FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Moron, JA Zakharova, I Ferrer, JV Merrill, GA Hope, B Lafer, EM Lin, ZC Wang, JB Javitch, JA Galli, A Shippenberg, TS AF Moron, JA Zakharova, I Ferrer, JV Merrill, GA Hope, B Lafer, EM Lin, ZC Wang, JB Javitch, JA Galli, A Shippenberg, TS TI Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine transporter; trafficking; epitope-tagged-hDAT; HEK 293 cells; MAPK; biotinylation ID HUMAN NOREPINEPHRINE TRANSPORTER; MAP KINASE; SEROTONIN TRANSPORTERS; IN-VIVO; STRIATAL SYNAPTOSOMES; FUNCTIONAL REGULATION; TYROSINE KINASES; PHORBOL ESTERS; CELL-LINES; PHOSPHORYLATION AB The dopamine transporter (DAT) regulates the clearance of dopamine (DA) released into the extracellular space and is an important site on which psychostimulants act to produce their effects. Here, we show that mitogen-activated protein kinase (MAPK) regulates the transport capacity and intracellular trafficking of DAT. Incubation of striatal synaptosomes or epitope-tagged human DAT (hDAT) human embryonic kidney (HEK) 293 cells with the MAPK kinase (MEK) inhibitors 1,4-diamino-2,3-dicyano-1,4-bis(omicron-aminophenylmercapto) butadiene and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one decreased DA uptake in a concentration- and time-dependent manner. Kinetic studies revealed a decrease in the capacity of transport (V-max) but no change in K-m. Immunoblotting confirmed labeling of p42 and p44 MAPK in untreated striatal synaptosomes and HEK 293 cells, consistent with constitutive MAPK activation, and the inhibitors used decreased MAPK phosphorylation. Biotinylation and confocal imaging studies showed that MAPK inhibition promoted the clathrin-associated redistribution of hDAT from the plasma membrane to the cytosol. In contrast, transient transfection of hDAT-expressing cells with constitutively active MEK increased the V-max of DA transport without altering K-m. However, only a small increase in hDAT cell surface expression was seen. These data demonstrate an involvement of the MAPK cascade in regulating DAT transport capacity in striatum and that inhibition of this cascade decreases DAT cell surface expression in HEK 293 cells. Furthermore, they highlight the potential role of MAPK as a presynaptic mechanism that regulates DA signaling. C1 NIDA, Integrat Neurosci Sect, Intramural Res Program, Behav Neurosci Branch, Baltimore, MD 21224 USA. NIDA, Integrat Neurosci Sect, Intramural Res Program, Mol Neurobiol Branch, Baltimore, MD 21224 USA. Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. Brooke Army Med Ctr, Dept Clin Invest, Ft Sam Houston, TX 78234 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, Intramural Res Program, Behav Neurosci Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU NIDA NIH HHS [DA11495, DA14684]; NIMH NIH HHS [MH57324]; NINDS NIH HHS [R01 NS029051] NR 66 TC 133 Z9 139 U1 2 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 17 PY 2003 VL 23 IS 24 BP 8480 EP 8488 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 723VU UT WOS:000185452900007 PM 13679416 ER PT J AU Culmsee, C Siewe, J Junker, V Retiounskaia, M Schwarz, S Camandola, S El-Metainy, S Behnke, H Mattson, MP Krieglstein, J AF Culmsee, C Siewe, J Junker, V Retiounskaia, M Schwarz, S Camandola, S El-Metainy, S Behnke, H Mattson, MP Krieglstein, J TI Reciprocal inhibition of p53 and nuclear factor-kappa B transcriptional activities determines cell survival or death in neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE pifithrin; apoptosis; p300; DNA damage; cerebral ischemia; hippocampal cultures ID TUMOR-SUPPRESSOR GENE; HIPPOCAMPAL-NEURONS; EXCITOTOXIC INSULTS; INDUCED APOPTOSIS; DNA-DAMAGE; RAT-BRAIN; MITOCHONDRIAL DYSFUNCTION; SUPEROXIDE-DISMUTASE; CALCIUM HOMEOSTASIS; OXIDATIVE STRESS AB The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 precedes apoptosis in many cell types. Controversial reports exist on the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-kappaB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-kappaB activity declined significantly. The p53 inhibitor pifithrin-alpha (PFT) preserved NF-kappaB activity and protected neurons against apoptosis. Immunoprecipitation experiments revealed enhanced p53 binding to the transcriptional cofactor p300 after induction of DNA damage, whereas binding of p300 to NF-kappaB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-kappaB binding to p300 was enhanced. Most interestingly, similar results were observed after oxygen glucose deprivation in cultured neurons and in ischemic brain tissue. Ischemia-induced repression of NF-kappaB activity was prevented and brain damage was reduced by the p53 inhibitor PFT in a dose-dependent manner. It is concluded that a balanced competitive interaction of p53 and NF-kappaB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-kappaB binding to p300, thereby blocking NF-kappaB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-kappaB-induced survival signaling. C1 Univ Munich, Zentrum Arzneimittelforsch, Dept Pharm, D-81377 Munich, Germany. Univ Marburg, Inst Pharmakol, D-35037 Marburg, Germany. Univ Marburg, Klin Anasthesie & Intens Therapie, D-35037 Marburg, Germany. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Culmsee, C (reprint author), Univ Munich, Zentrum Arzneimittelforsch, Dept Pharm, Butenandtstr 9D, D-81377 Munich, Germany. RI Mattson, Mark/F-6038-2012 NR 63 TC 109 Z9 134 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 SEP 17 PY 2003 VL 23 IS 24 BP 8586 EP 8595 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 723VU UT WOS:000185452900019 PM 13679428 ER PT J AU Chang, SL Szabo, A Tjandra, N AF Chang, SL Szabo, A Tjandra, N TI Temperature dependence of domain motions of calmodulin probed by NMR relaxation at multiple fields SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL-SHIFT ANISOTROPY; TARGET RECOGNITION; DIPOLAR COUPLINGS; BACKBONE DYNAMICS; PROTEINS; SPECTROSCOPY; ORIENTATION; MACROMOLECULES; BIOMOLECULES; STABILITY AB Interdomain motions of Ca2+-ligated calmodulin were characterized by analyzing the nuclear magnetic resonance N-15 longitudinal relaxation rate R-1, transverse relaxation rate R-2, and steady-state {H-1}-N-15 NOE of the backbone amide group at three different magnetic field strengths (18.8, 14.1, and 8.5 T) and four different temperatures (21, 27, 35, and 43 degreesC). Between 35 and 43 degreesC, a larger than expected change in the amplitude and the time scale of the interdomain motion for both N- and C-domains was observed. We attribute this to the shift in population of four residues (74-77) in the central linker from predominantly helical to random coil in this temperature range. This is consistent with the conformation of these residues in the calmodulin-peptide complex, where they are nonhelical. The doubling of the disordered region of the central helix (residues 78-81 at room temperature) when temperature is raised from 35 to 43 degreesC results in larger amplitude interdomain motion. Our analysis of the NMR relaxation data quantifies subtle changes in the interdomain dynamics and provides an additional tool to monitor conformational changes in multidomain proteins. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 31 TC 54 Z9 54 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 17 PY 2003 VL 125 IS 37 BP 11379 EP 11384 DI 10.1021/ja034064w PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 721WQ UT WOS:000185341800060 PM 16220961 ER PT J AU Dobbin, K Shih, JH Simon, R AF Dobbin, K Shih, JH Simon, R TI Questions and answers on design of dual-label microarrays for identifying differentially expressed genes SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CDNA MICROARRAY; CLASS DISCOVERY; BREAST-CANCER; PROFILES; ADENOCARCINOMA; CARCINOMAS; MODELS; LUNG; CLASSIFICATION; HYBRIDIZATION C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Dobbin, K (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN 8124,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 34 TC 54 Z9 56 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 17 PY 2003 VL 95 IS 18 BP 1362 EP 1369 DI 10.1093/jnci/djg049 PG 8 WC Oncology SC Oncology GA 722AV UT WOS:000185352900007 PM 13130111 ER PT J AU Engel, LS Chow, WH Vaughan, TL Gammon, MD Risch, HA Stanford, JL Schoenberg, JB Mayne, ST Dubrow, R Rotterdam, H West, AB Blaser, M Blot, WJ Gail, MH Fraumeni, JF AF Engel, LS Chow, WH Vaughan, TL Gammon, MD Risch, HA Stanford, JL Schoenberg, JB Mayne, ST Dubrow, R Rotterdam, H West, AB Blaser, M Blot, WJ Gail, MH Fraumeni, JF TI Population attributable risks of esophageal and gastric cancers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; GASTROESOPHAGEAL REFLUX DISEASE; SQUAMOUS-CELL CARCINOMA; BODY-MASS INDEX; STOMACH-CANCER; CIGARETTE-SMOKING; UNITED-STATES; ALCOHOL-CONSUMPTION; DIETARY FACTORS; HISTOLOGIC TYPE AB Background: Several risk factors have been identified for esophageal adenocarcinoma, gastric cardia adenocarcinoma, esophageal squamous cell carcinoma, and noncardia gastric adenocarcinoma, but no study has comprehensively examined their contributions to the cancer burden in the general population. Herein, we estimate the population attributable risks (PARs) for various risk factors observed in a multicenter population-based case-control study. Methods: We calculated PARs by using 293 patients with esophageal adenocarcinoma, 261 with gastric cardia adenocarcinoma, 221 with esophageal squamous cell carcinoma, 368 with noncardia gastric adenocarcinoma, and 695 control subjects. We included smoking for all four tumor types and Helicobacter pylori infection for noncardia gastric adenocarcinoma as established causal risk factors as well as several other factors for which causality is under evaluation. Results: Ever smoking, body mass index above the lowest quartile, history of gastroesophageal reflux, and low fruit and vegetable consumption accounted for 39.7% (95% confidence interval [CI] = 25.6% to 55.8%),41.1% (95% CI = 23.8% to 60.9%), 29.7% (95% CI = 19.5% to 42.3%), and 15.3% (95% CI = 5.8% to 34.6%) of esophageal adenocarcinomas, respectively, with a combined PAR of 78.7% (95% CI = 66.5% to 87.3%). Ever smoking and body mass index above the lowest quartile were responsible for 45.2% (95% CI = 31.3% to 59.9%) and 19.2% (95% CI = 4.9% to 52.0%) of gastric cardia adenocarcinomas, respectively, with a combined PAR of 56.2% (95% CI = 38.1% to 72.8%). Ever smoking, alcohol consumption, and low fruit and vegetable consumption accounted for 56.9% (95% Cl = 36.6% to 75.1%), 72.4% (95% CI = 53.3% to 85.8%), and 28.7% (95% CI = 11.1% to 56.5%) of esophageal squamous cell carcinomas, respectively, with a combined PAR of 89.4% (95% CI = 79.1% to 95.0%). Ever smoking, history of gastric ulcers, nitrite intake above the lowest quartile, and H. pylori infection were responsible for 18.3% (95% CI = 6.5% to 41.8%), 9.7% (95% CI = 5.4% to 16.8%), 40.7% (95% CI = 23.4% to 60.7%), and 10.4% (95% CI = 0.3% to 79.6%) of noncardia gastric adenocrcinomas, respectively, with a combined PAR of 59.0% (95% CI = 16.2% to 91.4%). Conclusion: In this population, a few known risk factors account for a majority of esophageal and gastric cancers. These results suggest that the incidence of these cancers may be decreased by reducing the prevalence of smoking, gastroesophageal reflux, and being overweight and by increasing the consumption of fruits and vegetables. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. NYU, Dept Pathol, New York, NY 10016 USA. NYU, Sch Med, Dept Med, New York, NY USA. Int Epidemiol Inst, Rockville, MD USA. RP Engel, LS (reprint author), Mem Sloan Kettering Canc Ctr, Epidemiol Serv, 307 E 63rd St,3rd Floor, New York, NY 10021 USA. OI Engel, Lawrence/0000-0001-9268-4830 FU NCI NIH HHS [N01-CN05230, N02-CP40501, U01-CA57923, U01-CA57949, U01-CA57983] NR 85 TC 347 Z9 359 U1 2 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 17 PY 2003 VL 95 IS 18 BP 1404 EP 1413 DI 10.1093/jnci/djg047 PG 10 WC Oncology SC Oncology GA 722AV UT WOS:000185352900012 PM 13130116 ER PT J AU Taylor, PR Qiao, YL Abnet, CC Dawsey, SM Yang, CS Gunter, EW Wang, W Blot, WJ Dong, ZW Mark, SD AF Taylor, PR Qiao, YL Abnet, CC Dawsey, SM Yang, CS Gunter, EW Wang, W Blot, WJ Dong, ZW Mark, SD TI Prospective study of serum vitamin E levels and esophageal and gastric cancers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; ALPHA-TOCOPHEROL; CASE-COHORT; PROSPECTIVE BASEL; BETA-CAROTENE; FOLLOW-UP; RISK; SUPPLEMENTATION; MICRONUTRIENTS AB Participants in the General Population Trial, a randomized nutrition intervention trial in Linxian, China, who received a combination of selenium, beta-carotene, and vitamin E supplements, had statistically significantly lower cancer mortality rates than those who did not receive the supplements. In the current study, we used a case-cohort design to examine the association between pre-trial serum vitamin E levels and the risks of developing esophageal and gastric cancers during the trial. We measured serum alpha- and gamma-tocopherol and cholesterol levels in 1072 case patients with incident esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or gastric noncardia cancer (GNCC) and in 1053 control subjects. The relative risks for comparisons of the highest to the lowest quartiles of serum alpha-tocopherol were 0.63 (95% confidence interval [CI] = 0.44 to 0.91) for ESCC, 0.84 (95% CI = 0.55 to 1.26) for GCC, and 2.05 (95% CI = 0.89 to 4.75) for GNCC. Serum gamma-tocopherol level was not associated with the incidence of any of these cancers. Our findings provide support for the role of alpha-tocopherol in the etiology of upper gastrointestinal cancers. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. Rutgers State Univ, Piscataway, NJ USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. Int Epidemiol Inst, Rockville, MD USA. RP Taylor, PR (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, 6116 Execut Blvd,Rm 705, Bethesda, MD 20892 USA. RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 NR 23 TC 78 Z9 81 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 17 PY 2003 VL 95 IS 18 BP 1414 EP 1416 DI 10.1093/jnci/djg044 PG 3 WC Oncology SC Oncology GA 722AV UT WOS:000185352900013 PM 13130117 ER PT J AU Lim, HM Lewis, DEA Lee, HJ Liu, MF Adhya, S AF Lim, HM Lewis, DEA Lee, HJ Liu, MF Adhya, S TI Effect of varying the supercoiling of DNA on transcription and its regulation SO BIOCHEMISTRY LA English DT Article ID COLI RNA-POLYMERASE; SITE-SPECIFIC BINDING; ESCHERICHIA-COLI; GAL PROMOTERS; SALMONELLA-TYPHIMURIUM; IN-VITRO; SUPERHELICAL TURNS; GALACTOSE OPERON; RECEPTOR PROTEIN; ALPHA-SUBUNIT AB The effect of superhelicity of DNA templates on transcription is well documented in several cases. However, the amount of supercoiling that is needed to bring about any changes and the steps at which such effects are exerted were not systematically studied. We investigated the effect of DNA supercoiling on transcription from a set of promoters present on a plasmid by using a series of topoisomers with different superhelical densities ranging from totally relaxed to more than physiological. In vitro transcription assays with these topoisomers in the absence and presence of gene regulatory proteins showed that the effect of negative supercoiling on intrinsic transcription varies from promoter to promoter. Some of those promoters, in which DNA superhelicity stimulated transcription, displayed specific optima of superhelical density while others did not. The results also showed that the amounts of abortive RNA synthesis from two of the promoters decreased and full-length RNA increased with increasing supercoiling, indicating for the first time an inverse relationship between full-length and abortive RNA synthesis and supporting a role of DNA superhelicity in promoter clearance. DNA supercoiling might also influence the point of RNA chain termination. Furthermore, the effect of varying the amount of supercoiling on the action of gene regulatory proteins suggested the mode of action, which is consistent with previous results. Our results underscore the importance of DNA supercoiling in fine-tuning promoter activities, which should be relevant in cell physiology given that local changes in chromosomal supercoiling must occur in different environments. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Chungnam Natl Univ, Coll Nat Sci, Dept Biol, Taejon 305764, South Korea. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 62 TC 34 Z9 34 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 16 PY 2003 VL 42 IS 36 BP 10718 EP 10725 DI 10.1021/bi030110t PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 720LQ UT WOS:000185262600020 PM 12962496 ER PT J AU Labno, CM Lewis, CM You, DQ Leung, DW Takesono, A Kamberos, N Seth, A Finkelstein, LD Rosen, MK Schwartzberg, PL Burkhardt, JK AF Labno, CM Lewis, CM You, DQ Leung, DW Takesono, A Kamberos, N Seth, A Finkelstein, LD Rosen, MK Schwartzberg, PL Burkhardt, JK TI Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP SO CURRENT BIOLOGY LA English DT Article ID ALDRICH-SYNDROME PROTEIN; TEC FAMILY KINASES; APC CONTACT SITE; T-CELL RECEPTOR; TYROSINE KINASE; ARP2/3 COMPLEX; VAV PROTEINS; PHOSPHORYLATION; RECRUITMENT; SIGNALS AB Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse [1]. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes [2]. Since T cells from Rik-/-, Itk-/-, and Rik-/- X Itk-/- mice have defects in signaling and development [3], we asked whether Itk or Rik function in actin polymerization at the immune synapse. We find that Itk-/- and Rik-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse. C1 Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RP Burkhardt, JK (reprint author), Childrens Hosp Philadelphia, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. FU NIAID NIH HHS [R01 AI044835, R01-AI44835]; NIGMS NIH HHS [R01 GM056322, R01-GM56322] NR 29 TC 91 Z9 95 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 16 PY 2003 VL 13 IS 18 BP 1619 EP 1624 DI 10.1016/j.cub.2003.08.005 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 722YC UT WOS:000185404800022 PM 13678593 ER PT J AU Xue, YT Gibbons, R Yan, ZJ Yang, DF McDowell, TL Sechi, S Qin, J Zhou, SL Higgs, D Wang, WD AF Xue, YT Gibbons, R Yan, ZJ Yang, DF McDowell, TL Sechi, S Qin, J Zhou, SL Higgs, D Wang, WD TI The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SWI; SNF ID TRANSCRIPTIONAL REGULATOR ATRX; INTERACTING PROTEIN; MENTAL-RETARDATION; BINDING PROTEIN; SWI/SNF COMPLEX; X SYNDROME; APOPTOSIS; PML; MUTATIONS; DOMAINS AB ATRX syndrome is characterized by X-linked mental retardation associated with alpha-thalassemia. The gene mutated in this disease, ATRX, encodes a plant homeodomain-like finger and a SW12/SNF2-like ATPase motif, both of which are often found in chromatin-remodeling enzymes, but ATRX has not been characterized biochemically. By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx. The following evidence supports that ATRX and Daxx are components of an ATP-dependent chromatin-remodeling complex: (i) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; (ii) a proportion of Daxx cofractionates with ATRX as a complex of 1 MDa by gel-filtration analysis; (iii) in extract from cells of a patient with ATRX syndrome, the level of the Daxx-ATRX complex is correspondingly reduced; (iv) a proportion of ATRX and Daxx colocalize in promyelocytic leukemia nuclear bodies, with which Daxx had previously been located; and (v) the ATRX complex displays ATP-dependent activities that resemble those of other chromatin-remodeling complexes, including triple-helix DNA displacement and alteration of mononucleosome disruption patterns. But unlike the previously described SWI/SNF or NURD complexes, the ATRX complex does not randomize DNA phasing of the mononucleosomes, suggesting that it may remodel chromatin differently. Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex. The defects in ATRX syndrome may result from inappropriate expression of genes controlled by this complex. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. John Radcliffe Hosp, Inst Mol Med, Med Res Council Mol Haematol Unit, Oxford OX3 9DU, England. Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, 333 Cassell Dr,TRIAD Ctr Room 4000, Baltimore, MD 21224 USA. NR 45 TC 202 Z9 205 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2003 VL 100 IS 19 BP 10635 EP 10640 DI 10.1073/pnas.1937626100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300014 PM 12953102 ER PT J AU Luca, S White, JF Sohal, AK Filippov, DV van Boom, JH Grisshammer, R Baldus, M AF Luca, S White, JF Sohal, AK Filippov, DV van Boom, JH Grisshammer, R Baldus, M TI The conformation of neurotensin bound to its G protein-coupled receptor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; AGONIST BINDING-SITE; ANGLE-SPINNING NMR; ESCHERICHIA-COLI; ROTATING SOLIDS; CHEMICAL-SHIFTS; AMYLOID FIBRIL; PEPTIDE; RHODOPSIN AB G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of C-13,N-15-labeled NT(8-13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a beta-strand conformation. Our results provide a viable structural template for further pharmacological investigations. C1 Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. NIDDK, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Leiden Univ, Leiden Inst Chem, NL-2333 CC Leiden, Netherlands. RP Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. EM rkgriss@helix.nih.gov; maba@nmr.mpibpc.mpg.de RI Baldus, Marc/C-2737-2009; Grisshammer, Reinhard/C-3089-2015 OI Baldus, Marc/0000-0001-7068-5613; NR 57 TC 170 Z9 172 U1 2 U2 18 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 SEP 16 PY 2003 VL 100 IS 19 BP 10706 EP 10711 DI 10.1073/pnas.1834523100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300026 PM 12960362 ER PT J AU Agarwal, SK Novotny, EA Crabtree, JS Weitzman, JB Yaniv, M Burns, AL Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ AF Agarwal, SK Novotny, EA Crabtree, JS Weitzman, JB Yaniv, M Burns, AL Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ TI Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; C-JUN; ACTIVATED TRANSCRIPTION; CELL-PROLIFERATION; MOUSE DEVELOPMENT; IN-VITRO; AP-1; GENE; PROTEIN; BINDING AB Different components of the AP1 transcription factor complex appear to have distinct effects on cell proliferation and transformation. In contrast to other AN components, JwunD has been shown to inhibit cell proliferation. Also, in prior studies, JunD alone bound menin, product of the MEN1 tumor suppressor gene, and JunD's transcriptional activity was inhibited by menin, suggesting that JunD might achieve all or most of its unique properties through binding to menin. Analyses of JunD and menin effects on proliferation, morphology, and cyclin D1 in stable cell lines unmasked an unexpected growth promoting activity of JunD. Whereas stable overexpression of wild-type (wt) mouse JunD in JunD(-/-) immortalized fibroblasts inhibited their proliferation and reverted their transformed-like phenotype, overexpression of a missense mouse JunD mutant (mJunD(G42E)) with disabled binding to menin showed opposite or growth promoting effects. Similarly, stable overexpression of wt mouse JunD in wt immortalized fibroblasts inhibited growth. In contrast, its overexpression in Men1(-/-) immortalized fibroblasts enhanced their already transformed-like characteristics. To conclude, JunD changed from growth suppressor to growth promoter when its binding to menin was prevented by a JunD mutant unable to bind menin or by Men1-null genetic background. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Inst Pasteur, Dept Dev Biol, CNRS, Unit Gene Express & Dis,URA 1644, F-75015 Paris, France. NIDCD, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 9C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Agarwal, Sunita/D-1428-2016; OI Agarwal, Sunita/0000-0002-7557-3191; Weitzman, Jonathan/0000-0001-8445-0102 NR 31 TC 77 Z9 79 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2003 VL 100 IS 19 BP 10770 EP 10775 DI 10.1073/pnas.1834524100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300037 PM 12960363 ER PT J AU Cheng, HL Mostoslavsky, R Saito, S Manis, JP Gu, YS Patel, P Bronson, R Appella, E Alt, FW Chua, KF AF Cheng, HL Mostoslavsky, R Saito, S Manis, JP Gu, YS Patel, P Bronson, R Appella, E Alt, FW Chua, KF TI Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; DEPENDENT DEACETYLASE; SIR2-LIKE PROTEINS; SIR2-ALPHA PROTEIN; ACETYLATION; NAD; PHOSPHORYLATION; RECOMBINATION; APOPTOSIS AB SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To elucidate SIRT1 function in normal cells, we used gene-targeted mutation to generate mice that express either a mutant SIRT1 protein that lacks part of the catalytic domain or has no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice and cells had essentially the same phenotypes. SIRT1 mutant mice were small, and exhibited notable developmental defects of the retina and heart, and only infrequently survived postnatally. Moreover, SIRT1-deficient cells exhibited p53 hyper-acetylation after DNA damage and increased ionizing radiation-induced thymocyte apoptosis. In SIRT1-deficient embryonic fibroblasts, however, p53 hyper-acetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity. Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Tufts Univ, Sch Vet Med, North Grafton, MA 01536 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Ctr Blood Res, Boston, MA 02115 USA. NR 52 TC 633 Z9 672 U1 3 U2 29 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2003 VL 100 IS 19 BP 10794 EP 10799 DI 10.1073/pnas.1934713100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300041 PM 12960381 ER PT J AU Belnap, DM Watts, NR Conway, JF Cheng, N Stahl, SJ Wingfield, PT Steven, AC AF Belnap, DM Watts, NR Conway, JF Cheng, N Stahl, SJ Wingfield, PT Steven, AC TI Diversity of core antigen epitopes of hepatitis B virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE steric blocking; cryo-electron microscopy; macromolecular docking; discontinuous epitope ID CRYOELECTRON MICROSCOPY; MONOCLONAL-ANTIBODIES; DENSITY MAPS; IMMUNOCHEMICAL STRUCTURE; ELECTRON-MICROSCOPY; ESCHERICHIA-COLI; PROTEIN; PARTICLES; SURFACE; IMMUNOGENICITY AB Core antigen (cAg), the viral capsid, is one of the three major clinical antigens of hepatitis B virus. cAg has been described as presenting either one or two conformational epitopes involving the "immunodominant loop." We have investigated cAg antigenicity by cryo-electron microscopy at approximate to11-Angstrom resolution of capsids labeled with monoclonal Fabs, combined with molecular modeling, and describe here two conformational epitopes. Both Fabs bind to the dimeric external spikes, and each epitope has contributions from the loops on both subunits, explaining their discontinuous nature: however, their binding aspects and epitopes differ markedly. To date, four cAg epitopes have been characterized: all are distinct. Although only two regions of the capsid surface are accessible to antibodies, local clustering of the limited number of exposed peptide loops generates a potentially extensive set of discontinuous epitopes. This diversity has not been evident from competition experiments because of steric interference effects. These observations suggest an explanation for the distinction between cAg and e-antigen (an unassembled form of capsid protein) and an approach to immunodiagnosis, exploiting the diversity of cAg epitopes. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. Inst Biol Struct JP Ebel, Lab Microscopie Elect, F-38027 Grenoble, France. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. OI Conway, James/0000-0002-6581-4748 NR 42 TC 48 Z9 53 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 SEP 16 PY 2003 VL 100 IS 19 BP 10884 EP 10889 DI 10.1073/pnas.1834404100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300056 PM 12954985 ER PT J AU Kobayashi, SD Braughton, KR Whitney, AR Voyich, JM Schwan, TG Musser, JM DeLeo, FR AF Kobayashi, SD Braughton, KR Whitney, AR Voyich, JM Schwan, TG Musser, JM DeLeo, FR TI Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; TOLL-LIKE RECEPTOR-2; GENE-EXPRESSION; INFLAMMATION; PHAGOCYTOSIS; ACTIVATION; IDENTIFICATION; STREPTOCOCCUS; REGULATOR; DEATH AB Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against bacterial pathogens. Recent evidence suggests that PMN apoptosis facilitates resolution of inflammation during bacterial infection. Although progress has been made toward understanding apoptosis in neutrophils, very little is known about transcriptional regulation of this process during bacterial infection. To gain insight into the molecular processes that facilitate resolution of infection, we measured global changes in PMN gene expression during phagocytosis of a diverse group of bacterial pathogens. Genes encoding key effectors of apoptosis were up-regulated, and receptors critical to innate immune function were down-regulated during apoptosis induced by phagocytosis of Burkholderia cepacia, Borrelia hermsii, Listeria monocytogenes, Staphylococcus aureus, and Streptococcus pyogenes. Importantly, we identified genes that comprise a common apoptosis differentiation program in human PMNs after phagocytosis of pathogenic bacteria. Unexpectedly, phagocytosis of Str. pyogenes induced changes in neutrophil gene expression not observed with other pathogens tested, including down-regulation of 21 genes involved in responses to IFN. Compared with other bacteria, PMN apoptosis was significantly accelerated by Str. pyogenes and was followed by necrosis. Thus, we hypothesize that there are two fundamental outcomes for the interaction of bacterial pathogens with neutrophils: (i) phagocytosis of bacteria induces an apoptosis differentiation program in human PMNs that contributes to resolution of bacterial infection, or (ii) phagocytosis of microorganisms such as Str. pyogenes alters the apoptosis differentiation program in neutrophils, resulting in pathogen survival and disease. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. OI DeLeo, Frank/0000-0003-3150-2516 NR 22 TC 216 Z9 228 U1 0 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 SEP 16 PY 2003 VL 100 IS 19 BP 10948 EP 10953 DI 10.1073/pnas.1833375100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300067 PM 12960399 ER PT J AU Garey, J Goodwillie, A Frohlich, J Morgan, M Gustafsson, JA Smithies, O Korach, KS Ogawa, S Pfaff, DW AF Garey, J Goodwillie, A Frohlich, J Morgan, M Gustafsson, JA Smithies, O Korach, KS Ogawa, S Pfaff, DW TI Genetic contributions to generalized arousal of brain and behavior SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE estrogen; motivation; mice; genomics; estrogen receptor ID OVARIECTOMIZED FEMALE MICE; FEAR-RELATED BEHAVIORS; STATISTICAL-ANALYSIS; ESTROGEN; NARCOLEPSY; SLEEP; NEURONS; CORTEX; RAT AB We have identified a generalized arousal component in the behavior of mice. Analyzed by mathematical/statistical approaches across experiments, investigators, and mouse populations, it accounts for about 1/3 of the variance in arousal-related measures. Knockout of the gene coding for the classical estrogen receptor (ER-alpha), a ligand-activated transcription factor, greatly reduced arousal responses. In contrast, disrupting the gene for a likely gene duplication product, ER-beta, did not have these effects. A combination of mathematical and genetic approaches to arousal in an experimentally tractable mammal opens up analysis of a CNS function of considerable theoretical and practical significance. C1 Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. Karolinska Inst, S-14186 Huddinge, Sweden. Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pfaff, DW (reprint author), Rockefeller Univ, Neurobiol & Behav Lab, 1230 York Ave, New York, NY 10021 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NICHD NIH HHS [HD-0575]; PHS HHS [15125] NR 25 TC 59 Z9 60 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2003 VL 100 IS 19 BP 11019 EP 11022 DI 10.1073/pnas.1633773100 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300079 PM 12930901 ER PT J AU Nicolelis, MAL Dimitrov, D Carmena, JM Crist, R Lehew, G Kralik, JD Wise, SP AF Nicolelis, MAL Dimitrov, D Carmena, JM Crist, R Lehew, G Kralik, JD Wise, SP TI Chronic, multisite, multielectrode recordings in macaque monkeys SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NEURONAL INTERACTIONS; MOVEMENT DIRECTION; CORTICAL-NEURONS; INFORMATION; CORTEX; ENSEMBLES; DYNAMICS; SYSTEM; SPACE AB A paradigm is described for recording the activity of single cortical neurons from awake, behaving macaque monkeys. Its unique features include high-density microwire arrays and multichannel instrumentation. Three adult rhesus monkeys received microwire array implants, totaling 96-704 microwires per subject, in up to five cortical areas, sometimes bilaterally. Recordings 3-4 weeks after implantation yielded 421 single neurons with a mean peak-to-peak voltage of 115 +/- 3 muV and a signal-to-noise ratio of better than 5:1. As many as 247 cortical neurons were recorded in one session, and at least 58 neurons were isolated from one subject 18 months after implantation. This method should benefit neurophysiological investigation of learning, perception, and sensorimotor integration in primates and the development of neuroprosthetic devices. C1 Duke Univ, Dept Neurobiol, Durham, NC 27710 USA. Duke Univ, Div Neurosurg, Durham, NC 27710 USA. Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. Duke Univ, Ctr Neuroengn, Durham, NC 27710 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Nicolelis, MAL (reprint author), Duke Univ, Dept Neurobiol, Durham, NC 27710 USA. RI Kipke, Daryl/A-2167-2009 NR 28 TC 375 Z9 396 U1 7 U2 46 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 SEP 16 PY 2003 VL 100 IS 19 BP 11041 EP 11046 DI 10.1073/pnas.1934665100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300083 PM 12960378 ER PT J AU Daly, JW Garraffo, HM Spande, TF Clark, VC Ma, JY Ziffer, H Cover, JF AF Daly, JW Garraffo, HM Spande, TF Clark, VC Ma, JY Ziffer, H Cover, JF TI Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ION VINYLSILANE CYCLIZATIONS; DEPENDENT SODIUM-CHANNEL; SKIN ALKALOIDS; DIET SPECIALIZATION; SYNTHETIC ANALOGS; A ALKALOIDS; CLASSIFICATION; DECAHYDROQUINOLINES; QUINOLIZIDINES; PYRROLIZIDINES AB Dendrobatid poison frogs readily accumulate alkaloids from diet into skin, where such compounds serve as a chemical defense against predators. Arthropods seem to be the source of decahydroquinolines (DHQs), several izidines, coccinellines, spiropyrrolizidines, pumiliotoxins (PTXs), and allopumiliotoxins (aPTXs). A DHQ iso-223F, and PTX (+)-251D were fed to poison frogs of the dendrobatid genera Dendrobates, Epipedobates, and Phyllobates. The two alkaloids were accumulated in skin unchanged except for the three species of Dendrobates, where approximate to80% of accumulated PTX (+)-251D was stereoselectively hydroxylated to aPTX (+)-267A. The unnatural enantiomer PTX (-)-251D was accumulated efficiently when fed to Dendrobates auratus, but was not hydroxylated. The enantiomers of IPTX 251D and their desmethyl analogs were synthesized from N-Boc-protected (-)- and (+)-proline methyl esters. Both PTX (+)-251D and aPTX (+)-267A proved to be potent convulsants in mice, with (+)-267A being approximate to5-fold more toxic than (+)-251D. Both alkaloids were hyperalgesic at the site of injection. The unnatural PTX (-)-251D caused no overt effect in mice. Thus, the evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs. C1 NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Natl Aquarium, Baltimore, MD 21202 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 45 TC 46 Z9 50 U1 1 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 SEP 16 PY 2003 VL 100 IS 19 BP 11092 EP 11097 DI 10.1073/pnas.1834430100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 723CR UT WOS:000185415300092 PM 12960405 ER PT J AU Chae, CU Albert, CM Glynn, RJ Guralnik, JM Curhan, GC AF Chae, CU Albert, CM Glynn, RJ Guralnik, JM Curhan, GC TI Mild ronal insufficiency and risk of congestive heart failure in men and women >= 70 years of age SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHRONIC RENAL-DISEASE; CARDIOVASCULAR-DISEASE; SERUM CREATININE; SYSTOLIC FUNCTION; HYPERTENSION; DYSFUNCTION; PREDICTION; POPULATION; PRESSURE; IMPACT AB Mild renal insufficiency is increasingly recognized as an independent risk factor for cardiovascular disease. However, few data exist regarding its relation to risk of congestive heart failure (CHF), a major public health I problem in the elderly. To determine if mild renal insufficiency is associated with risk of incident CHIF in the elderly, we analyzed data from 3,618 participants in the prospective, community-based Established Populations for Epidemiologic Studies of the Elderly (EPESE), who had no known CHIF and had serum creatinine levels measured from 1987 to 1989. Mean age of the study population was 78.3 +/- 5.4 years; 84% had creatinine values < 1.5 mg/di and 98% had creatinine values less than or equal to2.0 mg/dl. Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault equation. During 3.9 years of follow-up, 488 subjects developed incident CHIF as defined by hospital discharge and death certificate data. In a multivariate proportional hazards model, CrCl was inversely associated with CHIF risk (p value for trend <0.001). Those in the lowest quartile of CrCl (less than or equal to36.9 ml/min) had a nearly twofold (hazards ratio [HR] 1.99, 95% confidence intervals [Cl] 1.43 to 2.79) greater risk of incident CHIF compared with those in the highest quartile (>57.4 ml/min). Renal insufficiency, defined as creatinine greater than or equal to1.5 mg/cll in men and greater than or equal to1.3 mg/dl in, women, was also associated with increased CHIF risk (multivariate HR 1.43, 95% Cl 1.17 to 1.74). Thus, mild renal insufficiency was a strong independent predictor of CHIF in this cohort, suggesting that serum creatinine may offer a readily accessible tool to identify elderly patients at risk for CHF. (C) 2003 by Excerpta Medica, Inc. C1 Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Clin Epidemiol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Sch Med, Boston, MA 02115 USA. NIA, Bethesda, MD 20892 USA. RP Chae, CU (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. FU NHLBI NIH HHS [K08 HL 04154]; NIA NIH HHS [AG 1027] NR 29 TC 46 Z9 48 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 SEP 15 PY 2003 VL 92 IS 6 BP 682 EP 686 DI 10.1016/S0002-9149(03)00822-1 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 721RR UT WOS:000185330800007 PM 12972106 ER PT J AU Glover, CJ Hite, K DeLosh, R Scudiero, DA Fivash, MJ Smith, LR Fisher, RJ Wu, JW Shi, YG Kipp, RA McLendon, GL Sausville, EA Shoemaker, RH AF Glover, CJ Hite, K DeLosh, R Scudiero, DA Fivash, MJ Smith, LR Fisher, RJ Wu, JW Shi, YG Kipp, RA McLendon, GL Sausville, EA Shoemaker, RH TI A high-throughput screen for identification of molecular mimics of Smac/DIABLO utilizing a fluorescence polarization assay SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE apoptosis; IAP; mitochondria; Smac/DIABLO; high-throughput screening; fluorescence polarization assay ID PROTEIN-COUPLED RECEPTORS; CASPASE ACTIVATION; APOPTOSIS PROTEIN; STRUCTURAL BASIS; DRUG DISCOVERY; IAP PROTEINS; BINDING; INHIBITOR; XIAP; SMAC AB Resistance to apoptosis is afforded by inhibitor of apoptosis proteins (IAPs) which bind to and inhibit the caspases responsible for cleavage of substrates leading to apoptotic cell death. Smac (or DIABLO), a proapoptotic protein released from the mitochondrial intermembrane space into the cytosol, promotes apoptosis by binding to IAPs, thus reversing their inhibitory effects on caspases. We have developed a high-throughput fluorescence polarization assay utilizing a fluorescein-labeled peptide similar to the "IAP binding" domain of Smac N terminus complexed with the BIR3 domain of X-linked IAP (XIAP) to identify small-molecule mimics of the action of Smac. The IC(50)s of peptides and a tetrapeptidomimetic homologous to the N terminus of Smac demonstrated the specificity and utility of this assay. We have screened the National Cancer Institute "Training Set" of 230 compounds, with well-defined biological actions, and the "Diversity Set" of 2000 chemically diverse structures for compounds which significantly reduced fluorescence polarization. Highly fluorescing or fluorescence-quenching compounds (false positives) were distinguished from those which interfered with Smac peptide binding to the XIAP-BIR3 in a dose-dependent manner (true positives). This robust assay offers potential for high-throughput screening discovery of novel compounds simulating the action of Smac/DIABLO. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Dev Therapeut Program, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Glover, CJ (reprint author), NCI, Dev Therapeut Program, Frederick, MD 21702 USA. RI Fisher, Robert/B-1431-2009 NR 44 TC 27 Z9 29 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2003 VL 320 IS 2 BP 157 EP 169 DI 10.1016/S0003-2697(03)00389-0 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 717CM UT WOS:000185068100001 PM 12927820 ER PT J AU Bektas, M Jolly, PS Milstien, S Spiegel, S AF Bektas, M Jolly, PS Milstien, S Spiegel, S TI A specific ceramide kinase assay to measure cellular levels of ceramide SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE ceramide; diacylglycerol kinase; ceramide kinase ID DIGLYCERIDE KINASE; ACIDIC SPHINGOMYELINASE; APOPTOSIS; 2ND-MESSENGERS; GENERATION; PATHWAYS; SIGNAL; DEATH; CELLS AB Human ceramide kinase was recently cloned and characterized. Recombinant ceramide kinase is highly active and ceramide is the only lipid that it phosphorylates, indicating that it should be useful for the measurement of ceramide levels in biological samples by conversion to ceramide-1-phosphate, in a manner analogous to that of the widely used Escherichia coli diacylglycerol kinase method. Using recombinant ceramide kinase, we have now developed a rapid and specific enzymatic method to quantify mass levels of long-chain ceramides in cellular lipid extracts. This new ceramide kinase assay is more specific than the commonly used diacylglycerol kinase method because the ubiquitous lipid diacylglycerol, the preferred substrate for diacyglycerol kinase which is usually present at higher concentrations than ceramide and can interfere with ceramide phosphorylation, is completely inactive with ceramide kinase. Moreover, this high specificity eliminates the need for analysis of the lipid product by thin-layer chromatography since ceramide-1-phosphate is the only radiolabeled lipid in organic solvent extracts of ceramide kinase reactions. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Richmond, VA 23298 USA. NIMH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, 1101 E Marschall St,Sanger Hall Rm 2-011,Box 9806, Richmond, VA 23298 USA. FU NCI NIH HHS [CA61774] NR 27 TC 17 Z9 18 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2003 VL 320 IS 2 BP 259 EP 265 DI 10.1016/S0003-2697(03)00388-9 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 717CM UT WOS:000185068100013 PM 12927832 ER PT J AU Beguin, C Andurkar, SV Jin, AY Stables, JP Weaver, DF Kohn, H AF Beguin, C Andurkar, SV Jin, AY Stables, JP Weaver, DF Kohn, H TI Functionalized amido ketones: New anticonvulsant agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID AMINO-ACID-DERIVATIVES; ANTIEPILEPTIC DRUG DEVELOPMENT; N-BENZYLACETAMIDE DERIVATIVES; ASYMMETRIC PRODUCTS; CHIRAL EDUCTS; SUBSTITUENT; ANALOGS; SERIES; ALA AB We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. Dalhousie Univ, Dept Chem, Halifax, NS B3H 4J3, Canada. NINDS, Epilepsy Branch, NIH, Rockville, MD 20852 USA. Queens Univ, Dept Chem, Kingston, ON K7L 3N6, Canada. Midwestern Univ, Sch Pharm, Downers Grove, IL 60515 USA. Univ Houston, Dept Chem, Houston, TX 77204 USA. RP Kohn, H (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM harold_kohn@unc.edu NR 45 TC 17 Z9 18 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 15 PY 2003 VL 11 IS 19 BP 4275 EP 4285 DI 10.1016/S0968-0896(03)00434-6 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 721NL UT WOS:000185322400012 PM 12951158 ER PT J AU Camphausen, K Sproull, M Tantama, S Sankineni, S Scott, T Menard, C Coleman, CN Brechbiel, MW AF Camphausen, K Sproull, M Tantama, S Sankineni, S Scott, T Menard, C Coleman, CN Brechbiel, MW TI Evaluation of copper chelation agents as anti-angiogenic therapy SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID WILSONS-DISEASE; TUMOR-GROWTH; TETRATHIOMOLYBDATE; SUPPRESSION; DERIVATIVES; ANTICOPPER; CANCER; CELLS; BRAIN; IONS AB The design, synthesis and evaluation of N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5,-triaminocyclohexane (tachpyr, 1) derivatives as novel anti-angiogenic agents were performed in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity. The selective nature of the anti-angiogenic agents for human umbilical vein endothelial cells (HUvec) was compared to a normal fibroblast cell line and a human Glioma cell line to evaluate these compounds. N,N',N"-tris(2-mercaptoethyl)-cis,cis-1,3,5-triaminocyclohexane trihydrochloride (3b) was superior to tachpyr in terms of selectivity of its inhibitory activity toward the proliferation of Huvec compared to the fibroblast and human Glioma cell lines. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10,10 Ctr Dr,Bldg 10,Room B3 B69, Bethesda, MD 20892 USA. NR 25 TC 12 Z9 12 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 15 PY 2003 VL 11 IS 19 BP 4287 EP 4293 DI 10.1016/S0968-0896(03)00401-2 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 721NL UT WOS:000185322400013 PM 12951159 ER PT J AU Liu, DG Gao, Y Voigt, JH Lee, K Nicklaus, MC Wu, L Zhang, ZY Burke, TR AF Liu, DG Gao, Y Voigt, JH Lee, K Nicklaus, MC Wu, L Zhang, ZY Burke, TR TI Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID TYROSINE-PHOSPHATASE 1B; LIGAND; MOLECULES AB Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI Frederick, CCR, Lab Med Chem, NIH, Ft Detrick, MD 21702 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. RP Burke, TR (reprint author), NCI Frederick, CCR, Lab Med Chem, NIH, Ft Detrick, MD 21702 USA. RI Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; OI Nicklaus, Marc/0000-0002-4775-7030 NR 11 TC 24 Z9 24 U1 0 U2 0 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 SEP 15 PY 2003 VL 13 IS 18 BP 3005 EP 3007 DI 10.1016/S0960-894X(03)00635-8 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 719TR UT WOS:000185221400013 PM 12941322 ER PT J AU Salcedo, R Zhang, X Young, HA Michael, N Wasserman, K Ma, WH Martins-Green, M Murphy, WJ Oppenheim, JJ AF Salcedo, R Zhang, X Young, HA Michael, N Wasserman, K Ma, WH Martins-Green, M Murphy, WJ Oppenheim, JJ TI Angiogenic effects of prostaglandin E-2 are mediated by up-regulation of CXCR4 on human microvascular endothelial cells SO BLOOD LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; CAPILLARY-TUBE FORMATION; PROTEIN-KINASE-C; GROWTH-FACTOR; PROSTACYCLIN PRODUCTION; RHEUMATOID-ARTHRITIS; ARACHIDONIC-ACID; IN-VIVO; FUNCTIONAL EXPRESSION; TUMOR PROGRESSION AB Stimulation of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increases the expression of CXCR4 on endothelial cells, rendering these cells more responsive to stromal-derived factor 1 (SDF-1), an anglogenic CXC chemokine and unique ligand for CXCR4. Here, we show that prostaglandin E-2 (PGE(2)) mediates the effects of bFGF and VEGF in up-regulating CXCR4 expression on human microvascular endothelial cells (HMECs). Forskolin or 3-isobutyl-1-methyl xanthine (IBMX), 2 inducers of adenylate cyclase, markedly enhanced, whereas cyclooxygenase (COX) inhibitors including aspirin, piroxicam, and NS398 markedly inhibited CXCR4 expression on HMECs. Furthermore, the ability of PGE2 to augment in vitro tubular formation in SDF-1alpha containing matrigel was inhibited completely by blocking CXCR4. Treatment of bFGF- or VEGF-stimulated HMECs with COX inhibitors blocked tubular formation by about 50% to 70%. Prostaglandin-induced human endothelial cell organization and subsequent vascularization can be inhibited to a greater extent by a neutralizing antibody to human CXCR4 in severe combined immunodeficient mice. Additionally, VEGF- and bFGF-induced angiogenesis in vivo was also inhibited by about 50% by NS-398 or piroxicam, and this inhibitory effect was accompanied by decreased expression of CXCR4 on murine endothelial cells. Consequently, by inducing CXCR4 expression, prostaglandin accounts for about 50% of the tubular formation in vitro and in vivo angiogenic effects of VEGF and bFGF. Moreover, augmentation of CXCR4 expression by VEGF, bFGF, and PGE2 involves stimulation of transcription factors binding to the Sp1-binding sites within the promoter region of the CXCR4 gene. These findings indicate that PGE2 is a mediator of VEGF- and bFGF-induced CXCR4-dependent neovessel assembly in vivo and show that anglogenic effects of PGE2 require CXCR4 expression. C1 NCI, Mol Immunoregulat Lab, Expt Immunol Lab,Intramural Res Support Program, Ctr Canc Res,SAIC, Frederick, MD 21702 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. RP Salcedo, R (reprint author), NCI, Mol Immunoregulat Lab, Expt Immunol Lab,Intramural Res Support Program, Ctr Canc Res,SAIC, Bldg 567,Rm 210, Frederick, MD 21702 USA. RI Zhang, Xia/B-8152-2008 OI Zhang, Xia/0000-0002-9040-1486 FU NCI NIH HHS [N01 CO 12400] NR 76 TC 110 Z9 114 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 SEP 15 PY 2003 VL 102 IS 6 BP 1966 EP 1977 DI 10.1182/blood-2002-11-3400 PG 12 WC Hematology SC Hematology GA 721NQ UT WOS:000185322800015 PM 12791666 ER PT J AU Schwartz, GN Vance, BA Levine, BM Fukazawa, M Telford, WG Cesar, D Hellerstein, M Gress, RE AF Schwartz, GN Vance, BA Levine, BM Fukazawa, M Telford, WG Cesar, D Hellerstein, M Gress, RE TI Proliferation kinetics of subpopulations of human marrow cells determined by quantifying in vivo incorporation of [H-2(2)]-glucose into DNA of S-phase cells SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; BONE-MARROW; NONHUMAN-PRIMATES; BROMODEOXYURIDINE; EXPRESSION; QUIESCENCE; TURNOVER; CULTURES; MARKER AB This report investigated in vivo turnover kinetics of marrow hematopoietic progenitors and precursors using a recently developed stable isotope-mass spectrometric technique (SIMST). Human subjects were administered a 2-day infusion of 6,6-[H-2(2)]-glucose, a nontoxic stable isotope-labeled form of glucose, which becomes incorporated into DNA of all S-phase cells. The percent [H-2(2)]-glucose incorporated into DNA in the form of [H-2(2)]-deoxyadenosine (%[H-2(2)]-dA enrichment) was determined by gas chromatography-mass spectrometry. The rate constant of replacement of unlabeled by labeled DNA strands (labeling kinetics) was used to calculate population turnover kinetics of CD34(+) cells, CD133(+) cells, and CD133(-)CD34(+) cells. The observed mean replacement half-life (t(1/2)) was 2.6 days for CD34(+) cells, 2.5 days for CD133(-)CD34(+) cells, and 6.2 days for CD133(+) cells. Results from the estimated rate constant of replacement of labeled by unlabeled DNA (delabeling kinetics) also demonstrated slower turnover rates for CD133(+) cells than for CD133(-)CD34(+) cells. Although there was a relatively rapid initial decrease in the %[H-2(2)]-dA enrichment, low levels of labeled DNA persisted in CD34(+) cells for at least 4 weeks. The results indicate the presence of subpopulations of CD34(+) cells with relatively rapid turnover rates and subpopulations With a slower t(1/2) of 28 days. Results also demonstrate that in vivo [H-2(2)]-glucose-SIMST is sensitive enough to detect differences in turnover kinetics between erythroid and megakaryocyte lineage cells. These studies are the first to demonstrate the use of in Vivo [H-2(2)]-glucose-SIMST to measure in vivo turnover kinetics of subpopulations of CD34(+) cells and precursors in healthy human subjects. C1 NCI, ETIB, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Nutr Sci, Berkeley, CA 94720 USA. RP Gress, RE (reprint author), NCI, ETIB, Med Branch, NIH, Bldg 10,Rm 12S237,MSC 1907,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 41401, AI 43866] NR 36 TC 11 Z9 12 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2003 VL 102 IS 6 BP 2068 EP 2073 DI 10.1182/blood-2003-01-0139 PG 6 WC Hematology SC Hematology GA 721NQ UT WOS:000185322800028 PM 12763933 ER PT J AU Pfeiffer, R McShane, L Wargovich, M Burt, R Kikendall, W Lawson, M Lanza, E Schatzkin, A AF Pfeiffer, R McShane, L Wargovich, M Burt, R Kikendall, W Lawson, M Lanza, E Schatzkin, A TI The effect of a low-fat, high fiber, fruit and vegetable intervention on rectal mucosal proliferation SO CANCER LA English DT Article DE rectal mucosal cell proliferation; Polyp Prevention Trial; dietary intervention; adenoma recurrence; intermediate endpoint ID EPITHELIAL-CELL PROLIFERATION; RANDOMIZED CONTROLLED-TRIAL; POLYP PREVENTION TRIAL; SPORADIC ADENOMA PATIENTS; CALCIUM SUPPLEMENTATION; COLORECTAL ADENOMAS; COLON-CANCER; DAIRY FOODS; HIGH-RISK; DIFFERENTIATION AB BACKGROUND. Because studies of diet and colorectal carcinoma tend to be large and complex, researchers have long been interested in the investigation of dietary exposures in relation to putative intermediate markers of large bowel malignancy, such as colorectal epithelial cell proliferation. The basic hypothesis underlying these investigations is that specific dietary components may reduce or increase the rate of cell proliferation, which, in turn, may reduce or increase neoplastic changes in the large bowel. METHODS. The authors assessed the effects of a 4-year, low-fat, high-fiber, fruit and vegetable-enriched dietary intervention on colorectal epithelial cell proliferation among 399 participants from the Polyp Prevention Trial, a randomized multicenter trial with adenoma recurrence as the primary endpoint. Rectal biopsies were taken from flat, normal appearing mucosa on patients at baseline, after I year, and after 4 years. Two assays, bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA), were used to evaluate two summary measures of proliferation: the labeling index (LI) and the proliferative height (PH). RESULTS. There were no significant differences between changes in LI and PH over the 4-year period for the intervention and control groups. This finding parallels the finding in the larger primary study, in which the dietary intervention did not alter adenoma recurrence rates. CONCLUSIONS. A low-fat, high-fiber, fruit and vegetable-enriched dietary intervention did not alter rectal mucosal cell proliferation rates. Published 2003 by the American Cancer Society. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ S Carolina, Sch Med, Columbia, SC USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Walter Reed Army Med Ctr, Dept Med, Washington, DC 20307 USA. Kaiser Permanente, Dept Med, Sacramento, CA USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pfeiffer, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS-8030, Bethesda, MD 20892 USA. RI Pfeiffer, Ruth /F-4748-2011 NR 23 TC 6 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2003 VL 98 IS 6 BP 1161 EP 1168 DI 10.1002/cncr.11608 PG 8 WC Oncology SC Oncology GA 720TV UT WOS:000185276800007 PM 12973839 ER PT J AU Mariotto, A Warren, JL Knopf, KB Feuer, EJ AF Mariotto, A Warren, JL Knopf, KB Feuer, EJ TI The prevalence of patients with colorectal carcinoma under care in the US SO CANCER LA English DT Article DE colorectal carcinoma; care prevalence; initial diagnosis; monitoring; recurrent/metastatic disease; terminal care ID HEALTH MAINTENANCE ORGANIZATIONS; CANCER-PATIENTS; FOLLOW-UP; SURVIVAL; RATES AB BACKGROUND. Prevalence usually is defined as the proportion of individuals alive who previously had a diagnosis of the disease, regardless of whether the individuals still are receiving treatment or are cured. The objective of this study was to estimate the proportion of elderly patients with colorectal carcinoma (CRC) in the U.S. that actually were receiving care for their disease as a better quantification of the burden of CRC. METHODS. The authors used data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program linked to Medicare claims. Four phases of CRC care were defined: initial diagnosis and treatment, postdiagnostic monitoring, treatment for recurrent/metastatic disease, and terminal care. CRC care prevalence measures by phase were extrapolated to the U.S. population age 65 years and older. RESULTS. For all patients with CRC who were diagnosed between 1975 and 1996, 62% received at least I service related to their CRC in 1996, and patients received an average of 2.1 months per person of CRC care. Among the U.S. population age 65 years and older, 1.81% had I diagnosis of CRC, and (1.81% X 0.62%) 1.12% received at least I service related to their CRC. This translated to 380,783 individuals who received care and 1,210,121 person months of care during 1996. CONCLUSIONS. To the authors' knowledge, this is the first report in which care prevalence has been estimated directly. The classification of CRC care by phases of care provides a very detailed picture of the amount of care delivered in the U.S. population. Person-month estimates can be used to estimate the cost of CRC. Published 2003 by the American Cancer Society. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Annapolis Canc Ctr, Annapolis, MD USA. RP Mariotto, A (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Suite 504 MSC 8317, Bethesda, MD 20892 USA. NR 12 TC 16 Z9 16 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2003 VL 98 IS 6 BP 1253 EP 1261 DI 10.1002/cncr.11631 PG 9 WC Oncology SC Oncology GA 720TV UT WOS:000185276800018 PM 12973850 ER PT J AU Swan, J Edwards, BK AF Swan, J Edwards, BK TI Cancer rates among American Indians and Alaska Natives - Is there a national perspective? SO CANCER LA English DT Article DE cancer surveillance; health disparities; cancer rates; American Indian; Alaska Native; cancer trends; cancer incidence; cancer mortality; cancer death rate; data collection ID AREA SOCIOECONOMIC PATTERNS; UNITED-STATES; BREAST-CANCER; EPIDEMIOLOGY; SURVEILLANCE; MORTALITY; SURVIVAL; PROGRAM AB BACKGROUND. Two important goals of cancer surveillance are to provide milestones in the effort to reduce the cancer burden and to generate observations that form the basis for cancer research and intervention for cancer prevention and control. Determination of the cancer burden among American Indians and Alaska Natives (AIAN) has been difficult largely due to lack of data collection efforts in many areas of the country and misclassification of racial data that results in undercounting of Native Americans. There is a revitalized commitment to improve data collection among the national agencies and organizations. METHODS. Data on cancer trends from 12 areas covered by the Surveillance, Epidemiology and End Results (SEER) Program were reviewed for incidence and death rates for 1992-2000. AIAN trends were examined and compared with trends among other racial/ethnic population groups. Reference was made to studies of disease-specific survival for nine of the SEER areas for 1988-1997. RESULTS. in SEER areas, cancer incidence rates for AIAN populations appeared to be decreasing significantly for lung and breast cancers among women and for prostate cancer among men. However, death rates rose, although not significantly, over the same period, except for a significant decrease in prostate cancer. Among the cancers with rising death rates were lung cancer (ALAN women) and colorectal cancer (AIAN men). In addition, survival often was lower for AIAN populations. CONCLUSIONS. Although the incidence was stable or decreased among AIAN populations, increased death rates and lower survival rates indicate the need for intensified application of cancer prevention and control measures, including screening and treatment. Difficulties in interpretation of data include small population size and substantial interregional differences in rates. Published 2003 by the American Cancer Society. C1 NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Swan, J (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Room 5033, Bethesda, MD 20892 USA. NR 31 TC 38 Z9 38 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2003 VL 98 IS 6 BP 1262 EP 1272 DI 10.1002/cncr.11633 PG 11 WC Oncology SC Oncology GA 720TV UT WOS:000185276800019 PM 12973851 ER PT J AU Sabichi, AL Demierre, MF Hawk, ET Lerman, CE Lippman, SM AF Sabichi, AL Demierre, MF Hawk, ET Lerman, CE Lippman, SM TI Frontiers in cancer prevention research SO CANCER RESEARCH LA English DT Review ID SURGICAL-ADJUVANT-BREAST; FAMILIAL ADENOMATOUS POLYPOSIS; ORAL PREMALIGNANT LESIONS; AFRICAN-AMERICAN SMOKERS; SQUAMOUS-CELL CARCINOMA; ACID RECEPTOR-BETA; 2ND PRIMARY TUMORS; BOWEL-PROJECT P-1; FOLLOW-UP CARE; COLORECTAL ADENOMAS C1 Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. NCI, Gastrointestinal & Other Canc Res Grp, NIH, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Lippman, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, 1515 Holcombe Blvd,Unit 236, Houston, TX 77030 USA. FU NCI NIH HHS [CA16672] NR 128 TC 22 Z9 22 U1 5 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 SEP 15 PY 2003 VL 63 IS 18 BP 5649 EP 5655 PG 7 WC Oncology SC Oncology GA 727RN UT WOS:000185672600001 PM 14522879 ER PT J AU Qiu, CP Shan, L Yu, MS Snyderwine, EG AF Qiu, CP Shan, L Yu, MS Snyderwine, EG TI Deregulation of the cyclin D1/Cdk4 retinoblastoma pathway in rat mammary gland carcinomas induced by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SO CANCER RESEARCH LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE; BREAST CANCERS; D1; EXPRESSION; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; PROGRESSION; IMBALANCE; P27(KIP1); PROMOTER; GROWTH AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a suspected human breast carcinogen found in cooked meat that induces mammary gland cancer in rats. By real time PCR analysis, PhIP-induced rat mammary gland carcinomas showed statistically higher expression of the G(1)-S cyclin D1 (5-fold) and its kinase partner cyclin-dependent kinase (Cdk)-4 (37-fold) in comparison with normal mammary gland, whereas cyclin D2, cyclin D3, and Cdk6 were not statistically changed. Amplification of cyclin D1 was observed by real time PCR in 24% of carcinomas (15 of 63). Only 1 of 47 carcinomas showed Cdk4 amplification. By Western blotting, the level of phospho-Rb was >2-fold higher in carcinomas than in normal mammary gland. By immunohistochemical analysis, cyclin D1, Cdk4, and phospho-Rb nuclear protein expression was 5.7-, 3.9-, and 2.3-fold higher, respectively, in carcinomas than in normal mammary gland, whereas the expression of cyclin D2, cyclin D3, and Cdk6 was similar. Among carcinomas, Cdk4 and phospho-Rb levels were positively correlated with cell proliferation. Previous studies by this laboratory indicated that these carcinomas harbor a high frequency of H-ras mutations. The H-ras pathway is linked to the cell cycle via cyclin D1. The results from the current study implicate cyclin D1/Cdk4, phospho-Rb as a central pathway in PhIP-induced rat mammary gland carcinogenesis. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bldg 37,Room 4146,37 Convent Dr, Bethesda, MD 20892 USA. NR 31 TC 14 Z9 17 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 SEP 15 PY 2003 VL 63 IS 18 BP 5674 EP 5678 PG 5 WC Oncology SC Oncology GA 727RN UT WOS:000185672600004 PM 14522882 ER PT J AU Kataoka, H Bonnefin, P Vieyra, D Feng, XL Hara, Y Miura, Y Joh, T Nakabayashi, H Vaziri, H Harris, CC Riabowol, K AF Kataoka, H Bonnefin, P Vieyra, D Feng, XL Hara, Y Miura, Y Joh, T Nakabayashi, H Vaziri, H Harris, CC Riabowol, K TI ING1 represses transcription by direct DNA binding and through effects on p53 SO CANCER RESEARCH LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; ALPHA-FETOPROTEIN GENE; HEPATOCELLULAR-CARCINOMA; ALTERNATIVE TRANSCRIPTS; REDUCED EXPRESSION; DEPENDENT MANNER; HUMAN HEPATOMA; P33(ING1); PROTEIN; ATBF1 AB The ING family of proteins is involved in the regulation of diverse processes ranging from cell cycle and cellular senescence to apoptosis. These effects are most likely through activation of acetylation-dependent pathways that ultimately alter gene expression. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 function has not been elucidated. In this study, we found that a subset of ING family members strongly repressed human a-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. The p47(ING1a) isoform also repressed AFP promoter activity, but in contrast to other ING isoforms, it repressed the p21(WAF1) promoter. p47(ING3) up-regulated p21(WAF1) promoter activity, but it did not have any effect on the AFP promoter. ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. Indeed, electrophoretic mobility shift assays confirmed that HNF1 binds to AT-motifs, but we found, surprisingly, that the ING1 complexes binding to these AT-motifs were devoid of HNF1 protein. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. In addition, we found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382). These findings provide novel evidence that p33(ING1b) represses AFP transcription by at least two mechanisms, one of which includes p53. The first is by binding to the AT-motif and excluding HNF1 binding while possibly targeting HAT activity to promoter regions, and the second is by increasing the levels of active, acetylated p53 via binding and inhibiting the ability of hSIR2 to deacetylate p53 protein. C1 Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. Univ Calgary, Dept Oncol, Calgary, AB T2N 4N1, Canada. Nagoya City Univ, Grad Sch Med Sci, Dept Mol Neurobiol, Nagoya, Aichi 4678601, Japan. Nagoya City Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulat, Nagoya, Aichi 4678601, Japan. Hokkaido Univ, Grad Sch Med, Dept Biochem, Sapporo, Hokkaido 0608638, Japan. Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. NCI, NIH, Bethesda, MD 20892 USA. RP Riabowol, K (reprint author), 370 HMRB,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. NR 52 TC 81 Z9 87 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2003 VL 63 IS 18 BP 5785 EP 5792 PG 8 WC Oncology SC Oncology GA 727RN UT WOS:000185672600022 PM 14522900 ER PT J AU Cabelof, DC Guo, ZM Raffoul, JJ Sobol, RW Wilson, SH Richardson, A Heydari, AR AF Cabelof, DC Guo, ZM Raffoul, JJ Sobol, RW Wilson, SH Richardson, A Heydari, AR TI Base excision repair deficiency caused by polymerase beta haploinsufficiency: Accelerated DNA damage and increased mutational response to carcinogens SO CANCER RESEARCH LA English DT Article ID HEPATOCARCINOGEN 2-NITROPROPANE; OXIDATIVE STRESS; NUCLEAR-DNA; POLY(ADP-RIBOSE) POLYMERASE; IN-VIVO; LESIONS; CELLS; MICE; XRCC1; METHYLATION AB The base excision repair pathway (BER) is believed to maintain genomic integrity by repairing DNA damage arising spontaneously or induced by oxidizing and alkylating agents. To establish the role of DNA polymerase beta (beta-pol) in BER and beta-pol-dependent BER in maintaining genomic stability, we have measured the impact of a gene-targeted disruption in the beta-pol gene on DNA repair capacity and on in vivo sensitivity to carcinogens. We have extensively phenotyped the DNA beta-pol heterozygous (beta-pol(+/-)) mouse as expressing similar to50% less beta-pol mRNA and protein and as exhibiting an equivalent reduction in the specific activity of beta-pol. We measured BER activity by in vitro G:U mismatch and (8-OH)G:C repair and find that there is a significant reduction in the ability of extracts from beta-pol(+/-) mice to repair these types of DNA damage. In vivo, the beta-pol(+/-) mice sustain higher levels of DNA single-strand breaks as well as increased chromosomal aberrations as compared with beta-pol(+/+) littermates. Additionally, we show that reduction in beta-pol expression and BER activity results in increased mutagenicity of dimethyl sulfate as evidenced by a 2-fold increase in LacI mutation frequency. Importantly, the beta-pol(+/-) mice do not exhibit increased sensitivity to DNA damage induced by N-nitroso-N-ethylurea, ionizing radiation, or UV radiation, which induce damage processed by alternative repair pathways, demonstrating that this model is specifically a BER-deficient model. C1 Wayne State Univ, Dept Nutr & Food Sci, Detroit, MI 48202 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78284 USA. RP Heydari, AR (reprint author), Wayne State Univ, Dept Nutr & Food Sci, 3009 Sci Hall, Detroit, MI 48202 USA. RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 FU NIA NIH HHS [1P01-AG14674, 1P30-AG13319, P01-AG19316]; NIDDK NIH HHS [1R21-DK62256] NR 50 TC 71 Z9 75 U1 1 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 SEP 15 PY 2003 VL 63 IS 18 BP 5799 EP 5807 PG 9 WC Oncology SC Oncology GA 727RN UT WOS:000185672600024 PM 14522902 ER PT J AU Zhang, FJ Pao, W Umphress, SM Jakowlew, SB Meyer, AM Dwyer-Nield, LD Nielsen, LD Takeda, K Gelfand, EW Fisher, JH Zhang, LN Malkinson, AM Mason, RJ AF Zhang, FJ Pao, W Umphress, SM Jakowlew, SB Meyer, AM Dwyer-Nield, LD Nielsen, LD Takeda, K Gelfand, EW Fisher, JH Zhang, LN Malkinson, AM Mason, RJ TI Serum levels of surfactant protein D are increased in mice with lung tumors SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR-I; AIRWAY HYPERRESPONSIVENESS; PULMONARY ADENOCARCINOMAS; CARCINOEMBRYONIC ANTIGEN; EXPRESSION; CANCER; GENE; DIFFERENTIATION; CARCINOMAS; BIOMARKERS AB Most marine lung tumors are composed of differentiated epithelial cells. We have reported previously that surfactant protein (SP)-D is expressed in urethane-induced tumors. Serum levels of SP-D are increased in patients with interstitial lung disease and acute respiratory distress syndrome and in rats with acute lung injury but have not been measured in mice. In this study, we sought to determine whether SP-D could be detected in murine serum and discovered that it was increased in mice bearing lung tumors. Serum SP-D concentration was 5.0 +/- 0.2 ng/ml in normal C57BL/6 mice, essentially absent in SP-D nulls, and 63.6 +/- 9.0 ng/ml in SP-D-overexpressing mice. SP-D in serum was verified by immunoblotting. Serum SP-D was increased in mice bearing tumors induced by three different protocols, and the SP-D level correlated with tumor volume. However, in mice with a single adenoma or a few adenomas, SP-D levels were usually within the normal range. SP-D was expressed by the tumor cells, and there was also a field effect whereby type II cells near the tumor expressed more SP-D than type II cells in the remainder of the lung. Serum SP-D was also increased by lung inflammation. In airway inflammation induced by aerosolized ovalbumin in sensitized BALB/c mice, the serum levels were elevated after challenge. In conclusion, serum SP-D concentration is increased in mice bearing lung tumors and generally reflects the tumor burden but is also elevated during lung inflammation. C1 Natl Jewish Med & Res Ctr, Denver, CO 80206 USA. Denver Hlth & Hosp, Denver, CO 80204 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. NCI, Rockville, MD 20850 USA. RP Mason, RJ (reprint author), Natl Jewish Med & Res Ctr, 1400 Jackson St, Denver, CO 80206 USA. FU NCI NIH HHS [CA33497, K12-CA09712, CA09712, CA96133]; NHLBI NIH HHS [HL-67671, HL-61005, HL-36577] NR 40 TC 17 Z9 17 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 SEP 15 PY 2003 VL 63 IS 18 BP 5889 EP 5894 PG 6 WC Oncology SC Oncology GA 727RN UT WOS:000185672600036 PM 14522914 ER PT J AU Liang, XJ Shen, DW Garfield, S Gottesman, MM AF Liang, XJ Shen, DW Garfield, S Gottesman, MM TI Mislocalization of membrane proteins associated with multidrug resistance in cisplatin-resistant cancer cell lines SO CANCER RESEARCH LA English DT Article ID TRANS-GOLGI NETWORK; CROSS-RESISTANCE; BINDING-PROTEINS; EPITHELIAL-CELLS; CYSTIC-FIBROSIS; ACIDIFICATION; ACCUMULATION; ENDOCYTOSIS; ENDOSOMES; METALS AB The accumulation of [C-14]carboplatin and [H-3]methotrexate is reduced in single-step KB epidermoid adenocarcinoma (KB-CP) cells, which are cross-resistant to carboplatin, methotrexate, and sodium arsenite. In these KB-CP cells, multidrug resistance is accompanied by mislocalization of multidrug resistance associated protein (MRP) 1 and other membrane proteins such as folate-binding protein. MRP1 was not decreased in amount in single-step variants but accumulates in a cytoplasmic fraction, and its apparent molecular weight was altered probably because of reduced glycosylation in resistant cells. This low-density compartment was partially labeled with antibodies to lectin-GSII (a Golgi marker) and Bip/GRP78 (an endoplasmic reticulum marker). Pulse-chase labeling of MRP1 with S-35-methionine and S-35-cysteine and pulse-chase biotinylation of cell surface MRP1 suggests that membrane protein mislocalization is caused mainly by a defect of plasma membrane protein recycling, manifested also as a defect in acidification of lysosomes. The reduced accumulation of cytotoxic compounds in the KB-CP cells is presumed to result from the failure of carrier proteins and/or transporters to localize to the plasma membrane. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 1A09,37 Convent Dr MSC 4254, Bethesda, MD 20892 USA. NR 30 TC 71 Z9 75 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2003 VL 63 IS 18 BP 5909 EP 5916 PG 8 WC Oncology SC Oncology GA 727RN UT WOS:000185672600039 PM 14522917 ER PT J AU Weinreich, DM Elaraj, DM Puhlmann, M Hewitt, SM Carroll, NM Feldman, ED Turner, EM Spiess, PJ Alexander, HR AF Weinreich, DM Elaraj, DM Puhlmann, M Hewitt, SM Carroll, NM Feldman, ED Turner, EM Spiess, PJ Alexander, HR TI Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; PATIENT SURVIVAL; IN-VIVO; ADHESION MOLECULES; TUMOR ANGIOGENESIS; MESSENGER-RNA; BREAST-CANCER; LUNG-CANCER; EXPRESSION; METASTASIS AB Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PNML (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted > 1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Durm). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers. C1 NCI, Ctr Canc Res, Surg Branch, Surg Metab Sect, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Surg Branch, Immunol Sect, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Ctr Canc Res, Surg Branch, Surg Metab Sect, Bldg 10,Room 2B07,10 Ctr Dr, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 41 TC 39 Z9 39 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 SEP 15 PY 2003 VL 63 IS 18 BP 5957 EP 5961 PG 5 WC Oncology SC Oncology GA 727RN UT WOS:000185672600044 PM 14522922 ER PT J AU Schild, LJ Divi, RL Beland, FA Churchwell, MI Doerge, DR da Costa, GG Marques, MM Poirier, MC AF Schild, LJ Divi, RL Beland, FA Churchwell, MI Doerge, DR da Costa, GG Marques, MM Poirier, MC TI Formation of tamoxifen-DNA adducts in multiple organs of adult female cynomolgus monkeys dosed with tamoxifen for 30 days SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER PATIENTS; ENDOMETRIAL SAMPLES; MASS-SPECTROMETRY; LIVER; RATS; GENOTOXICITY; TOREMIFENE; MICE; 4-HYDROXYTAMOXIFEN; IDENTIFICATION AB The use of the antiestrogen tamoxifen (TAM) is associated with an increase in endometrial cancer. TAM-induced endometrial carcinogenesis may proceed through a genotoxin-mediated pathway, although the detection of endometrial TAM-DNA adducts in exposed women is still controversial. In this study, a monkey model has been used to investigate the question of TAM-DNA adduct formation in primates. Two methods have been used to determine TAM-DNA adducts: a TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), using an antiserum that has specificity for (E)-alpha-(deoxyguanosin-N-2-yl)-tamoxifen (dG-TAM) and (E)-alpha-(deoxyguanosin-N-2-yl)-N-desmethyltamoxifen (dG-desmethyl-TAM) and electrospray ionization tandem mass spectrometry (ES-MS/MS) coupled with on-line sample preparation and high-performance liquid chromatography (HPLC). Mature (19 year old) cynomolgus monkeys were given either vehicle control (n = 1) or TAM (n = 3) twice daily for a total dose of 2 mg of TAM/kg body weight (bw)/day for 30 days by naso-gastric intubation. Tissues were harvested, and DNA was isolated from uterus, ovary, liver, brain cortex, and kidney. By TAM-DNA CIA, values for uterine TAM-DNA adducts in two monkeys were 0.9 and 1.7 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts in the same animals were 0.4 and 0.5 adducts/10(8) nucleotides. Liver, brain cortex, and kidney DNA samples from the three exposed monkeys had TAM-DNA levels of 2.1-4.2 adducts/108 nucleotides, 0.4-5.0 adducts/10(8) nucleotides, and 0.7-2.1 adducts/10(8) nucleotides, respectively. By HPLC-ES-MS/MS, the levels of TAM-DNA adducts detected in all tissues were comparable with those observed by TAM-DNA CIA. Thus, values for uterine DNA adducts ranged from 0.5 to 1.4 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts, measurable in two monkeys, were 0.2 and 0.3 adducts/10(8) nucleotides. Liver DNA contained the highest TAM-DNA adduct levels (7.0-11.1 adducts/10(8) nucleotides), whereas brain cortex DNA contained lower adduct levels (0.6-4.8 adducts/10(8) nucleotides) and the lowest levels were measured in the kidney (0.2-0.4 adducts/10(8) nucleotides). This study indicates that cynomolgus monkeys are capable of metabolizing TAM to genotoxic intermediates that form TAM-DNA adducts in multiple tissues. C1 NCI, Carcinogen DNA Interact Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. Univ Tecn Lisboa, Ctr Quim Estrutural, Inst Super Tecn, P-1049001 Lisbon, Portugal. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Canc Res Ctr, NIH, Bldg 37,Room 4032,37 Convent Dr, Bethesda, MD 20892 USA. EM poirierm@exchange.iiih.gov RI Marques, M. Matilde/E-2535-2012 OI Marques, M. Matilde/0000-0002-7526-4962 NR 44 TC 28 Z9 28 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2003 VL 63 IS 18 BP 5999 EP 6003 PG 5 WC Oncology SC Oncology GA 727RN UT WOS:000185672600049 PM 14522927 ER PT J AU Hu, YC Komorowski, RA Graewin, S Hostetter, G Kallioniemi, OP Pitt, HA Ahrendt, SA AF Hu, YC Komorowski, RA Graewin, S Hostetter, G Kallioniemi, OP Pitt, HA Ahrendt, SA TI Thymidylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DISSEMINATED COLORECTAL-CANCER; PROTEIN EXPRESSION; CURATIVE RESECTION; TISSUE MICROARRAY; IMPROVES SURVIVAL; PROGNOSTIC VALUE; RECTAL-CANCER; NECK-CANCER; CHEMOTHERAPY; CHEMORADIATION AB Purpose: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and TS expression may determine clinical response and survival, after therapy with 5-FU in colorectal cancer. 5-FU is also widely used in the adjuvant therapy of pancreatic cancer. Therefore, we explored the hypothesis that TS expression was associated with patient prognosis and the response to adjuvant therapy in pancreatic cancer. Experimental Design: Cylindrical tissue cores from a large retrospective, nonrandomized series covering 132 resected patients were used to build a pancreatic cancer tissue microarray. TS expression was determined using immunohistochemistry. Results: High intratumoral TS expression and low intratumoral TS expression were present in 83 of 132 (63%) and 49 of 132 (37%) tumors, respectively. Median survival among patients with low intratumoral TS expression (18 months) was longer than that among patients with high TS expression (12 months). In multivariate analysis, more advanced pathological stage [risk ratio (RR) = 1.70; P = 0.015], poorly differentiated histology (RR = 1.71; P = 0.015), management with adjuvant therapy (RR = 0.49; P = 0.011), and high TS expression [RR = 1.66; 95% confidence interval (CI) = 1.05-2.63; P = 0.029] were independent predictors of mortality. The risk of death was significantly reduced by any adjuvant therapy (RR = 0.40; 95% CI = 0.18-0.90; P = 0.001) among patients with high TS expression. This difference in survival among patients with low- and high-TS-expressing tumors became more significant when the analysis was restricted to the 73 patients receiving 5-FU-based adjuvant therapy (RR = 0.37; 95% CI = 0.16-0.86; P = 0.0006). In contrast, 5-FU-based adjuvant therapy did not influence survival among patients with low-TS-expressing pancreatic cancer. Conclusions: High TS expression is a marker of poor prognosis in resected pancreatic cancer. Patients with high intratumoral TS expression benefit from adjuvant therapy. C1 Univ Rochester, Dept Surg, Rochester, NY 14642 USA. Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Surg, Milwaukee, WI 53226 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ahrendt, SA (reprint author), Univ Rochester, Dept Surg, Box SURG,601 Elmwood Ave, Rochester, NY 14642 USA. 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 37 TC 53 Z9 54 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 SEP 15 PY 2003 VL 9 IS 11 BP 4165 EP 4171 PG 7 WC Oncology SC Oncology GA 727RU UT WOS:000185673300019 PM 14519641 ER PT J AU Bray, M Wright, ME AF Bray, M Wright, ME TI Role of antibody in recovery from severe vaccinia virus infection - Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID PROGRESSIVE VACCINIA; GAMMA-GLOBULIN; PROTECTION; MECHANISM; DISEASE C1 NIAID, Biodef Clin Res Branch, OCR, OD,NIH, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, OCR, OD,NIH, Rm 5132,6700A Rockledge Dr, Bethesda, MD 20892 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2003 VL 37 IS 6 BP 865 EP 866 DI 10.1086/377282 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 718EA UT WOS:000185131100030 ER PT J AU Haley, M Retter, AS Fowler, D Gea-Banacloche, J O'Grady, NP AF Haley, M Retter, AS Fowler, D Gea-Banacloche, J O'Grady, NP TI The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; IMMUNE GLOBULIN; ECHOVIRUS MENINGOENCEPHALITIS; LINKED AGAMMAGLOBULINEMIA; HEMORRHAGIC-FEVER; ANIMAL VIRUSES; PREVENTION; INFECTION; NEUTRALIZATION; HEPATITIS AB Intravenous immunoglobulin (IVIG) with high titers toWest Nile virus was used as an adjuvant therapy for a patient with West Nile virus encephalitis that did not respond to supportive care. We present this case report and review the evidence supporting the use of high-titer IVIG. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP O'Grady, NP (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, 10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. NR 23 TC 37 Z9 41 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2003 VL 37 IS 6 BP E88 EP E90 DI 10.1086/377172 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 718EA UT WOS:000185131100040 PM 12955669 ER PT J AU Chiusaroli, R Sanjay, A Henriksen, K Engsig, MT Horne, WC Gu, H Baron, R AF Chiusaroli, R Sanjay, A Henriksen, K Engsig, MT Horne, WC Gu, H Baron, R TI Deletion of the gene encoding c-Cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones SO DEVELOPMENTAL BIOLOGY LA English DT Article ID INTEGRIN SIGNALING PATHWAY; SYK TYROSINE KINASE; GROWTH-FACTOR; NEGATIVE REGULATOR; CELL-ADHESION; RING FINGER; MICE; SRC; PROTEIN; RECEPTOR AB During development of the skeleton, osteoclast (OC) recruitment and migration are required for the vascular invasion of the cartilaginous anlage and the ossification of long bones. c-Cbl lies downstream of the vitronectin receptor and forms a complex with c-Src and Pyk2 in a signaling pathway that is required for normal osteoclast motility. To determine whether the decreased motility we observed in vitro in c-Cbl(-/-) OCs translated into decreased cell migration in vivo, we analyzed the long bones of c-Cbl(-/-) mice during development. Initiation of vascularization and replacement of cartilage by bone were delayed in c-Cbl(-/-) mice, due to decreased osteoclast invasion of the hypertrophic cartilage through the bone collar. Furthermore, c-Cbl(-/-) mice show a delay in the formation of secondary centers of ossification, a thicker hypertrophic zone of the growth plate, and a prolonged presence of cartilaginous remnants in the spongiosa, confirming a decrease in resorption of the calcified cartilage. Thus, the decrease in motility of c-Cbl(-/-) osteoclasts observed in vitro results in a decreased ability of osteoclasts to invade and resorb bone and mineralized cartilage in vivo. These results confirm that c-Cbl plays an important role in osteoclast motility and resorbing activity. (C) 2003 Elsevier Inc. All rights reserved. C1 Yale Univ, Sch Med, Dept Orthopaed, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06520 USA. Nord Biosci, Copenhagen, Denmark. NIAID, NIH, Rockville, MD 20852 USA. RP Baron, R (reprint author), Yale Univ, Sch Med, Dept Orthopaed, 333 Cedar St, New Haven, CT 06520 USA. FU NIAMS NIH HHS [AR42927]; NIDCR NIH HHS [DE04724] NR 37 TC 48 Z9 48 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 2003 VL 261 IS 2 BP 537 EP 547 DI 10.1016/S0012-1606(03)00299-9 PG 11 WC Developmental Biology SC Developmental Biology GA 723YZ UT WOS:000185460300017 PM 14499658 ER PT J AU Behar, TN Colton, CA AF Behar, TN Colton, CA TI Redox regulation of neuronal migration in a down syndrome model SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE migration; chemotaxis; glutamate; NMDA; oxidative stress; antioxidants; free radicals ID INTRACELLULAR CA2+ FLUCTUATIONS; EMBRYONIC CORTICAL-NEURONS; DEVELOPING CEREBRAL-CORTEX; D-ASPARTATE RECEPTOR; NMDA RECEPTORS; TRISOMY-16 MOUSE; ALZHEIMERS-DISEASE; BRAIN-DEVELOPMENT; CELL-MIGRATION; ANIMAL-MODEL AB Down syndrome (DS), one of the major genetic causes of mental retardation, is characterized by disrupted corticogenesis produced, in part, by an abnormal layering of neurons in cortical laminas II and III. Because defects in the normal migration of neurons during corticogenesis can result in delayed, cortical radial expansion and abnormalities in cortical layering, we have examined neuronal migration in routine trisomy 16 (Ts16), a mouse model for DS. Using an in vitro assay for chemotaxis, our data demonstrate that the number of acutely dissociated Ts16 cortical neurons migrating in response to glutamate or N-methyl-D-aspartate (NMDA), known chemotactic factors, was decreased compared to normal littermates, suggesting a defect in NMDA receptor- (NMDA(R)-) mediated events. Ts16 neurons did not lack NMDA(R) since expression of mRNA and protein for NMDA(R) subunits was observed in Ts16 cells. However, the number of cells that generated an observable current in response to NMDA was decreased compared to normal littermates. Similar to DS, Ts16 CNS demonstrated an inherent oxidative stress likely caused by the triplication of genes such as SOD1. To determine if the abnormal redox state was a factor in the failure of NMDA(R)-mediated migration in Ts16, we treated Ts16 neurons with either n-acetyl cysteine (NAC) or dithiothrietol (DTT), known antioxidants. The reduction in NMDA(R)(-)mediated migration observed in Ts16 neurons was returned to normal littermate values by NAC or DTT. Our data indicate that oxidative stress may play a key role in the abnormal glutamate-mediated responses during cortical development in the Ts16 mouse and may have an impact on neuronal migration at critical stages. (C) 2003 Elsevier. C1 Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Behar, TN (reprint author), Duke Univ, Med Ctr, Div Neurol, Bryan Res Bldg,Box 2900, Durham, NC 27710 USA. NR 58 TC 23 Z9 23 U1 0 U2 3 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 SEP 15 PY 2003 VL 35 IS 6 BP 566 EP 575 DI 10.1016/S0891-5849(03)00329-0 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 718UE UT WOS:000185164200003 PM 12957649 ER PT J AU Bialkowski, K Kasprzak, KS AF Bialkowski, K Kasprzak, KS TI Inhibition of 8-oxo-2 '-deoxyguanosine 5 '-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) activity of the antimutagenic human MTH1 protein by nucleoside 5 '-diphosphates SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE MTH 1; 8-oxo-dGTPase; 8-oxo-dGTP pyrophosphohydrolase; antimutagenic enzyme; oxidative damage; activity inhibition; free radicals ID HUMAN MUTT HOMOLOG; ENCODING 8-OXO-DGTPASE; HUMAN-CELLS; CADMIUM(II); NUCLEOTIDE; MICE; DNA; ELIMINATION; RECOGNITION; NICKEL(II) AB The hMTH1 protein, a human homologue of E. coli MutT protein, is an enzyme converting 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) to 8-oxo-2'-deoxyguanosine 5'-monophosphate (8-oxo-dGMP) and inorganic pyrophosphate. It is thought to play an antimutagenic role by preventing, the incorporation of promutagenic 8-oxo-dGTP into DNA. As found in our previous investigations, 8-oxo-2'-deoxyguanosine 5'-diphosphate (8-oxod-GDP) strongly inhibited 8-oxo-dGTPase activity of MTH1. Following this finding, in the present study we have tested the canonical ribo- and deoxyribonucleoside 5'-diphosphates (NDPs and dNDPs) for possible inhibition of 8-oxo-dGTP hydrolysis by hMTH1 extracted from CCRF-CEM cells (a human leukemia cell line). Among them, the strongest inhibitors appeared to be dGDP (Ki = 74 muM), dADP (Ki = 147 muM), and GDP (Ki = 502 muM). Other dNDPs and NDPs, such as dCDP, dTDP, ADP, CDP, and UDP were much weaker inhibitors, with Ki in the millimolar range. Based on the present results and published data, we estimate that the strongest inhibitors, dGDP and dADP. at physiological concentrations not exceeding 5 AM and GDP at mean concentration of 30 AM, taken together, can decrease the cellular hMTH1 enzymatic activity vs. 8-oxo-dGTP (expected to remain below 500 pM) by up to 15%. The other five NDPs and dNDPs tested cannot markedly affect this activity. (C) 2003 Elsevier. C1 Ludwik Rydygier Med Univ, Dept Clin Biochem, PL-85092 Bydgoszcz, Poland. Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD USA. RP Bialkowski, K (reprint author), Ludwik Rydygier Med Univ, Dept Clin Biochem, Karlowicza 24, PL-85092 Bydgoszcz, Poland. RI Bialkowski, Karol/E-2328-2014 NR 24 TC 9 Z9 11 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 SEP 15 PY 2003 VL 35 IS 6 BP 595 EP 602 DI 10.1016/S0891-5849(03)00362-9 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 718UE UT WOS:000185164200006 PM 12957652 ER PT J AU Barrantes, ID Davidson, G Grone, HJ Westphal, H Niehrs, C AF Barrantes, ID Davidson, G Grone, HJ Westphal, H Niehrs, C TI Dkk1 and noggin cooperate in mammalian head induction SO GENES & DEVELOPMENT LA English DT Article DE Dkk1; noggin; Wnt; BMP; Spemann organizer; gastrula ID ANTERIOR NEURAL PLATE; MOUSE EMBRYO; FOREBRAIN DEVELOPMENT; VISCERAL ENDODERM; PRIMITIVE ENDODERM; SPEMANNS ORGANIZER; PRECHORDAL PLATE; XENOPUS EMBRYOS; SONIC-HEDGEHOG; GENE AB Growth factor antagonists play important roles in mediating the inductive effects of the Spemann organizer in amphibian embryos and its equivalents in other vertebrates. Dual inhibition of Wnt and BMP signals has been proposed to confer head organizer activity. We tested the requirement of this coinhibition in Xenopus and mice. In Xenopus, simultaneous reduction of the BMP antagonists chordin and noggin, and the Writ antagonist dick-kopf1 (dkk1) leads to anterior truncations. In mice, compound mutants for dkk1 and noggin display severe head defects, with deletion of all head structures anterior to the mid-hindbrain boundary. These defects arise as a result of a failure in anterior specification at the gastrula stage. The results provide genetic evidence for the dual inhibition model and indicate that dkk1 and noggin functionally cooperate in the head organizer. C1 Deutsch Krebsforschungszentrum, Immunochem Abt, Div Mol Embryol, D-69120 Heidelberg, Germany. Deutsch Krebsforschungszentrum, Immunochem Abt, Dept Mol & Cellular Pathol, D-69120 Heidelberg, Germany. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Niehrs, C (reprint author), Deutsch Krebsforschungszentrum, Immunochem Abt, Div Mol Embryol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM Niehrs@DKFZ-Heidelberg.de RI Davidson, Gary/J-6059-2013 NR 63 TC 58 Z9 61 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD SEP 15 PY 2003 VL 17 IS 18 BP 2239 EP 2244 DI 10.1101/gad.269103 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 722NG UT WOS:000185381700004 ER PT J AU Davis-Hayman, SR Hayman, JR Nash, TE AF Davis-Hayman, SR Hayman, JR Nash, TE TI Encystation-specific regulation of the cyst wall protein 2 gene in Giardia lamblia by multiple cis-acting elements SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Giardia lamblia; encystation; transcription; negative regulation; developmental regulation; protozoa ID PROMOTER; IDENTIFICATION; EXPRESSION; BILE AB Giardia lamblia, a worldwide cause of diarrhoea, must differentiate into environmentally resistant cysts for dissemination and completion of its life cycle. Although G. lamblia is an early diverging eukaryote, encystation involves many complex cellular changes including formation of the cyst wall that contains at least two cyst wall proteins, cyst wall proteins 1 and 2. Cwp genes are transcribed only during encystation. In this study, we examine the regulatory elements for the encystation-specific gene cwp2. The 64 bp immediately upstream of the cwp2 open reading frame (-64 to -1 relative to ATG) was shown to be sufficient for the encystation-specific expression of luciferase. To determine which region(s) within this 64 bp contributed to encystation-specific expression in vivo, a series of deletions were cloned into a Giardia luciferase expression vector and their ability to control encystation-specific expression of luciferase was assessed. Deletion of elements in the -64 to -23 region of the cwp2 promoter significantly increased expression of luciferase in vegetative trophozoites, suggesting that this area contains a negative cis-acting element. Deletions of elements from -23 to -10 led to decreased expression in encysting cells, suggesting that this region may contain positive cis-acting elements. When the A/T-rich initiator was deleted but the cis-acting elements (-64 to -10) were retained, encystation-specific expression of luciferase was maintained but an aberrant transcriptional start site was utilised. These results indicate that Giardia has developed a classic repressor mechanism(s) that allows tight, encystation-specific control by the cwp2 promoter. Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. E Tennessee State Univ, James H Quillen Coll Med, Dept Microbiol, Johnson City, TN 37614 USA. RP Nash, TE (reprint author), Bldg 4 Room B1-06,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. NR 18 TC 31 Z9 31 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD SEP 15 PY 2003 VL 33 IS 10 BP 1005 EP 1012 DI 10.1016/S0020-7519(03)00177-2 PG 8 WC Parasitology SC Parasitology GA 727LD UT WOS:000185659000002 PM 13129521 ER PT J AU Worthington, SE Roitberg, AE Krauss, M AF Worthington, SE Roitberg, AE Krauss, M TI Kinetic isotope effects in the active site of B-subtilis chorismate mutase SO INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY LA English DT Article DE kinetic isotope effects; chorismate mutase B. subtilis; enzyme active site; free energy; zero point energies; ab initio reaction path ID EFFECTIVE FRAGMENT POTENTIALS; COMPACT EFFECTIVE POTENTIALS; EXPONENT BASIS-SETS; CLAISEN REARRANGEMENT; TRANSITION-STATE; PREPHENATE REARRANGEMENT; ELECTROSTATIC CATALYSIS; SHIKIMATE METABOLITES; MECHANISM; ENZYME AB Kinetic isotope effects are determined for the enzyme-catalyzed Claisen rearrangement of chorismate to prephenate using computational methods. The calculated kinetic isotope effects (KIEs) compare reasonably with the few available experimental values with both the theory and experiment obtaining a large KIE for the ether oxygen, indicating large polarization of the transition-state geometry. Because there is a question of the extent that the experimental rate constants are for chemistry as the rate-limiting step, the KIEs for all the atoms of the substrate are reported with the exception of the carboxylate groups. A substantial number of large regular and inverse isotope effects are predicted for the hydrogens on the cyclohexadienyl ring related to activation of the reactant and charge reorganization in the transition state. A large KIE is predicted for the hydrogen atom bound to the ether carbon atom because the largest valency change and charge transfer occurs at the ether bond in both the reactant and tansition state. Observation of the overall pattern of predicted KIEs would ensure that conditions are favorable for the rate-limiting chemistry. (C) 2003 Wiley Periodicals, Inc. C1 Univ Florida, Quantum Theory Project, Gainesville, FL 32601 USA. NIDDK, NIH, Bethesda, MD 20892 USA. NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Roitberg, AE (reprint author), Univ Florida, Quantum Theory Project, Gainesville, FL 32601 USA. NR 35 TC 3 Z9 3 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7608 J9 INT J QUANTUM CHEM JI Int. J. Quantum Chem. PD SEP 15 PY 2003 VL 94 IS 5 BP 287 EP 292 DI 10.1002/qua.10641 PG 6 WC Chemistry, Physical; Mathematics, Interdisciplinary Applications; Physics, Atomic, Molecular & Chemical SC Chemistry; Mathematics; Physics GA 716GC UT WOS:000185019600005 ER PT J AU Poliak, S Salomon, D Elhanany, H Sabanay, H Kiernan, B Pevny, L Stewart, CL Xu, XR Chiu, SY Shrager, P Furley, AJW Peles, E AF Poliak, S Salomon, D Elhanany, H Sabanay, H Kiernan, B Pevny, L Stewart, CL Xu, XR Chiu, SY Shrager, P Furley, AJW Peles, E TI Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1 SO JOURNAL OF CELL BIOLOGY LA English DT Article DE axon; node of Ranvier; myelin; cell adhesion; Schwann cell ID POTASSIUM CHANNELS; ADHESION MOLECULE; GLIA INTERACTIONS; NERVOUS-SYSTEM; DEVELOPING CNS; PROTEIN CASPR; SCHWANN-CELLS; PDZ DOMAINS; NEUREXIN; FIBERS AB In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane. C1 Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. Univ Sheffield, Sch Med & Biomed Sci, Ctr Dev Genet, Sheffield S10 2TN, S Yorkshire, England. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA. Univ Wisconsin, Sch Med, Dept Physiol, Madison, WI 53706 USA. RP Peles, E (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RI Furley, Andrew/D-4798-2013; OI Furley, Andrew/0000-0001-5549-8668 FU NINDS NIH HHS [NS17965, R01 NS017965]; PHS HHS [R01-23375] NR 44 TC 248 Z9 252 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 15 PY 2003 VL 162 IS 6 BP 1149 EP 1160 DI 10.1083/jcb.200305018 PG 12 WC Cell Biology SC Cell Biology GA 722WR UT WOS:000185401500017 PM 12963709 ER PT J AU Grieshaber, SS Grieshaber, NA Hackstadt, T AF Grieshaber, SS Grieshaber, NA Hackstadt, T TI Chlamydia trachomatis uses host cell dynein to traffic to the microtubule-organizing center in a p50 dynamitin-independent process SO JOURNAL OF CELL SCIENCE LA English DT Article DE Chlamydia; cytoskeleton; Microtubules; dynein; dynactin ID CYTOPLASMIC DYNEIN; INCLUSION MEMBRANE; PLASMA-MEMBRANE; AXONAL-TRANSPORT; MOTOR PROTEINS; INFECTED-CELLS; GOLGI-COMPLEX; DYNACTIN; VIRUS; PSITTACI AB Chlamydiae are pathogenic obligate intracellular bacteria with a biphasic developmental cycle that involves cell types adapted for extracellular survival (elementary bodies, EBs) and intracellular multiplication (reticulate bodies, RBs). The intracellular development of chlamydiae occurs entirely within a membrane-bound vacuole termed an inclusion. Within 2 hours after entry into host cells, Chlamydia trachomatis EBs are trafficked to the perinuclear region of the host cell and remain in close proximity to the Golgi apparatus, where they begin to fuse with a subset of host vesicles containing sphingomyelin. Here, we provide evidence that chlamydial migration from the cell periphery to the peri-Golgi region resembles host cell vesicular trafficking. Chlamydiae move towards the minus end of microtubules and aggregate at the microtubule-organizing center (MTOC). In mammalian cells the most important minus-end-directed microtubule motor is cytoplasmic dynein. Microinjection of antibodies to a subunit of cytoplasmic dynein inhibited movement of chlamydiae to the MTOC, whereas microinjection of antibodies to the plus-directed microtubule motor, kinesin, had no effect. Surprisingly, overexpression of the protein p50 dynamitin, a subunit of the dynactin complex that links vesicular cargo to the dynein motor in minus directed vesicle trafficking, did not abrogate chlamydial migration even though host vesicle transport was inhibited. Nascent chlamydial inclusions did, however, colocalize with the P150((Glued)) dynactin subunit, which suggests that p150((Glued)) may be required for dynein activation or processivity but that the cargo-binding activity of dynactin, supplied by p50 dynamitin subunits and possibly other subunits, is not. Because chlamydial transcription and translation were required for this intracellular trafficking, chlamydial proteins modifying the cytoplasmic face of the inclusion membrane are probable candidates for proteins fulfilling this function. C1 NIAID, Rocky Mt Lab, Lab Intracellular Parasites, Host Parasite Interact Sect,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Rocky Mt Lab, Lab Intracellular Parasites, Host Parasite Interact Sect,NIH, Hamilton, MT 59840 USA. NR 47 TC 102 Z9 104 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2003 VL 116 IS 18 BP 3793 EP 3802 DI 10.1242/jcs.00695 PG 10 WC Cell Biology SC Cell Biology GA 755GK UT WOS:000187395000014 PM 12902405 ER PT J AU Harlan, LC Clegg, LX Trimble, EL AF Harlan, LC Clegg, LX Trimble, EL TI Trends in surgery and chemotherapy for women diagnosed with ovarian cancer in the united states SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT THERAPY; DATA-BASE; PATTERNS; CARE; CYCLOPHOSPHAMIDE; PACLITAXEL; CISPLATIN; CARCINOMA AB Purpose : We examined patterns of care in a population-based sample of 601 ovarian cancer patients diagnosed in 1991, and a sample of 566 women was selected in 1996 to examine trends in care. Patients and Methods: Patient cases were sampled from within the Surveillance, Epidemiology, and End Results program. Medical records were reabstracted, and treatment data were verified with the treating physician. Results: Across these two time periods, the percentage of women with presumptive stage I, II, and IV disease who received lymph node dissection increased. However, a significant number still were not precisely staged. More than 65% of women with ovarian cancer were given cyclophosphamide in 1991 compared with about 14% in 1996. Paclitaxel increased from 1% to 62% during that time. After adjusting for age, race or ethnicity, registry, income, insurance status, Charlson score, residency training program, and marital status, women with early-stage disease were significantly more often given National Institutes of Health Consensus Development Conference guideline therapy in 1996 than in 1991. However, for women with stage III and IV disease, the use of guideline therapy did not significantly increase. Older women and minorities consistently received less guideline therapy, and the lack of private insurance was an impediment for both Hispanic and nonHispanic black women. Conclusion: Despite guidelines presented by several organizations, significant numbers of women with ovarian cancer are not being provided with appropriate care. This is particularly true for older and minority women, especially those without private insurance. Educational strategies must be devised to increase the number of women receiving guideline therapy and decrease disparities across population groups. (C) 2003 by American Society of Clinical Oncology. C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. NCI, Surveillance Res Program, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Harlan, LC (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. NR 22 TC 96 Z9 96 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2003 VL 21 IS 18 BP 3488 EP 3494 DI 10.1200/JCO.2003.01.061 PG 7 WC Oncology SC Oncology GA 721ZA UT WOS:000185347300018 PM 12972525 ER PT J AU Rosenwald, A Wright, G Leroy, K Yu, X Gaulard, P Gascoyne, RD Chan, WC Zhao, T Haioun, C Greiner, TC Weisenburger, DD Lynch, JC Vose, J Armitage, JO Smeland, EB Kvaloy, S Holte, H Delabie, J Campo, E Montserrat, E Lopez-Guillermo, A Ott, G Muller-Hermelink, HK Connors, JM Braziel, R Grogan, TM Fisher, RI Miller, TP LeBlanc, M Chiorazzi, M Zhao, H Yang, LM Powell, J Wilson, WH Jaffe, ES Simon, R Klausner, RD Staudt, LM AF Rosenwald, A Wright, G Leroy, K Yu, X Gaulard, P Gascoyne, RD Chan, WC Zhao, T Haioun, C Greiner, TC Weisenburger, DD Lynch, JC Vose, J Armitage, JO Smeland, EB Kvaloy, S Holte, H Delabie, J Campo, E Montserrat, E Lopez-Guillermo, A Ott, G Muller-Hermelink, HK Connors, JM Braziel, R Grogan, TM Fisher, RI Miller, TP LeBlanc, M Chiorazzi, M Zhao, H Yang, LM Powell, J Wilson, WH Jaffe, ES Simon, R Klausner, RD Staudt, LM TI Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE gene expression profiling; microarray; outcome prediction; PMBL; DLBCL ID TUMOR-IMMUNITY; EXPRESSION; GENE; B7-H1; DISEASE; PROLIFERATION; ACTIVATION; SCLEROSIS; MECHANISM; PATTERNS AB Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Hop Henri Mondor, Dept Pathol, F-94000 Creteil, France. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Prevent & Social Med, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE 68198 USA. Norwegian Radium Hosp, Dept Immunol, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Oncol, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway. Univ Barcelona, Hosp Clin, Barcelona 08036, Spain. Univ Wurzburg, Dept Pathol, D-97070 Wurzburg, Germany. British Columbia Canc Ctr, Vancouver, BC V5Z 4E6, Canada. Oregon Hlth Sci Univ, SW Oncol Grp, Portland, OR 97239 USA. Oregon Hlth Sci Univ, Dept Pathol, Portland, OR 97239 USA. Univ Arizona, Ctr Canc, Dept Pathol, Tucson, AZ 85724 USA. Univ Arizona, Ctr Canc, Dept Med, Tucson, AZ 85724 USA. Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Bioinformat & Mol Anal Sect, CBEL, CIT, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Rm 4N114, Bethesda, MD 20892 USA. RI Leroy, Karen/E-9235-2011; OI Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU NCI NIH HHS [U01 CA084967, U01-CA84967] NR 36 TC 546 Z9 568 U1 3 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 15 PY 2003 VL 198 IS 6 BP 851 EP 862 DI 10.1084/jem.20031074 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 723DB UT WOS:000185416200002 PM 12975453 ER PT J AU Zhao, XY Sato, A Dela Cruz, CS Linehan, M Luegering, A Kucharzik, T Shirakawa, AK Marquez, G Farber, JM Williams, I Iwasaki, A AF Zhao, XY Sato, A Dela Cruz, CS Linehan, M Luegering, A Kucharzik, T Shirakawa, AK Marquez, G Farber, JM Williams, I Iwasaki, A TI CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer's patch CD11b(+) dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; ACTIVATION-REGULATED CHEMOKINE; THYMUS-EXPRESSED CHEMOKINE; SMALL-INTESTINAL MUCOSA; MOLECULAR-CLONING; RECEPTOR CCR9; LYMPHOCYTES; TECK; LOCALIZATION; HOMEOSTASIS AB The follicle-associated epithelium (FAE) secretes chemokines important in the recruitment of various cell types including CCL20 (MIP-3alpha). CCL20 is chemotactic to the CD11b(+) dendritic cells (DCs) distributed in the subepithelial dome regions of the Peyer's patches, and mice deficient in the receptor for CCL20, CCR6, have been reported to be devoid of the CD11b(+) DCs in the dome regions. Here, we describe another chemokine specifically secreted from the FAE of mouse Peyer's patches, CCL9 (MIP-1gamma, CCF18, MRP-2). By in situ hybridization, we demonstrated that CCL9 mRNA was expressed by the FAE but not by the villus epithelium. At the protein level, CCL9 was detected on the FAE and on extracellular matrix structures within the dome regions of the Peyer's patches. By RT-PCR, we demonstrated that one of the putative receptors for CCL9, CCR1, was expressed by the Peyer's patch CD11b(+) DCs and in a chemotaxis assay, CD11b(+) DCs migrated toward CCL9. To compare the abilities of the chemokines CCL20 and CCL9 to recruit CD11b(+) DCs to the dome regions, we examined the in vivo distribution of these cells in CCR6-deficient, CCL9-blocked wild type, or CCL9-blocked CCR6-deficient mice. To our surprise, using a sensitive immunofluorescence analysis, we observed that CD11b(+) DCs were present in the dome regions of the CCR6-deficient mice. In contrast, Ab neutralization of CCL9 in vivo resulted in significant reduction of the CD11b(+) DC number in the subepithelial dome regions of Peyer's patches of both wild type and CCR6 -/- mice. Taken together, these results demonstrate an important role of CCL9 in CD11b(+) DC recruitment to the dome regions of mouse Peyer's patches. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. NIAID, Inflammat Biol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. Univ Autonoma Madrid, Dept Immunol & Oncol, Ctr Nacl Biotecnol, Consejo Super Invest Cient, Madrid, Spain. RP Iwasaki, A (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 60 Coll St,LEPH 716, New Haven, CT 06520 USA. RI Williams, Ifor/D-3648-2011 OI Williams, Ifor/0000-0002-8810-2911 NR 32 TC 113 Z9 119 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 SEP 15 PY 2003 VL 171 IS 6 BP 2797 EP 2803 PG 7 WC Immunology SC Immunology GA 720DY UT WOS:000185247300010 PM 12960300 ER PT J AU Rabin, RL Alston, MA Sircus, JC Knollmann-Ritschel, B Moratz, C Ngo, D Farber, JM AF Rabin, RL Alston, MA Sircus, JC Knollmann-Ritschel, B Moratz, C Ngo, D Farber, JM TI CXCR3 is induced early on the pathway of CD4(+) T cell differentiation and bridges central and peripheral functions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR EXPRESSION; DENDRITIC CELLS; IFN-GAMMA; IN-VIVO; B-CELLS; CHEMOTACTIC RESPONSIVENESS; LYMPHOID ORGANS; TH2 CELLS; LYMPHOCYTES; MEMORY AB Chemokine receptors on T cells are frequently categorized as functioning either in immune system homeostasis within lymphoid organs, or in peripheral inflammation. CXCR3 is in the latter category and is reported to be expressed selectively on Th1 cells. We found that CXCR3 was expressed in vivo on newly activated tonsillar CD4(+) T cells. Using CD4(+) T cells from cord blood, we found that CXCR3 was induced by cellular activation in vitro independently of the cytokine milieu, although on resting cells, expression was maintained preferentially on those that had been activated in type 1 conditions. In inflamed tonsils, CXCR3(+)CD4(+) T cells were localized around and within germinal centers. The inference that CXCR3 has a role in germinal center reactions was supported by the finding that the CXCR3 ligand CXC chemokine ligand 9 was expressed in a pattern demarcating a subset of germinal centers both in tonsil and in lymph nodes from an HIV-infected individual. We next investigated the role of CXCR3 on peripheral effector/memory CD4(+) T cells by comparing its pattern of expression with that of CCR5, another Th1-cell associated chemokine receptor. Analysis of cells directly from peripheral blood and after activation in vitro suggested that CXCR3 expression preceded that of CCR5, supporting a model of sequential induction of chemokine receptors during CD4(+) T cell differentiation. Taken together, our data show that CXCR3 can be expressed at all stages of CD4(+) T cell activation and differentiation, bridging central function in lymphoid organs and effector function in peripheral tissues. