor reversed these effects. Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. These data suggest a novel mechanism of action of sulfonylurea, which may have a therapeutic impact on the treatment of type 2 diabetes. C1 Univ Roma Tor Vergata, Dept Internal Med, Mol Med Lab, I-00133 Rome, Italy. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Sesti, G (reprint author), Univ Roma Tor Vergata, Dept Internal Med, Mol Med Lab, Via Tor Vergata 135, I-00133 Rome, Italy. RI Sesti, Giorgio/B-1509-2012; Federici, Massimo/G-9940-2012; OI Federici, Massimo/0000-0003-4989-5194; Liu, Yong-Yu/0000-0002-7968-0162; Lauro, Davide/0000-0002-8597-4415; Sesti, Giorgio/0000-0002-1618-7688 NR 40 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2001 VL 59 IS 2 BP 322 EP 330 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394XG UT WOS:000166549200021 PM 11160869 ER PT J AU Gardner, EL AF Gardner, EL TI Reward behaviors as a function of hypo-dopaminergic activity: Animal models of RDS SO MOLECULAR PSYCHIATRY LA English DT Meeting Abstract C1 NIDA, Intramural Res Program, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2001 VL 6 SU 1 BP S4 EP S4 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 404JR UT WOS:000167094700010 ER PT J AU Uhl, G AF Uhl, G TI Dopaminergic genes in the context of drug abuse vulnerability genetics SO MOLECULAR PSYCHIATRY LA English DT Meeting Abstract C1 NIDA, Intramural Res Program, Neuromol Branch, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2001 VL 6 SU 1 BP S3 EP S3 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 404JR UT WOS:000167094700007 ER PT J AU Uhl, GR Volkow, N AF Uhl, GR Volkow, N TI Perspectives on reward circuitry, neurobiology, genetics and pathology: Dopamine and addiction SO MOLECULAR PSYCHIATRY LA English DT Editorial Material C1 NIDA, IRP, Baltimore, MD 21224 USA. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Uhl, GR (reprint author), NIDA, IRP, POB 5180, Baltimore, MD 21224 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2001 VL 6 SU 1 BP S1 EP S1 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 404JR UT WOS:000167094700002 ER PT J AU Richert, ND Ostuni, JL Bash, CN Leist, TP McFarland, HF Frank, JA AF Richert, ND Ostuni, JL Bash, CN Leist, TP McFarland, HF Frank, JA TI Interferon beta-1b and intravenous methylprednisolone promote lesion recovery in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Article DE multiple sclerosis; intravenous methylprednisolone; MRI; magnetization transfer imaging; interferon beta-1b gadolinium; contrast enhancing lesions ID SERIAL MAGNETIZATION-TRANSFER; LYSOLECITHIN-INDUCED DEMYELINATION; APPEARING WHITE-MATTER; HIGH-DOSE STEROIDS; MS LESIONS; TRANSFER RATIO; CEREBROSPINAL-FLUID; ENHANCING LESIONS; AXONAL DAMAGE; DOUBLE-BLIND AB Objective: To determine whether lesion evolution in relapsing-remitting multiple sclerosis (RRMS) patients is altered by treatment with interferon beta -1b (IFN beta -1b) or by intravenous methylprednisolone (IVMP) as measured by magnetization transfer imaging Methods: Magnetization transfer ratios (MTR) of 225 contrast enhancing lesions (CEL), in four RRMS patients were serially determined for 12 months before and 12-18 months after contrast enhancement in a baseline vs treatment trial with IFN beta -1b. During the baseline period 185 new CEL were identified: 76 were treated with IVMP (1 g/day x 5 days) and designated steroid CEL (S-CEL); the remaining 109 were considered baseline lesions (B-CEL). During IFN beta -1b treatment, 40 CEL (IFN-CEL) were identified. After image co-registration, regions of interest (ROIs) defining new CEL were transferred to the MTR image set to determine the mean lesion MTR on each monthly exam. The lesion MTR was compared to MTR of normal appearing white matter (NAWM) on the some exam. Results: As early os IZ months prior to enhancement the MTR of CEL was reduced compared to NAWM (mean 9.43 +/- 3.2%; P< 0.001). The further reduction in MTR (28% 4.0) at the time of contrast enhancement was not significantly different for B-CEL S-CEL or IFN-CEL Following enhancement lesion recovery for IFN-CEL (P=0.02) and S-CEL (P=0.002) was significantly higher than B-CEL Conclusion: IFN beta -1b and IVMP reduce tissue damage and promote lesion recovery in RRMS patients. The additional benefit of IVMP compared to IFN beta -1b may be related to its inhibitory effect on demyelination. C1 Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD USA. NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. Childrens Natl Med Ctr, Dept Diagnost Imaging & Radiol, Washington, DC USA. RP Richert, ND (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,B1N256, Bethesda, MD 20892 USA. NR 59 TC 80 Z9 80 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2001 VL 7 IS 1 BP 49 EP 58 DI 10.1191/135245801669116174 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 424BE UT WOS:000168211600009 PM 11321194 ER PT J AU Navaneetham, D Penn, AS Howard, JF Conti-Fine, BM AF Navaneetham, D Penn, AS Howard, JF Conti-Fine, BM TI Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit SO MUSCLE & NERVE LA English DT Article DE acetylcholine receptor; autoimmunity; human; myasthenia gravis; thymus ID MESSENGER-RNA EXPRESSION; MYASTHENIA-GRAVIS; ALPHA-SUBUNIT; EPITHELIAL-CELLS; GENE-EXPRESSION; ASSOCIATION; ISOFORMS; THYMOMAS; GAMMA; LINE AB In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an immune response that might begin in the thymus. The thymus expresses binding sites for specific ligands of muscle AChR, a complex protein composed of alpha, beta, gamma (or epsilon) and delta subunits. The thymus expresses the AChR cr subunit, but there is controversy regarding the expression in the thymus of the gamma, epsilon and delta subunits. We investigated the presence of messenger RNA (mRNA) for the different muscle AChR subunits in thymus tissue from 20 healthy subjects and 13 myasthenic patients, We detected mRNA for the alpha and epsilon subunits in all samples, for the beta subunit in all but one sample and for the gamma subunit in most samples although at lower levels than the epsilon subunit. Myasthenic thymuses expressed levels of gamma subunit mRNA similar to control thymuses but more abundant epsilon subunit mRNA. None of the myasthenic thymuses and only two control thymuses expressed detectable delta subunit mRNA. This supports the hypothesis that human thymus may express AChR proteins that do not include the delta subunit. Such receptors, which would have different antigenic structure than the muscle AChRs, might have a role in triggering the autoimmune response that causes MG. (C) 2001 John Wiley & Sons, Inc. C1 Univ Minnesota, Dept Biochem Mol Biol & Biophys, St Paul, MN 55108 USA. Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. RP Conti-Fine, BM (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, 1479 Gortner Ave, St Paul, MN 55108 USA. FU NINDS NIH HHS [NS23919] NR 29 TC 23 Z9 25 U1 0 U2 3 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD FEB PY 2001 VL 24 IS 2 BP 203 EP 210 DI 10.1002/1097-4598(200102)24:2<203::AID-MUS50>3.0.CO;2-F PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 394RU UT WOS:000166537700005 PM 11180203 ER PT J AU Murphy, WJ Eizirik, E Johnson, WE Zhang, YP Ryder, OA O'Brien, SJ AF Murphy, WJ Eizirik, E Johnson, WE Zhang, YP Ryder, OA O'Brien, SJ TI Molecular phylogenetics and the origins of placental mammals SO NATURE LA English DT Article ID ENDEMIC AFRICAN MAMMALS; TREE TOPOLOGIES; EVOLUTION; ORDER; POSITION AB The precise hierarchy of ancient divergence events that led to the present assemblage of modern placental mammals has been an area of controversy among morphologists, palaeontologists and molecular evolutionists. Here we address the potential weaknesses of limited character and taxon sampling in a comprehensive molecular phylogenetic analysis of 64 species sampled across all extant orders of placental mammals. We examined sequence variation in 18 homologous gene segments (including nearly 10,000 base pairs) that were selected for maximal phylogenetic informativeness in resolving the hierarchy of early mammalian divergence. Phylogenetic analyses identify four primary superordinal clades: (I) Afrotheria (elephants, manatees, hyraxes, tenrecs, aardvark and elephant shrews); (II) Xenarthra (sloths, anteaters and armadillos); (III) Glires (rodents and lagomorphs), as a sister taxon to primates, flying lemurs and tree shrews; and (IV) the remaining orders of placental mammals (cetaceans, artiodactyls, perissodactyls, carnivores, pangolins, bats and core insectivores). Our results provide new insight into the pattern of the early placental mammal radiation. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. Chinese Acad Sci, Kunming Inst Zool, Key Lab Cellular & Mol Evolut, Kunming, Peoples R China. Zool Soc San Diego, Ctr Reprod Endangered Species, San Diego, CA 92112 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@mail.ncifcrf.gov RI Eizirik, Eduardo/K-8034-2012; Johnson, Warren/D-4149-2016 OI Eizirik, Eduardo/0000-0002-9658-0999; Johnson, Warren/0000-0002-5954-186X NR 30 TC 888 Z9 956 U1 22 U2 190 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 1 PY 2001 VL 409 IS 6820 BP 614 EP 618 DI 10.1038/35054550 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 397JJ UT WOS:000166692300043 PM 11214319 ER PT J AU Tzung, SP Kim, KM Basanez, G Giedt, CD Simon, J Zimmerberg, J Zhang, KYJ Hockenbery, DM AF Tzung, SP Kim, KM Basanez, G Giedt, CD Simon, J Zimmerberg, J Zhang, KYJ Hockenbery, DM TI Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3 SO NATURE CELL BIOLOGY LA English DT Article ID GROWTH-FACTOR-ALPHA; MITOCHONDRIAL-MEMBRANE; CYTOCHROME-C; PERMEABILITY TRANSITION; NUCLEAR APOPTOSIS; BCL-X(L); BAX; BINDING; CHANNEL; PROTEIN AB The Bcl-2-related survival proteins confer cellular resistance to a wide range of agents. Bcl-x(L)-expressing hepatocyte cell lines are resistant to tumour necrosis factor and anti-cancer drugs, but are more sensitive than isogenic control cells to antimycin A, an inhibitor of mitochondrial electron transfer. Computational molecular docking analysis predicted that antimycin A interacts with the Bcl-2 homology domain 3 (BH3)-binding hydrophobic groove of Bclx(L). We demonstrate that antimycin A and a Bak BH3 peptide bind competitively to recombinant Bcl-2. Antimycin A and BH3 peptide both induce mitochondrial swelling and loss of Delta Psi (m), on addition to mitochondria expressing Bcl-x(L). The 2-methoxy derivative of antimycin A(3) is inactive as an inhibitor of cellular respiration but still retains toxicity for Bcl-(+)(L) cells and mitochondria. Finally, antimycin A inhibits the pore-forming activity of Bcl-x(L) in synthetic liposomes, demonstrating that a small non-peptide ligand can directly inhibit the function of Bcl-2-related proteins. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Hockenbery, DM (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N, Seattle, WA 98109 USA. RI Zhang, Kam/B-3552-2012; Basanez, Gorka/L-9509-2014 OI Zhang, Kam/0000-0002-9282-8045; Basanez, Gorka/0000-0002-7475-7861 FU NCI NIH HHS [CA15704-26] NR 48 TC 359 Z9 372 U1 0 U2 8 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD FEB PY 2001 VL 3 IS 2 BP 183 EP 191 DI 10.1038/35055095 PG 9 WC Cell Biology SC Cell Biology GA 399CG UT WOS:000166793000020 PM 11175751 ER PT J AU Greener, T Grant, B Zhang, YH Wu, XF Greene, LE Hirsh, D Eisenberg, E AF Greener, T Grant, B Zhang, YH Wu, XF Greene, LE Hirsh, D Eisenberg, E TI Caenorhabditis elegans auxilin: a J-domain protein essential for clathrin-mediated endocytosis in vivo SO NATURE CELL BIOLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; UNCOATING ATPASE; GENETIC INTERFERENCE; COATED VESICLES; DISSOCIATION; EXPRESSION; BASKETS AB The budding of clathrin-coated vesicles is essential for protein transport. After budding, clathrin must be uncoated before the Vesicles can fuse with other membranous structures. In vitro, the molecular chaperone Hsc70 uncoats clathrin-coated vesicles in an ATP-dependent process that requires a specific J-domain protein such as auxilin. However, there is little evidence that either Hsc70 or auxilin is essential in vivo. Here we show that C. elegans has a single auxilin homologue that is identical to mammalian auxilin in its in vitro activity. When RNA-mediated interference (RNAi) is used to inhibit auxilin expression in C. elegans, oocytes show markedly reduced receptor-mediated endocytosis of yolk protein tagged with green fluorescent protein (GFP). In addition, most of these worms arrest during larval development, exhibit defective distribution of GFP-clathrin in many cell types, and show a marked change in clathrin dynamics, as determined by fluorescence recovery after photobleaching (FRAP). We conclude that auxilin is required for in vivo clathrin-mediated endocytosis and development in C. elegans. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Eisenberg, E (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. OI Grant, Barth/0000-0002-5943-8336; Zhang, Yinhua/0000-0003-0592-9153 FU NIGMS NIH HHS [F32 GM019167, F32 GM019167-01, F32 GM019167-02] NR 26 TC 71 Z9 75 U1 1 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD FEB PY 2001 VL 3 IS 2 BP 215 EP 219 DI 10.1038/35055137 PG 5 WC Cell Biology SC Cell Biology GA 399CG UT WOS:000166793000025 PM 11175756 ER PT J AU Crisponi, L Deiana, M Loi, A Chiappe, F Uda, M Amati, P Bisceglia, L Zelante, L Nagaraja, R Porcu, S Ristaldi, MS Marzella, R Rocchi, M Nicolino, M Lienhardt-Roussie, A Nivelon, A Verloes, A Schlessinger, D Gasparini, P Bonneau, D Cao, A Pilia, G AF Crisponi, L Deiana, M Loi, A Chiappe, F Uda, M Amati, P Bisceglia, L Zelante, L Nagaraja, R Porcu, S Ristaldi, MS Marzella, R Rocchi, M Nicolino, M Lienhardt-Roussie, A Nivelon, A Verloes, A Schlessinger, D Gasparini, P Bonneau, D Cao, A Pilia, G TI The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome SO NATURE GENETICS LA English DT Article ID PREMATURE OVARIAN FAILURE; HELIX GENE; EYELID DEVELOPMENT; CHROMOSOME 3Q23; HUMAN HOMOLOG; CLEFT-PALATE; BLEPHAROPHIMOSIS; MOUSE; PTOSIS; POSITION AB In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel. putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat. C1 Univ Cagliari, CNR, Ist Ric Talassemie & Anemie Mediterranee, Cagliari, Italy. Univ Cagliari, Osped Reg Microcitemie, Dipartimento Sci Biomed & Biotecnol, Cagliari, Italy. Ctr Hosp Univ Poitiers, Serv Genet Med, Poitiers, France. Osped CSS, IRCCS, Serv Genet Med, I-71013 San Giovanni Rotondo, Italy. NIA, Genet Lab, Baltimore, MD 21224 USA. Univ Bari, DAPEG, Sezione Genet, Bari, Italy. Hop Debrousse, Serv Endocrinol Pediat, Lyon, France. Ctr Hosp Univ Limoges, Serv Pediat, Limoges, France. Ctr Hosp Univ Dijion, Serv Genet, Dijon, France. Univ Liege, Wallonia Ctr Human Genet, Liege, Belgium. RP Pilia, G (reprint author), Univ Cagliari, CNR, Ist Ric Talassemie & Anemie Mediterranee, Cagliari, Italy. RI Rocchi, Mariano/B-8451-2011; Bonneau, Dominique/K-6110-2015; Bisceglia, Luigi/B-8720-2017; OI Bisceglia, Luigi/0000-0001-5367-8518; , Alain/0000-0003-4819-0264 FU Telethon [E.0357] NR 52 TC 565 Z9 595 U1 0 U2 25 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2001 VL 27 IS 2 BP 159 EP 166 DI 10.1038/84781 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 399XH UT WOS:000166839200016 PM 11175783 ER PT J AU LaVaute, T Smith, S Cooperman, S Iwai, K Land, W Meyron-Holtz, E Drake, SK Miller, G Abu-Asab, M Tsokos, M Switzer, R Grinberg, A Love, P Tresser, N Rouault, TA AF LaVaute, T Smith, S Cooperman, S Iwai, K Land, W Meyron-Holtz, E Drake, SK Miller, G Abu-Asab, M Tsokos, M Switzer, R Grinberg, A Love, P Tresser, N Rouault, TA TI Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice SO NATURE GENETICS LA English DT Article ID RESPONSIVE ELEMENT; CEREBRAL-CORTEX; RNA-BINDING; SYSTEM; DEGRADATION; EXPRESSION; MEMBRANES; ACONITASE; FEATURES; FERRITIN AB In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells(1,2). Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ire62(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Director, Bethesda, MD USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. NeuroSci Associates, Knoxville, TN USA. NICHHD, Lab Mammalian Genet & Dev, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RI Meyron-Holtz, Esther/B-5991-2013; OI Abu-Asab, Mones/0000-0002-4047-1232 NR 30 TC 317 Z9 325 U1 0 U2 13 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2001 VL 27 IS 2 BP 209 EP 214 DI 10.1038/84859 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 399XH UT WOS:000166839200025 PM 11175792 ER PT J AU Murphy, PM AF Murphy, PM TI Viral exploitation and subversion of the immune system through chemokine mimicry SO NATURE IMMUNOLOGY LA English DT Review ID PROTEIN-COUPLED RECEPTOR; IMMUNODEFICIENCY-VIRUS TYPE-1; SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN CYTOMEGALOVIRUS; KAPOSIS-SARCOMA; MURINE CYTOMEGALOVIRUS; HIV-1 INFECTION; BETA-CHEMOKINE; FUNCTIONAL CHEMOKINE; ALPHA-CHEMOKINE AB The chemokine superfamily of leukocyte chemo-attractants coordinates development and deployment of the immune system by signaling through a family of G protein-coupled receptors. The importance of this system to antimicrobial host defense has been supported by the discovery of numerous herpesviruses and poxviruses that encode chemokine mimics able to block chemokine action. However, specific herpesviruses and lentiviruses can also exploit the immune system through chemokine mimicry, for example, to facilitate viral dissemination or, as in the case of HIV-1, to directly infect leukocyte target cells. The study of viral mimicry of chemokines and chemokine receptors is providing important new concepts in viral immunopathogenesis, new anti-inflammatory drug leads and new targets and concepts for antiviral drug and vaccine development. C1 NIAID, Host Def Lab, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Host Def Lab, Mol Signaling Sect, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 107 TC 233 Z9 242 U1 1 U2 7 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2001 VL 2 IS 2 BP 116 EP 122 DI 10.1038/84214 PG 7 WC Immunology SC Immunology GA 398WD UT WOS:000166778700006 PM 11175803 ER PT J AU Dorfman, JR Stefanova, I Yasutomo, K Germain, RN AF Dorfman, JR Stefanova, I Yasutomo, K Germain, RN TI Class II essential for CD4 survival - Response SO NATURE IMMUNOLOGY LA English DT Letter ID T-CELL-RECEPTOR; MHC CLASS-II; LYMPHOCYTES-T; COMPLEX; REQUIRES; EXPANSION; MOLECULES; MEMORY; NAIVE; PROLIFERATION C1 NIH, Lymphocyte Biol Sect, Immunol Lab, Bethesda, MD 20892 USA. Univ Tokushima, Sch Med, Dept Pediat, Tokushima 7708853, Japan. RP Dorfman, JR (reprint author), NIH, Lymphocyte Biol Sect, Immunol Lab, Bldg 10,Room 11N311, Bethesda, MD 20892 USA. RI Dorfman, Jeffrey/B-4854-2011 OI Dorfman, Jeffrey/0000-0001-9938-8911 NR 27 TC 8 Z9 8 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2001 VL 2 IS 2 BP 136 EP 137 DI 10.1038/84231 PG 2 WC Immunology SC Immunology GA 398WD UT WOS:000166778700010 ER PT J AU De Rosa, SC Herzenberg, LA Herzenberg, LA Roederer, M AF De Rosa, SC Herzenberg, LA Herzenberg, LA Roederer, M TI 11-color, 13-parameter flow cytometry: Identification of human naive T cells by phenotype, function, and T-cell receptor diversity SO NATURE MEDICINE LA English DT Article ID ANTIRETROVIRAL THERAPY; HIV-INFECTION; L-SELECTIN; SUBSETS; CD4(+); AGE C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 FU NCI NIH HHS [CA-42509-14, CA-81543-02] NR 18 TC 269 Z9 274 U1 1 U2 11 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2001 VL 7 IS 2 BP 245 EP 248 DI 10.1038/84701 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 398KU UT WOS:000166756300044 PM 11175858 ER PT J AU Wang, XQ Hall, TMT AF Wang, XQ Hall, TMT TI Structural basis for recognition of AU-rich element RNA by the HuD protein SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID MESSENGER-RNA; SEX-LETHAL; CRYSTAL-STRUCTURE; BINDING PROTEIN; DROSOPHILA; HEL-N1; INCREASES; ELAV; GENE; TRANSLATION AB Hu proteins bind to adenosine-uridine (AU)-rich elements (AREs) in the 3' untranslated regions of many short-lived mRNAs, thereby stabilizing them, Here we report the crystal structures of the first two RNA recognition motif (RRM) domains of the HuD protein in complex with an 11-nucleotide fragment of a class I ARE (the c-fos ARE; to 1.8 Angstrom), and with an 11-nucleotide fragment of a class II ARE (the tumor necrosis factor alpha ARE; to 2.3 Angstrom). These structures reveal a consensus RNA recognition sequence that suggests a preference for pyrimidine-rich sequences and a requirement for a central uracil residue in the clustered AUUUA repeats found in class II AREs, Comparison to structures of other RRM domain-nucleic acid complexes reveals two base recognition pockets in all the structures that interact with bases using residues in conserved ribonucleoprotein motifs and at the C-terminal ends of RRM domains. Different conformations of nucleic acid can be bound by RRM domains by using different combinations of base recognition pockets and multiple RRM domains. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 34 TC 166 Z9 167 U1 1 U2 6 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD FEB PY 2001 VL 8 IS 2 BP 141 EP 145 DI 10.1038/84131 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 397NV UT WOS:000166702500019 PM 11175903 ER PT J AU Nelson, RG AF Nelson, RG TI Diabetic renal disease in transitional and disadvantaged populations SO NEPHROLOGY LA English DT Review DE birth weight; diabetic nephropathy; genetics; glomerular filtration rate; intrauterine environment; linkage analysis; risk factors; segregation analysis; type 2 diabetes mellitus ID CONVERTING-ENZYME GENE; URINARY ALBUMIN EXCRETION; INTRAUTERINE GROWTH-RETARDATION; ALDOSE REDUCTASE GENE; PIMA-INDIANS; ESSENTIAL-HYPERTENSION; IDDM PATIENTS; AUSTRALIAN ABORIGINES; ANGIOTENSINOGEN GENE; SEGREGATION ANALYSIS AB Diabetes mellitus has reached epidemic proportions throughout much of the world, and people from developing countries and disadvantaged groups from developed countries are affected disproportionately. Not only is diabetes more common in these populations, but it develops at an earlier age. Accordingly, patients have more years of life in which to develop the chronic complications of diabetes and the risk of complications is often further enhanced by limited access to health care. Renal disease is a frequent consequence of diabetes in these populations, and a number of factors related to poverty, malnutrition and accelerated lifestyle changes may lead to even greater rates in the future. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. NR 75 TC 8 Z9 8 U1 1 U2 2 PU BLACKWELL SCIENCE ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 1320-5358 J9 NEPHROLOGY JI Nephrology PD FEB PY 2001 VL 6 IS 1 BP 9 EP 17 DI 10.1046/j.1440-1797.2001.00025.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 414AM UT WOS:000167643800003 ER PT J AU Agodoa, L AF Agodoa, L TI Hypertensive kidney disease in African Americans SO NEPHROLOGY LA English DT Review DE end-stage renal disease; ethnicity; haemodialysis; hypertension; kidney disease; race ID STAGE RENAL-DISEASE; NEPHROSCLEROSIS; MEN AB End-stage renal disease is a significant public health problem in both developed and developing countries. The magnitude and pattern of renal disease varies between countries. This variability could probably be explained by the racial and ethnic composition. The United States is a typical example, showing significant racial and ethnic differences in the magnitude and pattern of renal disease. African Americans, Native Americans and Pacific Islanders are disproportionately afflicted with end-stage kidney failure (ESRD), compared with Caucasians and Asians. Whereas diabetes mellitus, primarily type 2, is the predominant cause of renal disease (and ESRD) in the US, and prominently in Native Americans, hypertensive kidney disease is the most prevalent cause of ESRD in African Americans. Some of the suggested reasons for the increased incidence and prevalence of hypertensive kidney disease in African Americans include the higher prevalence and severity of hypertension, especially in the early years of life, lower socio-economic status leading to inadequate health care, a greater propensity towards developing intrinsic renal vascular disease, a greater tendency towards developing target organ damage at 'normal' blood pressure levels, and the use of drugs that are less renoprotective to treat their blood pressure. C1 NIDDK, DKUHD, NIH, Bethesda, MD 20892 USA. RP Agodoa, L (reprint author), NIDDK, DKUHD, NIH, Democracy 2,Room 930,6702 Democracy Bldg, Bethesda, MD 20892 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL SCIENCE ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 1320-5358 J9 NEPHROLOGY JI Nephrology PD FEB PY 2001 VL 6 IS 1 BP 25 EP 31 DI 10.1046/j.1440-1797.2001.00030.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 414AM UT WOS:000167643800005 ER PT J AU Russo, C Salis, S Dolcini, V Venezia, V Song, XH Teller, JK Schettini, G AF Russo, C Salis, S Dolcini, V Venezia, V Song, XH Teller, JK Schettini, G TI Identification of amino-terminally and phosphotyrosine-modified carboxy-terminal fragments of the amyloid precursor protein in Alzheimer's disease and Down's syndrome brain SO NEUROBIOLOGY OF DISEASE LA English DT Article ID A-BETA 3-PYROGLUTAMYL; TRANSGENIC MICE; INTRACELLULAR DOMAIN; SENILE PLAQUES; IN-VITRO; PEPTIDE; FE65; PRESENILIN-1; MUTATIONS; SECRETASE AB The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered beta -amyloid (A beta) precursors as well as molecular species that are both amyloidogenic and neurotoxic by themselves in vitro or in animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analylzed OTFs extracted from brains of subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. Iii) CTFs modified at their N-terminus appear to be the direct precursors of likewise N-terminally modified A beta peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated A beta peptides are rather formed directly at beta -secretase level and not through a progressive proteolysis of full-length A beta1-40/42. (iii) Among the differently cleaved CTFs, only the 22- and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects. (C) 2001 Academic Press. C1 Case Western Reserve Univ, Dept Neuropathol, Cleveland, OH 44106 USA. Univ Genoa, Dept Oncol Biol Genet, Genoa, Italy. Natl Canc Inst, Adv Biotechnol Ctr, Sect Pharmacol & Neurosci, Genoa, Italy. RP Teller, JK (reprint author), Case Western Reserve Univ, Dept Neuropathol, Cleveland, OH 44106 USA. OI russo, claudio/0000-0002-2520-2958 FU NIA NIH HHS [AG08155, AG08012, AG14359]; NINDS NIH HHS [NS37392] NR 37 TC 60 Z9 60 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2001 VL 8 IS 1 BP 173 EP 180 DI 10.1006/nbdi.2000.0357 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 403XY UT WOS:000167069500017 PM 11162251 ER PT J AU Gaillard, WD Grandin, CB Xu, B AF Gaillard, WD Grandin, CB Xu, B TI Developmental aspects of pediatric fMRI: Considerations for image acquisition, analysis, and interpretation SO NEUROIMAGE LA English DT Editorial Material ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; WORKING-MEMORY TASK; FUNCTIONAL MRI; BRAIN-DEVELOPMENT; LANGUAGE DOMINANCE; PREFRONTAL CORTEX; GLUCOSE-METABOLISM; LONGITUDINAL MRI; AUDITORY-CORTEX AB Functional MRI provides a powerful means to identify and trace the evolution, development, and consolidation of cognitive neural networks through normal childhood. Neural network perturbations due to disease and other adverse factors during development can also be explored. Studies performed to date suggest that normal children older than 5 years show activation maps comparable to adults for similar cognitive paradigms. Minor differences in adult and pediatric activation maps may reflect age dependent strategies or maturation of cognitive networks. However, there are important physiologic and anatomic differences in children, varying with age, that may affect the acquisition, analysis, and interpretation of pediatric fMRI data. Differences between children and adult fRIRI comparison studies may reflect technical aspects of data acquisition as much as developmental and brain maturation factors. (C) 2001 Academic Press. C1 George Washington Univ, Sch Med, Dept Neurol, Childrens Natl Med Ctr, Washington, DC 20052 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. Univ Catholique Louvain, St Luc Univ Hosp, Dept Radiol, B-1348 Louvain, Belgium. RP Gaillard, WD (reprint author), George Washington Univ, Sch Med, Dept Neurol, Childrens Natl Med Ctr, Washington, DC 20052 USA. FU NINDS NIH HHS [K08 NS01663] NR 80 TC 117 Z9 119 U1 1 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2001 VL 13 IS 2 BP 239 EP 249 DI 10.1006/nimg.2000.0681 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 397ZM UT WOS:000166729100001 PM 11162265 ER PT J AU Betancur, C Lepee-Lorgeoux, I Cazillis, M Accili, D Fuchs, S Rostene, W AF Betancur, C Lepee-Lorgeoux, I Cazillis, M Accili, D Fuchs, S Rostene, W TI Neurotensin gene expression and behavioral responses following administration of psychostimulants and antipsychotic drugs in dopamine D-3 receptor deficient mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine D-3 receptor; neurotensin; cocaine; amphetamine; haloperidol; in situ hybridization; behavioral sensitization ID FOS MESSENGER-RNA; HUMAN COCAINE FATALITIES; VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; RAT NEOSTRIATUM; ACUTE METHAMPHETAMINE; LOCOMOTOR-ACTIVITY; BASAL GANGLIA; UP-REGULATION; NEUROMEDIN-N AB Exposure to psychostimulants and antipsychotics increases neurotensin (NT)gene expression in the striatum and nucleus accumbens. To investigate the contribution of D-3 receptors to these effects toe used mice with targeted disruption of the D-3 receptor gene. Basal NT mRNA expression was similar in D-3 receptor mutant mice and wild-type animals. Acute administration of haloperidol increased NT gene expression in the striatum in D-3 +/+, D-3 +/- and D-3 -/- mice. Similarly, acute cocaine and amphetamine induced NT mRNA expression in the nucleus accumbens shell and olfactory tubercle to a comparable extent in D-3 mutants and wild-type mice. Daily injection of cocaine for seven days increased NT mRNA in it restricted population of neurons in the dorsomedial caudal striatum of D-3 +/+ mice, but not in D-3 -/- and D-3 +/- animals. No differences were observed between D-3 receptor mutant mice and wild-type littermates in the locomotor activity and stereotyped behaviors induced by repeated cocaine administration. These findings demonstrate that dopamine D-3 receptors are not necessary for the acute NT mRNA response to drugs of abuse and antipsychotics but appear to play a role in the regulation of NT gene induction in striatal neurons after repented cocaine. In addition, ota results indicate that the acute locomotor response to cocaine and development of psychostimulant-induced behavioral sensitization do not require functional D-3 receptors. [Neuropsychopharmacology 24:170-182, 2001] (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Hop St Antoine, INSERM, U339, F-75571 Paris, France. Hop St Antoine, INSERM, U142 515, F-75571 Paris, France. NIDDKD, Diabet Branch, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. RP Betancur, C (reprint author), Fac Med, INSERM, U513, 8 Rue Gen Sarrail, F-94010 Creteil, France. RI Rostene, William/F-2754-2017 NR 62 TC 38 Z9 38 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2001 VL 24 IS 2 BP 170 EP 182 DI 10.1016/S0893-133X(00)00179-2 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 385RT UT WOS:000166018000006 PM 11120399 ER PT J AU Albert, MR Ostheimer, KG Breman, JG AF Albert, MR Ostheimer, KG Breman, JG TI The last smallpox epidemic in Boston and the vaccination controversy, 1901-1903 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 NCI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Breman, JG (reprint author), Fogarty Int Ctr, NIH, 31 Center Dr, MSC 2220, Bethesda, MD 20892 USA. NR 36 TC 37 Z9 37 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 1 PY 2001 VL 344 IS 5 BP 375 EP 379 DI 10.1056/NEJM200102013440511 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 397CM UT WOS:000166675800011 PM 11172172 ER PT J AU Miranda, KM Espey, MG Wink, DA AF Miranda, KM Espey, MG Wink, DA TI A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Griess assay; vanadium(III) reduction; nitric oxide; nitrate; nitrite ID L-ARGININE ANALOGS; GRIESS REACTION; BIOLOGICAL-FLUIDS; CHEMI-LUMINESCENCE; MESSENGER MOLECULE; AQUEOUS-SOLUTION; NITROGEN-OXIDES; REDUCTASE; OXIDATION; PLASMA AB Numerous methods are available for measurement of nitrate (NO3-). However, these assays can either be time consuming or require specialized equipment (e.g., nitrate reductase, chemiluminescent detector). We have developed a method for simultaneous evaluation of nitrate and nitrite concentrations in a microtiter plate format. The principle of this assay is reduction of nitrate by vanadium(III) combined with detection by the acidic Griess reaction. This assay is sensitive to 0.5 muM NO3- and is useful in a variety of fluids including cell culture media, serum, and plasma. S-Nitrosothiols and L-arginine derivatives were found to be potential interfering agents. However, these compounds are generally minor constituents of biological fluids relative to the concentration of nitrate/nitrite. This report introduces a new, convenient assay for the stable oxidation products of nitrogen oxide chemistry in biological samples. (C) zool Academic Press. C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Miranda, KM (reprint author), NCI, Radiat Biol Branch, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 56 TC 1167 Z9 1195 U1 24 U2 186 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD FEB PY 2001 VL 5 IS 1 BP 62 EP 71 DI 10.1006/niox.2000.0319 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 407KV UT WOS:000167271500008 PM 11178938 ER PT J AU Deitsch, KW Driskill, CL Wellems, TE AF Deitsch, KW Driskill, CL Wellems, TE TI Transformation of malaria parasites by the spontaneous uptake and expression of DNA from human erythrocytes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PLASMODIUM-FALCIPARUM; EUKARYOTIC CELLS; HIGHLY EFFICIENT; MAMMALIAN-CELLS; GENE-TRANSFER; PLASMID DNA; LIPOSOMES; DELIVERY; CULTURE; IMPORT AB The uptake and expression of extracellular DNA has been established as a mechanism for horizontal transfer of genes between bacterial species. Such transfer can support acquisition of advantageous elements, including determinants that affect the interactions between infectious organisms and their hosts. Here we show that erythrocyte-stage Plasmodium falciparum malaria parasites spontaneously take up DNA from the host cell cytoplasm into their nuclei. We have exploited this finding to produce levels of reporter expression in P.falciparum that are substantially improved over those obtained by electroporation protocols currently used to transfect malaria parasites, Parasites were transformed to a drug-resistant state when placed into cell culture with erythrocytes containing a plasmid encoding the human dihydrofolate reductase sequence. The findings reported here suggest that the malaria genome may be continually exposed to exogenous DNA from residual nuclear material in host erythrocytes. C1 NIAID, Malaria Genet Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, Malaria Genet Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tew@helix.nih.gov NR 28 TC 148 Z9 153 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 1 PY 2001 VL 29 IS 3 BP 850 EP 853 DI 10.1093/nar/29.3.850 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398ZL UT WOS:000166786300032 PM 11160909 ER PT J AU Zhang, J Klebanoff, MA Roberts, JM AF Zhang, J Klebanoff, MA Roberts, JM TI Prediction of adverse outcomes by common definitions of hypertension in pregnancy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID LOW-DOSE ASPIRIN; PREECLAMPSIA; PREVENTION; WOMEN AB Objective: To examine the ability of five common definitions of hypertension in pregnancy to predict adverse maternal and perinatal outcomes. Methods: We studied 9133 singleton nulliparous pregnancies with early prenatal care from the Collaborative Perinatal Project, a large cohort study conducted between 1959 and 1965. Definitions from five different groups were evaluated. Severe maternal and perinatal morbidity and mortality were used as the outcome measurements. Sensitivity, specificity, and positive predictive value for outcomes were compared across various definitions. Results: Blood pressure alone had very poor discriminatory power to predict adverse outcomes. Positive predictive values of adverse outcomes by the diagnosis of preeclampsia were 18-20% based on antepartum and intrapartum blood pressures and 22-36% based on antepartum blood pressure only. Mild hypertension occurring for the first time in labor and isolated mild systolic hypertension were not associated with adverse outcomes. Similarly, an increase in diastolic blood pressure of 15 mmHg that did not achieve an absolute value of 90 mmHg did not predict adverse outcome. Conclusion: Neither blood pressure nor blood pressure and proteinuria are accurate predictors of severe adverse maternal and perinatal outcomes. Mild hypertension occurring for the first time in labor and isolated mild systolic hypertension should not be considered indicators for hypertensive disorders in pregnancy in a research definition. (Obstet Gynecol 2001;97:261-7. (C) 2001 by The American College of Obstetricians and Gynecologists.). C1 NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 13 TC 60 Z9 64 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2001 VL 97 IS 2 BP 261 EP 267 DI 10.1016/S0029-7844(00)01125-X PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 401CX UT WOS:000166910500018 PM 11165592 ER PT J AU Sayle, AE Savitz, DA Thorp, JM Hertz-Picciotto, I Wilcox, AJ AF Sayle, AE Savitz, DA Thorp, JM Hertz-Picciotto, I Wilcox, AJ TI Sexual activity during late pregnancy and risk of preterm delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID COITUS LATE; INTERCOURSE; MEMBRANES; FREQUENCY; BEHAVIOR; RUPTURE; BIRTH; LABOR AB Objective: To examine the association between sexual activity during late pregnancy and preterm delivery. Methods: Women at least 16 years old and carrying singleton fetuses were recruited between 24 and 29 weeks' gestation from prenatal clinics in central North Carolina. They were interviewed by telephone about sexual activity before and during pregnancy. One hundred eighty-seven women delivered between 29 and 36 weeks and had a follow-up interview after delivery. Four hundred nine women who were selected randomly from the cohort served as controls and had a follow-up interview between 29 and 36 weeks (mean gestational age 39.2 weeks). Results: Intercourse during late pregnancy was associated with a reduced risk of preterm delivery. The conditional odds ratio (OR) was 0.34 and 95% confidence interval (CI) 0.23, 0.51 for preterm delivery within 2 weeks after intercourse. Similar decreased risk for preterm delivery was found with recent female orgasm. Adjusting for race, age, education, and living with a partner had little effect on results. Cases were more likely than controls to report poorer health, medical reasons for reducing sexual activity, less interest in sex, and receipt of advice to restrict sexual activity during pregnancy. Results did not differ substantially according to presence or absence of bacterial vaginosis at 28 weeks. Conclusion: These data provide evidence against the hypothesis that sexual activity generally increases risk of preterm delivery between 29 and 36 weeks. However, we cannot exclude the possibility that a small subgroup of susceptible women might have adverse consequences of sexual activity. [Obstet Gynecol 2001;97:283-9. (C) 2001 by The American College of Obstetricians and Gynecologists.). C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Savitz, DA (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, CB 7400, Chapel Hill, NC 27599 USA. OI Wilcox, Allen/0000-0002-3376-1311 FU NICHD NIH HHS [HD28684]; PHS HHS [U64/CCU412273, S455/16-17] NR 25 TC 30 Z9 32 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2001 VL 97 IS 2 BP 283 EP 289 DI 10.1016/S0029-7844(00)01147-9 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 401CX UT WOS:000166910500022 PM 11165596 ER PT J AU Goldenberg, RL Wright, LL AF Goldenberg, RL Wright, LL TI Repeated courses of antenatal corticosteroids SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PREMATURE-INFANTS; FETAL; BETAMETHASONE; THERAPY; DEXAMETHASONE; TRIAL AB A single course of corticosteroids given to women before an anticipated preterm birth reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, and neonatal death. For women who do not deliver within 1 week, repeated courses of corticosteroids have become common obstetric practice, despite little evidence of efficacy. Emerging data suggest little benefit and potential harm from that practice, so corticosteroids to improve perinatal outcomes should be restricted to a single course unless future randomized trial data prove additional courses to be beneficial. (Obstet Gynecol 2001;97:316-7. (C) 2001 by The American College of Obstetricians and Gynecologists.). C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. NICHD, Ctr Res Mothers & Children, Bethesda, MD USA. RP Goldenberg, RL (reprint author), Univ Alabama, Dept Obstet & Gynecol, 619 3rd Ave S,CIRC 320, Birmingham, AL 35294 USA. NR 12 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2001 VL 97 IS 2 BP 316 EP 317 DI 10.1016/S0029-7844(00)01153-4 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 401CX UT WOS:000166910500028 PM 11165602 ER PT J AU Offer, H Milyavsky, M Erez, N Matas, D Zurer, I Harris, CC Rotter, V AF Offer, H Milyavsky, M Erez, N Matas, D Zurer, I Harris, CC Rotter, V TI Structural and functional involvement of p53 in BER in vitro and in vivo SO ONCOGENE LA English DT Article DE p53; BER; transactivation; DNA repair ID NUCLEOTIDE-EXCISION-REPAIR; INHIBITS DNA-REPLICATION; TATA-BINDING PROTEIN; CELL NUCLEAR ANTIGEN; TRANSCRIPTIONAL ACTIVATION; TERMINAL DOMAIN; 3'-TO-5' EXONUCLEASE; WILD-TYPE; IN-VIVO; APOPTOSIS AB p53 is involved in several DNA repair pathways. Some of these require the specific transactivation of p53-dependent genes and others involve direct interactions between the p53 protein and DNA repair associated proteins. Previously, we have shown that p53 acts directly in Base Excision Repair (BER) when assayed under in vitro conditions. Our present data indicate that this involvement is independent of the transcriptional activity of the p53 molecule. We found that under both in vitro and in vivo conditions, a p53 transactivation-deficient molecule, p53-22-23,was more efficient in BER activity than was wild type p53. However, mutations in the core domain or C-terminal alterations strongly reduced p53-mediated BER activity, These results are consistent with the hypothesis that the involvement of p53 in BER activity, a housekeeping DNA repair pathway, is a prompt and immediate one that does not involve the activation of D53 transactivation-dependent mechanisms, but rather concerns with the p53 protein itself. In an endogenous DNA damage status p53 is active in BER pathways as a protein and not as a transcription factor. C1 Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20896 USA. RP Rotter, V (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RI Milyavsky, Michael/E-8306-2011 NR 48 TC 57 Z9 58 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 1 PY 2001 VL 20 IS 5 BP 581 EP 589 DI 10.1038/sj.onc.1204120 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 398KE UT WOS:000166755000005 PM 11313990 ER PT J AU Streckfus, C Bigler, L Dellinger, T Dai, XL Cox, WJ McArthur, A Kingman, A Thigpen, JT AF Streckfus, C Bigler, L Dellinger, T Dai, XL Cox, WJ McArthur, A Kingman, A Thigpen, JT TI Reliability assessment of soluble c-erbB-2 concentrations in the saliva of healthy women and men SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID BREAST-CANCER; SERUM; EXPRESSION; HER-2/NEU; CARCINOMA; TUMORS; WHOLE AB Background. The protein c-erbB-2, also known as Her2/neu, is a prognostic breast cancer marker assayed in tissue biopsy specimens from women diagnosed with malignant tumors. Current studies suggest that soluble fragments of the c-erbB-2 oncogene may be released from the cell surface and become detectable in patients with a carcinoma Of the breast. Consequently, the purpose of this study is to assay soluble c-erbB-2 protein in the saliva of healthy men and women to determine the reliability of the assay. Methods. To determine the diagnostic utility of this oncogene, we assayed the soluble form of the c-erbB-2 protein in the saliva with an enzyme-linked immunosorbent assay. The study population consisted of 10 healthy women and 9 healthy men who were serially sampled for saliva 3 times a day for a 5-day period. Saliva was collected from each subject at 9 AM, 4 PM, and 9 PM during the 5-day period. Results. We found the presence of c-erbB-2 protein in the saliva of both groups of subjects. The salivary levels of c-erbB-2 were not significantly different when compared for gender differences. Likewise, the results suggest that sampling during various rimes of the day for salivary c-erbB-2 levels has no effect on marker concentration. Reliability analyses showed that supervised salivary collections were more reliable than unsupervised collections. Conclusions. The results of this pilot study suggest that the assay for salivary c-erbB-2 protein is reliable and might have potential use in the initial detection and follow-up screening for the recurrence of breast cancer in both men and women. C1 Univ Mississippi, Med Ctr, Res Dept, Sch Dent, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Med, Div Oncol, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Restorat Dent, Sch Dent, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Biostat Core, NIDCR,NIH, Jackson, MS 39216 USA. RP Streckfus, C (reprint author), Univ Mississippi, Med Ctr, Res Dept, Sch Dent, 2500 N State St, Jackson, MS 39216 USA. FU NIDCR NIH HHS [1 R55 DE/OD12414-01] NR 17 TC 21 Z9 21 U1 0 U2 1 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 FEB PY 2001 VL 91 IS 2 BP 174 EP 179 DI 10.1067/moe.2001.111758 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 403PH UT WOS:000167051300012 PM 11174594 ER PT J AU Follmann, DA Schron, EB AF Follmann, DA Schron, EB TI Essentials of randomized clinical trials SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Review C1 NHLBI, Rockledge Ctr 2, Bethesda, MD 20892 USA. RP Follmann, DA (reprint author), NHLBI, Rockledge Ctr 2, Room 8216, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 0 U2 2 PU FUTURA PUBL CO PI ARMONK PA 135 BEDFORD RD, PO BOX 418, ARMONK, NY 10504-0418 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD FEB PY 2001 VL 24 IS 2 BP 254 EP 259 DI 10.1046/j.1460-9592.2001.00254.x PG 6 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 411CL UT WOS:000167480500023 PM 11270712 ER PT J AU Nash, TE AF Nash, TE TI Treatment of Giardia lamblia infections SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Review ID LINKED-IMMUNOSORBENT-ASSAY; ALBENDAZOLE; DUODENALIS; CHILDREN; EFFICACY C1 NIAID, Parasit Dis Lab, Gastrointestinal Parasites Sect, NIH, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, Gastrointestinal Parasites Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 6 Z9 8 U1 1 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 FEB PY 2001 VL 20 IS 2 BP 193 EP 195 DI 10.1097/00006454-200102000-00015 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 402UL UT WOS:000167006500013 PM 11224841 ER PT J AU Obarzanek, E Kimm, SYS Barton, BA Van Horn, L Kwiterovich, PO Simons-Morton, DG Hunsberger, SA Lasser, NL Robson, AM Franklin, FA Lauer, RM Stevens, VJ Friedman, LA Dorgan, JF Greenlick, MR AF Obarzanek, E Kimm, SYS Barton, BA Van Horn, L Kwiterovich, PO Simons-Morton, DG Hunsberger, SA Lasser, NL Robson, AM Franklin, FA Lauer, RM Stevens, VJ Friedman, LA Dorgan, JF Greenlick, MR CA DISC Collaborative Res Grp TI Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: Seven-year results of the Dietary Intervention Study in Children (DISC) SO PEDIATRICS LA English DT Article DE children; fat intake; serum cholesterol; saturated fat ID SEXUAL-MATURATION; NATIONAL-HEALTH; FAT; ADOLESCENTS; PUBERTY; TRIAL; YOUTH AB Objective. Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. Methods. Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' followup. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. Results. Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. Conclusion. Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Family Med & Clin Epidemiol, Pittsburgh, PA USA. Maryland Med Res Inst, Baltimore, MD USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. Johns Hopkins Univ, Sch Med, Div Lipid Res Atherosclerosis, Baltimore, MD USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA. Childrens Hosp, New Orleans, LA USA. Childrens Hosp Alabama, Birmingham, AL USA. Univ Iowa, Div Pediat Cardiol, Iowa City, IA USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Kaiser Fdn Hosp, Portland, OR USA. RP Obarzanek, E (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Rm 8136, Bethesda, MD 20892 USA. OI Barton, Bruce/0000-0001-7878-8895 FU NHLBI NIH HHS [U01-HL37947, U01-HL-37966, U01-HL37962, U01-HL37948, U01-HL37954, U01-HL37975, U01-HL38110] NR 40 TC 153 Z9 163 U1 3 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 256 EP 264 DI 10.1542/peds.107.2.256 PG 9 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000021 PM 11158455 ER PT J AU Wang, SS FitzSimmons, SC O'Leary, LA Rock, MJ Gwinn, ML Khoury, MJ AF Wang, SS FitzSimmons, SC O'Leary, LA Rock, MJ Gwinn, ML Khoury, MJ TI Early diagnosis of cystic fibrosis in the newborn period and risk of Pseudomonas aeruginosa acquisition in the first 10 years of life: A registry-based longitudinal study SO PEDIATRICS LA English DT Article DE cystic fibrosis; Pseudomonas aeruginosa; neonatal screening; Kaplan Meier; epidemiology ID PULMONARY-DISEASE; MANAGEMENT; INFECTION AB Objective. Controlled clinical trial data have suggested that identifying asymptomatic cystic fibrosis (CF) patients through newborn screening improves health outcomes of affected children in the first decade of life. However, it is unclear whether these improvements also include a reduction in risk for bronchial infection, the major determinant of CF morbidity. The authors therefore investigated the association between early CF diagnosis and acquisition of Pseudomonas aeruginosa, the major bronchial pathogen, in the first decade of life. Methodology. Longitudinal data on 3625 CF patients diagnosed between 1982 and 1990 and before 36 months of age were ascertained from the National Cystic Fibrosis Patient Registry. We compared P aeruginosa acquisition in the first 10 years of life among 4 groups: EAD (early asymptomatic diagnosis)-< 6 weeks, by pre/neonatal screening, genotype, family history (n = 157); ESD (early symptomatic diagnosis) (n = 227); LAD (late asymptomatic diagnosis)-6 weeks to 36 months (n = 161); and LSD (late symptomatic diagnosis) (n = 3080). P aeruginosa acquisition was determined from yearly sputum and/or bronchoscopy cultures. Children whose CF diagnoses followed meconium ileus or whose cultures were obtained only from nasal samples were excluded from the study. Results. Kaplan Meier analyses for P aeruginosa acquisition were conducted for each diagnostic group. Regression models were used to generate adjusted relative hazards with EAD as the referent group. Relative hazards were 0.9 (95% confidence interval [CI]: 0.7-1.2) for ESD, 0.8 (95% CI: 0.6-1.2) for LAD, and 1.0 (95% CI: 0.7-1.2) for LSD. The risk of acquiring P aeruginosa was therefore not significantly different between children diagnosed early, late, asymptomatically, or symptomatically. Conclusions. These data suggest that, despite improvements in other health outcomes from newborn screening for CF, early asymptomatic diagnosis of CF does not affect P aeruginosa acquisition. C1 Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. Cyst Fibrosis Fdn, Bethesda, MD USA. Ctr Dis Control & Prevent, Off Genet & Dis Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. Ctr Dis Control & Prevent, Epidem Intelligence Serv, Div Appl Publ Hlth Training, Epidemiol Program Off, Atlanta, GA USA. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd, Rockville, MD 20854 USA. NR 22 TC 37 Z9 37 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 274 EP 279 DI 10.1542/peds.107.2.274 PG 6 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000024 PM 11158458 ER PT J AU Lester, BM ElSohly, M Wright, LL Smeriglio, VL Verter, J Bauer, CR Shankaran, S Bada, HS Walls, HC Huestis, MA Finnegan, LP Maza, PL AF Lester, BM ElSohly, M Wright, LL Smeriglio, VL Verter, J Bauer, CR Shankaran, S Bada, HS Walls, HC Huestis, MA Finnegan, LP Maza, PL TI The maternal lifestyle study: Drug use by meconium toxicology and maternal self-report SO PEDIATRICS LA English DT Article DE cocaine; opiates; polydrug use; pregnancy substance abuse; meconium; self-report; multisite; gas chromatography/mass spectrometry; low birth weight; prenatal drug exposure ID COCAINE USE; DEPENDENT MOTHERS; AMNIOTIC-FLUID; BIRTH-WEIGHT; EXPOSURE; URINE; PREGNANCY; INFANTS; METABOLITES; ABUSE AB Objective. The objective of this study was to describe drug use by pregnant women participating in the 4-site Maternal Lifestyle Study of in utero cocaine and/or opiate exposure. Methods. Meconium specimens of 8527 newborns were analyzed by immunoassay with GC/MS confirmation for metabolites of cocaine, opiates, cannabinoids, amphetamines, and phencyclidine. Maternal self-report of drug use was determined by hospital interview. Results. The prevalence of cocaine/opiate exposure in the 4 sites was 10.7% with the majority (9.5%) exposed to cocaine based on the combination of meconium analysis and maternal self-report. However, exposure status varied by site and was higher in low birth weight infants (18.6% for very low birth weight and 21.1% for low birth weight). Gas chromatography/mass spectrometry (GC/MS) confirmation of presumptive positive cocaine screens was 75.5%. In the cocaine/opiate-exposed group, 38% were cases in which the mother denied use but the meconium was positive. There was 66% agreement between positive meconium results and positive maternal report. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49 times more likely to use another drug if they used cocaine. Conclusion. Accurate identification of prenatal drug exposure is improved with GC/MS confirmation and when the meconium assay is coupled with a maternal hospital interview. However, the use of GC/MS may have different implications for research than for public policy. We caution against the use of quantitative analysis of drugs in meconium to estimate the degree of exposure. Our study also highlights the polydrug nature of what used to be thought of as a cocaine problem. C1 Brown Univ, Women & Infants Hosp, Infant Dev Ctr, Brown Med Sch, Providence, RI 02905 USA. Adm Children Youth & Families, Washington, DC USA. Ctr Substance Abuse Treatment, Rockville, MD USA. NIDA, Baltimore, MD USA. Univ Miami, Forens Toxicol Lab, Miami, FL 33152 USA. Univ Tennessee, Coll Med, Memphis, TN 38163 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Miami, Sch Med, Miami, FL USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. NICHHD, Bethesda, MD 20892 USA. ElSohly Labs Inc, Oxford, MS USA. Bradley Hosp, Providence, RI USA. RP Lester, BM (reprint author), Brown Univ, Women & Infants Hosp, Infant Dev Ctr, Brown Med Sch, 101 Dudley St, Providence, RI 02905 USA. FU NICHD NIH HHS [U10 HD 19897, 5-U10-HD27904-02, U10 HD 21385, U10 HD 21397, U10 HD 27856, U10 HD 27904] NR 43 TC 179 Z9 184 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 309 EP 317 DI 10.1542/peds.107.2.309 PG 9 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000030 PM 11158464 ER PT J AU Cunniff, C Frias, JL Kaye, C Moeschler, JB Panny, SR Trotter, TL AF Cunniff, C Frias, JL Kaye, C Moeschler, JB Panny, SR Trotter, TL CA Comm Genetics TI Maternal phenylketonuria SO PEDIATRICS LA English DT Article ID HYPERPHENYLALANINEMIA; MALFORMATIONS AB Elevated maternal phenylalanine levels during pregnancy are teratogenic and may result in growth retardation, significant psychomotor handicaps, and birth defects in the offspring of unmonitored and untreated pregnancies. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninemia, should receive counseling concerning their risks for adverse fetal effects optimally before conceiving. The best outcomes occur when strict control of maternal phenylalanine levels is achieved before conception and continued throughout the pregnancy. C1 NICHHD, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NR 19 TC 2 Z9 2 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 427 EP 428 PG 2 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000051 ER PT J AU Cunniff, C Frias, JL Kaye, C Moeschler, JB Panny, SR Trotter, TL AF Cunniff, C Frias, JL Kaye, C Moeschler, JB Panny, SR Trotter, TL CA Comm Genetics TI Health supervision for children with Down syndrome SO PEDIATRICS LA English DT Article ID ATLANTO-AXIAL INSTABILITY; YOUNG-CHILDREN; INDIVIDUALS AB These guidelines are designed to assist the pediatrician in caring for the child in whom the diagnosis of Down syndrome has been confirmed by karyotype. Although the pediatrician's initial contact with the child is usually during infancy, occasionally the pregnant woman who has been given the prenatal diagnosis of Down syndrome will be referred for counseling. Therefore, these guidelines offer advice for this situation as well. C1 NIH, Bethesda, MD 20892 USA. NR 23 TC 174 Z9 185 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 442 EP 449 PG 8 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000055 ER PT J AU Walsh-Sukys, M Faranoff, A Verter, J Wright, L AF Walsh-Sukys, M Faranoff, A Verter, J Wright, L TI Pulmonary hypertension-hyperventilation versus alkali infusion - Reply SO PEDIATRICS LA English DT Letter C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. George Washington Univ, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. RP Walsh-Sukys, M (reprint author), Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2001 VL 107 IS 2 BP 452 EP 452 PG 1 WC Pediatrics SC Pediatrics GA 397TT UT WOS:000166714000063 ER PT J AU Corchero, J Pimprale, S Kimura, S Gonzalez, FJ AF Corchero, J Pimprale, S Kimura, S Gonzalez, FJ TI Organization of the CYP1A cluster on human chromosome 15: implications for gene regulation SO PHARMACOGENETICS LA English DT Article DE cytochromes P450; CYP1A gene cluster; CYP1A1; CYP1A2; XRE; xenobiotics ID AMINO-ACID SEQUENCE; MESSENGER-RNA; CYTOCHROME P4501A1; INDUCIBILITY; POLYMORPHISM; EXPRESSION; METABOLISM; INDUCTION; REGION; MOUSE AB The sequence and organization of the CYP1A cluster on human chromosome 15 was determined. A human genomic clone from a BAC library, containing both CYP1A1 and CYP1A2 genes, was isolated and sequenced. The results of Southern blot analysis using human genomic DNA were compatible with the structure of the BAC clone. The CYP1A1 and CYP1A2 genes are separated by a 23 kb segment that contains no other open reading frames, The CYP1A1 and CYP1A2 genes are in opposite orientation, revealing that the 5' flanking region is in common between the two genes. Analysis of the sequence obtained revealed the presence of xenobiotic response elements (XREs) previously reported for CYP1A1 and CYP1A2 and several additional consensus sequences for putative XREs, The presence of all the XREs upstream of both genes suggest that some of the regulatory elements known to control CYP1A1 gene expression, could also control CYP1A2 gene expression. Pharmacogenetics 11:1-6 (C) 2001 Lippincott Williams & Wilkins. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3E24, Bethesda, MD 20892 USA. NR 21 TC 68 Z9 72 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD FEB PY 2001 VL 11 IS 1 BP 1 EP 6 DI 10.1097/00008571-200102000-00001 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 396VC UT WOS:000166656300001 PM 11207026 ER PT J AU Diehl, SR White, PS AF Diehl, SR White, PS TI Cambridge Healthtech Institute's Third Annual Conference on Human Genetic Variation - 16-18 October 2000, Philadelphia, Pennsylvania, USA SO PHARMACOGENOMICS LA English DT Editorial Material DE gene mapping; genetic disease; genetic epidemiology; linkage disequilibrium; SNP discovery; SNP genotyping; SNP scoring AB A major goal of pharmacogenomics is to identify the human genetic variation that influences susceptibility to complex diseases. Recently, theoretical statistical analyses have suggested that genes for complex diseases may be found by linkage disequilibrium (i.e., association). Single nucleotide polymorphism (SNP) susceptibility alleles for common diseases can occur at high frequencies in various populations and, thus, have a major impact on morbidity and mortality. To be successful, SNP mapping studies require successful teamwork, integrating clinicians, epidemiologists, molecular genetics experts, laboratory automation engineers, bioinformatics and database experts. New statistical methods are also developing rapidly and promise to further increase the power of these studies. A recent conference on human genetic variation provided an opportunity for experts in all of these disciplines to exchange ideas. At present, great technological challenges need to be overcome in order to increase the throughput greatly while lowering cost and still maintaining high accuracy for SNP genotyping. Although this approach is relatively new (at least on the scale now being contemplated), the large payoffs anticipated to accrue from the successful mapping of SNPs in disease genes has led the area to be very strongly supported by both public and private funding sources. The potential payoff for improving disease diagnosis and therapeutic efficacy, with better avoidance of adverse events based on SNP associations, is providing a tremendous incentive to move this effort forward at an ever-accelerating pace. C1 NIDCR, Craniofacial Epidemiol & Genet Branch, NIH, Bethesda, MD 20892 USA. Los Alamos Natl Lab, Biosci Div, Ctr Human Genome Studies, Los Alamos, NM 87545 USA. RP Diehl, SR (reprint author), NIDCR, Craniofacial Epidemiol & Genet Branch, NIH, Natcher Bldg Rm 4AS-43G,45 Ctr Dr, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 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 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD FEB PY 2001 VL 2 IS 1 BP 79 EP 84 DI 10.1517/14622416.2.1.79 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 499NJ UT WOS:000172577000009 PM 11258201 ER PT J AU Pandeya, SN Manjula, H Stables, JP AF Pandeya, SN Manjula, H Stables, JP TI Design of semicarbazones and their bio-isosteric analogues as potential anticonvulsants SO PHARMAZIE LA English DT Article AB A series of semicarbazones and hydrazones were prepared and evaluated for anticonvulsant activity. Some compounds provided significant protection against maximal electroshock (MES) and subcutaneous strychnine induced seizures (ScSty). Compound 2a emerged as the most active compound at a dose of 30 mg/kg in ScSty test. The compounds 1a. 1g and 2a-e showed significant potentiation of sedative and hypnotic activity of pentobarbitone sodium. Thus compound 2a could serve as a prototype for future developments. C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NINDS, NIH, Bethesda, MD USA. RP Pandeya, SN (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NR 8 TC 31 Z9 32 U1 0 U2 0 PU GOVI-VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCHER VERLAG GINNHEIMER STRASSE 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD FEB PY 2001 VL 56 IS 2 BP 121 EP 124 PG 4 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 401CB UT WOS:000166908400002 PM 11234338 ER PT J AU Ali, M Ansari, SH Grever, MR AF Ali, M Ansari, SH Grever, MR TI Cytotoxic alkaloids from Tylophora indica SO PHARMAZIE LA English DT Article ID TUMOR CELL-LINES C1 Jamia Hamdard, Fac Pharm, New Delhi 110062, India. NCI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Ansari, SH (reprint author), Jamia Hamdard, Fac Pharm, Hamdard Nagar, New Delhi 110062, India. NR 14 TC 11 Z9 11 U1 0 U2 5 PU GOVI-VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCHER VERLAG GINNHEIMER STRASSE 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD FEB PY 2001 VL 56 IS 2 BP 188 EP 190 PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 401CB UT WOS:000166908400020 PM 11234356 ER PT J AU Greiner, RS Moriguchi, T Slotnick, BM Hutton, A Salem, N AF Greiner, RS Moriguchi, T Slotnick, BM Hutton, A Salem, N TI Olfactory discrimination deficits in n-3 fatty acid-deficient rats SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE DHA; docosahexaenoic acid; omega-3 fatty acids; olfaction; odor discrimination; essential fatty acids; behavior; n-3 fatty acid deficiency ID ALPHA-LINOLENIC ACID; VISUAL-ACUITY DEVELOPMENT; DOCOSAHEXAENOIC ACID; PRETERM INFANTS; RHESUS-MONKEYS; ODOR MEMORY; ARACHIDONIC-ACID; RANDOMIZED TRIAL; LEARNING-TASKS; GUINEA-PIG AB Docosahexaenoic acid (DHA), a long chain n - 3 fatty acid, is present in high concentrations in the central nervous system. Although the role that DHA may play in neural function is not well understood, infants fed formulas containing low levels of n- 3 fatty acids have decreased visual acuity and neurodevelopmental test scores. The present experiment assessed whether dietary manipulations that decrease the concentration of DHA in the brain interfered with olfactory-based learning. We fed rats a diet that provided adequate n - 3 fatty acids or a diet that was deficient in n - 3 fatty acids for two generations. The second generation n - 3-deficient group had 81% less brain DHA (82% less in olfactory bulb) compared to the n - 3-adequate group and made significantly more errors in a series of olfactory-cued, 2-odor discrimination tasks compared to the adequate group. These results suggest that lower levels of central nervous system DHA lead to poorer performance in a series of simple odor discrimination tasks. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIAAA, Div Intramural Clin & Biol Res, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. American Univ, Dept Psychol, Washington, DC 20016 USA. RP Salem, N (reprint author), NIAAA, Div Intramural Clin & Biol Res, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Pk 5 Bldg Room 158, Rockville, MD 20852 USA. NR 43 TC 53 Z9 55 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB PY 2001 VL 72 IS 3 BP 379 EP 385 DI 10.1016/S0031-9384(00)00437-6 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 413RT UT WOS:000167626300013 PM 11274681 ER PT J AU McClure, RK AF McClure, RK TI The visual backward masking deficit in schizophrenia SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE backward masking; intermediate phenotype; neurocognitive deficits; schizophrenia; visual masking; visual-spatial working memory ID LATERAL GENICULATE-NUCLEUS; PREFRONTAL CORTEX; AXON TERMINALS; PERCEPTION; CHANNELS; VULNERABILITY; PERFORMANCE; ADOLESCENTS; MEDICATION; TRANSIENT AB 1. Subjects with schizophrenia have an impairment very early in visual information processing, requiring a longer minimal stimulus duration than normal controls to identify a target stimulus. Subjects with schizophrenia have a deficit in visual backward masking, identifying fewer target stimuli than normal controls when the target is briefly obscured by a second visual stimulus When interstimulus interval is increased parametrically, subjects with schizophrenia have trouble identifying target stimuli at intervals that do not affect the performance of normal controls. 2. The visual backward masking deficit: is trait-related; is associated with negative symptoms but has also been associated with measures of thought disorder; may or may not be related to treatment with neuroleptic medication or other neurocognitive deficits of schizophrenia; is of unclear etiology, though researchers have speculated that it involves magnocellular channels acid/or the cortical dorsal visual processing stream; has been shown to be heritable in one study. 3. If visual information processing deficits are observed in the unaffected siblings of schizophrenic patients, it may be a candidate intermediate phenotype. C1 NIMH, Bethesda, MD 20892 USA. RP McClure, RK (reprint author), 10 Ct Dr,Rm 4D18-20, Bethesda, MD 20892 USA. NR 49 TC 28 Z9 28 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD FEB PY 2001 VL 25 IS 2 BP 301 EP 311 DI 10.1016/S0278-5846(00)00166-4 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 413EG UT WOS:000167596500001 PM 11294477 ER PT J AU Bello-Deocampo, D Kleinman, HK Deocampo, ND Webber, MM AF Bello-Deocampo, D Kleinman, HK Deocampo, ND Webber, MM TI Laminin-1 and alpha 6 beta 1 integrin regulate acinar morphogenesis of normal and malignant human prostate epithelial cells SO PROSTATE LA English DT Article DE acinar morphogenesis; extracellular matrix; integrins; laminin; prostate cancer ID FOCAL ADHESION KINASE; DIFFERENTIAL EXPRESSION; MEDIATED ACTIVATION; NEOPLASTIC PROSTATE; CANCER PROGRESSION; IDENTIFICATION; PHENOTYPE; LINES AB BACKGROUND. Cell-matrix interactions via integrin receptors are critical for acinar morphogenesis. The non-tumorigenic, human prostate epithelial cell line RWPE-1 was used in a three-dimensional (3D) cell culture model to identify the matrix protein and its integrin receptor required for acinar morphogenesis. METHODS. 3D cultures, immunostaining, confocal microscopy, and Western blot analysis were used to examine acinar formation on matrix proteins and to determine integrin receptor expression. RESULTS. RWPE-1 cells differentiate into acini of polarized cells with a distinct lumen in 3D Matrigel culture. In contrast, the malignant WPE1-NB26 prostate epithelial cells form solid cell masses. In 3D gels of laminin-1, type IV collagen, or fibronectin, RWPE-1 cells form acini only in laminin-1. Anti-laminin-1 antibody reduces acinar formation in a dose-dependent manner. Polarized RWPE-1 cells showed basal expression of alpha6 and beta1 integrin subunits. Blocking antibodies to alpha6 or beta1 reduced acinar formation to 9 and 6% of control, respectively. The beta1 integrin colocalized beta1 with focal adhesion kinase (FAK). Inhibition of extracellular signal-regulated kinase kinase activity significantly reduced acinar formation to 38% of control, suggesting that beta1 integrin-mediated signal transduction may be regulated through a FAK pathway. CONCLUSIONS. While basal expression of alpha6 beta1 integrin in RWPE-1 cells correlates with their ability to polarize and form acini, a decrease or loss of alpha6, and diffused beta1 expression in WPE1-NB26 cells correlates with loss of acinar-forming ability. Results show that laminin-1 and a functional alpha6 beta1 integrin receptor are required fur acinar morphogenesis. This novel 3D cell culture model is useful for elucidating regulation of acinar morphogenesis and its loss during prostate carcinogenesis. Prostate 46:142-153, 2001. (C) 2001 Wiley-Liss, Inc. C1 Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bethesda, MD USA. Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. RP Webber, MM (reprint author), Michigan State Univ, Dept Zool, S-350 Plant Biol Bldg, E Lansing, MI 48824 USA. NR 32 TC 57 Z9 57 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 1 PY 2001 VL 46 IS 2 BP 142 EP 153 DI 10.1002/1097-0045(20010201)46:2<142::AID-PROS1018>3.0.CO;2-B PG 12 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 398JC UT WOS:000166752500007 PM 11170142 ER PT J AU Sinha, N Tsai, CJ Nussinov, R AF Sinha, N Tsai, CJ Nussinov, R TI A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer SO PROTEIN ENGINEERING LA English DT Article DE amyloid; beta-hairpin; beta-turn; domain swapping; hinge bending; misfolding; polymerization; structural motif ID HYDROPHOBIC FOLDING UNITS; PROTEINS; TRANSTHYRETIN; MECHANISM; ASSOCIATION; EVOLUTION; STATE AB We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta -sheet conformations, characteristic of amyloids, Some cases of amyloid formation can be explained through a 'domain swapping' event, where the swapped segment is either a beta -hairpin or an unstable conformation which can partially unfold and assume a beta -hairpin structure. As in domain swapping, here the swapped beta -hairpin is at the edge of the structure, has few (if any) salt bridges and hydrogen bonds connecting it to the remainder of the structure and variable extents of buried non-polar surface areas. Additionally, in both cases the swapped piece constitutes a transient 'building block' of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha -helix, loop, strand or an entire domain, but so far not a beta -hairpin, despite the large number of cases in which it was already detected, here swapping may involve such a structural motif, We show how the swapping of beta -hairpins would form an interdigitated, twisted beta -sheet conformation, explaining the remarkable high stability of the protofibril in vitro. Such a swapping mechanism is attractive as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with structural superpositioning of mutational variants, While the overall r.m.s.d.s of the wild-type and mutants are small, the proposed hinge-bending region consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regardless of their location in the sequence or in the structure. Nevertheless, above all, we stress that this proposition is hypothetical, since it is based on assumptions lacking definitive experimental support. C1 NCI, Intramural Res Support Program, SAIC, Lab Expt & Computat Biol,FCRDC, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Intramural Res Support Program, SAIC, Lab Expt & Computat Biol,FCRDC, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 43 TC 47 Z9 48 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD FEB PY 2001 VL 14 IS 2 BP 93 EP 103 DI 10.1093/protein/14.2.93 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 425ZF UT WOS:000168324000004 PM 11297667 ER PT J AU Miyamoto, S Qin, J Safer, B AF Miyamoto, S Qin, J Safer, B TI Detection of early gene expression changes during activation of human primary lymphocytes by in vitro synthesis of proteins from polysome-associated mRNAs SO PROTEIN SCIENCE LA English DT Article DE translation; gene expression; T cells; proteins; mRNA; protein synthesis; lymphocytes ID MEMBRANE-BOUND POLYSOMES; MESSENGER-RNA; ANTIGEN RECEPTOR; TRANSLATION; PROHIBITIN; CELLS; ACTIN; CYTOSKELETAL; ACTINOMYCIN; TUBULIN AB The rapid increase in protein synthesis during the mitogenic stimulation of human peripheral blood lymphocyte is the result of global and specific translational control mechanisms. To study some of these mechanisms, we examined the in vitro translatability of mRNAs associated with the polyribosome fraction. Polyribosome fractions were isolated from lymphocytes after activation with ionomycin and the phorbol ester PMA. The associated PAmRNAs were translated in the presence of mRNA-depleted rabbit reticulocyte lysate and [S-35]Met, and the protein products were analyzed by SDS-PAGE and autoradiography. There was little synthesis of protein from the PAmRNAs isolated from unactivated T cells, but the PAmRNAs isolated from activated T cells showed a rapid increase in translatability. Translation of the PAmRNAs was sensitive to edeine and m7GTP, suggesting their cap-dependent translation. With activation, the majority of proteins showed increasing in vitro translation, but two proteins, p72 and p33, were found to have increased synthesis within 30 min, which decreased in 1 h. Transcription inhibitors were used to ascertain if regulation of their expression was transcriptional or translational. To identify these proteins, we used biotinylated lysine during the in vitro translation reaction, and we extracted the biotinylated protein by using streptavidin magnetic beads. The protein product was analyzed by mass spectrometry. p33 was identified as a prohibitin-like protein (BAP37), but the identification of p72 was not found in the databases. The distinct up-regulation acid down-regulation of their protein expression suggest their tightly controlled regulation during early T cell activation. C1 NHLBI, Mol Hematol Branch, Sect Prot & RNA Biosynth, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Safer, B (reprint author), NHLBI, Mol Hematol Branch, Sect Prot & RNA Biosynth, Bldg 10, Bethesda, MD 20892 USA. NR 40 TC 7 Z9 8 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2001 VL 10 IS 2 BP 423 EP 433 DI 10.1110/ps.21301 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 418ZZ UT WOS:000167926000020 PM 11266628 ER PT J AU Wehrle, JP Barrick, D AF Wehrle, JP Barrick, D TI Review of the Fifth Annual Johns Hopkins Protein Folding Meeting SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Editorial Material C1 NIGMS, NIH, Bethesda, MD 20205 USA. Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD USA. RP Wehrle, JP (reprint author), NIGMS, NIH, Bethesda, MD 20205 USA. NR 6 TC 0 Z9 0 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 0887-3585 J9 PROTEINS JI Proteins PD FEB 1 PY 2001 VL 42 IS 2 BP 141 EP 147 DI 10.1002/1097-0134(20010201)42:2<141::AID-PROT10>3.0.CO;2-C PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 388QN UT WOS:000166193200001 PM 11119638 ER PT J AU Dickey, B Normand, SL Norton, EC Rupp, A Azeni, H AF Dickey, B Normand, SL Norton, EC Rupp, A Azeni, H TI Managed care and children's behavioral health services in Massachusetts SO PSYCHIATRIC SERVICES LA English DT Article ID MEDICAID AB Objective: The authors investigated changes in treatment patterns and costs of care for children after the implementation of the Massachusetts Medicaid carve-out managed care plan. Methods: The authors hypothesized that after the introduction of managed care, per-child expenditures would be reduced, continuity of care would not improve, and per-child mental health expenditures would undergo larger reductions for disabled children, compared with children enrolled in the Aid to Families With Dependent Children program. Using data from Medicaid and the Massachusetts Department of Mental Health, the authors studied 16,864 Massachusetts Medicaid beneficiaries aged one to 17 years for whom reimbursement claims were submitted for psychiatric or substance use disorder treatment at least once during the two years before the introduction of managed care (1991 to 1992) or during the two years afterward (1994 to 1995). Multivariate analysis was used to estimate changes in probability of admission, and, among patients admitted, to identify factors accounting for variation in length of stay. To assess the variation in expenditures, we regressed the same variables, using the natural logarithm function to transform total mental health expenditures data and inpatient expenditures data to reduce skewness. Results: After the introduction of managed care, per-child expenditures were lower, especially for disabled children, and the Department of Mental Health was used as a safety net for the most seriously ill children without increasing state expenditures. Continuity of care appeared to decline for disabled children. Conclusions: It is likely that a combination of factors related to the reported changes in patterns of care and expenditures were responsible for the overall per-child expenditures. C1 Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. Univ N Carolina, Sch Publ Hlth, Dept Hlth Policy & Adm, Chapel Hill, NC USA. NIMH, Res Serv, Bethesda, MD 20892 USA. NIMH, Clin Epidemiol Branch, Bethesda, MD 20892 USA. RP Dickey, B (reprint author), Cambridge Hosp, Dept Psychiat, 1493 Cambridge St, Cambridge, MA 02139 USA. RI Norton, Edward/B-2211-2009 OI Norton, Edward/0000-0003-4555-0631 FU NIMH NIH HHS [R01-MH-46522] NR 11 TC 19 Z9 19 U1 0 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD FEB PY 2001 VL 52 IS 2 BP 183 EP 188 DI 10.1176/appi.ps.52.2.183 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 398HC UT WOS:000166750000011 PM 11157116 ER PT J AU Altemus, M Dale, JK Michelson, D Demitrack, MA Gold, PW Straus, SE AF Altemus, M Dale, JK Michelson, D Demitrack, MA Gold, PW Straus, SE TI Abnormalities in response to vasopressin infusion in chronic fatigue syndrome SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE vasopressin; ACTH; CRH; chronic fatigue syndrome; cortisol; HPA axis ID CORTICOTROPIN-RELEASING-FACTOR; PITUITARY-ADRENAL AXIS; POSTTRAUMATIC-STRESS-DISORDER; LOW-DOSE HYDROCORTISONE; PARAVENTRICULAR NUCLEUS; MEDIATED ACTIVATION; HEALTHY-VOLUNTEERS; ATOPIC-DERMATITIS; SALIVARY CORTISOL; FACTOR CRF AB Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. Lilly Res Labs, Indianapolis, IN USA. RP Altemus, M (reprint author), Cornell Univ, Weill Med Coll, Box 244,1300 York Ave, New York, NY 10021 USA. RI Demitrack, Mark/I-7697-2013 NR 74 TC 24 Z9 25 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD FEB PY 2001 VL 26 IS 2 BP 175 EP 188 DI 10.1016/S0306-4530(00)00044-5 PG 14 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 391QZ UT WOS:000166367800005 PM 11087963 ER PT J AU Hall, FS Sora, I Uhl, GR AF Hall, FS Sora, I Uhl, GR TI Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice SO PSYCHOPHARMACOLOGY LA English DT Article DE transgenic mice; mu-opiate receptor; ethanol; reward; conditioned place preference ID DELTA-OPIOID RECEPTORS; ALCOHOL-PREFERRING AA; MORPHINE-INDUCED ANALGESIA; NUCLEUS-ACCUMBENS; PLACE-PREFERENCE; DBA/2 MICE; NALTREXONE BLOCKS; DOPAMINE RELEASE; ACCESS PROCEDURE; ORAL ETHANOL AB Rationale: Differences in mu -opiate receptor (MOR) gene expression may modulate the rewarding effects of ethanol. Objective. The effects of MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption, conditioned place preference produced by ethanol, and locomotor responses to ethanol in separate groups of mice. Methods: Voluntary ethanol consumption (2-32% v/v) was examined in a two-bottle home-cage consumption test. The conditioned place preference paradigm was a biased design. Mice received four pairings of ethanol (2.0 g/kg IP) on the initially preferred side and four pairings on the initially non-preferred side with saline. The difference in time spent on the initially non-preferred side (pre- versus post-conditioning) was the measure of drug-induced preference. After habituation to a novel locomotor test chamber mice were tested, on subsequent sessions, for ethanol induced locomotion (0.0, 0.5, 1.0, and 2.0 g/kg IP). Results: Heterozygous and homozygous MOR KO mice consumed less ethanol than wildtype mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. These effects on ethanol reward were produced by reductions in MOR expression levels as small as 50%. MOR KO mice exhibited less ethanol-stimulated locomotion than did wild-type mice, an effect that was also largest in females. Conclusions: These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of human alcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism. C1 NIDA, Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD 21224 USA. RP Hall, FS (reprint author), NIDA, Intramural Res Program, Mol Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 76 TC 137 Z9 142 U1 3 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2001 VL 154 IS 1 BP 43 EP 49 DI 10.1007/s002130000622 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 408WR UT WOS:000167350400007 PM 11292005 ER PT J AU Samuni, Y DeGraff, W Chevion, M Mitchell, JB Cook, JA AF Samuni, Y DeGraff, W Chevion, M Mitchell, JB Cook, JA TI Radiation sensitization of mammalian cells by metal chelators SO RADIATION RESEARCH LA English DT Article ID PLANT AMINO-ACID; RIBONUCLEOTIDE REDUCTASE; DNA-REPLICATION; LEUCAENA-LEUCOCEPHALA; IRON CHELATORS; CANCER CELLS; MIMOSINE; INHIBITION; CYCLE; GROWTH AB The cell cycle effects, alteration in radiation response, and inherent cytotoxicity of the metal chelators mimosine, desferrioxamine (DFO), N,N'-bis(o-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), and deferiprone (L1) were studied in exponentially growing Chinese hamster V79 cells. Incubation of cells with 200-1000 muM mimosine for 12 h reduced clonogenic survival to 50-60%, while incubation for 24 h reduced survival further to 0.5%. Mimosine treatment resulted in cell cycle blocks at the G(1)/S-phase border and in S phase. Pulse labeling with 5-bromodeoxyuridine indicated that the S-phase cells ceased to actively replicate DNA after only 2 h of mimosine treatment and were unable to replicate DNA for extended periods. Treatment of V79 cells with 600 muM minosine for 12 h resulted in radiosensitization, yielding a sensitizer enhancement ratio (SER) of 2.7 +/- 0.3 at the 10% survival level. To study the kinetics of the sensitization, V79 cells were incubated with mimosine for various times up to 12 h and irradiated with a single 10-Gy dose of X rays. It was found that the radiosensitization increased continually up to 8 h (from a 3- to a 100-fold difference in survival) and then reached a plateau after 8 h. Mimosine also equally radiosensitized human lung cancer cells having either a normal or mutated TP53 gene, suggesting a TP53-independent mechanism. To test whether iron binding by mimosine was responsible for the observed radiosensitization, additional experiments were performed using the iron chelators DFO, HEED and L1. V79 cells treated with 500 muM of these agents for 8 h followed by various doses of X rays gave SERs similar to that for mimosine (2.0-2.7). These studies indicate that metal chelators are potent radiosensitizers in V79 and human cells. Importantly, when the DFO was preloaded together with Fe3+ [Fe(III)-DFO], the radiosensitizing effect was lost. These preliminary findings warrant further studies for the possible application of metal chelators as radiation sensitizers in radiation oncology. (C) 2001 by Radiation Research Society. C1 NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Sch Med, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Sch Dent, IL-91120 Jerusalem, Israel. RP Cook, JA (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 36 TC 11 Z9 11 U1 0 U2 7 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2001 VL 155 IS 2 BP 304 EP 310 DI 10.1667/0033-7587(2001)155[0304:RSOMCB]2.0.CO;2 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 397RF UT WOS:000166708800005 PM 11175665 ER PT J AU Miller, RW AF Miller, RW TI Historical vignette: Hiroshima, 1955 SO RADIATION RESEARCH LA English DT Letter C1 NCI, Clin Genet Branch, Bethesda, MD 20892 USA. RP Miller, RW (reprint author), NCI, Clin Genet Branch, EPS-7018, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2001 VL 155 IS 2 BP 378 EP 378 DI 10.1667/0033-7587(2001)155[0378:HVH]2.0.CO;2 PG 1 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 397RF UT WOS:000166708800014 PM 11229329 ER PT J AU Patronas, NJ Courcoutsakis, N Bromley, CM Katzman, GL MacCollin, M Parry, DM AF Patronas, NJ Courcoutsakis, N Bromley, CM Katzman, GL MacCollin, M Parry, DM TI Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype SO RADIOLOGY LA English DT Article DE genes and genetics; neurofibromatosis; spinal cord, MR; spinal cord, neoplasms ID GERM-LINE MUTATIONS; TYPE-2 NEUROFIBROMATOSIS; GENE; NF2; DISEASE; SUPPRESSOR; SEVERITY; CORD AB PURPOSE: To determine the appearance of spinal tumors on magnetic resonance (MR) images of patients with neurofibromatosis 2 (NF2), to assess the biologic behavior of these tumors, and to determine the correlation between NF2 germline mutations and these tumors. MATERIALS AND METHODS: Spinal MR images in 49 patients with NF2 were reviewed retrospectively. Intramedullary and intradural extramedullary tumors were counted, and imaging features and growth patterns of intramedullary tumors were determined. Medical records were reviewed for spinal tumor surgery. Data on spinal tumors and NF2 germline mutations in 37 patients from 19 families were analyzed for genotype-phenotype correlation. RESULTS: Thirty-one patients (63%) had spinal tumors: Twenty-six (53%) had intramedullary tumors, 27 (55%) had intradural extramedullary tumors, and 22 (45%) had at least one tumor of each type. Three (12%) patients with intramedullary tumors versus 16 (59%) with extramedullary tumors had undergone surgery for the respective types of tumors. Compared with patients with all other types of mutations, a higher percentage of patients with nonsense and frameshift mutations had intramedullary tumors (P < .025); these patients also had higher mean numbers of all tumors (P < .001), intramedullary tumors (P < .001), and nerve sheath tumors (NSTs) (P < .001). CONCLUSION: in patients with NF2 and spinal tumors, extramedullary tumors (predominantly NSTs) were present in higher numbers and were associated with more surgery than were intramedullary tumors. Our data suggest that the association between nonsense and frameshift mutations and severe NF2 may extend to specific categories of spinal tumors. C1 NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Northwestern Mem Hosp, Dept Radiol, Chicago, IL USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Patronas, NJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, 10 Ctr Dr,MSC 1182,Rm 1C660, Bethesda, MD 20892 USA. NR 21 TC 47 Z9 50 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2001 VL 218 IS 2 BP 434 EP 442 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397ZE UT WOS:000166728200020 PM 11161159 ER PT J AU Pineda, DA Lopera, F Henao, GC Palacio, JD Castellanos, FX AF Pineda, DA Lopera, F Henao, GC Palacio, JD Castellanos, FX CA Grp Investigacion Fundema TI Confirmation of the high prevalence of attention deficit disorder in a Colombian community SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE attention deficit hyperactivity disorder; Colombia ID 11 YEARS OLD; DEFICIT/HYPERACTIVITY DISORDER; CHILDREN; HYPERACTIVITY; DIAGNOSIS; PARENTS; SCALE AB Introduction. Using a shortened rating scale, the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) has been reported to be very higher in a Colombian population. However, these data require clinical confirmation. Objective. To confirm clinically the prevalence of ADHD in Colombian children and adolescents. Patients and methods. A randomized sample of 4 to 17 year old children and adolescents-184 males and 157 females-was selected from the schools. Sample was stratified in two socioeconomic status: high (4, 5, 6) and low (1, 2, 3). Several parents' and teachers' rating scales for the diagnosis of ADHD, standardized and validated in the Colombian population, were applied to the sample. The diagnosis of ADHD was confirmed using a semi-structured psychiatric and neurological interview, and medical histories revisions. Results. Analysis found that prevalence of ADHD is 17.1%. Distribution for ADHD types was: combined 9,4%, inattentive 6.7% and hyperactive-impulsive 1%. Prevalence for boys was significant higher (21.8%) than for girls (10.9%) (chi (2) = 11.8, p< 0.01). In male predominate combined type and in female inattentive. Higher prevalence was found in low socioeconomic strata. Preschool children have lower prevalence (6.2%) than school 6 to 11 year old children (22.6%) and adolescents (21.6%). Conclusion A higher prevalence of ADHD was confirmed in Colombian population. C1 Univ Antioquia, Grp Neurociencias, Medellin, Colombia. Univ San Buenaventura, Medellin, Colombia. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Univ Manizales, Grp Invest Fdn, Manizales, Colombia. NR 24 TC 38 Z9 52 U1 2 U2 3 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD FEB 1 PY 2001 VL 32 IS 3 BP 217 EP 222 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 420LY UT WOS:000168007500004 PM 11310271 ER PT J AU Peculis, BA AF Peculis, BA TI snoRNA nuclear import and potential for cotranscriptional function in pre-rRNA processing SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE nuclear import; processing; ribosomal RNA; ribosome; snoRNA; U8 snoRNA; U22 snoRNA ID SMALL NUCLEOLAR RNAS; EXTERNAL TRANSCRIBED SPACER; XENOPUS-LAEVIS OOCYTES; ESSENTIAL BINDING-SITE; RIBOSOMAL-RNA; U3 SNRNA; PRENUCLEOLAR BODIES; MUTATIONAL ANALYSIS; PRERIBOSOMAL RNA; MATURATION AB Several snoRNAs are essential for the sequence of cleavage events required to produce the mature forms of 18S, 5.8S, and 28S rRNA from the large precursor molecule. In the absence! of U22, mature 18S rRNA fails to accumulate; US snoRNA is essential for accumulation of both 5.8S and 28S rRNA, The mechanisms by which snoRNAs facilitate these cleavage events is not known and might include direct cleavage or assisting the rate or efficiency of ribosome assembly. To learn more about the mechanisms of snoRNA-mediated pre-rRNA processing, an examination of the kinetics of pre-rRNA processing in Xenopus oocytes was undertaken. Correct pre-rRNA processing can be restored in snoRNA-depleted oocytes following cytoplasmic injection of the corresponding in vitro-synthesized snoRNA, Analysis of the kinetics of pre-rRNA processing in these snoRNA-rescue experiments demonstrated that the rate of accumulation of mature rRNAs was slower than that seen in untreated oocytes. The snoRNAs were imported into the nucleus at a rate and overall efficiency less than that of U1 snRNA, used as a control for import. However, sufficient levels of snoRNA were present in the nucleus to yield a functional phenotype (rescue of rRNA processing) several hours before the snoRNAs were directly detectable in the nucleus via autoradiography, This indicated that very low amounts of the snoRNA in the nucleus were sufficient for rescue. Finally, transcriptional inhibitors were used to separate transcription and processing, Failure to rescue snoRNA-mediated processing of pre-accumulated precursors is consistent with a scenario in which US and U22 must be present during transcription of pre-rRNA. C1 NIDDKD, GBB, NIH, Bethesda, MD 20892 USA. RP Peculis, BA (reprint author), NIDDK, GBB, NIH, Bldg 10,Room 8N322,10 Ctr Dr,MSC 1766, Bethesda, MD 20892 USA. NR 49 TC 17 Z9 17 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD FEB PY 2001 VL 7 IS 2 BP 207 EP 219 DI 10.1017/S1355838201001625 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400RB UT WOS:000166884500006 PM 11233978 ER PT J AU Trawoger, R Cereda, M Kolobow, T AF Trawoger, R Cereda, M Kolobow, T TI A standardized method of oleic acid infusion in experimental acute respiratory failure SO SCANDINAVIAN JOURNAL OF CLINICAL & LABORATORY INVESTIGATION LA English DT Article DE acute respiratory failure; microdroplets standardized; oleic acid; oleic acid lung injury; sheep ID INDUCED LUNG INJURY; FLOW AB Commonly, acute respiratory failure (ARF) in laboratory animals is induced through the intravenous infusion of oleic acid (OA). The methods by which OA is infused, and the methods by which droplets are generated, differ greatly among investigators. The resulting ARF, and the distribution of the underlying pulmonary pathology, are not highly reproducible. A method was developed that generated a reproducible, known spectrum of OA microdroplets. This method was applied to infuse a known volume of OA into the vena cava superior (VCS) in sheep, to induce ARF. In vitro studies were conducted in an observation chamber filled with saline or plasma. The distal end was cut off a 7F Swan Ganz catheter. The catheter was immersed in an observation chamber. Through one of the channels OA was infused at a low flow rate while saline was infused at variable high flow rates through a second channel. The size and the distribution spectrum of the so generated OA droplets were determined from flash photographic studies. The distribution and the size of the microdroplets depended on the media in the observation chamber, and on the saline infusion rate. In vivo studies were conducted in six anesthetized and ventilated sheep. We chose in our in vivo studies a saline flow rate of 126 mL/min and at an OA flow rate of 3 mL/min, that generated OA microdroplets 125+/-32 mum SD in size. OA microdroplets were generated in situ in the VCS and where then embolized into small pulmonary vessels. A total dose of 0.06 mL/kg of OA was administered in three separate doses of 0.02 mL/kg, each 10 min apart. The evolving ARF was manifested by a progressive deterioration in arterial blood gases, and a uniform opacification of all lung fields on chest X-ray films. At autopsy the lungs were diffusely consolidated. Conclusion: A method was developed to standardize the infusion of OA in laboratory animals that resulted in diffuse involvement of the all lungs, with a predictable and reproducible severe acute respiratory failure. C1 Univ Innsbruck Hosp, Dept Pediat, Neonatal Intens Care Unit, A-6020 Innsbruck, Austria. NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Trawoger, R (reprint author), Univ Innsbruck, Kinder & Jugendheilkunde Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria. EM Rudolf.Trawoeger@uibk.ac.at NR 12 TC 4 Z9 4 U1 1 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0036-5513 J9 SCAND J CLIN LAB INV JI Scand. J. Clin. Lab. Invest. PD FEB PY 2001 VL 61 IS 1 BP 75 EP 81 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 409MV UT WOS:000167388200010 PM 11300614 ER PT J AU Schrump, DS Waheed, I AF Schrump, DS Waheed, I TI Strategies to circumvent SV40 oncoprotein expression in malignant pleural mesotheliomas SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE malignant pleural mesothelioma; SV40 T; t antigen; antisense; cell cycle; flavopiridol; apoptosis ID LARGE-T-ANTIGEN; DEPENDENT KINASE INHIBITOR; CYCLIN D1 OVEREXPRESSION; TUMOR-SUPPRESSOR; GROWTH ARREST; CARCINOMA CELLS; CDK INHIBITORS; G(1) ARREST; IN-VITRO; SIMIAN-VIRUS-40 AB Although nearly 60% of mesotheliomas contain SV40 early region DNA sequences, the role of T/t antigens in initiating and maintaining the transformed state of mesothelioma cells remains unclear. The majority of mesothelioma cells which contain SV40 early region sequences exhibit extremely low basal expression of SV40 oncoproteins; however T/t antigen expression can he induced under conditions of cellular stress. Abrogation of SV40 T/t expression by antisense techniques induces apoptosis in part via restoration of p53 function, and enhances chemosensitivity in SV40(+) MPM cells by mechanisms which have not been fully elucidated. This review briefly summarizes our ongoing efforts to define the role of SV40 oncoproteins in modulating the malignant phenotype of mesothelioma cells, and highlights strategies which may prove efficacious in vivo for circumventing SV40 T/t antigen expression in mesotheliomas. C1 NCI, Thorac Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, 10 Ctr Dr,Room 2B07, Bethesda, MD 20892 USA. NR 55 TC 13 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2001 VL 11 IS 1 BP 73 EP 80 DI 10.1006/scbi.2000.0348 PG 8 WC Oncology SC Oncology GA 409ZR UT WOS:000167416000009 PM 11243901 ER PT J AU Moss, B Shisler, JL AF Moss, B Shisler, JL TI Immunology 101 at poxvirus U: Immune evasion genes SO SEMINARS IN IMMUNOLOGY LA English DT Review DE chemokine; cytokine; interferon; poxvirus ID COMPLEMENT-CONTROL PROTEIN; NECROSIS-FACTOR RECEPTOR; MOLLUSCUM CONTAGIOSUM VIRUS; DOUBLE-STRANDED-RNA; INFLAMMATION MODULATORY PROTEIN; BROAD SPECIES-SPECIFICITY; COMPLETE DNA-SEQUENCE; RABBIT FIBROMA VIRUS; VACCINIA VIRUS; MYXOMA VIRUS AB Poxviruses, unlike some other large DNA viruses, do not undergo a latent stage but rely on the expression of viral proteins to evade host immune responses. Of the many poxviral evasion genes identified, most target cytokines or other innate immune defenses. Resistance to interferons appears to be a priority as there are viral proteins that prevent their induction, receptor binding, and action. Additional poxviral proteins inhibit complement activation, chemokines, IL-1 beta and tumor necrosis factor. The identification of viral immune evasion genes and the determination of their roles in virus survival and spread contribute to our understanding of immunology and microbiology. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 80 TC 95 Z9 99 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 59 EP 66 DI 10.1006/smim.2000.0296 PG 8 WC Immunology SC Immunology GA 422YE UT WOS:000168146200007 PM 11289800 ER PT J AU Shisler, JL Moss, B AF Shisler, JL Moss, B TI Immunology 102 at poxvirus U: Avoiding apoptosis SO SEMINARS IN IMMUNOLOGY LA English DT Review DE apoptosis; cell death; poxvirus; caspase ID HAMSTER OVARY CELLS; VIRUS-INFECTED CELLS; DOUBLE-STRANDED-RNA; FAS-MEDIATED APOPTOSIS; VACCINIA VIRUS; MYXOMA VIRUS; COWPOX VIRUS; INTERLEUKIN-1-BETA-CONVERTING ENZYME; HOST-RANGE; RABBITPOX VIRUS AB Poxviruses are large complex viruses that replicate in the cytoplasm of cells without integrating their DNA into the host genome or undergoing a latent intracellular stage. In addition to viral enzymes for DNA and RNA synthesis, poxviruses encode many proteins that modulate host responses. These include inhibitors of apoptosis induced by ligand binding to cell surface receptors, peroxides, ultraviolet light, DNA damaging agents and other cell signaling pathways. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 69 TC 28 Z9 28 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 67 EP 72 DI 10.1006/smim.2000.0297 PG 6 WC Immunology SC Immunology GA 422YE UT WOS:000168146200008 PM 11289801 ER PT J AU Anderson, WF Hawk, E Berg, CD AF Anderson, WF Hawk, E Berg, CD TI Secondary chemoprevention of upper aerodigestive tract tumors SO SEMINARS IN ONCOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; 2ND PRIMARY TUMORS; THERAPEUTIC ANTICANCER AGENTS; OPTICAL COHERENCE TOMOGRAPHY; PUTATIVE PRENEOPLASTIC CELLS; PREVENT ORAL CARCINOGENESIS; VITAMIN SUPPLEMENT USE; LOW-DOSE ISOTRETINOIN; SURROGATE END-POINTS; ACID RECEPTOR-BETA C1 NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, Execut Plaza N,Room 211L,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 148 TC 7 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2001 VL 28 IS 1 BP 106 EP 120 DI 10.1053/sonc.2001.20743 PG 15 WC Oncology SC Oncology GA 401YT UT WOS:000166957400009 PM 11254870 ER PT J AU Burstein, GR Zenilman, JM Gaydos, CA Diener-West, M Howell, MR Brathwaite, W Quinn, TC AF Burstein, GR Zenilman, JM Gaydos, CA Diener-West, M Howell, MR Brathwaite, W Quinn, TC TI Predictors of repeat Chlamydia trachomatis infections diagnosed by DNA amplification testing among inner city females SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article DE chlamydia; adolescents; sexually transmitted diseases ID FAMILY-PLANNING CLINICS; SEXUALLY-TRANSMITTED DISEASES; LIGASE CHAIN-REACTION; ADOLESCENT FEMALES; COST-EFFECTIVENESS; URINE SPECIMENS; CONDOM USE; WOMEN; PREVENTION; PERSISTENCE AB Objective: To describe the epidemiology of prevalent and incident chlamydia infection in order to assess the appropriate interval for chlamydia screening; and to identify risk factors predictive of infection and repeat infections. Design: Prospective longitudinal study of a consecutive sample of 3860 sexually active females aged 12-60 years tested for C trachomatis by polymerase chain reaction in Baltimore City clinics during 11 904 patient visits over a 33 month period. Results: Chlamydia prevalence, incidence, and frequency to diagnosis of infection varied by age. Among 2073 females <25 years, chlamydia infection was found in 31.2%. The median times to first and repeat incident infections were 7.0 months and 7.6 months, respectively. Among 1787 females 25 years, chlamydia infection was found in 9.6%. Median times to first and repeat incident infections were 13.8 months and 11.0 months, respectively. Age <25 years yielded the highest risk of infection. Conclusions: Since a high burden of chlamydia was found among mostly asymptomatic females <25 years in a spectrum of clinical settings, we recommend chlamydia screening for all sexually active females <25 years at least twice yearly. C1 Johns Hopkins Univ, Div Infect Dis, Baltimore, MD USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD USA. Baltimore City Hlth Dept, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Burstein, GR (reprint author), Ctr Dis Control & Prevent, Div Adolescent & Sch Hlth, 4770 Buford Hwy NE,MS K-33, Atlanta, GA 30341 USA. RI Gaydos, Charlotte/E-9937-2010 NR 46 TC 62 Z9 64 U1 1 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD FEB PY 2001 VL 77 IS 1 BP 26 EP 32 DI 10.1136/sti.77.1.26 PG 7 WC Infectious Diseases SC Infectious Diseases GA 401BY UT WOS:000166908100007 PM 11158688 ER PT J AU Avis, NE Stellato, R Crawford, S Bromberger, J Ganz, P Cain, V Kagawa-Singer, M AF Avis, NE Stellato, R Crawford, S Bromberger, J Ganz, P Cain, V Kagawa-Singer, M TI Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE menopause; symptoms; ethnicity; culture; United States ID LOGISTIC-REGRESSION MODELS; WOMENS HEALTH; MIDLIFE; EXPERIENCES; FIT AB In recent years, research on menopausal symptomalogy has focused on identifying symptom groupings experienced by women as they progress from premenopausal to postmenopausal status. However, most of these studies have been conducted among Caucasian women from western cultures. This leaves open the question of whether the findings from these studies can be extended to women of other racial/ethnic groups or cultures. Furthermore, many of the previous studies have been conducted on relatively small samples. This paper addresses the diversity of the menopause experience by comparing symptom reporting in a large cross-sectional survey of women aged 40-55 years among racial/ethnic groups of women in the United States (Caucasian, African-American, Chinese, Japanese, and Hispanic). Evaluation of the extent to which symptoms group together and consistently relate to menopausal status across these five samples provides evidence for or against a universal menopausal syndrome. The specific research questions addressed in this paper are: (1) How does the factor structure of symptoms among mid-aged women compare across racial/ethnic groups? (2) Is symptom reporting related to race/ethnicity or menopausal status? and (3) Does the relation between menopausal status and symptoms vary across racial/ethnic groups? Analyses are based on 14,906 women who participated in the multi-ethnic, multi-race, multi-site study of mid-aged women called the Study of Women's Health Across the Nation (SWAN). Study participants completed a 15-min telephone or in-person interview that contained questions on a variety of health-related topics. Items of interest for these analyses include symptoms, menstrual history (to assess menopausal status), health status, and sociodemographics. Factor analysis results showed that across all five racial/ethnic groups, two consistent factors emerged; one consisting of clearly menopausal symptoms - hot flashes and night sweats - and the other consisting of psychological and psychosomatic symptoms. Results of regression analyses showed racial/ethnic differences in symptom reporting, as well as differences by menopausal status. Controlling for age, education, health, and economic strain, Caucasian women reported significantly more psychosomatic symptoms than other racial/ethnic groups. African-American women reported significantly more vasomotor symptoms. Perimenopausal women, hormone users, and women who had a surgical menopause reported significantly more vasomotor symptoms. All of these groups, plus postmenopausal women, reported significantly more vasomotor symptoms than premenopausal women. The pattern of results argues against a universal menopausal syndrome consisting of a variety of vasomotor and psychological symptoms. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 New England Res Inst, Watertown, MA 02472 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15261 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Avis, NE (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. FU NIA NIH HHS [U01 AG12495, U01 AG12531]; NINR NIH HHS [U01 NR04061] NR 44 TC 321 Z9 334 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2001 VL 52 IS 3 BP 345 EP 356 DI 10.1016/S0277-9536(00)00147-7 PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 384TV UT WOS:000165962500002 PM 11330770 ER PT J AU Bartlett, DL Libutti, SK Figg, WD Fraker, DL Alexander, HR AF Bartlett, DL Libutti, SK Figg, WD Fraker, DL Alexander, HR TI Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer SO SURGERY LA English DT Article ID TUMOR-NECROSIS-FACTOR; ISOLATED LIVER PERFUSION; RANDOMIZED TRIAL; INTRAARTERIAL FLOXURIDINE; SYSTEMIC FLUOROURACIL; ARTERIAL FLOXURIDINE; PROGNOSTIC FACTORS; FACTOR-ALPHA; PHASE-II; MELPHALAN AB Background. Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This stud presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases. Methods. Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degreesC to 40 degreesC). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M-2/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival. Results. There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during per fusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater. Conclusions. IHP can be performed with acceptability low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 44 TC 88 Z9 91 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD FEB PY 2001 VL 129 IS 2 BP 176 EP 187 DI 10.1067/msy.2001.110365 PG 12 WC Surgery SC Surgery GA 401BP UT WOS:000166907300010 PM 11174711 ER PT J AU Burchiel, SW Knall, CM Davis, JW Paules, RS Boggs, SE Afshari, CA AF Burchiel, SW Knall, CM Davis, JW Paules, RS Boggs, SE Afshari, CA TI Analysis of genetic and epigenetic mechanisms of toxicity: Potential roles of toxicogenomics and proteomics in toxicology SO TOXICOLOGICAL SCIENCES LA English DT Article AB The article highlighted in this issue is "An Aryl Hydrocarbon Receptor Independent Mechanism of JP-8 Jet Fuel Immunotoxicity in Ah-Responsive and Ah-Nonresponsive Mice" by Andrew C. Dudley, Margie M. Peden-Adams, Jackie EuDaly, Richard S. Pollenz, and Deborah E. Keil (pp. 251-259). C1 Univ New Mexico, Coll Pharm, Toxicol Program, Albuquerque, NM 87131 USA. NIEHS, Res Triangle Pk, NC 27711 USA. Lovelace Resp Res Inst, Albuquerque, NM USA. RP Burchiel, SW (reprint author), Univ New Mexico, Coll Pharm, Toxicol Program, 2502 Marble NE, Albuquerque, NM 87131 USA. NR 11 TC 34 Z9 37 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2001 VL 59 IS 2 BP 193 EP 195 DI 10.1093/toxsci/59.2.193 PG 3 WC Toxicology SC Toxicology GA 396LR UT WOS:000166638300001 PM 11158710 ER PT J AU Davis, BJ Price, HC O'Connor, RW Fernando, R Rowland, AS Morgan, DL AF Davis, BJ Price, HC O'Connor, RW Fernando, R Rowland, AS Morgan, DL TI Mercury vapor and female reproductive toxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE mercury vapor; menstrual cycle; female reproductive toxicity ID OCCUPATIONAL EXPOSURE; INORGANIC MERCURY AB Epidemiological studies finding menstrual cycle abnormalities among women occupationally exposed to Hg degrees prompted us to investigate the mechanisms of reproductive toxicity of Hg degrees in the female rat. Nose-only Hg degrees vapor inhalation exposures were conducted on regularly cycling rats 80-90 days of age in dose-response and acute time-course studies, which have previously proven useful as a model to identify ovarian toxicants. Vaginal smears were evaluated daily and serum hormone levels were correlated with cycle and with ovarian morphology at necropsy. Exposure concentration-related effects of Hg degrees were evaluated by exposing rats to 0, 1, 2, or 4 mg/m(3) Hg degrees vapor 2 h/day for 11 consecutive days. Tissue Hg levels correlated with exposure concentration and duration. Exposure of rats to 4 mg/m(3) (but not 1 or 2 mg/m(3)) Hg vapor for II days resulted in significant decreases in body weights relative to controls. Estrous cycles were slightly prolonged in the 2 and 4 mg/m(3) dose groups, and serum estradiol and progesterone levels were significantly different in the 4 mg/m3 group compared to controls. The alterations in cycle and hormones at the 4 mg/m(3) exposure concentration were attributed to body weight loss and generalized toxicity. In the time-course study, rats were exposed to 2 mg/m3 Hg degrees or air beginning in metestrus and evaluated daily for 8 days. A lengthening of the cycle was detected and morphological changes were observed in the corpora lutea (CL) after exposure for 6 days. To determine if changes in the CL and cyclicity correlated with a functional defect, rats were exposed to Hg degrees vapor and evaluated for pregnancy outcome. There were no significant effects on pregnancy rate or numbers of implantation sites when rats were exposed to I or 2 mg/m(3) Hg degrees for 8 days prior to breeding, or when exposed for 8 days after breeding. These studies indicate that exposure to Hg degrees vapor altered estrous cyclicity, but had no significant effect on ovulation, implantation, or maintenance of first pregnancy during exposure of short duration in female rats. C1 Natl Inst Environm Sci, Res Triangle Pk, NC 27709 USA. Mantech Environm Technol Inc, Res Triangle Pk, NC 27709 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Davis, BJ (reprint author), Natl Inst Environm Sci, MD A2-01, Res Triangle Pk, NC 27709 USA. NR 23 TC 36 Z9 37 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2001 VL 59 IS 2 BP 291 EP 296 DI 10.1093/toxsci/59.2.291 PG 6 WC Toxicology SC Toxicology GA 396LR UT WOS:000166638300013 PM 11158722 ER PT J AU Nossal, R AF Nossal, R TI Energetics of clathrin basket assembly SO TRAFFIC LA English DT Article DE cage formation; clathrin; coated vesicles; curvature; endocytosis ID TRANSMISSION ELECTRON-MICROSCOPY; COATED VESICLES; ENDOCYTOSIS; PROTEIN; MEMBRANES; CHOLESTEROL; ORGANIZATION; DOMAINS; NUMBER; AP180 AB A minimal thermodynamic model is used to study the in vitro equilibrium assembly of reconstituted clathrin baskets. The model contains parameters accounting for i) the combined bending and flexing rigidities of triskelion legs and hubs, ii) the intrinsic curvature of an isolated triskelion, and iii) the free energy changes associated with interactions between legs of neighboring triskelions. Analytical expressions for basket size distributions are derived, and published size distribution data (Zaremba S, Keen JH. J Cell Biol 1983;97: 1339-1347) are then used to provide estimates for net total basket assembly energies. Results suggest that energies involved in adding triskelions to partially formed clathrin lattices are small (of the order of k(B)T), in accord with the notion that lattice remodeling during basket formation occurs as a result of thermodynamic fluctuations. In addition, analysis of data showing the effects of assembly proteins (APs) on basket size indicates that the binding of APs increases the intrinsic curvature of an elemental triskelial subunit, the stabilizing energy of leg interactions, and the effective leg/hub rigidity. Values of effective triskelial rigidity determined in this investigation are similar to those estimated by previous analysis of shape fluctuations of isolated triskelia. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Nossal, R (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NR 48 TC 66 Z9 67 U1 0 U2 5 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD FEB PY 2001 VL 2 IS 2 BP 138 EP 147 DI 10.1034/j.1600-0854.2001.020208.x PG 10 WC Cell Biology SC Cell Biology GA 400VN UT WOS:000166892500008 PM 11247304 ER PT J AU Stroncek, D Anderlini, P AF Stroncek, D Anderlini, P TI Mobilized PBPC concentrates: a maturing blood component SO TRANSFUSION LA English DT Editorial Material ID COLONY-STIMULATING FACTOR; STEM-CELL TRANSPLANTATION; ACUTE ARTERIAL THROMBOSIS; PERIPHERAL-BLOOD; MARROW TRANSPLANTATION; HODGKINS-DISEASE; NORMAL DONORS; BONE-MARROW; G-CSF; FILGRASTIM C1 NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Stroncek, D (reprint author), NIH, Bethesda, MD 20892 USA. NR 30 TC 6 Z9 6 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 FEB PY 2001 VL 41 IS 2 BP 168 EP 171 DI 10.1046/j.1537-2995.2001.41020168.x PG 4 WC Hematology SC Hematology GA 410BQ UT WOS:000167420500004 PM 11239217 ER PT J AU Celli, S Matzinger, P AF Celli, S Matzinger, P TI Liver transplants induce deletion of liver-specific T cells SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 NIAID, LCMI, Ghost Lab, NIH, Bethesda, MD 20892 USA. RP Celli, S (reprint author), NIAID, LCMI, Ghost Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 111, Bethesda, MD 20892 USA. RI Celli, Susanna/M-7138-2014 NR 3 TC 7 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 102 EP 103 DI 10.1016/S0041-1345(00)01926-6 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900035 PM 11266728 ER PT J AU Xu, H Elster, E Batty, D Berning, J Burkly, L Kampen, R Swanson, S Tadaki, D Harlan, D Kirk, A AF Xu, H Elster, E Batty, D Berning, J Burkly, L Kampen, R Swanson, S Tadaki, D Harlan, D Kirk, A TI Effects of dose and duration of anti-CD154 antibody therapy in preventing renal allograft rejection in a nonhuman primate model SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 USN, Med Res Ctr, NIDDK, Navy Transplantat & Autoimmun Branch, Bethesda, MD USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. Biogen Inc, Cambridge, MA 02142 USA. RP Kirk, A (reprint author), 11-S-219,Bldg 10,Ctr Dr, Bethesda, MD 20891 USA. FU NIAID NIH HHS [AI43900-01] NR 3 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 223 EP 224 DI 10.1016/S0041-1345(00)01983-7 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900095 PM 11266788 ER PT J AU Elster, EA Xu, H Tadaki, DK Burkly, LC Berning, JD Baumgartner, RE Cruzata, F Patterson, NB Harlan, DM Kirk, AD AF Elster, EA Xu, H Tadaki, DK Burkly, LC Berning, JD Baumgartner, RE Cruzata, F Patterson, NB Harlan, DM Kirk, AD TI Primate skin allotransplantation with anti-CD154 monotherapy SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID RENAL-ALLOGRAFT REJECTION; LONG-TERM SURVIVAL; T-CELLS; ANTIBODY C1 NIDDK, Navy Transplantat & Autoimmun Branch, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Dept Gen Surg, Bethesda, MD USA. Biogen Inc, Cambridge, MA 02142 USA. RP Kirk, AD (reprint author), NIDDK, Navy Transplantat & Autoimmun Branch, Room 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 FU NIAID NIH HHS [AI43900-01] NR 6 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 675 EP 676 DI 10.1016/S0041-1345(00)02197-7 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900319 PM 11267012 ER PT J AU Ojo, AO Meier-Kriesche, HU Arndorfer, JA Leichtman, AB Magee, JC Cibrik, DM Wolfe, RA Port, FK Agodoa, L Kaufman, DB Kaplan, B AF Ojo, AO Meier-Kriesche, HU Arndorfer, JA Leichtman, AB Magee, JC Cibrik, DM Wolfe, RA Port, FK Agodoa, L Kaufman, DB Kaplan, B TI Long-term benefit of kidney-pancreas transplants in Type 1 diabetics SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID RENAL-TRANSPLANTATION; GLUCOSE CONTROL; MELLITUS; NEPHROPATHY; IMPROVEMENT; RECIPIENTS; NEUROPATHY; MORTALITY; SURVIVAL; QUALITY C1 NIDDK, Dept Med, Bethesda, MD USA. NIDDK, Dept Surg, Bethesda, MD USA. NIDDK, Dept Biostat, Bethesda, MD USA. NIDDK, Dept Epidemiol, Bethesda, MD USA. NIDDK, Div Kidney Urol & Digest Dis, Bethesda, MD USA. Northwestern Univ, Sch Med, Dept Surg, Chicago, IL 60611 USA. RP Kaplan, B (reprint author), Univ Michigan, Med Ctr, Dept Nephrol, TC 3914,Box 0364, Ann Arbor, MI 48109 USA. NR 24 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 1670 EP 1672 DI 10.1016/S0041-1345(00)02635-X PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900770 PM 11267463 ER PT J AU Welniak, LA Blazar, BR Wiltrout, RH Anver, MR Murphy, WJ AF Welniak, LA Blazar, BR Wiltrout, RH Anver, MR Murphy, WJ TI Role of interleukin-12 in acute graft-versus-host disease SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID BONE-MARROW TRANSPLANTATION; INDUCTION; GAMMA; IL-12 C1 NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci,Lab Leukocyte Biol, SAIC Frederick,Pathol & Histotechnol Lab, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC Frederick, Bldg 567,Room 210, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000]; NHLBI NIH HHS [R01 HL63452, R37 HL56067]; NIAID NIH HHS [P01 AI35225, R01 AI34495] NR 7 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 1752 EP 1753 DI 10.1016/S0041-1345(00)02666-X PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900805 PM 11267498 ER PT J AU Kondrashov, AS AF Kondrashov, AS TI Sex and U SO TRENDS IN GENETICS LA English DT Editorial Material ID DELETERIOUS MUTATION-RATES; DROSOPHILA-MELANOGASTER; MITOCHONDRIAL GENOME; CODON USAGE; SELECTION; EVOLUTION; PATTERNS; CONSERVATION; ELEGANS; FITNESS AB Resolution of several unsettled problems in genetics depends on the genomic rate of deleterious mutation, U.Selection against mutations can be a major factor in evolution only if U greater than or equal to1. Recently, significant progress has been made in measuring U in multicellular eukaryotes. An indirect estimate, based on a human-chimpanzee pseudogene comparison, produced U>3 for hominoids. By contrast, an estimate for Drosophila based on comparison of synonymous protein-coding sites produced U<0.1. However, the Drosophila figure might be underestimated because of selection at synonymous sites. Perhaps,the best way to measure U is to observe mutations shortly after they appear. So far, this direct approach has been applied only to humans and Caenorhabditis elegans, yielding high estimates of mutation rates. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Kondrashov, AS (reprint author), NIH, Natl Ctr Biotechnol Informat, 45 Center Dr,MSC 6600, Bethesda, MD 20892 USA. NR 46 TC 28 Z9 28 U1 2 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2001 VL 17 IS 2 BP 75 EP 77 DI 10.1016/S0168-9525(00)02188-0 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 432WD UT WOS:000168718000017 PM 11173114 ER PT J AU Ross, J Morrone, MC Goldberg, ME Burr, DC AF Ross, J Morrone, MC Goldberg, ME Burr, DC TI Changes in visual perception at the time of saccades SO TRENDS IN NEUROSCIENCES LA English DT Review ID LATERAL GENICULATE-NUCLEUS; EYE-MOVEMENTS; MOTION PERCEPTION; RESPONSE PROPERTIES; VOLUNTARY SACCADES; IMAGE DISPLACEMENT; APPARENT POSITION; PARIETAL CORTEX; NEURAL ACTIVITY; AWAKE CATS AB We frequently reposition our gaze by making rapid ballistic eye movements that are called saccades. Saccades pose problems for the visual system, because they generate rapid, large-field motion on the retina and change the relationship between the object position in external space and the image position on the retina. The brain must ignore the one and compensate for the other. Much progress has been made in recent years in understanding the effects of saccades on visual function and elucidating the mechanisms responsible for them. Evidence suggests that saccades trigger two distinct neural processes: (1) a suppression of visual sensitivity, specific to the magnocellular pathway, that dampens the sensation of motion and (2) a gross perceptual distortion of visual space in anticipation of the repositioning of gaze. Neurophysiological findings from several laboratories are beginning to identify the neural substrates involved in these effects. C1 Univ Western Australia, Dept Psychol, Nedlands, WA 6907, Australia. Univ Vita Salute San Raffaele, I-20132 Milan, Italy. CNR, Ist Neurofisiol, I-56010 Pisa, Italy. NEI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20057 USA. Univ Florence, Dipartimento Psicol, Florence, Italy. RP Ross, J (reprint author), Univ Western Australia, Dept Psychol, Nedlands, WA 6907, Australia. RI Morrone, Maria Concetta/C-6756-2014; OI Morrone, Maria Concetta/0000-0002-1025-0316 NR 101 TC 317 Z9 321 U1 3 U2 49 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD FEB PY 2001 VL 24 IS 2 BP 113 EP 121 DI 10.1016/S0166-2236(00)01685-4 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 433NF UT WOS:000168765800018 PM 11164942 ER PT J AU Cohen, JI Sato, H Srinivas, S Lekstrom, K AF Cohen, JI Sato, H Srinivas, S Lekstrom, K TI Varicella-zoster virus (VZV) ORF65 virion protein is dispensable for replication in cell culture and is phosphorylated by casein kinase II, but not by the VZV protein kinases SO VIROLOGY LA English DT Article ID COMPLETE DNA-SEQUENCE; SHORT UNIQUE REGION; PSEUDORABIES VIRUS; MEMBRANE-PROTEIN; VIRAL REPLICATION; GLYCOPROTEIN-I; US9; TYPE-1; GENE; HERPESVIRUS AB The unique short region of varicella tester virus (VZV) encodes four genes. One of these, ORF65, is predicted to encode an 11-kDa protein. Antibody to ORF65 protein immunoprecipitated a 16-kDa protein from the membrane fraction of VZV-infected cells. ORF65 protein was shown to be phosphorylated by casein kinase II. The VN ORF47 or ORF66 protein kinases were not required for phosphorylation of ORF65. VN with a large deletion in ORF65 was constructed and was shown to be dispensable for replication of virus in cell culture. The herpes simplex virus homolog of VZV ORF65 has been reported to be located in the nucleus of infected calls and in virions as a tegument protein, whereas the pseudorabies virus homolog is located in the Golgi apparatus of infected cells and in virions as a type II membrane protein. The ORF65 protein localized to the Golgi apparatus in virus-infected cells and was located in virions, most likely as a type II membrane protein. Thus, VN ORF65 more closely resembles its pseudorabies virus homolog in its localization in infected cells and virions. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Room 11N214, Bethesda, MD 20892 USA. NR 30 TC 21 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 1 PY 2001 VL 280 IS 1 BP 62 EP 71 DI 10.1006/viro.2000.0741 PG 10 WC Virology SC Virology GA 405BG UT WOS:000167136900007 PM 11162819 ER PT J AU Parasuraman, R Martin, A AF Parasuraman, R Martin, A TI Interaction of semantic and perceptual processes in repetition blindness SO VISUAL COGNITION LA English DT Article ID ATTENTIONAL BLINK; EXPERIMENTAL-PSYCHOLOGY; TOKEN INDIVIDUATION; MEMORY; KNOWLEDGE; FAILURE; COLOR; IDENTIFICATION; RECOGNITION; DIFFICULT AB Two experiments examined the effect of activation of higher-level semantic representations on lower-level perceptual representations. A forced-choice discrimination paradigm was used, a method known to produce repetition blindness (RB) for words unconfounded by memory demands or response bias. In Experiment 1, equivalent reductions in RB (as measured by omission error rate and by d') occurred when successive word pairs were identical in: (1) form, pronunciation, and meaning (both uppercase versions of the same word); (2) pronunciation and meaning but not form (lowercase versus uppercase; lexical identity); and (3) pronunciation, but not form or meaning (homonyms; phonological identity), relative to when the words were unrelated on all dimensions. The RB effect was markedly attenuated, but not eliminated, when the words were semantically related. Similar results were obtained in Experiment 2 using a larger group of subjects. These findings show that higher-order semantic representations can have a top-down influence on judgements based on lower-order perceptual representations. The results are discussed within the framework of a cascade model of object processing in the human brain. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr MSC 1366, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 44 TC 11 Z9 11 U1 1 U2 2 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1350-6285 J9 VIS COGN JI Vis. Cogn. PD FEB PY 2001 VL 8 IS 1 BP 103 EP 118 PG 16 WC Psychology, Experimental SC Psychology GA 392VZ UT WOS:000166434400005 ER PT J AU Lightfoot, T Gallelli, J Matsuo, K Kwon, SW Leitman, SF Stroncek, DF AF Lightfoot, T Gallelli, J Matsuo, K Kwon, SW Leitman, SF Stroncek, DF TI Evaluation of solutions for the storage of granulocyte colony-stimulating factor-mobilized granulocyte concentrates SO VOX SANGUINIS LA English DT Article DE granulocytes; granulocyte concentrates; granulocyte transfusions; neutrophils ID PROGRAMMED CELL-DEATH AB Background High cell counts in granulocyte colony-stimulating factor (G-CSF)mobilized granulocytes are detrimental to concentrate storage. An eightfold dilution with autologous plasma improves storage, but this method is impractical, The purpose of this study was to identify an infusible solution that could be used in place of autologous plasma to dilute and store granulocytes. Materials and Methods Granulocytes collected from donors given dexamethasone (8 mg per os) and/or G-CSF (5 mug/kg subcutaneously [SQ]) were diluted eightfold in the following cell culture media: X-Vivo 10, Dulbecco's modified Eagle's minimal essential medium (DMEM) or Iscoves modified Dulbecco's medium (IMDM); or in the following infusible solutions: Plasma-Lyre A; Normosol R; lactated ringers, supplemented with 1% human serum albumin and 50 mM histidine (LRAH); or Plasma-Lyre A supplemented with 50 mM histidine buffer or 25 mu HEPES buffer plus 1% human serum albumin. The granulocytes were stored for 48 h at room temperature. White blood cell (WBC) counts, WBC viability and pH were measured after approximate to 2 h, 24 h and 48 h of storage. Results Cell counts, viability and pH were maintained after 2 h, 24 h and 48 h in cells stored in the three cell culture media. The pH fell slightly after 48 h to 68.6 +/- 0.10 in granulocyte concentrates diluted in LRAH, but fell to a greater extent after 24 h and 48 h, to 6.36 +/- 0.23 (48-h value) in granulocyte concentrates diluted in Plasma-Lyre A and to 6.40 +/- 0.19 (48-h value) in granulocyte concentrates diluted in Normosol R. The cell counts of concentrates diluted in LRAH were stable for 48 h, but fell in granulocyte concentrates stored in Plasma-Lyre A and Normosol R. Plasma-Lyre A supplemented with histidine maintained the pH of diluted granulocyte concentrates better than Plasma-Lyre A supplemented with HEPES; 6.91 +/- 0.10 and 6.65 +/- 0.11, respectively, after 24 h. Cell counts were maintained best in granulocyte concentrates diluted in Plasma-Lyre A supplemented with albumin and one or both of the buffers. Conclusions Culture media were best for granulocyte storage, but they are not approved for in vivo use. Infusible solutions are not buffered adequately and lack sufficient protein, but infusible solutions, such as lactated Ringer's solution or Plasma-Lyte A supplemented with buffers and albumin, hold promise as effective and licensable solutions for granulocyte storage. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, 10 Ctr Dr,MSC-1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD FEB PY 2001 VL 80 IS 2 BP 106 EP 111 DI 10.1046/j.1423-0410.2001.00017.x PG 6 WC Hematology SC Hematology GA 426NR UT WOS:000168355700005 PM 11378965 ER PT J AU Schrump, DS Nguyen, DM AF Schrump, DS Nguyen, DM TI Targets for molecular intervention in multistep pulmonary carcinogenesis SO WORLD JOURNAL OF SURGERY LA English DT Review ID CELL LUNG-CANCER; EPIDERMAL GROWTH-FACTOR; WILD-TYPE P53; CYCLIN D1 OVEREXPRESSION; RETINOBLASTOMA SUSCEPTIBILITY GENE; RAS ONCOGENE ACTIVATION; TUMOR-SUPPRESSOR P53; NONSMALL CELL; FACTOR RECEPTOR; FORMER SMOKERS AB Lung cancers are a leading cause of mortality worldwide, and most of these neoplasms are directly attributable to tobacco abuse. Recent studies have begun to elucidate molecular mechanisms of multistep aerodigestive tract carcinogenesis, revealing novel targets for intervention in lung cancers and their precursor lesions. This review summarizes the molecular biology of lung cancers in relation to the prognosis and treatment of patients with these neoplasms. C1 NCI, Thorac Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, NIH, Bldg 10,Room 2B-07,10 Ctr Dr, Bethesda, MD 20892 USA. NR 139 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2001 VL 25 IS 2 BP 174 EP 183 PG 10 WC Surgery SC Surgery GA 422QV UT WOS:000168131500013 PM 11338019 ER PT J AU Ferretti, JA AF Ferretti, JA TI The homeobox and genetic disease: Structure and dynamics of wild type and mutant homeodomain proteins SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE homeobox; homeodomain; vnd/NK-2 ID VND/NK-2 HOMEODOMAIN; DNA-BINDING; MUTATIONS; SPECTROSCOPY; DROSOPHILA; NK-2 AB Structural and physical properties of type wild type and various selected mutants of the vnd/NK-2 homeodomain, the protein product of the homeobox, and the implication in genetic disease are reviewed. The structure, dynamics and thermodynamics have been investigated by NMR and by calorimetry. The interactions responsible for the nucleotide sequence-specific binding of the homeodomain to its consensus DNA binding site have been identified, There is a strong correlation between significant structural alterations within the homeodomain or its DNA complex and the appearance of genetic disease. Mutations in positions known to be important in genetic disease have been examined carefully. For example, mutation of position 52 of vnd/NK-2 results in a significant structural modification and mutation of position 54 alters the DNA binding specificity and affinity. The N-15 relaxation behavior and heteronuclear Overhauser effect data was used to characterize and describe the protein backbone dynamics. These studies were carried out on the wild type and the double mutant proteins both in the free and in the DNA bound states. Finally, the thermodynamic properties associated with DNA binding are described for the vnd/NK-2 homeodomain. These thermodynamic measurements reinforce the hypothesis that water structure around a protein and around DNA significantly contribute to the protein-DNA binding behavior. The results, taken together, demonstrate that structure and dynamic studies of proteins combined with thermodynamic measurements provide a significantly more complete picture of the solution behavior than the individual studies. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ferretti, JA (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 8 Z9 8 U1 2 U2 4 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD JAN 31 PY 2001 VL 34 IS 1 BP 1 EP 7 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 396TJ UT WOS:000166652400001 ER PT J AU Kwon, H Kim, KS Park, S Lee, DK Yang, CH AF Kwon, H Kim, KS Park, S Lee, DK Yang, CH TI Inhibitory effect of Paeoniflorin on Fos-Jun-DNA complex formation and stimulation of apoptosis in HL-60 cells SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Paeoniflorin; AP-1 site; Fos-Jun heterodimer; HL-60 ID C-JUN; PROTO-ONCOGENE; PAEONIAE RADIX; AP-1; PROLIFERATION; EXPRESSION; TRANSFORMATION; PROTOONCOGENE; PRODUCT; RATS AB The Fos-Jun heterodimers are part of the regulatory network of gene expression and nuclear proteins encoded by proto-oncogenes. The activation of Fos-Jun is important in the transmission of the tumor-promoting signal from the extracellular environment to the nuclear transcription mechanism. To search for the inhibitors of the Fos-Jun DNA complex formation, several natural products were screened and water-soluble paeoniflorin reduced the binding activity of the Fos-Jun heterodimer. This active compound was purified by silica gel column chromatography and HPLC. The electrophoresis mobility shift assay and reverse-phase HPLC test showed that paeoniflorin reduced the AP-1 function. The cytotoxic effect of paeoniflorin was observed in HL-60. These results indicate that paeoniflorin blocks the Fos-Jun heterodimer-binding site of the AP-1 DNA and it also has cytotoxic effects on human leukemia cell lines. C1 Seoul Natl Univ, Sch Chem & Mol Engn, Seoul 151742, South Korea. NIH, Bethesda, MD USA. RP Yang, CH (reprint author), Seoul Natl Univ, Sch Chem & Mol Engn, Seoul 151742, South Korea. NR 24 TC 4 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD JAN 31 PY 2001 VL 34 IS 1 BP 28 EP 32 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 396TJ UT WOS:000166652400005 ER PT J AU Sharifi, N Diehl, N Yaswen, L Brennan, MB Hochgeschwender, U AF Sharifi, N Diehl, N Yaswen, L Brennan, MB Hochgeschwender, U TI Generation of dynorphin knockout mice SO MOLECULAR BRAIN RESEARCH LA English DT Article DE homologous targeting; mouse; RT/PCR ID MU-OPIOID-RECEPTOR; MORPHINE-INDUCED ANALGESIA; PRODYNORPHIN GENE; OPIATE RECEPTOR; LACKING; EXPRESSION; WITHDRAWAL; RESPONSES; DEFICIENT; RETENTION AB The opioid system has important roles in controlling pain, reward and addiction, and is implicated in numerous other processes within and outside the nervous system, such as mood states, immune responses, and prenatal developmental processes. The effects of the opioid system are mediated by at least three ligands, enkephalin, endorphin, and dynorphin, which act through the opioid receptors mu, delta, and kappa. In order to dissect the roles of individual components of the opioid system, mutant mice lacking single ligands or receptors are instrumental. We report here on the generation and initial characterization of a mutant mouse strain lacking pre-prodynorphin, Dynorphin 'knockout' mice are viable, healthy, and fertile and show no overt behavioral differences to wildtype littermates. Dynorphin knockout mice constitute a valuable tool for many research areas, among them research into pain, substance abuse, and epilepsy. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Oklahoma Med Res Fdn, Dev Biol Program, Oklahoma City, OK 73104 USA. NIMH, Clin Neurosci Branch, Mol Genet Unit, Bethesda, MD 20892 USA. Eleanor Roosevelt Inst Canc Res, Denver, CO 80206 USA. RP Hochgeschwender, U (reprint author), Oklahoma Med Res Fdn, Dev Biol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. NR 30 TC 34 Z9 34 U1 0 U2 3 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 JAN 31 PY 2001 VL 86 IS 1-2 BP 70 EP 75 DI 10.1016/S0169-328X(00)00264-3 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 397WP UT WOS:000166721100010 ER PT J AU Mizoguchi, T Maeda, I Yagi, K Kador, PF AF Mizoguchi, T Maeda, I Yagi, K Kador, PF TI Effect of bovine small intestine thioredoxin on aldose reductase activity SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 10th Conference on Enzymology and Molecular Biology of Carbonyl Metabolism CY JUL 01-05, 2000 CL TAOS, NEW MEXICO DE aldose reductase; bovine small intestine; thioredoxin ID OXIDATIVE STRESS; MIXED DISULFIDES; THIOLTRANSFERASE; CELLS; PURIFICATION; PROTEINS; LENS; GSH AB Under oxidative stress mediated by H2O2, significant activation of purified aldose reductase from bovine small intestine was observed in the presence of purified thioredoxin from bovine small intestine. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Otemae Jr Coll, Itami, Hyogo 6640861, Japan. Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka 5650871, Japan. NEI, NIH, Bethesda, MD 20892 USA. RP Mizoguchi, T (reprint author), Otemae Jr Coll, 2-2-2 Inano, Itami, Hyogo 6640861, Japan. NR 17 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 30 PY 2001 VL 130 IS 1-3 SI SI BP 609 EP 615 DI 10.1016/S0009-2797(00)00287-8 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 415FT UT WOS:000167710700055 PM 11306079 ER PT J AU Murata, M Ohta, N Sakurai, S Alam, S Tsai, JY Kador, PF Sato, S AF Murata, M Ohta, N Sakurai, S Alam, S Tsai, JY Kador, PF Sato, S TI The role of aldose reductase in sugar cataract formation: aldose reductase plays a key role in lens epithelial cell death (apoptosis) SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 10th Conference on Enzymology and Molecular Biology of Carbonyl Metabolism CY JUL 01-05, 2000 CL TAOS, NEW MEXICO DE aldose reductase; lens epithelial cells; apoptosis; sugar cataract; dog ID POLYOL ACCUMULATION; DOG LENS; PREVENTION; INHIBITOR AB Since aldose reductase is localized primarily in lens epithelial cells, osmotic insults induced by the accumulation of sugar alcohols occur first in these cells. To determine whether the accumulation of sugar alcohols can induce lens epithelial cell death, galactose-induced apoptosis has been investigated in dog lens epithelial cells. Dog lens epithelial cells were cultured in Dulbecco's modified Eagle's mimimum essential medium (DMEM) supplemented with 20% fetal calf serum (FCS). After reaching confluence at fifth passage, the medium was replaced with the same DMEM medium containing 50 mM D-galactose and the cells were cultured for an additional 2 weeks. Almost all of the cells cultured in galactose medium were stained positively for apoptosis with the terminal deoxynucleotidyl transferance-mediated biotin-dUTP nick end labeling (TUNEL) technique. Agarose gel electrophoresis of these cells displayed obvious DNA fragmentation, known as a ladder formation. All of these apoptotic changes were absent in similar cells cultured in galactose medium containing 1 muM of the aldose reductase inhibitor AL 1576. Addition of AL 1576 also reduced the cellular galactitol levels from 123 +/- 10 mug/10(6) cells (n = 5) to 3.9 +/- 1.9 mug/10(6) cells (n = 5). These observations confirm that galactose induced apoptosis occurs in dog lens epithelial cells. Furthermore, the prevention of apoptosis by an aldose reductase inhibitor suggests that this apoptosis is linked to the accumulation of sugar alcohols. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. RP Sato, S (reprint author), NEI, Lab Ocular Therapeut, NIH, Rm 10-10B09,10 Ctr Dr,MSC 1850, Bethesda, MD 20892 USA. NR 17 TC 37 Z9 41 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 30 PY 2001 VL 130 IS 1-3 SI SI BP 617 EP 625 DI 10.1016/S0009-2797(00)00289-1 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 415FT UT WOS:000167710700056 PM 11306080 ER PT J AU Song, BJ Soh, Y Bae, MA Pie, JE Wan, J Jeong, KS AF Song, BJ Soh, Y Bae, MA Pie, JE Wan, J Jeong, KS TI Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-Terminal protein kinase pathway SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 10th Conference on Enzymology and Molecular Biology of Carbonyl Metabolism CY JUL 01-05, 2000 CL TAOS, NEW MEXICO DE apoptosis; 4-hydroxy-2-nonenal; c-Jun protein kinase; lipid aldehyde ID JNK ACTIVATION; SYMPATHETIC NEURONS; LIPID-PEROXIDATION; SIGNALING PATHWAYS; OXIDATIVE STRESS; DEATH; INDUCTION; PHOSPHORYLATION; INHIBITOR; CYTOKINES AB Cytotoxic lipid peroxides such as 4-hydroxy-2-nonenal (HNE) are produced when cells are exposed to toxic chemicals. However, the mechanism by which HNE induces cell death has been poorly understood. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in PC12 cells by measuring the activities of the mitogen-activated protein (MAP) kinases involved in early signal transduction pathways. Within 15-30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before returning to control level after 1 h post-treatment. In contrast, activities of extracellular signal regulated kinase (ERK) and p38 MAP kinase remained unchanged from their basal levels. SEK1, an upstream kinase of JNK, was also activated (phosphorylated) within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 was demonstrated by the transient transfection of cDNA for wild type SEK1 and JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when the dominant negative mutant of SEK1 was co-transfected with JNK. Pretreatment of PC12 cells with a survival promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, caused neither apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p35 MBP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the HNE-mediated apoptosis of PC12 cells is likely to be mediated through the selective activation of the SEK1-JNK pathway without activation of ERK or p38 MAP kinase. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. Kyung Hee Univ, Grad Sch East West Med Sci, Dept Neurosci, Seoul, South Korea. Anyang Univ, Dept Nutr & Food Sci, Anyang, South Korea. Korea Res Inst Biosci & Biotechnol, Taejon, South Korea. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 12420 Parklawn Dr, Rockville, MD 20852 USA. NR 31 TC 42 Z9 42 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 30 PY 2001 VL 130 IS 1-3 SI SI BP 943 EP 954 DI 10.1016/S0009-2797(00)00247-7 PG 12 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 415FT UT WOS:000167710700084 PM 11306108 ER PT J AU Laitinen, PJ Brown, KM Piippo, K Swam, H Devaney, JM Brahmbhatt, B Donarum, EA Marino, M Tiso, N Viitasalo, M Toivonen, L Stephan, DA Kontula, K AF Laitinen, PJ Brown, KM Piippo, K Swam, H Devaney, JM Brahmbhatt, B Donarum, EA Marino, M Tiso, N Viitasalo, M Toivonen, L Stephan, DA Kontula, K TI Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia SO CIRCULATION LA English DT Article DE ryanodine receptor calcium release channel; sarcoplastic reticulum; tachycardia; genetics ID MUSCLE SARCOPLASMIC-RETICULUM; CALCIUM RELEASE CHANNEL; LONG QT SYNDROME; MOLECULAR-CLONING; CHROMOSOME 1Q42-Q43; HEART-FAILURE; CARDIOMYOPATHY; IDENTIFICATION; DISEASE; LOCUS AB Background-Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximate to 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). Methods and Results-In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Conclusions-Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling. C1 Univ Helsinki, Dept Med, FIN-00290 Helsinki, Finland. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Transgenom Inc, Gaithersburg, MD USA. Univ Padua, Dept Biol, Padua, Italy. RP Kontula, K (reprint author), Univ Helsinki, Dept Med, FIN-00290 Helsinki, Finland. RI Tiso, Natascia/E-2182-2011 OI Tiso, Natascia/0000-0002-5444-9853 NR 33 TC 404 Z9 425 U1 3 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 30 PY 2001 VL 103 IS 4 BP 485 EP 490 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412FN UT WOS:000167544500015 PM 11157710 ER PT J AU Zhang, Y Chang, CB Gehling, DJ Hemmati-Brivanlou, A Delynck, R AF Zhang, Y Chang, CB Gehling, DJ Hemmati-Brivanlou, A Delynck, R TI Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TGF-BETA SUPERFAMILY; CONJUGATING ENZYME; TUMOR-SUPPRESSOR; PROTEIN LIGASE; IDENTIFICATION; RECEPTOR; FAMILY; LOCALIZATION; SMAD4/DPC4; ANTAGONIST AB Smad proteins are key intracellular signaling effecters for the transforming growth factor-beta superfamily of peptide growth factors. Following receptor-induced activation, Smads move into the nucleus to activate transcription of a select set of target genes. The activity of Smad proteins must be tightly regulated to exert the biological effects of different ligands in a timely manner. Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3. In Xenopus embryos, ectopic Smurf2 expression specifically inhibits Smad1 responses and thereby affects embryonic patterning by bone morphogenetic protein signals. These findings suggest that Smurf2 may regulate the competence of a cell to respond to transforming growth factor-beta /bone morphogenetic protein signaling through a distinct degradation pathway that is similar to, yet independent of, Smurf1. C1 NCI, Cellular & Mol Biol Lab, Div Basic Sci, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Growth & Dev, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cell Biol Program, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Dev Biol, San Francisco, CA 94143 USA. Rockefeller Univ, Mol Embryol Lab, New York, NY 10021 USA. RP Zhang, Y (reprint author), NCI, Cellular & Mol Biol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RI Zhang, Ying/G-3657-2015; Tang, Amy/L-3226-2016; OI Zhang, Ying/0000-0003-2753-7601; Tang, Amy/0000-0002-5772-2878; Gehling, Daniel/0000-0002-0164-4794 FU NCI NIH HHS [CA63101, R01 CA063101]; NICHD NIH HHS [HD32105, R01 HD032105] NR 36 TC 320 Z9 347 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 974 EP 979 DI 10.1073/pnas.98.3.974 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300041 PM 11158580 ER PT J AU Loftin, CD Trivedi, DB Tiano, HF Clark, JA Lee, CA Epstein, JA Morham, SG Breyer, MD Nguyen, M Hawkins, BM Goulet, JL Smithies, O Koller, BH Langenbach, R AF Loftin, CD Trivedi, DB Tiano, HF Clark, JA Lee, CA Epstein, JA Morham, SG Breyer, MD Nguyen, M Hawkins, BM Goulet, JL Smithies, O Koller, BH Langenbach, R TI Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADVANCING GESTATIONAL-AGE; PLACENTAL-TRANSFER; PROSTAGLANDIN E-2; GENE DISRUPTION; INDOMETHACIN; LABOR; CONSTRICTION AB The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role for prostaglandins in regulating the closure of this vessel has been supported by pharmacological and genetic studies. The production of prostaglandins is dependent on two cyclooxygenases (COX-1. and COX-2), which ape encoded by separate genes. We report: here that the absence of either or both COX isoforms in mice does not result in premature closure of the DA in utero. However, 35% of COX-2(-/-) mice die with a patent DA within 48 h of birth. In contrast, the absence of only the COX-1 isoform does not affect closure of the DA. The mortality (35%) and patent DA incidence due to absence of COX-2 is, however, significantly increased (79%) when one copy of the gene encoding COX-1 is also inactivated. Furthermore, 100% of the mice deficient in both isoforms die with a patent DA within 12 h of birth, indicating that in COX-2-deficient mice, the contribution of COX-I to DA closure is gene dosage-dependent. Together, these data establish roles for COX-I, and especially for COX-2, in the transition of the cardiopulmonary circulation at birth. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Comparat Med Branch, NIH, Res Triangle Pk, NC 27709 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Myriad Genet Inc, Salt Lake City, UT 84108 USA. Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. RP Langenbach, R (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [HL66537, R01 HL066537] NR 26 TC 131 Z9 136 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 JAN 30 PY 2001 VL 98 IS 3 BP 1059 EP 1064 DI 10.1073/pnas.031573498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300055 PM 11158594 ER PT J AU Crabtree, JS Scacheri, PC Ward, JM Garrett-Beal, L Emmert-Buck, MR Edgemon, KA Lorang, D Libutti, SK Chandrasekharappa, SC Marx, SJ Spiegel, AM Collins, FS AF Crabtree, JS Scacheri, PC Ward, JM Garrett-Beal, L Emmert-Buck, MR Edgemon, KA Lorang, D Libutti, SK Chandrasekharappa, SC Marx, SJ Spiegel, AM Collins, FS TI A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LASER CAPTURE MICRODISSECTION; MEN1 GENE; PARATHYROID TUMORS; SUPPRESSOR GENE; MUTATIONS; MICE; EXPRESSION; GASTRULATION; HYPERPLASIA; PRODUCT AB Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1? gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated th rough homologous recombination of the mouse homolog Men 1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bldg 31,Room 4B09, Bethesda, MD 20892 USA. NR 47 TC 270 Z9 279 U1 3 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 1118 EP 1123 DI 10.1073/pnas.98.3.1118 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300065 PM 11158604 ER PT J AU Hong-Geller, E Holowka, D Siraganian, RP Baird, B Cerione, RA AF Hong-Geller, E Holowka, D Siraganian, RP Baird, B Cerione, RA TI Activated Cdc42/Rac reconstitutes Fc epsilon RI-mediated Ca2+ mobilization and degranulation in mutant RBL mast cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GTP-BINDING PROTEINS; RHO-GTPASES; RECEPTOR; PATHWAYS; CALCIUM; RAC; ORGANIZATION; MECHANISM; EXCHANGE; ONCOGENE AB Antigen stimulation of mast cells via Fc epsilon RI, the high-affinity receptor for IgE, triggers a signaling cascade that requires Ca2+ mobilization for exocytosis of secretory granules during an allergic response. This study investigates critical signaling components by using mutant RBL mast cells that are defective in antigen-stimulated phospholipase C gamma (PLC gamma) activation, as well as other signaling activities downstream of stimulated tyrosine phosphorylation. We show that the expression of activated versions of the Cdc42 or Rac1 GTPase restores antigen-stimulated Ca2+ mobilization necessary for degranulation in these mutant cells. Wild-type Cdc42 and Rac1, as well as activated Cdc42 containing effector domain mutations, all fail to restore antigen-stimulated signaling leading to exocytosis, Expression of oncogenic Dbl, a guanine nucleotide exchange factor for Cdc42 and Rac1, partially restores sustained Ca2+ mobilization and degranulation, suggesting that activation of endogenous Cdc42 and/or Rac1 is impaired in the mutant cells. Overexpression of PLC gamma1 with either activated Cdc42 or Rad synergistically stimulates degranulation, consistent with a critical defect in PLC gamma activation in these cells. Thus, our results point to activation of Cdc42 and/or Rad playing an essential role in antigen stimulation of early events that culminate in mast cell degranulation. C1 Cornell Univ, Dept Mol Med, Ctr Vet Med, Ithaca, NY 14853 USA. Cornell Univ, Dept Chem & Biol Chem, Ithaca, NY 14853 USA. NIDR, NIH, Bethesda, MD 20892 USA. RP Cerione, RA (reprint author), Cornell Univ, Dept Mol Med, Ctr Vet Med, C3-155, Ithaca, NY 14853 USA. FU NIAID NIH HHS [R01 AI022449, AI22449]; NIGMS NIH HHS [R01 GM047458, GM47458] NR 26 TC 37 Z9 38 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 JAN 30 PY 2001 VL 98 IS 3 BP 1154 EP + DI 10.1073/pnas.98.3.1154 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300071 PM 11158610 ER PT J AU Vaitkevicius, PV Lane, M Spurgeon, H Ingram, DK Roth, GS Egan, JJ Vasan, S Wagle, DR Ulrich, P Brines, M Wuerth, JP Cerami, A Lakatta, EG AF Vaitkevicius, PV Lane, M Spurgeon, H Ingram, DK Roth, GS Egan, JJ Vasan, S Wagle, DR Ulrich, P Brines, M Wuerth, JP Cerami, A Lakatta, EG TI A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PRESSURE; AGE; AMINOGUANIDINE; LOAD AB Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyt-4.5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after II intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke Volume index (SVindex) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SVindex, an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SVindex, an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased. C1 NIA, Gerontol Res Ctr, Intramural Res Program, Lab Cardiovasc Sci,NIH, Baltimore, MD 21224 USA. Kenneth S Warren Labs, Tarrytown, NY 10591 USA. Alteon Inc, Ramsey, NJ 07446 USA. RP Lakatta, EG (reprint author), NIA, Gerontol Res Ctr, Intramural Res Program, Lab Cardiovasc Sci,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 16 TC 173 Z9 182 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 1171 EP 1175 DI 10.1073/pnas.98.3.1171 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300074 PM 11158613 ER PT J AU Hunsberger, S Murray, D Davis, CE Fabsitz, RR AF Hunsberger, S Murray, D Davis, CE Fabsitz, RR TI Imputation strategies for missing data in a school-based multi-centre study: the Pathways study SO STATISTICS IN MEDICINE LA English DT Article ID RANDOMIZATION; DESIGN; TRIALS AB Pathways is a multi-centre school-based trial sponsored by the National Heart, Lung, and Blood Institute resting the efficacy of an obesity prevention intervention in American Indian children. During the study's protocol development, we prepared an analysis plan that accounted for missing data. In this paper, we present a case study of the process we used to decide upon the final analysis plan. The primary endpoint of the Pathways study is a comparison of per cent body fat between treatment and usual care groups at the end of a three-year intervention. Other studies on children and Native Americans have had moderate to large amounts of missing data. As a result we were concerned that missing data in Pathways would affect the type I error rate and power of the test of our primary endpoint. We present results from our evaluation of three alternative procedures in this paper. The first is a multiple imputation procedure in which we replace missing values with resampled values from the observed data. The second is based on the Wilcoxon rank sum test; missing data in the intervention group receive the worst ranks. In the third, we use a multiple imputation procedure and replace missing values with predicted values from a regression equation with the coefficients estimated from observed follow-up data and baseline values. We found that the multiple imputation procedure that replaces missing values with predicted values had the best properties of the procedures we considered. The results from our simulation study showed that, for missing data patterns that are relevant to the Pathways study, this procedure has high power and maintains the type I error rate. Published in 2001 by John Wiley & Sons, Ltd. C1 NCI, Bethesda, MD 20892 USA. Memphis State Univ, Dept Psychol, Memphis, TN 38152 USA. CSCC, Dept Biostat, Chapel Hill, NC 27514 USA. II Rockledge Ctr, Bethesda, MD 20892 USA. RP Hunsberger, S (reprint author), NCI, Execut Plaza N,Rm 739,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 19 TC 17 Z9 17 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 JAN 30 PY 2001 VL 20 IS 2 BP 305 EP 316 DI 10.1002/1097-0258(20010130)20:2<305::AID-SIM645>3.0.CO;2-M PG 12 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 398RL UT WOS:000166769400010 PM 11169604 ER PT J AU Stowers, AW Zhang, YL Shimp, RL Kaslow, DC AF Stowers, AW Zhang, YL Shimp, RL Kaslow, DC TI Structural conformers produced during malaria vaccine production in yeast SO YEAST LA English DT Article DE malaria; Plasmodium falciparum; recombinant protein; disulphide bonds; structural conformers ID MEROZOITE SURFACE PROTEIN-1; EPIDERMAL GROWTH-FACTOR; TRANSMISSION-BLOCKING ANTIBODIES; PLASMODIUM-FALCIPARUM; SACCHAROMYCES-CEREVISIAE; TERMINAL FRAGMENT; AOTUS MONKEYS; IMMUNOGENICITY; SECRETION; CANDIDATE AB A recombinant protein expression system based on Saccharomyces cerevisiae has been used to express malarial vaccine candidate antigens, The antigens so produced have been used in three Phase 1 clinical trials and numerous preclinical non-human primate trials, Further Phase I trials are planned using these candidate vaccine antigens, These molecules were identified as attractive candidates for antimalarial vaccines, as they are all surface-exposed at some stage in the parasite's life cycle. They all share an unusual structural feature: epidermal growth factor (EGF)-like motifs, When these proteins are expressed in our S, cerevisiae expression system, they are produced as a series of stable structural conformers, each with a different disulphide bonding pattern. This leads to both biochemical and, more importantly, antigenic differences between the conformers (e.g. presence or absence of an antibody B cell epitope), These findings have important ramifications for other EGF-domain-containing proteins expressed in S, cerevisiae, or for proteins which contain other cysteine-folding motifs not normally expressed by this organism, both for vaccine production or for research/reagent purposes. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, Rockville, MD 20852 USA. RP Stowers, AW (reprint author), NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 103, Rockville, MD 20852 USA. NR 22 TC 22 Z9 22 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JAN 30 PY 2001 VL 18 IS 2 BP 137 EP 150 DI 10.1002/1097-0061(20010130)18:2<137::AID-YEA657>3.3.CO;2-O PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 397TX UT WOS:000166714400004 PM 11169756 ER PT J AU Luo, HY Eberly, N Rogers, RD Brechbiel, MW AF Luo, HY Eberly, N Rogers, RD Brechbiel, MW TI Syntheses and characterizations of metal complexes derived from cis,cis-1,3,5-triaminocyclohexane-N,N ',N ''-triacetic acid SO INORGANIC CHEMISTRY LA English DT Article ID LIPOPHILIC HEXADENTATE ALUMINUM; CRYSTAL-STRUCTURE; LIGAND COMPLEXES; IRON COMPLEXES; GALLIUM; INDIUM AB A convenient six-step procedure is developed to routinely prepare the hexadentate ligand cis,cis-1,3,5-triaminocyclohexane-N,Nd ' ,N " -tri acetic acid (H(3)tachta) as an HCl salt. Complexes of gallium(III) and indium(III), [Ga(tachta)] and [In(tachta)], are synthesized from the reactions of the ligand and the corresponding metal precursors. Copper(II), palladium(II), and cobalt(II) complexes, [Cu(Htachta)], [Pd(Htachta)], and [Co(Htachta)], are obtained from the reactions of H(3)tachta with the corresponding metal chlorides. The structures of H(3)tachta . 3HCl . 2H(2)O (C12H28C13N3O8) and [Ga(tachta)] (C12H18GaN3O6) are characterized. The crystal of H(3)tachta . 3HCl . 2H(2)O is monoclinic, of the space group P2(1/c), with a = 15.1688 (4) Angstrom, b = 8.4708(2) Angstrom, c = 15.9408(2) Angstrom, P = 108.058(1)degrees, and Z = 4; that of [Ga(tachta)] is cubic, of space group Pa3, with a = 14.0762(1) Angstrom and Z = 8. The gallium atom of [Ga(tachta)] is six-coordinated in the solid state, and the complex assumes a pseudooctahedronal geometry with the completely deprotonated hexadentate ligand encapsulating the metal ion. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 25 TC 11 Z9 11 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 J9 INORG CHEM JI Inorg. Chem. PD JAN 29 PY 2001 VL 40 IS 3 BP 493 EP 498 DI 10.1021/ic000603b PG 6 WC Chemistry, Inorganic & Nuclear SC Chemistry GA 396ZZ UT WOS:000166669400012 PM 11209606 ER PT J AU Wood, RJ Gearhart, PJ Neuberger, MS AF Wood, RJ Gearhart, PJ Neuberger, MS TI Hypermutation in antibody genes - Preface SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Editorial Material C1 Imperial Canc Res Fund, Clare Hall Labs, Potters Bar EN6 3LD, Herts, England. NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Wood, RJ (reprint author), Imperial Canc Res Fund, Clare Hall Labs, Potters Bar EN6 3LD, Herts, England. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JAN 29 PY 2001 VL 356 IS 1405 BP 3 EP 4 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 396NF UT WOS:000166642400001 ER PT J AU Winter, DB Gearhart, PJ AF Winter, DB Gearhart, PJ TI Altered spectra of hypermutation in DNA repair-deficient mice SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting on Hypermutation in Antibody Genes CY JUL 05-06, 2000 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE nucleotide excision repair; base excision repair; mismatch repair; ataxia-telangiectasia mutated; DNA polymerases ID IMMUNOGLOBULIN VARIABLE GENES; MISMATCH REPAIR; SOMATIC HYPERMUTATION; B-CELLS; XERODERMA-PIGMENTOSUM; GERMINAL-CENTERS; IMMUNE-RESPONSE; MUTATION; MSH2; ANTIBODY AB Affinity maturation of the humoral immune response is based on the ability of immunoglobulin variable genes to undergo a process of rapid and extensive somatic mutation followed by antigenic selection for antibodies with higher affinity. While the behaviour of this somatic hypermutation phenomenon has been well characterized over the last 20 years, the molecular mechanism responsible for inserting mutations has remained shrouded. To better understand this mechanism, we studied the interplay between hypermutation and other DNA associated activities such as DNA repair. There was no effect on the frequency and pattern of hypermutation in mice deficient for nucleotide excision repair, base excision repair and ataxia-telangiectasia mutated gene repair of double strand breaks. However, variable genes from mice lacking some components of mismatch repair had an increased frequency of tandem mutations and had more mutations of G and C nucleotides. These results suggest that the DNA polymerase(s) involved in the hypermutation pathway produces a unique spectra of mutations, which is then altered by mismatch repair and antigenic selection. We also describe the differential pattern of expression of some nuclear DNA polymerases in hypermutating versus non-hypermutating B lymphocytes. The rapidly dividing germinal centre B cells expressed DNA polymerases alpha, beta, delta, epsilon and zeta, whereas the resting non-germinal centre cells did not express polymerases alpha or epsilon at detectable levels, although they did express polymerases beta, delta and zeta. The lack of expression of polymerase epsilon in the non-germinal centre cells suggests that this enzyme has a critical role in chromosomal replication but does not participate in DNA repair in these cells. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. NR 42 TC 7 Z9 7 U1 0 U2 0 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JAN 29 PY 2001 VL 356 IS 1405 BP 5 EP 11 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 396NF UT WOS:000166642400002 PM 11205330 ER PT J AU McDonald, JP Tissier, A Frank, EG Iwai, S Hanaoka, F Woodgate, R AF McDonald, JP Tissier, A Frank, EG Iwai, S Hanaoka, F Woodgate, R TI DNA polymerase iota and related Rad30-like enzymes SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting on Hypermutation in Antibody Genes CY JUL 05-06, 2000 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE DNA polymerase eta; Rad30; Rad30B; DNA polymerase kappa; xeroderma pigmentosum variant ID XERODERMA-PIGMENTOSUM VARIANT; ESCHERICHIA-COLI DINB; SOMATIC HYPERMUTATION; SACCHAROMYCES-CEREVISIAE; INDUCED MUTAGENESIS; UV-MUTAGENESIS; THYMINE DIMER; TRANSLESION SYNTHESIS; SEQUENCE-ANALYSIS; MOUSE HOMOLOGS AB Until recently, the molecular mechanisms of translesion DNA synthesis (TLS), a process whereby a damaged base is used as a template for continued replication, was poorly understood. This area of scientific research has, however, been revolutionized by the finding that proteins long implicated in TLS are, in fact, DNA polymerases. Members of this so-called UmuC/DinB/Rev1/Rad30 superfamily of polymerases have been identified in prokaryotes, eukaryotes and archaea. Biochemical studies with the highly purified polymerases reveal that some, but not all, can traverse blocking lesions in template DNA. All of them share a common feature, however, in that they exhibit low fidelity when replicating undamaged DNA. Of particular interest to us is the Rad30 subfamily of polymerases found exclusively in eukaryotes. Humans possess two Rad30 paralogs, Rad30A and Rad30B. The RAD30A gene encodes DNA polymerase eta and defects in the protein lead to the xeroderma pigmentosum variant (XP-V) phenotype in humans. Very recently RAD30B has also been shown to encode a novel DNA polymerase, designated as Pol iota. Based upon in vitro studies, it appears that Pol iota has the lowest fidelity of any eukaryotic polymerase studied to date and we speculate as to the possible cellular functions of such a remarkably error-prone DNA polymerase. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. Biomol Engn Res Inst, Osaka 5650874, Japan. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 5650871, Japan. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Suita, Osaka 5650871, Japan. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 74 TC 56 Z9 58 U1 1 U2 2 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JAN 29 PY 2001 VL 356 IS 1405 BP 53 EP 60 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 396NF UT WOS:000166642400008 PM 11205331 ER PT J AU Ma, C Staudt, LM AF Ma, C Staudt, LM TI Molecular definition of the germinal centre stage of B-cell differentiation SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting on Hypermutation in Antibody Genes CY JUL 05-06, 2000 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE microarray; Lymphochip; germinal centre; B-cell differentiation; gene expression; genomics ID CD40-DEFICIENT MICE; T-CELLS; A-MYB; EXPRESSION; ANTIGEN; LYMPHOCYTES; BCL-6; GENE; TRANSCRIPTION; INFLAMMATION AB Genomic-scale gene expression analysis provides views of biological processes as a whole that are difficult to obtain using traditional single-gene experimental approaches. In the case of differentiating systems, gene expression profiling can define a stage of differentiation by the characteristic expression of hundreds of genes. Using specialized DNA microarrays termed 'Lymphochips', gene expression during mature B-cell differentiation has been defined. Germinal centre B cells represent a stage of differentiation that can be defined by a gene expression signature that is not shared by other highly proliferative B-cell populations such as mitogenically activated peripheral blood B cells. The germinal centre gene expression signature is maintained to a significant degree in lymphoma cell lines derived from this stage of differentiation, demonstrating that this gene expression programme does not require ongoing interactions with other germinal centre cell types. Analysis of representative cDNA libraries prepared from resting and activated peripheral blood B cells, germinal centre centroblasts, centrocytes and tonsillar memory B cells has confirmed and extended the results of DNA microarray gene expression analysis. C1 NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. NR 32 TC 9 Z9 9 U1 0 U2 1 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JAN 29 PY 2001 VL 356 IS 1405 BP 83 EP 89 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 396NF UT WOS:000166642400012 PM 11205335 ER PT J AU Gopich, IV Ovchinnikov, AA Szabo, A AF Gopich, IV Ovchinnikov, AA Szabo, A TI Long-time tails in the kinetics of reversible bimolecular reactions SO PHYSICAL REVIEW LETTERS LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; DIFFUSION-CONTROLLED REACTIONS AB A new approach is developed to study the relaxation of concentrations to equilibrium in reversible bimolecular reactions. For A + B reversible arrow C. a general analytic expression is derived for the amplitude of the power law (t(-d/2)) asymptotics for arbitrary diffusion coefficients and concentrations of the reactants. Our formalism is based on the analysis of the time correlation functions describing the equilibrium fluctuations of the concentrations. This powerful and simple procedure can be readily used to study other bimolecular reactions such as A + B reversible arrow C + D. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Phys Complex Syst, D-01187 Dresden, Germany. RP Gopich, IV (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 16 TC 34 Z9 34 U1 0 U2 5 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JAN 29 PY 2001 VL 86 IS 5 BP 922 EP 925 DI 10.1103/PhysRevLett.86.922 PG 4 WC Physics, Multidisciplinary SC Physics GA 396FN UT WOS:000166625800044 PM 11177974 ER PT J AU Ricciardi, R Foley, DP Quarfordt, SH Saavedra, JE Keefer, LK Wheeler, SM Donohue, SE Callery, MP Meyers, WC AF Ricciardi, R Foley, DP Quarfordt, SH Saavedra, JE Keefer, LK Wheeler, SM Donohue, SE Callery, MP Meyers, WC TI V-PYRRO/NO: An hepato-selective nitric oxide donor improves porcine liver hemodynamics and function after ischemia reperfusion SO TRANSPLANTATION LA English DT Article ID INFARCT SIZE; RAT-LIVER; INJURY; MODULATION; INHIBITION; ARTERIAL; SINGLE; DAMAGE; FK409; HEART AB Background. explored theThe role of nitric oxide (NO) in ischemia reperfusion (I/R) injury is controversial as both beneficial and harmful effects have been reported. We explored the potential role of a pharmacological agent recently shown to generate NO metabolically in the liver in an animal model of transplantation, Methods. The effect of a selective hepatic NO donor, O-2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diol (V-PYRRO/NO), on hepatic hemodynamics and biliary function was evaluated in both the in situ and I/R pig liver. Results. V-PYRRO/NO significantly reduced in situ hepatic vascular resistance (HVR) without altering systolic blood pressure. Portal vein now was essentially unchanged during in situ infusions while hepatic artery flow nearly doubled (P=0.03). After IIR,V-PYRRO/NO infusions significantly reduced both portal vein pressure (PVP) and HVR (P=0.04). Also, serum bile acid clearance increased from 15% when taurocholate (TC) was infused alone to 46% (P=0.007) when infused simultaneously: with V-PYRRO/NO. Aqueous bile production tripled with TC and V-PYRRO/NO as compared to TC alone (P=0.04). Analysis of bile outputs revealed a significant increase in biliary cholesterol, biliary phospholipid, and biliary bile acid (P<0.05) with V-PYRRO/NO infusion. Conclusions. The hepato-selective nitric oxide donor, V-PYRRO/NO, reduced hepatic resistance parameters of the pig Liver both before and after I/R and improved the plasma clearance of bile acid and biliary outputs of bile acid-dependent compounds. The augmented function observed after I/R may be due to improvements in hepatic blood flow secondary to altered hepatic hemodynamics. C1 Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA 01655 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. RP Ricciardi, R (reprint author), Univ Massachusetts, Sch Med, Dept Surg, 55 Lake Ave, N Worcester, MA 01655 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 29 TC 36 Z9 37 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2001 VL 71 IS 2 BP 193 EP 198 DI 10.1097/00007890-200101270-00004 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 399KP UT WOS:000166810500004 PM 11213058 ER PT J AU Remaley, AT Stonik, JA Demosky, SJ Neufeld, EB Bocharov, AV Vishnyakova, TG Eggerman, TL Patterson, AP Duverger, NJ Santamarina-Fojo, S Brewer, HB AF Remaley, AT Stonik, JA Demosky, SJ Neufeld, EB Bocharov, AV Vishnyakova, TG Eggerman, TL Patterson, AP Duverger, NJ Santamarina-Fojo, S Brewer, HB TI Apolipoprotein specificity for lipid efflux by the human ABCAI transporter SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Tangier disease; HDL; ABCAI; ABC transporters ID BINDING CASSETTE TRANSPORTER-1; TANGIER-DISEASE; A-I; CELLULAR CHOLESTEROL; REMOVAL; PHOSPHOLIPIDS; MACROPHAGES; MUTATIONS AB ABCAI, a member of the ATP binding cassette family, mediates the efflux of excess cellular lipid to HDL and is defective in Tangier disease. The apolipoprotein acceptor specificity for Lipid efflux by ABCAI was examined in stably transfected Hela cells, expressing a human ABCAI-GFP fusion protein. ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. Expression of ABCAI in Hela cells also resulted in a marked increase in specific binding of both apoA-I (Kd = 0.60 mug/mL) and apoA-II (Kd = 0.58 mug/mL) to a common binding site. In summary, ABCAI-mediated cellular binding of apolipoproteins and lipid efflux is not specific for only apoA-I but can also occur with other apolipoproteins that contain multiple amphipathic helical domains. (C) 2001 Academic Press. C1 NHLBI, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Aventis Pharma, Dept Genom, Every, France. RP Remaley, AT (reprint author), NHLBI, NIH, Bldg 10,7H115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 216 Z9 222 U1 0 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 26 PY 2001 VL 280 IS 3 BP 818 EP 823 DI 10.1006/bbrc.2000.4219 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 397LN UT WOS:000166697300035 PM 11162594 ER PT J AU Rothman, N Wacholder, S Caporaso, NE Garcia-Closas, M Buetow, K Fraumeni, JF AF Rothman, N Wacholder, S Caporaso, NE Garcia-Closas, M Buetow, K Fraumeni, JF TI The use of common genetic polymorphisms to enhance the epidemiologic study of environmental carcinogens SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Article DE cancer; susceptibility; environment; genetics; gene-environment interaction ID OCCUPATIONAL CASE-CONTROL; SAMPLE-SIZE CALCULATIONS; COMPLEX HUMAN-DISEASES; OLIGO BASE EXTENSION; MASS-SPECTROMETRY; METHYLENETETRAHYDROFOLATE REDUCTASE; LINKAGE DISEQUILIBRIUM; CANCER; SUSCEPTIBILITY; ASSOCIATION AB Overwhelming evidence indicates that environmental exposures, broadly defined, are responsible for most cancer. There is reason to believe, however. that relatively common polymorphisms in a wide spectrum of genes may modify the effect of these exposures. We discuss the rationale for using common polymorphisms to enhance our understanding of how environmental exposures cause cancer and comment on epidemiologic strategies to assess these effects, including study design, genetic and statistical analysis, and sample size requirements. Special attention is given to sources of potential bias in population studies of gene-environment interactions, including exposure and genotype misclassification and population stratification (i.e., confounding by ethnicity). Nevertheless, by merging epidemiologic and molecular approaches in the twenty-first century, there will be enormous opportunities for unraveling the environmental determinants of cancer. In particular, studies of genetically susceptible subgroups may enable the detection of low levels of risk due to certain common exposures that have eluded traditional epidemiologic methods. Further, by identifying susceptibility genes and their pathways of action, it may be possible to identify previously unsuspected carcinogens. Finally, by gaining a more comprehensive understanding of environmental and genetic risk factors, there should emerge new clinical and public health strategies aimed at preventing and controlling cancer. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Rothman, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 NR 60 TC 76 Z9 78 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD JAN 26 PY 2001 VL 1471 IS 2 BP C1 EP C10 DI 10.1016/S0304-419X(00)00021-4 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 400ZN UT WOS:000166902700006 PM 11342183 ER PT J AU McMahon, M Woods, D AF McMahon, M Woods, D TI Regulation of the p53 pathway by Ras, the plot thickens SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Ras; Raf; p53; cell cycle inhibitor; senescence ID CELL-CYCLE ARREST; PROTEIN-KINASE ACTIVATION; TRANSCRIPTION FACTOR DMP1; LUNG-CANCER CELLS; ONCOGENIC RAS; GENE-EXPRESSION; RETINOBLASTOMA PROTEIN; INDUCED PROLIFERATION; GROWTH ARREST; DNA-DAMAGE C1 Univ Calif San Francisco, Mt Zion Comprehens Canc Ctr, Canc Res Inst, San Francisco, CA 94115 USA. Univ Calif San Francisco, Mt Zion Comprehens Canc Ctr, Dept Mol & Cellular Pharmacol, San Francisco, CA 94115 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP McMahon, M (reprint author), Univ Calif San Francisco, Mt Zion Comprehens Canc Ctr, Canc Res Inst, 2340 Sutter St,S-329,POB 0128, San Francisco, CA 94115 USA. RI McMahon, Martin/L-3303-2013 OI McMahon, Martin/0000-0003-2812-1042 NR 85 TC 31 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD JAN 26 PY 2001 VL 1471 IS 2 BP M63 EP M71 DI 10.1016/S0304-419X(00)00027-5 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 400ZN UT WOS:000166902700002 PM 11342185 ER PT J AU Ghazanfari, FA Stewart, RR AF Ghazanfari, FA Stewart, RR TI Characteristics of endothelial cells derived from the blood-brain barrier and of astrocytes in culture SO BRAIN RESEARCH LA English DT Article DE endothelial cell; astroglia; GFAP; cyanide; RT-PCR ID RAT-BRAIN; CORTICAL-NEURONS; SLICE CULTURES; GROWTH-FACTOR; EXPRESSION; DIFFERENTIATION; TISSUE; MODEL; REGENERATION; PURIFICATION AB In this study, cultures of astrocytes and capillary endothelial cells from the blood-brain barrier (BBB) of the postnatal (P1) mouse cerebral cortex were analyzed with the aim of acquiring information on the distinguishing characteristics of each cell type. For isolation and purification of astrocyte cells, the methods of McCarthy and DeVellis [J. Cell Biol. 85 (1980) 890] were employed. The methods of Chen et al. [Lab. Invest. 78 (1998) 353], Duport et al. [Proc. Natl. Acad. Sci. USA 95 (1998) 1840], Rubin et al. [J Cell Biol. 115 (1991) 1725] and Tontsch and Bauer [Microvasc. Res. 37 (1989) 148] were utilized for culturing of cells from the BBB. A simple protocol was also created for isolating and purifying brain endothelial cells with 10 mM sodium cyanide. The vascular system of the cerebral cortex is derived from the leptomeningeal blood vessels [Qin and Sate, Dev. Dyn. 102 (1995) 172; Risau et al., EMBO J. 5 (1986) 3179]. With this in mind, cultures of the P1 mouse meninges were used as a comparative cell type in order to differentiate between BBB cells and astrocytes. In this regard, the expression of a number of markers were correlated, and an antibody double labeling technique was employed. The staining of these markers was then compared to cells cultured from leptomeninges and to two other types of endothelial cells, human umbilical vein and bovine aortic. Reverse transcription-polymerase chain reaction (RT-PCR) was performed on total RNA isolated from adult mouse brain, cells cultured from P1 mouse cortex or meninges, bovine aortic endothelial cells and human umbilical vein endothelial cells (HUV-EC) to detect the expression of glial fibrillary acidic protein (GFAP), Von Willebrand factor (factor VIII-related antigen) and fibronectin. These analyses revealed the presence of GFAP mRNA in the cultures of cortical and leptomeningeal cells and of protein in all cell types; Von Willebrand factor mRNA was detectable in HUV-EC cells but undetectable in cortical, leptomeningeal and bovine aortic endothelial cells. Fibronectin mRNA and protein were present in all of the cell types. Given the results of our investigations we conclude that in culture, astrocytes are actually brain endothelial cells. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Rockville, MD 20852 USA. ROW Sci Inc, Rockville, MD 20850 USA. RP Stewart, RR (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, Pk Bldg,Room 118,12420 Parklawn Dr, Rockville, MD 20852 USA. NR 52 TC 23 Z9 25 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 26 PY 2001 VL 890 IS 1 BP 49 EP 65 DI 10.1016/S0006-8993(00)03053-5 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 397CU UT WOS:000166676400006 PM 11164768 ER PT J AU Abbott, GW Butler, MH Bendahhou, S Dalakas, MC Ptacek, LJ Goldstein, SAN AF Abbott, GW Butler, MH Bendahhou, S Dalakas, MC Ptacek, LJ Goldstein, SAN TI MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis SO CELL LA English DT Article ID GATED ION CHANNELS; LONG QT SYNDROME; K+ CHANNELS; RAT-BRAIN; MESSENGER-RNA; FUNCTIONAL EXPRESSION; IK(A) CHANNELS; INACTIVATION; GENE; MUTATIONS AB The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3.4. MiRP2-Kv3.4 channels differ from Kv3.4 channels in unitary conductance, voltage-dependent activation, recovery from inactivation, steady-state open probability, and block by a peptide toxin. Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency. A mis-sense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease. Mutant MiRP2-Kv3.4 complexes exhibit reduced current density and diminished capacity to set RMP. Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology. C1 Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Pediat, New Haven, CT 06536 USA. Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Cellular & Mol Physiol, New Haven, CT 06536 USA. Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Goldstein, SAN (reprint author), Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Pediat, 333 Cedar St, New Haven, CT 06536 USA. FU NCRR NIH HHS [MO1-RR00064] NR 55 TC 196 Z9 217 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 26 PY 2001 VL 104 IS 2 BP 217 EP 231 DI 10.1016/S0092-8674(01)00207-0 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 400PB UT WOS:000166879700006 PM 11207363 ER PT J AU Bebenek, K Matsuda, T Masutani, C Hanaoka, F Kunkel, TA AF Bebenek, K Matsuda, T Masutani, C Hanaoka, F Kunkel, TA TI Proofreading of DNA polymerase eta-dependent replication errors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PIGMENTOSUM VARIANT CELLS; XERODERMA-PIGMENTOSUM; THYMINE DIMER; FIDELITY; PHOTOPRODUCTS; PROTEIN; HYPERMUTABILITY; MUTATIONS; BYPASS AB Human DNA polymerase eta, the product of the skin cancer susceptibility gene XPV, bypasses UV photoproducts in template DNA that block synthesis by other DNA polymerases. Pol eta lacks an intrinsic proofreading exonuclease and copies DNA with low fidelity, such that pol eta errors could contribute to mutagenesis unless they are corrected. Here we provide evidence that pol eta can compete with other human polymerases during replication of duplex DNA, and in so doing it lowers replication fidelity. However, we show that pol eta has low processivity and extends mismatched primer termini less efficiently than matched termini, These properties could provide an opportunity for extrinsic exonuclease(s) to proofread pol eta -induced replication errors. When we tested this hypothesis during replication in human cell extracts, pol eta -induced replication infidelity was found to be modulated by changing the dNTP concentration and to be enhanced by adding dGMP to a replication reaction. Both effects are classical hallmarks of exonucleolytic proofreading. Thus, pol eta is ideally suited for its role in reducing W-induced mutagenesis and skin cancer risk, in that its relaxed base selectivity may facilitate efficient bypass of UV photoproducts, while subsequent proofreading by extrinsic exonuclease(s) may reduce its mutagenic potential. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 5650871, Japan. CREST, Japan Sci & Technol Corp, Suita, Osaka 5650871, Japan. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. RP Kunkel, TA (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Masutani, Chikahide/I-6160-2014 NR 32 TC 62 Z9 65 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2001 VL 276 IS 4 BP 2317 EP 2320 DI 10.1074/jbc.C000690200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YV UT WOS:000166784800003 PM 11113111 ER PT J AU Territo, PR French, SA Dunleavy, MC Evans, FJ Balaban, RS AF Territo, PR French, SA Dunleavy, MC Evans, FJ Balaban, RS TI Calcium activation of heart mitochondrial oxidative phosphorylation - Rapid kinetics of m(V) over dot (O2), NADH, and light scattering SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOCHROME-C-OXIDASE; RABBIT CARDIAC MYOCYTES; NUCLEAR-MAGNETIC-RESONANCE; PHOSPHATE ENERGY SHUTTLE; FREE CA2+ CONCENTRATION; ATP-ADP TRANSLOCASE; CREATINE-KINASE; MUSCLE-CELLS; INTRACELLULAR CALCIUM; INNER MEMBRANE AB Parallel activation of heart mitochondria NADH and ATP production by Ca2+ has been shown to involve the Ca2+-sensitive dehydrogenases and the F0F1-ATPase, In the current study we hypothesize that the response time of Ca2+-activated ATP production is rapid enough to support step changes in myocardial workload (similar to 100 ms). To test this hypothesis, the rapid kinetics of Ca2+ activation of m(V)over dot (O2) [NADH], and light scattering were evaluated in isolated porcine heart mitochondria at 37 degreesC using a variety of optical techniques. The addition of Ca2+ was associated with an initial response time (IRT) of m(V)over dot (O2), that was dose-dependent with a minimum IRT of 0.27 +/- 0.02 a (n = 41) at 535 mM Ca2+. The IRTs for NADH fluorescence and light scattering in response to Ca2+ additions were similar to m(V)over dot (O2). The Ca2+ IRT for m(V)over dot(O2) was significantly shorter than 1.6 mM ADP (2.36 +/- 0.47 a; p less than or equal to 0.001, n = 13), 2.2 mM P-i (2.32 +/- 0.29,p less than or equal to 0.001, n = 13), or 10 mM creatine (15.6. +/- 1.18 s,p less than or equal to 0.001, n = 18) under similar experimental conditions. Calcium effects were inhibited with 8 muM ruthenium red (2.4 +/- 0.31 s;p less than or equal to 0.001, n = 16) and reversed with EG;TA (1.6 +/- 0.44;p less than or equal to 0.01, n = 6), Estimates of Ca2+ uptake into mitochondria using optical Ca2+ indicators trapped in the matrix revealed a sufficiently rapid uptake to cause the metabolic effects observed. These data are consistent with the notion that extramitochondrial Ca2+ can modify ATP production, via an increase in matrix Ca2+ content, rapidly enough to support cardiac work transitions in vivo. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Rm B1D-400, Bethesda, MD 20892 USA. EM territop@zeus.nhlbi.nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 100 TC 104 Z9 108 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2001 VL 276 IS 4 BP 2586 EP 2599 DI 10.1074/jbc.M002923200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YV UT WOS:000166784800042 PM 11029457 ER PT J AU Kutty, RK Kutty, G Samuel, W Duncan, T Bridges, CC El-Sherbeeny, A Nagineni, CN Smith, SB Wigger, B AF Kutty, RK Kutty, G Samuel, W Duncan, T Bridges, CC El-Sherbeeny, A Nagineni, CN Smith, SB Wigger, B TI Molecular characterization and developmental expression of NORPEG, a novel gene induced by retinoic acid SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PIGMENT EPITHELIAL-CELLS; MESSENGER-RNA; ALTERNATIVE POLYADENYLATION; BINDING PROTEIN; MOUSE; RECEPTOR; COMPLEX; LINE; DIFFERENTIATION; TRANSCRIPTS AB We have characterized NORPEG, a novel gene from human retinal pigment epithelial cells (ARPE-19), in which its expression is induced by all-trans-retinoic acid. Two transcripts (similar to3 and similar to5 kilobases in size) have been detected for this gene, which is localized to chromosome band 5p13.2-13.3. Placenta and testis showed the highest level of expression among various human tissues tested. Six ankyrin repeats and a long coiled-coil domain are present in the predicted sequence of the NORPEG protein, which contains 980 amino acid residues. This similar to 110-kDa protein was transiently expressed in COS-7 cells as a FLAG fusion protein and immunolocalized to the cytoplasm, Confocal microscopic analysis of the NORPEG protein in ARPE-19 cells showed threadlike projections in the cytoplasm reminiscent of the cytoskeleton, Consistent with this localization, the expressed NORPEG protein showed resistance to solubilization by Triton X-100 and KCl. An ortholog of NORPEG characterized from mouse encoded a protein that showed 91% sequence similarity to the human NORPEG protein. The expression of Norpeg mRNA was detected in mouse embryo at embryonic day 9.5 by in situ hybridization, and the expression appears to be developmentally regulated. In adult mouse, the highest level of expression was detected in the seminiferous tubules of testis. C1 NEI, LRCMB, NIH, Biochem Sect, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Immunol & Virol Sect, Bethesda, MD 20892 USA. Med Coll Georgia, Dept Cellular Biol, Augusta, GA 30912 USA. Med Coll Georgia, Dept Anat, Augusta, GA 30912 USA. Med Coll Georgia, Dept Ophthalmol, Augusta, GA 30912 USA. RP Kutty, RK (reprint author), NEI, LRCMB, NIH, Biochem Sect, 6 Ctr Dr,Rm 338, Bethesda, MD 20892 USA. OI Bridges, Christy/0000-0003-1603-1445 FU NEI NIH HHS [EY 13089] NR 52 TC 23 Z9 25 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2001 VL 276 IS 4 BP 2831 EP 2840 DI 10.1074/jbc.M007421200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YV UT WOS:000166784800074 PM 11042181 ER PT J AU Biswas, I Obmolova, G Takahashi, M Herr, A Newman, MA Yang, W Hsieh, P AF Biswas, I Obmolova, G Takahashi, M Herr, A Newman, MA Yang, W Hsieh, P TI Disruption of the helix-u-turn-helix motif of MutS protein: Loss of subunit dimerization, mismatch binding and ATP hydrolysis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA repair; mismatch repair; MutS; hereditary non-polyposis colon cancer; microsatellite instability ID DNA-BASE PAIRS; ESCHERICHIA-COLI; MICROSATELLITE INSTABILITY; REPAIR PROTEINS; REPLICATION FIDELITY; THERMUS-AQUATICUS; COLORECTAL-CANCER; HELICASE-II; GENE; RECOMBINATION AB The DNA mismatch repair protein, MutS, is a dimeric protein that recognizes mismatched bases and has an intrinsic ATPase activity. Here, a series of Tag MutS proteins having C-terminal truncations in the vicinity of a highly conserved helix-u-turn-helix (HuH) motif are assessed for subunit oligomerization, ATPase activity and DNA mismatch binding. Those proteins containing an intact HuH region are dimers; those without the HuH region are predominantly monomers in solution. Steady-state kinetics of truncated but dimeric MutS proteins reveals only modest decreases in their ATPase activity compared to full-length protein. Ln contrast, disruption of the HuH region results in a greatly attenuated ATPase activity. In addition, only dimeric MutS proteins are proficient for mismatch binding. Finally, an analysis of the mismatch repair competency of truncated Escherichia coli MutS proteins in a rifampicin mutator assay confirms that the HuH region is critical for in vivo function. These findings indicate that dimerization is critical for both the ATPase and DNA mismatch binding activities of MutS, and corroborate several key features of the MutS structure recently deduced from X-ray crystallographic studies. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Nantes, Nantes 3, France. CNRS, Nantes 3, France. RP Hsieh, P (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 46 TC 41 Z9 41 U1 1 U2 5 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 26 PY 2001 VL 305 IS 4 BP 805 EP 816 DI 10.1006/jmbi.2000.4367 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398GJ UT WOS:000166748300012 PM 11162093 ER PT J AU Evdokimov, AG Anderson, DE Routzahn, KM Waugh, DS AF Evdokimov, AG Anderson, DE Routzahn, KM Waugh, DS TI Structural basis for oligosaccharide recognition by Pyrococcus furiosus maltodextrin-binding protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE thermostable protein; carbohydrate-binding; maltose-binding protein; maltodextrin-binding protein; Pyrococcus furiosus ID MALTOSE-BINDING; ESCHERICHIA-COLI; LIGAND-BINDING; ACTIVE-TRANSPORT; 2 MODES; BETA-CYCLODEXTRIN; CRYSTAL-STRUCTURE; RESOLUTION; STABILITY; CRYSTALLOGRAPHY AB maltodextrin-binding protein from Pyococcus furiosus (PfuMBP) has been overproduced in Escherichia coli, purified, and crystallized. The crystal structure of the protein bound to an oligosaccharide ligand was determined to 1.85 Angstrom resolution. The fold of I;PfuMBP is very similar to that of the orthologous MBP from E. coli (EcoMBP), despite the moderate level of sequence identity between the two proteins (27% identity, 46% similarity). PfuMBP is extremely resistant to heat and chemical denaturation, which may be attributed to a number of factors, such as a tightly packed hydrophobic core, clusters of isoleucine residues, salt-bridges, and the presence of proline residues in key positions. Surprisingly, an attempt to crystallize the complex of PfuMBP with maltose resulted in a structure that contained maltotriose in the ligand-binding site. The structure of the complex suggests that there is a considerable energy gain upon binding of maltotriose in comparison to maltose. Moreover, isothermal titration calorimetry experiments demonstrated that the binding of maltotriose to the protein is exothermic and tight, whereas no thermal effect was observed upon addition of maltose at three temperatures. Therefore, PfuMBP evidently is designed to bind oligosaccharides composed of three or more glucopyranose units. C1 NCI, Frederick Canc Res & Dev, Prot Engn Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev, Struct Biol Core Facil, Program Struct Biol, Frederick, MD 21702 USA. RP Evdokimov, AG (reprint author), NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 48 TC 45 Z9 47 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 26 PY 2001 VL 305 IS 4 BP 891 EP 904 DI 10.1006/jmbi.2000.4202 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398GJ UT WOS:000166748300019 PM 11162100 ER PT J AU Perry, G Avila, J Espey, MG Wink, DA Atwood, CS Smith, MA AF Perry, G Avila, J Espey, MG Wink, DA Atwood, CS Smith, MA TI Biochemistry of neurodegeneration SO SCIENCE LA English DT Letter C1 Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. Univ Autonoma Madrid, Ctr Biol Mol, E-28049 Madrid, Spain. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Perry, G (reprint author), Case Western Reserve Univ, Inst Pathol, 2085 Adelbert Rd, Cleveland, OH 44106 USA. RI Smith, Mark/A-9053-2009; Perry, George/A-8611-2009 OI Perry, George/0000-0002-6547-0172 NR 7 TC 11 Z9 11 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 JAN 26 PY 2001 VL 291 IS 5504 BP 595 EP 596 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 396BG UT WOS:000166616000024 PM 11229401 ER PT J AU Prigozy, TI Naidenko, O Qasba, P Elewaut, D Brossay, L Khurana, A Natori, T Koezuka, Y Kulkarni, A Kronenberg, M AF Prigozy, TI Naidenko, O Qasba, P Elewaut, D Brossay, L Khurana, A Natori, T Koezuka, Y Kulkarni, A Kronenberg, M TI Glycolipid antigen processing for presentation by CD1d molecules SO SCIENCE LA English DT Article ID ALPHA-GALACTOSIDASE; T-CELLS; MOUSE; GLYCOSIDASES; RECOGNITION; SPECIFICITY; DEGRADATION; REACTIVITY AB The requirement for processing glycolipid antigens in T cell recognition was examined with mouse CD1d-mediated responses to glycosphingolipids (GSLs). Although some disaccharide GSL antigens can be recognized without processing, the responses to three other antigens, including the disaccharide GSL Gal(alpha1-->2)GalCer (Gal, galactose; GalCer, galactosylceramide), required removal of the terminal sugars to permit interaction with the T cell receptor. A Lysosomal enzyme, alpha -galactosidase A, was responsible for the processing of Gal(alpha1-->2)GalCer to generate the antigenic monosaccharide epitope. These data demonstrate a carbohydrate antigen processing system analogous to that used for peptides and an ability of T cells to recognize processed fragments of complex glycolipids. C1 La Jolla Inst Allergy & Immunol, Div Dev Immunol, San Diego, CA 92121 USA. NINCDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Kirin Brewery Co Ltd, Pharmaceut Res Lab, Gunma 37012, Japan. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, Bethesda, MD 20892 USA. RP Kronenberg, M (reprint author), La Jolla Inst Allergy & Immunol, Div Dev Immunol, 10355 Sci Ctr Dr, San Diego, CA 92121 USA. RI Elewaut, Dirk/K-6831-2014 FU NCI NIH HHS [CA52511]; NIAID NIH HHS [AI40617] NR 23 TC 231 Z9 236 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 26 PY 2001 VL 291 IS 5504 BP 664 EP 667 DI 10.1126/science.291.5504.664 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 396BG UT WOS:000166616000047 PM 11158680 ER PT J AU Olden, K Guthrie, J AF Olden, K Guthrie, J TI Genomics: implications for toxicology SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE genomics; toxicogenomics; environmental genome project; risk assessment ID HUMAN-GENETICS; POLYMORPHISMS; DISEASE; ALCOHOLISM; LINKAGE; CANCER AB The primary goal of the Environmental Genome Project (EGP) is the identification of human polymorphisms indicative of susceptibility to specific environmental agents. Despite evidence for a substantial genetic contribution to disease variation in the population. progress towards identifying specific genes has been slow. To date, most of the advances in our understanding of human diseases has come from genetic analyses of monogenic diseases that affect a relatively small portion of the population. The principal strategy of the EGP involves resequencing DNA samples from populations representative of the US racial and ethnic groups to develop a database of variations. Polymorphisms in specific genes may also be detected by gene-expression profiling. The identification of polymorphisms by resequencing is straightforward, and can be accomplished with minimal difficulty. Gene-expression profiling is still problematic; however, determining the functional significance of the allelic variations will be a monumental challenge involving sophisticated proteomics and population-based and animal model studies. These studies will change radically the practice of public health and clinical medicine, and the approach to the development of pharmaceuticals. (C) 2001 Elsevier science B.V. All rights: reserved. C1 NIEHS, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. NIH, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 21 TC 27 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 25 PY 2001 VL 473 IS 1 BP 3 EP 10 DI 10.1016/S0027-5107(00)00161-5 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 400QL UT WOS:000166883000002 PM 11166022 ER PT J AU Felix, K Kovalchuk, AL Park, SS Coleman, AE Ramsay, ES Qian, M Kelliher, KA Jones, GM Ried, T Bornkamm, GW Janz, S AF Felix, K Kovalchuk, AL Park, SS Coleman, AE Ramsay, ES Qian, M Kelliher, KA Jones, GM Ried, T Bornkamm, GW Janz, S TI Inducible mutagenesis in TEPC 2372, a mouse plasmacytoma cell line that harbors the transgenic shuttle vector lambda LIZ SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE lambda LIZ-based transgenic mutagenicity assay; pristane (2,6,10,14-tetramethylpentadecane); peritoneal plasmacytomagenesis; BALB/c mice ID IN-VIVO MUTATIONS; ENDOGENOUS HPRT GENE; C-MYC RECOMBINATIONS; CHROMOSOMAL TRANSLOCATIONS; MUTANT FREQUENCIES; LACI TRANSGENE; GENOMIC INSTABILITY; INHALATION EXPOSURE; MOLECULAR ANALYSIS; LYMPHOID-TISSUES AB The plasmacytoma cell line, TEPC 2372, was derived from a malignant plasma cell tumor that developed in the peritoneal cavity of a BALB/c mouse that harbored the transgenic shuttle vector for the assessment of mutagenesis in vivo, lambda LIZ, TEPC 2372 was found to display the typical features of a BALB/c plasmacytoma. It consisted of pleomorphic plasma cells that secreted a monoclonal immunoglobulin (IgG2b/lambda), was initially dependent on the presence of IL-6 to grow in cell culture, contained a hyperdiploid chromosome complement with a tendency to undergo tetraploidization, and harbored a constitutively active c-myc gene by virtue of a T(6;15) chromosomal translocation. TEPC 2372 was further characterized by the ability to respond to in vitro exposure with 4-NQO (4-nitroqninoline-1-oxide), an oxidative model mutagen, with a vigorous dose-dependent increase in mutagenesis that peaked at a 7.85-fold elevation of mutant rates in lambda LIZ when compared to background mutant rates in untreated controls. Cotreatment with 4-NQO and BSO (buthionine sulfoximine), a glutathione-depleting compound that causes endogenous oxidative stress, resulted in a 9.03-fold increase in the mutant frequency in lambda LIZ, These results demonstrated that TEPC 2372, the malignant plasma cell counterpart of the lambda LIZ-based in vivo mutagenesis assay, may be useful as an in vitro reference point for the further elucidation of oxidative mutagenesis in lymphoid tissues. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Genet Lab, DBS, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. GSF, Inst Mol Biol & Tumor Genet, Munich, Germany. RP Felix, K (reprint author), NCI, Genet Lab, DBS, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 59 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 25 PY 2001 VL 473 IS 1 BP 121 EP 136 DI 10.1016/S0027-5107(00)00143-3 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 400QL UT WOS:000166883000011 PM 11166031 ER PT J AU McKenna, IM Ramakrishna, G Diwan, BA Shiao, YH Kasprzak, KS Powell, DA Anderson, LM AF McKenna, IM Ramakrishna, G Diwan, BA Shiao, YH Kasprzak, KS Powell, DA Anderson, LM TI K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE K-ras; mutations; lung tumors; preconceptional carcinogenesis; chromium ID ONCOGENE ACTIVATION; GENE-MUTATIONS; PROGNOSTIC MARKER; POINT MUTATION; EARLY-STAGE; A/J MICE; X-RAYS; CANCER; CARCINOGENESIS; CELL AB Preconceptional exposure of male NIH swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the R-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816 +/- 175 days for controls, 904 +/- 164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-rns mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P = 0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas. (C) 2001 Elsevier Science B.V. All rights reserved. C1 US EPA, Off Pollut Prevent & Tox Subst, Washington, DC 20460 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Comp & Stat Serv, Data Management Serv, Frederick, MD 21702 USA. RP McKenna, IM (reprint author), US EPA, Off Pollut Prevent & Tox Subst, Washington, DC 20460 USA. FU NCI NIH HHS [N01-CO-5600] NR 47 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JAN 25 PY 2001 VL 490 IS 1 BP 57 EP 65 DI 10.1016/S1383-5718(00)00153-4 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 397ZQ UT WOS:000166729600007 PM 11152972 ER PT J AU Djimde, A Doumbo, OK Cortese, JF Kayentao, K Doumbo, S Diourte, Y Dicko, A Su, XZ Nomura, T Fidock, DA Wellems, TE Plowe, CV Coulibaly, D AF Djimde, A Doumbo, OK Cortese, JF Kayentao, K Doumbo, S Diourte, Y Dicko, A Su, XZ Nomura, T Fidock, DA Wellems, TE Plowe, CV Coulibaly, D TI A molecular marker for chloroquine-resistant falciparum malaria SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PLASMODIUM-FALCIPARUM; PFMDR1 GENE; IN-VIVO; AFRICA; ANTIMALARIALS; AMPLIFICATION; POLYMORPHISMS; EPIDEMIOLOGY; MUTATIONS; CAMEROON AB Background: Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. Methods: To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. Results: The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine (Y86) for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). Conclusions: This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria. (N Engl J Med 2001;344:257-63.) Copyright (C) 2001 Massachusetts Medical Society. C1 Univ Maryland, Sch Med, Ctr Vaccine Dev, Malaria Sect, Baltimore, MD 21201 USA. Univ Mali, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali. NIAID, Malaria Genet Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Malaria Sect, 685 W Baltimore St,HSF 480, Baltimore, MD 21201 USA. OI Fidock, David/0000-0001-6753-8938; Su, Xinzhuan/0000-0003-3246-3248 FU NIAID NIH HHS [N01-AI-85346, R01 AI050234, 5P50AI39469] NR 36 TC 599 Z9 626 U1 0 U2 33 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 25 PY 2001 VL 344 IS 4 BP 257 EP 263 DI 10.1056/NEJM200101253440403 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 394WA UT WOS:000166545200003 PM 11172152 ER PT J AU Inga, A Monti, P Fronza, G Darden, T Resnick, MA AF Inga, A Monti, P Fronza, G Darden, T Resnick, MA TI p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay SO ONCOGENE LA English DT Article DE p53; yeast; enhanced transactivation; dominance ID TUMOR-SUPPRESSOR P53; WILD-TYPE; DNA-BINDING; SEQUENCE-SPECIFICITY; GENE-EXPRESSION; TERMINAL DOMAIN; CORE DOMAIN; CELL-LINES; CANCER; MUTATIONS AB Changes in promoter specificity and binding affinity that may be associated with p53 mutations or post-translational modifications are useful in understanding p53 structure/ function relationships and categorizing tumor mutations. We have exploited variable expression of human p53 in yeast to identify mutants with novel phenotypes that would correspond to altered promoter selectivity and affinity. The p53 cDNA regions coding for the DNA binding and tetramerization domains were subjected to random PCR mutagenesis and were cloned directly by recombination in yeast into a vector with a GAL1 promoter whose level of expression could be easily varied. p53 variants exhibiting higher than wild type levels of transactivation (supertrans) for the RGC responsive element were identified at low level of p53 protein expression. All the p53 mutants obtained with this screen were located in the DNA binding domain. Two out of 17 supertrans mutants have been found in tumors. Six mutations were in the L1 loop region between amino acids 115 and 124, The transactivation potential of a panel of supertrans p53 mutants on different promoters was evaluated using the p53 responsive elements, RGC, PIG3, p21 and bax. Although all mutants retained some activity with all promoters, we found different patterns of induction based on strength and promoter specificity. In particular none of the mutants was supertrans for the p21 responsive element, Interestingly, further analysis in yeast showed that the transactivation function could be retained even in the presence of dominant-negative p53 tumor mutations that could inhibit wild type p53, Five mutants were also characterized in human cells in terms of growth suppression and transactivation of various promoters. These novel supertrans p53 mutants may be useful in studies aimed at dissecting p53 downstream pathways, understanding specific interactions between p53 and the DNA, and could replace wild type p53 in cancer gene therapy protocols. The approach may also prove useful in identifying p53 tumor mutations. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NCI, IST, Mutagenesis Lab, I-16132 Genoa, Italy. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Mail Drop D3-01,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 57 TC 37 Z9 38 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 25 PY 2001 VL 20 IS 4 BP 501 EP 513 DI 10.1038/sj.onc.1204116 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 395DB UT WOS:000166562500010 PM 11313981 ER PT J AU Guru, SC Prasad, NB Shin, EJ Hemavathy, K Lu, JN Ip, YT Agarwal, SK Marx, SJ Spiegel, AM Collins, FS Oliver, B Chandrasekharappa, SC AF Guru, SC Prasad, NB Shin, EJ Hemavathy, K Lu, JN Ip, YT Agarwal, SK Marx, SJ Spiegel, AM Collins, FS Oliver, B Chandrasekharappa, SC TI Characterization of a MEN1 ortholog from Drosophila melanogaster SO GENE LA English DT Article DE MEN1; menin; tumor suppressor; DJun; JunD ID ENDOCRINE NEOPLASIA TYPE-1; GENE-EXPRESSION; MURINE HOMOLOG; TRANSCRIPTION; ZEBRAFISH; PROTEIN AB Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by tumors of the parathyroid, entero-pancreatic neuroendocrine and pituitary tissues and caused by inactivating mutations in the MEN1 gene. Menin, the 610-amino acid nuclear protein encoded by MEN1, binds to the transcription factor JunD and can repress JunD-induced transcription. We report here the identification of a MEN1 ortholog in Drosophila melanogaster, Menin1, that encodes a 763 amino acid protein sharing 46% identity with human menin. Additionally, 69% of the missense mutations and in-frame deletions reported in MEN1 patients appear in amino acid residues that are identical in the Drosophila and human protein, suggesting the importance of the conserved regions. Drosophila Menin1 gene transcripts use alternative polyadenylation sites resulting in 4.3 and 5-kb messages. The 4.3-kb transcript appears to be largely maternal, while the 5-kb transcript appears mainly zygotic. The binding of Drosophila menin to human JunD or Drosophila Jun could not be demonstrated by the yeast two-hybrid analysis. The identification of the MEN1 ortholog from Drosophila melanogaster will provide an opportunity to utilize Drosophila genetics to enhance our understanding of the function of human menin. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHGRI, GMBB, NIH, Bethesda, MD 20892 USA. NIH, Metab Dis Branch, Bethesda, MD 20892 USA. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. RP Chandrasekharappa, SC (reprint author), NHGRI, GMBB, NIH, Bldg 49,Rm 3E13,49 Convent Dr, Bethesda, MD 20892 USA. RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 25 TC 27 Z9 28 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 JAN 24 PY 2001 VL 263 IS 1-2 BP 31 EP 38 DI 10.1016/S0378-1119(00)00562-X PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 408XN UT WOS:000167352400003 PM 11223240 ER PT J AU Timmons, L Court, DL Fire, A AF Timmons, L Court, DL Fire, A TI Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans SO GENE LA English DT Article DE RNAi; HT115(DE3); dsRNA; T7 polymerase ID COLI POLYNUCLEOTIDE PHOSPHORYLASE; BACTERIOPHAGE-T7 RNA-POLYMERASE; SEX-DETERMINING GENE; ESCHERICHIA-COLI; RIBONUCLEASE-III; MESSENGER; PROTEIN; ACID; SEQUENCES; CLEAVAGE AB Genetic interference mediated by double-stranded RNA (RNAi) has been a valuable tool in the analysis of gene function in Caenorhabditis elegans. Here we report an efficient induction of RNAi using bacteria to deliver double-stranded RNA. This method makes use of bacteria that are deficient in RNaseIII, an enzyme that normally degrades a majority of dsRNAs in the bacterial cell. Bacteria deficient for RNaseIII were engineered to produce high quantities of specific dsRNA segments. When fed to C. elegans, such engineered bacteria were found to produce populations of RNAi-affected animals with phenotypes that were comparable in expressivity to the corresponding loss-of-function mutants. We found the method to be most effective in inducing RNAi for non-neuronal tissue of late larval and adult hermaphrodites, with decreased effectiveness in the nervous system, in early larval stages, and in males. Bacteria-induced RNAi phenotypes could be maintained over the course of several generations with continuous feeding, allowing for convenient assessments of the biological consequences of specific genetic interference and of continuous exposure to dsRNAs. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Carnegie Inst Washington, Dept Embryol, Baltimore, MD 21210 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Fire, A (reprint author), Carnegie Inst Washington, Dept Embryol, 115 W Univ Pkwy, Baltimore, MD 21210 USA. FU NICHD NIH HHS [F32HD08353]; NIGMS NIH HHS [R01 GM037706, R01GM37706] NR 41 TC 960 Z9 1008 U1 19 U2 115 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 24 PY 2001 VL 263 IS 1-2 BP 103 EP 112 DI 10.1016/S0378-1119(00)00579-5 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 408XN UT WOS:000167352400011 PM 11223248 ER PT J AU Podlutsky, AJ Dianova, II Wilson, SH Bohr, VA Dianov, GL AF Podlutsky, AJ Dianova, II Wilson, SH Bohr, VA Dianov, GL TI DNA synthesis and dRPase activities of polymerase beta are both essential for single-nucleotide patch base excision repair in mammalian cell extracts SO BIOCHEMISTRY LA English DT Article ID 5'-TERMINAL DEOXYRIBOSE PHOSPHATE; DAMAGED DNA; GLYCOSYLASE; RESIDUES; BINDING; ENDONUCLEASES; 8-OXOGUANINE; DEFICIENT; PATHWAY; PROTEIN AB In mammalian cells the majority of altered bases in DNA are processed through a single nucleotide patch base excision repair mechanism, Base excision repair is initiated by a DNA glycosylase that removes a damaged base and generates an abasic site (AP site). This AP site is further processed by an AP endonuclease activity that incises the phosphodiester bond adjacent to the AP site and generates a strand break containing 3'-OH and 5'-sugar phosphate ends. In mammalian cells, the 5'-sugar phosphate is removed by the AP lyase activity of DNA polymerase beta (Pol beta). The same enzyme also fills the gap, and the DNA ends are finally rejoined by DNA ligase. We measured repair of oligonucleotide substrates containing a single AP site in cell extracts prepared from normal and Pol beta -null mouse cells and show that the reduced repair in Pol beta -null extracts can be complemented by addition of purified Pol beta. Using this complementation assay, we demonstrate that mutated Pol beta without dRPase activity is able to stimulate long patch BER. Mutant Pol beta deficient in DNA synthesis, but with normal dRPase activity, does not stimulate repair in Pol beta -null cells, However, under conditions where we measure base excision repair accomplished exclusively through a single-nucleotide patch BER, neither dRPase nor DNA synthesis mutants of Pol beta alone, or the two together, were able to complement the repair defect, These data suggest that the dRPase and DNA synthesis activities of Pol beta are coupled and that both of these Pol beta functions are essential during short patch BER and cannot be efficiently substituted by other cellular enzymes. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Dianov, GL (reprint author), MRC, Radiat & Genome Stabil Unit, Didcot OX11 0RD, Oxon, England. RI Podlutsky, Andrej/F-5421-2015 NR 34 TC 43 Z9 46 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 JAN 23 PY 2001 VL 40 IS 3 BP 809 EP 813 DI 10.1021/bi002064s PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 393YJ UT WOS:000166497000023 PM 11170398 ER PT J AU Zhu, J Petersen, S Tessarollo, L Nussenzweig, A AF Zhu, J Petersen, S Tessarollo, L Nussenzweig, A TI Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice SO CURRENT BIOLOGY LA English DT Article ID PROTEIN COMPLEX; REPAIR; DNA; BRCA1; RADIATION; CELLS; MOUSE; HYPERSENSITIVITY; SENSITIVITY; INSTABILITY AB Nijmegen breakage syndrome (NBS) is a rare autosomal recessive human disease whose clinical features include growth retardation, immunodeficiency, and increased susceptibility to lymphoid malignancies. Cells from NBS patients exhibit gamma -irradiation sensitivity, S-phase checkpoint defects, and genomic instability. Recently, it was demonstrated that this chromosomal breakage syndrome is caused by mutations in the NBS1 gene that result in a total loss of full-length NBS1 expression [1, 2], Here we report that in contrast to the viability of NBS patients, targeted inactivation of NBS1 in mice leads to early embryonic lethality in utero and is associated with poorly developed embryonic and extraembryonic tissues. Mutant blastocysts showed greatly diminished expansion of the inner cell mass in culture, and this finding suggests that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Together, our results indicate that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mammalian Genet Lab, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 21 TC 245 Z9 251 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 23 PY 2001 VL 11 IS 2 BP 105 EP 109 DI 10.1016/S0960-9822(01)00019-7 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 438WA UT WOS:000169076200019 PM 11231126 ER PT J AU Zumberg, MS Procter, JL Lottenberg, R Kitchens, CS Klein, HG AF Zumberg, MS Procter, JL Lottenberg, R Kitchens, CS Klein, HG TI Autoantibody formation in the alloimmunized red blood cell recipient - Clinical and laboratory implications SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HEMOLYTIC TRANSFUSION REACTIONS; DISEASE; ERYTHROCYTE; MANAGEMENT AB Alloimmunization to erythrocyte antigens is a well-characterized complication in heavily transfused patients. Less well recognized, however, is the frequency of autoantibody formation in these previously alloimmunized patients. The autoantibodies are heterogeneous and of variable clinical significance. We describe the clinical history, laboratory evaluation, diagnosis, and treatment in 4 patients who developed autoantibodies in temporal association with alloantibody formation. In one case, the autoantibody found on routine screening had no clinical significance. In another case, the autoantibody made accurate blood typing and subsequent transfusion exceedingly difficult. Two patients experienced hemolysis as a consequence of the autoantibody. The management of both patients included supportive measures, while one patient required glucocorticosteroids and red blood cell transfusion. We review the published literature concerning autoimmunization in the transfused alloimmunized host. The spectrum of clinical consequences is important for the general practitioner to recognize, as these complications may occur during routine blood transfusions. C1 Univ Florida, Dept Med, Div Hematol Oncol, Gainesville, FL 32610 USA. NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Zumberg, MS (reprint author), Univ Florida, Dept Med, Div Hematol Oncol, Box 100277, Gainesville, FL 32610 USA. NR 25 TC 16 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 22 PY 2001 VL 161 IS 2 BP 285 EP 290 DI 10.1001/archinte.161.2.285 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 393QE UT WOS:000166480500021 PM 11176745 ER PT J AU Ma, DW Zhang, T Wang, GQ Kozikowski, AP Lewin, NE Blumberg, PM AF Ma, DW Zhang, T Wang, GQ Kozikowski, AP Lewin, NE Blumberg, PM TI Synthesis of 7,8-disubstituted benzolactam-V8 and its binding to protein kinase C SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID SELECTIVE INHIBITORS; DELTA; CLARIFICATION; SPECIFICITY; TELEOCIDIN; ANALOGS; DOMAIN AB 7-Methoxy-8-decynyl-benzolactam 4 is synthesized using a catalytic asymmetric alkylation reaction as a key step. This compound shows potent activity to three PKC isozymes tested (K-i = 45.6, 91.1, and 121.3 nM to PKC alpha, delta, and epsilon, respectively), indicating that introduction of a suitable substituent at the 7-position of 8-decynyl-benzolactam-V8 only slightly reduces the PKC binding affinity. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China. Georgetown Univ, Med Ctr, Inst Cognit & Computat Sci, Drug Discovery Lab, Washington, DC 20007 USA. NCI, Bethesda, MD 20892 USA. RP Ma, DW (reprint author), Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, 354 Fenglin Lu, Shanghai 200032, Peoples R China. FU NCI NIH HHS [CA79601] NR 13 TC 19 Z9 20 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 22 PY 2001 VL 11 IS 2 BP 99 EP 101 DI 10.1016/S0960-894X(00)00609-0 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 396QM UT WOS:000166648100004 PM 11206480 ER PT J AU McNulty, J Mao, J Gibe, R Mo, RW Wolf, S Pettit, GR Herald, DL Boyd, MR AF McNulty, J Mao, J Gibe, R Mo, RW Wolf, S Pettit, GR Herald, DL Boyd, MR TI Studies directed towards the refinement of the pancratistatin cytotoxic pharmacophore SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID AMARYLLIDACEAE ALKALOIDS; ANTINEOPLASTIC AGENTS; (+)-PANCRATISTATIN; LYCORICIDINE; ANALOGS AB Two deoxy-analogues of the anticancer/antiviral agent pancratistatin containing functionality complementary to the minimum structural pharmacophore were synthesized and subjected to anticancer screening. One of the analogues exhibited selective inhibition of certain tumor cell lines but was significantly less potent than the natural products. The minimum structural pharmacophore has now been refined from eight to three possible structures. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Brock Univ, Dept Chem, Inst Mol Catalysis, St Catharines, ON L2S 3A1, Canada. Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem, Tempe, AZ 85287 USA. NCI, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP McNulty, J (reprint author), Brock Univ, Dept Chem, Inst Mol Catalysis, St Catharines, ON L2S 3A1, Canada. RI McNulty, James/E-7871-2011 FU NCI NIH HHS [CA-44344-10-12] NR 23 TC 62 Z9 62 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 22 PY 2001 VL 11 IS 2 BP 169 EP 172 DI 10.1016/S0960-894X(00)00614-4 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 396QM UT WOS:000166648100019 PM 11206451 ER PT J AU Derby, EG Reddy, V Nelson, EL Kopp, WC Baseler, MW Dawson, JR Malyguine, AM AF Derby, EG Reddy, V Nelson, EL Kopp, WC Baseler, MW Dawson, JR Malyguine, AM TI Correlation of human CD56(+) cell cytotoxicity and IFN-gamma production SO CYTOKINE LA English DT Article DE ELISPOT; NK; IFN-gamma; cytotoxicity; NK-sensitivity ID NATURAL-KILLER-CELLS; NK CELLS; SECRETING CELLS; ELISPOT ASSAY; T-LYMPHOCYTES; INTERFERON; ENUMERATION; FREQUENCY; APOPTOSIS; ALPHA AB The use of an IFN-gamma ELISPOT assay to evaluate cellular immune responses has gained increasing popularity, especially as a surrogate measure for cytotoxic T lymphocyte (CTL) responses. We have compared the IFN-gamma ELISPOT assay and the traditional Cr-51 release assay for detection of human natural killer (NK) cell activity. The cell populations used for evaluation of these assays included freshly isolated and IL-2-activated peripheral blood mononuclear cells (PBMC), CD56-positive cells were demonstrated to be the primary source of the IFN-gamma signal when PBMC were evaluated with NK-sensitive targets in the IFN-gamma ELISPOT assay. IFN-gamma ELISPOT and Cr-51 release assays showed excellent correlation suggesting that NK activity can be reliably evaluated with methods other than the traditional Cr-51 release assays. (C) 2001 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. Duke Univ, Med Ctr, Durham, NC USA. RP Malyguine, AM (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, POB B, Frederick, MD 21702 USA. FU PHS HHS [N01-C0-56000] NR 21 TC 7 Z9 7 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 1043-4666 J9 CYTOKINE JI Cytokine PD JAN 21 PY 2001 VL 13 IS 2 BP 85 EP 90 DI 10.1006/cyto.2000.0804 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 397DZ UT WOS:000166679200003 PM 11145847 ER PT J AU Nahin, RL Straus, SE AF Nahin, RL Straus, SE TI Research into complementary and alternative medicine: problems and potential SO BRITISH MEDICAL JOURNAL LA English DT Article ID CLINICAL-TRIALS; UNITED-STATES; ACUPUNCTURE; THERAPIES C1 NIH, Div Extramural Res Training & Review, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Nahin, RL (reprint author), NIH, Div Extramural Res Training & Review, Natl Ctr Complementary & Alternat Med, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 96 Z9 100 U1 2 U2 3 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8138 J9 BRIT MED J JI Br. Med. J. PD JAN 20 PY 2001 VL 322 IS 7279 BP 161 EP 164 DI 10.1136/bmj.322.7279.161 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 396AZ UT WOS:000166615300033 PM 11159578 ER PT J AU Trimble, EL AF Trimble, EL TI Prospects for improving staging of ovarian cancers SO LANCET LA English DT Editorial Material ID CARCINOMA C1 NCI, Canc Therapy Evaluat Programme, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), NCI, Canc Therapy Evaluat Programme, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JAN 20 PY 2001 VL 357 IS 9251 BP 159 EP 160 DI 10.1016/S0140-6736(00)03583-2 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 395QX UT WOS:000166593700003 PM 11213087 ER PT J AU Komanduri, KV Donahoe, SM Moretto, WJ Schmidt, DK Gillespie, G Ogg, GS Roederer, M Nixon, NF McCune, JM AF Komanduri, KV Donahoe, SM Moretto, WJ Schmidt, DK Gillespie, G Ogg, GS Roederer, M Nixon, NF McCune, JM TI Direct measurement of CD4+ and CD8+ T-cell responses to CMV in HIV-1-infected subjects SO VIROLOGY LA English DT Article DE AIDS; HIV; infectious immunity virus; T lymphocytes; human; FACS ID ANTIRETROVIRAL THERAPY; FLOW-CYTOMETRY; LYMPHOCYTE RESPONSES; VIRAL-INFECTION; PROTEIN PP65; IN-VIVO; ANTIGEN; CYTOMEGALOVIRUS; MICE; IMMUNODEFICIENCY AB Data from murine models of chronic viral infection suggest that CD4+ T-cell responses to viral pathogens are important in sustaining the number and/or function of CD8+ cytotoxic T-cell (CTL) effecters. In this study, we used cytokine flow cytometry (CFC), staining with HLA-A*0201-peptide tetramers, and peptide stimulation with epitopic peptides to study functional CD4+ and CD8+ T-cell responses to cytomegalovirus (CMV) in human subjects coinfected with CMV and the human immunodeficiency virus, type 1 (HIV-1). We show that strong CD4+ and CD8+ T-cell responses to CMV antigens are sustained over time in HIV-1-infected individuals. Those who maintain a strong CD4+ T-cell response to CMV are also likely to maintain higher frequencies of CD8+ T cells capable of binding to HLA-A*0201-CMV pp65 (A2-pp65) tetramers as well as responses to pp65 peptide stimulation with effector cytokine production. These data support the hypothesis that declines in frequencies of CD4+ T-cell responses to CMV are associated with an inability to sustain high levels of CMV-specific CD8+ T-cell responses in HIV-1-infected subjects. These declines may precede the onset of CMV-associated end organ disease. (C) 2001 Academic Press. C1 Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA. Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. Inst Mol Med, MRC, Human Immunol Unit, Oxford OX3 9DS, England. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP McCune, JM (reprint author), MD Anderson Canc Ctr, Dept Blood & Marrow Transplantat, Sect Transplantat Immunol, 1515 Holcombe Blvd, Houston, TX 77030 USA. RI Roederer, Mario/G-1887-2011; Komanduri, Krishna/G-6012-2011; OI Komanduri, Krishna/0000-0003-3715-5236; Nixon, Douglas/0000-0002-2801-1786 FU NCRR NIH HHS [5-MO1-RR00083]; NIAID NIH HHS [R01 AI43864, R01 AI47062] NR 32 TC 68 Z9 70 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2001 VL 279 IS 2 BP 459 EP 470 DI 10.1006/viro.2000.0697 PG 12 WC Virology SC Virology GA 397KN UT WOS:000166695000011 PM 11162802 ER PT J AU Fisher, LW Torchia, DA Fohr, B Young, MF Fedarko, NS AF Fisher, LW Torchia, DA Fohr, B Young, MF Fedarko, NS TI Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SIBLING; bone sialoprotein; osteopontin; NMR structure; flexible structure ID IMPERFECTA TYPE-II; GENOMIC ORGANIZATION; CAUSATIVE ROLE; GENE; EXPRESSION; SEQUENCE; PATHOGENESIS; LOCALIZATION; EXCLUSION; CANCER AB Bone sialoprotein (BSP) and osteopontin (OPN) are two members of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family of genetically related proteins that are clustered on human chromosome 4. We present evidence that this entire family is the result of duplication and subsequent divergent evolution of a single ancient gene. The solution structures of these two post-translationally modified recombinant proteins were solved by one dimensional proton NMR and transverse relaxation times. The polypeptide backbones of both free BSP and OPN rapidly sample an ensemble of conformations consistent with them both being completely unstructured in solution. This flexibility appears to enable these relatively small glycoproteins to rapidly associate with a number of different binding partners including other proteins as well as the mineral phase of bones and teeth. These proteins often function by bridging two proteins of fixed structures into a biologically active complex. (C) 2001 Academic Press. C1 NIDCR, CSDB, NIH, Bethesda, MD 20892 USA. NIDCR, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Div Geriatr, Baltimore, MD 21224 USA. RP Fisher, LW (reprint author), NIDCR, CSDB, NIH, Room 228,Bldg 30, Bethesda, MD 20892 USA. OI Fedarko, Neal/0000-0001-6055-6279 NR 17 TC 378 Z9 392 U1 2 U2 23 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 19 PY 2001 VL 280 IS 2 BP 460 EP 465 DI 10.1006/bbrc.2000.4146 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 397LL UT WOS:000166697100007 PM 11162539 ER PT J AU Chiang, YH Morales, M Zhou, FC Borlongan, C Hoffer, BJ Wang, Y AF Chiang, YH Morales, M Zhou, FC Borlongan, C Hoffer, BJ Wang, Y TI Fetal intra-nigral ventral mesencephalon and kidney tissue bridge transplantation restores the nigrostriatal dopamine pathway in hemi-parkinsonian rats SO BRAIN RESEARCH LA English DT Article DE transplantation; Parkinson's disease; 6-hydroxydopamine; tyrosine hydroxylase; dopamine; neurorepair ID MICE LACKING GDNF; NEURONS IN-VIVO; NEUROTROPHIC FACTOR; NERVOUS-SYSTEM; MORPHOGENETIC PROTEIN; SUBSTANTIA-NIGRA; FIBER OUTGROWTH; STRIATUM; GRAFTS; EXPRESSION AB We have previously demonstrated that intranigral transplantation of fetal ventral mesencephalic (VM) tissue and nigrostriatal administration of glial cell line-derived neurotrophic factor (GDNF) restores striatal dopamine input in hemiparkinsonian rats, Since it has been found that GDNF is highly expressed in fetal kidney, we examined the possibility that fetal kidney tissue may provide trophic support, similar to GDNF, to an intranigral dopamine (DA) transplant and restore the nigrostriatal pathway. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Completeness of the lesion was evaluated by measuring amphetamine-induced rotation. One month after 6-OHDA lesioning, fetal VM cells were grafted into the lesioned nigral area followed by transplantation of fetal kidney tissue or vehicle along a pathway from nigra to striatum. Animals receiving these transplants showed a significant decrease both in amphetamine-induced rotation and in postural asymmetry 1 to 3 months after grafting. Immunocytochemical studies demonstrated tyrosine hydroxylase (TH) positive fiber tracts in the lesioned striatum. Control animals that received vehicle injection after the intranigral graft or no transplantation showed no alterations in amphetamine-induced turning and no TH-positive fibers in the lesioned striatum. These results indicate that combinations of fetal nigral and kidney transplants may restore the nigrostriatal DA pathway in Parkinsonian rats. As fetal kidney contains a variety of trophic proteins, it may provide a synergistic admixture to optimally promote DA fiber outgrowth. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Natl Def Med Ctr, Tri Serv Gen Hosp, Dept Neurol Surg, Taipei, Taiwan. Indiana Univ, Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. NIDA, NIH, Baltimore, MD 21224 USA. RP Chiang, YH (reprint author), Natl Def Med Ctr, Tri Serv Gen Hosp, Dept Neurol Surg, Taipei, Taiwan. OI Borlongan, Cesar/0000-0002-2966-9782 NR 37 TC 24 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 19 PY 2001 VL 889 IS 1-2 BP 200 EP 207 DI 10.1016/S0006-8993(00)03133-4 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 399NG UT WOS:000166818800023 PM 11166704 ER PT J AU Weber, HC Walters, J Leyton, J Casibang, M Purdom, S Jensen, RT Coy, DH Ellis, C Clark, G Moody, TW AF Weber, HC Walters, J Leyton, J Casibang, M Purdom, S Jensen, RT Coy, DH Ellis, C Clark, G Moody, TW TI A bombesin receptor subtype-3 peptide increases nuclear oncogene expression in a MEK-1 dependent manner in human lung cancer cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE lung cancer; bombesin receptor subtype-3; Elk-1; mitogen activated protein kinase; c-fos mRNA ID ACTIVATED PROTEIN-KINASE; GASTRIN-RELEASING PEPTIDE; HUMAN ORPHAN RECEPTOR; SWISS 3T3 CELLS; MOLECULAR-CLONING; MAP KINASE; IN-VIVO; C-FOS; GROWTH; PHOSPHORYLATION AB A synthetic peptide, (D-Phe(6), beta -Ala(11) Phe(13), Nle(14))bombesin-(6- 14) was used to investigate the signal transduction mechanisms of bombesin receptor subtype-3. Using NCI-1299#5 human lung cancer cells stably transfected with bombesin receptor subtype-3, 100 nM (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) elevated the cytosolic Ca2+ from 150 to 250 nM within 10 s. Addition of (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused phosphorylation of mitogen activated protein kinase in a time- and concentration-dependent manner. The mitogen activated protein kinase phosphorylation caused by (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by 2'-amino-3'-methyoxyflavone (PD98059), a mitogen activated protein kinase kinase (MEK-1) inhibitor. Using a luciferase reporter gene construct, (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused Elk-1 activation after 10 min and the increase in Elk-1 activation caused by (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059 as well as a dominant-negative MEK-1. (D-Phe(6), P-Ala(11), Phe(13), Nle(14))bombesin-(6- 14) caused increased c-fos as well as c-jun mRNAs 1 h after addition to NCI-H1299#5 cells. The 47-fold increase in c-fos mRNA caused by 100 nM (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059, a dominant-negative MEK-1 and a substance P antagonist but not (3-phenylpropanoyl-D-Ala(24), pro(26), pSi(26,27),Phe(27))GRP(20-27) (BW2258U89), a GRP receptor antagonist. These results indicate that (D-Phe(6), beta -Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused increased nuclear oncogene expression and upstream events include mitogen activated protein kinase phosphorylation and Elk-1 activation. (C) 2001 Published by Elsevier Science B.V. C1 NCI, Cell & Canc Biol Dept, Med Branch, Rockville, MD 20850 USA. Boston Univ, Sch Med, Gastroenterol Sect, Boston, MA 02118 USA. NIDDKD, Digest Dis Branch, Bethesda, MD 20892 USA. Tulane Univ, Peptide Res Labs, Dept Med, New Orleans, LA 70112 USA. RP Moody, TW (reprint author), NCI, Cell & Canc Biol Dept, Med Branch, Bldg KWC,Rm 300,9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 40 TC 21 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 19 PY 2001 VL 412 IS 1 BP 13 EP 20 DI 10.1016/S0014-2999(00)00941-9 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 398RE UT WOS:000166768800002 PM 11166731 ER PT J AU Gao, B Shen, XN Kunos, G Meng, QH Goldberg, ID Rosen, EM Fan, SJ AF Gao, B Shen, XN Kunos, G Meng, QH Goldberg, ID Rosen, EM Fan, SJ TI Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells SO FEBS LETTERS LA English DT Article DE breast cancer susceptibility gene 1; Janus kinase; signal transducer and activator transcription factor 3; breast cancer; prostate cancer ID DNA-BINDING ACTIVITY; TUMOR-SUPPRESSOR; OVARIAN-CANCER; GENE BRCA1; STAT3; TRANSCRIPTION; BREAST; PROTEIN; SUSCEPTIBILITY; ALPHA(1B)AR AB Germ-line mutations of the breast cancer susceptibility gene 1 (BRCA1) confer a high risk for breast and ovarian cancer in women and prostate cancer in men. The BRCA1 protein contributes to cell proliferation, cell cycle regulation, DNA repair and apoptosis; howe, er, the mechanisms underlying these functions of BRCA1 remain largely unknown, Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in constitutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation, Moreover, Janus kinase 1 (JAK1) and JAK2, the upstream activators of STAT3, were also activated by BRCA1, Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2, Blocking STAT3 activation using antisense oligonucleotides significantly inhibited cell proliferation and triggered apoptosis in Du-145 cells with enhanced expression of BRCA1, These findings indicate that BRCA1 interacts with the components of the JAK-STAT signaling cascade and modulates its activation, which may provide a new critical survival signal for the growth of breast, ovarian and prostate cancers in the presence of normal BRCA1, (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Albert Einstein Coll Med, Long Isl Jewish Med Ctr, Dept Radiat Oncol, Mol Oncol Lab, New Hyde Park, NY 11040 USA. RP Gao, B (reprint author), NIAAA, NIH, Rockville, MD 20852 USA. FU NCI NIH HHS [R29CA72681]; NIAAA NIH HHS [R01AA12637, R03AA11823] NR 43 TC 75 Z9 77 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 19 PY 2001 VL 488 IS 3 BP 179 EP 184 DI 10.1016/S0014-5793(00)02430-3 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 397QW UT WOS:000166707800014 PM 11163768 ER PT J AU Miranda, KM Espey, MG Yamada, K Krishna, M Ludwick, N Kim, S Jourd'heuil, D Grisham, MB Feelisch, M Fukuto, JM Wink, DA AF Miranda, KM Espey, MG Yamada, K Krishna, M Ludwick, N Kim, S Jourd'heuil, D Grisham, MB Feelisch, M Fukuto, JM Wink, DA TI Unique oxidative mechanisms for the reactive nitrogen oxide species, nitroxyl anion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PEROXYNITRITE-MEDIATED OXIDATION; FREE NITRIC-OXIDE; CARBON-DIOXIDE; SUPEROXIDE-DISMUTASE; BIOLOGICAL-ACTIVITY; HYDROGEN-PEROXIDE; NITROSYL HYDRIDE; NO; NITRATION; DIHYDRORHODAMINE-123 AB The nitroxyl anion (NO-) is a highly reactive molecule that may be involved in pathophysiological actions associated with increased formation of reactive nitrogen oxide species. Angeli's salt (Na2N2O3; AS) is a NO- donor that has been shown to exert marked cytotoxicity. However, its decomposition intermediates have not been well characterized. In this study, the chemical reactivity of AS was examined and compared with that of peroxynitrite (ONOO-) and NO/N2O3. Under aerobic conditions, AS and ONOO- exhibited similar and considerably higher affinities for dihydrorhodamine (DHR) than NO/N2O3. Quenching of DHR oxidation by azide and nitrosation of diaminonaphthalene were exclusively observed with NO/N2O3. Additional comparison of ONOO- and AS chemistry demonstrated that ONOO- was a far more potent one-electron oxidant and nitrating agent of hydroxyphenylacetic acid than was AS. However, AS was more effective at hydroxylating benzoic acid than was ONOO-. Taken together, these data indicate that neither NO/N2O3 nor ONOO- is an intermediate of AS decomposition. Evaluation of the stoichiometry of AS decomposition and O-2 consumption revealed a 1:1 molar ratio. Indeed, oxidation of DHR mediated by AS proved to be oxygen dependent. Analysis of the end products of AS decomposition demonstrated formation of NO2- and NO3- in approximately stoichiometric ratios. Several mechanisms are proposed for O-2 adduct formation followed by decomposition to NO3- or by oxidation of an HN2O3- molecule to form NO2-. Given that the cytotoxicity of AS is far greater than that of either NO/N2O3 or NO + O-2(-) this study provides important new insights into the implications of the potential endogenous formation of NO- under inflammatory conditions in vivo. C1 NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Mol Pharmacol, Los Angeles, CA 90269 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. RP Miranda, KM (reprint author), NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bldg 10,Rm B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009; Feelisch, Martin/C-3042-2008; Yamada, Ken-ichi/E-6318-2012 OI Feelisch, Martin/0000-0003-2320-1158; NR 43 TC 101 Z9 103 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 1720 EP 1727 DI 10.1074/jbc.M006174200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000011 PM 11042174 ER PT J AU Yan, B Heus, J Lu, N Nichols, RC Raben, N Plotz, PH AF Yan, B Heus, J Lu, N Nichols, RC Raben, N Plotz, PH TI Transcriptional regulation of the human acid alpha-glucosidase gene - Identification of a repressor element and its transcription factors Hes-1 and YY1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOOP-HELIX FACTORS; ACHAETE-SCUTE HOMOLOG-1; CELL FATE; MAMMALIAN HAIRY; NERVOUS-SYSTEM; DROSOPHILA; ENHANCER; SPLIT; DIFFERENTIATION; NOTCH AB Acid alpha -glucosidase, the product of a housekeeping gene, is a lysosomal enzyme that degrades glycogen. A deficiency of this enzyme is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenesis type II. We have previously demonstrated that the human acid alpha -glucosidase gene expression is regulated by a silencer within intron 1, which is located in the 5'-untranslated region. In this study, we have used deletion analysis, electrophoretic mobility shift assay, and footprint analysis to further localize the silencer to a 25-base pair element, The repressive effect on the TK promoter was about 50% in both orientations in expression plasmid, and two transcriptional factors were identified with antibodies binding specifically to the element. Mutagenesis and functional analyses of the element demonstrated that the mammalian homologue 1 of Drosophila hairy and Enhancer of split (Hes-l) binding to an E box (CACGCG) and global transcription factor-YY1 binding to its core site function as a transcriptional repressor, Furthermore, the overexpression of Hes-l significantly enhanced the repressive effect of the silencer element. The data should be helpful in understanding the expression and regulation of the human acid alpha -glucosidase gene as well as other lysosomal enzyme genes. C1 NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Pharming Technol BV, NL-2333 CA Leiden, Netherlands. Dartmouth Med Sch, Lebanon, NH 03756 USA. RP Plotz, PH (reprint author), NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NR 33 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 1789 EP 1793 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000020 PM 11038350 ER PT J AU Phylip, LH Lees, WE Brownsey, BG Bur, D Dunn, BM Winther, JR Gustchina, A Li, M Copeland, T Wlodawer, A Kay, J AF Phylip, LH Lees, WE Brownsey, BG Bur, D Dunn, BM Winther, JR Gustchina, A Li, M Copeland, T Wlodawer, A Kay, J TI The potency and specificity of the interaction between the IA(3) inhibitor and its target aspartic proteinase from Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CATHEPSIN-D; SUBSTRATE-SPECIFICITY; CRYSTAL-STRUCTURES; PORCINE PEPSIN; YEAST; PURIFICATION; RESOLUTION; EXPRESSION; CLONING; ENZYME AB The yeast IA, polypeptide consists of only 68 residues, and the free inhibitor has little intrinsic secondary structure. IA, showed subnanomolar potency toward its target, proteinase A from Saccharomyces cerevisiae, and did not inhibit any of a large number of aspartic proteinases with similar sequences/structures from a wide variety of other species. Systematic truncation and mutagenesis of the IA, polypeptide revealed that the inhibitory activity is located in the N-terminal half of the sequence. Crystal structures of different forms of Lc, complexed with proteinase A showed that residues in the N-terminal half of the IA, sequence became ordered and formed an almost perfect cr-helix in the active site of the enzyme. This potent, specific interaction was directed primarily by hydrophobic interactions made by three key features in the inhibitory sequence. Whereas IA,was cut as a substrate by the nontarget aspartic proteinases, it mas not cleaved by proteinase A. The random coil IA, polypeptide escapes cleavage by being stabilized in a helical conformation upon interaction with the active site of proteinase A. This results, paradoxically, in potent selective inhibition of the target enzyme. C1 Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales. Univ Wales, Coll Med, Dept Med, Cardiff CF14 4XN, S Glam, Wales. Hoffmann La Roche Ag, CH-4070 Basel, Switzerland. Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. Carlsberg Lab, Dept Yeast Genet, DK-2500 Copenhagen Valby, Denmark. NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Program Core, DBS, Frederick, MD 21702 USA. RP Kay, J (reprint author), Cardiff Univ, Sch Biosci, POB 911, Cardiff CF10 3US, S Glam, Wales. RI Winther, Jakob/K-4451-2014 OI Winther, Jakob/0000-0001-6995-9154 NR 27 TC 29 Z9 29 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 2023 EP 2030 DI 10.1074/jbc.M008520200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000052 PM 11042188 ER PT J AU Mehrani, T Wu, KC Morasso, MI Bryan, JT Marekov, LN Parry, DAD Steinert, PM AF Mehrani, T Wu, KC Morasso, MI Bryan, JT Marekov, LN Parry, DAD Steinert, PM TI Residues in the 1A rod domain segment and the linker L2 are required for stabilizing the A(11) molecular alignment mode in keratin intermediate filaments SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COILED-COIL; CROSS-LINKING; II KERATINS; EXPRESSION; DISEASE; HETERODIMER; MECHANISM; DISTINCT; PROTEINS; INVITRO AB Both analyses of x-ray diffraction patterns of well oriented specimens of trichocyte keratin intermediate filaments (IF) and in vitro cross-linking experiments on several types of IF have documented that there are three modes of alignment of pairs of antiparallel molecules in all IF: A(11), A(22), and A(12), based on which parts of the major rod domain segments are overlapped. Here we have examined which residues may be important for stabilizing the A(11) mode. Using the K5/R14 system, we have made point mutations of charged residues along the chains and examined the propensities of equimolar mixtures of wild type and mutant chains to reassemble using as criteria: the formation (or not) of IF in vitro or in vivo; and stabilities of one- and two-molecule assemblies. We identified that the conserved residue Arg(10) of the 1A rod domain, and the conserved residues Glu(4) and Glu(6) of the linker L2, were essential for stability. Additionally, conserved residues Lys(31) of 1A and Asp(1) of 2A and non-conserved residues Asp/Asn(9) of 1A, Asp/Asn(3) of 2A, and Asp(7) of L2 are important for stability. Notably, these groups of residues lie close to each other when two antiparallel molecules are aligned in the A(11) mode, and are located toward the ends of the overlap region. Although other sets of residues might theoretically also contribute, we conclude that these residues in particular engage in favorable intermolecular ionic and/or H-bonding interactions and thereby may play a role in stabilizing the A(11) mode of alignment in keratin IF. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Massey Univ, Inst Fundamental Sci, Palmerston North, New Zealand. RP Steinert, PM (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 6,Rm 425, Bethesda, MD 20892 USA. NR 23 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 2088 EP 2097 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000061 PM 11022041 ER PT J AU Chang, WT Kang, JJ Lee, KY Wei, K Anderson, E Gotmare, S Ross, JA Rosen, GD AF Chang, WT Kang, JJ Lee, KY Wei, K Anderson, E Gotmare, S Ross, JA Rosen, GD TI Triptolide and chemotherapy cooperate in tumor cell apoptosis - A role for the p53 pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MULTISITE PHOSPHORYLATION; TRIPTERYGIUM-WILFORDII; THYMIDYLATE SYNTHASE; DNA-DAMAGE; IN-VIVO; EXPRESSION; PROTEIN; ACTIVATION; REPRESSION; RADIATION AB Triptolide (PG490), a diterpene triepoxide, is a potent immunosuppressive agent extracted from the Chinese herb Tripterygium wilfordii. We have previously shown that triptolide blocks NF-kappaB activation and sensitizes tumor necrosis factor (TNF-alpha)-resistant tumor cell lines to TNF-alpha -induced apoptosis. We show here that triptolide enhances chemotherapy-induced apoptosis. In triptolide-treated cells, the expression of p53 increased but the transcriptional function of p53 was inhibited, and we observed a down-regulation of p21(waf1/cip1), a p53-responsive gene. The increase in levels of the p53 protein was mediated by enhanced translation of the p53 protein. Additionally, triptolide induced accumulation of cells in S phase and blocked doxorubicin-mediated accumulation of cells in G(2)/M and doxorubicin-mediated induction of p21. Our data suggest that triptolide, by blocking p21-mediated growth arrest, enhances apoptosis in tumor cells. C1 Stanford Univ, Med Ctr, Div Pulm & Crit Care Med, Stanford, CA 94305 USA. NIH, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Dankook Univ Hosp, Dept Internal Med, Div Pulmonol, Cheonan 330180, Chungnam, South Korea. RP Rosen, GD (reprint author), Stanford Univ, Med Ctr, Div Pulm & Crit Care Med, 300 Pasteur Dr, Stanford, CA 94305 USA. NR 27 TC 124 Z9 147 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 2221 EP 2227 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000076 PM 11053449 ER PT J AU Shou, M Dai, R Cui, D Korzekwa, KR Baillie, TA Rushmore, TH AF Shou, M Dai, R Cui, D Korzekwa, KR Baillie, TA Rushmore, TH TI A kinetic model for the metabolic interaction of two substrates at the active site of cytochrome P450 3A4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-LIVER-MICROSOMES; ALPHA-NAPHTHOFLAVONE; ACTIVATION; OXIDATION; LOSARTAN; PHARMACOKINETICS; HYDROXYLATION; INHIBITION; PHARMACODYNAMICS; COOPERATIVITY AB In many cases, CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrates that coexist at the active site. In the present study, we observed that alpha -naphthoflavone (alpha -NF) exhibited a differential effect on CYP3A4 mediated product formation as shown by an increase and decrease, respectively, of the carboxylic acid (P-2) and omega -3-hydroxylated (P-1) metabolites of losartan, while losartan was found to be an inhibitor of the formation of the 5,6-epoxide of alpha -NF. Thus, to address this problem, a kinetic model was developed on the assumption that CYP3A4 can accommodate two distinct and independent binding domains for the substrates within the active site, and the resulting velocity equations were employed to predict the kinetic parameters for all possible enzyme-substrate species. Our results indicate that the predicted values had a good fit with the experimental observations. Therefore, the kinetic constants can be used to adequately describe the nature of the metabolic interaction between the two substrate. Applications of the model provide some new insights into the mechanism of drug-drug interactions at the level of CYP3A4. C1 Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Camitro Corp, Menlo Park, CA 94025 USA. RP Shou, M (reprint author), Merck Res Labs, Dept Drug Metab, WP75A-203, W Point, PA 19486 USA. NR 49 TC 100 Z9 102 U1 2 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2001 VL 276 IS 3 BP 2256 EP 2262 DI 10.1074/jbc.M008799200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 394MN UT WOS:000166528000081 PM 11054425 ER PT J AU Ishima, R Louis, JM Torchia, DA AF Ishima, R Louis, JM Torchia, DA TI Characterization of two hydrophobic methyl clusters in HIV-1 protease by NMR spin relaxation in solution SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE retroviral protease; internal motion; protein; conformational change ID MAGNETIC-RESONANCE RELAXATION; DRUG-RESISTANT MUTANTS; MODEL-FREE APPROACH; ROTATIONAL DIFFUSION; C-13 RELAXATION; MOLECULAR-BASIS; INHIBITORS; PROTEINS; MACROMOLECULES; FLEXIBILITY AB Nearly 50 % of the amino acid residues of HIV-1 protease contain methyl side-chains, most of which appear to be organized into two clusters: the inner cluster that nearly surrounds the active site and the outer cluster that contains the hydrophobic core which stabilizes the inhibitor-free protease structure. NMR relaxation experiments sensitive to motions of methyl groups on the sub-nanosecond and the milli-microsecond timescales revealed flexible methyl groups in residues that link the two clusters, the methyl groups of L10, L23, V75, and L76. We hypothesize that flexibility at the junctions of these clusters allows the protease to minimize conformational changes upon drug-binding. The two-methyl cluster motif appears to be a common structural feature among retroviral proteases and may play a similar role throughout this family of enzymes. (C) 2001 Academic Press. C1 Natl Inst Dent & Craniofacial REs, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Craniofacial REs, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NR 37 TC 42 Z9 44 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2001 VL 305 IS 3 BP 515 EP 521 DI 10.1006/jmbi.2000.4321 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 416BW UT WOS:000167760800013 PM 11152609 ER PT J AU Tzeng, SF Cheng, H Lee, YS Wu, JP Hoffer, BJ Kuo, JS AF Tzeng, SF Cheng, H Lee, YS Wu, JP Hoffer, BJ Kuo, JS TI Expression of neural cell adhesion molecule in spinal cords following a complete transection SO LIFE SCIENCES LA English DT Article DE neural cellular adhesion molecule (NCAM); glia; spinal cord injury; neuronal regeneration ID ADULT PARAPLEGIC RATS; MOUSE SCIATIC-NERVE; N-CAM; RECOGNITION MOLECULES; NCAM; L1; SCHIZOPHRENIA; HIPPOCAMPUS; REGENERATION; ZEBRAFISH AB Neural cell adhesion molecule (NCAM) regulates tissue organization during development and in the adult. NCAM upregulation occurs after an injury to brains and sciatic nerves. However, little is known about NCAM expression after spinal cord injury (SCI). By using a complete spinal cord transection with a 5 mm tissue removal, an increase in the NCAM level is detected in spinal cord stumps proximal and distal to the transection site at 1 d and 3 d post injury, while its expression at 8 d is declined to a lower level than that observed in sham-operated spinal cords. The strong NCAM expression is present in motor neurons at 3 d post transection whereas the intensive NCAM immunostaining is localized in dorsal sensory and corticospinal fiber tracts at 8 d following injury. Collectively, NCAM level is elevated and strongly expressed in dorsal fiber tracts after SCI, implying that the endogenous process for spinal cord regeneration may take place after SCI. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Taichung Vet Gen Hosp, Dept Res & Educ, Taichung 40705, Taiwan. Vet Gen Hosp, Inst Neurol, Neural Regenerat Lab, Taipei, Taiwan. NIDA, NIH, Baltimore, MD 21224 USA. RP Tzeng, SF (reprint author), Taichung Vet Gen Hosp, Dept Res & Educ, 160 Sec,3 Taichung Kang Rd, Taichung 40705, Taiwan. NR 31 TC 17 Z9 17 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JAN 19 PY 2001 VL 68 IS 9 BP 1005 EP 1012 DI 10.1016/S0024-3205(00)01003-1 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 394RG UT WOS:000166536600005 PM 11212863 ER PT J AU Bell, AC West, AG Felsenfeld, G AF Bell, AC West, AG Felsenfeld, G TI Gene regulation - Insulators and boundaries: Versatile regulatory elements in the eukaryotic genome SO SCIENCE LA English DT Review ID CHROMATIN DOMAIN BOUNDARY; ENHANCER BLOCKING ACTIVITY; BETA-GLOBIN LOCUS; BITHORAX COMPLEX; DNA METHYLATION; DROSOPHILA; PROTEIN; EXPRESSION; REGION; POLYCOMB AB Insulators mark the boundaries of chromatin domains by limiting the range of action of enhancers and silencers. Although the properties of insulators have been well studied, their role in vivo has Largely been a subject of speculation. Recent results make it possible to ascribe specific and essential functions to the insulators of Drosophila, yeast, and vertebrates. In some cases, insulator activity can Se modulated by nearby regulatory elements, bound cofactors, or covalent modification of the DNA. Not simply passive barriers, insulators are active participants in eukaryotic gene regulation. C1 NIDDKD, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 52 TC 278 Z9 286 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 19 PY 2001 VL 291 IS 5503 BP 447 EP 450 DI 10.1126/science.291.5503.447 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393UF UT WOS:000166487500030 PM 11228144 ER PT J AU Pham, P Bertram, JG O'Donnell, M Woodgate, R Goodman, MF AF Pham, P Bertram, JG O'Donnell, M Woodgate, R Goodman, MF TI A model for SOS-lesion-targeted mutations in Escherichia coli SO NATURE LA English DT Article ID DNA-POLYMERASE-III; MUTAGENESIS; REPAIR; RECA; PROTEINS; COMPLEX; DAMAGE; CLAMP AB The UmuD'C-2 protein complex (Escherichia coli pol V)(1-3) is a low-fidelity DNA polymerase (pol) that copies damaged DNA in the presence of RecA, single-stranded-DNA binding protein (SSB) and the beta,gamma -processivity complex of E. coli pol III (ref. 4). Here we propose a model to explain SOS-lesion-targeted mutagenesis, assigning specific biochemical functions for each protein during translesion synthesis. (SOS lesion-targeted mutagenesis occurs when pol V is induced as part of the SOS response to DNA damage and incorrectly incorporates nucleotides opposite template lesions.) Pol V plus SSB catalyses RecA filament disassembly in the 3' to 5' direction on the template, ahead of the polymerase, in a reaction that does not involve ATP hydrolysis. Concurrent ATP-hydrolysis-driven filament disassembly in the 5' to 3' direction results in a bidirectional stripping of RecA from the template strand. The bidirectional collapse of the RecA filament restricts DNA synthesis by pol V to template sites that are proximal to the lesion, thereby minimizing the occurrence of untargeted mutations at undamaged template sites. C1 Univ So Calif, Dept Biol Sci & Chem, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. Rockefeller Univ, New York, NY 10021 USA. Howard Hughes Med Inst, New York, NY 10021 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci & Chem, Hedco Mol Biol Labs, Univ Pk, Los Angeles, CA 90089 USA. NR 19 TC 94 Z9 94 U1 0 U2 6 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 18 PY 2001 VL 409 IS 6818 BP 366 EP 370 DI 10.1038/35053116 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 392VY UT WOS:000166434300053 PM 11201748 ER PT J AU Blagosklonny, MV AF Blagosklonny, MV TI Do VHL and HIF-1 mirror p53 and Mdm-2? Degradation-transactivation loops of oncoproteins and tumor suppressors SO ONCOGENE LA English DT Review DE p53; VHL; HIF-1 alpha; mdm-2; beta-catenin ID INDUCIBLE FACTOR 1-ALPHA; DNA-DAMAGE; PROTEIN; HYPOXIA; GENE; TRANSCRIPTION; STABILIZATION; ACTIVATION; STABILITY; PROMOTES AB Recently it has been shown that the VHL tumor suppressor targets the hypoxia-inducible transcription factor (HIF-1) for ubiquitin-dependent degradation by the proteasome, Past mysteries of the p53 tumor suppressor help to solve the present puzzles of the VHL tumor suppressor. Thus, Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome, but, in addition, the p53 transcription factor induces Mdm-2, thus, establishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF-1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and accumulation transcriptionally active HIF-1 and p53, More detailed analysis depicts the VHL/HIF-1 pair as the p53/mdm-2 pair that is turned upside down, suggesting that VHL may be a HIF-1-inducible gene of the feedback loop. The extended model proposes that an oncoprotein and a tumor suppressor due to transactivation coupled with feedback protein degradation might form functional pairs (Rb/E7, E2F/Rb, E2F/Mdm-2, catenin/APC, p27, cyclin D1, Rb/gankyrin), thus, predicting missing links. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NR 37 TC 27 Z9 30 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 18 PY 2001 VL 20 IS 3 BP 395 EP 398 DI 10.1038/sj.onc.1204055 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 392KV UT WOS:000166411000014 PM 11313969 ER PT J AU Lee, SH Shin, MS Kim, HS Lee, HK Park, WS Kim, SY Lee, JH Han, SY Park, JY Oh, RR Kang, CS Kim, KM Jang, JJ Nam, SW Lee, JY Yoo, NJ AF Lee, SH Shin, MS Kim, HS Lee, HK Park, WS Kim, SY Lee, JH Han, SY Park, JY Oh, RR Kang, CS Kim, KM Jang, JJ Nam, SW Lee, JY Yoo, NJ TI Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma SO ONCOGENE LA English DT Article DE mutation; TRAIL-receptor 1; TRAIL-receptor 2; non-Hodgkin's lymphoma ID FAS APO-1/CD95 GENE; CYTOTOXIC LIGAND TRAIL; INDUCED APOPTOSIS; MELANOMA-CELLS; LUNG-CANCER; DEATH; CARCINOMAS; REGIONS; DOMAIN; DNA AB Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-RI and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL), Because TRAIL/TRAIL, receptor system plays an important role in lymphocyte homeostasis, we hypothesized that the mutations of TRAIL-RI and TRAIL-R2 may be involved in the development of NHL and that such mutations may be responsible for the allelic losses of 8p21-22 in NHL, In this study, we analysed the entire coding region of TRAIL-R2 gene and the death domain region of TRAIL-RI gene for the detection of the somatic mutations in a series of 117 human NHLs using polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis. Overall, eight tumors (6.8%) were found to have two TRAIL-RI gene mutations or six TRAIL-R2 gene mutations. Interestingly, of the eight mutations, six missense mutations (two TRAIL-RI and four TRAIL-R2) were detected in the death domains and one nonsense mutation of TRAIL-R2 was detected just before the death domain. Our data suggest that somatic mutations of TRAIL-RI and TRAIL-R2 genes may play a role in the pathogenesis of some NHLs and that TRAIL-R2 and TRAIL-R2 genes might be the relevant genes to the frequent loss of chromosome 8p21-22 in human NHL. C1 Catholic Univ Korea, Coll Med, Dept Pathol, Socho Gu, Seoul 137701, South Korea. Catholic Univ Korea, Coll Med, Dept Clin Pathol, Seoul 137701, South Korea. Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Canc Res Ctr, Seoul 110799, South Korea. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Yoo, NJ (reprint author), Catholic Univ Korea, Coll Med, Dept Pathol, Socho Gu, 505 Banpo Dong, Seoul 137701, South Korea. RI Jang, JaJune/F-6647-2011; Seoul National University, Pathology/B-6702-2012 NR 37 TC 104 Z9 107 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 18 PY 2001 VL 20 IS 3 BP 399 EP 403 DI 10.1038/sj.onc.1204103 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 392KV UT WOS:000166411000015 PM 11313970 ER PT J AU Wendler, D Dickert, N AF Wendler, D Dickert, N TI The consent process for cadaveric organ procurement - How does it work? How can it be improved? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DONORS; DONATION; ISSUES; CARDS AB Context Understanding the consent process that organ procurement organizations (OPOs) use is crucial to improving the process and thereby reducing the number of individuals who die each year for want of an organ transplant. However, no data exist on OPOs' current consent practices. Objective To assess whose wishes OPOs follow when procuring solid organs from deceased individuals and whether advance directives and computerized registries might improve the consent process for solid organ procurement. Design, Setting, and Participants Telephone survey conducted from June to August 1999 of all 61 active OPOs, Main Outcome Measures Responses to the 49-question survey addressing consent practices in specific scenarios of deceased and next of kin wishes. Results Widespread divergence exists in OPOs' consent practices for cadaveric solid organ procurement. Regarding overall consent practices, 19 (31%) OPOs reported that they follow the deceased's wishes, 19 (31%) follow the next of kin's wishes, 13 (21%) procure organs if neither party objects, 8 (13%) procure organs if either party consents or neither objects, and 2 (3%) do not follow any of these 4 overall practices. These differences appear to be traceable to implicit ethical disagreements about whose wishes should be followed. A total of 29 (48%) OPOs reported having an official policy to address whether they follow the family's or deceased's wishes. Regarding factors that influence OPOs' choice of consent practice, 29 (48%) respondents ranked impact on the deceased's family as the most important factor, 13 (21%) ranked state law as most important, and 7 (11%) ranked the priority of the deceased's wishes as most important. Durable power of attorney appeared to have substantial weight in OPOs' decisions; for example, in the scenario in which the deceased supported organ donation and the next of kin opposed it, 34 (56%) OPOs reported they were likely to procure organs based on the consent of the holder of the deceased's durable power of attorney, whereas only 7 (11%) reported they were likely to procure organs based on a document of gift (a living will, donor card, or driver's license). Conclusions Expanding the legal scope of living wills to cover individuals' organ donation preferences would likely have little impact on procurement rates. In contrast, expanding the legal scope of durable powers of attorney for health care may have a significant impact. A national discussion should take place addressing the underlying ethical issues that appear to account for much of the divergence among OPOs' consent practices for cadaveric solid organ procurement. C1 NIH, Ctr Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Ctr Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 13 TC 55 Z9 57 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 17 PY 2001 VL 285 IS 3 BP 329 EP 333 DI 10.1001/jama.285.3.329 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 390XD UT WOS:000166324300025 PM 11176844 ER PT J AU Fisher, B Dignam, J Tan-Chiu, E Anderson, S Fisher, ER Wittliff, JL Wolmark, N AF Fisher, B Dignam, J Tan-Chiu, E Anderson, S Fisher, ER Wittliff, JL Wolmark, N TI Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TERM FOLLOW-UP; COMPARING TOTAL MASTECTOMY; RECEPTOR-POSITIVE TUMORS; STAGE-I T1N0M0; CANCER PATIENTS; SEQUENTIAL METHOTREXATE; ADJUVANT CHEMOTHERAPY; NATURAL-HISTORY; CARCINOMA; SURVIVAL AB Background: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Methods: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy, Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy, End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of .05 or less; all statistical tests were two-sided. Results: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06), Survival was similar in both groups (93% and 91%; P = .65), The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen), Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01), Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types. Conclusions: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes. C1 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Louisville, Hormone Receptor Lab, Louisville, KY 40292 USA. RP Fisher, B (reprint author), 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, Suite 602, Pittsburgh, PA 15212 USA. OI Anderson, Stewart/0000-0001-8948-0650 FU NCI NIH HHS [U10CA12027, U10CA37377, U10CA69651] NR 42 TC 93 Z9 95 U1 0 U2 4 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2001 VL 93 IS 2 BP 112 EP 120 DI 10.1093/jnci/93.2.112 PG 9 WC Oncology SC Oncology GA 391NM UT WOS:000166362100010 PM 11208880 ER PT J AU Olsen, JH Hahnemann, JM Borresen-Dale, AL Brondum-Nielsen, K Hammarstrom, L Kleinerman, R Kaatriainen, H Lonnqvist, T Sankila, R Seersholm, N Tretli, S Yuen, J Boice, JD Tucker, M AF Olsen, JH Hahnemann, JM Borresen-Dale, AL Brondum-Nielsen, K Hammarstrom, L Kleinerman, R Kaatriainen, H Lonnqvist, T Sankila, R Seersholm, N Tretli, S Yuen, J Boice, JD Tucker, M TI Cancer in patients with ataxia-telangiectasia and in their relatives in the Nordic countries SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BREAST-CANCER; MALIGNANT NEOPLASMS; NO EVIDENCE; ATM GENE; FAMILIES; HETEROZYGOTES; MUTATION; RISK AB Background: Epidemiologic studies of the families of patients with ataxia-telangiectasia (A-T), a recessive genetic neurologic disorder caused by mutation of the ATM gene, suggest that heterozygous carriers of an ATM mutation are at increased risk of cancer. A population-based study of cancer incidence in A-T families with unbiased selection and tracing of relatives would confirm this hypothesis. Methods: We conducted a study in the Nordic countries of 1218 blood relatives of 56 A-T patients from 50 families. The relatives were identified from population registries, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. All statistical tests were two-sided. Results: Among the 56 patients with A-T, we observed six cases of cancer (four leukemias and two non-Hodgkin's lymphomas) compared with 0.16 expected, yielding a standardized incidence ratio (SIR) of 37 (95% confidence interval [CI] = 13 to 80). Among the 1218 relatives, 150 cancers were recorded, with 126 expected (SIR = 1.19; 95% CI = 1.01 to 1.40), Invasive breast cancer occurred in 21 female relatives of A-T patients (SIR = 1.54; 95% CI = 0.95 to 2.36), including five of the 50 mothers tall of whom are obligate ATM mutation carriers) (SIR = 7.1; 95% CI = 2.3 to 17), Relatives who were less likely to be carriers of a mutant ATM allele had no increase or only a modest, statistically nonsignificant increase in the risk of breast cancer. There was no evidence of increased risk for cancer at any other site. Conclusions: We confirmed the previously recognized high risk of lymphoma and leukemia in A-T patients. Our data are also consistent with an increased risk of breast cancer among blood relatives of A-T patients. The epidemiologic findings suggest, however, that, even if ATM mutations are responsible for some breast cancer cases, ATM is a relatively weak genetic risk factor for the disease. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. John F Kennedy Inst, DK-2600 Glostrup, Denmark. Norwegian Radium Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. Huddinge Hosp, Karolinska Inst, Div Clin Immunol, S-14186 Huddinge, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Family Federat Finland, Dept Med Genet, Helsinki, Finland. Univ Helsinki, Hosp Children & Adolescents, Unit Child Neurol, FIN-00014 Helsinki, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Inst Epidemiol Canc Res, Canc Registry Norway, Oslo, Norway. Swedish Univ Agr Sci, Uppsala, Sweden. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Int Epidemiol Inst, Rockville, MD USA. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen, Denmark. RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 FU NCI NIH HHS [N01CP61038, N01CP91046] NR 33 TC 130 Z9 136 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2001 VL 93 IS 2 BP 121 EP 127 DI 10.1093/jnci/93.2.121 PG 7 WC Oncology SC Oncology GA 391NM UT WOS:000166362100011 PM 11208881 ER PT J AU Vahteristo, P Syrjakoski, K Eerola, H Kainu, T Holli, K Blomqvist, C Kallioniemi, OP Nevanlinna, H AF Vahteristo, P Syrjakoski, K Eerola, H Kainu, T Holli, K Blomqvist, C Kallioniemi, OP Nevanlinna, H TI Re: Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00029 Helsinki, Finland. Tampere Univ, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Oncol, Tampere, Finland. Univ Helsinki, Cent Hosp, Dept Oncol, FIN-00029 Helsinki, Finland. Univ Uppsala Hosp, Dept Oncol, S-75185 Uppsala, Sweden. Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD USA. RP Nevanlinna, H (reprint author), Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, POB 140,Haartmaninkatu 2, FIN-00029 Helsinki, Finland. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 7 TC 0 Z9 0 U1 1 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2001 VL 93 IS 2 BP 153 EP 154 DI 10.1093/jnci/93.2.153 PG 2 WC Oncology SC Oncology GA 391NM UT WOS:000166362100020 ER PT J AU Wacholder, S Rothman, N Caporaso, N AF Wacholder, S Rothman, N Caporaso, N TI Re: Population stratification in epidemiologic studies of common genetic variants and cancer: Quantification of bias - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wacholder, S (reprint author), NIH, EPS 8046,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 3 TC 4 Z9 4 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2001 VL 93 IS 2 BP 157 EP 158 DI 10.1093/jnci/93.2.157 PG 2 WC Oncology SC Oncology GA 391NM UT WOS:000166362100023 ER PT J AU Harris, DR Gonin, R Alter, HJ Wright, EC Buskell, ZJ Hollinger, FB Seeff, LB AF Harris, DR Gonin, R Alter, HJ Wright, EC Buskell, ZJ Hollinger, FB Seeff, LB CA Natl Heart Lung Blood Inst Study G TI The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID C VIRUS-INFECTION; LIVER-DISEASE; PROGRESSION; PREVALENCE; DONORS; RISK AB Background: Although concomitant alcoholism is widely believed to enhance liver disease progression in persons with hepatitis C virus (HCV) infection, this relationship has not been well quantified. Objective: To quantify the relationship of transfusion-associated HCV infection and history of heavy alcohol abuse to development of cirrhosis. Design: Retrospective cohort study. Setting: river clinics in university and government hospitals. Patients: Extended follow-up of 1030 patients in prospective investigations of transfusion-associated viral hepatitis conducted in the United States between 1968 and 1980. Measurements: Development of cirrhosis and history of heavy alcohol abuse were determined from review of interviews with patients or their proxies, medical records, death certificates, and autopsy and biopsy reports. Logistic regression was used to estimate the risk for cirrhosis associated with transfusion-associated HCV infection and history of heavy alcohol abuse. Results: The absolute risk for cirrhosis was 17% among patients with transfusion-associated HCV; 3.2% among patients with transfusion-associated non-A, non-B, non-C hepatitis; and 2.8% among controls. Patients with transfusion-associated HCV were more likely than controls to develop cirrhosis (odds ratio, 7.8 [95% CI, 4.0 to 15.1]). A history of heavy alcohol abuse was associated with a fourfold increased risk for cirrhosis. Hepatitis C virus infection plus a history of heavy alcohol abuse led to a substantial increase in risk for cirrhosis (odds ratio, 31.1 [CI, 11.4 to 84.5]) compared with controls without such a history. Conclusions: Heavy alcohol abuse greatly exacerbates the risk for cirrhosis among patients with HCV infection. This finding emphasizes the need to counsel such patients about their drinking habits. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. New England Res Inst, Watertown, MA 02172 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Washington, DC USA. Baylor Coll Med, Houston, TX 77030 USA. RP Seeff, LB (reprint author), NIDDKD, NIH, 31 Ctr Dr,Room 9A18,Mail Drop MSC2560, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HB-37093, N01-HB-87047] NR 19 TC 114 Z9 122 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 16 PY 2001 VL 134 IS 2 BP 120 EP 124 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 391KW UT WOS:000166356000005 PM 11177315 ER PT J AU Hawk, ET Viner, JL AF Hawk, ET Viner, JL TI Chemoprevention in ulcerative colitis: Narrowing the gap between clinical practice and research SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PRIMARY SCLEROSING CHOLANGITIS; FOLIC-ACID SUPPLEMENTATION; COLORECTAL-CANCER; URSODEOXYCHOLIC-ACID; RISK; DYSPLASIA; THERAPY C1 NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, EPN, Bethesda, MD 20892 USA. RP Hawk, ET (reprint author), NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, EPN, Suite 201,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 17 TC 10 Z9 10 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 16 PY 2001 VL 134 IS 2 BP 158 EP 160 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 391KW UT WOS:000166356000010 PM 11177320 ER PT J AU Berlett, BS Levine, RL Chock, PB Chevion, M Stadtman, ER AF Berlett, BS Levine, RL Chock, PB Chevion, M Stadtman, ER TI Antioxidant activity of Ferrozine-iron-amino acid complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYDROGEN-PEROXIDE; OXIDATION; REAGENT; DISMUTATION AB Amino acid-fe(II)-chelator complexes exhibit strong antioxidant activity. Taking advantage of the unique spectral characteristics of the complexes formed when Ferrozine (Fz) is used as the chelator, we now show that the primary blue complex (epsilon (max) at 632 nm) decomposes by two independent pathways: (i) a nonoxidative pathway involving dissociation of the amino add component and formation of a purple complex (epsilon (max) at 562 nm) and (ii) an oxidative pathway leading to Fe(lll) and colorless products. Quantitative conversion of the blue to purple complex yields an isosbestic point (i.p.) at 601 nm, whereas no i.p. is formed during quantitative oxidation of the blue complex. However, under some experimental conditions, decomposition of the blue product occurs by both pathways, leading to occurrence of a clean i.p. at wavelengths varying from 601 to 574 nm. Results of simulation experiments, confirmed by direct analysis, demonstrate that shifts in the i.p. reflect differences in the fractions of blue compound that decompose by the oxidative and nonoxidative pathways. Indeed, the fraction of blue that is converted to the purple complex is readily deduced from the wavelength of the i.p. These results suggest that identification of a physiological chelator that can replace Ferrozine in amino acid-iron complexes might have important physiological and pharmacological applications. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 222, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 9 TC 19 Z9 20 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2001 VL 98 IS 2 BP 451 EP 456 DI 10.1073/pnas.021552298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393TG UT WOS:000166485300019 PM 11149957 ER PT J AU Hayashi, T Su, TP AF Hayashi, T Su, TP TI Regulating ankyrin dynamics: Roles of sigma-1 receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; INTERNAL CA2+ RELEASE; METHYL-D-ASPARTATE; INOSITOL TRISPHOSPHATE; CARDIAC MYOCYTES; IMMUNE-SYSTEMS; BINDING-SITES; IP3 RECEPTOR; RAT-BRAIN; LIGANDS AB Ankyrin is a cytoskeletal adaptor protein that controls important cellular functions, including Ca2+ efflux at inositol 1,4,5-trisphosphate receptors (IP3R) on the endoplasmic reticulum, The present study found that sigma-1 receptors (Sig-1R), unique endoplasmic reticulum proteins that bind certain steroids, neuroleptics. and psychotropic drugs, form a trimeric complex with ankyrin B and IP2R type 3 (IP3R-3) in NG-108 cells. The trimeric complex could be coimmunoprecipitated by antibodies against any of the three proteins. Sig-1R agonists such as pregnenolone sulfate and cocaine caused the dissociation of an ankyrin B isoform (ANK 220) from IP3R-3, This effect caused by Sig-1R agonists was blocked by a Sig-1R antagonist. The degree of dissociation of ANK 220 from IP3R-3 caused by Sig-1R ligands correlates excellently with the ligands' efficacies in potentiating the bradykinin-induced increase in cytosolic free Ca2+ concentration. Immunocytohistochemistry showed that Sig-1R, ankyrin B, and IP3R-3 are colocalized in NG-108 cells in perinuclear areas and in regions of cell-to-cell communication. These results suggest that Sig-1R and associated ligands may play important roles in cells by controlling the function of cytoskeletal proteins and that the Sig-1R/ANK220/IP3R-3 complex regulating Ca2+ signaling may represent a site of action for neurosteroids and cocaine. C1 NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov RI Hayashi, Teruo/A-9690-2008 NR 43 TC 201 Z9 209 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2001 VL 98 IS 2 BP 491 EP 496 DI 10.1073/pnas.021413698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393TG UT WOS:000166485300026 PM 11149946 ER PT J AU Princiotta, MF Schubert, U Chen, WS Bennink, JR Myung, J Crews, CM Yewdell, JW AF Princiotta, MF Schubert, U Chen, WS Bennink, JR Myung, J Crews, CM Yewdell, JW TI Cells adapted to the proteasome inhibitor 4-hydroxy5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone require enzymatically active proteasomes for continued survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CLASS-I MOLECULES; ANTIGEN PRESENTATION; BETA-SUBUNITS; PEPTIDES; DEGRADATION; LACTACYSTIN; PROTEOLYSIS; GENERATION; MECHANISM; PROTEINS AB The proteasome is the primary protease used by cells for degrading proteins and generating peptide ligands for class I molecules of the major histocompatibility complex, Based on the properties of cells adapted to grow in the presence of the proteasome inhibitor 4-hydroxy-5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone (NLVS), it was proposed that proteasomes can be replaced by alternative proteolytic systems, particularly a large proteolytic complex with a tripeptidyl peptidase II activity. Here we show that NLVS-adapted cells retain sensitivity to a number of highly specific proteasome inhibitors with regard to antigenic peptide generation, accumulation of polyubiquitinated proteins, degradation of p53, and cell viability. In addition, we show that in the same assays (with a single minor exception), NLVS-adapted cells are about as sensitive as nonselected cells to Ala-Ala-Phe-chloromethylketone, a specific inhibitor of tripeptidyl peptidase II activity. Based on these findings, we conclude that proteasomes still have essential proteolytic functions in adapted cells that are not replaced by Ala-Ala-Phe-chloromethylketone-sensitive proteases. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, D-20251 Hamburg, Germany. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA. RP Bennink, JR (reprint author), NIH, Room 211,Bldg 4,4 Ctr Dr,MSC 0440, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Chen, Weisan/E-7828-2012 FU NIGMS NIH HHS [R01 GM062120, R01 GM062120-04] NR 19 TC 64 Z9 64 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2001 VL 98 IS 2 BP 513 EP 518 DI 10.1073/pnas.021132398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393TG UT WOS:000166485300030 PM 11149939 ER PT J AU Buetow, KH Edmonson, M MacDonald, R Clifford, R Yip, P Kelley, J Little, DP Strausberg, R Koester, H Cantor, CR Braun, A AF Buetow, KH Edmonson, M MacDonald, R Clifford, R Yip, P Kelley, J Little, DP Strausberg, R Koester, H Cantor, CR Braun, A TI High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EXTENSION; MAP AB We describe here a system for the rapid identification, assay development, and characterization of gene-based single nucleotide polymorphisms (SNPs). This system couples informatics tools that mine candidate SNPs from public expressed sequence tag resources and automatically designs assay reagents with detection by a chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. As a proof of concept of this system, a genomewide collection of reagents for 9,115 gene-based SNP genetic markers was rapidly developed and validated. These data provide preliminary insights into patterns of polymorphism in a genomewide collection of gene-based polymorphisms. C1 NCI, Lab Populat Genet, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Off Genom, Bethesda, MD 20892 USA. Sequenom Inc, San Diego, CA 92121 USA. RP Buetow, KH (reprint author), NCI, Lab Populat Genet, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 10 TC 381 Z9 396 U1 3 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2001 VL 98 IS 2 BP 581 EP 584 DI 10.1073/pnas.021506298 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393TG UT WOS:000166485300042 PM 11136232 ER PT J AU Igarashi, T Brown, CR Endo, Y Buckler-White, A Plishka, R Bischofberger, N Hirsch, V Martin, MA AF Igarashi, T Brown, CR Endo, Y Buckler-White, A Plishka, R Bischofberger, N Hirsch, V Martin, MA TI Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4(+) T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; SIV INFECTION; REPLICATION; AIDS; IDENTIFICATION; PLASMA; QUANTITATION; INHIBITION; PREVENTION; DISEASE AB The highly pathogenic simian immunodeficiency virus/HIV type 1 (SHIV) chimeric virus SHIVDH12R induces a systemic depletion of CD4(+) T lymphocytes in rhesus monkeys during the initial 3-4 weeks of infection. Nonetheless, high levels of viral RNA production continue unabated for an additional 2-5 months. In situ hybridization and immunohistochemical analyses revealed that tissue macrophage in the lymph nodes, spleen, gastrointestinal tract, liver, and kidney sustain high plasma virus loads in the absence of CD4(+) T cells. Quantitative confocal immunofluorescence analysis indicated that greater than 95% of the virus-producing cells in these tissues are macrophage and less than 2% are T lymphocytes. Interestingly, the administration of a potent reverse transcriptase inhibitor blocked virus production during the early T cell phase but not during the later macrophage phase of the SHIVDH12R infection. When interpreted in the context of HIV-1 infections these results implicate tissue macrophage as an important reservoir of virus in vivo. They become infected during the acute infection, gradually increase in number over time, and can be a major contributor to total body virus burden during the symptomatic phase of the human infection. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Gilead Sci Inc, Foster City, CA 94404 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NR 45 TC 245 Z9 245 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2001 VL 98 IS 2 BP 658 EP 663 DI 10.1073/pnas.021551798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393TG UT WOS:000166485300056 PM 11136236 ER PT J AU Feng, DL D'Agostino, RB Silbershatz, H Lipinska, I Massaro, J Levy, D Benjamin, EJ Wolf, PA Tofler, GH AF Feng, DL D'Agostino, RB Silbershatz, H Lipinska, I Massaro, J Levy, D Benjamin, EJ Wolf, PA Tofler, GH TI Hemostatic state and atrial fibrillation (The Framingham Offspring Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID FIBRIN D-DIMER; PLASMA-FIBRINOGEN; INDUSTRIAL-POPULATION; HYPERCOAGULABLE STATE; BASELINE DATA; FACTOR-VIII; DISEASE; THROMBOGENESIS; COAGULATION; SMOKING AB Atrial fibrillation (AF) is strongly associated with thromboembolic complications, although the mechanism for the increased risk has not been fully explained. To determine whether AF might be associated with a hypercoagulable state, we studied hemostatic factors in subjects with or without AF in the Framingham Heart Study. In 3,577 subjects, we measured fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (tPA) antigen, and plasminogen activator inhibitor-1 antigen. Forty-seven subjects had AF at the index clinic examination and 15 had AF on a prior examination, but not on the current examination. Before matching, the 47 subjects with prevalent AF had higher levels of fibrinogen, van Willebrand factor, and tPA antigen than those without AF, all p less than or equal to 0.03. Compared with 167 referent subjects matched for age, sex, and other risk factors, those with AF had higher tPA antigen levels than those without AF, 11.8 +/- 4.0 ng/ml versus 10.5 +/- 3.9 ng/ml (p = 0.04). However, when further stratified according to their cardiovascular disease status, the differences in hemostatic factors were no longer significant. We conclude that the prothrombotic profile associated with AF was explained by the risk factors of the subjects and the presence of cardiovascular disease. Nonetheless, the hemostatic changes may contribute toward the propensity for thromboembolic complications in AF. Further prospective studies are needed to evaluate whether measurement of these and other hemostatic factors will identify patients with AF who are at increased risk for thromboembolic complications, and who may therefore benefit from more intensive therapy. (C) 2001 by Excerpta Medica, Inc. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Inst Prevent Cardiovasc Dis, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. NHLBI Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Royal N Shore Hosp, Sydney, NSW, Australia. RP Feng, DL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Inst Prevent Cardiovasc Dis, One Autumn St,5th Floor, Boston, MA 02215 USA. OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-38038]; NINDS NIH HHS [5-RO1-NS-17950]; PHS HHS [R01-38038] NR 28 TC 65 Z9 71 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 JAN 15 PY 2001 VL 87 IS 2 BP 168 EP 171 DI 10.1016/S0002-9149(00)01310-2 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 392MA UT WOS:000166413800008 PM 11152833 ER PT J AU Castelli, W AF Castelli, W TI From phenotype to genotype SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Editorial Material ID HYPERTENSION AB Through the work of Roger Williams, the role of family history has been enhanced. C1 NHLBI, Med Ctr Framingham Heart Study, Framingham, MA 01701 USA. RP Castelli, W (reprint author), NHLBI, Med Ctr Framingham Heart Study, 118 Lincoln St, Framingham, MA 01701 USA. NR 5 TC 0 Z9 0 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 JAN 15 PY 2001 VL 87 IS 2 BP 208 EP + DI 10.1016/S0002-9149(00)01318-7 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 392MA UT WOS:000166413800016 PM 11152841 ER PT J AU Brown, LM Hoover, R Silverman, D Baris, D Hayes, R Swanson, GM Schoenberg, J Greenberg, R Liff, J Schwartz, A Dosemeci, M Pottern, L Fraumeni, JF AF Brown, LM Hoover, R Silverman, D Baris, D Hayes, R Swanson, GM Schoenberg, J Greenberg, R Liff, J Schwartz, A Dosemeci, M Pottern, L Fraumeni, JF TI Excess incidence of squamous cell esophageal cancer among US black men: Role of social class and other risk factors SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; case-control studies; diet; esophageal neoplasms; racial stocks; risk factors; social class; tobacco ID HUMAN PAPILLOMAVIRUS INFECTION; UNITED-STATES; SOCIOECONOMIC-STATUS; ATTRIBUTABLE RISK; MARITAL-STATUS; WHITE MEN; ALCOHOL; TOBACCO; DETERMINANTS; PREVALENCE AB Data from a population-based case-control study were used to evaluate the relation between social class factors and squamous cell esophageal cancer and the extent to which alcohol, tobacco, diet, and low income contribute to the higher incidence among Black men than among White men in the United States. A total of 347 male cases (119 White, 228 Black) and 1,354 male controls (743 White, 611 Black) were selected from three US geographic areas (Atlanta, Georgia, Detroit, Michigan, and New Jersey). Cases were residents of the study areas aged 30-79 years who had been diagnosed with histologically confirmed esophageal cancer between 1986 and 1989. The adjusted odds ratios for subjects with annual incomes less than $10,000 versus incomes of $25,000 or more were 4.3 (95% confidence interval: 2.1, 8.7) for Whites and 8.0 (95% confidence interval: 4.3, 15.0) for Blacks. The combination of all four major risk factors-low income, moderate/heavy alcohol intake, tobacco use, and infrequent consumption of raw fruits and vegetables-accounted for almost all of the squamous cell esophageal cancers in Whites (98%) and Blacks (99%) and for 99% of the excess incidence among Black men. Thus, lifestyle modifications, especially a lowered intake of alcoholic beverages, would markedly decrease the incidence of squamous cell esophageal cancer in both racial groups and would narrow the racial disparity in risk. Further studies on the determinants of social class may help to identify a new set of exposures for this tumor that are amenable to intervention. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Michigan State Univ, Ctr Canc, E Lansing, MI 48824 USA. New Jersey State Dept Hlth, Trenton, NJ 08625 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Karmanos Canc Inst, Dept Epidemiol, Detroit, MI USA. NHLBI, Womens Hlth Initiat, Bethesda, MD 20892 USA. RP Brown, LM (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8026,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-51090, N01-CP-51092, N01-CP-51089] NR 41 TC 151 Z9 151 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2001 VL 153 IS 2 BP 114 EP 122 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 391HR UT WOS:000166351000004 PM 11159155 ER PT J AU Tierney, E Nwokoro, NA Porter, FD Freund, LS Ghuman, JK Kelley, RI AF Tierney, E Nwokoro, NA Porter, FD Freund, LS Ghuman, JK Kelley, RI TI Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry CY OCT 19-24, 1999 CL CHICAGO, IL SP Amer Acad Child & Adolescent Psychiat DE Smith-Lemli-Opitz syndrome; behavior phenotype cholesterol; 7-dehyrocholesterol; metabolic disorder; autism; Autism Diagnostic Interview (ADI); Sensory Profile; Screen for Social Interaction; temperament dysregulation; multiple congenital disorder; opisthokinesis; Temperament and Atypical Behavior Scale (TABS) ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; SENSORY PROFILE; RSH SYNDROME; RATING FORM; CHILDREN; AUTISM; DISABILITIES; PERFORMANCE; DISORDERS AB The behavior phenotype of Smith-Lemli-Opitz syndrome (SLOS) was studied by assessing behavior, social, and communication abilities, sensory hyperreactivity, and the deficits associated with autistic disorder. Fifty-six SLOS subjects, age 0.3 to 32.3 years, were evaluated by multiple age-dependent questionnaires and telephone interviews. Of the 56 subjects, 50 (89%) had a history of repeated self-injury: 30 (54%) bit themselves; 27 (48%) head-banged; and 30 (54%) threw themselves backward in a highly characteristic upper body movement ("opisthokinesis"). Forty-seven of these subjects were also evaluated by direct observation and by direct interview of the parent or caregiver. Of 11 subjects 10 years or older, three (27%) had a stereotypic stretching motion of the upper body accompanied by hand flicking. Additional measures showed sensory hyperreactivity, temperament dysregulation, sleep disturbance, and social and communication deficits. Nine of 17 subjects (53%) met the diagnostic criteria for autistic disorder by the Autism Diagnostic Interview-Revised (ADI-R) algorithm questions [Lord et al,, 1993, 1994]. Thus, SLOS is a metabolic disorder that can be associated with autism and other behavioral characteristics that define a distinctive and diagnostically important behavioral disorder. (C) 2001 Wiley-Liss, Inc. C1 Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Kennedy Krieger Inst, Div Intermediary Metab, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Tierney, E (reprint author), Kennedy Krieger Inst, Dept Psychiat, 1750 E Fairmount Ave, Baltimore, MD 21231 USA. EM tierney@kennedykrieger.org FU NIMH NIH HHS [K23 MH001883-01A1] NR 43 TC 111 Z9 113 U1 0 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 15 PY 2001 VL 98 IS 2 BP 191 EP 200 DI 10.1002/1096-8628(20010115)98:2<191::AID-AJMG1030>3.0.CO;2-M PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 389BE UT WOS:000166217900013 PM 11223857 ER PT J AU Hall, D AF Hall, D TI Use of optical biosensors for the study of mechanistically concerted surface adsorption processes SO ANALYTICAL BIOCHEMISTRY LA English DT Review ID BIOMOLECULAR INTERACTION ANALYSIS; PLASMON RESONANCE SPECTROSCOPY; PROTEIN-PROTEIN INTERACTIONS; ANTIBODY-ANTIGEN INTERACTIONS; RANDOM SEQUENTIAL ADSORPTION; MASS-TRANSPORT LIMITATION; EVANESCENT-WAVE BIOSENSOR; INTERACTION ANALYSIS BIA; LOCALLY PLANAR SURFACES; ORDER KINETIC-BEHAVIOR AB The advent of commercial optical biosensors, such as the BIAcore from Pharmacia and IAsys from Affinity Sensors, has made available to the biochemist a powerful means to examine and characterize the interaction of biological macromolecules with a binding surface. By analysis of the kinetic and equilibrium aspects of the observed experimental adsorption isotherms, rate and affinity constants can be determined. This Review focuses on pertinent aspects of the technology and its use for the performance and quantitative characterization of some various types of mechanistically concerted adsorption behavior. (C) 2001 Academic Press. C1 NIDDKD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. RP Hall, D (reprint author), NIDDKD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. RI Hall, Damien/D-9927-2012 OI Hall, Damien/0000-0003-1538-7618 NR 159 TC 60 Z9 62 U1 2 U2 11 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JAN 15 PY 2001 VL 288 IS 2 BP 109 EP 125 DI 10.1006/abio.2000.4851 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 393VQ UT WOS:000166490700001 PM 11152582 ER PT J AU London, RE Gabel, SA AF London, RE Gabel, SA TI Development and evaluation of a boronate inhibitor of gamma-glutamyl transpeptidase SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID ALPHA-AMINO-ACIDS; CANCER CELL-LINES; TRANSFERASE TRANSPEPTIDASE; RAT-LIVER; INTRACELLULAR GLUTATHIONE; CARCINOMA CELLS; HEPATOCARCINOGENESIS; RESISTANCE; TRANSPORT; ACIVICIN AB gamma -Glutamyl transpeptidase (gamma -GT) plays a central role in the metabolism of glutathione and is also a marker for neoplasia and cell transformation. We have investigated the compound L-2-amino-4-boronobutanoic acid (ABBA) as a structural analog of the putative ternary complex formed by the enzyme, L-serine, and borate, proposed to function as a transition state analog inhibitor. ABBA was found to be a potent inhibitor of the enzyme, with K-i = 17 nM using typical assay conditions (pH 8, gamma -glutamyl-p-nitroanilide substrate, 20 mM glycyl-glycine acceptor). ABBA is a stable amino acid analog with pd:values determined from C-13 and B-11 NMR to be 2.3, 11.0 (amino titration), and 7.9 (boronate titration). The structural similarity to glutamate suggested that it might function as a glutamate analog for some glutamate-dependent enzymes or receptors. Transamination of pyruvate by ABBA to yield alanine in the presence of glutamic pyruvic transaminase was demonstrated by C-13 NMR. The 2-keto-4-boronobutanoic acid transamination product is apparently fairly labile to hydrolysis, leading to formation of 2-ketobutanoic acid plus borate. The latter is also subsequently transaminated to yield 2-aminobutanoic acid. Both of these metabolites were observed in the C-13 NMR spectrum. However, the corresponding transamination of oxaloacetate by ABBA in the presence of glutamic oxaloacetic transaminase was not observed. Effects of ABBA on the growth of cultured rat liver cell lines ARL-15C(1) (nontumorigenic, low gamma -GT activity) and ARL-16T(2) (tumorigenic, high gamma -GT activity) were also investigated, both in standard Williams Media as well as in a low cysteine growth medium. A high concentration (1 mM) of ABBA inhibited the growth of both cell Lines in both media, with the degree of inhibition greater in the low cysteine medium. Alternatively, growth inhibition by 10 muM ABBA could be observed only in the low cysteine media. In general, there were no significant differences between the two cell lines in terms of sensitivity to ABBA. (C) 2001 Academic Press. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, POB 12233,MR-01, Res Triangle Pk, NC 27709 USA. NR 59 TC 30 Z9 32 U1 0 U2 3 PU ACADEMIC PRESS INC 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 JAN 15 PY 2001 VL 385 IS 2 BP 250 EP 258 DI 10.1006/abbi.2000.2169 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 393VP UT WOS:000166490600003 PM 11368005 ER PT J AU Cocco, L Martelli, AM Gilmour, RS Rhee, SG Manzoli, FA AF Cocco, L Martelli, AM Gilmour, RS Rhee, SG Manzoli, FA TI Nuclear phospholipase C and signaling SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE nucleus; inositol lipid; phospholipase; signaling ID PROTEIN-KINASE-C; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE-BINDING PROTEIN; ADP-RIBOSYLATION-FACTOR; RAT-LIVER NUCLEI; SWISS 3T3 CELLS; OSTEOSARCOMA SAOS-2 CELLS; GREEN FLUORESCENT PROTEIN; GTPASE-ACTIVATING PROTEIN; I-INDUCED MITOGENESIS; CANINE KIDNEY-CELLS C1 Univ Bologna, Dept Anat Sci & Skeletal Muscle Pathophysiol, Cellular Signaling Lab, I-40126 Bologna, Italy. Univ Auckland, Sch Med, Auckland, New Zealand. NHLBI, Lab Cell Signalling, NIH, Bethesda, MD 20892 USA. RP Cocco, L (reprint author), Univ Bologna, Dept Anat Sci & Skeletal Muscle Pathophysiol, Cellular Signaling Lab, Via Irnerio 48, I-40126 Bologna, Italy. NR 118 TC 81 Z9 85 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JAN 15 PY 2001 VL 1530 IS 1 BP 1 EP 14 DI 10.1016/S1388-1981(00)00169-4 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 396QL UT WOS:000166648000001 PM 11341954 ER PT J AU Ketter, TA Kimbrell, TA George, MS Dunn, RT Speer, AM Benson, BE Willis, MW Danielson, A Frye, MA Herscovitch, P Post, RM AF Ketter, TA Kimbrell, TA George, MS Dunn, RT Speer, AM Benson, BE Willis, MW Danielson, A Frye, MA Herscovitch, P Post, RM TI Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder SO BIOLOGICAL PSYCHIATRY LA English DT Review DE PET; cerebral metabolism; bipolar disorders; depression; rapid cycling ID POSITRON EMISSION TOMOGRAPHY; SEASONAL AFFECTIVE-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; LATE-LIFE DEPRESSION; MAJOR DEPRESSION; BLOOD-FLOW; UNIPOLAR DEPRESSION; COMPUTERIZED-TOMOGRAPHY; SLEEP-DEPRIVATION; BRAIN ACTIVITY AB Background: Functional brain imaging studies in unipolar lar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. Methods: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. Results: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism, Increased normalized cerebello-posterior cortical metabolism,vas seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. Conclusions: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology, In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predorninantly rapid-cycling patients pertain to community samples remains to be established. (C) 2001 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. Vet Adm Med Ctr, N Little Rock, AR USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, Bldg 10,Room 3N212,10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. NR 103 TC 190 Z9 198 U1 7 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2001 VL 49 IS 2 BP 97 EP 109 DI 10.1016/S0006-3223(00)00975-6 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 397CD UT WOS:000166675000002 PM 11164756 ER PT J AU Newton, DL Hansen, HJ Mikulski, SM Goldenberg, DM Rybak, SM AF Newton, DL Hansen, HJ Mikulski, SM Goldenberg, DM Rybak, SM TI Potent and specific antitumor effects of an anti-CD22-targeted cytotoxic ribonuclease: potential for the treatment of non-Hodgkin lymphoma SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; MONOCLONAL-ANTIBODIES; RICIN-A; PHASE-I; CD22-RECOMBINANT RICIN; PSEUDOMONAS EXOTOXIN; EPITOPE SPECIFICITY; SCID MICE; IMMUNOTOXINS; PROTEIN AB LL2, an anti-cDaa monoclonal antibody against B-cell lymphoma, was covalently linked to the amphibian ribonuclease, onconase, a member of the pancreatic RNase A superfamily, LL2 increased in vitro potency (10 000-fold) and specificity against human Daudi Burkitt lymphoma cells while decreasing systemic toxicity of onconase. Monensin further increased potency of LL2-onconase on Daudi cells (IC50, 20 and 1.5 pM, absence and presence of monensin, respectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to significant antitumor activity against disseminated Daudi lymphoma in mice with severe combined immunodeficiency disease. In mice inoculated with tumor cells intraperitoneally (ip), LL2-onconase (100 mug 5 times ip every day) increased the life span of animals with minimal disease 200%. The life span of mice with advanced disseminated Daudi lymphoma (tumor cells inoculated intravenously) was increased 135%, Mice injected with LL2-onconase tolerated a dose as high as 300 mg/kg. Because both onconase and LL2 are in clinical trials as cancer therapeutics, the covalently linked agents should be considered for treatment of non-Hodgkin lymphoma. (C) 2001 by The American Society of Hematology. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. Immunomed Inc, Morris Plains, NJ USA. Garden State Canc Ctr, Belleville, NJ USA. Alfacell Corp, Bloomfield, NJ USA. NCI, Frederick Canc Res & Dev Ctr, Pharmaceut Expt Therapeut Sect,Dev Therapeut Prog, Lab Drug Discovery Res & Dev,Div Canc Treatment &, Frederick, MD 21701 USA. RP Rybak, SM (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Bldg 567,Rm 162, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000, CA39841] NR 49 TC 95 Z9 99 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2001 VL 97 IS 2 BP 528 EP 535 DI 10.1182/blood.V97.2.528 PG 8 WC Hematology SC Hematology GA 392AG UT WOS:000166388000028 PM 11154233 ER PT J AU Achanzar, WE Diwan, BA Liu, J Quader, ST Webber, MM Waalkes, MP AF Achanzar, WE Diwan, BA Liu, J Quader, ST Webber, MM Waalkes, MP TI Cadmium-induced malignant transformation of human prostate epithelial cells SO CANCER RESEARCH LA English DT Article ID MATRIX METALLOPROTEINASES; SECRETION; CULTURES; LINES AB Prostate cancer has become epidemic, and environmental factors such as cadmium may be partly responsible. This study reports malignant transformation of the nontumorigenic human prostatic epithelial cell line RWPE-1 by in vitro cadmium exposure. The cadmium-transformed cells exhibited a loss of contact inhibition in vitro and rapidly formed highly invasive and occasionally metastatic adenocarcinomas upon inoculation into mice. The transformed cells also showed increased secretion of MMP-2 and MMP-9, a phenomenon observed in human prostate tumors and linked to aggressive behavior. Cadmium-induced malignant transformation of human prostate epithelial cells strongly fortifies the evidence for a potential role of cadmium in prostate cancer. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, MD F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. FU PHS HHS [N01-C0-56000] NR 20 TC 104 Z9 106 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 JAN 15 PY 2001 VL 61 IS 2 BP 455 EP 458 PG 4 WC Oncology SC Oncology GA 399NT UT WOS:000166819800009 PM 11212230 ER PT J AU Urasaki, Y Laco, G Takebayashi, Y Bailly, C Kohlhagen, G Pommier, Y AF Urasaki, Y Laco, G Takebayashi, Y Bailly, C Kohlhagen, G Pommier, Y TI Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site SO CANCER RESEARCH LA English DT Article ID MEDIATED DNA CLEAVAGE; INHIBITION; MECHANISM; COMPOUND; IDENTIFICATION; REBECCAMYCIN; CYTOTOXICITY; DERIVATIVES; INDUCTION; J-107088 AB NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this study, we used a series of camptothecin (CPT)-resistant cell lines with known top1 alterations, We show that three mutations in different domains of the top1 enzyme that confer CPT resistance also confer cross-resistance to NB-506. The CPT-resistant cell lines and corresponding mutations were: human prostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibroblasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S), This result suggests that NB-506 and CPT share a common binding site in the top1-DNA complex, We next used these three cell lines and their parental cells to study the relationship between top1 poisoning by NB-506 and antiproliferative activity, We Pound that the CPT-resistant cells were only 2-10-fold resistant to NB-506, which suggests that NB-506 targets other cellular processes/pathways besides top1, This conclusion was further supported by the limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cells (2-fold). Cross-resistance was also limited for J-109,382, an isomer of NB-506 that does not intercalate into DNA, indicating that the non-top1-mediated antiproliferative activity of NB-506 is not attributable to DNA intercalation,Together, these data indicate that NB-506 and indolocarbazoles are promising agents to overcome CPT resistance. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E28, Bethesda, MD 20892 USA. NR 36 TC 36 Z9 46 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 JAN 15 PY 2001 VL 61 IS 2 BP 504 EP 508 PG 5 WC Oncology SC Oncology GA 399NT UT WOS:000166819800020 PM 11212241 ER PT J AU Mitsiades, N Yu, WH Poulaki, V Tsokos, M Stamenkovic, I AF Mitsiades, N Yu, WH Poulaki, V Tsokos, M Stamenkovic, I TI Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity SO CANCER RESEARCH LA English DT Article ID INDUCED APOPTOSIS; ANTICANCER DRUGS; DOWN-REGULATION; SOLUBLE FORM; EXPRESSION; ACTIVATION; CANCER; INHIBITORS; METASTASIS; CARCINOMA AB Recent evidence suggests that one mechanism whereby cytotoxic drugs, such as doxorubicin, kill tumors is the induction or up-regulation of Fas ligand (FasL) expression on the tumor cell surface. The ensuing engagement of Fas by FasL on adjacent cells leads to apoptosis. However, despite cytotoxic drug-induced Fast expression, Fas-sensitive tumors frequently resist chemotherapy, suggesting that they may possess a mechanism that prevents or inactivates Fas-FasL interactions. In the present work, we addressed the involvement of the FasL/Fas signaling pathway in doxorubicin-indureed apoptosis and the ability of matrix metalloproteinases (MMPs) to proteolytically cleave Fast in tumor cells. Doxorubicin-induced apoptosis was inhibited by expression of soluble Fas or incubation of the tumor cells with MMP-7 but not with MMP-2 or MMP-9. Resistance to doxorubicin was also induced by expression in the tumor cells of constitutively active MMP-7 but not of a catalytically inactive mutant. Conversely, inhibition of MMP-7 expression in tumor cells by transfection of MMP-7 cDNA in antisense orientation resulted in sensitization to doxorubicin. MMP-7 efficiently cleaved recombinant Fast in vitro and reduced cell surface FasL expression. Our observations provide evidence that one mechanism whereby MMP-7 may promote tumor survival and resistance to doxorubicin is by cleaving Fast and reducing its effectiveness in triggering Fas-mediated apoptosis. C1 Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. NCI, Bethesda, MD 20892 USA. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M57,44 Binney St, Boston, MA 02115 USA. OI Yu, Wei-Hsuan/0000-0002-1782-3738 NR 32 TC 224 Z9 245 U1 2 U2 14 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 JAN 15 PY 2001 VL 61 IS 2 BP 577 EP 581 PG 5 WC Oncology SC Oncology GA 399NT UT WOS:000166819800031 PM 11212252 ER PT J AU Vale, T Ngo, TT White, MA Lipsky, PE AF Vale, T Ngo, TT White, MA Lipsky, PE TI Raf-induced transformation requires an interleukin 1 autocrine loop SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; MAP KINASE-KINASE; SIGNAL-TRANSDUCTION PATHWAYS; TRANSCRIPTION FACTOR; IKK-ALPHA; RECEPTOR ANTAGONIST; MAMMALIAN-CELLS; ACTIVATION; EXPRESSION; COMPLEX AB The c-Raf-1 serine/threonine protein kinase plays a critical role in the proliferation of most cell types that have been examined. As such, the Raf proto-oncogene Is thought to play a central role in the development of human tumors. Although the c-mf-1 gene itself rarely appears to be mutated in human tumors, the kinase activity of Raf is frequently found to be more active in tumor cells, likely through constitutive activation of upstream activators of Raf, The downstream events triggered by Raf that are involved in transformation have been studied less extensively. We show in this study that Raf-induced transformation of NIH 3T3 cells requires the activation of the ubiquitously expressed transcription factor, nuclear faetor-kappaB, by Raf, Furthermore, through the use of CrmA, interleukin 1 (IL-1) receptor antagonist, and a dominant-negative form of TRAF6, we demonstrate a requirement for IL-1 production and signaling from the IL-1 receptor as necessary components of Raf-induced transformation. These results indicate that IL-1 may be used as an autocrine growth factor by a number of tumors in which activation of Raf plays an important role in transformation and suggest that blockade of IL-1 signaling may be an approach to limiting the growth of certain tumors. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Harold C Simmons Arthrit Res Ctr, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Cell Biol & Neurosci, Dallas, TX 75235 USA. RP Lipsky, PE (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. NR 56 TC 26 Z9 26 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 JAN 15 PY 2001 VL 61 IS 2 BP 602 EP 607 PG 6 WC Oncology SC Oncology GA 399NT UT WOS:000166819800035 PM 11212256 ER PT J AU Poirot, E Zhang, XD Whittaker, NF Kovac, P AF Poirot, E Zhang, XD Whittaker, NF Kovac, P TI Syntheses of the L-manno and some other analogs of the terminal determinants of the O-PS of Vibrio cholerae O : 1 SO CARBOHYDRATE RESEARCH LA English DT Article DE Vibrio cholerae O : 1; Yersinia enterocolitica; Brucella abortus; perosamine ID METHYL ALPHA-GLYCOSIDE; STEREOSPECIFIC SYNTHESIS; RHAMNOPYRANOSYL LINKAGE; ANTIGENIC DETERMINANTS; POLYSACCHARIDE CHAIN; REPEATING UNIT; SEROTYPE-OGAWA; LIPOPOLYSACCHARIDE; HOMOPOLYMER; INABA AB Analogs of the methyl alpha -glycosides of the terminal residues of the O-specific polysaccharides (O-PS) of Vibrio cholerae O:1, serotype Inaba and Ogawa, have been prepared as probes to study their interaction with anti V. cholerae O:1 antibodies. They differ from the termini of the respective O-PSs in anomeric or absolute configuration of perosamine, position of the O-methyl group in D-perosamine, and nature of the N-acyl side chain. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIH, Bldg 8,Room B1A24, Bethesda, MD 20892 USA. NR 23 TC 7 Z9 8 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JAN 15 PY 2001 VL 330 IS 1 BP 7 EP 20 DI 10.1016/S0008-6215(00)00265-2 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 396TK UT WOS:000166652500002 PM 11217964 ER PT J AU Requena, JR Levine, RL AF Requena, JR Levine, RL TI Thioredoxin converts the Syrian hamster (29-231) recombinant prion protein to an insoluble form SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE thioredoxin; prion; disulfide bridge reduction; aggregation; free radicals ID SCRAPIE; PRP; RESISTANT; REDUCTASE; CELLS AB The prion protein (PrP) is an essential, and probably the only, component of the infectious agent responsible for the transmissible spongiform encephalopathies. In its cellular (PrPC) form, it is a soluble, a-helix-rich protein of yet unknown function attached to the outer membrane of neurons through a glycosylphosphatidyl inositol anchor. In its pathogenic, "scrapie" form (PrPSc), it appears as an aggregate showing no detectable covalent modifications but displaying a profoundly altered conformation enriched in P-sheet structure. Reduction of the single disulfide bridge in the prion protein with millimolar concentrations of dithiothreitol results in transformation of the alpha -helix-rich to the P-sheet-rich conformation, with concomitant decrease in solubility. We report here that thioredoxin coupled with thioredoxin reductase and NADPH efficiently reduces recombinant Syrian hamster (29-231) prion protein under physiologically relevant conditions. The reduced prion protein immediately becomes insoluble and precipitates, although it does not gain significant resistance to proteinase K. The thioredoxin/thioredoxin reductase system is similar to 7000 times more efficient than dithiothreitol. (C) 2001 Elsevier Science Inc. C1 NHLBI, NIH, Biochem Lab, Bethesda, MD 20892 USA. RP Requena, JR (reprint author), NHLBI, NIH, Biochem Lab, 3 Ctr Dr,Bldg 3,Room 118, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 30 TC 16 Z9 17 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 JAN 15 PY 2001 VL 30 IS 2 BP 141 EP 147 DI 10.1016/S0891-5849(00)00430-5 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 391AW UT WOS:000166332800001 PM 11163530 ER PT J AU Samuni, AM Afeworki, M Stein, W Yordanov, AT DeGraff, W Krishna, MC Mitchell, JB Brechbiel, MW AF Samuni, AM Afeworki, M Stein, W Yordanov, AT DeGraff, W Krishna, MC Mitchell, JB Brechbiel, MW TI Multifunctional antioxidant activity of HBED iron chelator SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE free radicals; redox-activity; oxidative damage; antioxidant; iron chelator; metal ions; cytoprotection; H-donation ID CLEARING PROPERTIES; DEFEROXAMINE; OVERLOAD; THERAPY; DESFERRIOXAMINE; THALASSEMIA; ANALOGS; MODEL AB The use of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) for iron chelation therapy is currently being tested. Besides its affinity for iron, bioavailability, and efficacy in relieving iron overload, it is important to assess its anti- and/or pro-oxidant activity. To address these questions, the antioxidant/pro-oxidant effects of HEED in a cell-free solution and on cultured Chinese hamster V79 cells were studied using UV-VIS spectrophotometry, oximetry, spin trapping, and electron paramagnetic resonance (EPR) spectrometry. The results indicate that HEED facilitates Fe(II) oxidation but blocks O-2(.-)-induced reduction of Fe(III) and consequently pre-empts production of (OH)-O-. or hypervalent iron through the Haber-Weiss reaction cycle. The efficacy of HEED as a 1-electron donor (H-donation) was demonstrated by reduction of the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate)-derived nitrogen-centered radical cation (ABTS(.+)), accompanied by formation of a short-lived phenoxyl radical. HEED also provided cytoprotection against toxicity of H2O2 and t-BuOOH. Our results show that HEED can act both as a H-donating antioxidant and as an effective chelator lacking pro-oxidant capacity, thus substantiating its promising use in iron chelation therapy. (C) 2001 Elsevier Science Inc. C1 NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. NR 29 TC 22 Z9 23 U1 0 U2 4 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 JAN 15 PY 2001 VL 30 IS 2 BP 170 EP 177 DI 10.1016/S0891-5849(00)00459-7 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 391AW UT WOS:000166332800005 PM 11163534 ER PT J AU Dikalov, SI Mason, RP AF Dikalov, SI Mason, RP TI Spin trapping of polyunsaturated fatty acid-derived peroxyl radicals: Reassignment to alkoxyl radical adducts SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE lipid; PUFA; lipoxygenase; peroxyl radical; alkoxyl radical; spin trap; radical adduct; DMPO; free radicals ID SOYBEAN LIPOXYGENASE; LINOLEIC-ACID; LIPID-PEROXIDATION; RESONANCE-SPECTRA; HYDROPEROXIDES; IDENTIFICATION; SPECTROSCOPY; DMPO; 5,5-DIMETHYL-1-PYRROLINE-N-OXIDE; 2-METHYL-2-NITROSOPROPANE AB Polyunsaturated fatty acid (PUFA) peroxyl radicals play a crucial role in lipid oxidation. ESR spectroscopy with the spin-trapping technique is one of the most direct methods for radical detection. There are many reports of the detection of PUFA peroxyl radical adducts; however, it has recently been reported that attempted spin trapping of organic peroxyl radicals at room temperature formed only alkoxyl radical adducts in detectable amounts. Therefore, we have reinvestigated spin trapping of the linoleic, arachidonic, and linolenic acid-derived PUFA peroxyl radicals. The slow-flow technique allowed us to obtain well-resolved ESR spectra of PUFA-derived radical adducts in a mixture of soybean lipoxygenase, PUFA, and the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). However, interpretation of the ESR spectra was complicated by the overlapping of the PUFA-derived alkoxyl radical adduct spectra. In order to understand these spectra, PUFA-derived alkoxyl radical adducts were modeled by various alkoxyl radical adducts. For the first time, we synthesized a wide range of DMPO adducts with primary and secondary alkoxyl radicals. It was found that many ESR spectra previously assigned as DMPO/peroxyl radical adducts based on their close similarity to the ESR spectrum of the DMPO/superoxide radical adduct, in conjunction with their insensitivity to superoxide dismutase, are indeed alkoxyl radical adducts. We have reassigned the PUFA alkylperoxyl radical adducts to their corresponding alkoxyl radical adducts. Using hyperfine coupling constants of model DMPO/alkoxyl radical adducts, the computer simulation of DMPO/PUFA alkoxyl radical adducts was performed. It was found that the trapped, oxygen-centered PUFA-derived radical is a secondary, chiral alkoxyl radical. The presence of a chiral carbon atom leads to the formation of two diastereomers of the DMPO/PUFA alkoxyl radical adduct. Therefore, attempted spin trapping of the PUFA peroxyl radical by DMPO at room temperature leads to the formation of the PUFA alkoxyl radical adduct. (C) 2001 Elsevier Science Inc. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Dikalov, SI (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 35 TC 88 Z9 88 U1 0 U2 8 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 JAN 15 PY 2001 VL 30 IS 2 BP 187 EP 197 DI 10.1016/S0891-5849(00)00456-1 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 391AW UT WOS:000166332800007 PM 11163536 ER PT J AU Xing, LP Venegas, AM Chen, A Garrett-Beal, L Boyce, BF Varmus, HE Schwartzberg, PL AF Xing, LP Venegas, AM Chen, A Garrett-Beal, L Boyce, BF Varmus, HE Schwartzberg, PL TI Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival SO GENES & DEVELOPMENT LA English DT Article DE Src; RANK; osteoclast; apoptosis ID HUMAN-COLON CARCINOMA; STIMULATING FACTOR-I; NF-KAPPA-B; C-SRC; TYROSINE PHOSPHORYLATION; MEDIATED ACTIVATION; OSTEOCLAST FUNCTION; ADHESION KINASE; BONE-RESORPTION; PROTEIN-KINASE AB Mutant src(-/-) mice have osteopetrosis resulting from defective osteoclasts, the cells that resorb bone. However, signaling pathways involving Src family members in osteoclasts remain unclear. We demonstrate that expression of a truncated Src molecule, Src251, lacking the kinase domain, induces osteopetrosis in wild-type and src(+/-) mice and worsens osteopetrosis in src(-/-) mice by a novel mechanism, increased osteoclast apoptosis. Induction of apoptosis by Src251 requires a functional SH2, but not an SH3, domain and is associated with reduced ART kinase activity. Expression of Src251 dramatically reduces osteoclast survival in response to RANKL/TRANCE/OPGL, providing evidence that Src family kinases are required in vivo for survival signaling pathways downstream from TNF family receptors. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Univ Rochester, Dept Pathol, Rochester, NY 14627 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [R01 AR043510, AR-43510] NR 57 TC 80 Z9 82 U1 0 U2 0 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 JAN 15 PY 2001 VL 15 IS 2 BP 241 EP 253 DI 10.1101/gad.840301 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 397FZ UT WOS:000166683800011 PM 11157779 ER PT J AU Miyoshi, K Cui, YZ Riedlinger, G Robinson, P Lehoczky, J Zon, L Oka, T Dewar, K Hennighausen, L AF Miyoshi, K Cui, YZ Riedlinger, G Robinson, P Lehoczky, J Zon, L Oka, T Dewar, K Hennighausen, L TI Structure of the mouse Stat 3/5 locus: Evolution from Drosophila to zebrafish to mouse SO GENOMICS LA English DT Article ID MAMMARY-GLAND DEVELOPMENT; APOPTOSIS; KINASE; MICE AB Signal transducers and activators of transcription (Stat) are transcription factors that can be activated by many cytokines. While Drosophila contains only one Stat (d-Stat), mammals contain seven, with STATs 3, 5a, and 5b being the closest functional relatives. To understand the evolutionary relationship between d-Stat and vertebrate STATs 3 and 5, we isolated, sequenced, and analyzed the zebrafish Stat3 (z-Stat3) gene and a 500-kb region spanning mouse chromosome 11, 60.5 cM containing three Stat genes (m-Stats). Within this region we identified the genes encoding m-Stats 3, 5a, and 5b, Cnp1, Hcrt/Orexin, Ptrf, GCN5, mDj11, and four new genes. The 5' ends of the m-Stat5a and m-Stat5b genes are juxtaposed to each other, and the 3' ends of the m-Stat3 and Stat5a genes face each other. While the m-Stat5a and m-Stat3 genes have one promoter each, which are active in many tissues, the m-Stat5b gene acquired two distinct promoters. The distal promoter is expressed ubiquitously and transcription from the proximal promoter is restricted to Liver, muscle, and mammary tissue. Through a comparison of exon-intron boundaries from the m-Stat3, m-Stat5a, and m-Stat5b, z-Stat3, and d-Stat genes, we deduced their evolutionary relationship. We propose that the Stat3 and Stat5 Lineages are derived from the duplication of a common primordial gene and that d-Stat is a part of the Stat5 lineage. (C) zool Academic Press. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, 9000 Rockville Pike,Bldg 8,Room 101, Bethesda, MD 20892 USA. NR 18 TC 32 Z9 38 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JAN 15 PY 2001 VL 71 IS 2 BP 150 EP 155 DI 10.1006/geno.2000.6433 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 401YR UT WOS:000166957200003 PM 11161808 ER PT J AU King, LM Francomano, CA AF King, LM Francomano, CA TI Characterization of a human gene encoding nucleosomal binding protein NSBP1 SO GENOMICS LA English DT Article ID GROUP CHROMOSOMAL-PROTEINS; MESSENGER-RNA DEGRADATION; HUMAN CDNA SEQUENCE; AU-RICH ELEMENTS; 3'-UNTRANSLATED REGION; INSTABILITY ELEMENTS; MULTIGENE FAMILY; EXPRESSION; HMG-14; DNA AB We characterize the cDNA and genomic structure of NSBP1, and demonstrate that it is a nuclear protein and the homologue of mouse Nsbp1, which is known to encode a nucleosomal binding and transcriptional activating protein related to the HMG-14/-17 chromosomal proteins. The encoded NSBP1 protein has 86% amino acid similarity to Nsbp1, including identity in nucleosomal binding domains of the HMG-14/-17 proteins. Our radiation hybrid data localize NSBP1 and Nsbp1 to homologous regions of chromosome X, with NSBP1 in Xq13.3 between DXS983 and DXS995 and Nsbp1 in the interval DXMitB5 and DXMit39, Although Nsbp1 produces one mRNA transcript, NSBP1 produces three transcripts with alternate polyadenylated sites. The 3' untranslated region (UTR) of NSPB1 mRNA also contains several AU-rich elements (AREs), which are associated with rapid mRNA turnover. Northern analysis of NSBP1/Nsbp1 shows differences in transcript abundance among adult and fetal tissues, with predominant expression in liver, kidney, trabecular bone, and bone marrow stromal cells. However, a reverse transcriptase-PCR analysis shows nearly ubiquitous expression of the three NSBP1 transcripts in all tissues examined, although the abundance of each transcript was not quantified. NSBP1 is encoded by six exons and has exon-intron boundaries identical to the HMG-14/-17 genes. The last exon and the 3' UTR of NSBP1 contain retrotransposon sequences of HAL1, HERV-H, and L1MB7, suggesting that these retrotransposons were involved in the origin of NSPB1 from an ancestral-like HMG-14/-17 gene. The similarities among NSBP1, Nsbp1, and the HMG-14/-17 proteins suggest that NSBP1 may function as a nucleosomal binding and transcriptional activating element. Further, the AREs in the 3' UTR of NSPB1 suggest that alternate poly(A) site selection may mediate the mRNA stability of this gene. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP King, LM (reprint author), NIDCR, NIH, Bldg 30,Room 231,30 Convent Dr, Bethesda, MD 20892 USA. NR 39 TC 28 Z9 37 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JAN 15 PY 2001 VL 71 IS 2 BP 163 EP 173 DI 10.1006/geno.2000.6443 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 401YR UT WOS:000166957200005 PM 11161810 ER PT J AU Abel, A Walcott, J Woods, J Duda, J Merry, DE AF Abel, A Walcott, J Woods, J Duda, J Merry, DE TI Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID NEURONAL INTRANUCLEAR INCLUSIONS; BULBAR MUSCULAR-ATROPHY; CREB-BINDING-PROTEIN; HUNTINGTONS-DISEASE; TRINUCLEOTIDE REPEAT; MOUSE MODEL; GENE; AGGREGATION; LENGTH; BRAIN AB Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. This disease is unusual among the polyglutamine diseases in that it involves lower motor and sensory neurons, with relative sparing of other brain structures, We describe the development of transgenic mice, created with a truncated, highly expanded androgen receptor driven by the neurofilament light chain promoter, which develop many of the motor symptoms of SBMA. In addition, transgenic mice created with the prion protein promoter develop widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases, Thus, in these experiments, the distribution of neurologic symptoms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function, The transgenic mice described here develop neuronal Intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We have shown these inclusions to be ubiquitinated and to sequester molecular chaperones, components of the 26S proteasome and the transcriptional activator CREB-binding protein, Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting that the neurologic phenotypes observed in these mice were the result of neuronal dysfunction rather than neuronal degeneration. These mice will provide a useful resource for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseases. C1 Thomas Jefferson Univ, Dept Biochem & Mol Pharmacol, Newtown Sq, PA 19073 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Grad Program Pharmacol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol, Philadelphia, PA 19104 USA. RP Merry, DE (reprint author), Thomas Jefferson Univ, Dept Biochem & Mol Pharmacol, 208 Bluemle Life Sci Bldg,233 S 10th St, Newtown Sq, PA 19073 USA. FU NIA NIH HHS [AG00255]; NINDS NIH HHS [R01-NS32214] NR 49 TC 81 Z9 82 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2001 VL 10 IS 2 BP 107 EP 116 DI 10.1093/hmg/10.2.107 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 394WR UT WOS:000166547800003 PM 11152658 ER PT J AU Everett, LA Belyantseva, IA Noben-Trauth, K Cantos, R Chen, A Thakkar, SI Hoogstraten-Miller, SL Kachar, B Wu, DK Green, ED AF Everett, LA Belyantseva, IA Noben-Trauth, K Cantos, R Chen, A Thakkar, SI Hoogstraten-Miller, SL Kachar, B Wu, DK Green, ED TI Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID SENSORINEURAL HEARING-LOSS; UNCONVENTIONAL MYOSIN; VESTIBULAR AQUEDUCT; GENE PDS; MUTATIONS; DEAFNESS; MICE; LETHALITY; COCHLEA; FAMILY AB Following the positional cloning of PDS, the gene mutated in the deafness/goitre disorder Pendred syndrome (PS), numerous studies have focused on defining the role of PDS in deafness and PS as well as elucidating the function of the PDS-encoded protein (pendrin), To facilitate these efforts and to provide a system for more detailed study of the inner-ear defects that occur in the absence of pendrin, we have generated a Pds-knockout mouse, Pds(-/-) mice are completely deaf and also display signs of vestibular dysfunction. The inner ears of these mice appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week, severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy, The ultrastructural defects seen in the Pds(-/-) mice provide important clues about the mechanisms responsible for the inner-ear pathology associated with PDS mutations. C1 NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. NHGRI, Embryon Stem Cell Transgen Mouse Core, Bethesda, MD 20892 USA. NHGRI, Off Lab Anim Med, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RI Cantos Coll, Raquel /A-6318-2013 OI Cantos Coll, Raquel /0000-0002-5516-0074 NR 53 TC 238 Z9 246 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2001 VL 10 IS 2 BP 153 EP 161 DI 10.1093/hmg/10.2.153 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 394WR UT WOS:000166547800008 PM 11152663 ER PT J AU Xu, LH Chow, J Bonacum, J Eisenberger, C Ahrendt, SA Spafford, M Wu, L Lee, SM Piantodosi, S Tockman, MS Sidransky, D Jen, J AF Xu, LH Chow, J Bonacum, J Eisenberger, C Ahrendt, SA Spafford, M Wu, L Lee, SM Piantodosi, S Tockman, MS Sidransky, D Jen, J TI Microsatellite instability at AAAG repeat sequences in respiratory tract cancers SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE AAAG repeats; microsatellite instability; NSCLC; tumor detection; cancer genetics ID CELL LUNG-CANCER; BLADDER-CANCER; MUTATION; ABNORMALITIES; MINISATELLITE; POLYMORPHISM; DNA AB We surveyed the occurrence of novel alleles at microsatellite sequences in non-small cell lung cancers (NSCLC) using 61 tetranucleotide repeat markers. The presence of at least one new allele, consistent with microsatellite instability (MSI), was observed in 26 of 61 (43%) markers involving 30 of 47 (64%) NSCLC, Twelve of the 26 markers detected new alleles in 2 or more tumors and 11 of these 12 markers contained an AAAG repeat sequence. Using this panel of 12 markers, MSI was detected in 24 of 47 (51%) NSCLC and 10 of 18 (56%) head and neck cancers but was only observed in 8 of 38 (21%) bladder cancers and 3 of 25 (12%) kidney cancers. Our results suggested that about 50% of respiratory tract cancers exhibited microsatellite instability predominantly at AAAG sequences. This distinct type of instability was termed EMAST for elevated microsatellite alterations at selected tetranucleotide repeats. The identification of markers with EMAST should have potential application for the molecular detection of respiratory tract cancers. (C) 2001 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Head & Neck Canc Res, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Sch Publ Hyg, Baltimore, MD USA. RP Jen, J (reprint author), NCI, Lab Populat Genet, Bldg 41,Room D702,41 Lib Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA58184] NR 28 TC 48 Z9 48 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 JAN 15 PY 2001 VL 91 IS 2 BP 200 EP 204 DI 10.1002/1097-0215(200002)9999:9999<::AID-IJC1031>3.0.CO;2-0 PG 5 WC Oncology SC Oncology GA 388CE UT WOS:000166159200009 PM 11146445 ER PT J AU Vergani, V Garofalo, A Bani, MR Borsotti, P Parker, MP Drudis, T Mazzarol, G Viale, G Giavazzi, R Stetler-Stevenson, WG Taraboletti, G AF Vergani, V Garofalo, A Bani, MR Borsotti, P Parker, MP Drudis, T Mazzarol, G Viale, G Giavazzi, R Stetler-Stevenson, WG Taraboletti, G TI Inhibition of matrix metalloproteinases by overexpression of tissue inhibitor of metalloproteinase-2 inhibits the growth of experimental hemangiomas SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE TIMP-2; matrix metalloproteinases; endothelioma; endothelial cells; angiogenesis ID MIDDLE-T-ONCOGENE; HOST-CELL RECRUITMENT; TUMOR PROGRESSION; OVER-EXPRESSION; IN-VIVO; INVASION; METASTASIS; TIMP-2; ANGIOGENESIS; CANCER AB Inhibitors of proteases prevent tumor-associated matrix degradation, affecting tumor growth, angiogenesis and metastasis, Our study was designed to investigate the effect of inhibition of matrix metalloproteinases (MMPs) on the growth of experimental hemangiomas, using the model of murine endothelioma eEnd.1 cells. In nude mice, these cells generate hemangiomas, consisting mostly of host-recruited endothelial cells, whose growth requires the activity of MMPs. In vitro, eEnd.1 cells produce factors that recruit endothelial cells and stimulate them to release MMPs. Overexpression of TIMP-2, following retrovirus-mediated gene transfer, decreased tumor growth in vivo. The infected clone CR1, which produces high levels of TIMP-2 (as assessed by Northern blot, ELISA and reverse zymography), formed slow-growing tumors that did not grow beyond 0.4 g, while clone 1H, which produces little TIMP-2, grew not dissimilarly to mock-infected cells and parental e.End.1 cells. Histologically, control tumors presented the features of cavernous hemangiomas, while CR1 tumors had a more solid pattern, showing foci of apoptotic cells. In vitro, TIMP-2 over-expression had no autocrine anti-proliferative effect on endothelioma cells but reduced their ability to recruit endothelial cells. CRI cells lacked the capacity of mock-infected or parental eEnd.1 cells to stimulate endothelial cell motility and invasiveness. Antibodies against TIMP-2 restored the ability of CRI to induce endothelial cell invasion. We conclude that, in this model, genetic increase of TIMP-2 inhibits tumor growth, apparently by affecting the recruitment and organization of host endothelial cells by the transformed cells. (C) 2001 Wiley-Liss, Inc. C1 Mario Negri Inst Pharmacol Res, Dept Oncol, I-24125 Bergamo, Italy. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. IEO, Pathol Lab, Milan, Italy. RP Taraboletti, G (reprint author), Mario Negri Inst Pharmacol Res, Dept Oncol, Via Gavazzeni 11, I-24125 Bergamo, Italy. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 39 TC 20 Z9 29 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 JAN 15 PY 2001 VL 91 IS 2 BP 241 EP 247 DI 10.1002/1097-0215(200002)9999:9999<::AID-IJC1035>3.3.CO;2-G PG 7 WC Oncology SC Oncology GA 388CE UT WOS:000166159200016 PM 11146452 ER EF