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. USN, Med Ctr, Dept Pathol, Bethesda, MD 20814 USA. RP Farber, JM (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11N228,MSC 1888,10 Ctr Dr, Bethesda, MD 20892 USA. NR 51 TC 52 Z9 54 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 SEP 15 PY 2003 VL 171 IS 6 BP 2812 EP 2824 PG 13 WC Immunology SC Immunology GA 720DY UT WOS:000185247300012 PM 12960302 ER PT J AU Biddison, WE Turner, RV Gagnon, SJ Lev, A Cohen, CJ Reiter, Y AF Biddison, WE Turner, RV Gagnon, SJ Lev, A Cohen, CJ Reiter, Y TI Tax and M1 peptide/HLA-A2-specific Fabs and T cell receptors recognize nonidentical structural features on peptide/HLA-A2 complexes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; HUMAN RECOMBINANT ANTIBODIES; VIRUS MATRIX PROTEIN; IN-SITU DETECTION; CLASS-II COMPLEX; MHC CLASS-II; MONOCLONAL-ANTIBODY; LIGAND RECOGNITION; MULTIPLE-SCLEROSIS; CRYSTAL-STRUCTURE AB Both TCRs and Ab molecules are capable of MHC-restricted recognition of peptide/MHC complexes. However, such MHC restriction is the predominant mode of recognition by T cells, but is extremely rare for B cells. The present study asks whether the dichotomy in Ag recognition modes of T and B cells could be due to fundamental differences in the methods by which TCRs and Abs recognize peptide/MHC complexes. We have compared MHC and peptide recognition by panels of CTL lines specific for the Tax and M1 peptides presented by HLA-A2 plus Tax and M1 peptide/HLA-A2-specific human Fabs that were selected from a naive phage display library. Collectively, the results indicate both striking similarities and important differences between Fab and TCR recognition of MHC and peptide components of the Tax and M1/HLA-A2 complexes. These findings suggest that these two classes of immunoreceptors have solved the problem of specific recognition of peptide/MHC complexes by nonidentical mechanisms. This conclusion is important in part because it indicates that Ab engineering approaches could produce second-generation Ab molecules that more closely mimic TCR fine specificity. Such efforts may produce more efficacious diagnostic and therapeutic agents. The Journal of Immunology, 2003. C1 NIH, Mol Immunol Sect, Neuroimmunol Branch, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Fac Biol, Haifa, Israel. RP Biddison, WE (reprint author), NIH, Mol Immunol Sect, Neuroimmunol Branch, Natl Inst Neurol Disorders & Stroke, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. NR 46 TC 26 Z9 27 U1 1 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 SEP 15 PY 2003 VL 171 IS 6 BP 3064 EP 3074 PG 11 WC Immunology SC Immunology GA 720DY UT WOS:000185247300042 PM 12960332 ER PT J AU Jaruga, B Hong, F Sun, R Radaeva, S Gao, B AF Jaruga, B Hong, F Sun, R Radaeva, S Gao, B TI Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: Up-regulating eotaxins and IL-5 and recruiting leukocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID A-INDUCED HEPATITIS; PRIMARY BILIARY-CIRRHOSIS; CHEMOKINE RECEPTOR CCR3; CONCANAVALIN-A; LIVER-INJURY; EOSINOPHIL RECRUITMENT; AUTOIMMUNE HEPATITIS; IN-VIVO; INFLAMMATION; DISEASE AB T cell-mediated immune responses are implicated in the pathogenesis of a variety of liver disorders; however, the underlying mechanism remains obscure. Con A injection is a widely accepted mouse model to study T cell-mediated liver injury, in which STAT6 is rapidly activated. Disruption of the IL-4 and STAT6 gene by way of genetic knockout abolishes Con A-mediated liver injury without affecting IFN-gamma/STAT1, IL-6/STAT3, or TNF-alpha/NF-kappaB signaling or affecting NKT cell activation. Infiltration of neutrophils and eosinophils in Con A-induced hepatitis is markedly suppressed in IL-4(-/-) and STAT6(-/-) mice compared with wild-type mice. IL-4 treatment induces expression of eotaxins in hepatocytes and sinusoidal endothelial cells isolated from wildtype mice but not from STAT6(-/-) mice. Con A injection induces expression of eotaxins in the liver and elevates serum levels of IL-5 and eotaxins; such induction is markedly attenuated in IL-4(-/-) and STAT6(-/-) mice. Finally, eotaxin blockade attenuates Con A-induced liver injury and leukocyte infiltration. Taken together, these findings suggest that IL-4/STAT6 plays a critical role in Con A-induced hepatitis, via enhancing expression of eotaxins in hepatocytes and sinusoidal endothelial cells, and induces IL-5 expression, thereby facilitating recruitment of eosinophils and neutrophils into the liver and resulting in hepatitis. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg,Room 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. NR 63 TC 106 Z9 108 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2003 VL 171 IS 6 BP 3233 EP 3244 PG 12 WC Immunology SC Immunology GA 720DY UT WOS:000185247300063 PM 12960353 ER PT J AU Morgan, RA Dudley, ME Yu, YYL Zheng, ZL Robbins, PF Theoret, MR Wunderlich, JR Hughes, MS Restifo, NP Rosenberg, SA AF Morgan, RA Dudley, ME Yu, YYL Zheng, ZL Robbins, PF Theoret, MR Wunderlich, JR Hughes, MS Restifo, NP Rosenberg, SA TI High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; SEVERE COMBINED IMMUNODEFICIENCY; BONE-MARROW TRANSPLANTATION; METASTATIC MELANOMA; MONOCLONAL-ANTIBODIES; RETROVIRAL VECTORS; DONOR LEUKOCYTES; THERAPY; IMMUNOTHERAPY; RESPONSES AB The alpha- and beta-chains of the TCR from a highly avid anti-gp100 CTL clone were isolated and used to construct retroviral vectors that can mediate high efficiency gene transfer into primary human lymphocytes. Expression of this TCR gene was confirmed by Western blot analysis, immunocytometric analysis, and HLA Ag tetramer staining. Gene transfer efficiencies of >50% into primary lymphocytes were obtained without selection for transduced cells using a method of prebinding retroviral vectors to cell culture vessels before the addition of lymphocytes. The biological activity of transduced cells was confirmed by cytokine production following coculture with stimulator cells pulsed with gp100 peptides, but not with unrelated peptides. The ability of this anti-gp100 TCR gene to transfer high avidity Ag recognition to engineered lymphocytes was confirmed in comparison with highly avid antimelanoma lymphocytes by the high levels of cytokine production (>200,000 pg/ml IFN-gamma), by recognition of low levels of peptide (<200 pM), and by HLA class I-restricted recognition and lysis of melanoma tumor cell lines. CD4(+) T cells engineered with this anti-gp100 TCR gene were Ag reactive, suggesting CD8-independent activity of the expressed TCR. Finally, nonmelanoma-reactive tumor-infiltrating lymphocyte cultures developed antimelanoma activity following anti-gp100 TCR gene transfer. In addition, tumor-infiltrating lymphocytes with reactivity against non-gp100 melanoma Ags acquired gp100 reactivity and did not lose the recognition of autologous melanoma Ags following gp100 TCR gene transfer. These results suggest that lymphocytes genetically engineered to express anti-gp100 TCR may be of value in the adoptive immunotherapy of patients with melanoma. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B04,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 41 TC 152 Z9 157 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 SEP 15 PY 2003 VL 171 IS 6 BP 3287 EP 3295 PG 9 WC Immunology SC Immunology GA 720DY UT WOS:000185247300069 PM 12960359 ER PT J AU Hoe, NP Fullerton, KE Liu, MY Peters, JE Gackstetter, GD Adams, GJ Musser, JM AF Hoe, NP Fullerton, KE Liu, MY Peters, JE Gackstetter, GD Adams, GJ Musser, JM TI Molecular genetic analysis of 675 group A Streptococcus isolates collected in a carrier study at Lackland Air Force Base, San Antonio, Texas SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID COMPLEMENT-INHIBITING PROTEIN; BETA-HEMOLYTIC STREPTOCOCCI; INVASIVE DISEASE; UNITED-STATES; INFECTIONS; SEROTYPE; PHARYNGITIS; EPIDEMIOLOGY; CHILDREN; STRAINS AB Contemporary molecular genetic analysis methods have not been used to study large samples of carriage isolates of group A Streptococcus. To determine the emm types causing asymptomatic carriage and pharyngitis in a closed population, we analyzed 675 isolates recovered from a population-based surveillance study of 10,634 recruits at Lackland Air Force Base, Texas, during 4 months in 1993-1994. Strains with emm1 and emm6 alleles accounted for only 22% of the isolates recovered from asymptomatic recruits at entrance to training. However, these 2 emm types caused 69% of the pharyngitis cases identified during training and represented 51% of the isolates recovered from the throat on exit from training. Sequence analysis of the hypervariable sic gene documented that distinct emm1 subclones disseminated in specific training groups called flights. The preferential increase in the prevalence of emm1 and emm6 isolates during the 6-week training period indicates an enhanced ability of these strains to disseminate and cause disease in this population. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. McHenry Cty Coll, Dept Biol, Crystal Lake, IL USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. Baylor Coll Med, Dept Family & Community Med, Houston, TX 77030 USA. RP Musser, JM (reprint author), Baylor Coll Med, Dept Pathol, 1 Baylor Plaza, Houston, TX 77030 USA. NR 47 TC 17 Z9 17 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 SEP 15 PY 2003 VL 188 IS 6 BP 818 EP 827 DI 10.1086/377644 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 719QN UT WOS:000185215600004 PM 12964112 ER PT J AU Biggar, RJ Cassol, S Kumwenda, N Lema, V Janes, M Pilon, R Senzani, V Yellin, F Taha, TET Broadhead, RL AF Biggar, RJ Cassol, S Kumwenda, N Lema, V Janes, M Pilon, R Senzani, V Yellin, F Taha, TET Broadhead, RL TI The risk of human immunodeficiency virus-1 infection in twin pairs born to infected mothers in Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TO-CHILD TRANSMISSION; POLYMERASE-CHAIN-REACTION; PERINATAL TRANSMISSION; HIV TRANSMISSION; VAGINAL DELIVERY; CLINICAL-TRIAL; TYPE-1 RNA; PLASMA; INFANTS; WOMEN AB We examined birth order and delivery route as risk factors for mother-to-child transmission of human immunodeficiency virus (HIV)-1 in 315 twin pairs born in Malawi during 1994-1998. No antiretroviral drugs were administered to these subjects. Infections were detected by polymerase chain reaction and were stratified as having occurred either in utero, perinatally, or postnatally. Risk of in utero infection for 630 infants (39 infections) did not differ by birth order (first born, 6.3%; second born, 6.0%). Similarly, in 260 vaginally delivered infants evaluated for perinatal infection (45 infections), risk did not differ by birth order (first born, 15.9%; second born, 18.7%); risk of perinatal infection was significantly lower in cesarean-delivered infants ( \odds ratio, 0.19 [95% confidence interval, 0.02-0.78]). There was no effect on postnatal transmission rates. Thus, in contrast to the authors of earlier studies, we did not find birth order to be an important risk factor for infection in twins. These findings indicate that birth-canal exposure is not a major contributor to a newborn's risk of HIV-1 infection. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Comp Sci Corp, Rockville, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Ottawa, Ottawa, ON, Canada. Johns Hopkins Univ, Coll Med, Res Project, Baltimore, MD 21218 USA. Univ Malawi, Coll Med, Blantyre, Malawi. RP Biggar, RJ (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. NR 33 TC 12 Z9 13 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 SEP 15 PY 2003 VL 188 IS 6 BP 850 EP 855 DI 10.1086/377584 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 719QN UT WOS:000185215600008 PM 12964116 ER PT J AU Dorak, MT Tang, JM Tang, SH Penman-Aguilar, A Coutinho, RA Goedert, JJ Detels, R Kaslow, RA AF Dorak, MT Tang, JM Tang, SH Penman-Aguilar, A Coutinho, RA Goedert, JJ Detels, R Kaslow, RA TI Influence of human leukocyte antigen-B22 alleles on the course of human immunodeficiency virus type 1 infection in 3 cohorts of white men SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th Conference on Retroviruses and Opportunistic Infection CY FEB 24-28, 2002 CL SEATTLE, WASHINGTON ID HLA CLASS-I; HIV-1 INFECTION; DISEASE PROGRESSION; HOMOSEXUAL-MEN; HEPATITIS-C; T-CELLS; CCR5; HAPLOTYPES; AIDS; ASSOCIATIONS AB The human leukocyte antigen (HLA)-B22 serogroup-which consists of the alleles B*54, B*55, and B*56-has been associated with rapidly progressive disease in white patients with human immunodeficiency virus (HIV) infection. Subjects from 3 cohorts of men who have sex with men (N=671), all of whom experienced HIV-1 seroconversion at roughly the same time, were molecularly typed at HLA-A, -B, and -C loci. Mean HIV RNA loads during early HIV infection were higher in B22-positive men than in B22-negative men (difference, 0.481 log(10) HIV RNA copies/mL; 95% confidence interval [CI], 0.156-0.806 log(10) HIV RNA copies/mL; P=.004). Independent of accepted markers of progression, time-to-AIDS was shorter in B22-positive seroconverters (adjusted hazard ratio, 1.98; 95% CI, 1.27-3.10; P=.003). White B22 serogroup alleles (B*55 and *56) appear to predispose to unfavorable outcome of HIV infection as strongly as some or all B*35 and B*53 alleles. This finding may have greater implications for Asians, because the marker frequency for B22 is higher among Asians than among whites (similar to10% vs. similar to4%). C1 Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Multictr AIDS Cohort Study, Los Angeles, CA 90024 USA. Dept Publ Hlth & Environm, Municipal Hlth Serv Amsterdam, Amsterdam Cohort Study, Amsterdam, Netherlands. RP Kaslow, RA (reprint author), Univ Alabama, Sch Publ Hlth, Dept Epidemiol, 1665 Univ Blvd,Ryals Bldg 220A, Birmingham, AL 35294 USA. OI Tang, Jianming/0000-0003-0137-7486 FU NCRR NIH HHS [5-M01-RR-00722]; NIAID NIH HHS [U01-AI-37613, R01 AI41951, U01-AI-35039, U01-AI-35040, U01-AI-35041, U01-AI-35042, U01-AI-35043, U01-AI-37984] NR 46 TC 21 Z9 26 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 SEP 15 PY 2003 VL 188 IS 6 BP 856 EP 863 DI 10.1086/378071 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 719QN UT WOS:000185215600009 PM 12964117 ER PT J AU Hisada, M Chatterjee, N Zhang, MD Battjes, RJ Goedert, JJ AF Hisada, M Chatterjee, N Zhang, MD Battjes, RJ Goedert, JJ TI Increased hepatitis C virus load among injection drug users infected with human immunodeficiency virus and human T lymphotropic virus type II SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th International Meeting on HCV and Related Viruses CY JUL 07-11, 2002 CL LA JOLLA, CALIFORNIA ID STAGE LIVER-DISEASE; PERIPHERAL-BLOOD; NATURAL-HISTORY; FOLLOW-UP; HTLV-II; RISK; COINFECTION; HEMOPHILIA; MORTALITY; HIV AB Coinfection of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) and/or human T-lymphotropic virus type II (HTLV-II) is common among drug users. We compared HCV RNA detection and load in a cohort of 6570 injection drug users from 9 US cities during 1987-1991. Of 385 subjects selected from 16 strata by sex, race (black or nonblack), and HIV/HTLV-II group (HIV positive [HIV+]/HTLV-II+, HIV+/HTLV-II negative [HTLV-II-], HIV-/HTLV-II+, and HIV-/HTLV-II-), 376 had HCV antibodies, of whom 305 had detectable HCV load. HCV RNA detection was unrelated to sex, race, and virus groups, but differed by study site. The mean HCV load was 5.4 log(10) IU/mL and was 0.24 log(10) higher in men than in women. Virus load increment with HIV or HTLV-II infection was higher among white subjects than among other subjects. Compared with HIV-/HTLV-II- subjects, virus load was 0.50, 0.22, and 0.56 log(10) higher in HIV+/HTLV-II-, HIV-/HTLV-II+, and HIV+/HTLV-II+ subjects, respectively. HTLV-II infection significantly increased HCV load in white subjects but not in other racial groups. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NIDA, Rockville, MD USA. Friends Res Inst, Baltimore, MD USA. RP Hisada, M (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,FPS 8008, Rockville, MD 20852 USA. NR 36 TC 13 Z9 15 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 SEP 15 PY 2003 VL 188 IS 6 BP 891 EP 897 DI 10.1086/377585 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 719QN UT WOS:000185215600013 PM 12964121 ER PT J AU Savory, J Herman, MM Ghribi, O AF Savory, J Herman, MM Ghribi, O TI Intracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Article; Proceedings Paper CT 5th Keele Meeting on Aluminium CY FEB 23-25, 2003 CL KEELE, ENGLAND DE aluminum; apoptosis; caspase-3; caspase-12; gadd 153; endoplasmic reticulum; lithium ID CEREBELLAR GRANULE CELLS; BCL-X-L; ENDOPLASMIC-RETICULUM; CYTOCHROME-C; PERMEABILITY TRANSITION; CASPASE-3 ACTIVATION; ALZHEIMERS-DISEASE; LITHIUM; MITOCHONDRIA; BAX AB Loss of neurons is a hallmark of neurodegenerative disorders and there is increasing evidence suggesting that apoptosis is a key mechanism by which neurons die in these diseases. Mitochondrial dysfunction has been implicated in this process of neuronal cell death, but there is a growing body of evidence suggesting also an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondria, or in concert with mitochondrial-initiated pathways. Investigations in our laboratory have focused on neuronal injury resulting from the administration of aluminum maltolate, via the intracisternal route, to New Zealand white rabbits. This treatment induces both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent aluminum-induced neuronal death by interfering with the mitochondrial and/or the endoplasmic reticulum-mediated apoptosis cascade. Cytochrome c release from mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis cascade; this is prevented by lithium treatment. GDNF also protects against aluminum-induced apoptosis but by upregulation of Bcl-X-L, thereby preventing the binding of cytochrome c to Apaf-1. This animal model system involving neurotoxicity induced by an aluminum compound provides new information on mechanisms of neurodegeneration and neuroprotection. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Savory, J (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Pathol, POB 800214, Charlottesville, VA 22908 USA. NR 30 TC 58 Z9 70 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD SEP 15 PY 2003 VL 97 IS 1 BP 151 EP 154 DI 10.1016/S0162-0134(03)00258-7 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 729GL UT WOS:000185764800019 PM 14507471 ER PT J AU Yao, SY Osborne, CS Bharadwaj, RR Pasceri, P Sukonnik, T Pannell, D Recillas-Targa, F West, AG Ellis, J AF Yao, SY Osborne, CS Bharadwaj, RR Pasceri, P Sukonnik, T Pannell, D Recillas-Targa, F West, AG Ellis, J TI Retrovirus silencer blocking by the cHS4 insulator is CTCF independent SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BETA-GLOBIN INSULATOR; HEMATOPOIETIC STEM-CELLS; LOCUS-CONTROL REGION; ENHANCER-BLOCKING; TRANSGENIC MICE; CHROMATIN INSULATOR; TRANSCRIPTIONAL REPRESSION; HISTONE DEACETYLATION; ATTACHMENT REGION; DROSOPHILA EMBRYO AB Silencing of retrovirus vectors poses a significant obstacle to genetic manipulation of stem cells and their use in gene therapy. We describe a mammalian silencer blocking assay using insulator elements positioned between retrovirus silencer elements and an LCRbeta-globin reporter transgene. In transgenic mice, we show that retrovirus silencers are blocked by the cHS4 insulator. Silencer blocking is independent of the CTCF binding site and is most effective when flanking the internal reporter transgene. These data distinguish silencer blocking activity by cHS4 from its enhancer blocking activity. Retrovirus vectors can be created at high titer with one but not two internal dimer cHS4 cores. cHS4 in the LTRs has no effect on expression in transduced F9 cells, suggesting that position effect blocking is not sufficient to escape silencing. The Drosophila insulators gypsy and Scs fail to block silencing in transgenic mice, but gypsy stimulates vector expression 2-fold when located in the LTRs of an infectious retrovirus. The silencer blocking assay complements existing insulator assays in mammalian cells, provides new insight into mechanisms of insulation and is a valuable tool to identify additional silencer blocking insulators that cooperate with cHS4 to improve stem cell retrovirus vector design. C1 Hosp Sick Children, Dev Biol Program, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON, Canada. Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Mol Genet, Mexico City 04510, DF, Mexico. NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. RP Ellis, J (reprint author), Hosp Sick Children, Dev Biol Program, Room 8154,Elm Bldg,555 Univ Ave, Toronto, ON M5G 1X8, Canada. RI Ellis, James/F-4789-2011; OI West, Adam/0000-0003-3502-7804 NR 34 TC 45 Z9 47 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2003 VL 31 IS 18 BP 5317 EP 5323 DI 10.1093/nar/gkg742 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 722AY UT WOS:000185353200011 PM 12954767 ER PT J AU Shabalina, SA Ogurtsov, AY Lipman, DJ Kondrashov, AS AF Shabalina, SA Ogurtsov, AY Lipman, DJ Kondrashov, AS TI Patterns in interspecies similarity correlate with nucleotide composition in mammalian 3 ' UTRs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MESSENGER-RNA DEGRADATION; CAENORHABDITIS-BRIGGSAE; UNTRANSLATED REGIONS; NONCODING SEQUENCES; INTERGENIC REGIONS; GENES; DNA; SUBSTITUTION; VERTEBRATES; EUKARYOTES AB Post-transcriptional regulation and the formation of mRNA 3' ends are crucial for gene expression in eukaryotes. Interspecies conservation of many sequences within 3' UTRs reveals selective constraint due to similar function. To study the pattern of conservation within 3' UTRs, we compiled and aligned 50 sets of complete orthologous 3' UTRs from four orders of mammals. We observed a mosaic pattern of conservation, with alternating regions of high ( phylogenetic footprints) and low similarity. Conservation in 3' UTRs correlates with their base composition and also with the synonymous substitution rate in corresponding coding regions. The non-uniform distribution of conservation is more pronounced for 3' UTRs with a moderate or low level of overall conservation, where invariant nucleotides are more numerous, and their runs of lengths 4 - 7 occur more frequently than if conservation were random. Many runs of invariant nucleotides are AU-rich or pyrimidine-rich. Some of these runs coincide with known functional cis-elements of eukaryotic mRNAs, such as the U-rich upstream element, polyadenylation signal and DICE regulatory signal. More divergent regions of multiple alignments of 3' UTRs are often more G- and/or C-rich. Our results provide evidence on the importance of moderately conserved regions in 3' UTRs and suggest that regulatory functions of 3' UTRs might utilize gene-specific information in these regions. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Shabalina, SA (reprint author), NIH, Natl Ctr Biotechnol Informat, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 NR 36 TC 17 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2003 VL 31 IS 18 BP 5433 EP 5439 DI 10.1093/nar/gkg751 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 722AY UT WOS:000185353200024 PM 12954780 ER PT J AU Sun, GY Kertesz, M Kurti, J Baughman, RH AF Sun, GY Kertesz, M Kurti, J Baughman, RH TI Dimensional change as a function of charge injection in graphite intercalation compounds: A density functional theory study SO PHYSICAL REVIEW B LA English DT Article ID INITIO MOLECULAR-DYNAMICS; WALLED CARBON NANOTUBES; BOND-LENGTH; ELECTRONIC-STRUCTURE; INTERPLANAR BINDING; NEUTRON-DIFFRACTION; PSEUDOPOTENTIALS; GEOMETRIES; SURFACES; DIAMOND AB Charge-induced dimensional changes as a function of charge injection are predicted for graphite intercalation compounds by the means of geometry optimization with density functional theory. A plane wave basis set with periodic boundary condition and ultrasoft pseudopotentials are used in the generalized gradient approximation. Agreement with experiment is obtained for the calculated strain-charge relationship for the graphite sheet and for the calculated inter-layer distances of KC8, XC6 (X=K, Li, Ca, and Ba), C6Cl, C18PF6, and C24AsF6. When the interlayer distances are increased from the optimized values up to 10 A, the charge transfer and basal plane strain in KC6 decrease whereas they remain unchanged in C6Cl. The results of the full calculations, which include specific counterions, are consistent with the results from jellium calculations (in which the counterions are represented by a uniformly distributed background charge). This shows that hybridization between the ions and the graphite sheets is not significant. All of the investigated models provide calculated charge-strain relationships for graphite that are asymmetric with respect to the sign of charge transfer. Expansion occurs for negative charge injection and contraction occurs for positive charge injection, due to the electron-hole symmetry breaking effect of second neighbor antibonding interactions. C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. Eotvos Lorand Univ, Dept Biol Phys, Budapest, Hungary. Univ Texas, Dept Chem, Richardson, TX 75083 USA. Univ Texas, NanoTech Inst, Richardson, TX 75083 USA. RP NCI, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM kertesz@georgetown.edu RI Kertesz, Miklos/E-7122-2010 OI Kertesz, Miklos/0000-0002-7930-3260 NR 47 TC 19 Z9 19 U1 1 U2 9 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2469-9950 EI 2469-9969 J9 PHYS REV B JI Phys. Rev. B PD SEP 15 PY 2003 VL 68 IS 12 AR 125411 DI 10.1103/PhysRevB.68.125411 PG 7 WC Physics, Condensed Matter SC Physics GA 731AG UT WOS:000185861900080 ER PT J AU Olden, K AF Olden, K TI Genomics in environmental health research opportunities and challenges SO TOXICOLOGY LA English DT Meeting Abstract CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol C1 NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. NR 0 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 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 15 PY 2003 VL 191 IS 1 BP 3 EP 3 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 725LM UT WOS:000185544700006 ER PT J AU Waalkes, MP Liu, H Chen, H Diwan, BA AF Waalkes, MP Liu, H Chen, H Diwan, BA TI Mechanisms underlying arsenic carcinogenesis SO TOXICOLOGY LA English DT Meeting Abstract CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol C1 NIEHS, NCI, Res Triangle Pk, NC 27709 USA. NR 0 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 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 15 PY 2003 VL 191 IS 1 BP 4 EP 5 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 725LM UT WOS:000185544700009 ER PT J AU Wexler, P AF Wexler, P TI Toxicology resources from the National Library of Medicine SO TOXICOLOGY LA English DT Meeting Abstract CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol C1 NIH, Toxicol & Environm Hlth Informat Program, Natl Lib Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 15 PY 2003 VL 191 IS 1 BP 17 EP 17 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 725LM UT WOS:000185544700040 ER PT J AU Hong, HL Ton, TV Devereux, TR Moomaw, C Clayton, N Chan, P Dunnick, JK Sills, RC AF Hong, HL Ton, TV Devereux, TR Moomaw, C Clayton, N Chan, P Dunnick, JK Sills, RC TI Chemical-specific alterations in ras, p53, and beta-catenin genes in hemangiosarcomas from B6C3F1 mice exposed to o-nitrotoluene or riddelliine for 2 years SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID DNA ADDUCT FORMATION; VINYL-CHLORIDE; LIVER-TUMORS; RISK-ASSESSMENT; LUNG-TUMORS; MUTATIONS; MOUSE; CARCINOMAS; CARCINOGENESIS; TUMORIGENESIS AB The most prominent neoplastic lesions in mice in the 2-year studies of o-nitrotoluene and riddelliine were hemangiosarcomas. Fifteen o-nitrotoluene-induced hemangiosarconnas of the skeletal muscle, subcutaneous tissue, and mesentery; 12 riddelliine-induced hemangiosarcomas of the liver; and 15 spontaneous subcutaneous hemangiosarcomas were examined for genetic alterations in ras, p53, and beta-catenin genes. Mutations in at least one of these genes were identified in 13 of 15 (87%) of the o-nitrotoluene-induced hemangiosarcomas with missense mutations in p53 exons 5-8 detected in 11 of 15 (73%) of these neoplasms. Seven of 15 (47%) hemangiosarcomas from mice exposed to o-nitrotoluene had deletions at exon 2 splice sites or smaller deletions in the beta-catenin gene. K-ras mutation was detected in only I of the 15 (7%) o-nitrotoluene-induced hemangiosarcomas. In contrast to the o-nitrotoluene study, 7/12 (58%) riddellime-induced hemangiosarcomas had K-ras codon 12 GTT mutations and, when screened by immunohistochemistry, 9/12 (75%) had strong staining for the p53 protein in malignant endothelial cells, the cells of origin of hemangiosarcomas. Riddellime-induced hemangiosarcomas were negative for the beta-catenin protein. Spontaneous hemangiosarcomas from control mice lacked both p53 and beta-catenin protein expression and ras mutations. Our data indicated that P53 and beta-catenin mutations in the o-nitrotoluene-induced hemangiosarcomas and K-ras mutations and p53 protein expression in riddellime-induced hemangiosarcomas most likely occurred as a result of the genotoxic effects of these chemicals. It also suggests that these mutations play a role in the pathogenesis of the respective hemangiosarcomas in B6C3F1(1) mice. (C) 2003 Elsevier Inc. All rights reserved. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Gen Toxicol, Res Triangle Pk, NC 27709 USA. RP Hong, HL (reprint author), 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hong@niehs.nih.gov NR 31 TC 21 Z9 22 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2003 VL 191 IS 3 BP 227 EP 234 DI 10.1016/S0041-008X(03)00165-0 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 725EU UT WOS:000185531500004 PM 13678655 ER PT J AU Pavletic, SZ Bociek, RG Foran, JM Rubocki, RJ Kuszynski, CA Wisecarver, JL Hatcher, L Lucas, DM Byrd, JC Grever, MR Joshi, SS Hardiman, P Smith, LM McGuire, TR Bierman, PJ Vose, JM Armitage, JO Talmadge, JE AF Pavletic, SZ Bociek, RG Foran, JM Rubocki, RJ Kuszynski, CA Wisecarver, JL Hatcher, L Lucas, DM Byrd, JC Grever, MR Joshi, SS Hardiman, P Smith, LM McGuire, TR Bierman, PJ Vose, JM Armitage, JO Talmadge, JE TI Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation SO TRANSPLANTATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; THERAPY; CYTOREDUCTION AB Nonmyeloablative allogeneic stem-cell transplantation (alloNST) is the focus of investigations searching for less-toxic transplantation regimens. We report studies on the kinetics of lymphodepletion and safety of pentostatin (PT) conditioning in alloNST. Patients with hematologic malignancy received mobilized blood from human leukocyte antigen-matched related (n=4) or unrelated (n=8) donors. PT 4 mg/m(2) was administered on days -21, -20, and -19 and 200 cGy of total-body irradiation was administered on day -1, followed by cyclosporine A and mycophenolate mofetil. Mononuclear cell adenosine deaminase after PT was inhibited 84%. The absolute CD3(+) cells decreased significantly by day -7 (49%) and CD19(+) cells declined 92% by day -1. CD4(+) cells were depressed more than CD8(+) cells. Neutrophils and monocytes were minimally affected by PT. Median posttransplant peripheral blood chimerism on day 70 showed 95% donor leukocytes and 82.5% donor CD3 lymphocytes. PT demonstrated lymphodepleting effects and promising safety, supporting alloNST as early as 7 days after initiation of PT. C1 Univ Nebraska, Med Ctr, Dept Internal Med, Hematol Oncol Sect, Omaha, NE USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. Univ Nebraska, Med Ctr, Dept Prevent & Societal Med, Omaha, NE USA. Univ Nebraska, Med Ctr, Coll Pharm, Omaha, NE USA. Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. RP Pavletic, SZ (reprint author), NCI, Expt Transplantat & Immunol Branch, Graft Versus Host & Autoimmun Unit, Bldg 10,Room 12S241,10 Ctr Dr, Bethesda, MD 20892 USA. RI Talmadge, James/A-5916-2008; Lucas, David/E-3555-2011 OI Talmadge, James/0000-0002-6328-6056; NR 10 TC 14 Z9 14 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 SEP 15 PY 2003 VL 76 IS 5 BP 877 EP 881 DI 10.1097/01.TP.0000084869.08639.A0 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 722KV UT WOS:000185374700027 PM 14501873 ER PT J AU Pletnev, AG St Claire, M Elkins, R Speicher, J Murphy, BR Chanock, RM AF Pletnev, AG St Claire, M Elkins, R Speicher, J Murphy, BR Chanock, RM TI Molecularly engineered live-attenuated chimeric West Nile/dengue virus vaccines protect rhesus monkeys from West Nile virus SO VIROLOGY LA English DT Article ID TICK-BORNE ENCEPHALITIS; DENGUE TYPE-4 VIRUSES; CANDIDATE; CELLS; MICE; NEUROVIRULENCE; IMMUNOGENICITY; RECOMBINANT; MUTAGENESIS; FLAVIVIRUS AB Two molecularly engineered, live-attenuated West Nile virus (WN) vaccine candidates were highly attenuated and protective in rhesus monkeys. The vaccine candidates are chimeric viruses (designated WN/DEN4) bearing the membrane precursor and envelope protein genes of WN on a backbone of dengue 4 virus (DEN4) with or without a deletion of 30 nucleotides (Delta30) in the 3' noncoding region of DEN4. Viremia in WN/DEN4- infected monkeys was reduced 100-fold compared to that in WN- or DEN4-infected monkeys. WN/DEN4-3'Delta30 did not cause detectable viremia, indicating that it is even more attenuated for monkeys. These findings indicate that chimerization itself and the presence of the Delta30 mutation independently contribute to the attenuation phenotype for nonhuman primates. Despite their high level of attenuation in monkeys, the chimeras induced a moderate-to-high titer of neutralizing antibodies and prevented viremia in monkeys challenged with WN. The more attenuated vaccine candidate, WN/DEN4-3'Delta30, will be evaluated first in our initial clinical studies. (C) 2003 Elsevier Inc. All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD 20852 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6351,50 S Dr MSC 8007, Bethesda, MD 20892 USA. NR 23 TC 69 Z9 72 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2003 VL 314 IS 1 BP 190 EP 195 DI 10.1016/S0042-6822(03)00450-1 PG 6 WC Virology SC Virology GA 728PT UT WOS:000185726100019 PM 14517072 ER PT J AU Ma, K Wang, K AF Ma, K Wang, K TI Malleable conformation of the elastic PEVK segment of titin: non-co-operative interconversion of polyproline II helix, beta-turn and unordered structures SO BIOCHEMICAL JOURNAL LA English DT Article DE circular dichroism (CD); elastic protein; nuclear magnetic resonance (NMR); polyproline II helix-coil (PhC) motif; titin; trans-to-cis-proline isomerization ID PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM; STRIATED-MUSCLE; SKELETAL-MUSCLE; GIANT PROTEIN; IDENTIFICATION; SPECTROSCOPY; PEPTIDE; DOMAIN; MOTIF AB To understand the structural basis of molecular elasticity and protein interaction of the elastic PEVK (Pro-Glu-Val-Lys) segment of the giant muscle protein titin, we carried out a detailed analysis of a representative PEVK module and a 16-module PEVK protein under various environmental conditions. Three conformational states, polyproline II (PPII) helix, beta-turn and unordered coil were identified by CID and NMR. These motifs interconvert without Iona-range co-operativity. As a general trend, the relative content of PPII increases with lower temperature and higher polarity, beta-turn increases with lower temperature and lower polarity, and unordered coil increases with higher temperature and higher polarity. NMR studies demonstrate that trans-proline residues are the predominant form at room temperature (22 degreesC), with little trans-to-cis isomerization below 35 degreesC. Ionic strength affects salt bridges between charged side chains, but not the backbone conformation. We conclude that titin PEVK conformation is malleable and responds to subtle environmental changes without cooperativity. This gradual conformational transition may represent a regulatory mechanism for fine-tuning protein interactions and elasticity. C1 NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, K (reprint author), NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NR 50 TC 36 Z9 37 U1 0 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD SEP 14 PY 2003 VL 374 BP 687 EP 695 DI 10.1042/BJ20030702 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 725MK UT WOS:000185546800011 PM 12816538 ER PT J AU Jackson, JB Musoke, P Fleming, T Guay, LA Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Owor, M Ducar, C Deseyve, M Mwatha, A Emel, L Duefield, C Mirochnick, M Fowler, MG Mofenson, L Miotti, P Gigliotti, M Bray, D Mmiro, F AF Jackson, JB Musoke, P Fleming, T Guay, LA Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Owor, M Ducar, C Deseyve, M Mwatha, A Emel, L Duefield, C Mirochnick, M Fowler, MG Mofenson, L Miotti, P Gigliotti, M Bray, D Mmiro, F TI Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VERTICAL TRANSMISSION; RECEIVING NEVIRAPINE; ORAL ZIDOVUDINE; COTE-DIVOIRE; SOUTH-AFRICA; DOUBLE-BLIND; WOMEN; TYPE-1; REGIMEN AB Background In 1999, we reported safety and efficacy data for short-course nevirapine from a Ugandan perinatal HIV-1 prevention trial when 496 babies were followed up to age 14-16 weeks. Safety and efficacy data are now presented for all babies followed up to 18 months of age. Methods From November, 1997, to April, 1999, HIV-1 infected pregnant women in Kampala, Uganda, were randomly assigned nevirapine (200 mg at labour onset and 2 mg/kg for babies within 72 h of birth; regimen A) or zidovudine (600 mg orally at labour onset and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily for babies for 7 days, regimen B). Infant HIV-1 testing was done at birth, age 6-8 and 14-16 weeks, and age 12 months by HIV-1 RNA PCR, and by HIV-1 antibody at 18 months. HIV-1 transmission and HIV-1-free survival were assessed using Kaplan-Meier analysis. We recorded adverse experiences through 6-8 weeks postpartum for mothers, and 18 months for babies. Efficacy analyses were by intention to treat. Findings We enrolled 645 mothers to the study: 313 were assigned regimen A, 313 regimen B, and 19 placebo. Eight mothers were lost to follow-up before delivery. 99% of babies were breastfed (median duration 9 months). Estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were 10.3% and 8.1% at birth (p=0.35); 20.0% and 11.8% by age 6-8 weeks (p=0.0063); 22.1% and 13.5% by age 14-16 weeks (p=0.0064); and 25.8% and 15.7% by age 18 months (p=0.0023). Nevirapine was associated with a 41% (95% CI 16-59) reduction in relative risk of transmission through to age 18 months. Both regimens were well-tolerated with few serious side-effects. Interpretation Intrapartum/neonatal nevirapine significantly lowered HIV-1 transmission risk in a breastfeeding population in Uganda compared with a short intrapartum/neonatal zidovudine regimen. The absolute 8.2% reduction in transmission at 6-8 weeks was sustained at age 18 months (10.1% [95% CI 3.5-16.6]). This simple, inexpensive, well-tolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. Makerere Univ, Dept Pediat, Kampala, Uganda. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. Makerere Univ, Dept Obstet & Gynaecol, Kampala, Uganda. Family Hlth Int, Durham, NC USA. Boston Univ, Dept Pediat, Boston, MA 02215 USA. NIAID, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. GlaxoWellcome, London, England. RP Jackson, JB (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Carnegie Bldg Room 420,600 N Wolfe St, Baltimore, MD 21287 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [U01-AI-48054, N01-AI-35173, N01-AI-45200, N0I-AI-35173-417, U01-AI-46745] NR 33 TC 319 Z9 327 U1 0 U2 19 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 13 PY 2003 VL 362 IS 9387 BP 859 EP 868 DI 10.1016/S0140-6736(03)14341-3 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 721RH UT WOS:000185329400010 PM 13678973 ER PT J AU Enunlu, I Papai, G Cserpan, I Udvardy, A Jeang, KT Boros, I AF Enunlu, I Papai, G Cserpan, I Udvardy, A Jeang, KT Boros, I TI Different isoforms of PRIP-interacting protein with methyltransferase domain/trimethylguanosine synthase localizes to the cytoplasm and nucleus SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE PIMT; Tgs1; WAIT-1; DTL; methyltransferase; cytoskeleton; yeast two-hybrid ID EVOLUTIONARY CONSERVATION; HYPERMETHYLATION; REQUIRES; CLONING; DOMAIN; PIMT AB A protein family including the recently identified PIMT/Tgs1 (PRIP-interacting protein with methyltransferase domain/trimethylguanosine synthase) was identified by searching databases for homologues of a newly identified Drosophila protein with RNA-binding activity and methyltransferase domain. Antibodies raised against a short peptide of the mammalian homologue show a 90-kDa isoform expressed specifically in rat brain and testis and a 55-kDa form expressed ubiquitously. In HeLa cells, the larger isoform of the protein is nuclear and associated with a 600-kDa complex, while the smaller isoform is mainly cytoplasmic and co-localizes to the tubulin network. Inhibition of PIMT/Tgs1 expression by siRNA in HeLa cells resulted in an increase in the percentage of cells in G2/M phases. In yeast two-hybrid and in vitro GST pull down experiments, the conserved C-terminal region of PIMT/Tgs1 interacted with the WD domain containing EED/WAIT-1 that acts as a polycomb-type repressor in the nucleus and also binds to integrins in the cytoplasm. Our experiments, together with earlier data, indicate that isoforms of the PIMT/Tgs1 protein with an RNA methyltransferase domain function both in the nucleus and in the cytoplasm and associate with both elements of the cytoskeletal network and nuclear factors known to be involved in gene regulation. (C) 2003 Elsevier Inc. All rights reserved. C1 Inst Biochem, H-6726 Szeged, Hungary. Inst Genet, Biol Res Ctr, H-6726 Szeged, Hungary. NIAID, Mol Virol Sect LMM, NIH, Bethesda, MD 20892 USA. Univ Szeged, Dept Genet & Mol Biol, H-6726 Szeged, Hungary. RP Boros, I (reprint author), Inst Biochem, Temesvari Krt 62, H-6726 Szeged, Hungary. RI Jeang, Kuan-Teh/A-2424-2008 NR 16 TC 12 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 12 PY 2003 VL 309 IS 1 BP 44 EP 51 DI 10.1016/S0006-291X(03)01514-6 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 718WA UT WOS:000185168400008 PM 12943661 ER PT J AU Gieffers, J Tamplin, V Maass, M Belland, RJ Caldwell, HD AF Gieffers, J Tamplin, V Maass, M Belland, RJ Caldwell, HD TI Micromanipulation of the Chlamydia pneumoniae inclusion: implications for cloning and host-pathogen interactions SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE micromanipulation; microinjection; mycoplasma; cloning; Chlamydia ID CURRENT KNOWLEDGE; TRACHOMATIS; MYCOPLASMA; DECONTAMINATION; CONTAMINATION; MEMBRANE; STRAINS AB The Chlamydia trachomatis inclusion is fragile, rendering it incompatible to micromanipulation. We show that the Chlamydia pneumoniae inclusion differs, being resistant to micromanipulation as shown by direct microinjection of the infected host cytosol or the inclusion itself. We have used micromanipulation to clone C pneumoniae and to free it from mycoplasma contamination. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. Med Univ Lubeck, Inst Med Microbiol & Hyg, D-23538 Lubeck, Germany. NIAID, Microscopy Branch, NIH, Hamilton, MT 59840 USA. RP Gieffers, J (reprint author), NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. NR 13 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD SEP 12 PY 2003 VL 226 IS 1 BP 45 EP 49 DI 10.1016/S0378-1097(03)00563-9 PG 5 WC Microbiology SC Microbiology GA 724PQ UT WOS:000185496300007 PM 13129606 ER PT J AU Murphy, PJM Morishima, Y Chen, HF Galigniana, MD Mansfield, JF Simons, SS Pratt, WB AF Murphy, PJM Morishima, Y Chen, HF Galigniana, MD Mansfield, JF Simons, SS Pratt, WB TI Visualization and mechanism of assembly of a glucocorticoid receptor center dot Hsp70 complex that is primed for subsequent Hsp90-dependent opening of the steroid binding cleft SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK-PROTEIN; 7-AMINO ACID SEQUENCE; CHAPERONE SYSTEM; PROGESTERONE-RECEPTOR; LIGAND-BINDING; CONFORMATIONAL-CHANGES; ESCHERICHIA-COLI; AMINO-TERMINUS; REACTION CYCLE; HSP90 AB A minimal system of five proteins, hsp90, hsp70, Hop, hsp40, and p23, assembles glucocorticoid receptor (GR).hsp90 heterocomplexes and causes the simultaneous opening of the steroid binding cleft to access by steroid. The first step in assembly is the ATP-dependent and hsp40 (YDJ-1)-dependent formation of a GR.hsp70 complex that primes the receptor for subsequent ATP-dependent activation by hsp90, Hop, and p23. This study focuses on three aspects of the GR priming reaction with hsp70. First, we have visualized the primed GR.hsp70 complexes by atomic force microscopy, and we find the most common stoichiometry to be 1: 1, with some complexes of a size similar to1: 2 and a few complexes of larger size. Second, in a recent study of progesterone receptor priming, it was shown that hsp40 binds first, leading to the notion that it targets hsp70 to the receptor. We show here that hsp40 does not perform such a targeting function in priming the GR. Third, we focus on a short amino-terminal segment of the ligand binding domain that is required for GR.hsp90 heterocomplex assembly. By using two glutathione S-transferase (GST)/ligand binding domain fusions with (GST/520C) and without (GST/ 554C) hsp90 binding and steroid binding activity, we show that the priming step with hsp70 occurs with GST/ 554C, and it is the subsequent assembly step with hsp90 that is defective. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. Univ Michigan, Coll Engn, N Campus Electron Microbeam Anal Lab, Ann Arbor, MI 48109 USA. NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD 20892 USA. RP Pratt, WB (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 Med Sci Res Bldg 3, Ann Arbor, MI 48109 USA. OI GALIGNIANA, MARIO/0000-0002-9130-8574 FU NCI NIH HHS [CA28010]; NIDDK NIH HHS [DK31573] NR 40 TC 33 Z9 36 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 34764 EP 34773 DI 10.1074/jbc.M304469200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400007 PM 12807878 ER PT J AU Ten Hagen, KG Tran, DT Gerken, TA Stein, DS Zhang, ZY AF Ten Hagen, KG Tran, DT Gerken, TA Stein, DS Zhang, ZY TI Functional characterization and expression analysis of members of the UDP-GalNAc : polypeptide N-acetylgalactosaminyltransferase family from Drosophila melanogaster SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACETYL-D-GALACTOSAMINE; MOLECULAR-CLONING; CDNA CLONING; CAENORHABDITIS-ELEGANS; O-GLYCANS; MUCIN; GENE; GLYCOSYLATION; SEQUENCE; N-ACETYLGALACTOSAMINYLTRANSFERASE-T3 AB Here we report the cloning and functional characterization of eight members of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase gene family from Drosophila melanogaster (polypeptide GalNAc transferase = pgant1-8). Full-length cDNAs were isolated from a Drosophila embryonic library based on homology to known ppGaNTases. Alignments with characterized mammalian isoforms revealed strong sequence similarities between certain fly and mammalian isoforms, highlighting putative orthologues between the species. In vitro activity assays demonstrated biochemical transferase activity for each gene, with three isoforms requiring glycosylated substrates. Comparison of the activities of Drosophila and mammalian orthologues revealed conservation of substrate preferences against a panel of peptide and glycopeptide substrates. Furthermore, Edman degradation analysis demonstrated that preferred sites of GalNac addition were also conserved between certain fly and mammalian orthologues. Semi-quantitative PCR amplification of Drosophila cDNA revealed expression of most isoforms at each developmental stage, with some isoforms being less abundant at certain stages relative to others. In situ hybridization to Drosophila embryos revealed specific staining of pgant5 and pgant6 in the salivary glands and pgant5 in the developing hindgut. Additionally, pgant5 and pgant6 expression within the egg chamber was restricted to the follicle cells, cells known to be involved in egg formation and subsequent embryonic patterning. The characterization reported here provides additional insight into the use of this model system to dissect the biological role of this enzyme family in vivo during both fly and mammalian development. C1 NIDDK, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. Univ Texas, Inst Mol & Cellular Biol, Sect Mol Cell & Dev Biol, Austin, TX 78712 USA. RP Ten Hagen, KG (reprint author), NIDDK, Sect Biol Chem, NIH, 9000 Rockville Pike,Bldg 50,Rm 4120, Bethesda, MD 20892 USA. OI Zhang, Zhenyu/0000-0001-6655-053X FU NCI NIH HHS [R01 CA078834]; NIGMS NIH HHS [GM52761] NR 38 TC 48 Z9 56 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 35039 EP 35048 DI 10.1074/jbc.M303836200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400037 PM 12829714 ER PT J AU Tapia, JA Garcia-Marin, LJ Jensen, RT AF Tapia, JA Garcia-Marin, LJ Jensen, RT TI Cholecystokinin-stimulated protein kinase C-delta kinase activation, tyrosine phosphorylation, and translocation are mediated by Src tyrosine kinases in pancreatic acinar cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY RECEPTOR; PKC-DELTA; V-SRC; SIGNAL-TRANSDUCTION; PHOSPHOLIPASE-C; FAMILY KINASES; PHORBOL ESTERS; IN-VITRO; GROWTH; ASSOCIATION AB Protein kinase C-delta (PKC-delta) is involved in growth, differentiation, tumor suppression, and regulation of other cellular processes. PKC-delta activation causes translocation, tyrosine phosphorylation, and serine-threonine kinase activity. However, little is known about the ability of G protein-coupled receptors to activate these processes or the mediators involved. In the present study, we explored the ability of the neurotransmitter/hormone, CCK, to stimulate these changes in PKC-delta and explored the mechanisms. In rat pancreatic acini under basal conditions, PKC-delta is almost exclusively located in cytosol. CCK and TPA stimulated a rapid PKC-delta translocation to membrane and nuclear fractions, which was transient with CCK. CCK stimulated rapid tyrosine phosphorylation of PKC-delta and increased kinase activity. Using tyrosine kinase (B44) and a tyrosine phosphatase inhibitor ( orthovanadate), changes in both CCK- and TPA-stimulated PKC-delta tyrosine phosphorylation were shown to correlate with changes in its kinase activity but not translocation. Both PKC-delta tyrosine phosphorylation and activation occur exclusively in particulate fractions. The Src kinase inhibitors, SU6656 and PP2, but not the inactive related compound, PP3, inhibited CCK- and TPA-stimulated PKC-delta tyrosine phosphorylation and activation. In contrast, PP2 also had a lesser effect on CCK- but not TPA-stimulated PKC-delta translocation. CCK stimulated the association of Src kinases with PKC-delta, demonstrated by co-immunoprecipitation. These results demonstrate that CCKA receptor activation results in rapid translocation, tyrosine phosphorylation, and activation of PKC-delta. Stimulation of PKC-delta translocation precedes tyrosine phosphorylation, which is essential for activation to occur. Activation of Src kinases is essential for the tyrosine phosphorylation and kinase activation to occur and plays a partial role in translocation. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Extremadura, Dept Fisiol, Caceres 10071, Spain. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. RI Garcia-Marin, Luis /L-4680-2014; Tapia, Jose/C-5181-2008 OI Garcia-Marin, Luis /0000-0002-1795-7381; Tapia, Jose/0000-0002-3614-6867 NR 74 TC 47 Z9 47 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 35220 EP 35230 DI 10.1074/jbc.M303119200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400059 PM 12842900 ER PT J AU Zhang, WW Mendez, S Ghosh, A Myler, P Ivens, A Clos, J Sacks, DL Matlashewski, G AF Zhang, WW Mendez, S Ghosh, A Myler, P Ivens, A Clos, J Sacks, DL Matlashewski, G TI Comparison of the A2 gene locus in Leishmania donovani and Leishmania major and its control over cutaneous infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMASTIGOTE-SPECIFIC PROTEIN; STAGE-SPECIFIC GENE; AXENIC AMASTIGOTES; VIRULENCE FACTOR; LIPOPHOSPHOGLYCAN; EXPRESSION; TROPICA AB In Old World Leishmania infections, Leishmania donovani is responsible for fatal visceral leishmaniasis, and L. major is responsible for non-fatal cutaneous leishmaniasis in humans. The genetic differences between these species which govern the pathology or site of infection are not known. We have therefore carried out detailed analysis of the A2 loci in L. major and L. donovani because A2 is expressed in L. donovani but not L. major, and A2 is required for survival in visceral organs by L. donovani. We demonstrate that although L. major contains A2 gene regulatory sequences, the multiple repeats that exist in L. donovani A2 protein coding regions are absent in L. major, and the remaining corresponding A2 sequences appear to represent non-expressed pseudogenes. It was possible to restore amastigote-specific A2 expression to L. major, confirming that A2 regulatory sequences remain functional in L. major. Although L. major is a cutaneous parasite in rodents and humans, restoring A2 expression to L. major inhibited its ability to establish a cutaneous infection in susceptible BALB/c or resistant C57BL6 mice, a phenotype typical of L. donovani. There was no detectable cellular immune response against L. major after cutaneous infection with A2-expressing L. major, suggesting that the lack of growth was not attributable to acquired host resistance but to an A2-mediated suppression of parasite survival in skin macrophages. These observations argue that the lack of A2 expression in L. major contributed to its divergence from L. donovani with respect to the pathology of infection. C1 McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Sanger Inst, Cambridge CB10 1SA, England. Bernhard Nocht Inst Trop Med, Leishmaniasis Unit, D-20359 Hamburg, Germany. RP Matlashewski, G (reprint author), McGill Univ, Dept Microbiol & Immunol, 3775 Univ St, Montreal, PQ H3A 2B4, Canada. OI Myler, Peter/0000-0002-0056-0513 NR 25 TC 72 Z9 73 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 35508 EP 35515 DI 10.1074/jbc.M305030200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400093 PM 12829719 ER PT J AU Li, BS Ma, W Jaffe, H Zheng, YL Takahashi, S Zhang, L Kulkarni, AB Pant, HC AF Li, BS Ma, W Jaffe, H Zheng, YL Takahashi, S Zhang, L Kulkarni, AB Pant, HC TI Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE; CELL-SURVIVAL; NEGATIVE REGULATION; REGULATORY SUBUNIT; SIGNALING PATHWAYS; CDC2-LIKE KINASE; CEREBRAL-CORTEX; NERVOUS-SYSTEM; GROWTH-FACTOR; MICE LACKING AB The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5 -/- mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. NIMH, Behav & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D24,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 72 TC 105 Z9 114 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 35702 EP 35709 DI 10.1074/jbc.M302004200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400116 PM 12824184 ER PT J AU Hatakeyama, J Sreenath, T Hatakeyama, Y Thyagarajan, T Shum, L Gibson, CW Wright, JT Kulkarni, AB AF Hatakeyama, J Sreenath, T Hatakeyama, Y Thyagarajan, T Shum, L Gibson, CW Wright, JT Kulkarni, AB TI The receptor activator of nuclear factor-B ligand-mediated osteoclastogenic pathway is elevated in amelogenin-null mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERIODONTAL-LIGAMENT CELLS; ENAMEL MATRIX PROTEINS; PRIMARY RNA TRANSCRIPT; GENE SPLICE PRODUCTS; ROOT RESORPTION; INDUCE OSTEOCLASTOGENESIS; TRANSLATION PRODUCT; TNF-RECEPTOR; IN-VITRO; EXPRESSION AB Amelogenins, major components of developing enamel, are predominantly involved in the formation of tooth enamel. Although amelogenins are also implicated in cementogenesis, their precise spatial expression pattern and molecular role are not clearly understood. Here, we report for the first time the expression of two alternate splice forms of amelogenins, M180 and the leucine-rich amelogenin peptide ( LRAP), in the periodontal region of mouse tooth roots. Lack of M180 and LRAP mRNA expression correlated with cementum defects observed in the amelogenin-null mice. The cementum defects were characterized by an increased presence of multinucleated cells, osteoclasts, and cementicles. These defects were associated with an increased expression of the receptor activator of the nuclear factor-kappaB ligand ( RANKL), a critical regulator of osteoclastogenesis. These findings indicate that the amelogenin splice variants, M180 and LRAP, are critical in preventing abnormal resorption of cementum. C1 NIDCR, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. Univ N Carolina, Dept Pediat Dent, Chapel Hill, NC 27599 USA. RP Kulkarni, AB (reprint author), NIDCR, Funct Genom Unit, NIH, 30 Convent Dr,Bldg 30,Rm 527, Bethesda, MD 20892 USA. NR 49 TC 58 Z9 60 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 12 PY 2003 VL 278 IS 37 BP 35743 EP 35748 DI 10.1074/jbc.M306284200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718UG UT WOS:000185164400121 PM 12851394 ER PT J AU Yue, WW Grizot, S Buchanan, SK AF Yue, WW Grizot, S Buchanan, SK TI Structural evidence for iron-free citrate and ferric citrate binding to the TonB-dependent outer membrane transporter FecA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE FecA; TonB; outer membrane protein; active transport; ferric citrate ID ESCHERICHIA-COLI K-12; FUNCTION SIGMA-FACTOR; PSEUDOMONAS-AERUGINOSA; CELL-SURFACE; TRANSCRIPTION INITIATION; CYTOPLASMIC MEMBRANE; CRYSTAL-STRUCTURES; RECEPTOR FECA; FHUA PROTEIN; IN-VIVO AB Escherichia coli possesses a TonB-dependent transport system, which exploits the iron-binding capacity of citrate and its natural abundance. Here, we describe three structures of the outer membrane ferric citrate transporter FecA: unliganded and complexed with iron-free or diferric dicitrate. We show the structural mechanism for discrimination between the iron-free and ferric siderophore: the binding of diferric dicitrate, but not iron-free dicitrate alone, causes major conformational rearrangements in the transporter. The structure of FecA bound with iron-free dicitrate represents the first structure of a TonB-dependent transporter bound with an iron-free siderophore. Binding of diferric dicitrate to FecA results in changes in the orientation of the two citrate ions relative to each other and in their interactions with FecA, compared to the binding of iron-free dicitrate. The changes in ligand binding are accompanied by conformational changes in three areas of FecA: two extracellular loops, one plug domain loop and the periplasmic TonB-box motif. The positional and conformational changes in the siderophore and transporter initiate two independent events: ferric citrate transport into the periplasm and transcription induction of the JecABCDE transport genes. From these data, we propose a two-step ligand recognition event: FecA binds iron-free dicitrate in the non-productive state or first step, followed by siderophore displacement to form the transport-competent, diferric dicitrate-bound state in the second step. Published by Elsevier Ltd. C1 NIDDKD, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ London Birkbeck Coll, Dept Crystallog, London WC1E 7HX, England. RP Buchanan, SK (reprint author), NIDDKD, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov NR 60 TC 113 Z9 116 U1 2 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 12 PY 2003 VL 332 IS 2 BP 353 EP 368 DI 10.1016/S0022-2836(03)00855-6 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721FQ UT WOS:000185306700006 PM 12948487 ER PT J AU Tatusov, RL Fedorova, ND Jackson, JD Jacobs, AR Kiryutin, B Koonin, EV Krylov, DM Mazumder, R Mekhedov, SL Nikolskaya, AN Rao, BS Smirnov, S Sverdlov, AV Vasudevan, S Wolf, YI Yin, JJ Natale, DA AF Tatusov, RL Fedorova, ND Jackson, JD Jacobs, AR Kiryutin, B Koonin, EV Krylov, DM Mazumder, R Mekhedov, SL Nikolskaya, AN Rao, BS Smirnov, S Sverdlov, AV Vasudevan, S Wolf, YI Yin, JJ Natale, DA TI The COG database: an updated version includes eukaryotes SO BMC BIOINFORMATICS LA English DT Article ID HORIZONTAL GENE-TRANSFER; GENOME SEQUENCE; PROTEIN FAMILIES; EVOLUTION; ARCHAEAL; CLASSIFICATION; BACTERIAL; CONTEXT; PERSPECTIVE; PROKARYOTES AB Background: The availability of multiple, essentially complete genome sequences of prokaryotes and eukaryotes spurred both the demand and the opportunity for the construction of an evolutionary classification of genes from these genomes. Such a classification system based on orthologous relationships between genes appears to be a natural framework for comparative genomics and should facilitate both functional annotation of genomes and large-scale evolutionary studies. Results: We describe here a major update of the previously developed system for delineation of Clusters of Orthologous Groups of proteins (COGs) from the sequenced genomes of prokaryotes and unicellular eukaryotes and the construction of clusters of predicted orthologs for 7 eukaryotic genomes, which we named KOGs after eukaryotic orthologous groups. The COG collection currently consists of 138,458 proteins, which form 4873 COGs and comprise 75% of the 185,505 ( predicted) proteins encoded in 66 genomes of unicellular organisms. The eukaryotic orthologous groups ( KOGs) include proteins from 7 eukaryotic genomes: three animals ( the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and Homo sapiens), one plant, Arabidopsis thaliana, two fungi ( Saccharomyces cerevisiae and Schizosaccharomyces pombe), and the intracellular microsporidian parasite Encephalitozoon cuniculi. The current KOG set consists of 4852 clusters of orthologs, which include 59,838 proteins, or -54% of the analyzed eukaryotic 110,655 gene products. Compared to the coverage of the prokaryotic genomes with COGs, a considerably smaller fraction of eukaryotic genes could be included into the KOGs; addition of new eukaryotic genomes is expected to result in substantial increase in the coverage of eukaryotic genomes with KOGs. Examination of the phyletic patterns of KOGs reveals a conserved core represented in all analyzed species and consisting of -20% of the KOG set. This conserved portion of the KOG set is much greater than the ubiquitous portion of the COG set (-1% of the COGs). In part, this difference is probably due to the small number of included eukaryotic genomes, but it could also reflect the relative compactness of eukaryotes as a clade and the greater evolutionary stability of eukaryotic genomes. Conclusion: The updated collection of orthologous protein sets for prokaryotes and eukaryotes is expected to be a useful platform for functional annotation of newly sequenced genomes, including those of complex eukaryotes, and genome-wide evolutionary studies. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM tatusov@ncbi.nlm.nih.gov; fedorova@ncbi.nlm.nih.gov; jjackson@ncbi.nlm.nih.gov; jacobs@ncbi.nlm.nih.gov; kiryutin@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov; krylov@ncbi.nlm.nih.gov; rm285@georgetown.edu; mekhedov@ncbi.nlm.nih.gov; ann2@georgetown.edu; rao@ncbi.nlm.nih.gov; smirnov@ncbi.nlm.nih.gov; asverdlo@ncbi.nlm.nih.gov; vasudeva@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov; yin@ncbi.nlm.nih.gov; dan5@georgetown.edu RI Abrams, Natalie/F-4845-2011 OI Abrams, Natalie/0000-0001-9698-2819 NR 60 TC 2090 Z9 2160 U1 25 U2 141 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 11 PY 2003 VL 4 AR 41 DI 10.1186/1471-2105-4-41 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 739JT UT WOS:000186341900001 PM 12969510 ER PT J AU Sridhar, J Wei, ZL Nowak, I Lewin, NE Ayres, JA Pearce, LV Blumberg, PM Kozikowski, AP AF Sridhar, J Wei, ZL Nowak, I Lewin, NE Ayres, JA Pearce, LV Blumberg, PM Kozikowski, AP TI New bivalent PKC ligands linked by a carbon spacer: Enhancement in binding affinity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; PHORBOL ESTER BINDING; CYSTEINE-RICH DOMAINS; RATIONAL DESIGN; DOWN-REGULATION; LYNGBYATOXIN-A; ANALOGS; DELTA; ALPHA; SELECTIVITY AB Protein kinase C (PKC) is known to play an important role in many signal transduction pathways involved in hormone release, mitogenesis, and tumor promotion. In continuation of our efforts to find highly potent activators of PKC for possible use as Alzheimer's disease therapeutics, we designed and synthesized molecules containing two binding moieties (amides of benzolactams or esters of naphthylpyrrolidones) connected by a flexible spacer chain, which could theoretically bind to both the C1a and C1b activator binding domains of the catalytic region or to the C1 domains of two adjacent PKC molecules. The dimers 2a- g of benzolactam showed a 200-fold increase in affinity to PKCalpha and -delta as the spacer length increased from 4 to 20 carbon atoms. Replacement of the oligomethylene chain with an oligoethylene glycol unit (compounds 2h, 2i) showed a 4000- to 7000-fold decrease in affinity to PKCalpha. The dimers of naphthylpyrrolidones 4a-g did not show any marked improvement in binding affinities to PKC in comparison to the monomers synthesized earlier. The dimer of benzolactam. 2e did not show much selectivity for PKCalpha, -betaI, -delta, -epsilon, and -gamma. The high binding affinity of compounds 2d-g to PKCs gives us the impetus to design additional molecules that would retain this enhanced activity and would also show selectivity for the PKC isoforms. C1 Georgetown Univ, Ctr Med, Dept Neurol, Drug Discovery Program, Washington, DC 20057 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Kozikowski, AP (reprint author), Georgetown Univ, Ctr Med, Dept Neurol, Drug Discovery Program, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM kozikowa@georgetown.edu FU NCI NIH HHS [CA79601] NR 41 TC 22 Z9 22 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 11 PY 2003 VL 46 IS 19 BP 4196 EP 4204 DI 10.1021/jm0302041 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 719YM UT WOS:000185232700026 PM 12954072 ER PT J AU Finkel, T AF Finkel, T TI Ageing - A toast to long life SO NATURE LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; CALORIE RESTRICTION; SPAN EXTENSION; SIR2 C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 19 Z9 22 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 11 PY 2003 VL 425 IS 6954 BP 132 EP 133 DI 10.1038/425132a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 719ZT UT WOS:000185236000023 PM 12968159 ER PT J AU Cannon, RO AF Cannon, RO TI Assessing risk in hypertrophic cardiomyopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 11 Z9 11 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 11 PY 2003 VL 349 IS 11 BP 1016 EP 1018 DI 10.1056/NEJMp038122 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 719UH UT WOS:000185223100002 PM 12968084 ER PT J AU Anderson, WF AF Anderson, WF TI Puberty and genetic susceptibility to breast cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 6 Z9 6 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 11 PY 2003 VL 349 IS 11 BP 1088 EP 1089 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 719UH UT WOS:000185223100016 PM 12971365 ER PT J AU Anzick, SL Azorsa, DO Simons, SS Meltzer, PS AF Anzick, SL Azorsa, DO Simons, SS Meltzer, PS TI Phenotypic alterations in breast cancer cells overexpressing the nuclear receptor co-activator AIBI SO BMC CANCER LA English DT Article ID CREB-BINDING-PROTEIN; PROGESTERONE RECEPTORS; INDUCTION PROPERTIES; AGONIST ACTIVITY; ESTROGEN; TRANSCRIPTION; GENE; CBP; EXPRESSION; ACTIVATION AB Background: Estrogen signaling plays a critical role in a number of normal physiological processes and has important implications in the treatment of breast cancer. The p160 nuclear receptor coactivator, AIB1 (amplified in breast cancer 1), is frequently amplified and overexpressed in human breast cancer and has been shown to enhance estrogen-dependent transactivation. Methods: To better understand the molecular and physiological consequences of AIB1 overexpression in breast cancer cells, an AIB1 cDNA was transfected into the low AIB1 expressing, estrogen-receptor (ER) negative breast cancer cell line, MDA-MB-436. The features of a derivative cell line, designated 436.1, which expresses high levels of AIB1, are described and compared with the parental cell line. Results: A significant increase in the levels of CREB binding protein (CBP) was observed in 436.1 cells and immunofluorescent staining revealed altered AIB1 and CBP staining patterns compared to the parental cells. Further, transient transfection assays demonstrated that the overall estrogen-dependent transactivation in 436.1 cells is approximately 20-fold higher than the parental cells and the estrogen dose-response curve is repositioned to the right. Finally, cDNA microarray analysis of approximately 7,100 cDNAs identified a number of differentially expressed genes in the 436.1 cells. Conclusion: These observations lend insight into downstream signaling pathways that are influenced by AIB1. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. George Washington Univ, Columbia Sch Arts & Sci, Program Mol & Cellular Oncol, Washington, DC 20037 USA. Translat Genom Res Inst, Phoenix, AZ 85004 USA. NIDDK, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. RP Meltzer, PS (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NR 35 TC 8 Z9 9 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 10 PY 2003 VL 3 AR 22 DI 10.1186/1471-2407-3-22 PG 11 WC Oncology SC Oncology GA 727MW UT WOS:000185663500001 PM 12964942 ER PT J AU Svarovsky, SA Barchi, JJ AF Svarovsky, SA Barchi, JJ TI Highly efficient preparation of tumor antigen-containing glycopeptide building blocks from novel pentenyl glycosides SO CARBOHYDRATE RESEARCH LA English DT Article DE T-Antigen; O-glycopeptide; stereoselective; pentenylation ID HUMAN MONOCLONAL-ANTIBODIES; SOLID-PHASE; THOMSEN-FRIEDENREICH; CHEMOENZYMATIC SYNTHESIS; O-GLYCOPROTEINS; ACID; VACCINES; CANCER; DERIVATIVES; MUCIN AB O-Glycosylated amino acids containing the tumor-associated T(T-f)-antigen (beta-D-Gal-(l-->3)-alpha-D-GalNAc) disaccharide unit were conveniently synthesized in seven steps starting from D-galactose via an n-pentenyl glycoside (NPG) building block. Azidonitration of 3,4,6-tri-O-acetyl-D-galactal, followed by nitrate displacement with simultaneous acetate hydrolysis with sodium 4-penten-l-oxide, afforded n-pentenyl 2-deoxy-2-azidogalactoside (3) in near quantitative yield. Subsequent high-yielding transformations resulted in the synthesis of the key glycosyl donor n-pentenyl beta-disaccharide 5 that was employed for the stereospecific preparation of glycosyl amino acids via NIS-promoted glycosylations with serine or threonine acceptors. The surprising utility of the reaction of sodium 4-penten-1-oxide with anomeric nitrates encouraged the detailed exploration of the action of a variety of nucleophiles on anomeric nitrates for the synthesis of useful 2-azido glycosyl donors directly from the 'classic' Lemieux azidonitration product of protected galactals. This expedient synthesis (28% overall yield from 1 to 7a) that makes use of heretofore rarely exploited pentenyl 2'-azidoglycosides, should be a valuable entry in the armamentarium of routes to biologically relevant glycopeptides in both mono-and multivalent forms. Published by Elsevier Ltd. C1 NCI, Ctr Canc Res, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Ctr Canc Res, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 NR 46 TC 25 Z9 26 U1 1 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 SEP 10 PY 2003 VL 338 IS 19 BP 1925 EP 1935 DI 10.1016/S0008-6215(03)00323-9 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 721GV UT WOS:000185309400002 PM 14499569 ER PT J AU Buydens-Branchey, L Branchey, M McMakin, DL Hibbeln, JR AF Buydens-Branchey, L Branchey, M McMakin, DL Hibbeln, JR TI Polyunsaturated fatty acid status and aggression in cocaine addicts SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE cocaine addiction; aggression; polyunsaturated fatty acids ID FRONTAL-CORTEX; DOCOSAHEXAENOIC ACID; CEREBROSPINAL-FLUID; BEHAVIOR; BRAIN; METABOLITES; SEROTONIN; DOPAMINE; SUICIDE; VIOLENT AB Background: There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of aggressive disorders. PUFA status is influenced by nutritional factors and because of our observation that some substance abusers have poor dietary habits, we explored the possibility that the fatty acids (FA) profiles of cocaine addicts with and without aggressive tendencies would differ. We also explored the possibility that their FA levels would change after a 2 week stay on an inpatient unit where a standard diet would be provided. Methods: Plasma levels of FAs were measured in 24 cocaine addicts admitted to an inpatient substance abuse unit. Six patients had a past history of aggression and 18 did not. Results: A comparison of the FA levels of aggressive and non-aggressive patients performed 3.7+/-2.0 days after their admission did not reveal any significant difference in saturated FAs (SFAs) or monounsaturated FAs (MFAs). Aggressive patients had significantly lower levels of the n-6 PUFA docosapentaenoic acid (E)PA), of total n-3 PUFAs and of the n-3 PUFA docosahexaenoic acid (DHA), and a marginally significant increase in the ratio of n-6 to n-3 PUFAs. Measurements performed 18.4+/-1.3 days after admission showed that most FAs had increased in the two patient groups. Some PUFAs, especially those of the n-3 series, increased more sharply in the aggressive patients. As a result, PUFA differences between groups that were present shortly after admission became non-significant. Conclusions: These data suggest that patients' diets prior to their hospitalization were less than optimal and that the diet of the aggressive individuals might have been particularly deficient in n-3 rich nutrients. These data also give additional support to evidence indicating a possible link between an n-3 deficiency and aggression in humans. Published by Elsevier Science Ireland Ltd. C1 SUNY Hlth Sci Ctr, Dept Psychiat, Brooklyn, NY 11209 USA. Vet Affairs New York Harbor Healthcare Syst, Brooklyn, NY 11209 USA. NIAAA, Rockville, MD 20852 USA. RP Buydens-Branchey, L (reprint author), SUNY Hlth Sci Ctr, Dept Psychiat, Brooklyn, NY 11209 USA. NR 19 TC 28 Z9 29 U1 0 U2 1 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 SEP 10 PY 2003 VL 71 IS 3 BP 319 EP 323 DI 10.1016/S0376-8716(03)00168-6 PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 723QN UT WOS:000185443200010 PM 12957349 ER PT J AU Rellahan, BL Graham, LJ Tsygankov, AY DeBell, KE Veri, MC Noviello, C Bonvini, E AF Rellahan, BL Graham, LJ Tsygankov, AY DeBell, KE Veri, MC Noviello, C Bonvini, E TI A dynamic constitutive and inducible binding of c-Cbl by PLC gamma 1 SH3 and SH2 domains (negatively) regulates antigen receptor-induced PLC gamma l activation in lymphocytes SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; PROTEIN-TYROSINE KINASES; JURKAT T-CELLS; PHOSPHOLIPASE C-GAMMA-1; SIGNAL-TRANSDUCTION; PROTOONCOGENE PRODUCT; CSF-1 RECEPTOR; RING FINGER; ASSOCIATION; PHOSPHORYLATION AB We investigated the structural requirements for c-Cbl-mediated inhibition of Ag receptor-induced PLCgamma1 activation. Analysis of site-specific c-Cbl mutants indicated that tyrosine phosphorylation of c-Cbl was required for down-regulation of the PLCgamma1/Ca2+ pathway. Coprecipitation experiments indicated that c-Cbl and PLCgamma1 constitutively interact through a PLCgamma1 SH3 domain-dependent mechanism and that c-Cbl and PLCgamma1 can inducibly interact through the SH2(C) domain of PLCgamma1. Additional data indicate that the SH3 domain of PLCgamma1 binds to both canonical and noncanonical SH3 domain-binding sites in the proline-rich region of c-Cbl. Overexpression of c-Cbl in a PLCgamma-deficient B cell line, P10-14, stably reconstituted with wild-type PLCgamma1 led to a significant decrease in B cell receptor-induced NF-AT-dependent transcription, a PLCgamma- and Ca2+-dependent event. In contrast, c-Cbl overexpression in P10-14 cells reconstituted with a PLCgamma1 SH3 domain mutant had little effect on receptor-induced NF-AT activation. These data suggest that c-Cbl-mediated regulation of PLCgamma1 requires an interaction between c-Cbl and PLCgamma1 that is primarily mediated by the SH3 domain of PLCgamma1. The interaction of c-Cbl with PLCgamma1 may negatively effect events required for PLCgamma1 activation. (C) 2003 Elsevier Science (USA). All rights reserved. C1 CBER, Div Monoclonal Antibodies, Immunobiol Lab, Bethesda, MD 20892 USA. Temple Univ, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA. RP Rellahan, BL (reprint author), CBER, Div Monoclonal Antibodies, Immunobiol Lab, NIH Campus,29B-4G03,8800 Rockville Pike, Bethesda, MD 20892 USA. EM rellahan@cber.fda.gov NR 53 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2003 VL 289 IS 1 BP 184 EP 194 DI 10.1016/S0014-4827(03)00260-X PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 718VL UT WOS:000185167100018 PM 12941616 ER PT J AU Chobanian, AV Roccella, EJ AF Chobanian, AV Roccella, EJ CA JNC 7 Comm TI The JNC 7 hypertension guidelines SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Boston Univ, Med Ctr, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP Chobanian, AV (reprint author), Boston Univ, Med Ctr, Boston, MA 02215 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 10 PY 2003 VL 290 IS 10 BP 1314 EP 1315 DI 10.1001/jama.290.10.1314-c PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 719DP UT WOS:000185188600015 ER PT J AU Trachtman, H Cnaan, A Christen, E Gibbs, K Zhao, SY Acheson, DWK Weiss, R Kaskel, FJ Spitzer, A Hirschman, GH AF Trachtman, H Cnaan, A Christen, E Gibbs, K Zhao, SY Acheson, DWK Weiss, R Kaskel, FJ Spitzer, A Hirschman, GH CA Investigators HUS-SYNSORB Pk Multic TI Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ESCHERICHIA-COLI O157-H7; MONOCLONAL-ANTIBODY TMA-15; INFECTIONS; EPIDEMIOLOGY; PATHOGENESIS; CHROMOSORB; PK AB Context Diarrhea-associated hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children. Most cases are caused by an intestinal infection with Shiga toxin-producing strains of Escherichia coli. Objective To determine if administration of an oral agent that binds Shiga toxin could diminish the severity of diarrhea-associated HUS in pediatric patients. Design, Setting, and Patients Multicenter, randomized, double-blind, placebo-controlled clinical trial of 145 children (96 experimental and 49 placebo) aged 6 months to 18 years with diarrhea-associated HUS conducted between July 27, 1997, and April 14, 2001, at 26 tertiary care pediatric nephrology centers in the United States and Canada. Trial included 2 phases, the hospital course for treatment of the acute illness and a 60-day outpatient follow-up period after discharge from the hospital. Intervention Patients were assigned to receive the binding agent, 500 mg/kg daily, or cornmeal placebo orally for 7 days in a 2:1 randomization scheme. Main Outcome Measures Combined frequency of death or serious extrarenal events and need for dialysis in the experimental vs placebo group. Results A total of 62 patients (43%) were male and 123 (85%) were white. The median age of the patients was 4.2 years. Most patients (59%) were transferred from other hospitals to participating sites. The severity of disease at the time of randomization was comparable in the 2 groups. The prevalence of death or serious extrarenal events was 18% and 20% in the experimental and placebo groups, respectively (P=.82). Dialysis was required in 42% of experimental and 39% of placebo groups (P=.86). Conclusions Oral therapy with a Shiga toxin-binding agent failed to diminish the severity of disease in pediatric patients with diarrhea-associated HUS. C1 N Shore Long Isl Jewish Med Ctr, Schneider Childrens Hosp, Dept Pediat, Div Nephrol, New Hyde Pk, NY 11040 USA. Childrens Hosp Philadelphia, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. Childrens Hosp Montefiore, Dept Pediat, Bronx, NY USA. NIDDKD, NIH, Kidney & Urol Program, Bethesda, MD 20892 USA. RP Trachtman, H (reprint author), N Shore Long Isl Jewish Med Ctr, Schneider Childrens Hosp, Dept Pediat, Div Nephrol, 269-0176th Ave,Room SCH365, New Hyde Pk, NY 11040 USA. FU NIDDK NIH HHS [1R01-DK52147] NR 28 TC 88 Z9 94 U1 0 U2 2 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 SEP 10 PY 2003 VL 290 IS 10 BP 1337 EP 1344 DI 10.1001/jama.290.10.1337 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 719DP UT WOS:000185188600026 PM 12966125 ER PT J AU Parker, CL Ventura, ON Burt, SK Cachau, RE AF Parker, CL Ventura, ON Burt, SK Cachau, RE TI DYNGA: a general purpose QM-MM-MD program. I. Application to water SO MOLECULAR PHYSICS LA English DT Article ID MOLECULAR-ORBITAL METHODS; DENSITY-FUNCTIONAL-THEORY; GAUSSIAN-TYPE BASIS; BASIS-SETS; ORGANIC-MOLECULES; FORCE-FIELDS; SIMULATIONS AB We present a general purpose QM-MM-MD engine (DYNGA) designed to test alternative hybrid Hamiltonians geared towards the treatment of problems of interest in structural biology including the use of experimental data constraints. In this first presentation we use DYNGA to explore the behaviour of a traditional QM-MM approach in the treatment of the water-water interaction. We find the potential energy hypersurface for the water dimer computed with the HF 4-31G*/TIP3P hybrid Hamiltonian tends to be too. at. We also explore the effect of using traditional QM-MM techniques on proton wires and conclude there is a need for improvement, possibly addressed by using polarizable force fields. C1 NCI, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. UDELAR, Fac Quim, DEQUIFIM, CCPG, Montevideo 11800, Uruguay. RP Cachau, RE (reprint author), NCI, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. EM cachau@ncifcrf.gov NR 28 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0026-8976 J9 MOL PHYS JI Mol. Phys. PD SEP 10 PY 2003 VL 101 IS 17 BP 2659 EP 2668 DI 10.1080/0026897031000137698 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 724DX UT WOS:000185472800002 ER PT J AU Arnaoutova, I Smith, AM Coates, LC Sharpe, JC Dhanvantari, S Snell, CR Birch, NP Loh, YP AF Arnaoutova, I Smith, AM Coates, LC Sharpe, JC Dhanvantari, S Snell, CR Birch, NP Loh, YP TI The prohormone processing enzyme PC3 is a lipid raft-associated transmembrane protein SO BIOCHEMISTRY LA English DT Article ID REGULATED SECRETORY PATHWAY; CHROMAFFIN-GRANULE MEMBRANE; PITUITARY INTERMEDIATE LOBE; CARBOXYPEPTIDASE-E; SORTING RECEPTOR; PROPROTEIN CONVERTASES; PRECURSOR PROTEINS; PLASMA-MEMBRANE; CPE(FAT) MICE; IN-VITRO AB The biosynthesis of most biologically active peptides involves the action of prohomone convertases, including PC3 (also known as PC1), that catalyze limited proteolysis of precursor proteins. Proteolysis of prohormones occurs mainly in the granules of the regulated secretory pathway. It has been proposed that the targeting of these processing enzymes to secretory granules involves their association with lipid rafts in granule membranes. We now provide evidence for the interaction of the 86 and 64 kDa forms of PC3 with secretory granule membranes. Furthermore, both forms of PC3 were resistant to extraction with TX-100, were floated to low-density fractions in sucrose gradients, and were partially extracted upon cholesterol depletion by methyl-beta-cyclodextrin, indicating that they were associated with lipid rafts in the membranes. Protease protection assays, immunolabeling, and biotinylation of proteins in intact secretory granules identified an similar to115-residue cytoplasmic tail for 86 kDa PC3. Using two-dimensional gel electrophoresis and a specific antibody, a novel, raft-associated form of 64 kDa PC3 that contains a transmembrane domain consisting of residues 619-638 was identified. This form was designated as 64 kDa PC3-TM. and differs from the 64 kDa mature form of PC3. We present a model of the membrane topology of PC3, where it is anchored to lipid rafts in secretory granule membranes via the transmembrane domain. We demonstrate that the transmembrane domain of PC3 alone was sufficient to target the extracellular domain of the IL2 receptor alpha-subunit (Tac) to secretory granules. C1 NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Auckland, Sch Biol Sci, Lab Mol Neuroendocrinol, Auckland 1, New Zealand. Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, Biochem Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. Medvir UK Ltd, Cambridge CB1 9PT, England. RP Loh, YP (reprint author), NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bldg 49,Rm 5A-38,49 Convent Dr,MSC 4480, Bethesda, MD 20892 USA. RI Birch, Nigel/H-2498-2011; Dhanvantari, Savita/B-5362-2015 OI Birch, Nigel/0000-0002-8417-3587; NR 48 TC 34 Z9 34 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 9 PY 2003 VL 42 IS 35 BP 10445 EP 10455 DI 10.1021/bi0342277y PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 718WW UT WOS:000185170300012 PM 12950171 ER PT J AU Lee, KH Ichiba, M Zhang, JS Tomokuni, K Hong, YC Ha, M Kwon, HJ Koh, SB Choi, HR Lee, KH Park, CG Cho, SH Hirvonen, A Strickland, PT Vermeulen, R Hayes, RB Kang, DH AF Lee, KH Ichiba, M Zhang, JS Tomokuni, K Hong, YC Ha, M Kwon, HJ Koh, SB Choi, HR Lee, KH Park, CG Cho, SH Hirvonen, A Strickland, PT Vermeulen, R Hayes, RB Kang, DH TI Multiple biomarkers study in painters in a shipyard in Korea SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE polycyclic aromatic hydrocarbon; shipyard; 1-hydroxypyrene glucuronide; genetic polymorphism; glutathione S-transferases ID GLYCOPHORIN-A LOCUS; POLYCYCLIC AROMATIC-HYDROCARBONS; BUTADIENE-POLYMER WORKERS; SOMATIC-CELL MUTATIONS; ATOMIC-BOMB SURVIVORS; COKE-OVEN WORKERS; WHITE BLOOD-CELLS; S-TRANSFERASE M1; URINARY 1-HYDROXYPYRENE; GENETIC POLYMORPHISMS AB Shipbuilding workers are exposed to a variety of genotoxic compounds including polycyclic aromatic hydrocarbons (PAHs). A limited number of studies have been conducted to evaluate biomarkers related to PAH exposure in painters in the shipyard industry. We examined this in 208 workers recruited from a shipyard located in South Korea. Employees were grouped into three exposure groups: (1) 111 painters using coal tar paints, (2) 70 painters using general paints, and (3) 27 on-site controls using no paints. Levels of urinary 1-hydroxypyrene glucuromide (1-OHPG), as internal dose of PAH exposure, were measured by synchronous fluorescence spectroscopy. Glutathione S-transferase (GST) M1 and T1 genotypes were assessed by a multiplex polymerase chain reaction (PCR)-based method, aromatic-DNA adducts in peripheral white blood cells were measured by P-32-postlabeling, and glycophorin A (GPA) variant frequencies in red blood cells were assessed by flow cytometry. Information on demographic characteristics, smoking habits, diet, job title and use of personal protective equipment (e.g. respiratory and dermal) were collected by self-administered questionnaire. Average urinary 1-OHPG levels in coal tar paint (2.24 mumol/mol creatinine) and general paint (1.38 mumol/mol creatinine) users were significantly higher than in on-site controls (0.62 mumol/mol creatinine) (P < 0.001). Paint use, irrespective of the type of paints, and smoking (yes/no) were positively associated with urinary 1-OHPG levels, whereas green tea consumption (yes/no) was negatively associated with the 1-OHPG levels. No significant effect in the 1-OHPG levels were observed for the GSTM1 and GSTT1 genotypes. Aromatic-DNA adduct levels tended to be higher in coal tar paint users (P = 0.06) and painters (P = 0.07) compared to on-site controls. No differences in adduct levels were observed, between the two groups of painters, and the combined group showed greater adduct levels than on-site controls (P = 0.05). GPA mutation frequencies measured in 55 individuals with MN heterozygote genotypes were not significantly different among the three exposure groups, and no correlation was observed between urinary 1-OHPG levels and aromatic-DNA adducts or GPA mutation frequency. These results suggest that painters in the shipyard were exposed to significant amounts of PAHs and possibly to other genotoxic aromatic compounds, and that urinary 1-OHPG may be a potential biomarker of PAH exposure in this population. (C) 2003 Elsevier B.V. All rights reserved. C1 Seoul Natl Univ, Coll Med, SNUMRC, Inst Environm Med,Dept Prevent Med, Seoul 110799, South Korea. Saga Med Sch, Dept Social & Environm Med, Saga, Japan. Inha Univ, Coll Med, Dept Occupat & Environm Med, Inchon, South Korea. DanKook Univ, Cheonan, South Korea. Okpo DaeWoo Hosp, Cheonan, South Korea. Seoul Natl Univ, Coll Med, Dept Microbiol, Seoul, South Korea. Finnish Inst Occupat Hlth, Dept Ind Hyg & Toxicol, Helsinki 00250, Finland. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kang, DH (reprint author), Seoul Natl Univ, Coll Med, SNUMRC, Inst Environm Med,Dept Prevent Med, 28 Yongon Dong, Seoul 110799, South Korea. RI Park, Chung-Gyu/C-3596-2011; Kang, Dae Hee/E-8631-2012; Hong, Yun-Chul/J-5725-2012; Cho, Soo-Hun/J-5668-2012; Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; Park, Chung-Gyu/0000-0003-4083-8791 NR 38 TC 18 Z9 20 U1 0 U2 3 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 SEP 9 PY 2003 VL 540 IS 1 BP 89 EP 98 DI 10.1016/S1383-5718(03)00173-6 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 726UJ UT WOS:000185618600008 PM 12972061 ER PT J AU Frohman, EM Goodin, DS Calabresi, PA Corboy, JR Coyle, PK Filippi, M Frank, JA Galetta, SL Grossman, RI Hawker, K Kachuck, NJ Levin, MC Phillips, JT Racke, MK Rivera, VM Stuart, WH AF Frohman, EM Goodin, DS Calabresi, PA Corboy, JR Coyle, PK Filippi, M Frank, JA Galetta, SL Grossman, RI Hawker, K Kachuck, NJ Levin, MC Phillips, JT Racke, MK Rivera, VM Stuart, WH TI The utility of MRI in suspected MS - Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID CLINICALLY ISOLATED SYNDROMES; DEFINITE MULTIPLE-SCLEROSIS; ISOLATED DEMYELINATING SYNDROMES; CSF OLIGOCLONAL BANDS; TERM FOLLOW-UP; OPTIC NEURITIS; DIAGNOSTIC-CRITERIA; PREDICT CONVERSION; PARACLINICAL TESTS; EVOKED-POTENTIALS AB Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely. C1 Univ Texas, SW Med Sch, Dept Neurol, SW Med Ctr, Dallas, TX 75235 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Colorado, Denver, CO 80202 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Univ Milan, I-20122 Milan, Italy. NIH, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. NYU, New York, NY USA. Univ So Calif, Los Angeles, CA USA. Univ Tennessee, Knoxville, TN 37996 USA. Baylor Coll Med, Houston, TX 77030 USA. Peachtree Neurol Clin, Atlanta, GA USA. RP Frohman, EM (reprint author), Univ Texas, SW Med Sch, Dept Neurol, SW Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. NR 46 TC 116 Z9 122 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 9 PY 2003 VL 61 IS 5 BP 602 EP 611 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 719CX UT WOS:000185187000004 PM 12963748 ER PT J AU Bluml, S Philippart, M Schiffmann, R Seymour, K Ross, BD AF Bluml, S Philippart, M Schiffmann, R Seymour, K Ross, BD TI Membrane phospholipids and high-energy metabolites in childhood ataxia with CNS hypomyelination SO NEUROLOGY LA English DT Article ID VANISHING WHITE-MATTER; MAGNETIC-RESONANCE SPECTROSCOPY; NERVOUS-SYSTEM HYPOMYELINATION; INITIATION-FACTOR EIF2B; HUMAN BRAIN; ABSOLUTE QUANTITATION; LEUKOENCEPHALOPATHY; TRANSLATION; DISEASE; WATER AB Background: Childhood ataxia with CNS hypomyelination (CACH) is a leukodystrophy with extreme rarefaction of white matter caused by mutations in one of the five subunits of the translation initiation factor 2B (eIF2B). Methods: Seven children with this disease and nine age-matched control subjects were studied with proton-decoupled phosphorus magnetic resonance (MR) spectroscopy. Results: In patients with CACH, cerebral concentrations of high-energy phosphate metabolites were abnormal. Of the metabolites involved in biosynthesis and catabolism of membrane phospholipids, glycerophosphorylethanolamine was reduced (0.24+/-0.18 mmol/kg brain vs 0.44+/-0.14; p<0.02), and phosphorylethanolamine was increased (2.32&PLUSMN;0.53 vs 1.53&PLUSMN;0.22; p<0.01), whereas the choline-containing phosphorylated metabolites were unchanged. Nucleoside triphosphate (NTP) was reduced (2.44+/-0.34 mmol/kg brain tissue vs 3.09+/-0.58; p<0.01), phosphocreatine was elevated (4.11&PLUSMN;0.63 vs 3.27&PLUSMN;0.33; p<0.01), and inorganic phosphate was reduced (0.77+/-0.32 vs 1.06+/-0.26; p<0.05). Intracellular pH was elevated in patients (7.03&PLUSMN;0.04 vs 6.99&PLUSMN;0.02; p<0.02). Conclusions: The authors found an altered energy state of the residual cell population investigated. Together with previously identified replacement of white matter by CSF, the present findings raise the possibility that the genetic defect in eIF2B may result in impairment of myelin membrane synthesis or myelin membrane transport in the in vivo CACH brain. Ethanolamine metabolites constitute the plasmalogens, and the present findings may include a defect in plasmalogen metabolism. C1 Huntington Med Res Inst, Magnet Resonance Spect Unit, Pasadena, CA 91105 USA. Schulte Res Inst, Santa Barbara, CA USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Ross, BD (reprint author), Huntington Med Res Inst, Magnet Resonance Spect Unit, 660 S Fair Oaks Ave, Pasadena, CA 91105 USA. NR 23 TC 11 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 9 PY 2003 VL 61 IS 5 BP 648 EP 654 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 719CX UT WOS:000185187000012 PM 12963756 ER PT J AU Bazzano, LA He, J Ogden, LG Loria, CM Whelton, PK AF Bazzano, LA He, J Ogden, LG Loria, CM Whelton, PK TI Dietary fiber intake and reduced risk of coronary heart disease in US men and women - The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE; INSULIN AB Background: Prospective studies suggest that dietary fiber intake, especially water-soluble fiber, may be inversely associated with the risk of coronary heart disease (CHD). Methods: We examined the relationship between total and soluble dietary fiber intake and the risk of CHD and cardiovascular disease (CVD) in 9776 adults who participated in the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study and were free of CVD at baseline. A 24-hour dietary recall was conducted at the baseline examination, and nutrient intakes were calculated using Food Processor software. Incidence and mortality data for CHD and CVD were obtained from medical records and death certificates during follow-up. Results: During an average of 19 years of follow-up, 1843 incident cases of CHD and 3762 incident cases of CVD were documented. Compared with the lowest quartile of dietary fiber intake (median, 5.9 g/d), participants in the highest quartile (median, 20.7 g/d) had an adjusted relative risk of 0.88 (95% confidence interval [CI], 0.74-1.04; P=.05 for trend) for CHD events and of 0.89 (95% CI, 0.80-0.99; P=.01 for trend) for CVD events. The relative risks for those in the highest (median, 5.9 g/d) compared with those in the lowest (median, 0.9 g/d) quartile of water-soluble dietary fiber intake were 0.85 (95% CI, 0.74-0.98; P=.004 for trend) for CHD events and 0.90 (95% CI, 0.82-0.99; P=.01 for trend) for CVD events. C1 Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1430 Tulane Ave,Mail Stop SL18, New Orleans, LA 70112 USA. EM jhe@tulane.edu FU NHLBI NIH HHS [R01 HL60300] NR 30 TC 128 Z9 136 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 8 PY 2003 VL 163 IS 16 BP 1897 EP 1904 DI 10.1001/archinte.163.16.1897 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 720ZB UT WOS:000185291600006 PM 12963562 ER PT J AU Murabito, JM Evans, JC Larson, MG Nieto, K Levy, D Wilson, PWF AF Murabito, JM Evans, JC Larson, MG Nieto, K Levy, D Wilson, PWF TI The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death - The Framingham study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; BLOOD-PRESSURE INDEX; INTERMITTENT CLAUDICATION; ARM INDEX; CARDIOVASCULAR HEALTH; HEART-DISEASE; FOLLOW-UP; MORTALITY; MEN; ATHEROSCLEROSIS AB Background: A low ankle-brachial index (ABI) is associated with an increased risk of death and cardiovascular disease. Limited data exist regarding the relation between a low ABI and stroke. We sought to examine the relation between a low ABI and stroke, coronary heart disease, and death in the elderly. Methods: We examined 251 men and 423 women with a mean age of 80 years who had a Framingham Study examination from 1994 to 1995. A low ABI was defined as less than 0.9. Persons were followed up for 4 years for occurrence of stroke or transient ischemic attack, coronary disease, and death. Cox proportional hazards models were used to assess the relation between a low ABI and each outcome after adjusting for age, sex, and prevalent cardiovascular disease. Results: A low ABI was detected in 20% of our sample Only 18% of the participants with a low ABI reported claudication symptoms. One third of those with a normal ABI and 55% of those with a low ABI had cardiovascular disease at baseline. Results of multivariable Cox proportional hazards analysis demonstrated a statistically significant increase in the risk of stroke or transient ischemic attack in persons with a low ABI (hazards ratio, 2.0; 95% confidence interval, 1.1-3.7). No significant relation between a low ABI and coronary heart disease (hazards ratio, 1.2; 95% confidence interval, 0.7-2.1) or death (hazards ratio, 1.4; 95% confidence interval, 0.9-2.1) was observed. Conclusions: A low ABI is associated with risk of stroke or transient ischemic attack in the elderly. These results need to be confirmed in larger studies. C1 NHLBI, Framingham Heart Dis Epidemiol Study, NIH, Framingham, MA 01702 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, NIH, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-38083] NR 31 TC 185 Z9 207 U1 0 U2 5 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 SEP 8 PY 2003 VL 163 IS 16 BP 1939 EP 1942 DI 10.1001/archinte.163.16.1939 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 720ZB UT WOS:000185291600011 PM 12963567 ER PT J AU Lloyd-Lones, DM Wilson, PWF Larson, MG Leip, E Beiser, A D'Agostino, RB Cleeman, JI Levy, D AF Lloyd-Lones, DM Wilson, PWF Larson, MG Leip, E Beiser, A D'Agostino, RB Cleeman, JI Levy, D TI Lifetime risk of coronary heart disease by cholesterol levels at selected ages SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; HEALTH-CARE PROFESSIONALS; SERUM-CHOLESTEROL; CLINICAL-PRACTICE; TASK-FORCE; FRAMINGHAM; MEN; PREVENTION; MORTALITY; ADULTS AB Background: We sought to assess how cholesterol levels at different ages modify the remaining lifetime risk of coronary heart disease (CHD). Methods: We included all Framingham Heart Study participants examined from 1971 through 1996 who did not have CHD and were not receiving lipid-lowering therapy. At index ages of 40, 50, 60, 70, and 80 years, participants were stratified by total cholesterol level and by cholesterol subfractions. Lifetime risk of CHD was calculated with death free of CHD as a competing event. Results: Among 3269 men and 4019 women, 1120 developed CHD and 1365 died free of CHD during followup. At each index age, lifetime risk of CHD increased with higher cholesterol levels, and time to event decreased. At age 40 years, the lifetime risks of CHD through age 80 years for men with total cholesterol levels less than 200 mg/dL (<5.20 mmol/L), 200 to 239 mg/dL (5.20-6.19 mmol/L), and 240 mg/dL or greater (greater than or equal to6.20 mmol/L), respectively, were 31%, 43%, and 57%; for women, the lifetime risks were 15%, 26%, and 33%, respectively. Lifetime risks contrasted sharply with shorter-term risks: at age 40 years, the 10-year cumulative risks of CHD were 3%, 5%, and 12% for men, and 1%, 2%, and 5% for women, respectively. Conclusions: Lifetime risk of CHD increases sharply with higher total cholesterol levels for men and women at all ages. These data support an important role for cholesterol screening in younger patients, and they may help target high-risk patients for lifestyle modification or drug therapy. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. NHLBI, Bethesda, MD USA. RP Lloyd-Lones, DM (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [K23 HL04253, N01-HC-25195] NR 30 TC 61 Z9 62 U1 1 U2 3 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 SEP 8 PY 2003 VL 163 IS 16 BP 1966 EP 1972 DI 10.1001/archinte.163.16.1966 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 720ZB UT WOS:000185291600015 PM 12963571 ER PT J AU Lodmell, DL Parnell, MJ Weyhrich, JT Ewalt, LC AF Lodmell, DL Parnell, MJ Weyhrich, JT Ewalt, LC TI Canine rabies DNA vaccination: a single-dose intradermal injection into ear pinnae elicits elevated and persistent levels of neutralizing antibody SO VACCINE LA English DT Article DE canine rabies; ear pinnae; vaccination ID NONHUMAN-PRIMATES; GENE GUN; PROTECTIVE IMMUNITY; VIRUS-INFECTION; IMMUNIZATION; RESPONSES; MICE; OLIGODEOXYNUCLEOTIDES; POSTEXPOSURE; VACCINES AB Rabid dog exposures cause >99% of human rabies deaths world-wide. In developing countries, where dogs are the viral reservoir, the 30-50% vaccination coverage of dog populations is insufficient to break the disease transmission cycle. In addition, many vaccines currently used in developing countries fail to maintain detectable levels of neutralizing antibody. The poor vaccination coverage with inadequate vaccines, in addition to the difficulty in locating dogs for booster vaccinations, suggest that an inexpensive vaccine that elicits long-term immunity after a single-dose vaccination could improve control of canine rabies in developing countries. One solution could be a DNA vaccine. This study was designed to evaluate in dogs the ability of different methods of a single-dose DNA vaccination to elicit enhanced levels of neutralizing antibody. Intradermal (i.d.) vaccination into ear pinnae elicited elevated and long-lasting levels of neutralizing antibody. Minimal or undetectable levels of neutralizing antibody were detected after vaccination into quadriceps muscle, gene gun vaccination into ear pinnae or i.d. vaccination into the neck. Intramuscular (i.m.) or gene gun vaccinations did not "immunologically prime" a majority of dogs vaccinated by these routes. The passive transfer of sera from dogs that had been vaccinated i.d. in ear pinnae protected mice against rabies virus challenge. A single-dose i.d. rabies DNA vaccination into ear pinnae could aid in the control of canine rabies in developing countries. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Univ Montana, Lab Anim Resources, Missoula, MT 59812 USA. RP Lodmell, DL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. NR 24 TC 29 Z9 31 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 8 PY 2003 VL 21 IS 25-26 BP 3998 EP 4002 DI 10.1016/S0264-410X(03)00297-4 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 719YY UT WOS:000185233700062 PM 12922136 ER PT J AU Zhao, J Lou, YM Pinczewski, J Malkevitch, N Aldrich, K Kalyanaraman, VS Venzon, D Peng, B Patterson, LJ Edghill-Smith, Y Woodward, R Pavlakis, GN Robert-Guroff, M AF Zhao, J Lou, YM Pinczewski, J Malkevitch, N Aldrich, K Kalyanaraman, VS Venzon, D Peng, B Patterson, LJ Edghill-Smith, Y Woodward, R Pavlakis, GN Robert-Guroff, M TI Boosting of SIV-specific immune responses in rhesus macaques by repeated administration of Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinants SO VACCINE LA English DT Article DE Adenovirus-SIV recombinants; cellular immunity; rhesus macaques ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; HIV-1/SIV CHIMERIC VIRUS; NEUTRALIZING ANTIBODIES; HIV-INFECTION; DISEASE PROGRESSION; CD8(+) LYMPHOCYTES; GAMMA-INTERFERON; ELISPOT ASSAY; VACCINE AB Previous non-human primate studies have shown replication competent adenovirus (Ad) HIVenv/rev and SIVenv/rev recombinants to be promising vaccine candidates. To broaden induced immunity in rhesus macaques, an Ad type 5 host range (Ad5hr) mutant vector with an inserted SIV gag gene was added to the vaccine regimen. Immunity to the encoded SIV Env, Rev, and Gag gene products was evaluated following two immunizations with the same recombinants. The vaccines were administered intranasally plus orally via stomach tube at weeks 0 and 12. The recombinants replicated well in the upper respiratory tract but poorly in the gut, suggesting enteric-coated capsules might improve oral delivery to the intestine. SIV-specific cellular immunity was induced in all 16 immunized macaques. Fourteen exhibited positive interferon-gamma (IFN-gamma) ELISPOT responses, and nine, including two lacking IFN-gamma responses, exhibited SIV-specific T-cell proliferative activity. IFN-gamma secreting peripheral blood mononuclear cells (PBMCs) in response to SIV Gag, Env, and Rev peptides were induced in 73, 53, and 27% of macaques, respectively, and were boosted two- to four-fold by the second immunization. A persistent response to Gag was evident at least 10 weeks thereafter. p11C tetramer staining confirmed elicitation of SIV Gag-specific CD8+ T-cells in Mamu-A*01 macaques. Proliferative responses were more frequent after the second immunization, and binding antibody titers to SIV gp120 were significantly boosted by the immunization regimen. We conclude that a second administration of recombinants based in the same Ad5hr vector can effectively boost immunity to inserted gene products, obviating development of several recombinants in different Ad serotypes for multiple immunizations. Published by Elsevier Science Ltd. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Adv Biosci Labs Inc, Kensington, MD 20895 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Frederick, MD 21702 USA. RP Robert-Guroff, M (reprint author), NCI, Basic Res Lab, NIH, 41 Library Dr MSC5055,Bldg 41,Room D804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 57 TC 34 Z9 34 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 8 PY 2003 VL 21 IS 25-26 BP 4022 EP 4035 DI 10.1016/S0264-410X(03)00266-4 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 719YY UT WOS:000185233700065 PM 12922139 ER PT J AU Gray, RH Li, XB Wawer, MJ Gange, SJ Serwadda, D Sewankambo, NK Moore, R Wabwire-Mangen, F Lutalo, T Quinn, TC AF Gray, RH Li, XB Wawer, MJ Gange, SJ Serwadda, D Sewankambo, NK Moore, R Wabwire-Mangen, F Lutalo, T Quinn, TC CA Rakai Project Grp TI Stochastic simulation of the impact of antiretroviral therapy and HIV vaccines on HIV transmission; Rakai, Uganda SO AIDS LA English DT Article DE HIV; antiretroviral therapy; vaccines; stochastic simulation; Rakai ID AIDS-PREVENTION; COMMUNITY TRIAL; SAN-FRANCISCO; INFECTION; SURVIVAL; COUNTRIES; DISEASE; ERA AB Objective: To model the effects of antiretroviral therapy (ART) and HIV vaccines on HIV transmission using empirical data from studies in Rakai, Uganda. Design: A stochastic simulation model estimated HIV incidence, probabilities of transmission per coital act and the reproductive number (R-0) with ART and HIV vaccines. Model inputs included Rakai data on HIV transmission probabilities per coital act by HIV viral load, age and gender, and sexual behaviors. The impacts of therapy were derived from US programs, and vaccine assumptions included preventive efficacies ranging from 25 to 75%. Component projection models estimated the numbers of HIV-infected persons over 20 years. Results: The model incidence [1.57/100 person years (PY)] closely fitted empirical data (1.5/100 PY). Simulations of ART using DHHS treatment guidelines, predicted declines in HIV incidence, but R-0 remained > 1.0, and the numbers of HIV-positive persons did not change substantially over 20 years. Preventive vaccines with > 50% efficacy and > 50% population coverage could reduce R-0 to < 1.0, and substantially reduce the number of HIV-infected persons over 20 years. Concurrent ART and a preventive vaccine can have substantial impact at lower levels of population coverage and would markedly reduce the HIV infected population over 20 years. However, behavioral disinhibition with increased numbers of sexual partners in either ART or vaccine recipients, increased HIV incidence and diminished intervention impact. Conclusion: ART alone cannot control the HIV epidemic in mature epidemics such as Rakai, and persons in need of therapy will increase over time. ART in combination with a low efficacy vaccine could control the epidemic, if behavioral disinhibition is prevented. (C) 2003 Lippincott Williams Wilkins. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat & Family Hlth Sci, Baltimore, MD USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Heilbrun Ctr Populat & Family Hlth, New York, NY USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Makerere Univ, Fac Med, Dept Med, Kampala, Uganda. Makerere Univ, Fac Med, Sch Publ Hlth, Kampala, Uganda. Uganda Virus Res Inst, Rakai Project, Entebbe, Uganda. Johns Hopkins Univ Hosp, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, 615 N Wolfe St,Suite 4030, Baltimore, MD 21205 USA. OI Sewankambo, Nelson/0000-0001-9362-053X; Gange, Stephen/0000-0001-7842-512X FU FIC NIH HHS [5D43TW00010]; NCRR NIH HHS [M01-RR00079, M01-RR00083]; NIAID NIH HHS [U01-AI-42590, R01 AI34826, R01 AI4326S, U01-AI-31834, U01-AI-34989, U01-AI-34993, U01-AI-34994, U01-AI-35004]; NICHD NIH HHS [5P30HD06826, U01-HD32632] NR 30 TC 107 Z9 108 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 5 PY 2003 VL 17 IS 13 BP 1941 EP 1951 DI 10.1097/01.aids.0000076313.76477.fc PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 717CH UT WOS:000185067700010 PM 12960827 ER PT J AU Gustafson, B Jack, MM Cushman, SW Smith, U AF Gustafson, B Jack, MM Cushman, SW Smith, U TI Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not C/EBP alpha - evidence for differential regulation of the aP2 and adiponectin genes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE adiponectin; PPAR; C/EBP; transcription; cytokines; thiazolidinediones ID PLASMA-PROTEIN ADIPONECTIN; TUMOR-NECROSIS-FACTOR; PPAR-GAMMA; INSULIN-RESISTANCE; 3T3-L1 ADIPOCYTES; BINDING-PROTEIN; EXPRESSION; ADIPOGENESIS; TOPIRAMATE; FAT AB We examined the role of PPARgamma2 and C/EBPalpha for adiponectin and aP2 gene activation in C/EBPalpha(-/-) fibroblasts by stably expressing PPARgamma2 or C/EBPalpha. PPARgamma2, but not PPARgamma1, mRNA markedly increased during the differentiation to adipocytes in cells expressing C/EBPalpha. Both infected cell lines differentiated to an adipocyte phenotype and the mRNA for both aP2 and adiponectin increased in parallel. However, adiponectin mRNA was considerably higher when C/EBPalpha was present, suggesting that this transcription factor is important for full gene activation. Thiazolidinediones markedly activated the gene in PPARgamma2-expressing cells in the absence of C/EBPalpha, suggesting that the adiponectin promoter may have functional PPARgamma-response elements. Several observations showed that the adiponectin and aP2 genes can be differentially regulated in adipocytes: (1) Topiramate, an anti-epileptic agent with weight-reducing properties, increased adiponectin mRNA levels and secretion, but did not, like the thiazolidinediones, increase aP2 expression; (2) IL-6 reduced adiponectin, but significantly increased, aP2 expression; and (3) TNFalpha inhibited adiponectin, but paradoxically increased, aP2 expression in PPARgamma2-infected C/EBPalpha null cells. These data show that activation of the adiponectin gene can be separated from effects on adipogenic genes. (C) 2003 Elsevier Inc. All rights reserved. C1 Gothenburg Univ, Sahlgrenska Acad, Lundberg Lab Diabet Res, Dept Internal Med, SE-41345 Gothenburg, Sweden. NIDDK, EMNS DB, NIH, Bethesda, MD 20892 USA. RP Smith, U (reprint author), Gothenburg Univ, Sahlgrenska Acad, Lundberg Lab Diabet Res, Dept Internal Med, SE-41345 Gothenburg, Sweden. NR 31 TC 86 Z9 93 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 5 PY 2003 VL 308 IS 4 BP 933 EP 939 DI 10.1016/S0006-291X(03)01518-3 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 718VY UT WOS:000185168200039 PM 12927809 ER PT J AU Mezey, E Parmalee, A Szalayova, I Gill, SP Cuajungco, MP Leyne, M Slaugenhaupt, SA Brownstein, MJ AF Mezey, E Parmalee, A Szalayova, I Gill, SP Cuajungco, MP Leyne, M Slaugenhaupt, SA Brownstein, MJ TI Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia? SO BRAIN RESEARCH LA English DT Article DE IKAP; mRNA; rat; pathogenesis; familial dysautonomia ID SPINAL MUSCULAR-ATROPHY; ELONGATOR COMPLEX; EXPRESSION; GENE; MUTATIONS; GANGLIA; PROTEIN; HOLOENZYME; COMPONENT AB Familial dysautonomia (FD) is the best-known and most common member of a group of congenital sensory/autonomic neuropathies characterized by widespread sensory and variable autonomic dysfunction. As opposed to the sensory/motor neuropathies, little is known about the causes of neuronal dysfunction and loss in the sensory/autonomic neuropathies. FD involves progressive neuronal degeneration, has a broad impact on the operation of many of the body's systems, and leads to a markedly reduced quality of life and premature death. In 2001, we identified two mutations in the IKBKAP gene that result in FD. IKBKAP encodes IKAP, a member of the putative human holo-Elongator complex, which may facilitate transcription by RNA polymerase II. Whether or not the Elongator plays this role is moot. The FD mutation found on >99.5% of FD chromosomes does not cause complete loss of function. Instead, it results in a tissue-specific decrease in splicing efficiency of the IKBKAP transcript; cells from patients retain some capacity to produce normal mRNA and protein. To better understand the relationship between the genotype of FD patients and their phenotype, we have used in situ hybridization histochemistry to map the IKAP mRNA in sections of whole rat embryos. The mRNA is widely distributed. Highest levels are in the nervous system, but substantial amounts are also present in peripheral organs. Published by Elsevier B.V. C1 NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Inst Human Genet, Boston, MA 02129 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Mezey, E (reprint author), NINDS, Basic Neurosci Program, NIH, Bldg 36,Rm 3D-06, Bethesda, MD 20892 USA. RI Cuajungco, Math/B-2647-2008 OI Cuajungco, Math/0000-0003-0749-9564 NR 34 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 5 PY 2003 VL 983 IS 1-2 BP 209 EP 214 DI 10.1016/S0006-8993(03)03090-7 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 721KT UT WOS:000185316100022 PM 12914982 ER PT J AU Exil, VJ Roberts, RL Sims, H McLaughlin, JE Malkin, RA Gardner, CD Ni, GM Rottman, JN Strauss, AW AF Exil, VJ Roberts, RL Sims, H McLaughlin, JE Malkin, RA Gardner, CD Ni, GM Rottman, JN Strauss, AW TI Very-long-chain acyl-coenzyme A dehydrogenase deficiency in mice SO CIRCULATION RESEARCH LA English DT Article DE inborn error of metabolism; mitochondrial beta-oxidation; cardiac lipidosis; ventricular arrhythmias; sudden infant death syndrome ID FATTY-ACID OXIDATION; DIFFERENTIATION-RELATED PROTEIN; SUDDEN-DEATH; CARDIOMYOPATHY; DISORDERS; IDENTIFICATION; ADIPOPHILIN; STIMULATION; PHENOTYPE; DISEASES AB Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor gamma coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress. C1 Vanderbilt Univ, Sch Med, Dept Pediat, Div Cardiol, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Internal Med, Div Cardiovasc Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. Washington Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, St Louis, MO 63110 USA. Univ Memphis, Joint Program Biomed Engn, Memphis, TN 38152 USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Exil, VJ (reprint author), Vanderbilt Childrens Hosp, 1161 21st Ave S,D-2220 MCN, Nashville, TN 37232 USA. OI Exil, Vernat/0000-0001-5935-4039 NR 25 TC 75 Z9 76 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 5 PY 2003 VL 93 IS 5 BP 448 EP 455 DI 10.1161/01.RES.0000088786.19197.E4 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 718FT UT WOS:000185135000011 PM 12893739 ER PT J AU Kristof, AS Marks-Konczalik, J Billings, E Moss, J AF Kristof, AS Marks-Konczalik, J Billings, E Moss, J TI Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; PROTEIN-KINASE-C; P70 S6 KINASE; CELL-GROWTH; PHOSPHATIDYLINOSITOL 3-KINASE; SERINE PHOSPHORYLATION; MAXIMAL ACTIVATION; UP-REGULATION; IFN-GAMMA; MTOR AB Mammalian target of rapamycin ( mTOR) and phosphatidylinositol 3-kinase (PI3K) regulate cell growth, protein synthesis, and apoptosis in response to nutrients and mitogens. As an important source of nitric oxide during inflammation, human inducible nitric oxide synthase also plays a role in the regulation of cytokine-driven cell proliferation and apoptosis. The role of mTOR and PI3K in the activation of human inducible nitric oxide synthase transcription by cytokines and lipopolysaccharide (LPS) was investigated in lung epithelial adenocarcinoma (A549) cells. LY294002, a dual mTOR and PI3K inhibitor, blocked human inducible nitric oxide synthase (hiNOS) promoter activation and mRNA induction by cytokines and LPS in a PI3K-independent fashion. On gene expression analysis, LY294002 selectively blocked the induction of a subset of 14 LPS/interferon-gamma (IFN-gamma)-induced genes, previously characterized as signal transducer and activator of transcription-1 (STAT1)-dependent. LY294002, but not wortmannin, inhibited LPS/IFN-gamma-dependent STAT1 phosphorylation at Ser-727 and STAT1 activity. Consistent with dual inhibition of mTOR and PI3K by LY294002, dominant-negative mTOR, anti-mTOR small interfering RNA, or rapamycin each inhibited phosphorylation of STAT1 only in the presence of wortmannin. LPS/IFN-gamma led to the formation of a macromolecular complex containing mTOR, STAT1, as well as protein kinase Cdelta, a known STAT1alpha kinase. Thus, LPS and IFN-gamma activate the PI3K and mTOR pathways, which converge to regulate STAT1-dependent transcription of pro-apoptotic and pro-inflammatory genes in a rapamycin-insensitive manner. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Bioinformat Core Facil, NIH, Bethesda, MD 20892 USA. RP Kristof, AS (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 5N307, Bethesda, MD 20892 USA. NR 47 TC 63 Z9 65 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 33637 EP 33644 DI 10.1074/jbc.M301053200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500007 PM 12807916 ER PT J AU Karahalil, B de Souza-Pinto, NC Parsons, JL Elder, RH Bohr, VA AF Karahalil, B de Souza-Pinto, NC Parsons, JL Elder, RH Bohr, VA TI Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVE DNA-DAMAGE; COLI ENDONUCLEASE III; BASE EXCISION-REPAIR; ESCHERICHIA-COLI; RAT-LIVER; SACCHAROMYCES-CEREVISIAE; SUBSTRATE SPECIFICITIES; THYMINE GLYCOLS; FREE-RADICALS; HOMOLOG AB Mitochondrial DNA is constantly exposed to high levels of endogenously produced reactive oxygen species, resulting in elevated levels of oxidative damaged DNA bases. A large spectrum of DNA base alterations can be detected after oxidative stress, and many of these are highly mutagenic. Thus, an efficient repair of these is necessary for survival. Some of the DNA repair pathways involved have been characterized, but others are not yet determined. A DNA repair activity for thymine glycol and other oxidized pyrimidines has been described in mammalian mitochondria, but the nature of the glycosylases involved in this pathway remains unclear. The generation of mouse strains lacking murine thymine glycol-DNA glycosylase (mNTH1) and/or murine 8-oxoguanine-DNA glycosylase (mOGG1), the two major DNA N-glycosylase/apurinic/apyrimidinic (AP) lyases involved in the repair of oxidative base damage in the nucleus, has provided very useful biological model systems for the study of the function of these and other glycosylases in mitochondrial DNA repair. In this study, mouse liver mitochondrial extracts were generated from mNTH1-, mOGG1-, and [ mNTH1, mOGG1]-deficient mice to ascertain the role of each of these glycosylases in the repair of oxidized pyrimidine base damage. We also characterized for the first time the incision of various modified bases in mitochondrial extracts from a double-knockout [ mNTH1, mOGG1]-deficient mouse. We show that mNTH1 is responsible for the repair of thymine glycols in mitochondrial DNA, whereas other glycosylase/ AP lyases also participate in removing other oxidized pyrimidines, such as 5-hydroxycytosine and 5-hydroxyuracil. We did not detect a backup glycosylase or glycosylase/ AP lyase activity for thymine glycol in the mitochondrial mouse extracts. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. Christie Hosp NHS Trust, Paterson Inst Canc Res, Carcinogenesis Grp, Canc Res UK, Manchester M20 4BX, Lancs, England. RP Bohr, VA (reprint author), NIA IRP, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 28 TC 44 Z9 46 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 33701 EP 33707 DI 10.1074/jbc.M301617200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500013 PM 12819227 ER PT J AU Hochbaum, D Tanos, T Ribeiro-Neto, F Altschuler, D Coso, OA AF Hochbaum, D Tanos, T Ribeiro-Neto, F Altschuler, D Coso, OA TI Activation of JNK by Epac is independent of its activity as a rap guanine nucleotide exchanger SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID JNK/SAPK SIGNALING PATHWAY; BINDING PROTEINS RAC1; MAP KINASE; C-JUN; STRESS; CAMP; PHOSPHORYLATION; FAMILY; CDC42; GTP AB Guanine nucleotide exchange factors ( GEFs) and their associated GTP-binding proteins (G-proteins) are key regulatory elements in the signal transduction machinery that relays information from the extracellular environment into specific intracellular responses. Among them, the MAPK cascades represent ubiquitous downstream effector pathways. We have previously described that, analogous to the Ras-dependent activation of the Erk-1/2 pathway, members of the Rho family of small G-proteins activate the JNK cascade when GTP is loaded by their corresponding GEFs. Searching for novel regulators of JNK activity we have identified Epac ( exchange protein activated by cAMP) as a strong activator of JNK-1. Epac is a member of a growing family of GEFs that specifically display exchange activity on the Rap subfamily of Ras small G-proteins. We report here that while Epac activates the JNK severalfold, a constitutively active (G12V) mutant of Rap1b does not, suggesting that Rap-GTP is not sufficient to transduce Epac-dependent JNK activation. Moreover, Epac signaling to the JNKs was not blocked by inactivation of endogenous Rap, suggesting that Rap activation is not necessary for this response. Consistent with these observations, domain deletion mutant analysis shows that the catalytic GEF domain is dispensable for Epac-mediated activation of JNK. These studies identified a region overlapping the Ras exchange motif domain as critical for JNK activation. Consistent with this, an isolated Ras exchange motif domain from Epac is sufficient to activate JNK. We conclude that Epac signals to the JNK cascade through a new mechanism that does not involve its canonical catalytic action, i.e. Rap-specific GDP/GTP exchange. This represents not only a novel way to activate the JNKs but also a yet undescribed mechanism of downstream signaling by Epac. C1 Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol & Celular, Lab Fisiol & Biol Mol, RA-1428 Buenos Aires, DF, Argentina. Consejo Nacl Invest Cient & Tecn, IFYBINE, RA-1428 Buenos Aires, DF, Argentina. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. RP Coso, OA (reprint author), Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol & Celular, Lab Fisiol & Biol Mol, RA-1428 Buenos Aires, DF, Argentina. NR 37 TC 45 Z9 46 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 33738 EP 33746 DI 10.1074/jbc.M305208200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500018 PM 12783872 ER PT J AU Calderwood, MS Gannoun-Zaki, L Wellems, TE Deitsch, KW AF Calderwood, MS Gannoun-Zaki, L Wellems, TE Deitsch, KW TI Plasmodium falciparum var genes are regulated by two regions with separate promoters, one upstream of the coding region and a second within the intron SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANTIGENIC VARIATION; IN-VIVO; SACCHAROMYCES-CEREVISIAE; MALARIA PARASITES; DNA-REPLICATION; BINDING-PROTEIN; NUCLEAR MATRIX; BIDIRECTIONAL PROMOTER; INFECTED ERYTHROCYTES; TRANSCRIPTION FACTORS AB Antigenic variation in Plasmodium falciparum malaria parasites results from switches in expression among members of the multicopy var gene family. This family is subject to allelic exclusion by which particular genes are expressed while the rest of the family remains transcriptionally silent. Evidence from reporter constructs indicates that var gene silencing involves a cooperative interaction between the var intron and an upstream element and requires transition of the parasites through S-phase of the cell cycle. These findings implicate chromatin assembly in the process of regulating var gene expression and antigenic variation. Here we characterize the var intron and the elements within it that are necessary for var transcriptional silencing. Alignments of var introns show a highly conserved structure that consists of three discreet regions with distinct base pair compositions. The middle region is highly AT-rich and is sufficient to silence an associated var promoter. Constructs that include a typical var intron upstream of a reporter gene or drug-selectable marker reveal that the intron also possesses promoter activity, presumably providing an explanation for the origin of the previously described var "sterile" transcripts. Deletions that disable the promoter activity of the intron also eliminate its ability to function as a silencer. These findings suggest that interactions between the regions of these two promoters and the generation of the sterile transcripts play a significant role in regulating var gene expression. C1 Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Deitsch, KW (reprint author), Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, 1300 York Ave,W-704,Box 62, New York, NY 10021 USA. FU NIAID NIH HHS [AI 52390] NR 50 TC 117 Z9 119 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34125 EP 34132 DI 10.1074/jbc.M213065200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500065 PM 12832422 ER PT J AU Sun, H Hu, XQ Moradel, EM Weight, FF Zhang, L AF Sun, H Hu, XQ Moradel, EM Weight, FF Zhang, L TI Modulation of 5-HT3 receptor-mediated response and trafficking by activation of protein kinase C SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; NMDA-RECEPTOR; XENOPUS-OOCYTES; NEUROTRANSMITTER RELEASE; FUNCTIONAL EXPRESSION; SYNAPTIC TRANSMISSION; GABA(C) RECEPTORS; PARTIAL AGONISTS; NERVOUS-SYSTEM; F-ACTIN AB Modulation of neurotransmitter-gated membrane ion channels by protein kinase C (PKC) has been the subject of a number of studies. However, less is known about PKC modulation of the serotonin type 3 (5-HT3) receptor, a ligand-gated membrane ion channel that can mediate fast synaptic transmission in the central and peripheral nervous system. Here, we show that PKC potentiated 5-HT3 receptor-mediated current in Xenopus oocytes expressing 5- HT3A receptors and mouse N1E-115 neuroblastoma cells. In addition, using a specific antibody directed to the extracellular N-terminal domain of the 5- HT3A receptor, treatment with the PKC activator, 4beta-phorbol 12-myristate 13-acetate (PMA), significantly increased surface immunofluorescence. PKC also increased the amount of 5- HT3A receptor protein in the cell membrane without affecting the amount receptor protein in the total cell extract. The magnitude of PMA potentiation of 5-HT3A receptor-mediated responses is correlated with the magnitude of PMA enhancement of the receptor abundance in the cell surface membrane. PMA potentiation is unlikely to occur via direct phosphorylation of the 5- HT3A receptor protein since the potentiation was not affected by point mutation of each of the putative sites for PKC phosphorylation. However, preapplication of phalloidin, which stabilizes the actin polymerization, significantly inhibited PMA potentiation of 5-HT-activated responses in both N1E-115 cells and oocytes expressing 5-HT3A receptors. On the other hand, latrunculin-A, which destabilizes actin cytoskeleton, enhanced the PMA potentiation of 5- HT3A receptors. The observations suggest that PKC can modulate 5- HT3A receptor function and trafficking through an F-actin-dependent mechanism. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, L (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, Pk Bldg,Rm 150, Bethesda, MD 20892 USA. NR 50 TC 32 Z9 34 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34150 EP 34157 DI 10.1074/jbc.M303584200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500068 PM 12791692 ER PT J AU Boja, ES Hoodbhoy, T Fales, HM Dean, J AF Boja, ES Hoodbhoy, T Fales, HM Dean, J TI Structural characterization of native mouse zona pellucida proteins using mass spectrometry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPERM RECEPTOR-ACTIVITY; FURIN CLEAVAGE-SITE; LINKED OLIGOSACCHARIDES; ENDOPLASMIC-RETICULUM; MONOCLONAL-ANTIBODIES; CHARGE-DISTRIBUTION; TRANSGENIC MICE; O-GLYCOSYLATION; COMBINING-SITE; EGG COAT AB The zona pellucida is an extracellular matrix consisting of three glycoproteins that surrounds mammalian eggs and mediates fertilization. The primary structures of mouse ZP1, ZP2, and ZP3 have been deduced from cDNA. Each has a predicted signal peptide and a transmembrane domain from which an ectodomain must be released. All three zona proteins undergo extensive co- and post-translational modifications important for secretion and assembly of the zona matrix. In this report, native zonae pellucidae were isolated and structural features of individual zona proteins within the mixture were determined by high resolution electrospray mass spectrometry. Complete coverage of the primary structure of native ZP3, 96% of ZP2, and 56% of ZP1, the least abundant zona protein, was obtained. Partial disulfide bond assignments were made for each zona protein, and the size of the processed, native protein was determined. The N termini of ZP1 and ZP3, but not ZP2, were blocked by cyclization of glutamine to pyroglutamate. The C termini of ZP1, ZP2, and ZP3 lie upstream of a dibasic motif, which is part of, but distinct from, a proprotein convertase cleavage site. The zona proteins are highly glycosylated and 4/4 potential N-linkage sites on ZP1, 6/6 on ZP2, and 5/6 on ZP3 are occupied. Potential O-linked carbohydrate sites are more ubiquitous, but less utilized. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Boja, ES (reprint author), NHLBI, Biophys Chem Lab, NIH, 50 South Dr,Rm 3122,Bldg 50, Bethesda, MD 20892 USA. NR 61 TC 111 Z9 118 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34189 EP 34202 DI 10.1074/jbc.M304026200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500073 PM 12799386 ER PT J AU Gavrilova, O Haluzik, M Matsusue, K Cutson, JJ Johnson, L Dietz, KR Nicol, CJ Vinson, C Gonzalez, FJ Reitman, ML AF Gavrilova, O Haluzik, M Matsusue, K Cutson, JJ Johnson, L Dietz, KR Nicol, CJ Vinson, C Gonzalez, FJ Reitman, ML TI Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILIAL PARTIAL LIPODYSTROPHY; LIPOATROPHIC A-ZIP/F-1 MICE; PPAR-GAMMA; ADIPOSE-TISSUE; GENE-EXPRESSION; INSULIN-RESISTANCE; DIABETES-MELLITUS; SKELETAL-MUSCLE; ADIPOCYTE DIFFERENTIATION; TRANSGENIC MICE AB Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that mediates the antidiabetic effects of thiazolidinediones. PPARgamma is present in adipose tissue and becomes elevated in fatty livers, but the roles of specific tissues in thiazolidinedione actions are unclear. We studied the function of liver PPARgamma in both lipoatrophic A-ZIP/F- 1 (AZIP) and wild type mice. In AZIP mice, ablation of liver PPARgamma reduced the hepatic steatosis but worsened the hyperlipidemia, triglyceride clearance, and muscle insulin resistance. Inactivation of AZIP liver PPARgamma also abolished the hypoglycemic and hypolipidemic effects of rosiglitazone, demonstrating that, in the absence of adipose tissue, the liver is a primary and major site of thiazolidinedione action. In contrast, rosiglitazone remained effective in non-lipoatrophic mice lacking liver PPARgamma, suggesting that adipose tissue is the major site of thiazolidinedione action in typical mice with adipose tissue. Interestingly, mice without liver PPARgamma, but with adipose tissue, developed relative fat intolerance, increased adiposity, hyperlipidemia, and insulin resistance. Thus, liver PPARgamma regulates triglyceride homeostasis, contributing to hepatic steatosis, but protecting other tissues from triglyceride accumulation and insulin resistance. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gavrilova, O (reprint author), NIDDK, Diabet Branch, NIH, Bldg 10,Rm 8N-250,10 Ctr Dr, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 NR 72 TC 399 Z9 416 U1 2 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34268 EP 34276 DI 10.1074/jbc.M300043200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500082 PM 12805374 ER PT J AU Servitja, JM Marinissen, MJ Sodhi, A Bustelo, XR Gutkind, JS AF Servitja, JM Marinissen, MJ Sodhi, A Bustelo, XR Gutkind, JS TI Rac1 function is required for Src-induced transformation - Evidence of a role for Tiam1 and Vav2 in RAC activation by Src SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; NUCLEOTIDE EXCHANGE FACTORS; HETEROTRIMERIC G-PROTEINS; RHO-INDEPENDENT PATHWAY; GROWTH-FACTOR RECEPTORS; SWISS 3T3 FIBROBLASTS; BREAST-CANCER CELLS; TYROSINE PHOSPHORYLATION; CYCLIN D1; PROTOONCOGENE PRODUCT AB The proto-oncogene c-Src has been implicated in the development and progression of a number of human cancers including those of colon and breast. Accumulating evidence indicates that activated alleles of Src may induce cell transformation through Ras-ERK-dependent and - independent pathways. Here we show that Rac1 activity is strongly elevated in Src-transformed cells and that this small G protein is a critical component of the pathway connecting oncogenic Src with cell transformation. We further show that Vav2 and the ubiquitously expressed Rac1 guanine nucleotide exchange factor Tiam1 are phosphorylated in tyrosine residues in cells transfected with active and oncogenic Src. Moreover, phosphorylation of Tiam1 in cells treated with pervanadate, a potent inhibitor of tyrosine phosphatases, was partially inhibited by the Src inhibitor SU6656. Using truncated mutants of Tiam1, we demonstrate that multiple sites can be tyrosine-phosphorylated by Src. Furthermore, Tiam1 cooperated with Src to induce activation of Rac1 in vivo and the formation of membrane ruffles. Similarly, activation of JNK and the c-jun promoter by Src were also potently increased by Tiam1. Together, these results suggest that Vav2 and Tiam1 may act as downstream effectors of Src, thereby regulating Rac1-dependent pathways that participate in Src-induced cell transformation. C1 NIDCD, Oral & Pharyngeal Canc Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Salamanca, CSIC, Ctr Invest Canc, Salamanca 37007, Spain. RP Gutkind, JS (reprint author), NIDCD, Oral & Pharyngeal Canc Branch, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; OI SERVITJA DUQUE, JOAN-MARC/0000-0002-1241-8004 NR 50 TC 121 Z9 127 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34339 EP 34346 DI 10.1074/jbc.M302960200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500090 PM 12810717 ER PT J AU Cristillo, AD Nie, LH Macri, MJ Bierer, BE AF Cristillo, AD Nie, LH Macri, MJ Bierer, BE TI Cloning and characterization of N4WBP5A, an inducible, cyclosporine-sensitive, Nedd4-binding protein in human T lymphocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL NA+ CHANNEL; WW DOMAIN; LIDDLES-SYNDROME; IMMUNE-SYSTEM; LIGASE NEDD4; UBIQUITINATION; FAMILY; IDENTIFICATION; MICE; ITCH AB We have cloned and characterized a human cDNA, designated N4WBP5A, that belongs to the family of Nedd4-binding proteins. We originally identified N4WBP5A as an unknown expressed sequence tag (AA770150) represented in a cDNA microarray analysis that was up-regulated upon activation of T cells and inhibited by cell treatment with the calcineurin phosphatase inhibitors, cyclosporine (CsA) and tacrolimus (FK506). The predicted N4WBP5A amino acid sequence of 242 amino acid residues reveals an open reading frame of 729 nucleotides with a corresponding molecular mass of 27.1 kDa. Detection of N4WBP5A mRNA by reverse transcription-PCR was consistent with the induction of N4WBP5A following mitogenic stimulation of T lymphocytes and inhibition by CsA. Immunoblot analysis revealed endogenous N4WBP5A protein to be up-regulated following T cell activation and inhibited by CsA. This regulation of N4WBP5A mRNA expression differed from that of its homologue (51% identical; 65% similar) N4WBP5. Like N4WBP5, however, expression of epitope-tagged N4WBP5A indicated that the protein is localized predominantly to the Golgi network. Here we show by co-precipitation experiments that N4WBP5A interacts with the WW domains of Nedd4, an E3 ubiquitin ligase. Taken together, our data suggest that N4WBP5A may play a regulatory role in modulating Nedd4 activity at the level of the Golgi apparatus in T lymphocytes. C1 NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Bierer, BE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 26 TC 17 Z9 18 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34587 EP 34597 DI 10.1074/jbc.M304723200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500120 PM 12796489 ER PT J AU Bebenek, K Garcia-Diaz, M Blanco, L Kunkel, TA AF Bebenek, K Garcia-Diaz, M Blanco, L Kunkel, TA TI The frameshift infidelity of human DNA polymerase lambda - Implications for function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; STRAND BREAK REPAIR; MU POL-MU; NUCLEOTIDE INCORPORATION; SOMATIC HYPERMUTATION; DELETION MUTATIONS; ESCHERICHIA-COLI; LIGASE-IV; Y-FAMILY; BETA AB DNA polymerase lambda (Pol lambda) is a member of the Pol X family having properties in common with several other mammalian DNA polymerases. To obtain clues to possible functions in vivo, we have determined the fidelity of DNA synthesis by human Pol lambda. The results indicate that the average single-base deletion error rate of Pol lambda is higher than those of other mammalian polymerases. In fact, unlike other DNA polymerases, Pol lambda generates single-base deletions at average rates that substantially exceed base substitution rates. Moreover, the sequence specificity for single-base deletions made by Pol lambda is different from that of other DNA polymerases and reveals that Pol lambda readily uses template-primers with limited base pair homology at the primer terminus. This ability, together with an ability to fill short gaps in DNA at low dNTP concentrations, is consistent with a role for mammalian Pol lambda in non-homologous end-joining. This may include non-homologous end-joining of strand breaks resulting from DNA damage, because Pol lambda has intrinsic 5', 2'-deoxyribose-5-phosphate lyase activity. C1 NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Blanco, Luis/I-1848-2015 NR 59 TC 93 Z9 94 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2003 VL 278 IS 36 BP 34685 EP 34690 DI 10.1074/jbc.M305705200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716UK UT WOS:000185047500129 PM 12829698 ER PT J AU Buscaglia, M Schuler, B Lapidus, LJ Eaton, WA Hofrichter, J AF Buscaglia, M Schuler, B Lapidus, LJ Eaton, WA Hofrichter, J TI Kinetics of intramolecular contact formation in a denatured protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE triplet state quenching; unfolded state; collapse; cold shock protein ID BACTERIUM THERMOTOGA-MARITIMA; COLD-SHOCK PROTEIN; POLYPEPTIDES; SCATTERING; DYNAMICS; PEPTIDE; STATE AB Quenching of the triplet state of tryptophan by cysteine has provided a new tool for measuring the rate of forming a specific intramolecular contact in disordered polypeptides. Here, we use this technique to investigate contact formation in the denatured state of CspTm, a small cold-shock protein from Thermotoga maritima, engineered to contain a single tryptophan residue (W29) and a single cysteine residue at the C terminus (C67). At all concentrations of denaturant, the decay rate of the W29 triplet of the unfolded protein is more than tenfold faster than the rate observed for the native protein (similar to10(4) s(-1)). Experiments on the unfolded protein without the added C-terminal cysteine residue show that this faster rate results entirely from contact quenching by C67. The quenching rate in the unfolded state by C67 increases at concentrations of denaturant that favor folding, indicating a compaction of the unfolded protein as observed previously in single-molecule Forster resonance energy transfer (FRET) experiments. Published by Elsevier Ltd. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Phys Biochem Univ, Potsdam, Germany. RP Eaton, WA (reprint author), NIDDKD, Phys Chem Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov; jim@sunder.niddk.nih.gov RI Buscaglia, Marco/C-2435-2008; Schuler, Benjamin/E-7342-2011 OI Buscaglia, Marco/0000-0001-5010-0278; Schuler, Benjamin/0000-0002-5970-4251 NR 20 TC 45 Z9 46 U1 1 U2 13 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 5 PY 2003 VL 332 IS 1 BP 9 EP 12 DI 10.1016/S0022-2836(03)00891-X PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716ND UT WOS:000185034400002 PM 12946342 ER PT J AU Gunasekaran, K Ma, BY Nussinov, R AF Gunasekaran, K Ma, BY Nussinov, R TI Triggering loops and enzyme function: Identification of loops that trigger and modulate movements SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE molecular dynamics simulation; protein flexibility; conformational change; ligand-binding mechanism; triggering loops ID MOLECULAR-DYNAMICS SIMULATIONS; HUMICOLA-LANUGINOSA LIPASE; CONFORMATIONAL CHANGE; CRYSTAL-STRUCTURE; PROTEIN FUNCTION; ESCHERICHIA-COLI; ENERGY FUNCTION; LIGAND BINDING; ACTIVE-SITE; ENOLASE AB Enzyme function often involves a conformational change. There is a general agreement that loops play a vital role in correctly positioning the catalytically important residues. Nevertheless, predicting the functional loops and most importantly their role in enzyme function remains a difficult task. A major reason for this difficulty is that loops that undergo conformational change are frequently not well conserved in their primary sequence. beta1,4-Galactosyltransferase is one such enzyme. There, the amino acid sequence of a long loop that undergoes a large conformational change upon substrate binding is not well conserved. Our molecular dynamics simulations show that the large conformational change in the long loop is brought about by a second, interacting loop. Interestingly, while the structural change of the second loop is much smaller than that of the long loop, its sequence (particularly glycine residues) is highly conserved. We further examine the generality of the proposition that there are loops that trigger movements but nevertheless show little or no structural changes in crystals. We focus on two other enzymes, enolase and lipase. We chose these enzymes, since they too undergo conformational change upon ligand binding, however, they have different folds and different functions. Through multiple sets of simulations we show that the conformational change of the functional loop(s) is brought about through communication of flexibility by triggering loops that have several glycine residues. We further propose that similar to the conservation of common favorable fold types and structural motifs, evolution has also conserved common "skillful" mechanisms. Mechanisms may be conserved across different folds, sequences and functions, with adaptation to specific enzymatic roles. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU PHS HHS [N01-C0-12400] NR 50 TC 28 Z9 29 U1 1 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 5 PY 2003 VL 332 IS 1 BP 143 EP 159 DI 10.1016/S0022-2836(03)00893-3 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716ND UT WOS:000185034400013 PM 12946353 ER PT J AU Yewdell, JW AF Yewdell, JW TI Hide and seek in the peptidome SO SCIENCE LA English DT Editorial Material ID TRANSLATION; DEGRADATION; PROTEINS C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 9 TC 18 Z9 19 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 5 PY 2003 VL 301 IS 5638 BP 1334 EP 1335 DI 10.1126/science.1089553 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717XQ UT WOS:000185116400024 PM 12958347 ER PT J AU Spiegel, A AF Spiegel, A TI beta-arrestin - Not just for G protein-coupled receptors SO SCIENCE LA English DT Editorial Material ID TRANSDUCTION C1 NIDDKD, Bethesda, MD 20892 USA. RP Spiegel, A (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 8 TC 10 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 SEP 5 PY 2003 VL 301 IS 5638 BP 1338 EP 1339 DI 10.1126/science.1089552 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717XQ UT WOS:000185116400028 PM 12958351 ER PT J AU Ellis, RJ Minton, AP AF Ellis, RJ Minton, AP TI Cell biology - Join the crowd SO NATURE LA English DT Editorial Material C1 Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. NIDDKD, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ellis, RJ (reprint author), Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. OI Minton, Allen/0000-0001-8459-1247 NR 3 TC 432 Z9 448 U1 6 U2 76 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 4 PY 2003 VL 425 IS 6953 BP 27 EP 28 DI 10.1038/425027a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717LD UT WOS:000185089200021 PM 12955122 ER PT J AU Fudala, PJ Bridge, TP Herbert, S Williford, WO Chiang, CN Jones, K Collins, J Raisch, D Casadonte, P Goldsmith, RJ Ling, W Malkerneker, U McNicholas, L Renner, J Stine, S Tusel, D AF Fudala, PJ Bridge, TP Herbert, S Williford, WO Chiang, CN Jones, K Collins, J Raisch, D Casadonte, P Goldsmith, RJ Ling, W Malkerneker, U McNicholas, L Renner, J Stine, S Tusel, D CA Buprenorphine Naloxone Collaborati TI Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONTROLLED CLINICAL-TRIAL; DRUG-ABUSE TREATMENT; OPIOID DEPENDENCE; INTRAVENOUS BUPRENORPHINE; CRIMINAL ACTIVITY; VOLUNTEERS; COMBINATIONS; PREVALENCE; METHADONE AB Background: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied. Methods: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. Results: The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. Conclusions: Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting. C1 Univ Penn, Sch Med, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NIDA, Div Treatment Res & Dev, NIH, Bethesda, MD 20892 USA. VA Cooperat Studies Program, Coordinating Ctr, Perry Point, MD USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ New Mexico, VA Cooperat Studies Program, Clin Res Pharm Coordinating Ctr, Albuquerque, NM 87131 USA. NYU, Sch Med, New York Harbor Hlth Care Syst, VA Med Ctr, New York, NY USA. VA Med Ctr, Cincinnati, OH USA. VA Med Ctr, Los Angeles, CA USA. VA Med Ctr, Hines, IL USA. Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02118 USA. VA Med Ctr, West Haven, CT USA. Univ Calif San Francisco, VA Med Ctr, San Francisco, CA 94143 USA. RP Fudala, PJ (reprint author), VA Med Ctr, Psychiat Serv, Ward 7E 116-7E,Univ & Woodland Aves, Philadelphia, PA 19104 USA. OI Stine, Susan/0000-0001-5426-4448 FU NIDA NIH HHS [3Y01-DA-30011-04] NR 32 TC 258 Z9 261 U1 4 U2 15 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 4 PY 2003 VL 349 IS 10 BP 949 EP 958 DI 10.1056/NEJMoa022164 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 717HJ UT WOS:000185081400006 PM 12954743 ER PT J AU Guttmacher, AE Collins, FS AF Guttmacher, AE Collins, FS TI Welcome to the genomic era SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MELANOCORTIN-4 RECEPTOR GENE; ACUTE RESPIRATORY SYNDROME; MEDICINE; SEQUENCE; MUTATIONS; CANCER; POLYMORPHISM; CORONAVIRUS; DISEASE; BREAST C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Guttmacher, AE (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 29 TC 144 Z9 149 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 4 PY 2003 VL 349 IS 10 BP 996 EP 998 DI 10.1056/NEJMe038132 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 717HJ UT WOS:000185081400014 PM 12954750 ER PT J AU Darstein, M Petralia, RS Swanson, GT Wenthold, RJ Heinemann, SF AF Darstein, M Petralia, RS Swanson, GT Wenthold, RJ Heinemann, SF TI Distribution of kainate receptor subunits at hippocampal mossy fiber synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article DE KA1 kainate receptor subunit; KA2 kainate receptor subunit; presynaptic kainate receptors; coassembly; knock-out mice; hippocampus; mossy fiber ID EXCITATORY SYNAPTIC-TRANSMISSION; HIGH-AFFINITY; RAT-BRAIN; GLUR6-DEFICIENT MICE; BINDING-SITES; ION CHANNELS; GLUTAMATE; CA3; EXPRESSION; PLASTICITY AB Kainate receptors function as mediators of postsynaptic currents and as presynaptic modulators of synaptic transmission at mossy fiber synapses. Despite intense research into the physiological properties of mossy fiber kainate receptors, their subunit composition in the presynaptic and postsynaptic compartments is unclear. Here we describe the distribution of kainate receptor subunits in mossy fiber synapses using subunit-selective antibodies and knock-out mice. We provide morphological evidence for the presynaptic localization of KA1 and KA2 receptor subunits at mossy fiber synapses. Immunogold staining for KA1 and KA2 was commonly seen at synaptic contacts and in vesicular structures. Postsynaptic labeling in dendritic spines was also observed. Although KA1 predominantly showed presynaptic localization, KA2 was concentrated to a greater degree on postsynaptic membranes. Both subunits coimmunoprecipitated from hippocampal membrane extracts with GluR6 but not GluR7 subunits. These results demonstrate that KA1 and KA2 subunits are localized presynaptically and postsynaptically at mossy fiber synapses where they most likely coassemble with GluR6 subunits to form functional heteromeric kainate receptor complexes. C1 Salk Inst Biol Studies, La Jolla, CA 92037 USA. Natl Inst Deafness & Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Pharmacol & Toxicol, Med Branch, Galveston, TX 77555 USA. RP Darstein, M (reprint author), Univ Freiburg, Inst Anat & Cell Biol 1, Albertstr 17, D-79104 Freiburg, Germany. NR 34 TC 91 Z9 94 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 SEP 3 PY 2003 VL 23 IS 22 BP 8013 EP 8019 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 717RC UT WOS:000185102800007 PM 12954862 ER PT J AU Domanski, M Krause-Steinrauf, H Deedwania, P Follmann, D Ghali, JK Gilbert, E Haffner, S Katz, R Lindenfeld, J Lowes, BD Martin, W McGrew, F Bristow, MR AF Domanski, M Krause-Steinrauf, H Deedwania, P Follmann, D Ghali, JK Gilbert, E Haffner, S Katz, R Lindenfeld, J Lowes, BD Martin, W McGrew, F Bristow, MR CA BEST Investigators TI The effect of diabetes on outcomes of patients with advanced-heart failure in the BEST trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID INTRINSIC SYMPATHOMIMETIC ACTIVITY; GLUCOSE-METABOLISM; BUCINDOLOL; SURVIVAL; METOPROLOL; ENALAPRIL; MELLITUS; CARVEDILOL; MYOCARDIUM; MORTALITY AB OBJECTIVES This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure (HF), and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus. BACKGROUND In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated. METHODS We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial (BEST). We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes, and the effect of beta-blocker therapy on mortality and HF progression or myocardial infarction (MI). The database was the 2,708 patients with advanced HF (36% with diabetes and 64% without diabetes) who were randomized to the beta-blocker bucindolol or placebo in BEST and followed for mortality, hospitalization, and MI for an average of two years. RESULTS Patients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes. Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, p = 0.001), but not in those with a nonischemic etiology (adjusted hazard ratio 0.98, 95% confidence interval 0.74 to 1.30, p = 0.89). Compared with patients without diabetes, in diabetic patients beta-blocker therapy was at least as effective in reducing death or. HF hospitalizations, total hospitalizations, HF hospitalizations, and MI. Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes. CONCLUSIONS Diabetes worsens prognosis in patients with advanced HF, but this worsening appears to be limited to patients with ischemic cardiomyopathy. In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes. (C) 2003 by the American College of Cardiology Foundation. C1 Natl Heart Lung & Blood Inst, Clin Trials Grp, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Fresno VAMC, Fresno, CA USA. Cardiac Ctr Louisiana, Shreveport, LA USA. Univ Utah, Ctr Hlth Sci, Salt Lake City, UT USA. George Washington Univ, Div Cardiol, Washington, DC USA. Univ Colorado, Div Cardiol, Denver, CO USA. St Louis VAMC, St Louis, MO USA. Baptist Mem Hosp, Memphis, TN USA. RP Domanski, M (reprint author), Natl Heart Lung & Blood Inst, Clin Trials Grp, 6701 Rockledge Dr,MSC 7936, Bethesda, MD 20892 USA. RI bristow, michael/G-7850-2011; OI Lowes, Brian/0000-0002-5919-2540 NR 32 TC 114 Z9 118 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 3 PY 2003 VL 42 IS 5 BP 914 EP 922 DI 10.1016/S0735-1097(03)00856-8 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 716RH UT WOS:000185029200025 PM 12957443 ER PT J AU Caporaso, N AF Caporaso, N TI The molecular epidemiology of oxidative damage to DNA and cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID LUNG-CANCER; MUTAGEN SENSITIVITY; COMET ASSAY; REPAIR; RISK; SUSCEPTIBILITY; STRESS; POLYMORPHISM; ANTIOXIDANTS; POPULATION C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Caporaso, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7116, Bethesda, MD 20892 USA. NR 37 TC 44 Z9 47 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 3 PY 2003 VL 95 IS 17 BP 1263 EP 1265 DI 10.1093/jnci/dig065 PG 3 WC Oncology SC Oncology GA 719ZE UT WOS:000185234400003 PM 12953074 ER PT J AU Weir, HK Thun, MJ Hankey, BF Ries, LAG Howe, HL Wingo, PA Jemal, A Ward, E Anderson, RN Edwards, BK AF Weir, HK Thun, MJ Hankey, BF Ries, LAG Howe, HL Wingo, PA Jemal, A Ward, E Anderson, RN Edwards, BK TI Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID HORMONE REPLACEMENT THERAPY; PROSTATE-CANCER; COLORECTAL-CANCER; BREAST-CANCER; UNITED-STATES; ADJUVANT CHEMOTHERAPY; INTERPRETING TRENDS; COLON-CANCER; SCREENING MAMMOGRAPHY; SOCIETY GUIDELINES AB Background: The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to update cancer rates and trends in the United States. This report updates statistics on lung, female breast, prostate, and colorectal cancers and highlights the uses of selected surveillance data to assist development of state-based cancer control plans. Methods: Age-adjusted incidence rates from 1996 through 2000 are from state and metropolitan area cancer registries that met NAACCR criteria for highest quality. Death rates are based on underlying cause-of-death data. Long-term trends and rates for major racial and ethnic populations are based on NCI and CDC data. Incidence trends from 1975 through 2000 were adjusted for reporting delays. State-specific screening and risk factor survey data are from the CDC and other federal and private organizations. Results: Cancer incidence rates for all cancer sites combined increased from the mid-1970s through 1992 and then decreased from 1992 through 1995. Observed incidence rates for all cancers combined were essentially stable from 1995 through 2000, whereas the delay-adjusted trend showed an increase that had borderline statistical significance (P = .05). Increases in the incidence rates of breast cancer in women and prostate cancer in men offset a long-term decrease in lung cancer in men. Death rates for all cancer sites combined decreased beginning in 1994 and stabilized from 1998 through 2000, resulting in part from recent revisions in cause-of-death codes. Death rates among men continued to decline throughout the 1990s, whereas trends in death rates among women were essentially unchanged from 1998 through 2000. Analysis of state data for the leading cancers revealed mixed progress in achieving national objectives for improving cancer screening, risk factor reduction, and decreases in mortality. Conclusions: Overall cancer incidence and death rates began to stabilize in the mid- to late 1990s. The recent increase in the delay-adjusted trend will require monitoring with additional years of data. Further reduction in the burden of cancer is possible but will require the continuation of strong federal, state, local, and private partnerships to increase dissemination of evidence-based cancer control programs to all segments of the population. C1 Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. Amer Canc Soc, Epidemiol & Surveillance Res Dept, Atlanta, GA 30329 USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. N Amer Assoc Cent Canc Registries, Springfield, IL USA. Ctr Dis Control & Prevent, Div Vital Stat, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Weir, HK (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, MS K-53,4770 Buford Hwy, Atlanta, GA 30341 USA. NR 113 TC 577 Z9 597 U1 1 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 3 PY 2003 VL 95 IS 17 BP 1276 EP 1299 DI 10.1093/jnci/djg040 PG 24 WC Oncology SC Oncology GA 719ZE UT WOS:000185234400010 PM 12953083 ER PT J AU Mbulaiteye, SM Biggar, RJ Bakaki, PM Pfeiffer, RM Whitby, D Owor, AM Katongole-Mbidde, E Goedert, JJ Ndugwa, CM Engels, EA AF Mbulaiteye, SM Biggar, RJ Bakaki, PM Pfeiffer, RM Whitby, D Owor, AM Katongole-Mbidde, E Goedert, JJ Ndugwa, CM Engels, EA TI Human herpesvirus 8 infection and transfusion history in children with sickle-cell disease in Uganda SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; RISK-FACTORS; BLOOD-DONORS; SEXUAL TRANSMISSION; DRUG-USERS; VIRUS; PERFORMANCE; PREVALENCE; AFRICA AB Background: Although human herpesvirus 8 (HHV-8), the etiologic agent for Kaposi's sarcoma, can be detected in peripheral blood, blood-borne transmission of this virus has not been demonstrated. We studied the association between HHV-8 seropositivity and transfusion history among children with sickle-cell disease in Uganda, where HHV-8 infection is common in blood donors. Methods: We studied 600 children (aged 0-16 years) with sickle-cell disease at Mulago Hospital, Kampala, from November 2001 through April 2002. By design, about half had previously been transfused. HHV-8 serostatus was determined using enzyme-linked immunosorbent assays for antibodies against HHV-8 proteins K8.1 and orf73. We used logistic regression to test for an association between HHV-8 serostatus and transfusion history and a Markov model to estimate the transmission risk per transfusion and the cumulative risk from community (i.e., nontransfusion) sources. Statistical tests were two-sided. Results: HHV-8 antibodies were detected in 117 of 561 (21%) children with unambiguous K8.1 results. HHV-8 seroprevalence among the never-transfused children increased with age from 7% in children aged 0-2 years to 32% in those aged 13-16 years (P-trend < .001). HHV-8 seropositivity was more frequent in transfused than never-transfused children (24% versus 17%, odds ratio = 1.48, 95% confidence interval [CI] = 0.97 to 2.26; P = .07). Seropositivity increased with number of reported transfusions, with age-adjusted odds ratios of 0.97 (95% CI = 0.54 to 1.75), 1.13 (95% CI = 0.59 to 2.17),1.76 (95% CI = 0.81 to 3.83), and 2.17 (95% CI = 1.18 to 3.99) for children with one, two, three, or four or more transfusions, respectively (P-trend = .007). Overall, the estimated HHV-8 transmission risk was 2.6% per transfusion (95% CI = 1.9% to 3.3%), whereas the annual risk of infection unrelated to transfusion was 2.7% (95% CI = 1.7% to 3.7%). Conclusion: Our study suggests that blood transfusion is associated with a small risk of HHV-8 transmission. In Uganda, this risk is approximately equivalent to the 1-year cumulative risk of infection from community sources. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Makerere Univ, Sch Med, Kampala, Uganda. Mulago Hosp, Kampala, Uganda. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,EPS Rm 8007, Rockville, MD 20852 USA. RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [N01-CO-12400, N02-CP-91027] NR 39 TC 50 Z9 52 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 3 PY 2003 VL 95 IS 17 BP 1330 EP 1335 DI 10.1093/jnci/djg039 PG 6 WC Oncology SC Oncology GA 719ZE UT WOS:000185234400014 PM 12953087 ER PT J AU Mattson, MP AF Mattson, MP TI Gene-diet interactions in brain aging and neurodegenerative disorders SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 8th Regenstrief Conference CY SEP 30-OCT 02, 2002 CL MARSHALL, INDIANA ID AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; EXPERIMENTAL-MODELS; HOMOCYSTEINE LEVELS; RESTRICTION; MICE; DAMAGE; DEGENERATION AB While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders. C1 NIA, Neurosci Lab, Gerontol Res Ctr 4F01, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr 4F01, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 28 TC 84 Z9 90 U1 1 U2 4 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 SEP 2 PY 2003 VL 139 IS 5 SU S BP 441 EP 444 PN 2 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 718FE UT WOS:000185133800012 PM 12965973 ER PT J AU Ritter, H Koch-Nolte, F Marquez, VE Schulz, GE AF Ritter, H Koch-Nolte, F Marquez, VE Schulz, GE TI Substrate binding and catalysis of Ecto-ADP-ribosyltransferase 2.2 from rat SO BIOCHEMISTRY LA English DT Article ID NICOTINAMIDE ADENINE-DINUCLEOTIDE; SITE-DIRECTED MUTAGENESIS; MONO-ADP-RIBOSYLTRANSFERASES; PERFRINGENS IOTA-TOXIN; T-CELL APOPTOSIS; CRYSTAL-STRUCTURE; POLY(ADP-RIBOSE) POLYMERASE; CLOSTRIDIUM-BOTULINUM; NAD GLYCOHYDROLASE; DIPHTHERIA-TOXIN AB The structures of beta-methylenethiazole-4-carboxamide adenine dinucleotide (TAD), NAD(+), and NADH as bound to ecto-ADP-ribosyltransferase 2.2 from rat and to its mutants E189I and E189A, respectively, have been established. The positions and conformations of NAD(+) and its analogues agree in general with those in other ADP-ribosyltransferases. The kinetic constants for NAD(+) hydrolysis were determined by RP-HPLC. The specific activity amounts to 26 units/mg, which is 6000-fold higher than a previously reported rate and 500-fold higher than the hydrolysis rates of other ADP-ribosyltransferases, confirming that hydrolysis is the major function of this enzyme. On the basis of structures and mutant activities, a catalytic mechanism is proposed. The known auto-ADP-ribosylation of the enzyme at the suggested position R184 is supported by one of the crystal structures where the nucleophile position is occupied by an Neta atom of this arginine which in turn is backed up by the base E159. C1 Univ Freiburg, Inst Organ Chem & Biochem, D-79104 Freiburg, Germany. Univ Klinikum Eppendorf, Inst Immunol, D-20246 Hamburg, Germany. NCI, Canc Res Ctr, Med Chem Lab, Frederick, MD 21702 USA. RP Schulz, GE (reprint author), Univ Freiburg, Inst Organ Chem & Biochem, Hugstetter Str 55, D-79104 Freiburg, Germany. NR 51 TC 26 Z9 28 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 SEP 2 PY 2003 VL 42 IS 34 BP 10155 EP 10162 DI 10.1021/bi034625w PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716JM UT WOS:000185025100011 PM 12939142 ER PT J AU Park, T Yi, SG Kang, SH Lee, S Lee, YS Simon, R AF Park, T Yi, SG Kang, SH Lee, S Lee, YS Simon, R TI Evaluation of normalization methods for microarray SO BMC BIOINFORMATICS LA English DT Article ID CDNA MICROARRAY; EXPRESSION DATA; GENES; VARIANCE; MODELS AB Background: Microarray technology allows the monitoring of expression levels for thousands of genes simultaneously. This novel technique helps us to understand gene regulation as well as gene by gene interactions more systematically. In the microarray experiment, however, many undesirable systematic variations are observed. Even in replicated experiment, some variations are commonly observed. Normalization is the process of removing some sources of variation which affect the measured gene expression levels. Although a number of normalization methods have been proposed, it has been difficult to decide which methods perform best. Normalization plays an important role in the earlier stage of microarray data analysis. The subsequent analysis results are highly dependent on normalization. Results: In this paper, we use the variability among the replicated slides to compare performance of normalization methods. We also compare normalization methods with regard to bias and mean square error using simulated data. Conclusions: Our results show that intensity-dependent normalization often performs better than global normalization methods, and that linear and nonlinear normalization methods perform similarly. These conclusions are based on analysis of 36 cDNA microarrays of 3,840 genes obtained in an experiment to search for changes in gene expression profiles during neuronal differentiation of cortical stem cells. Simulation studies confirm our findings. C1 Seoul Natl Univ, Dept Stat, Seoul, South Korea. Sejong Univ, Dept Appl Math, Seoul, South Korea. Hanyang Univ, Coll Med, Dept Biochem, Seoul 133791, South Korea. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Park, T (reprint author), Seoul Natl Univ, Dept Stat, Seoul, South Korea. NR 22 TC 80 Z9 85 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 2 PY 2003 VL 4 AR 33 DI 10.1186/1471-2105-4-33 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 727ND UT WOS:000185664200001 PM 12950995 ER PT J AU Nugent, ZJ AF Nugent, ZJ TI Alternatives to lindane SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Nugent, ZJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD SEP 2 PY 2003 VL 169 IS 5 BP 389 EP 389 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 717EH UT WOS:000185072300003 PM 12952794 ER PT J AU Rogozin, IB Wolf, YI Sorokin, AV Mirkin, BG Koonin, EV AF Rogozin, IB Wolf, YI Sorokin, AV Mirkin, BG Koonin, EV TI Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution SO CURRENT BIOLOGY LA English DT Article ID SPLICEOSOMAL INTRONS; ISOMERASE GENE; ORIGIN; MODEL; DROSOPHILA; FAMILIES; PLANT AB Sequencing of eukaryotic genomes allows one to address major evolutionary problems, such as the evolution of gene structure. We compared the intron positions in 684 orthologous gene sets from 8 complete genomes of animals, plants, fungi, and protists and constructed parsimonious scenarios of evolution of the exon-intron structure for the respective genes. Approximately one-third of the introns in the malaria parasite Plasmodium falciparum are shared with at least one crown group eukaryote; this number indicates that these introns have been conserved through >1.5 billion years of evolution that separate Plasmodium from the crown group. Paradoxically, humans share many more introns with the plant Arabidopsis thaliana than with the fly or nematode. The inferred evolutionary scenario holds that the common ancestor of Plasmodium and the crown group and, especially, the common ancestor of animals, plants, and fungi had numerous introns. Most of these ancestral introns, which are retained in the genomes of vertebrates and plants, have been lost in fungi, nematodes, arthropods, and probably Plasmodium. In addition, numerous introns have been inserted into vertebrate and plant genes, whereas, in other lineages, intron gain was much less prominent. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ London Birkbeck Coll, Sch Informat Syst & Comp Sci, London WC1E 7HX, England. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. OI Mirkin, Boris/0000-0001-5470-8635 NR 28 TC 264 Z9 275 U1 1 U2 19 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 2 PY 2003 VL 13 IS 17 BP 1512 EP 1517 DI 10.1016/S0960-9822(03)00558-X PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 718XG UT WOS:000185171300021 PM 12956953 ER PT J AU Kalra, A Garde, S Hummer, G AF Kalra, A Garde, S Hummer, G TI Osmotic water transport through carbon nanotube membranes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR-DYNAMICS; CONFINED FLUID; NUCLEIC-ACIDS; LIQUID WATER; FREE-ENERGY; SURFACES; HYDRATION; CHANNELS; PRESSURE; NANOSTRUCTURES AB We use molecular dynamics simulations to study osmotically driven transport of water molecules through hexagonally packed carbon nanotube membranes. Our simulation setup comprises two such semipermeable membranes separating compartments of pure water and salt solution. The osmotic force drives water flow from the pure-water to the salt-solution compartment. Monitoring the flow at molecular resolution reveals several distinct features of nanoscale flows. In particular, thermal fluctuations become significant at the nanoscopic length scales, and as a result, the flow is stochastic in nature. Further, the flow appears frictionless and is limited primarily by the barriers at the entry and exit of the nanotube pore. The observed flow rates are high (5.8 water molecules per nanosecond and nanotube), comparable to those through the transmembrane protein aquaporin-1, and are practically independent of the length of the nanotube, in contrast to predictions of macroscopic hydrodynamics. All of these distinct characteristics of nanoscopic water flow can be modeled quantitatively by a 1D continuous-time random walk. At long times, the pure-water compartment is drained, and the net flow of water is interrupted by the formation of structured solvation layers of water sandwiched between two nanotube membranes. Structural and thermodynamic aspects of confined water monolayers are studied. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Rensselaer Polytech Inst, Howard P Isermann Dept Chem & Biol Engn, Troy, NY 12180 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Garde, Shekhar/C-3060-2008; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 49 TC 538 Z9 551 U1 22 U2 210 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 SEP 2 PY 2003 VL 100 IS 18 BP 10175 EP 10180 DI 10.1073/pnas.1633354100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YX UT WOS:000185119300010 PM 12878724 ER PT J AU Bermudez, VP Maniwa, Y Tappin, I Ozato, K Yokomori, K Hurwitz, J AF Bermudez, VP Maniwa, Y Tappin, I Ozato, K Yokomori, K Hurwitz, J TI The alternative Ctf18-Dcc1-Ctf8-replication factor C complex required for sister chromatid cohesion loads proliferating cell nuclear antigen onto DNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID REPLICATION FACTOR-C; SACCHAROMYCES-CEREVISIAE; CHROMOSOME COHESION; SCHIZOSACCHAROMYCES-POMBE; FISSION YEAST; 5 SUBUNITS; ESTABLISH COHESION; DAMAGE CHECKPOINT; POLYMERASE-ALPHA; BINDING PROTEIN AB The linkage of sister chromatids after DNA replication ensures the faithful inheritance of chromosomes by daughter cells. In budding yeast, the establishment of sister chromatid cohesion requires Ctf8, Dcc1, and Ctf18, a homologue of the p140 subunit of the replication factor C (RFC). In this report we demonstrate that in 293T cells, Flag-tagged Ctf18 forms a seven-subunit cohesion-RFC complex comprised of Ctf18, Dcc1, Ctf8, RFCp40, RFCp38, RFCp37, and RFCp36 (Ctf 18-RFC). We demonstrate that a stoichiometric heteroheptameric Ctf 18-RFC complex can be assembled by coexpressing the seven proteins in baculovirus-infected insect cells. In addition, the two other stable subcomplexes were formed, which include a pentameric complex comprised of Ctf18, RFCp40, RFCp38, RFCp37, and RFCp36 and a dimeric Dcc1-Ctf8. Both the five- and seven-subunit Ctf18-RFC complexes bind to single-stranded and primed DNAs and possess weak ATPase activity that is stimulated by the addition of primed DNA and proliferating cell nuclear antigen (PCNA). These complexes catalyzed the ATP-dependent loading of PCNA onto primed and gapped DNA but not onto double-stranded nicked or single-stranded circular DNAs. Consistent with these observations, both Ctf18-RFC complexes substituted for the replicative RFC in the PCNA-dependent DNA polymerase delta-catalyzed DNA replication reaction. These results support a model in which sister chromatid cohesion is linked to DNA replication. C1 Mem Sloan Kettering Canc Ctr, Rockefeller Res Labs, Program Mol Biol, New York, NY 10021 USA. Univ Calif Irvine, Coll Med, Dept Biol Chem, Irvine, CA 92697 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Hurwitz, J (reprint author), Mem Sloan Kettering Canc Ctr, Rockefeller Res Labs, Program Mol Biol, 430 E 67th St, New York, NY 10021 USA. NR 53 TC 75 Z9 82 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 2 PY 2003 VL 100 IS 18 BP 10237 EP 10242 DI 10.1073/pnas.1434308100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YX UT WOS:000185119300020 PM 12930902 ER PT J AU Yang, YC Piek, E Zavadil, J Liang, D Xie, DL Heyer, J Pavlidis, P Kucherlapati, R Roberts, AB Bottinger, EP AF Yang, YC Piek, E Zavadil, J Liang, D Xie, DL Heyer, J Pavlidis, P Kucherlapati, R Roberts, AB Bottinger, EP TI Hierarchical model of gene regulation by transforming growth factor beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPITHELIAL-CELL PLASTICITY; SMAD7 PROMOTER; EXPRESSION; PROTEINS; SEQUENCE; IDENTIFICATION; TRANSCRIPTION; ACTIVATION; REPRESSION; INDUCTION AB Transforming growth factor betas (TGF-betas) regulate key aspects of embryonic development and major human diseases. Although Smad2, Smad3, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) have been proposed as key mediators in TGF-beta signaling, their functional specificities and interactivity in controlling transcriptional programs in different cell types and (patho)physiological contexts are not known. We investigated expression profiles of genes controlled by TGF-beta in fibroblasts with ablations of Smad2, Smad3, and ERK MAPK. Our results suggest that Smad3 is the essential mediator of TGF-beta signaling and directly activates genes encoding regulators of transcription and signal transducers through Smad3/Smad4 DNA-binding motif repeats that are characteristic for immediate-early target genes of TGF-beta but absent in intermediate target genes. In contrast, Smad2 and ERK predominantly transmodulated regulation of both immediate-early and intermediate genes by TGF-beta/Smad3. These results suggest a previously uncharacterized hierarchical model of gene regulation by TGF-beta in which TGF-beta causes direct activation by Smad3 of cascades of regulators of transcription and signaling that are transmodulated by Smad2 and/or ERK. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Columbia Univ, Columbia Genome Ctr, New York, NY 10032 USA. RP Bottinger, EP (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. RI Pavlidis, Paul/H-8406-2013 OI Pavlidis, Paul/0000-0002-0426-5028 FU NIDDK NIH HHS [R01DK60043, R01 DK056077, R01 DK060043, R01DK056077, U01 DK060995, U24 DK058768, U24 DK58768-A1] NR 31 TC 154 Z9 164 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 2 PY 2003 VL 100 IS 18 BP 10269 EP 10274 DI 10.1073/pnas.1834070100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YX UT WOS:000185119300026 PM 12930890 ER PT J AU Levantini, E Giorgetti, A Cerisoli, F Traggiai, E Guidi, A Martin, R Acampora, D Aplan, PD Keller, G Simeone, A Iscove, NN Hoang, T Magli, MC AF Levantini, E Giorgetti, A Cerisoli, F Traggiai, E Guidi, A Martin, R Acampora, D Aplan, PD Keller, G Simeone, A Iscove, NN Hoang, T Magli, MC TI Unsuspected role of the brain morphogenetic gene Otx1 in hematopoiesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BLOOD-CELL DIFFERENTIATION; HOMEOBOX GENES; STEM-CELLS; NERVOUS-SYSTEM; SINGLE CELLS; MICE LACKING; HOX GENES; SCL GENE; EXPRESSION; MOUSE AB Otx1 belongs to the paired class of homeobox genes and plays a pivotal role in brain development. Here, we show that Otx1 is expressed in hematopoietic pluripotent and erythroid progenitor cells. Moreover, bone marrow cells from mice lacking Otx1 exhibit a cell-autonomous impairment of the erythroid compartment. In agreement with these results, molecular analysis revealed decreased levels of erythroid genes that include the SCL and GATA-1 transcription factors. Accordingly, a gain of function of SCL rescues the erythroid deficiency in Otx1(-/-) mice. Taken together, our findings indicate a function for Otx1 in the regulation of blood cell production. C1 CNR, Inst Biomed Technol, I-56124 Pisa, Italy. Univ Montreal, Dept Pharmacol, Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. CNR, Inst Genet & Biophys, A Buzzati Traverso, I-80125 Naples, Italy. MRC, Ctr Dev Neurobiol, London SE1 9RT, England. NCI, Dept Genet, Div Clin Sci, Gaithersburg, MD 20877 USA. CUNY Mt Sinai Sch Med, Inst Gene Therapy & Mol Med, New York, NY 10029 USA. Univ Toronto, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. RP Magli, MC (reprint author), CNR, Inst Biomed Technol, I-56124 Pisa, Italy. RI traggiai, elisabetta/A-2316-2009; Cerisoli, Francesco/C-9711-2009; Acampora, Dario/C-2156-2013; Aplan, Peter/K-9064-2016; Giorgetti, Alessandra/D-3784-2016 OI Giorgetti, Alessandra/0000-0002-2747-6514 NR 44 TC 5 Z9 6 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 2 PY 2003 VL 100 IS 18 BP 10299 EP 10303 DI 10.1073/pnas.1734071100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YX UT WOS:000185119300031 PM 12934017 ER PT J AU Sotiriou, C Neo, SY McShane, LM Korn, EL Long, PM Jazaeri, A Martiat, P Fox, SB Harris, AL Liu, ET AF Sotiriou, C Neo, SY McShane, LM Korn, EL Long, PM Jazaeri, A Martiat, P Fox, SB Harris, AL Liu, ET TI Breast cancer classification and prognosis based on gene expression profiles from a population-based study SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESTROGEN-RECEPTOR; PATTERNS; METASTASIS; PROTEINS; PATHWAY; GROWTH; CELLS AB Comprehensive gene expression patterns generated from cDNA microarrays were correlated with detailed clinico-pathological characteristics and clinical outcome in an unselected group of 99 node-negative and node-positive breast cancer patients. Gene expression patterns were found to be strongly associated with estrogen receptor (ER) status and moderately associated with grade, but not associated with menopausal status, nodal status, or tumor size. Hierarchical cluster analysis segregated the tumors into two main groups based on their ER status, which correlated well with basal and luminal characteristics. Cox proportional hazards regression analysis identified 16 genes that were significantly associated with relapse-free survival at a stringent significance level of 0.001 to account for multiple comparisons. Of 231 genes previously reported by others [van't Veer, L. J., et aL (2002) Nature 415, 530-536] as being associated with survival, 93 probe elements overlapped with the set of 7,650 probe elements represented on the arrays used in this study. Hierarchical cluster analysis based on the set of 93 probe elements segregated our population into two distinct subgroups with different relapse-free survival (P < 0.03). The number of these 93 probe elements showing significant univariate association with relapse-free survival (P < 0.05) in the present study was 14, representing 11 unique genes. Genes involved in cell cycle, DNA replication, and chromosomal stability were consistently elevated in the various poor prognostic groups. In addition, glutathione S-transferase M3 emerged as an important survival marker in both studies. When taken together with other array studies, our results highlight the consistent biological and clinical associations with gene expression profiles. C1 NCI, Div Clin Sci, Ctr Adv Technol, Gaithersburg, MD 20877 USA. Free Univ Brussels, Microarray Facil, Inst Jules Bordet, B-1000 Brussels, Belgium. Genome Inst Singapore, Singapore 117528, Singapore. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Imperial Canc Res Fund, Oncol Mol Lab, Weatherall Inst Mol Med, Oxford OX3 9DS, England. RP Liu, ET (reprint author), NCI, Div Clin Sci, Ctr Adv Technol, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. RI Jazaeri, Amir/A-2400-2008; Liu, Edison/C-4141-2008; Jazaeri, Amir/I-3458-2015; OI Jazaeri, Amir/0000-0003-4335-4151; Harris, Adrian/0000-0003-1376-8409; Fox, Stephen/0000-0002-7648-8896 NR 24 TC 1125 Z9 1173 U1 8 U2 55 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 SEP 2 PY 2003 VL 100 IS 18 BP 10393 EP 10398 DI 10.1073/pnas.1732912100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 717YX UT WOS:000185119300048 PM 12917485 ER PT J AU Abashkin, YG Burt, SK AF Abashkin, YG Burt, SK TI Mn(salen)-catalyzed epoxidation reaction as a multi-channel process. Electronic tuning of asymmetric catalysis: A theoretical study. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NCI, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. EM abashkin@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 514-INOR BP U753 EP U753 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062403622 ER PT J AU Anfinrud, PA Schotte, F Wulff, M AF Anfinrud, PA Schotte, F Wulff, M TI Watching a protein as it functions with picosecond x-ray crystallography. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. European Synchrotron Radiat Facil, F-38043 Grenoble, France. EM anfinrud@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 434-PHYS BP U335 EP U335 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501716 ER PT J AU Barchi, JJ Svarovsky, S AF Barchi, JJ Svarovsky, S TI Synthesis and properties of carbohydrate- and glycopeptide-bearing nanoparticles. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NCI, Med Chem Lab, NIH, CCR, Frederick, MD 21702 USA. EM barchi@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 040-CARB BP U206 EP U206 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400890 ER PT J AU Bax, A AF Bax, A TI Weak alignment offers new opportunities in NMR structure determination of proteins and nucleic acids. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIH, Phys Chem Lab, Bethesda, MD 20892 USA. EM bax@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 111-CHED BP U241 EP U241 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401079 ER PT J AU Bear, S AF Bear, S TI 3 steps to better Medline searches. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIH, Natl Lib Med, MeSH, Bethesda, MD 20894 USA. EM bears@mail.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 052-CINF BP U300 EP U300 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401371 ER PT J AU Bryant, S Lazarus, LH Salvadori, S Guerrini, R Balboni, G Jinsmaa, Y AF Bryant, S Lazarus, LH Salvadori, S Guerrini, R Balboni, G Jinsmaa, Y TI Computational docking and opioidmimetics: Investigation of delta-opioid agonist and antagonist receptor interactions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIEHS, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM bryant2@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 245-COMP BP U461 EP U461 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402192 ER PT J AU Cho, HS Smirnov, A Anfinrud, PA AF Cho, HS Smirnov, A Anfinrud, PA TI Spectroscopic characterization of short-lived intermediates: A femtosecond transient absorbance study of MbCO in solution and in single crystals. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM hyunsunc@intra.niddk.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 328-PHYS BP U319 EP U319 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501612 ER PT J AU Chu, JW Trout, B Brooks, BR AF Chu, JW Trout, B Brooks, BR TI Super-linear minimization scheme for the nudged elastic band method. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 MIT, Dept Chem Engn, Cambridge, MA 02139 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 099-COMP BP U438 EP U438 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402047 ER PT J AU Colgate, KC Huang, XW Kolbanovskiy, A Skorvaga, M Van Houten, B AF Colgate, KC Huang, XW Kolbanovskiy, A Skorvaga, M Van Houten, B TI Effects of methylation and temperature on nucleotide excision repair of stereoisomeric benzo[a]pyrene diol epoxide-N-2-d adducts in A (5-me)CG*p53 codon 273 sequence context catalyzed by uvrabc proteins from B. caldotenax. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NYU, Dept Chem, New York, NY 10003 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. EM kcc208@nyu.edu RI kolbanovskiy, aleksandr/I-7278-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 068-TOXI BP U328 EP U328 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401513 ER PT J AU Costanzi, S Jacobson, KA AF Costanzi, S Jacobson, KA TI Structural comparison of P2Y receptors based on homology modeling. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. EM stefanoc@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 157-MEDI BP U29 EP U29 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500157 ER PT J AU Crowell, JA AF Crowell, JA TI Preclinical and clinical development of Polyphenon E for cancer prevention. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NCI, Div Canc Prevent, NIH, DHHS, Bethesda, MD 20892 USA. EM jc94h@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 064-AGFD BP U61 EP U61 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400179 ER PT J AU Dimitriadis, EK Pascual, J Horkay, F AF Dimitriadis, EK Pascual, J Horkay, F TI Effect of different cations on the conformation of DNA adsorbed on hydrophilic and hydrophobic surfaces. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIH, Div Bioengn & Phys Sci, OD, Bethesda, MD 20892 USA. EM dimitria@helix.nih.gov; horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 072-BIOL BP U161 EP U161 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400664 ER PT J AU Eaton, WA AF Eaton, WA TI Single molecule protein folding. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 95-PHYS BP U284 EP U284 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501383 ER PT J AU Gakh, AA Romanovich, AY Tuinman, AA Bax, A AF Gakh, AA Romanovich, AY Tuinman, AA Bax, A TI Thermodynamic rearrangement synthesis of "perfect" fullerenes C60X18-24-36-48. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. Univ Tennessee, Dept Chem, Knoxville, TN 37996 USA. NIH, Chem Phys Lab, Bethesda, MD USA. EM gakhaa@ornl.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 400-ORGN BP U179 EP U180 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500878 ER PT J AU Gopich, I Hummer, G Szabo, A AF Gopich, I Hummer, G Szabo, A TI Theory and single molecule experiments SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM gopich@nih.gov; attilas@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 112-PHYS BP U287 EP U287 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501400 ER PT J AU Grigorenko, B Nemukhin, AV Topol, IA Burt, SK AF Grigorenko, B Nemukhin, AV Topol, IA Burt, SK TI Practical implementation of the flexible effective fragment QM/MM method for modeling chemical reactions in condensed phases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. NCI, Adv Biomed Comp Ctr, Bethesda, MD 20892 USA. EM bella@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 245-PHYS BP U306 EP U306 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501531 ER PT J AU Horkay, F Berman, AS Horkayne-Szakaly, I Basser, PJ AF Horkay, F Berman, AS Horkayne-Szakaly, I Basser, PJ TI Osmotic observations on soft gels and biological tissue samples. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 249-BIOL BP U192 EP U192 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400836 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI SANS and osmotic observations on polyacrlylate networks swollen in physiological salt solutions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, Spectrometrie Phys Lab, CNRS UMR 5588, F-38041 Grenoble, France. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 543-POLY BP U438 EP U438 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062502305 ER PT J AU Horkayne-Szakaly, I Fadeyi, E Krishnan, J Chappie, A Horkay, F Boyle, L AF Horkayne-Szakaly, I Fadeyi, E Krishnan, J Chappie, A Horkay, F Boyle, L TI Intraoperative parathyroid evaluation as a diagnostic aid for parathyroid surgery. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. Washington Hosp Ctr, Dept Surg, Washington, DC 20010 USA. NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD USA. EM Iren.Horkayne-Szakaly@Medstar.net NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 323-MEDI BP U61 EP U61 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500321 ER PT J AU Hummer, G AF Hummer, G TI Protein dynamics from computer simulations compared to time-resolved X-ray crystallography. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 435-PHYS BP U335 EP U335 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501717 ER PT J AU Ivanic, J AF Ivanic, J TI Direct Cl and MCSCF method for multiple active spaces with variable occupations. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NCI, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. EM jivanic@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 89-PHYS BP U283 EP U283 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501377 ER PT J AU Kertesz, M Huang, JS Sun, GY AF Kertesz, M Huang, JS Sun, GY TI Partial bond breaking and bond making due to charge transfer in condensed phase. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. NCI, NIH, CCR, Med Chem Lab, Frederick, MD 21701 USA. EM kertesz@georgetown.edu; huangj2@georgetown.edu RI Huang, Jingsong/A-2789-2008 OI Huang, Jingsong/0000-0001-8993-2506 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 319-PHYS BP U317 EP U317 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501603 ER PT J AU Kim, SK Gao, ZG Van Rompaey, P Gross, AS Chen, AS Van Calenbergh, S Jacobson, KA AF Kim, SK Gao, ZG Van Rompaey, P Gross, AS Chen, AS Van Calenbergh, S Jacobson, KA TI Design of a neoceptor and complementary neoligand derived from the A2A adenosine receptor. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Med Chem Lab, B-9000 Ghent, Belgium. EM Soo-KyungK@intra.niddk.nih.gov RI Van Calenbergh, Serge/A-3167-2008; Jacobson, Kenneth/A-1530-2009 OI Van Calenbergh, Serge/0000-0002-4201-1264; Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 154-MEDI BP U28 EP U29 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500154 ER PT J AU Kirk, KL Dolensky, B Narayanan, J Nam, G Deng, WP Fan, JF AF Kirk, KL Dolensky, B Narayanan, J Nam, G Deng, WP Fan, JF TI Building blocks for the preparation of fluorinated bioimidazoles and bioindoles. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIDDK, Bioorgan Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 007-FLUO BP U519 EP U519 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402498 ER PT J AU Lee, YS Krauss, M AF Lee, YS Krauss, M TI Dynamics of proton transfer in bacteriorhodopsin. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Ctr Adv Res Biotechnol, Boulder, CO USA. EM leeys@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 402-PHYS BP U330 EP U330 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501684 ER PT J AU Levin, IW Fernandez, DC Huffman, SW Zuzak, KJ Bhargava, R AF Levin, IW Fernandez, DC Huffman, SW Zuzak, KJ Bhargava, R TI Approaches to infrared and visible reflectance spectroscopic imaging. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM iwl@helix.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 64-PHYS BP U280 EP U280 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501352 ER PT J AU Liotta, L AF Liotta, L TI LClinical proteomics: Diagnostic applications of mass spectrometry. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIH, Pathol Lab, Bethesda, MD 20892 USA. EM lance@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 145-ANYL BP U123 EP U123 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400533 ER PT J AU Lioy, PJ AF Lioy, PJ CA NIEHS EPA Collaborators TI Overview of the conditions lending to exposures that resulted from the collapse and fires at The World Trade Center. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Univ Med & Dent New Jersey, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. US EPA, NIEHS, EPA Collaborators, Piscataway, NJ 08854 USA. EM plioy@eohsi.rutgers.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 106-ENVR BP U484 EP U484 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402308 ER PT J AU Maderia, M Shenoy, S O'Keefe, B Marquez, VE Barchi, JJ AF Maderia, M Shenoy, S O'Keefe, B Marquez, VE Barchi, JJ TI Structural consequences of the incorporation of conformationally restricted nucleosides into DNA. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NCI, Frederick Canc Res & Dev Ctr, CCR, Lab Med Chem,NIH, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, CCR, Lab Drug Discovery Res,NIH, Frederick, MD 21702 USA. EM mmaderia@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 063-BIOL BP U160 EP U160 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400655 ER PT J AU Miller, MA Hazard, GF Hudson, VW Hilt, C Fang, J Mayer, D Callahan, L AF Miller, MA Hazard, GF Hudson, VW Hilt, C Fang, J Mayer, D Callahan, L TI ChemIDplus: A free, web-based portal to a variety of compound-based information. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 LION Biosci Inc, Midvale, UT 84047 USA. Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20894 USA. Cygnus Corp, Redwood City, CA 94063 USA. EM mitchell.miller@lionbioscience.com NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 093-CINF BP U305 EP U305 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401411 ER PT J AU Nemukhin, AV Grigorenko, B Topol, IA Burt, SK AF Nemukhin, AV Grigorenko, B Topol, IA Burt, SK TI Modeling chemical reactions in proteins by the QM/MM method based on the flexible effective fragment potential technique. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. NCI, Adv Biomed Comp Ctr, Bethesda, MD 20892 USA. EM anem@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 7-PHYS BP U271 EP U272 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501297 ER PT J AU Nikolovska-Coleska, Z Li, P Roller, PP Tomita, Y Wang, SM AF Nikolovska-Coleska, Z Li, P Roller, PP Tomita, Y Wang, SM TI Development of a fluorescence polarization assay for identification of inhibitors of the XIAP-SMAC protein-protein interaction. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 063-ANYL BP U110 EP U110 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400455 ER PT J AU Nikolovska-Coleska, Z Hu, ZG Fang, XL Tomita, Y Zhang, MC Xu, L Yang, DJ Lippman, ME Li, P Roller, PP Wang, SM AF Nikolovska-Coleska, Z Hu, ZG Fang, XL Tomita, Y Zhang, MC Xu, L Yang, DJ Lippman, ME Li, P Roller, PP Wang, SM TI Structure-based discovery of non-peptide, small molecule inhibitors of XIAP. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 106-MEDI BP U19 EP U20 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500106 ER PT J AU Ohno, M Kim, HS Xu, B Kim, HO Choi, Y Ji, XD Maddileti, S Marquez, VE Harden, TK Jacobson, KA AF Ohno, M Kim, HS Xu, B Kim, HO Choi, Y Ji, XD Maddileti, S Marquez, VE Harden, TK Jacobson, KA TI 2-substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: Enhanced potency as P2Y1 receptor antagonists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Div Chem & Mol Engn, Seoul 151, South Korea. Ctr Canc Res, Med Chem Lab, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. EM michihiroo@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009; Choi, Yongseok/F-8375-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; Choi, Yongseok/0000-0002-3622-3439 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 156-MEDI BP U29 EP U29 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500156 ER PT J AU Parascandola, JL AF Parascandola, JL TI Chemistry and medicine: The NIH Division of Chemistry, 1902-1947. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Natl Lib Med, Rockville, MD 20857 USA. EM jparascandola@psc.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 005-HIST BP U608 EP U608 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402895 ER PT J AU Patil, SS Zhang, XC Pais, GCG Kvaratskhelia, M Svarovskaia, ES Merchand, C Pathak, VK Pommier, Y Le Grice, S Burke, TR AF Patil, SS Zhang, XC Pais, GCG Kvaratskhelia, M Svarovskaia, ES Merchand, C Pathak, VK Pommier, Y Le Grice, S Burke, TR TI Analogues of caffeic acid phenylethyl ester (CAPE) as affinity covalent modifiers of HIV-1 integrase. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, CCR,NIH, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Pharmacol Lab, Frederick, MD 21702 USA. NIH, HIV Drug Resistant Program, Bethesda, MD 20892 USA. EM sachin@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 120-MEDI BP U22 EP U22 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500120 ER PT J AU Planalp, RP Lu, G Przyborowska, AM Brechbiel, MW Lai, SJ Park, G Broker, GA Rogers, RD Ma, R Torti, SV AF Planalp, RP Lu, G Przyborowska, AM Brechbiel, MW Lai, SJ Park, G Broker, GA Rogers, RD Ma, R Torti, SV TI Metal-complexation properties of tripodal hexadentate chelators: Effects of heterocycle donor arms, tripod framework and imine formation on Fe(II) chelation and cytotoxicity. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. Univ Alabama, Ctr Green Mfg, Tuscaloosa, AL 35487 USA. Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 058-INOR BP U680 EP U681 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062403171 ER PT J AU Przyborowska, AM Brokers, GA Rogers, RD Brechbiel, MW Planalp, RP AF Przyborowska, AM Brokers, GA Rogers, RD Brechbiel, MW Planalp, RP TI Electronic properties and structures of novel Cu(II) complexes of hexadentate aminopyridyl ligands and their alkylated derivatives. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. Univ Alabama, Ctr Green Mfg, Tuscaloosa, AL 35487 USA. NCI, NIH, Bethesda, MD 20892 USA. EM aniusia5@peoplepc.com; roy.planalp@unh.edu RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 486-INOR BP U748 EP U748 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062403594 ER PT J AU Sridhar, J Kozikowski, AP Lewin, N Ayers, JA Pearce, LV Blumberg, PM AF Sridhar, J Kozikowski, AP Lewin, N Ayers, JA Pearce, LV Blumberg, PM TI Synthesis of phorbol esters with oligoethylene glycol spacers and evaluation of their PKC isozyme selectivity - Identification of a ligand of high selectivity for PKC epsilon. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. EM js348@georgetown.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 66-MEDI BP U12 EP U12 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500067 ER PT J AU Sullivan, AE Goodman, JE Yager, JD AF Sullivan, AE Goodman, JE Yager, JD TI Catechol-O-methyltransferase (COMT) and catechol estrogens in breast cancer. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. NCI, Lab Human Carcinogenesis, Bethesda, MD 20892 USA. EM asulliva@jhsph.edu; jyager@jhsph.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 021-TOXI BP U319 EP U319 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401467 ER PT J AU Tchilibon, S Zhang, J Pollard, HP Jacobson, KA AF Tchilibon, S Zhang, J Pollard, HP Jacobson, KA TI Amphiphilic pyridinium salts suppress production of the proinflammatory cytokine IL-8 in cystic fibrosis lung epithelial cells. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Hlth Sci, F Edward Herbert Sch Med, Inst Mol Med, Dept Anat, Kansas City, MO 64106 USA. EM susannat@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 180-MEDI BP U34 EP U34 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500180 ER PT J AU Ulmer, TS Bax, A AF Ulmer, TS Bax, A TI Weak orientation allows a very precise NMR view of biomolecular structure. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Phys Chem Lab, Bethesda, MD 20892 USA. EM bax@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 051-BIOL BP U158 EP U158 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400643 ER PT J AU Venanzi, C Pandit, D Misra, M Gilbert, KM Matecka, D Prisinzano, T Rice, KC AF Venanzi, C Pandit, D Misra, M Gilbert, KM Matecka, D Prisinzano, T Rice, KC TI Analysis of conformational families of analogs of GBR 12909. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. NIDDK, Med Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. EM venanzi@adm.njit.edu; dnp5@njite.du RI Prisinzano, Thomas/B-7877-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 151-COMP BP U447 EP U447 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402099 ER PT J AU Wang, HD Bash, R Yodh, J Rager, GL Lohr, D Lindsay, SM AF Wang, HD Bash, R Yodh, J Rager, GL Lohr, D Lindsay, SM TI In-situ AFM investigation of the remodeling and salt behavior of chromatin. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Arizona State Univ, Dept Phys & Astron, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. Midwestern Univ, Arizona Coll Osteopath Med, Div Basic Sci, Glendale, AZ 85308 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM hongda.wang@asu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 406-PHYS BP U331 EP U331 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062501688 ER PT J AU Wang, YN Collins, JR Burt, SK AF Wang, YN Collins, JR Burt, SK TI Theoretical study on the roles of divalent metal-ions in GTP hydrolysis. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 SAIC, NCI Frederick, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. EM yanniw@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 124-COMP BP U442 EP U442 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062402072 ER PT J AU Wang, YZ Schnetz-Boutaud, N Kroth, H Yagi, H Sayer, JM Kumar, S Jerina, DM Stone, MP AF Wang, YZ Schnetz-Boutaud, N Kroth, H Yagi, H Sayer, JM Kumar, S Jerina, DM Stone, MP TI 1S and 1R trans-anti-benzo[c]phenanthrene alter the structure of the Salmonella typhimurium hisD3052 gene iterated repeated sequence containing the (CpG)3 frameshift hotspot. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 Vanderbilt Univ, Dept Chem, Ctr Mol Toxicol, Nashville, TN 37235 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SUNY Coll Buffalo, Great Lakes Lab, Buffalo, NY 14222 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 076-BIOL BP U162 EP U162 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400668 ER PT J AU Wolfe, MD AF Wolfe, MD TI Mechanistic insights revealed through characterization of a novel chromophore in selenophosphate synthetase from E. coli SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. EM wolfem@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 103-BIOL BP U167 EP U167 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062400695 ER PT J AU Yang, GL Edler, MC Jung, MK Hamel, E Bornmann, WG AF Yang, GL Edler, MC Jung, MK Hamel, E Bornmann, WG TI Biomimetic synthesis and biological evaluation of racemic rhazinilam analogues. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Mem Sloan Kettering Canc Ctr, Organ Synth Core Facil, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, New York, NY 10021 USA. NCI, SAIC, Frederick, MD 21701 USA. EM yang1@mskcc.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 393-ORGN BP U178 EP U178 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JG UT WOS:000187062500871 ER PT J AU Yeh, IC Hummer, G AF Yeh, IC Hummer, G TI Peptide dynamics from microsecond molecular dynamics simulations in explicit solvent. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NY SP Amer Chem Soc C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM icy@helix.nih.gov; hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP PY 2003 VL 226 MA 012-COMP BP U424 EP U424 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 751JF UT WOS:000187062401963 ER PT J AU Epstein, DH Preston, KL AF Epstein, DH Preston, KL TI Do adverse effects occur in patients who report no symptoms of a cannabis use disorder? A reply to Nixon SO ADDICTION LA English DT Letter C1 NIDA, IRP Treatment Sect, Baltimore, MD 21223 USA. RP Epstein, DH (reprint author), NIDA, IRP Treatment Sect, 5500 Nathan Shock Dr, Baltimore, MD 21223 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD SEP PY 2003 VL 98 IS 9 BP 1322 EP 1323 DI 10.1046/j.1360-0443.2003.00537.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 719RR UT WOS:000185218600024 ER PT J AU Hink, RL Hokanson, JE Shah, I Long, JC Goldman, D Sikela, JM AF Hink, RL Hokanson, JE Shah, I Long, JC Goldman, D Sikela, JM TI Investigation of DUSP8 and CALCA in alcohol dependence SO ADDICTION BIOLOGY LA English DT Article ID SEROTONIN TRANSPORTER; CALCITONIN GENE; MAP KINASE; LINKAGE; FUTURE; BRAIN; RISK; MEN; INHERITANCE; ASSOCIATION AB Evidence for genetic linkage to alcohol dependence was found on chromosome 11p.15.5 from an autosome-wide scan in a Southwestern Native American population. The purpose of this study was to identify genes that may underlie this linkage signal. Two genes, calcitonin/calcitonin-related polypeptide alpha (CALGA) and dual specificity phosphatase 8 (DUSP8), met our criteria for candidacy, and were sequenced to identify polymorphisms that may be relevant to disease. Both genes play a role in various pathways known to underlie the pathophysiological mechanisms leading to development of alcohol dependence. While no polymorphisms were found in CALCA, four novel polymorphisms were found in DUSP8, one of which led to an amino acid substitution. Genotyping of this functional variant in 463 Southwestern Native Americans revealed no significant association between the DUSP8 C712T (Ala193Val) polymorphism and alcohol dependence (odds ratio = 1.48 95% CI 0.6-3.92). C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Sikela, JM (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, 4200 E 9th Ave,Box C236, Denver, CO 80262 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIAAA NIH HHS [AA11853, AA03527] NR 35 TC 3 Z9 3 U1 0 U2 2 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD SEP PY 2003 VL 8 IS 3 BP 305 EP 312 DI 10.1080/13556210310001602211 PG 8 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 731QH UT WOS:000185897600006 PM 13129832 ER PT J AU Herman, AI Philbeck, JW Vasilopoulos, NL Depetrillo, PB AF Herman, AI Philbeck, JW Vasilopoulos, NL Depetrillo, PB TI Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population SO ALCOHOL AND ALCOHOLISM LA English DT Article ID GENE REGULATORY REGION; BINGE DRINKING; ASSOCIATION; PERSONALITY; VARIANT; TRAITS AB Aims and methods: In the present study, differences in alcohol consumption behaviour associated with the presence of the short variant (S) of the serotonin transporter promoter polymorphism (5-HTTLPR) was investigated in a Caucasian subset (n=204) of 268 college students. Results: Students who were homozygous for the S allele were more likely to engage in binge-drinking behaviour, drank more alcohol per occasion, and reported drinking to get drunk more often. Conclusions: In this Caucasian sample, the 5-HTTLPR strongly influences alcohol consumption in late pubescence. C1 NIAAA, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Intramural Res Program,NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP Depetrillo, PB (reprint author), NIAAA, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Intramural Res Program,NIH, 10-3C103,10 Ctr Dr MSC 1256, Bethesda, MD 20892 USA. NR 12 TC 47 Z9 48 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP-OCT PY 2003 VL 38 IS 5 BP 446 EP 449 DI 10.1093/alcalc/agg110 PG 4 WC Substance Abuse SC Substance Abuse GA 712ET UT WOS:000184784800015 PM 12915525 ER PT J AU Devereux, RB Roman, MJ Palmieri, V Liu, JE Lee, ET Best, LG Fabsitz, RR Rodeheffer, RJ Howard, BV AF Devereux, RB Roman, MJ Palmieri, V Liu, JE Lee, ET Best, LG Fabsitz, RR Rodeheffer, RJ Howard, BV TI Prognostic implications of ejection fraction from linear echocardiographic dimensions: The Strong Heart Study SO AMERICAN HEART JOURNAL LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; PRESSURE-OVERLOAD HYPERTROPHY; AMERICAN-INDIANS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; SYSTOLIC FUNCTION; RADIONUCLIDE ANGIOGRAPHY; ESSENTIAL-HYPERTENSION; RISK-FACTORS; MASS AB Background Although echocardiography is commonly used to assess left ventricular (LV) systolic function, few data are available concerning the prognostic significance of LV ejection fraction (EF) calculated from linear echocardiographic measurements or 2-dimensional (2-D) wall motion scores in population-based samples. Methods Echocardiography was used in the second Strong Heart Study (SHS) examination to calculate LV EF in 2948 American Indians without prevalent coronary heart disease; 2923 had 2-D wall motion scores. Results Mildly and severely reduced LV EF occurred in 10% and 2% of participants, was associated with older age, male sex, higher systolic pressure, heart rate and markers of renal disease and inflammation. During 37 +/- 9 months follow-up, cardiovascular death occurred in 2%, 5% and 12% of participants with normal, mildly reduced and severely reduced EF; all cause mortality rates were 6%, 10% and 32% (both P < .001). In Cox proportional hazards analyses, adjusting for covariates, cardiovascular death was higher with mildly reduced EF (risk ratio [RR] 2.9, 95% Cl 1.6-5.4, P = .0007) and especially with severely reduced EF (RR 6.9, 95% Cl 3.0-15.9, P < .0001); all-cause mortality was increased with severe LV dysfunction (RR 4.8, 95% Cl 2.8-8.1, P < .001) and marginally with mildly reduced EF (odds ratio 1.4, 95% Cl 0.95-2.15, P = .08). Segmental LV dysfunction and mildly and severely reduced EF from 2-D wall motion scores were associated with 3.3-fold (95% Cl 1.1-9.4, P = .02), 3.5-fold (95% Cl 2.1-5.8) and 3.8-fold (95% Cl 1.9-7.6) (all P <.001) increased rates of cardiovascular death. Conclusions LV EF from linear echocardiographic measurements as well as segmental LV dysfunction and EF from 2-D wall motion scores strongly and independently predict cardiovascular mortality. Reduced EF by simple echocardiographic method has estimated population-attributable risks of about 35% for cardiovascular death and 12% for all-cause mortality in a population-based sample of middle-aged to elderly adults. C1 Cornell Med Ctr, New York, NY USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Missouri Breaks Ind Res, Timber Lake, SD USA. NHLBI, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. Mayo Clin, Rochester, MN USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, 525 E 68th St, New York, NY 10021 USA. OI Palmieri, Vittorio/0000-0003-3732-524X FU NCRR NIH HHS [M10RR0047-34]; NHLBI NIH HHS [U01-HL41642, U01-HL41652, U01-HL41654] NR 40 TC 31 Z9 31 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2003 VL 146 IS 3 BP 527 EP 534 DI 10.1016/S0002-8703(03)00229-1 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 722AU UT WOS:000185352800025 PM 12947374 ER PT J AU Wendler, D Shah, S AF Wendler, D Shah, S TI Should children decide whether they are enrolled in nonbeneficial research? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE assent; dissent; autonomy; research; children; decision making; research ethics ID PARENTAL PERMISSION; PEDIATRIC PRACTICE; INFORMED CONSENT; ALTRUISM; ADOLESCENTS; BEHAVIOR; ASSENT; PARTICIPATION; PRESCHOOLERS AB The U.S. federal regulations require investigators conducting nonbeneficial research to obtain the assent of children who are capable of providing it. Unfortunately, there has been no analysis of which children are capable of assent or even what abilities ground the capacity to give assent. Why should investigators be required to obtain the positive agreement of some children, but not others, before enrolling them in research that does not offer a compensating potential for direct benefit? We argue that the scope of children's research decision making should be based on the principles of respect for autonomy and nonmaleficence. These principles imply that the threshold for assent should be fixed at 14 years of age, and a dissent requirement should be adopted for all children in the context of nonbeneficial research. C1 NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bethesda, MD 20892 USA. Stanford Law Sch, Stanford, CA USA. RP Wendler, D (reprint author), NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 24 TC 71 Z9 71 U1 0 U2 3 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FAL PY 2003 VL 3 IS 4 BP 1 EP 7 DI 10.1162/152651603322614382 PG 7 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 816QA UT WOS:000221123200002 PM 14744301 ER PT J AU Miller, FG AF Miller, FG TI Sham surgery - An ethical analysis SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE sham surgery; placebo controls; surgical research; research ethics ID PARKINSONS-DISEASE; CONTROLLED TRIAL; PLACEBO SURGERY; CLINICAL-RESEARCH; OSTEOARTHRITIS; KNEE AB Surgical clinical trials have seldom used a "sham" or placebo surgical procedure as a control, owing to ethical concerns. Recently, several ethical commentators have argued that sham surgery is either inherently or presumptively unethical. In this article I contend that these arguments are mistaken and that there are no sound ethical reasons for an absolute prohibition of sham surgery in clinical trials. Reflecting on three cases of sham surgery, especially on the recently reported results of a sham-controlled trial of arthroscopic surgery for arthritis of the knee, I present an ethical analysis that focuses on the methodological rationale for use of sham surgery, risk-benefit assessment, and informed consent. C1 NIH, Unit Clin Res, Dept Clin Bioeth, Bethesda, MD 20892 USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Unit Clin Res, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 26 TC 61 Z9 62 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FAL PY 2003 VL 3 IS 4 BP 41 EP 48 DI 10.1162/152651603322614580 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 816QA UT WOS:000221123200020 PM 14744332 ER PT J AU Cesari, M Penninx, BWJH Newman, AB Kritchevsky, SB Nicklas, BJ Sutton-Tyrrell, K Tracy, RP Rubin, SM Harris, TB Pahor, M AF Cesari, M Penninx, BWJH Newman, AB Kritchevsky, SB Nicklas, BJ Sutton-Tyrrell, K Tracy, RP Rubin, SM Harris, TB Pahor, M TI Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; CORONARY HEART-DISEASE; CAROTID ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; CYTOKINE RECEPTORS; OLDER-ADULTS; RISK; VARIABILITY; WOMEN AB This study investigates the association of several inflammatory markers with subclinical and clinical cardiovascular disease in older men and women. Data are from the baseline assessment of 3,045 well-functioning persons aged 70 to 79 years, participating in the Health, Aging and Body Composition study. The study sample was divided into 3 groups: "cardiovascular disease" (diagnosis of congestive heart failure; coronary artery disease, peripheral artery disease, or, stroke), "subclinical cardiovascular disease" (positive findings on the Rose questionnaire for angina, or claudication, ankle-brachial index <0.9, or electrocardiographic abnormalities), and "no cardiovascular disease." Serum levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and the soluble receptors IL-6 soluble receptor, IL-2 soluble receptor, TNF soluble receptor I, and TNF soluble receptor II were assessed. Of those with IL-6 levels in the highest compared with the lowest fertile, the odds ratio (OR) for subclinical cardiovascular disease was 1.58 (95% confidence interval [CI] 1.26 to 1.97) and for clinical cardiovascular disease was 2.35. (95% CI 1.79 to 3.09). A similar association was found for TNF-alpha (OR 1.48, 95% CI 1.16 to 1.88 and OR 2:05, 95% CI 1.55 to 2.72, respectively). In adjusted analyses, CRP was not significantly associated with overall subclinical or clinical cardiovascular disease, although additional analyses did find a strong specific association between CRP and congestive heart failure (OR 1.64, 95% CI 1.11 to 2.41). Of the soluble cytokine receptors, only TNF :soluble receptor I showed a significant association with clinical cardiovascular disease. Thus, our findings suggest an important role for IL-6 and TNF-alpha in clinical as well as subclinical cardiovascular disease. In this study, CRP had a weaker association with cardiovascular disease than the cytokines. (C) 2003 by Excerpta Medica, Inc. C1 Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Sacred Heart, Dept Geriatr, I-00168 Rome, Italy. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Cesari, M (reprint author), Wake Forest Univ, Sticht Ctr Aging, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. RI Cesari, Matteo/A-4649-2008; Newman, Anne/C-6408-2013; OI Cesari, Matteo/0000-0002-0348-3664; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIA NIH HHS [1P30-AG21332-01, N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106] NR 27 TC 182 Z9 188 U1 0 U2 14 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 SEP 1 PY 2003 VL 92 IS 5 BP 522 EP 528 DI 10.1016/S0002-9149(03)00718-5 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 716ZP UT WOS:000185060700006 PM 12943870 ER PT J AU Weinberg, CR Morris, RW AF Weinberg, CR Morris, RW TI Invited commentary: Testing for Hardy-Weinberg disequilibrium using a genome single-nucleotide polymorphism scan based on cases only SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID ASSOCIATION C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. OI Lee, Wen-Chung/0000-0003-3171-7672 NR 9 TC 19 Z9 19 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 1 PY 2003 VL 158 IS 5 BP 401 EP 403 DI 10.1093/aje/kwg151 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 716QX UT WOS:000185040800002 PM 12936893 ER PT J AU Norquist, GS AF Norquist, GS TI Improving the lives of the aging mentally ill population - The promise of services research SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Editorial Material ID HEALTH C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Norquist, GS (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7123,MSC 9626, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD SEP-OCT PY 2003 VL 11 IS 5 BP 478 EP 480 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 721QD UT WOS:000185326300001 PM 14506080 ER PT J AU Backinger, CL McDonald, P Ossip-Klein, DJ Colby, SM Maule, CO Fagan, P Husten, C Colwell, B AF Backinger, CL McDonald, P Ossip-Klein, DJ Colby, SM Maule, CO Fagan, P Husten, C Colwell, B TI Improving the future of youth smoking cessation SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article; Proceedings Paper CT National Conference on Tobacco or Health CY NOV 19-21, 2002 CL SAN FRANCISCO, CALIFORNIA DE adolescent smoking cessation research ID POPULATION-BASED RECRUITMENT; NICOTINE PATCH THERAPY; ADOLESCENT SMOKERS; TOBACCO; EFFICACY; PROGRAMS; RECOMMENDATIONS; APPROPRIATE; PREVENTION; DEPENDENCE AB Objectives: To provide recommendations that will build a better foundation for research on youth smoking cessation. Methods: The Youth Tobacco Collaborative Cessation panel evaluated youth tobacco cessation literature and convened meetings to reach consensus. Results: Methodological issues include design, recruitment and retention, follow-up, measurement, and youth vernacular. Research gaps include youth characteristics, theoretical approaches, delivery settings, and type of provider. Thirteen key research components for reporting are addressed. Conclusions: Given the dearth of studies on youth smoking cessation, scientifically rigorous studies need to be conducted with attention to methodological issues, research gaps, and reporting of key research components. C1 NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY USA. Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. Canadian Tobacco Control Res Initiat, CCS, NCIC Natl Off, Toronto, ON, Canada. NCI, Tobacco Control Res Branch, Behav Res Grp, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Off Smoking & Hlth, Epidemiol Branch, Atlanta, GA USA. Texas A&M Univ, Sch Rural Publ Hlth, Dept Social & Behav Hlth, College Stn, TX USA. RP Backinger, CL (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4036, Bethesda, MD 20892 USA. NR 49 TC 36 Z9 36 U1 1 U2 3 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD SEP-OCT PY 2003 VL 27 SU 2 BP S170 EP S184 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 758ZR UT WOS:000187713100007 PM 14521244 ER PT J AU McDonald, P Colwell, B Backinger, CL Husten, C Maule, CO AF McDonald, P Colwell, B Backinger, CL Husten, C Maule, CO TI Better practices for youth tobacco cessation: Evidence of review panel SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article; Proceedings Paper CT Canadian National Conference on Smoking or Health CY DEC, 2002 CL OTTAWA, CANADA DE smoking cessation; tobacco use; adolescent smoking cessation research ID SMOKING PREVENTION; PROGRAMS; INTERVENTIONS; EFFICACY; OUTCOMES; SMOKERS; IMPACT AB Objectives: To offer programmers, policy makers, and researchers a scientific basis for developing and selecting smoking cessation treatments for adolescents. Methods: An evidence review panel systematically rated published and unpublished reports of cessation treatments for youth to make recommendations on theoretical foundations, delivery settings, types of intervention, and provider type. Results: Twenty studies had sufficient validity to inform the recommendations. The 9 studies that reported treatments that increased cessation were based on social cognitive theory. Conclusions. Cognitive-behavioral interventions are a promising approach for helping young smokers quit smoking. Evidence is insufficient to draw other conclusions at this time. C1 Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. Texas A&M Univ, Sch Rural Publ Hlth, Dept Social & Behav Hlth, College Stn, TX 77843 USA. NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Off Smoking & Hlth, Epidemiol Branch, Atlanta, GA USA. RP McDonald, P (reprint author), Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. NR 38 TC 59 Z9 61 U1 1 U2 8 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD SEP-OCT PY 2003 VL 27 SU 2 BP S144 EP S158 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 758ZR UT WOS:000187713100005 PM 14521242 ER PT J AU Milton, MH Maule, CO Backinger, CL Gregory, DM AF Milton, MH Maule, CO Backinger, CL Gregory, DM TI Recommendations and guidance for practice in youth tobacco cessation SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE tobacco cessation; youth/adolescent; cognitive behavioral; tobacco control ID SMOKERS; SMOKING AB Objective: To summarize recommendations from Youth Tobacco Cessation: A Guide for Making Informed Decisions for careful consideration, selection, implementation, and evaluation of youth cessation interventions. Methods: Recommendations were developed from an evidence review and consensus from a multidisciplinary advisory panel. Results: Identified essential elements for selecting, planning, delivering, and evaluating youth cessation interventions. Conclusions: Until there is more evidence for effectiveness of youth specific cessation interventions, clinicians and practitoners should adopt treatments that use cognitive-behavioral approaches for youth cessation interventions that require careful planning and rigorous evaluation. C1 Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. Canadian Tobacco Control Res Initiat, CCS NCIC Natl Off, Toronto, ON, Canada. NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, Bethesda, MD 20892 USA. GKV Commun, Maryland Act Partnership, Baltimore, MD USA. RP Milton, MH (reprint author), Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd,MS E-87, Atlanta, GA 30333 USA. NR 16 TC 21 Z9 22 U1 0 U2 1 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD SEP-OCT PY 2003 VL 27 SU 2 BP S159 EP S169 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 758ZR UT WOS:000187713100006 PM 14521243 ER PT J AU Orleans, CT Arkin, EB Backinger, CL Best, A Crossett, L Grossman, D Husten, C Malarcher, A Marshall, T Maule, CO Thornton, AH AF Orleans, CT Arkin, EB Backinger, CL Best, A Crossett, L Grossman, D Husten, C Malarcher, A Marshall, T Maule, CO Thornton, AH TI Youth tobacco cessation collaborative and national blueprint for action SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE adolescent/young adult tobacco cessation AB Objectives: To describe the formation of the Youth Tobacco Cessation Collaborative (YTCC), a voluntary collaborative of leading funders of youth tobacco cessation research and services. Methods: The long-term goal and specific short-term (2-year) goals, strategies, and accomplishments are briefly described with reference to its guiding action plan: National Blueprint for Action: Youth and Young Adult Tobacco-Use Cessation. Results: Aiming to accelerate the pace of discovery and application, YTCC efforts have created a strategic vision for making progress toward filling key knowledge and intervention gaps. Conclusions: Lessons learned about effective partnership are reviewed, and future directions are described. C1 Robert Wood Johnson Fdn, Princeton, NJ 08543 USA. Ctr Advancement Hlth, Washington, DC USA. NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Vancouver Hosp & Hlth Sci Ctr, Ctr Clin Epidemiol & Evaluat, Vancouver, BC V5Z 1M9, Canada. Ctr Dis Control & Prevent, Div Adolescent & Sch Hlth, Atlanta, GA USA. Natl Inst Drug Abuse, Bethesda, MD USA. Ctr Dis Control & Prevent, Off Smoking & Hlth, Epidemiol Branch, Atlanta, GA USA. Ctr Dis Control & Prevent, Cardiovasc Hlth Branch, Atlanta, GA USA. Ctr Adv Hlth, Washington, DC USA. Canadian Tobacco Control Res Initiat, Toronto, ON, Canada. Amer Legacy Fdn, Washington, DC USA. RP Orleans, CT (reprint author), Robert Wood Johnson Fdn, Route 1 & Coll Rd E, Princeton, NJ 08543 USA. NR 30 TC 13 Z9 13 U1 0 U2 0 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD SEP-OCT PY 2003 VL 27 SU 2 BP S103 EP S119 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 758ZR UT WOS:000187713100002 PM 14521239 ER PT J AU Maibach, EW AF Maibach, EW TI Recreating communities to support active living: A new role for social marketing SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Editorial Material ID PHYSICAL-ACTIVITY; PUBLIC-HEALTH; DESIGN C1 Porter Novelli, Washington, DC USA. RP Maibach, EW (reprint author), NCI, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Maibach, Edward/0000-0003-3409-9187 NR 26 TC 13 Z9 13 U1 0 U2 1 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD SEP-OCT PY 2003 VL 18 IS 1 BP 114 EP 119 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 728YM UT WOS:000185744000015 PM 13677970 ER PT J AU Walsh, EC Mather, KA Schaffner, SF Farwell, L Daly, MJ Patterson, N Cullen, M Carrington, M Bugawan, TL Erlich, H Campbell, J Barrett, J Miller, K Thomson, G Lander, ES Rioux, JD AF Walsh, EC Mather, KA Schaffner, SF Farwell, L Daly, MJ Patterson, N Cullen, M Carrington, M Bugawan, TL Erlich, H Campbell, J Barrett, J Miller, K Thomson, G Lander, ES Rioux, JD TI An integrated haplotype map of the human major histocompatibility complex SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CLASS-II REGION; LINKAGE DISEQUILIBRIUM; MULTIPLE-SCLEROSIS; CEPH FAMILIES; HUMAN GENOME; MEIOTIC RECOMBINATION; GENETIC-BASIS; HLA; MHC; ASSOCIATION AB Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms ( SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region. C1 Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA. Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD 21701 USA. Roche Mol Syst, Dept Human Genet, Alameda, CA USA. RP Rioux, JD (reprint author), MIT, Whitehead Inst, Ctr Genome Res, 1 Kendall Sq,Bldg 300, Cambridge, MA 02139 USA. RI Schaffner, Stephen/D-1189-2011; Rioux, John/A-9599-2015 OI Rioux, John/0000-0001-7560-8326 FU NCI NIH HHS [N01CO12400, N01-CO-12400]; NIGMS NIH HHS [GM35326, R01 GM035326] NR 31 TC 110 Z9 120 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 2003 VL 73 IS 3 BP 580 EP 590 DI 10.1086/378101 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 718FG UT WOS:000185134000010 PM 12920676 ER PT J AU Castle, PE Garcia-Closas, M Franklin, T Chanock, S Puri, V Welch, R Rothman, N Vaught, J AF Castle, PE Garcia-Closas, M Franklin, T Chanock, S Puri, V Welch, R Rothman, N Vaught, J TI Effects of electron-beam irradiation on buccal-cell DNA SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOMIC DNA; COLLECTION; MOUTHWASH AB Buccal cells were collected from 29 participants, by use of mouthwash rinses, and were split into equal aliquots, with one aliquot irradiated by electron-beam (E-beam) irradiation equivalent to the sterilizing dosage used by the U. S. Postal Service and the other left untreated. Aliquots were extracted and tested for DNA yields (e.g., TaqMan assay for quantifying human genomic DNA), genomic integrity, and amplification-based analysis of genetic variants (e.g., single-nucleotide polymorphisms [SNPs] and single tandem repeats [STRs]). Irradiated aliquots had lower median DNA yields (3.7 mug/aliquot) than untreated aliquots (7.6 mug/aliquot) (P < .0005) and were more likely to have smaller maximum DNA fragment size, on the basis of genomic integrity gels, than untreated aliquots (P < .0005). Irradiated aliquots showed poorer PCR amplification of a 989- bp beta-globin target ( 97% for weak amplification and 3% for no amplification) than untreated aliquots (7% for weak amplification and 0% for no amplification) (P < .0005), but 536-bp and 268-bp β-globin targets were amplified from all aliquots. There was no detectable irradiation effect on SNP assays, but there was a significant trend for decreased detection of longer STRs (P = .01) in irradiated versus untreated aliquots. We conclude that E-beam irradiation reduced the yield and quality of buccal-cell specimens, and, although irradiated buccal-cell specimens may retain sufficient DNA integrity for some amplified analyses of many common genomic targets, assays that target longer DNA fragments (>989 bp) or require whole-genome amplification may be compromised. C1 NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH,US Dept HHS, Bethesda, MD 20892 USA. Amer Type Culture Collect, Cell Biol, Manassas, VA USA. NCI, Core Genotyping Facil, Ctr Adv Technol, Gaithersburg, MD USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,Room 7074,EPS MSC 7234, Bethesda, MD 20892 USA. RI Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 NR 12 TC 7 Z9 7 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 2003 VL 73 IS 3 BP 646 EP 651 DI 10.1086/378077 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 718FG UT WOS:000185134000017 PM 12917795 ER PT J AU Sprince, NL Zwerling, C Lynch, CF Whitten, PS Thu, K Gillette, PP Burmeister, LF Alavanja, MCR AF Sprince, NL Zwerling, C Lynch, CF Whitten, PS Thu, K Gillette, PP Burmeister, LF Alavanja, MCR TI Risk factors for falls among Iowa farmers: A case-control study nested in the Agricultural Health Study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE falls; injury; agricultural; farmer; farming; risk factors; fractures ID OCCUPATIONAL INJURIES; OLDER WORKERS; HAZARD SURVEILLANCE; PROSPECTIVE COHORT; FAMILY HEALTH; DISABILITIES; RETIREMENT; POPULATION; OPERATORS; ACCIDENTS AB Background Farmers are at increased risk for fall-related injury compared with other occupations. Little is known about risk factors for non-fatal falls on the farm. This case-control study, nested within the Agricultural Health Study, aimed to assess risk factors for work-related falls among Iowa farmers. Methods A screener questionnaire sent to 6,999 farmers in 1998 identified 79 farmers who reported a fall-related farm injury that required medical advice or treatment in the previous year Multivariable logistic regression analysis was used to assess several possible risk factors for injury among these farmers compared with 473 farmers with no injury in the previous year. Results There were significant associations between fall-related farm injury and age between 40 and 64 years (OR = 2.21; 95% CI = 1.20-4.07), doctor-diagnosed arthritis/ rheumatism (OR = 2.05; 95% Cl = 1.11-3.79), difficulty hearing normal conversation (even with a hearing aid, in the case of those who used one) (OR = 1.82; 95% CI = 1. 07-3.08), and taking medications regularly (OR = 1.80; 95% CI= 1.02-3.18). Conclusions Aging and health impairments, such as arthritis and hearing difficulties, are risk factors for which accommodations and preventive strategies can be devised to prevent fall-related injuries on the farm. (C) 2003 Wiley-Liss, Inc. C1 Univ Iowa, Coll Publ Hlth, Dept Environm & Occupat Hlth, Iowa City, IA 52242 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA 52242 USA. No Illinois Univ, Dept Anthropol, De Kalb, IL 60115 USA. NCI, Rockville, MD USA. RP Sprince, NL (reprint author), Univ Iowa, Coll Publ Hlth, Dept Environm & Occupat Hlth, 100 Oakdale Campus, Iowa City, IA 52242 USA. NR 46 TC 30 Z9 30 U1 2 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD SEP PY 2003 VL 44 IS 3 BP 265 EP 272 DI 10.1002/ajim.10267 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 719DV UT WOS:000185189100005 PM 12929146 ER PT J AU Bakalov, VK Chen, ML Baron, J Hanton, LB Reynolds, JC Stratakis, CA Axelrod, LE Bondy, CA AF Bakalov, VK Chen, ML Baron, J Hanton, LB Reynolds, JC Stratakis, CA Axelrod, LE Bondy, CA TI Bone mineral density and fractures in turner syndrome SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID HOMEOBOX GENE SHOX; SHORT STATURE; GONADAL-DYSGENESIS; YOUNG-WOMEN; BODY-SIZE; OSTEOPOROSIS; ABNORMALITIES; DENSITOMETRY; DIAGNOSIS; MORBIDITY AB PURPOSE: To determine whether women with Turner syndrome who were treated with estrogen were more likely to have osteoporosis and fractures. METHODS: Areal bone density at the lumbar spine and femoral neck was measured in 40 adult women with Turner syndrome and 43 age-matched healthy women using dual-energy X-ray absorptiometry. Histories of estrogen treatment and fractures were obtained by structured personal interviews. RESULTS: Mean (+/- SD) areal bone density was significantly lower at the lumbar spine (0.87 +/- 0.11g/cm(2) vs. 0.98 +/- 0.10 g/cm(2), P <0.001) and femoral neck (0.68 +/- 0.07 g/cm(2) vs. 0.83 +/- 0.08 g/cm(2), P <0.001) in women with Turner syndrome than in controls. The diagnostic criterion for osteoporosis (T-score <-2.5) was met by 8 women with Turner syndrome (20%) with scores at the lumbar spine and by 3 (8%) with scores at the femoral neck. All women diagnosed with osteoporosis were less than 150 cm in height. Areal bone density correlated significantly with height (lumbar spine: R-2 = 0.3, P <0.001; femoral neck: R-2 = 0.4, P <0.001). Adjustments for skeletal size reduced the differences between the groups as well as the number of women diagnosed with osteoporosis (e.g., from 8 to 2 women based on lumbar spine scores). The prevalence and type of fractures were similar in the two groups. CONCLUSION: The prevalence of osteoporosis and bone fractures is not increased significantly in women with Turner syndrome who are treated with standard estrogen therapy. Women less than 150 cm in height are likely to be misdiagnosed with osteoporosis when areal bone density is measured, unless adjustments for body size are made. (C) 2003 by Excerpta Medica Inc. C1 Natl Inst Child Hlth, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), Natl Inst Child Hlth, Dev Endocrinol Branch, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 43 Z9 43 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD SEP PY 2003 VL 115 IS 4 BP 259 EP 264 DI 10.1016/S0002-9343(03)00364-4 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 721TC UT WOS:000185332100001 PM 12967689 ER PT J AU Poggi, SH Goodwin, KM Hill, JM Brenneman, DE Tendi, E Schninelli, S Spong, CY AF Poggi, SH Goodwin, KM Hill, JM Brenneman, DE Tendi, E Schninelli, S Spong, CY TI Differential expression of c-fos in a mouse model of fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2003 CL SAN FRANCISCO, CALIFORNIA SP Soc Maternal Fetal Med DE fetal alcohol syndrome; c-fos; oxidative stress; mouse ID COCAINE; KINASE AB OBJECTIVE:Fetal alcohol syndrome (FAS) results in stillbirth, fetal growth restriction, and mental retardation with injury attributed to oxidative stress. Our objective was to identify signal transduction pathways expressed in a model of FAS and to quantify expression of c-fos, a gene in the stress signal pathway. STUDY DESIGN: Timed, pregnant C57BI6/J mice were injected on E8 with saline solution or alcohol. RNA was extracted from decidua and embryo 6 and 24 hours later. Microarray analysis was used to screen gene pathways. Differential gene expression was confirmed using real-time polymerase chain reaction with results presented as the ratio of c-fos concentration to that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: Differential gene expression between alcohol and control was noted for stress signal pathway genes including c-fos. Real-time polymerase chain reaction demonstrated that c-fos messenger RNA expression was greater in the alcohol than control decidua at 6 hours after injection (P <.01). This effect persisted at 24 hours (P <.01). There was no difference in c-fos expression in embryos whose mothers. received alcohol versus control after 6 hours (P =.12) or 24 hours (P =.89). CONCLUSION: Alcohol administration during pregnancy results in differential gene expression in the stress signal pathway, particularly in c-fos. C-fos expression in the decidua increases from 6 to 24 hours after alcohol injection, but does not change in the embryo, Which may contribute to alcohol-induced damage in FAS. C1 Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20007 USA. NICHD, Dev Neurobiol Lab, Sect Dev & Mol Pharmacol, NIH, Bethesda, MD USA. RP Poggi, SH (reprint author), Dept Obstet & Gynaecol, 3PHC,3800 Reservoir Rd, Washington, DC 20007 USA. NR 14 TC 10 Z9 10 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2003 VL 189 IS 3 BP 786 EP 789 DI 10.1067/S0002-9378(03)00841-X PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 728LK UT WOS:000185718500039 PM 14526314 ER PT J AU Poggi, SH Goodwin, K Hill, JM Brenneman, DE Tendi, E Schinelli, S Abebe, D Spong, CY AF Poggi, SH Goodwin, K Hill, JM Brenneman, DE Tendi, E Schinelli, S Abebe, D Spong, CY TI The role of activity-dependent neuroprotective protein in a mouse model of fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2003 CL SAN FRANCISCO, CALIFORNIA SP Soc Maternal Fetal Med DE activity-dependent neuroprotective protein; mouse; fetal alcohol syndrome ID VASOACTIVE-INTESTINAL-PEPTIDE; MICE AB OBJECTIVE: Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation. Peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL), related to activity-dependent neuroprotective. protein (ADNP), prevent alcohol-induced damage in a mouse model of FAS. Our objective was to characterize ADNP in this model to relate this protein to the mechanisms of damage and peptide neuroprotection. STUDY DESIGN: Timed, pregnant C57B16/J mice were treated on day 8. Groups were control, alcohol, peptide pretreatment, or peptide alone. Embryo and decidua were harvested at 6 and 24 hours and 10 days. To evaluate ADNP expression, real-time polymerase chain reaction was performed with results presented as the ratio of ADNP-to-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) concentration. Analysis of variance was performed for overall comparisons with P < .05 considered significant. RESULTS: At 6 hours, there was no difference in ADNP between alcohol-exposed embryos compared with control embryos. At 24 hours, there was an increase in ADNP in alcohol-exposed embryos compared with controls (P <.001); these findings persisted at 10 days (P < .001). In the decidua at 6 hours, there was no difference between alcohol and control. At 24 hours, there was greater ADNP in alcohol-exposed decidua compared with controls (P < .001), which did not persist at 10 days (P = .97). Peptide pretreatment did not prevent the alcohol-induced increase in ADNP in embryo or decidua. CONCLUSION: Alcohol increased embryonic and decidual ADNP expression at 24 hours and it persisted in the embryo for 10 days. Because ADNP is a known neuroprotectant, these findings suggest that it may be released as a protective mechanism in FAS. Changes in the embryo were persistent suggesting that the embryo is more vulnerable to alcohol-induced damage than the mother. C1 Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20007 USA. NICHD, Dev Neurobiol Lab, Sect Dev & Mol Pharmacol, NIH, Bethesda, MD USA. RP Poggi, SH (reprint author), Dept Obstet & Gynecol, 3PHC,3800 Reservoir Rd, Washington, DC 20007 USA. NR 15 TC 26 Z9 26 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2003 VL 189 IS 3 BP 790 EP 793 DI 10.1067/S0002-9378(03)00834-2 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 728LK UT WOS:000185718500040 PM 14526315 ER PT J AU Gorman, MW Ogimoto, K Savage, MV Jacobson, KA Feigl, EO AF Gorman, MW Ogimoto, K Savage, MV Jacobson, KA Feigl, EO TI Nucleotide coronary vasodilation in guinea pig hearts SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE adenosine 5 '-triphosphate; adenosine 5 '-diphosphate; adenosine 5 '-monophosphate; adenosine; P1 receptors; P2Y(1) receptors; N-6-methyl-2 '-deoxyadenosine 3 ',5 '-bisphosphate; MRS 2179 ID P2Y(1) RECEPTORS; PERFUSED HEART; RAT-HEART; ATP; RELEASE; ADENOSINE; METABOLISM; INHIBITION; RELAXATION; FLOW AB The role of P1 receptors and P2Y(1) receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-(p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y(1) antagonist N-6-methyl-2'-deoxyadenosine 3',5'-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y(1) blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y(1) blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y(1) receptors. ADP-induced vasodilation is largely due to P2Y(1) receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP. C1 Univ Washington, Dept Physiol & Biophys, Seattle, WA 98115 USA. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gorman, MW (reprint author), Univ Washington, Sch Med, Dept Physiol & Biophys, Box 357290, Seattle, WA 98195 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20]; NHLBI NIH HHS [HL 49822] NR 32 TC 20 Z9 20 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2003 VL 285 IS 3 BP H1040 EP H1047 DI 10.1152/ajpheart.00981.2002 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 711HM UT WOS:000184733600015 PM 12763753 ER PT J AU Zuzak, KJ Gladwin, MT Cannon, RO Levin, IW AF Zuzak, KJ Gladwin, MT Cannon, RO Levin, IW TI Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE peripheral vascular disease; cardiovascular pharmacology; blood flow ID TISSUE PERFUSION; RELAXING FACTOR; HUMAN-SKIN; BIOAVAILABILITY; INHIBITION; TRANSPORT; ANEMIA AB Sickle cell disease is characterized by microvascular occlusion and hemolytic anemia, factors that impair tissue oxygen delivery.We use visible reflectance hyperspectral imaging to quantitate skin tissue hemoglobin oxygen saturation (HbO(2)) and to determine whether changes in blood flow during nitric oxide ( NO) stimulation or gas administration ( therapies proposed for this disease) improve skin tissue oxygen saturation in five patients with sickle cell disease. Compared with six healthy African-American subjects, sickle cell patients exhibited higher forearm blood flows ( 7.4 +/- 1.8 vs. 3.2 +/- 0.4 ml . min(-1) . 100 ml tissue(-1), P = 0.037) but significantly reduced percentages of skin HbO(2) (61.0 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Administration of acetylcholine to patients increased blood flow by 15.1 +/- 3.8 ml . min(-1) . 100 ml tissue(-1) and the percentage of skin HbO(2) by 4.1 +/- 0.3% (P = 0.02, P < 0.001, respectively, from baseline values). Sodium nitroprusside, a direct NO donor, increased blood flow by 3.9 +/- 1.1 ml/min and the percentage of skin HbO(2) by 2.9 +/- 0.3% (P = 0.02, P < 0.001, respectively). NO inhalation had no effect on forearm blood flow, yet increased the percentage of skin HbO(2) by 2.3 +/- 0.3% ( P < 0.001). Percentages of skin HbO(2) were exponentially related to blood flow (R = 0.97, P < 0.001), indicating a limit to skin tissue oxygen saturation at high blood flows. Thus, for acetylcholine infusion leading to blood flows sevenfold greater than those of healthy resting African-American subjects, patients still exhibited lower percentages of skin HbO(2) ( 65.2 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Visible reflectance hyperspectral imaging demonstrates that either the stimulation or the administration of NO pharmacologically or by gas inhalation improves, but does not normalize, skin tissue oxygen saturation in patients with sickle cell disease. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Cardivasc Branch, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5,Rm B1-32,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 39 Z9 39 U1 2 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2003 VL 285 IS 3 BP H1183 EP H1189 DI 10.1152/ajpheart.00243.2003 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 711HM UT WOS:000184733600032 PM 12791593 ER PT J AU Castellanos, FX Sharp, WS Gottesman, RF Greenstein, DK Giedd, JN Rapoport, JL AF Castellanos, FX Sharp, WS Gottesman, RF Greenstein, DK Giedd, JN Rapoport, JL TI Anatomic brain abnormalities in monozygotic wins discordant for attention deficit hyperactivity disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT/HYPERACTIVITY DISORDER; LESIONS; TWINS; MRI AB Objective: To examine brain-behavior relationships in attention deficit hyperactivity disorder (ADHD), the authors obtained magnetic resonance imaging (MRI) scans of monozygotic twins discordant for ADHD. Method: National recruitment was followed by in-person assessment. MRI scans were measured algorithmically for nine pairs of monozygotic twins discordant for ADHD. Results: The affected twins had significantly smaller caudate volumes (mean difference=-0.56 ml, Cl=-0.92 to -0.21) than their unaffected co-twins. Conclusions: These results provide further support for striatal models of ADHD pathophysiology. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Castellanos, FX (reprint author), NYU, Sch Med, Ctr Child Study, Rm 204,577 1st Ave, New York, NY 10016 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Castellanos, Francisco/0000-0001-9192-9437 NR 12 TC 70 Z9 75 U1 2 U2 8 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2003 VL 160 IS 9 BP 1693 EP 1696 DI 10.1176/appi.ajp.160.9.1693 PG 4 WC Psychiatry SC Psychiatry GA 718PV UT WOS:000185156400023 PM 12944348 ER PT J AU Forsyth, AD AF Forsyth, AD TI Communicating complex information: The interpretation of statistical interaction in multiple logistic regression analysis - Response SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Forsyth, AD (reprint author), NIMH, NIH, 6001 Execut Blvd,Rm 6201,MSC 9619, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2003 VL 93 IS 9 BP 1377 EP 1377 DI 10.2105/AJPH.93.9.1377 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 716KL UT WOS:000185027300003 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Bicycling for pleasure and power SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 NIH, Natl Lib Med, Hist Med Div, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1 E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2003 VL 93 IS 9 BP 1409 EP 1409 DI 10.2105/AJPH.93.9.1409 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 716KL UT WOS:000185027300016 PM 12948953 ER PT J AU Srinivasan, S O'Fallon, LR Dearry, A AF Srinivasan, S O'Fallon, LR Dearry, A TI Creating healthy communities, healthy homes, healthy people: Initiating a research agenda on the built environment and public health SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PHYSICAL-ACTIVITY; UNITED-STATES; CHILDREN; POPULATION; COCKROACH; ASTHMA; RISK; CITY AB Mounting evidence suggests physical and mental health problems relate to the built environment, including human-modified places such as homes, schools, workplaces, parks, industrial areas, farms, roads and highways. The public health relevance of the built environment requires examination. Preliminary research demonstrates the health benefits of sustainable communities. However, the impact of mediating and moderating factors within the built environment on health must be explored further. Given the complexity of the built environment, understanding its influence on human health requires a community-based, multilevel, interdisciplinary research approach. The authors offer recommendations, based upon a recent conference sponsored by the National Institute of Environmental Health Sciences (NIEHS), for research and policy approaches, and suggest interagency research alliances for greater public health impact. C1 Natl Inst Environm Hlth Sci, Div Extramural Res, Res Triangle Pk, NC 27709 USA. RP Srinivasan, S (reprint author), Natl Inst Environm Hlth Sci, Div Extramural Res, 111 TW Alexander Dr,POB 12233,MD EC-21, Res Triangle Pk, NC 27709 USA. NR 51 TC 162 Z9 163 U1 3 U2 41 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2003 VL 93 IS 9 BP 1446 EP 1450 DI 10.2105/AJPH.93.9.1446 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 716KL UT WOS:000185027300024 PM 12948961 ER PT J AU Eichacker, PQ Banks, SM Natanson, C AF Eichacker, PQ Banks, SM Natanson, C TI Metaanalysis of tidal volume in ARDS SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID RESPIRATORY-DISTRESS SYNDROME; PERMISSIVE HYPERCAPNIA; MECHANICAL VENTILATION; LUNG INJURY C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2003 VL 168 IS 5 BP 612 EP 613 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 716QC UT WOS:000185039000019 ER PT J AU Keiser, PB Coulibaly, YI Keita, F Traore, D Diallo, A Diallo, DA Semnani, RT Doumbo, OK Traore, SF Klion, AD Nutman, TB AF Keiser, PB Coulibaly, YI Keita, F Traore, D Diallo, A Diallo, DA Semnani, RT Doumbo, OK Traore, SF Klion, AD Nutman, TB TI Clinical characteristics of post-treatment reactions to ivermectin/albendazole for Wuchereria bancrofti in a region co-endemic for Mansonella perstans SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LYMPHATIC FILARIASIS; IVERMECTIN; ALBENDAZOLE; EFFICACY; DIETHYLCARBAMAZINE; MICROFILAREMIA; ONCHOCERCIASIS; INFECTION; TRIAL; COMBINATION AB Post-treatment reactions to single-dose ivermectin (200 mug/kg) and albendazole (400 mg) were studied in a filarial endemic region of Mali. The prevalence of Wuchereria bancrofti in this region was 48.3% (69 of 143), and coinfection with Mansonella perstans was common (30 of 40, 75%). Microfilarial levels of M. perstans correlated positively with age (P = 0.006) and with W. bancrofti microfilarial levels (P 0.006). Forty individuals (28 infected and 12 uninfected) were treated, with mild post-treatment reactions occurring in 35.7% (7 of 28) of the W. bancrofti-infected subjects. Reaction severity correlated with pretreatment W. bancrofti microfilarial levels (P = 0.001). There were no significant differences in the prevalence or severity of post-treatment reactions in those who were co-infected with M. perstans. It is concluded that co-infection with M. perstans does not significantly alter the post-treatment reaction profile to single-dose ivermectin/albendazole in W. bancrofiti infection in this community, and that acute post-treatment reactions should not limit patient compliance in community-based programs to eliminate lymphatic filariasis. C1 NIAID, Parasit Dis Lab, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. Univ Mali, Sch Med, Dept Epidemiol, Bamako, Mali. Univ Mali, Sch Med, Dept Parasit Dis, Bamako, Mali. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. OI Klion, Amy/0000-0002-4986-5326 NR 28 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD SEP PY 2003 VL 69 IS 3 BP 331 EP 335 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 730NP UT WOS:000185837100024 PM 14628953 ER PT J AU Friedman, MA Xie, JW Wood, BJ AF Friedman, MA Xie, JW Wood, BJ TI Re: Histologic changes after hepatic radio-frequency ablation SO AMERICAN SURGEON LA English DT Letter ID TUMORS C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Friedman, MA (reprint author), NIH, Dept Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD SEP PY 2003 VL 69 IS 9 BP 820 EP 820 PG 1 WC Surgery SC Surgery GA 720AD UT WOS:000185237200024 PM 14509336 ER PT J AU Schuck, P AF Schuck, P TI On the analysis of protein self-association by sedimentation velocity analytical ultracentrifugation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE protein interactions; reversible associations; Lamm equation; sedimentation equilibrium ID SIZE-DISTRIBUTION ANALYSIS; CALF BRAIN TUBULIN; LAMM EQUATION; COEFFICIENT DISTRIBUTION; DEPENDENT SEDIMENTATION; INTERACTING PARTICLES; TRANSPORT EXPERIMENTS; GENERALIZED SYSTEMS; NUMERICAL-SOLUTIONS; NEUROTROPHIC FACTOR AB Analytical ultracentrifugation is one of the classical techniques for the study of protein interactions and protein self-association. Recent instrumental and computational developments have significantly enhanced this methodology. In this paper, new tools for the analysis of protein self-association by sedimentation velocity are developed, their statistical properties are examined, and considerations for optimal experimental design are discussed. A traditional strategy is the analysis of the isotherm of weight-average sedimentation coefficients s(w) as a function of protein concentration. From theoretical considerations, it is shown that integration of any differential sedimentation coefficient distribution c(s), ls-g*(s), or g(s*) can give a thermodynamically well-defined isotherm, as long as it provides a good model for the sedimentation profiles. To test this condition for the g(s*) distribution, a back-transform into the original data space is proposed. Deconvoluting diffusion in the sedimentation coefficient distribution c(s) can be advantageous to identify species that do not participate in the association. Because of the large number of scans that can be analyzed in the c(s) approach, its s(w) values are very precise and allow extension of the isotherm to very low concentrations. For all differential sedimentation coefficients, corrections are derived for the slowing of the sedimentation boundaries caused by radial dilution. As an alternative to the interpretation of the isotherm of the weight-average s value, direct global modeling of several sedimentation experiments with Lamm equation solutions was studied. For this purpose, a new software SEDPHAT is introduced, allowing the global analysis of several sedimentation velocity and equilibrium experiments. In this approach, information from the shape of the sedimentation profiles is exploited, which permits the identification of the association scheme and requires fewer experiments to precisely characterize the association. Further, under suitable conditions, fractions of incompetent material that are not part of the reversible equilibrium can be detected. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIH, Prot Biophys Resource, Div Bioengn & Phys Sci, ORS,OD, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), NIH, Prot Biophys Resource, Div Bioengn & Phys Sci, ORS,OD, Bethesda, MD 20892 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 97 TC 382 Z9 383 U1 6 U2 43 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 1 PY 2003 VL 320 IS 1 BP 104 EP 124 DI 10.1016/S0003-2697(03)00289-6 PG 21 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 712JH UT WOS:000184794200011 PM 12895474 ER PT J AU Beigi, F Wainer, IW AF Beigi, F Wainer, IW TI Syntheses of immobilized G protein-coupled receptor chromatographic stationary phases: Characterization of immobilized mu and kappa opioid receptors SO ANALYTICAL CHEMISTRY LA English DT Article ID AFFINITY-CHROMATOGRAPHY; GLUCOSE-TRANSPORTER; MEMBRANE-PROTEINS; CYTOCHALASIN-B; BINDING; ACTIVATION; SOLUBILIZATION; SELECTIVITY; MECHANISMS; ASSAY AB Opioid receptors are members of the superfamily of G protein-coupled receptors (GPCRs). liquid chromatographic stationary phases containing either the human mu or kappa opioid receptor subtypes have been developed to study the binding between the opioid receptors and their ligands. The receptors were obtained from chinese hamster ovary cells stably transfected with human mu or kappa receptor subtypes. The receptors were isolated through partial solubilization with sodium cholate detergent, and the partially purified receptor complex was immobilized in the phospholipid analogue monolayer of an immobilized artificial membrane liquid chromatographic stationary phase. The resulting phase was packed into a glass column (1.8 x 0.5 (i.d.) cm) and used in the on-line chromatographic determination of drug/ligand binding affinities to the immobilized opioid receptors. Preliminary on-line binding studies employing frontal chromatographic techniques were conducted with the known mu antagonist (naloxone) and a kappa agonist (U69593). The calculated dissociation constants (K-d) were 110 nM for naloxone and 84 nM for U69593. The results indicate that the immobilized receptors retained their ability to specifically bind ligands and were active for 1200 column volumes applied over two weeks. Zonal chromatographic experiments were also conducted, and competitive displacements of the marker ligands were observed. The results suggest that the immobilized opioid receptor stationary phases can be used to qualitatively assess the binding affinities of compounds to the immobilized receptors and represent the first example of the use of immobilized GPCRs in a chromatographic system. C1 NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 30 TC 34 Z9 35 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD SEP 1 PY 2003 VL 75 IS 17 BP 4480 EP 4485 DI 10.1021/ac034385q PG 6 WC Chemistry, Analytical SC Chemistry GA 719FE UT WOS:000185192300026 PM 14632053 ER PT J AU Gorbach, AM Heiss, J Kufta, C Sato, S Fedio, P Kammerer, WA Solomon, J Oldfield, EH AF Gorbach, AM Heiss, J Kufta, C Sato, S Fedio, P Kammerer, WA Solomon, J Oldfield, EH TI Intraoperative infrared functional imaging of human brain SO ANNALS OF NEUROLOGY LA English DT Article ID CEREBRAL BLOOD-FLOW; ELECTRICAL-STIMULATION; OXIDATIVE-METABOLISM; SENSORY STIMULATION; NEURONAL-ACTIVITY; TECHNICAL NOTE; TEMPERATURE; CORTEX; OXYGENATION; ACTIVATION AB We hypothesized that it would be possible to detect the distribution of cortical activation by using a sensitive, rapid, high-resolution infrared imaging technique to monitor changes in local cerebral blood flow induced by changes in focal cortical metabolism. In a prospective study, we recorded in 21 patients the emission of infrared radiation from the exposed human cerebral cortex at baseline, during language and motor tasks, and during stimulation of the contralateral median nerve using an infrared camera (sensitivity 0.02degreesC). The language and sensorimotor cortex was identified by standard mapping methods (cortical stimulation, median nerve somatosensory-evoked potential, functional magnetic resonance imaging), which were compared with infrared functional localization. The temperature gradients measured during surgery are dominated by changes in local cerebral blood flow associated with evoked functional activation. The distribution of the evoked temperature changes overlaps with, but extends beyond, functional regions identified by standard mapping techniques. The distribution observed via infrared mapping is consistent with distributed and complex functional representation of the cerebral cortex, rather than the traditional concept of discrete functional loci demonstrated by brief cortical stimulation during surgery and by noninvasive functional imaging techniques. By providing information on the spatial and temporal patterns of sensory-motor and language representation, infrared imaging may prove to be a useful approach to study brain function. C1 NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Anesthesiol, Bethesda, MD 20892 USA. Sensor Syst Inc, Sterling, VA USA. RP Oldfield, EH (reprint author), NINDS, NIH, Surg Neurol Branch, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. NR 30 TC 45 Z9 45 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2003 VL 54 IS 3 BP 297 EP 309 DI 10.1002/ana.10646 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 718QN UT WOS:000185158100004 PM 12953262 ER PT J AU Ng, SSW Figg, WD AF Ng, SSW Figg, WD TI Antitumor activity of herbal supplements in human prostate cancer xenografts implanted in immunodeficient mice SO ANTICANCER RESEARCH LA English DT Article DE herbal supplements; prostate cancer; testosterone; VEGF; microvessel density ID PC-SPES; IN-VITRO; GROWTH; ANGIOGENESIS; GENISTEIN; ESTROGEN; CELLS; CARCINOMA; LICORICE; MEN AB Background: Prostate cancer is the second leading cause of cancer death in American men. Therapeutic options for metatstatic prostate cancer are limited. The use of herbal therapies in the treatment of this malignancy remains controversial. Materials and Methods: We tested five herbal supplements, designated FB, FM, PP, HF and FBL101, which contain different combinations of various natural herbs such as licorice, black cohosh, Dong Quai, false unicorn and vitex berry root extracts, fennel seed extract, red clover blossoms extract as well as genistein and gamma oryzanol, for antitumor activity in severely combined immunodeficient mice bearing CWR22R and PC3 prostate cancer xenografts. Their mechanisms of action were also explored Results: FB, FM, PP, HF and FBL101 inhibited PC3 tumor growth by 53%, 75%, 80%, 81% and 87%, respectively. In CWR22R tumors, similar growth suppression was observed with all supplements. Total plasma testosterone levels were not significantly altered by the supplements relative to the untreated control. PP and FBL101 significantly reduced VEGF levels in PC3 and CWR22R tumors, respectively. Intratumoral microvessel density was decreased in PC3 tumors treated with all five supplements but only in CWR22R tumors treated with HE Conclusion: Our results demonstrated that herbal supplements containing the aforementioned extracts inhibit the growth of prostate tumor xenografts, possibly in part by antiangiogenic mechanisms. The potential use of these herbal supplements as preventive and therapeutic agents in prostate cancer warrants further investigation. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bldg 10,Rm 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 24 TC 14 Z9 16 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 2003 VL 23 IS 5A BP 3585 EP 3590 PG 6 WC Oncology SC Oncology GA 748VE UT WOS:000186881100002 PM 14666653 ER PT J AU Hoover, DM Wu, ZB Tucker, K Lu, WY Lubkowski, J AF Hoover, DM Wu, ZB Tucker, K Lu, WY Lubkowski, J TI Antimicrobial characterization of human beta-defensin 3 derivatives SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RABBIT NEUTROPHIL DEFENSINS; STAPHYLOCOCCUS-AUREUS; MEMBRANE PERMEABILIZATION; HUMAN BETA-DEFENSIN-3; INSECT DEFENSIN; ALPHA-DEFENSINS; PEPTIDE; MECHANISMS; CHANNELS; IMMUNITY AB Human beta-defensin 3 (hBD3) is a highly basic 45-amino-acid protein that acts both as an antimicrobial agent and as a chemoattractant molecule. Although the nature of its antimicrobial activity is largely electrostatic, the importance of the molecular structure on this activity is poorly understood. Two isoforms of hBD3 were synthesized: the first with native disulfide linkages and the second with normative linkages. In a third synthetic peptide, all cysteine residues were replaced with alpha-aminobutyric acid, creating a completely linear peptide. A series of six small, linear peptides corresponding to regions of hBD3 with net charges ranging from +4 to +8 (at pH 7) and lengths ranging from 9 to 20 amino acids were also synthesized. The linear full-length peptide showed the highest microbicidal activity against Escherichia coli and Staphylococcus aureus, while all three full-length forms showed equal activity against Candida albicans. The linear peptide also showed high activity against Enterococcus faecium and Pseudomonas aeruginosa.. Peptides corresponding to the C terminus showed higher activities when tested against E. coli, with the most active peptides being the most basic. However, only the peptide corresponding to the N terminus of hBD3 showed any activity against S. aureus and C. albicans. Further, N-terminal deletion mutants of native hBD3 showed diminished activities against S. aureus. Thus, the antimicrobial properties of hBD3 derivatives are determined by both charge and structure. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Opportunist Infect Lab, DCTD DTP, SAIC Frederick Inc, Frederick, MD 21702 USA. Univ Baltimore, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Lu, Wuyuan/B-2268-2010 FU PHS HHS [N01-C0-1240] NR 39 TC 138 Z9 149 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2003 VL 47 IS 9 BP 2804 EP 2809 DI 10.1128/AAC.47.9.2804-2809.2003 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 715TH UT WOS:000184988000013 PM 12936977 ER PT J AU Chen, X Yang, L Zhang, N Turpin, JA Buckheit, RW Osterling, C Oppenheim, JJ Howard, OMZ AF Chen, X Yang, L Zhang, N Turpin, JA Buckheit, RW Osterling, C Oppenheim, JJ Howard, OMZ TI Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ANTI-HIV ACTIVITY; CD8(+) T-CELLS; POTENT INHIBITION; CCR5 ANTAGONIST; SMALL-MOLECULE; RESISTANCE; RANTES; ENTRY; IDENTIFICATION; SPECIFICITY AB Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1alpha], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1alpha]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC(50)s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC50 of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents. C1 NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. TherImmune Res Corp, Gaithersburg, MD 20879 USA. Howpin Int Consulting, Frederick, MD 21703 USA. So Res Inst, Infect Dis Res Dept, Frederick, MD 21701 USA. RP Howard, OMZ (reprint author), NCI, Mol Immunoregulat Lab, BO Box B,Bldg 560 Rm 31-19, Frederick, MD 21702 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 NCI NIH HHS [N01CO12400]; PHS HHS [N01-C0-12400] NR 32 TC 100 Z9 112 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2003 VL 47 IS 9 BP 2810 EP 2816 DI 10.1128/AAC.47.9.2810-2816.2003 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 715TH UT WOS:000184988000014 PM 12936978 ER PT J AU Roy, CJ Baker, R Washburn, K Bray, M AF Roy, CJ Baker, R Washburn, K Bray, M TI Aerosolized cidofovir is retained in the respiratory tract and protects mice against intranasal cowpox virus challenge SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID POXVIRUS INFECTIONS; HPMPC CIDOFOVIR; PHARMACOKINETICS; BIOAVAILABILITY; METABOLISM; SMALLPOX; MONKEYPOX; ADEFOVIR; ANALOGS AB We employed a murine model to test the concept of using an aerosolized, long-acting antiviral drug to protect humans against smallpox. We previously showed that a low dose of aerosolized cidofovir (HPMPC [Vistide]) was highly protective against subsequent aerosolized cowpox virus challenge and was more effective than a much larger dose of drug given by injection, suggesting that aerosolized cidofovir is retained in the lung. Because the nephrotoxicity of cidofovir is a major concern in therapy, delivering the drug directly to the respiratory tract might be an effective prophylactic strategy that maximizes the tissue concentration at the site of initial viral replication, while minimizing its accumulation in the kidneys. In the present study, we found that treating mice with aerosolized C-14-labeled cidofovir (C-14-cidofovir) resulted in the prolonged retention of radiolabeled drug in the lungs at levels greatly exceeding those in the kidneys. In contrast, subcutaneous injection produced much higher concentrations of C-14-cidofovir in the kidneys than in the lungs over the 96-h time course of the study. As further evidence of the protective efficacy of aerosolized cidofovir, we found that aerosol treatment before or after infection was highly protective in mice challenged intranasally with cowpox virus. All or nearly all mice that were treated once by aerosol, from 2 days before to 2 days after challenge, survived intranasal infection, whereas all placebo-treated animals died. C1 USA, Dept Aerobiol & Prod Evaluat, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. USA, Dept Viral Therapeut, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. Stillmeadow Corp, Sugar Land, TX 77478 USA. NIAID, Biodef Clin Res Branch, Off Clin Res, NIH, Bethesda, MD 20892 USA. RP Roy, CJ (reprint author), USA, Dept Aerobiol & Prod Evaluat, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NR 25 TC 21 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2003 VL 47 IS 9 BP 2933 EP 2937 DI 10.1128/AAC.47.9.2933-2937.2003 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 715TH UT WOS:000184988000033 PM 12936997 ER PT J AU Fiero, PL Galper, DI Cox, DJ Phillips, LH Fryburg, DA AF Fiero, PL Galper, DI Cox, DJ Phillips, LH Fryburg, DA TI Thermal biofeedback and lower extremity blood flow in adults with diabetes: Is neuropathy a limiting factor? SO APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK LA English DT Article DE thermal biofeedback; diabetes; intermittent claudication; neuropathy ID DIGITAL TEMPERATURE; FOOT ULCERATION; HYPERTENSION; CIRCULATION; POPULATION; MELLITUS AB Thermal biofeedback may be a useful adjunctive technique for enhancing cutaneous blood flow in patients with lower-extremity vascular complications of diabetes. However, autonomic, sensory, and/or motor neuropathies may impair vasomotion and limit the ability to alter blood flow and achieve significant foot warming with thermal biofeedback. We examined nerve function associated with four common types of diabetic neuropathy (sympathetic autonomic, vagal-autonomic, sensory, and motor), hypothesizing that both sympathetic autonomic and sensory neuropathies would limit the acquisition of biofeedback-mediated foot warming. Twenty-four participants with diabetes mellitus (19 with type II and 5 with type I) received a nerve conduction study and neurological evaluation of the upper and lower extremities. Hand temperature, foot temperature, and electrodermal gradient at the toes were monitored across six thermal biofeedback sessions. Participants were able to significantly raise p < .01) foot temperatures across sessions, an average of 2.2&DEG;F. Consistent with our hypotheses, 41% of the variance in foot warming was explained by lower-extremity sympathetic-autonomic and sensory nerve function tests. This study demonstrated that a general diabetic population, including patients with mild-to-moderate neuropathy, can increase skin perfusion with thermal biofeedback. As hypothesized, lower-extremity sympathetic-autonomic and sensory neuropathies interfered with foot warming. C1 NCI, Tobacco Intervent Res Clin, Tobacco Control Res Branch, Div Canc Control & Populat Sci,SAIC Frederick, Rockville, MD 20852 USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Fiero, PL (reprint author), NCI, Tobacco Intervent Res Clin, Tobacco Control Res Branch, Div Canc Control & Populat Sci,SAIC Frederick, 6116 Executive Blvd,Suite 109,MSC 8318, Rockville, MD 20852 USA. FU NCRR NIH HHS [RR00036, RR00847]; NIDDK NIH HHS [DK20579, DK27085, T32DK07320, DK28288] NR 37 TC 4 Z9 4 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-0586 J9 APPL PSYCHOPHYS BIOF JI Appl. Psychophysiol. Biofeedback PD SEP PY 2003 VL 28 IS 3 BP 193 EP 203 DI 10.1023/A:1024681113746 PG 11 WC Psychology, Clinical SC Psychology GA 698JG UT WOS:000183994900002 PM 12964451 ER PT J AU Sperling, LC DiGiovanna, JJ AF Sperling, LC DiGiovanna, JJ TI "Curly" wood and tiger tails - An explanation for light and dark banding with polarization in trichothiodystrophy SO ARCHIVES OF DERMATOLOGY LA English DT Article ID DEFICIENT BRITTLE HAIR AB The mechanism causing the tiger tail phenomenon in trichothiodystrophy (alternating light and dark banding of hair shafts when examined with polarized light) has yet to be explained with certainty. However, we propose a simple and easily tested hypothesis to explain its striking aspect. Although the hair shafts we obtained from patients with trichothiodystrophy were fairly straight, the cortical hair fibers were not. We noticed that these fibers undulate up and down (or back and forth), a feature that is easily observed because of melanin granules embedded in each fiber. The undulations correspond exactly to the banding seen with polarization. Therefore, the tiger tail phenomenon seen in trichothiodystrophy and other hair shaft disorders is caused by a regular undulation of hair fibers within the shafts. Normal hair shafts do not exhibit the phenomenon because the hair fibers are straight and parallel to the long axis of the hair. It is the regular undulation of fibers that changes the optical properties of the hair shafts and causes a predictable banding when the shafts are examined by polarized light. C1 Uniformed Serv Univ Hlth Sci, Dept Dermatol, F Edward Hebert Sch Med, Bethesda, MD 20854 USA. Brown Med Sch, Dept Dermatopharmacol & Dermatol, Providence, RI USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sperling, LC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, F Edward Hebert Sch Med, 4301 Jones Bridge Rd, Bethesda, MD 20854 USA. NR 10 TC 13 Z9 13 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD SEP PY 2003 VL 139 IS 9 BP 1189 EP 1192 DI 10.1001/archderm.139.9.1189 PG 4 WC Dermatology SC Dermatology GA 721RM UT WOS:000185330100013 PM 12975162 ER PT J AU LaGasse, LL Messinger, D Lester, BM Seifer, R Tronick, EZ Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Finnegan, LP Maza, PL Liu, J AF LaGasse, LL Messinger, D Lester, BM Seifer, R Tronick, EZ Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Finnegan, LP Maza, PL Liu, J TI Prenatal drug exposure and maternal and infant feeding behaviour SO ARCHIVES OF DISEASE IN CHILDHOOD LA English DT Article ID COCAINE EXPOSURE; LIFE-STYLE; ABUSE; PREGNANCY; SUCKING; NEWBORN; ALCOHOL; INTERVENTION; STIMULATION; ENVIRONMENT AB Objective: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. Methods: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. Results: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions ( 638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts ( 29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants' feeding problems. Conclusions: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour. C1 Brown Univ, Women & Infants Hosp, Sch Med, Providence, RI USA. Bradley Hosp, Providence, RI USA. Univ Miami, Sch Med, Miami, FL USA. Brown Med Sch, Providence, RI USA. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Boston, MA 02115 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Kentucky, Coll Med, Lexington, KY USA. NICHHD, Bethesda, MD 20892 USA. NIDA, Bethesda, MD 20892 USA. NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. Adm Children Youth & Families, Washington, DC USA. RP LaGasse, LL (reprint author), Infant Dev Ctr, 79 Plain St, Providence, RI 02903 USA. FU NICHD NIH HHS [U10 HD 21385, U10 HD 21397, U10 HD 27856, N01-HD-2-3159, U10 HD 27904]; NIDA NIH HHS [U10 DA024119] NR 47 TC 23 Z9 23 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-9888 J9 ARCH DIS CHILD JI Arch. Dis. Child. PD SEP PY 2003 VL 88 IS 5 SI SI BP F391 EP F399 DI 10.1136/fn.88.5.F391 PG 9 WC Pediatrics SC Pediatrics GA 719QD UT WOS:000185214100008 PM 12937043 ER PT J AU Goldberg, TE Egan, MF Gscheidle, T Coppola, R Weickert, T Kolachana, BS Goldman, D Weinberger, DR AF Goldberg, TE Egan, MF Gscheidle, T Coppola, R Weickert, T Kolachana, BS Goldman, D Weinberger, DR TI Executive subprocesses in working memory - Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID CARD-SORTING-TEST; FIRST-DEGREE RELATIVES; PREFRONTAL CORTEX; NEUROPSYCHOLOGICAL DEFICITS; NONPSYCHOTIC RELATIVES; COGNITIVE IMPAIRMENTS; TWINS DISCORDANT; TEST-PERFORMANCE; RISK; DYSFUNCTION AB Background: Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Methods: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N=250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. Results: A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. Conclusions: A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environiriental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Intramural Res Program, Bethesda, MD USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, 10 Ctr Dr,Mail Stop Code 1379, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 53 TC 450 Z9 461 U1 4 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 2003 VL 60 IS 9 BP 889 EP 896 DI 10.1001/archpsyc.60.9.889 PG 8 WC Psychiatry SC Psychiatry GA 718PN UT WOS:000185155800004 PM 12963670 ER PT J AU Coryell, W Solomon, D Turvey, C Keller, M Leon, AC Endicott, J Schettler, P Judd, L Mueller, T AF Coryell, W Solomon, D Turvey, C Keller, M Leon, AC Endicott, J Schettler, P Judd, L Mueller, T TI The long-term course of rapid-cycling bipolar disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID LITHIUM-CARBONATE; DOUBLE-BLIND; DEPRESSION; IMIPRAMINE; VALIDITY; RELIABILITY; PHENOTYPE; CHILDREN; ILLNESS; RELAPSE AB Background: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. Methods: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. Results: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. Conclusions: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do. not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability. C1 NIMH, Collaborat Program Psychobiol Depress Clin Studie, Bethesda, MD 20892 USA. RP Coryell, W (reprint author), Univ Iowa, Room 2-205,Psychiat Res MEB, Iowa City, IA 52242 USA. FU NIMH NIH HHS [MH25416, MH51324, R01 MH025478] NR 30 TC 158 Z9 160 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 2003 VL 60 IS 9 BP 914 EP 920 DI 10.1001/archpsyc.60.9.914 PG 7 WC Psychiatry SC Psychiatry GA 718PN UT WOS:000185155800008 PM 12963673 ER PT J AU Sharon, D Sandberg, MA Caruso, RC Berson, EL Dryja, TP AF Sharon, D Sandberg, MA Caruso, RC Berson, EL Dryja, TP TI Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID NUCLEAR RECEPTOR GENE; RETINITIS-PIGMENTOSA; CLINICAL FINDINGS; NIGHT BLINDNESS; EPITHELIUM; ELECTRORETINOGRAM; IDENTIFICATION; MACULOPATHY; NRL AB Objectives: To determine if enhanced s-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD) are caused by mutations in the NR2E3 gene and to characterize the clinical findings in patients with NR2E3 mutations. Patients: One patient with ESCS, one with GFS, and 20 with CPRD. Methods: The coding regions of the NR2E3 and NRL genes and part of the THRB1 coding region were scanned for mutations using single-strand conformation and direct sequencing methods. We evaluated visual acuity, refractive error, visual fields, fundi, final dark-adaptation thresholds, and electroretinograms (ERGs). Results: The patients with ESCS and GFS and 9 of the 20 unrelated patients with CPRD had mutations in the NR2E3 gene. Six mutations were found in these 11 patients, including 2 novel mutations: the missense mutation Ala256Glu and the frameshift mutation Pro276del17 (the first obviously null allele reported). Three patients were mutant homozygotes, and 8 had 2 mutations. All but one of the mutations in the patients with ESCS and GFS were also found in patients with CPRD. All NR2E3 cases were hyperopes and had retinal vascular attenuation and reduced and delayed full-field ERGS. Clumped pigment deposits were recognized in the patients with ESCS and GFS. The CPRD patients without NR2E3 mutations had no detected mutations in NRL or THRB1. Conclusions: We found that ESCS, GFS, and CPRD can all have the same genetic basis. Clinical Relevance: The combination of night blindness, hyperopia, and clumped retinal pigment deposits should raise the suspicion that a patient has NR2E3 disease. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ocular Mol Genet Inst, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Berman Gund Lab Study Retinal Degenerat, Cambridge, MA 02138 USA. NEI, Bethesda, MD 20892 USA. RP Dryja, TP (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. RI Research Datalink, Clinical Practice/H-2477-2013; Sharon, Dror/P-4539-2015 OI Sharon, Dror/0000-0002-1789-5811 FU NEI NIH HHS [EY00169, EY08683] NR 33 TC 89 Z9 94 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2003 VL 121 IS 9 BP 1316 EP 1323 DI 10.1001/archopht.121.9.1316 PG 8 WC Ophthalmology SC Ophthalmology GA 721QT UT WOS:000185327600013 PM 12963616 ER PT J AU Cassarino, DS Quezado, MM Ghatak, NR Duray, PH AF Cassarino, DS Quezado, MM Ghatak, NR Duray, PH TI Lyme-Associated parkinsonism - A neuropathologic case study and review of the literature SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT 78th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 20-23, 2002 CL DENVER, COLORADO SP Amer Assoc Neuropathol ID BORRELIA-BURGDORFERI; NERVOUS-SYSTEM AB Neurological complications of Lyme disease include meningitis, encephalitis, dementia, and, rarely, parkinsonism. We present a case of striatonigral degeneration, a form of multiple system atrophy, in Lyme-associated parkinsonism. A 63-year-old man presented with erythema migrans rash, joint pains, and tremors. Serum and cerebrospinal fluid antibodies and polymerase chain reaction for Borrelia burgdorferi were positive. Clinical parkinsonism was diagnosed by several neurologists. Despite treatment, the patient continued to decline, with progressive disability, cognitive dysfunction, rigidity, and pulmonary failure. At autopsy, the brain showed mild basal ganglia atrophy and substantia nigra depigmentation, with extensive striatal and substantia nigral neuronal loss and astrogliosis. No Lewy bodies were identified; however, ubiquitin-positive glial cytoplasmic inclusions were identified in striatal and nigral oligodendroglia. There were no perivascular or meningeal infiltrates, the classic findings of neuroborreliosis. To our knowledge, this is the first report of striatonigral degeneration in a patient with B burgdorferi infection of the central nervous system and clinical Lyme-associated parkinsonism. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Pathol, Richmond, VA USA. Virginia Commonwealth Univ, Dept Neuropathol, Richmond, VA USA. RP Duray, PH (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N212,10 Ctr Dr, Bethesda, MD 20892 USA. NR 7 TC 17 Z9 18 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD SEP PY 2003 VL 127 IS 9 BP 1204 EP 1206 PG 3 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 720BF UT WOS:000185240300026 PM 12946221 ER PT J AU Chan, PC Mahler, J Peddada, S Lomnitski, L Nyska, A AF Chan, PC Mahler, J Peddada, S Lomnitski, L Nyska, A TI Forestomach tumor induction by 2,4-hexadienal in F344N rats and B6C3F1 mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE 2,4-hexadienal; forestomach tumors; rats; mice ID SECONDARY AUTOXIDATION PRODUCTS; LIPID-PEROXIDATION; CARBONYL-COMPOUNDS; LINOLEIC-ACID; CARCINOGENICITY; FAT; MUTAGENICITY; GLUTATHIONE; HYPERPLASIA; TOXICOLOGY AB 2,4-Hexadienal (2,4-Hx) was studied for its toxicity and carcinogenicity because of its alpha, beta-unsaturated aldehyde structure and potential link between exposure to lipid peroxidation products in the diet and human malignancies. Male and female F344N rats and B6C3F1 mice received 2,4-Hx in corn oil by gavage for 16 days, 14 weeks, or 2 years. In the 16-day studies 2,4-Hx induced forestomach necrosis and ulceration at 240 mg/kg and forestomach epithelial hyperplasia at 80 mg/kg in rats and mice. In the 14-week studies the chemical induced forestomach hyperplasia and nasal olfactory atrophy or necrosis at 120 mg/kg in rats and mice. In the 2-year studies 2,4-Hx induced squamous cell papilloma and carcinoma of the forestomach in male and female rats at 45 and 90 mg/kg and in male and female mice at 120 mg/kg. Two male mice in the 120 mg/kg group had uncommon squamous cell carcinoma of the oral cavity (tongue). Mechanistic studies indicated that the forestomach carcinogenesis in rats and mice may be due to depletion of glutathione as a result of oxidative stress induced by 2,4-Hx. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Bar Ilan Univ, Inst Life Sci Fac, IL-52900 Ramat Gan, Israel. RP Chan, PC (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Peddada, Shyamal/D-1278-2012 NR 38 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD SEP PY 2003 VL 77 IS 9 BP 511 EP 520 DI 10.1007/s00204-003-0481-8 PG 10 WC Toxicology SC Toxicology GA 722FY UT WOS:000185365800004 PM 12879212 ER PT J AU Thorburn, CM Ward, MM AF Thorburn, CM Ward, MM TI Hospitalizations for coronary artery disease among patients with systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RISK-FACTORS; ATHEROSCLEROSIS; MORBIDITY; WOMEN AB Objective. Although patients with systemic lupus erythematosus (SLE) have an increased risk of coronary artery disease (CAD) compared with persons without SLE, the burden of CAD among SLE patients is unknown. This study was undertaken to estimate this burden. Methods. We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project to estimate the number of hospitalizations for CAD among patients with SLE in the US in 1998. CAD diagnoses included acute myocardial infarction (MI), unstable angina, cardiac catheterization, percutaneous transluminal coronary angioplasty, or coronary artery bypass grafting as the primary reason for hospitalization. We compared these estimates with the frequency of hospitalization for other reasons. Results. There were an estimated 98,217 hospitalizations among patients with SLE in 1998. Of these, 11,947 (12%) were among men, 43,674 (44%) were among women <50 years of age, and 42,596 (43%) were among women greater than or equal to50 years of age. There were 4,951 hospitalizations for CAD, with 1,763 of these for acute MI. In women <50 years old, there were an estimated 311 hospitalizations for MI. Hospitalizations for CAD were less common than hospitalizations for SLE itself or for infections, and in young women, were less common than hospitalizations for complications of chronic renal failure. Conclusion. CAD is an important comorbid condition in patients with SLE, hut is not as common a reason for hospitalization as SLE itself, infections, and, in some patient subgroups, chronic renal failure. C1 Natl Inst Musculoskeletal & Skin Dis, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. RP Ward, MM (reprint author), Natl Inst Musculoskeletal & Skin Dis, Intramural Res Program, NIH, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. NR 15 TC 27 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 BP 2519 EP 2523 DI 10.1002/art.11241 PG 5 WC Rheumatology SC Rheumatology GA 723KQ UT WOS:000185431900016 PM 13130471 ER PT J AU Artlett, CM O'Hanlon, TP Lopez, AM Song, YW Miller, FW Rider, LG AF Artlett, CM O'Hanlon, TP Lopez, AM Song, YW Miller, FW Rider, LG TI HLA-DQA1 is not an apparent risk factor for microchimerism in patients with various autoimmune diseases and in healthy individuals SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-SCLEROSIS; JUVENILE DERMATOMYOSITIS; PERIPHERAL-BLOOD; MATERNAL PLASMA; T-LYMPHOCYTES; FETAL DNA; CELLS; HLA-DQA1-ASTERISK-0501; WOMEN; PCR AB Objective. Microchimeric cells have been identified in lesions and peripheral blood of patients with systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), and HLA-DQA1*0501 is a risk factor for these diseases in some populations. Furthermore, DQA1*0501 has been associated with T lymphocyte microchimerism in SSc. To better define the strength of this association, we assessed the relationship among DQA1 alleles and microchimerism. Methods. DNA from whole peripheral blood or magnetically sorted T cells was tested for microchimeric cells by polymerase chain reaction of the Y chromosome or of HLA-Cw in 87 SSc patients, 28 juvenile IIM patients, and 88 healthy controls. Thirty-seven mother-son pairs were also analyzed for microchimerism and DQA1*0501. Results. We were unable to demonstrate that DQA1*0501 is associated with microchimerism in T lymphocytes or in whole peripheral blood DNA in patients with SSc or juvenile IIM or in healthy individuals. In the 37 mother-son pairs, we were unable to demonstrate an association of DQA1*0501 with microchimerism in peripheral blood DNA or T lymphocytes, and compatibility between the donor's and recipient's HLA alleles did not influence microchimerism in the recipient. Conclusion. These data suggest that HLA-DQA1 alleles do not appear to play a role in the persistence of microchimerism in the peripheral blood or T lymphocytes of patients with selected autoimmune diseases or in healthy individuals. C1 Thomas Jefferson Univ, Div Rheumatol, Philadelphia, PA 19107 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. Seoul Natl Univ Hosp, Seoul 110744, South Korea. RP Artlett, CM (reprint author), Thomas Jefferson Univ, Div Rheumatol, 233 S 10th St, Philadelphia, PA 19107 USA. RI Song, Yeong Wook/J-2765-2012; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 19 TC 22 Z9 22 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 BP 2567 EP 2572 DI 10.1002/art.11235 PG 6 WC Rheumatology SC Rheumatology GA 723KQ UT WOS:000185431900021 PM 13130476 ER PT J AU Takada, K Aksentijevich, I Mahadevan, V Dean, JA Kelley, RI Kastner, DL AF Takada, K Aksentijevich, I Mahadevan, V Dean, JA Kelley, RI Kastner, DL TI Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ENCODING MEVALONATE KINASE; HYPER-IGD; MUTATIONS; MVK; PHENOTYPE; TNFRSF1A; ACIDURIA; GENE AB Objective. The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM 260920) is caused by recessive mutations in the mevalonate kinase gene (MVK), which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis. HIDS is characterized by persistently elevated polyclonal IgD and recurrent febrile episodes. Although abnormalities in tumor necrosis factor alpha (TNFalpha) are not the primary cause of HIDS, plasma TNFalpha levels are elevated in HIDS patients during attacks and thus may be a therapeutic target. This study assessed the effects of etanercept, a soluble p75 TNFalpha receptor-Fc fusion protein, in 2 patients with HIDS. Methods. We performed biochemical and molecular genetic analyses on 2 girls with periodic episodes of fever, skin rash, abdominal pain, and arthralgia, of whom 1 had elevated levels of serum IgD. After the diagnosis of HIDS was made, treatment with etanercept was initiated in both patients. Clinical response was recorded in a standardized diary, and serum levels of cytokines and their decoy receptors were serially measured in 1 of the 2 patients. Results. Urinary mevalonate levels were elevated in both girls. Patient 1 was heterozygous for a known MVK missense mutation (V377I) and a novel mutation that led to skipping of exon 3. Patient 2 was found to have V377I and a new missense mutation, S329R. Neither patient had mutations in TNFRSF1A or MEFV, the genes for the TNF receptor-associated periodic syndrome and familial Mediterranean fever, respectively. Etanercept reduced the frequency and severity of symptoms in both patients, whereas the levels of serum IgD and urine mevalonate remained unchanged. Conclusion. Our favorable experience with etanercept for the treatment of HIDS suggests that further investigation of this therapy is warranted. C1 NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. Kennedy Krieger Inst, Baltimore, MD USA. Johns Hopkins Univ, Baltimore, MD USA. RP Kastner, DL (reprint author), NIAMSD, Genet & Genom Branch, NIH, Bldg 10,Room 9N-214,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 13 TC 102 Z9 106 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 BP 2645 EP 2651 DI 10.1002/art.11218 PG 7 WC Rheumatology SC Rheumatology GA 723KQ UT WOS:000185431900030 PM 13130485 ER PT J AU Brescia, AC Thurber, DB Fischer, RT Hurt, E Staudt, L Phillips, TM Lipsky, PE Grammer, AC AF Brescia, AC Thurber, DB Fischer, RT Hurt, E Staudt, L Phillips, TM Lipsky, PE Grammer, AC TI Multiomic identification of genes that characterize Ig-secreting B cells in secondary lymphoid tissue or the periphery of active SLE patients. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1765 BP S674 EP S674 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801806 ER PT J AU Carrington, KL Austin, JS Townshend, JL Miranda-Acevedo, R Schuett, NM Mittleman, BB AF Carrington, KL Austin, JS Townshend, JL Miranda-Acevedo, R Schuett, NM Mittleman, BB TI Building and sustaining community partnerships to reduce health disparities in rheumatic diseases. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 US Dept HHS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 565 BP S251 EP S251 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800609 ER PT J AU Crosby, MB Svenson, JL Zhang, J Nicol, CJ Gonzalez, FJ Gilkeson, GS AF Crosby, MB Svenson, JL Zhang, J Nicol, CJ Gonzalez, FJ Gilkeson, GS TI Synthetic PPAR-gamma agonists inhibit NO production in the absence of PPAR-gamma: Evidence for an alternative target for these agents SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Med Univ S Carolina, Charleston, SC 29425 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1034 BP S416 EP S417 PG 2 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801078 ER PT J AU El-Gabalawy, HS Hitchon, CA Schumacher, HR Yarboro, C Duray, P Goldbach-Mansky, R AF El-Gabalawy, HS Hitchon, CA Schumacher, HR Yarboro, C Duray, P Goldbach-Mansky, R TI Synovial, histopathological features and RA autoantibodies predict persistence in patients with synovitis of recent onset. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Manitoba, Winnipeg, MB, Canada. Univ Penn, Philadelphia, PA 19104 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1743 BP S667 EP S667 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801784 ER PT J AU Fritsch, RD Olson, DP Illei, G Lipsky, PE AF Fritsch, RD Olson, DP Illei, G Lipsky, PE TI Characterization of differences in memory T cell subsets of SLE patients and healthy controls. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIAMS, Autoimmun Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 419 BP S197 EP S197 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800463 ER PT J AU Giannini, E Brunner, H Ruperto, N Reed, A James-Newton, L Sanghvi, T Feldman, B Finkel, R Huber, A Lindsley, C Lovell, D Malleson, P Pachman, L Passo, M Pilkington, C Rennebohm, R Russman, B Sherry, D Sundel, R Lachenbruch, P Miller, F AF Giannini, E Brunner, H Ruperto, N Reed, A James-Newton, L Sanghvi, T Feldman, B Finkel, R Huber, A Lindsley, C Lovell, D Malleson, P Pachman, L Passo, M Pilkington, C Rennebohm, R Russman, B Sherry, D Sundel, R Lachenbruch, P Miller, F TI Preliminary definitions of improvement for juvenile myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 DHHS, NIEHS, IMACS Grp, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1079 BP S433 EP S433 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801123 ER PT J AU Goldbach-Mansky, R Wilson, M Morrison, K Thornten, B Kempf, P Hill, S Lipsky, PE Yao, L AF Goldbach-Mansky, R Wilson, M Morrison, K Thornten, B Kempf, P Hill, S Lipsky, PE Yao, L TI Different patterns of bone marrow enhancement may define "active" carpal bone erosions in patients with rheumatoid arthritis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIAMS, NIH, Rehabil Dept, Bethesda, MD USA. NIH, Diagnost Radiol Dept, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 191 BP S116 EP S116 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800236 ER PT J AU Kanbe, K Xiang, C Takagishi, K Inoue, K Chen, Q AF Kanbe, K Xiang, C Takagishi, K Inoue, K Chen, Q TI Identification of mechanoresponsive genes in cartilage by large scale DNA microarray analysis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Tokyo Womens Med Univ, Daini Hosp, Tokyo, Japan. NIH, Bethesda, MD 20892 USA. Gunma Univ, Maebashi, Gumma 371, Japan. Rhode Isl Hosp, Brown Med Sch, Providence, RI USA. RI Chen, Qian/C-4354-2011 OI Chen, Qian/0000-0003-4406-5618 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 54 BP S67 EP S67 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800099 ER PT J AU Karasik, D Hannan, MT Broe, KE Cupples, LA Wilson, PWF O'Donnell, CJ Kiel, DP Felson, DT AF Karasik, D Hannan, MT Broe, KE Cupples, LA Wilson, PWF O'Donnell, CJ Kiel, DP Felson, DT TI Association between hand exostoses and aortic calcification: the Framingham study. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. BU Sch Publ Hlth, Boston, MA USA. BU Sch Med, Boston, MA USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1758 BP S672 EP S672 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801799 ER PT J AU Kok, MR Yamano, S Lodde, BM Wang, JH Couwenhoven, RI Yakar, S Voutetakis, A Leroith, D Pillemer, SR Tak, PP Chiorini, J Baum, BJ AF Kok, MR Yamano, S Lodde, BM Wang, JH Couwenhoven, RI Yakar, S Voutetakis, A Leroith, D Pillemer, SR Tak, PP Chiorini, J Baum, BJ TI Local adeno-associated virus mediated IL-10 gene transfer has disease modifying effects in a murine model of Sjogren's syndrome. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIDCR, GTTB, NIH, Bethesda, MD USA. NIDDK, Clin Diabet Branch, NIH, Bethesda, MD USA. Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 588 BP S259 EP S259 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800632 ER PT J AU Levine, SM Raben, N Plotz, P Rosen, A Casciola-Rosen, L AF Levine, SM Raben, N Plotz, P Rosen, A Casciola-Rosen, L TI Revelation of a neo-epitope at the granzyme B cleavage site of histidyl-tRNA synthetase: Implications for immunogenicity in myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Johns Hopkins Univ, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1082 BP S434 EP S434 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801126 ER PT J AU Ling, SM Bang, D Camacho, NP Yang, X Spencer, RG AF Ling, SM Bang, D Camacho, NP Yang, X Spencer, RG TI Micro-computed tomographic assessment of bone quality in an animal model of arthritis and unloading. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIA, Intramural Res Program, Clin Res Branch, Baltimore, MD 21224 USA. NIA, IRP, Clin Invest Lab, NMR Unit, Baltimore, MD USA. Hosp Special Surg, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1241 BP S491 EP S491 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801284 ER PT J AU Mamyrova, G Targoff, I Lindsley, C Wallace, C Haftel, H Oral, E Cawkwell, G Finkel, T Gewanter, H Goldsmith, D Higgins, G Jones, O Katona, I Knee, M Lawton, A Morishima, C Passo, M Perez, M Person, D Rivas-Chacon, R Sherry, D Szer, I Zemel, L Miller, F Rider, L AF Mamyrova, G Targoff, I Lindsley, C Wallace, C Haftel, H Oral, E Cawkwell, G Finkel, T Gewanter, H Goldsmith, D Higgins, G Jones, O Katona, I Knee, M Lawton, A Morishima, C Passo, M Perez, M Person, D Rivas-Chacon, R Sherry, D Szer, I Zemel, L Miller, F Rider, L TI Distinguishing clinical features of JDM associated with a myositis-associated autoantibody (MAA) directed against a 155 kd protein. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIEHS, DHHS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1304 BP S514 EP S514 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801347 ER PT J AU Mamyrova, G Kleiner, D Bingham, A Cochran, E Imundo, L Lindsley, C Morris, J Rivas-Chacon, R Jung, L Baer, A Miller, F Oral, E Rider, L AF Mamyrova, G Kleiner, D Bingham, A Cochran, E Imundo, L Lindsley, C Morris, J Rivas-Chacon, R Jung, L Baer, A Miller, F Oral, E Rider, L TI Non-alcoholic steatohepatitis (NASH) is a frequent complication of acquired lipodystrophy (LD)associated with juvenile dermatomyositis (JDM). SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIEHS, DHHS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1303 BP S514 EP S514 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801346 ER PT J AU Masi, AT Aldag, JC Cooling, MB Chatterton, RT Sipe, JD Malamet, RL AF Masi, AT Aldag, JC Cooling, MB Chatterton, RT Sipe, JD Malamet, RL TI Cigarette smoking increased rheumatoid arthritis risks in postmenopausal women and men independently of baseline C-reactive protein (CRP) and prolactin (PRL) levels. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Illinois, Coll Med, Peoria, IL 61656 USA. Northwestern Univ, Chicago, IL 60611 USA. NIH, Ctr Sci Review, Bethesda, MD 20892 USA. Osteoporosis & Clin Trials Ctr, Hagerstown, MD USA. NR 0 TC 1 Z9 1 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 971 BP S394 EP S394 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801015 ER PT J AU Morbach, H Samfass, U Singh, SK Lipsky, PE Girschick, HJ AF Morbach, H Samfass, U Singh, SK Lipsky, PE Girschick, HJ TI Expression of RAG1, RAG2 and VpreB genes in IgD+CD5+/- peripheral B cells during cyclophosphamide treatment in pediatric SLE. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Wurzburg, Childrens Hosp, Wurzburg, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 406 BP S192 EP S192 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800450 ER PT J AU Nagaraju, K Thapliyal, R O'Neill-Marshall, C Danning, C Rawat, R Rider, L Miller, F Plotz, P AF Nagaraju, K Thapliyal, R O'Neill-Marshall, C Danning, C Rawat, R Rider, L Miller, F Plotz, P TI Striking neovascularization and dendritic cells in close proximity to endothelial cells are found in myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIAMS, Arthritis & Rheumatism Branch, NIH, Bethesda, MD USA. NIEHS, Environm Autoimmun Grp, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 1084 BP S435 EP S435 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432801128 ER PT J AU Oddis, C Miller, F Koneru, B Feldman, B Giannini, E Brunner, H Ruperto, N Reed, A Rider, L AF Oddis, C Miller, F Koneru, B Feldman, B Giannini, E Brunner, H Ruperto, N Reed, A Rider, L CA IMACS Grp TI Development of consensus criteria on the conduct of clinical trials in adult and juvenile idiopathic inflammatory myopathy (IIM). SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIH, Bethesda, MD 20892 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. PRINTO, Genoa, Italy. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 724 BP S308 EP S309 PG 2 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800768 ER PT J AU Rider, L Giannini, E Brunner, H Ruperto, N Reed, A James-Newton, L Sanghvi, T Cronin, M Garcia-de la Torre, I Isenberg, D Kagen, L Levine, T Lundberg, I Oddis, C Rutkove, S Sivakumar, K Song, Y Targoff, I Vencovsky, J Wortmann, R Ytterberg, S Lachenbruch, P Miller, F AF Rider, L Giannini, E Brunner, H Ruperto, N Reed, A James-Newton, L Sanghvi, T Cronin, M Garcia-de la Torre, I Isenberg, D Kagen, L Levine, T Lundberg, I Oddis, C Rutkove, S Sivakumar, K Song, Y Targoff, I Vencovsky, J Wortmann, R Ytterberg, S Lachenbruch, P Miller, F CA IMACS Grp TI Preliminary definitions of improvement for adult myositis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIEHS, DHHS, IMACS, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 720 BP S307 EP S307 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800764 ER PT J AU Rider, L Reed, A James-Newton, L Feldman, B Ravelli, A Cabalar, I Villalba, M Rennebohm, R Pachman, L Lindsley, C Adams, E Passo, M Zemel, L Wallace, C White, P Myones, BL Plotz, P Isenberg, D Lachenbruch, P Miller, F AF Rider, L Reed, A James-Newton, L Feldman, B Ravelli, A Cabalar, I Villalba, M Rennebohm, R Pachman, L Lindsley, C Adams, E Passo, M Zemel, L Wallace, C White, P Myones, BL Plotz, P Isenberg, D Lachenbruch, P Miller, F CA IMACS Grp TI Assessing the extent and severity of damage in adult and juvenile myositis (IIM) by the Myositis Damage Index (MDI). SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIEHS, DHHS, IMACS Grp, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 721 BP S307 EP S307 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800765 ER PT J AU Siegel, JN Zhen, B Siegel, A Chauhan, N Keystone, E Landewe, R Wolfe, F van der Heijde, D Steven, F AF Siegel, JN Zhen, B Siegel, A Chauhan, N Keystone, E Landewe, R Wolfe, F van der Heijde, D Steven, F TI Evidence of effects of a TNF blocking agent in ACR20 non-responders. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 FDA, Rockville, MD USA. Univ Washington, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. Univ Toronto, Toronto, ON, Canada. Univ Hosp Maastricht, Maastricht, Netherlands. Natl Data Bank Rheumat Dis, Wichita, KS USA. Abbott Labs, Parsippany, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 221 BP S127 EP S128 PG 2 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800266 ER PT J AU Skapenko, A Lipsky, PE Niedobitek, GU Kalden, JR Schulze-Koops, H AF Skapenko, A Lipsky, PE Niedobitek, GU Kalden, JR Schulze-Koops, H TI Human Th1 immunity in vivo is regulated by IL-4 via CD4CD25 regulatory T cells. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Erlangen Nurnberg, Erlangen, Germany. NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 617 BP S270 EP S270 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800661 ER PT J AU Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H TI Generation and regulation of human Th1 inflammation in vivo. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Univ Erlangen Nurnberg, Erlangen, Germany. NIAMSD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 569 BP S252 EP S252 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800613 ER PT J AU Su, KH Wu, JM Edberg, JC Li, XL Ferguson, P Cooper, GS Langefeld, C Kimberly, RP AF Su, KH Wu, JM Edberg, JC Li, XL Ferguson, P Cooper, GS Langefeld, C Kimberly, RP TI An FCGR2B promoter haplotype, associated with autoimmunity, increases Fc gamma RIIb expression and function. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 Wake Forest Univ, Winston Salem, NC 27109 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Alabama, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 931 BP S380 EP S381 PG 2 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800975 ER PT J AU Valencia, X Olson, D He, LS Illei, G Lipsky, P AF Valencia, X Olson, D He, LS Illei, G Lipsky, P TI CD4+CD25+T regulatory cells in autoimmune diseases. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2003 VL 48 IS 9 SU S MA 411 BP S194 EP S194 PG 1 WC Rheumatology SC Rheumatology GA 723LA UT WOS:000185432800455 ER PT J AU Remaley, A Stonik, J Fairwell, T Demosky, S Neufeld, E Brewer, HB AF Remaley, A Stonik, J Fairwell, T Demosky, S Neufeld, E Brewer, HB TI Structural features of amphipathic helical peptides that promote lipid efflux SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 137 EP 137 DI 10.1016/S1567-5688(03)90588-5 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926500585 ER PT J AU Neufeld, E Stonik, JA Demosky, SJ Knapper, C Remaley, AT Santamarina-Fojo, S Brewer, HB AF Neufeld, E Stonik, JA Demosky, SJ Knapper, C Remaley, AT Santamarina-Fojo, S Brewer, HB TI The ABCA1 transporter modulates late endocytic trafficking SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NHLBI, NIH, Mol Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 138 EP 139 DI 10.1016/S1567-5688(03)90593-9 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926500590 ER PT J AU Kruth, H Huang, W Zhao, B Ishii, I Zhang, WY AF Kruth, H Huang, W Zhao, B Ishii, I Zhang, WY TI PMA activation of macrophages stimulates fluid-phase endocytic uptake of native LDL generating foam cells SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 139 EP 140 DI 10.1016/S1567-5688(03)90597-6 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926500594 ER PT J AU Kumon, Y Suehiro, T Ikeda, Y Arii, K Sipe, J Hashimoto, K AF Kumon, Y Suehiro, T Ikeda, Y Arii, K Sipe, J Hashimoto, K TI Serum amyloid A induces migration of human aortic smooth muscle cells (HASMC) and its migration is inhibited by statins and fibrates SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 Kochi Med Sch, Dept Endocrinol Metab & Nephrol, Kochi, Japan. NIH, Musculoskeletal & Dent Sci IRG, Ctr Sci Review, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 212 EP 212 DI 10.1016/S1567-5688(03)90904-4 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926500901 ER PT J AU Shamburek, R Nong, Z Hoyt, R Brewer, HB AF Shamburek, R Nong, Z Hoyt, R Brewer, HB TI Roles of cubilin and megalin in apolipoprotein A-I renal catabolism in the cubilin dysfunctional canine model SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 235 EP 235 DI 10.1016/S1567-5688(03)91009-9 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926501006 ER PT J AU Santamarina-Fojo, S Joyce, C Wu, J Basso, F Najib-Fruchart, J Paigen, B Brewer, HB AF Santamarina-Fojo, S Joyce, C Wu, J Basso, F Najib-Fruchart, J Paigen, B Brewer, HB TI The role of ABC transporters in atherosclerosis; Studies in transgenic mouse models SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NHLBI, MDB, NIH, Potomac, MD USA. Inst Pasteur, F-59019 Lille, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 270 EP 270 DI 10.1016/S1567-5688(03)91162-7 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926501159 ER PT J AU Brewer, HB AF Brewer, HB TI Treatment of dyslipoproteinemia in the 21st century: Potential targets for new drug development SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 274 EP 274 DI 10.1016/S1567-5688(03)91174-3 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926501171 ER PT J AU Iehara, N Imai, H Ida, H Yamada, Y AF Iehara, N Imai, H Ida, H Yamada, Y TI Modular cis-acting elements required for the alpha 2(IV) collagen promoter in tissue-specific transcription SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 13th International Symposium on Atherosclerosis CY SEP 28-OCT 02, 2003 CL KYOTO, JAPAN C1 Kyoto Univ Hosp, Nephrol Sect, Kyoto 606, Japan. NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD SEP PY 2003 VL 4 IS 2 BP 322 EP 323 DI 10.1016/S1567-5688(03)91384-5 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 749NH UT WOS:000186926501381 ER PT J AU Bossert, JM Liu, SY Shaham, Y AF Bossert, JM Liu, SY Shaham, Y TI Renewal of heroin seeking by contextual drug cues in a rat relapse model SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIDA, IRP, Behav Neurosci Branch, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S26 EP S26 PG 1 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700076 ER PT J AU Chen, G AF Chen, G TI The molecular and cellular actions of mood-stabilizers SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIMH, Mol Pathophysiol Lab, NIH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S4 EP S5 PG 2 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700013 ER PT J AU Desai, RI Kopajtic, A Newman, AH Katz, JL AF Desai, RI Kopajtic, A Newman, AH Katz, JL TI Relationship between in vivo occupancy at the dopamine transporter and behavioural effects of cocaine and analogs of benztropine (BZT) SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIDA, NIH, DHHS, Intramural Res Program,Psychobiol Sect, Baltimore, MD 21224 USA. NIDA, NIH, DHHS, Intramural Res Program,Med Chem Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S54 EP S54 PG 1 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700159 ER PT J AU Goldberg, SR AF Goldberg, SR TI The addictive potential of cannabinoids: Experimental studies with primates SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIDA, NIH, DHHS, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S13 EP S13 PG 1 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700038 ER PT J AU Krystal, JH Petrakis, IL D'Souza, DC Limoncelli, D Webb, E Trevisan, L Boutros, N Gueorguieva, R Charney, D AF Krystal, JH Petrakis, IL D'Souza, DC Limoncelli, D Webb, E Trevisan, L Boutros, N Gueorguieva, R Charney, D TI Alterations in NMDA receptor antagonist response associated with human alcohol dependence and familial risk for alcohol dependence SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIAAA, Ctr Translat Neurosci Alcoholism, VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S6 EP S7 PG 2 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700019 ER PT J AU Shaham, Y AF Shaham, Y TI Incubation of cue-controlled cocaine seeking after withdrawal SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 10th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY SEP 06-09, 2003 CL ANTWERP, BELGIUM SP European Behav Pharmacol Soc C1 NIDA, IRP, Behav Neurosci Branch, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2003 VL 14 SU 1 BP S15 EP S15 PG 1 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 737ME UT WOS:000186235700043 ER PT J AU Lochhead, PA Sibbet, G Kinstrie, R Cleghon, T Rylatt, M Morrison, DK Cleghon, V AF Lochhead, PA Sibbet, G Kinstrie, R Cleghon, T Rylatt, M Morrison, DK Cleghon, V TI dDYRK2: a novel dual-specificity tyrosine-phosphorylation-regulated kinase in Drosophila SO BIOCHEMICAL JOURNAL LA English DT Article DE development; Drosophila; dual-specificity kinase; dual-specificity tyrosine-phosphorylation regulated kinase (DYRK); minibrain ID ACTIVATED PROTEIN-KINASE; MYELIN BASIC-PROTEIN; SACCHAROMYCES-CEREVISIAE; MAP KINASE; GENE-EXPRESSION; GROWTH-FACTOR; DYRK FAMILY; CELL-CYCLE; SUBSTRATE; YEAST AB Dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are an emerging family of protein kinases that have been identified in all eukaryotic organisms examined to date. DYRK family members are involved in regulating key developmental and cellular processes such as neurogenesis, cell proliferation, cytokinesis and cellular differentiation. Two distinct subgroups exist, nuclear and cytosolic. In Drosophila, the founding family member minibrain, whose human orthologue maps to the Down syndrome critical region, belongs to the nuclear subclass and affects post-embryonic neurogenesis. In the present paper, we report the isolation of dDYRK2, a cytosolic DYRK and the putative product of the smell-impaired smi35A gene. This is the second such kinase described in Drosophila, but the first to be characterized at the molecular and biochemical level. dDYRK2 is an 81 kDa dual-specificity kinase that autophosphorylates on tyrosine and serine/threonine residues, but appears to phosphorylate exogenous substrates only on serine/threonine residues. It contains a YXY motif in the activation loop of the kinase domain in the same location as the TXY motif in mitogen-activated protein kinases. dDYRK2 is tyrosine-phosphorylated in vivo, and mutational analysis reveals that the activation loop tyrosines are phosphorylated and are essential for kinase activity. Finally, dDYRK2 is active at all stages of fly development, with elevated levels observed during embryogenesis and pupation. C1 Canc Res UK, Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Canc Res Ctr, Frederick, MD 21702 USA. RP Cleghon, V (reprint author), Canc Res UK, Beatson Inst Canc Res, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland. OI Kinstrie, Ross/0000-0001-7789-0601 NR 38 TC 30 Z9 31 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD SEP 1 PY 2003 VL 374 BP 381 EP 391 DI 10.1042/BJ20030500 PN 2 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721LL UT WOS:000185317800011 PM 12786602 ER PT J AU Kobayashi, H Kawamoto, S Star, RA Waldmann, TA Brechbiel, MW Choyke, PL AF Kobayashi, H Kawamoto, S Star, RA Waldmann, TA Brechbiel, MW Choyke, PL TI Activated clearance of a biotinylated macromolecular MRI contrast agent from the blood pool using an avidin chase SO BIOCONJUGATE CHEMISTRY LA English DT Article ID POLYAMIDOAMINE DENDRIMER CORE; MONOCLONAL-ANTIBODY; PHARMACOKINETIC PROPERTIES; TUMOR; BIODISTRIBUTION; ANGIOGRAPHY; INFUSION; ANTIGEN; ALBUMIN; SYSTEM AB The enhancement characteristics of a contrast agent are dependent on its pharmacokinetics within the body. In the case of macromolecular contrast agents, prolonged enhancement of the blood pool is seen after the first dose, limiting opportunities for repeated injection in the same session. If the enhancement within the blood pool could be intentionally switched off, the macromolecular contrast agents could be used both to define blood volume and vessel permeability, properties that could be useful in studying angiogenesis. In the current study, the avidin-biotin system was coupled to a dendrimer-based macromolecular MRI contrast agent to switch enhancement from the blood pool to the liver. Because avidin causes rapid trapping of the contrast agent in the liver, the blood pool cleared within 2 min of the injection of avidin. This system can be applied to all dendrimer-based macromolecular MRI contrast agents to investigate blood volume and vascular permeability. Moreover, it permits the repeated injection of the contrast agent and the "avidin switch" during a single MR experiment. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NCI, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, NIH, Bethesda, MD 20892 USA. NIDDKD, Renal Diagnost & Therapeut Univ, NIH, Bethesda, MD 20892 USA. Diagnost Radiol Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 23 TC 30 Z9 31 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD SEP-OCT PY 2003 VL 14 IS 5 BP 1044 EP 1047 DI 10.1021/bc034064l PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 723XP UT WOS:000185457100025 PM 13129410 ER PT J AU Phillips, ML Drevets, WC Rauch, SL Lane, R AF Phillips, ML Drevets, WC Rauch, SL Lane, R TI Neurobiology of emotion perception I: The neural basis of normal emotion perception SO BIOLOGICAL PSYCHIATRY LA English DT Review DE emotion; limbic; amygdala; ventral; dorsal; prefrontal ID ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; OBSESSIVE-COMPULSIVE DISORDER; FEARFUL FACIAL EXPRESSIONS; HUMAN ORBITOFRONTAL CORTEX; SCRIPT-DRIVEN IMAGERY; HUMAN AMYGDALA; HUMAN BRAIN; BASOLATERAL AMYGDALA; CONDITIONED FEAR AB There is at present limited understanding of the neurobiological basis of the different processes underlying emotion perception. We have aimed to identify potential neural correlates of three processes suggested by appraisalist theories as important for emotion perception: 1) the identification of the emotional significance of a stimulus; 2) the production of an affective state in response to 1; and 3) the regulation of the affective state. In a critical review, we have examined findings from recent animal, human lesion, and functional neuroimaging studies. Findings from these studies indicate that these processes may be dependent upon the functioning of two neural systems: a ventral system, including the amygdala, insula, ventral striatum, and ventral regions of the anterior cingulate gyrus and prefrontal cortex, predominantly important for processes 1 and 2 and automatic regulation of emotional responses; and a dorsal system, including the hippocampus and dorsal regions of anterior cingulate gyrus and prefrontal cortex, predominantly important for process 3. We suggest that the extent to which a stimulus is identified as emotive and is associated with the production of an affective state may be dependent upon levels of activity within these two neural systems. C1 Inst Psychiat, Div Psychol Med, London SE5 8AF, England. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ USA. RP Phillips, ML (reprint author), Inst Psychiat, Div Psychol Med, De Crespigny Pk, Denmark Hill, London SE5 8AF, England. NR 144 TC 1107 Z9 1136 U1 18 U2 163 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2003 VL 54 IS 5 BP 504 EP 514 DI 10.1016/S0006-3223(03)00168-9 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 714GZ UT WOS:000184906100002 PM 12946879 ER PT J AU Phillips, ML Drevets, WC Rauch, SL Lane, R AF Phillips, ML Drevets, WC Rauch, SL Lane, R TI Neurobiology of emotion perception II: Implications for major psychiatric disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE emotion; neuroanatomy; schizophrenia; bipolar disorder; depression ID CEREBRAL BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; SUBGENUAL PREFRONTAL CORTEX; BIPOLAR AFFECTIVE-DISORDER; HIPPOCAMPAL VOLUME REDUCTION; WORKING-MEMORY DYSFUNCTION; BRAIN METABOLIC CHANGES; MOOD DISORDERS; GLUCOSE-METABOLISM; DEPRESSED-PATIENTS AB To date, there has been little investigation of the neurobiological basis of emotion processing abnormalities in psychiatric populations. We have previously discussed two neural systems: 1) a ventral system, including the amygdala, insula, ventral striatum, ventral anterior cingulate gyrus, and prefrontal cortex, for identification of the emotional significance of a stimulus, production of affective states, and automatic regulation of emotional responses; and 2) a dorsal system, including the hippocampus, dorsal anterior cingulate gyrus, and prefrontal cortex, for the effortful regulation of affective states and subsequent behavior. In this critical review, we have examined evidence from studies employing a variety of techniques for distinct patterns of structural and Junctional abnormalities in these neural systems in schizophrenia, bipolar disorder, and major depressive disorder. In each psychiatric disorder, the pattern of abnormalities may be associated with specific symptoms, including emotional flattening, anhedonia, and persecutory delusions in schizophrenia, prominent mood swings, emotional lability and distractibility in bipolar disorder during depression and mania, and with depressed mood and anhedonia in major depressive disorder. We suggest that distinct patterns of structural and functional abnormalities in neural systems important for emotion processing are associated with specific symptoms of schizophrenia and bipolar and major depressive disorder. C1 Inst Psychiat, Div Psychol Med, London SE5 8AF, England. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ USA. RP Phillips, ML (reprint author), Inst Psychiat, Div Psychol Med, De Crespigny Pk, Denmark Hill, London SE5 8AF, England. NR 147 TC 951 Z9 975 U1 29 U2 145 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2003 VL 54 IS 5 BP 515 EP 528 DI 10.1016/S0006-3223(03)00171-9 PG 14 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 714GZ UT WOS:000184906100003 PM 12946880 ER PT J AU Penninx, BWJH Kritchevsky, SB Yaffe, K Newman, AB Simonsick, EM Rubin, S Ferrucci, L Harris, T Pahor, M AF Penninx, BWJH Kritchevsky, SB Yaffe, K Newman, AB Simonsick, EM Rubin, S Ferrucci, L Harris, T Pahor, M TI Inflammatory markers and depressed mood in older persons: Results from the Health, Aging and Body Composition study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE depression; inflammation; old age; interleukin-6; C-reactive protein; tumor necrosis factor alpha ID PITUITARY-ADRENAL AXIS; C-REACTIVE PROTEIN; ACUTE-PHASE PROTEINS; MAJOR DEPRESSION; CARDIOVASCULAR-DISEASE; PLASMA INTERLEUKIN-6; IMMUNE ACTIVATION; CANCER-PATIENTS; COMMUNITY; RISK AB Background: Patients with major depression have elevated levels of inflammatory cytokines. We examined the link between inflammatory markers and depressed mood in a community-based sample of older people. Methods: Data are from 3024 well-functioning older persons, 70-79 years of age, participating in the Health, Aging and Body Composition study. Depressed mood was defined as a Center for Epidemiologic Studies Depression scale score of 16 or higher. Plasma concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) were measured. Results: Compared with the 2879 nondepressed subjects, the 145 persons with depressed mood had higher median plasma levels of IL-6 (2.04 vs. 1.83 pg/mL, p=.02), TNF-alpha (3.43 vs. 3.16 pg/mL, p=.05), and CRP (1.96 vs. 1.66 mg/L, p=.03). After adjustment for health and demographic variables, depressed mood was especially prevalent among persons who had a high (above median) plasma level for at least two of the inflammatory markers. Compared with those without high levels, for persons with a high level for two or all three markers the risk of depressed mood was 2.45 (95% confidence interval [CI]=1.34-4.47) and 2.40 (95% CI=1.27-4.53), respectively. The association between depressed mood and serum level of IL-6 was significantly stronger in men than in women. Conclusions: In old age, depressed mood is associated with high levels of inflammatory markers, suggesting that depressed mood is causing and/or caused by systemic inflammation. C1 Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Natl Res Inst, Dept Geriatr, Florence, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Penninx, BWJH (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NIA NIH HHS [5P60 AG 10484-07, N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106] NR 39 TC 313 Z9 321 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2003 VL 54 IS 5 BP 566 EP 572 DI 10.1016/S0006-3223(03)01811-5 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 714GZ UT WOS:000184906100008 PM 12946885 ER PT J AU Dunson, DB Chen, Z Harry, J AF Dunson, DB Chen, Z Harry, J TI A Bayesian approach for joint modeling of cluster size and subunit-specific outcomes SO BIOMETRICS LA English DT Article DE continuation ratio; developmental toxicity; factor analysis; informative cluster size; litter size; multiple outcomes; probit model; random-length data ID LATENT VARIABLE MODELS; MULTIVARIATE BINARY DATA; LONGITUDINAL DATA; LITTER SIZE; DEVELOPMENTAL TOXICITY; REGRESSION-MODELS; RESIDUAL ANALYSIS; FETAL WEIGHT; TIME DATA; DISCRETE AB In applications that involve clustered data, such as longitudinal studies and developmental toxicity experiments, the number of subunits within a cluster is often correlated with outcomes measured on the individual subunits. Analyses that ignore this dependency can produce biased inferences. This article proposes a Bayesian framework for jointly modeling cluster size and multiple categorical and continuous outcomes measured on each subunit. We use a continuation ratio probit model for the cluster size and underlying normal regression models for each of the subunit-specific outcomes. Dependency between cluster size and the different outcomes is accommodated through a latent variable structure. The form of the model facilitates posterior computation via a simple and computationally efficient Gibbs sampler. The approach is illustrated with an application to developmental toxicity data, and other applications, to joint modeling of longitudinal and event time data, are discussed. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 49 Z9 51 U1 0 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2003 VL 59 IS 3 BP 521 EP 530 DI 10.1111/1541-0420.00062 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 719TE UT WOS:000185220100007 PM 14601753 ER PT J AU Dodd, LE Pepe, MS AF Dodd, LE Pepe, MS TI Partial AUC estimation and regression SO BIOMETRICS LA English DT Article DE diagnostic testing; Mann-Whitney U-statistic; regression; receiver operating characteristic curve ID OPERATING CHARACTERISTIC CURVES; PROSTATE-CANCER; DIAGNOSTIC-TESTS; ROC CURVES; MARKERS; AREA AB Accurate diagnosis of disease is a critical part of health care. New diagnostic and screening tests must be evaluated based on their abilities to discriminate diseased from nondiseased states. The partial area under the receiver operating characteristic (ROC) curve is a measure of diagnostic test accuracy. We present an interpretation of the partial area under the curve (AUC), which gives rise to a nonparametric estimator. This estimator is more robust than existing estimators, which make parametric assumptions. We show that the robustness is gained with only a moderate loss in efficiency. We describe a regression modeling framework for making inference about covariate effects on the partial AUC. Such models can refine knowledge about test accuracy. Model parameters can be estimated using binary regression methods. We use the regression framework to compare two prostate-specific antigen biomarkers and to evaluate the dependence of biomarker accuracy on the time prior to clinical diagnosis of prostate cancer. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Dodd, LE (reprint author), NCI, Biometr Res Branch, 6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [T32 HL07183]; NIGMS NIH HHS [R01 GM54438] NR 23 TC 148 Z9 151 U1 0 U2 9 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2003 VL 59 IS 3 BP 614 EP 623 DI 10.1111/1541-0420.00071 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 719TE UT WOS:000185220100016 PM 14601762 ER PT J AU Long, YQ Lung, FDT Roller, PP AF Long, YQ Lung, FDT Roller, PP TI Global optimization of conformational constraint on non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID SH2 DOMAIN; ADAPTER PROTEIN; HIGH-AFFINITY; BINDING; INHIBITORS; RECEPTOR; PHOSPHOTYROSINE; REQUIREMENTS; CANCER AB Following our earlier work on a phage library derived non-phosphorylated thioether-cyclized peptide inhibitor of Grb2 SH2 domain, a series of small peptide analogues with various cyclization linkage or various ring size were designed and synthesized and evaluated to investigate the optimal conformational constraint for this novel Grb2-SH2 blocker. Our previous SAR studies have indicated that constrained conformation as well as all amino acids except Leu(2) and Gly(7) in this lead peptide, cyclo(CH2CO-Glu(1)-Leu-Tyr-Glu-Asn-Val-Gly-Met-Tyr-Cys(10))-amide (termed GITE), was necessary for sustenance of the biological activity. In this study, in an effort to derive potent and bioavailable Grb2-SH2 inhibitor with minimal sequence, we undertook a systematic conformational study on this non-phosphorylated cyclic ligand by optimizing the ring linkage, ring configuration and ring size. The polarity and configuration of the cyclization linkage were implicated important in assuming the active conformation. Changing the flexible thioether linkage in G1TE into the relatively rigid sulfoxide linkage secured a 4-fold increase in potency (4, IC50= 6.5 muM). However, open chain, shortening or expanding the ring size led to a marked loss of inhibitory activity. Significantly, the introduction of omega-amino carboxylic acid linker in place of three C-terminal amino acids in G1TE can remarkably recover the apparently favorable conformation, which is otherwise lost because of the reduced ring size. This modification, combined with favorable substitutions of Gla for Glu(1) and Adi for Glu(4) in the resulting six-residue cyclic peptide, afforded peptide 19, with an almost equal potency (19, IC50 = 23.3 muM) relative to G1TE. Moreover, the lipophilic chain in omega-amino carboxylic acid may confer better cell membrane permeability to 19. These newly developed G1TE analogues with smaller ring size and less peptide character but equal potency can serve as templates to derive potent and specific non-phosphorylated Grb2-SH2 antagonists. (C) 2003 Elsevier Ltd. All rights reserved. C1 Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China. NCI, Med Chem Lab, Div Basic Sci, NIH,FCRDC, Frederick, MD 21702 USA. RP Long, YQ (reprint author), Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China. NR 23 TC 22 Z9 23 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 1 PY 2003 VL 11 IS 18 BP 3929 EP 3936 DI 10.1016/S0968-0896(03)00411-5 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 716PQ UT WOS:000185037900009 PM 12927853 ER PT J AU Grimm, JB Stables, JP Brown, ML AF Grimm, JB Stables, JP Brown, ML TI Design, synthesis, and development of novel caprolactam anticonvulsants SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID QUANTITATIVE STRUCTURE-ACTIVITY; CHANNELS; BINDING AB Epilepsy afflicts 1-2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, alpha-hydroxy-alpha-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED50 = 63 mg/kg and anti-subcutaneous Metrazol (scMet) ED50 = 74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques-including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach-in the hopes of determining the effect of caprolactam alpha-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: alpha-ethynyl-alpha-hydroxycaprolactam (10), alpha-benzyl-alpha-hydroxycaprolactam (11), and alpha-hydroxy-alpha-(phenylethynyl)caprolactam (13). Phase II results for II strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. NINDS, Anticonvulsant Drug Dev Program, Bethesda, MD 20892 USA. RP Brown, ML (reprint author), Univ Virginia, Dept Chem, Mccormick Rd,POB 400319, Charlottesville, VA 22904 USA. NR 9 TC 11 Z9 13 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 1 PY 2003 VL 11 IS 18 BP 4133 EP 4141 DI 10.1016/S0968-0896(03)00400-0 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 716PQ UT WOS:000185037900031 PM 12927875 ER PT J AU Ananthan, S Khare, NK Saini, SK Davis, P Dersch, CM Porreca, F Rothman, RB AF Ananthan, S Khare, NK Saini, SK Davis, P Dersch, CM Porreca, F Rothman, RB TI Novel ligands for the opioid receptors: Synthesis and structure-activity relationships among 5 '-aryl and 5 '-heteroaryl 17-cyclopropylmethyl-4,5 alpha-epoxypyrido[2 ',3 ': 6,7]morphinans SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID MESSAGE ADDRESS CONCEPT; ANTAGONISTS; BINDING; NALTRINDOLE; AFFINITY; AGONIST; SUBSTITUENT; SELECTIVITY; ANALOGS; DESIGN AB A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5'-position of the pyridine ring of 17-cyclopropylmethyl-4,5alpha-epoxypyrido[2,3:6,7]morphinan was synthesized and evaluated for binding and functional activity at the opioid delta, mu, and kappa receptors. All of these pyridomorphinans bound with higher affinity at the delta site than at mu or kappa sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (101), 2-nitrophenyl (10n), 2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the delta receptor with subnanomolar affinity. Compound 10c with the p-tolyl substituent displayed the highest mu/delta selectivity (ratio = 42) whereas compound 101 with the 2-chlorophenyl substituent displayed the highest kappa/delta selectivity (ratio 23). At 10 muM concentration, the in vitro functional activity determined using [S-35]GTP-gamma-S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the delta, mu, and kappa receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent 6 selective antagonist. In the [S-35]GTP-7-S assays this compound had a functional antagonist K-i value of 0.2, 4.52, and 7.62 nM at the delta, mu, and kappa receptors, respectively. In the smooth muscle assays 10c displayed delta antagonist potency with a K-e value of 0.88 nM. As an antagonist, it was 70-fold more potent at the 6 receptors in the MVD than at the mu receptors in the GPI. The in vitro delta antagonist profile of this pyridomorphinan 10c resembles that of the widely used delta selective antagonist ligand naltrindole. (C) 2003 Elsevier Ltd. All rights reserved. C1 So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. Natl Inst Drug Abuse, Clin Psychopharmacol Sect, IRP, Baltimore, MD 21224 USA. RP Ananthan, S (reprint author), So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. NR 38 TC 5 Z9 5 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 1 PY 2003 VL 11 IS 18 BP 4143 EP 4154 DI 10.1016/S0968-0896(03)00432-2 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 716PQ UT WOS:000185037900032 PM 12927876 ER PT J AU Xia, Y Yang, ZY Xia, P Bastow, KF Nakanishi, Y Nampoothiri, P Hamel, E Brossi, A Lee, KH AF Xia, Y Yang, ZY Xia, P Bastow, KF Nakanishi, Y Nampoothiri, P Hamel, E Brossi, A Lee, KH TI Antitumor agents. Part 226: Synthesis and cytotoxicity of 2-phenyl-4-quinolone acetic acids and their esters SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID BIOLOGICAL EVALUATION; TUBULIN AB 2-Phenyl-4-quinolone acetic acids and their esters were synthesized and evaluated for interaction with tubulin and for cytotoxicity against a panel of human tumor cell lines. 2-Phenyl- and 2-(2'-fluorophenyl)-4-quinolone-8-acetic acids (11 and 12) displayed potent cytotoxicity with ED50 values at nanomolar concentrations, but had minimal activity against tubulin polymerization. 2-(2'-Fluorophenyl)-4-quinolone-6-acetic acid (3) and 2-(2'-fluorophenyl)-4-quinolone-8-acetic acid methyl ester (10) moderately inhibited tubulin polymerization. (C) 2063 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, Sch Pharm, Natl Prod Lab, Chapel Hill, NC 27599 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Natl Prod Lab, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA-17625] NR 13 TC 48 Z9 49 U1 0 U2 0 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 SEP 1 PY 2003 VL 13 IS 17 BP 2891 EP 2893 DI 10.1016/S0960-894X(03)00624-3 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 713NT UT WOS:000184865300016 PM 14611851 ER PT J AU Graziano, G Lee, B AF Graziano, G Lee, B TI Entropy convergence in hydrophobic hydration: a scaled particle theory analysis SO BIOPHYSICAL CHEMISTRY LA English DT Article DE entropy convergence; work of cavity creation; scaled particle theory; general condition for entropy convergence ID TEMPERATURE-DEPENDENCE; LIQUID WATER; PROTEIN DENATURATION; AQUEOUS SOLUTIONS; NONPOLAR SOLUTES; HEAT-CAPACITY; FREE-ENERGIES; THERMODYNAMICS; MODEL; SOLUBILITY AB The occurrence of entropy convergence in hydrophobic hydration is verified from available experimental thermodynamic data for both noble gases and hydrocarbons. The entropy convergence phenomenon can be reproduced by means of the scaled particle theory, provided that a temperature-dependent hard sphere diameter is used for water molecules. The calculated work of cavity creation shows a non-monotonic temperature dependence with a flat maximum slightly above 100 degreesC, irrespective of the cavity size. The corresponding cavity entropy changes converge approximately 100 degreesC, in qualitative agreement with the experimental finding. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Sannio, Facsci, I-82100 Benevento, Italy. RP Lee, B (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bldg 37,Room 5120,37 Convent Dr,MSC 4262, Bethesda, MD 20892 USA. OI Graziano, Giuseppe/0000-0001-6935-8172 NR 50 TC 39 Z9 39 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD SEP PY 2003 VL 105 IS 2-3 BP 241 EP 250 DI 10.1016/S0301-4622(03)00073-5 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 725LV UT WOS:000185545400015 PM 14499896 ER PT J AU Mitkevich, VA Schulga, AA Ermolyuk, YS Lobachov, VM Chekhov, VO Yakovlev, GI Hartley, RW Pace, CN Kirpichnikov, MP Makarov, AA AF Mitkevich, VA Schulga, AA Ermolyuk, YS Lobachov, VM Chekhov, VO Yakovlev, GI Hartley, RW Pace, CN Kirpichnikov, MP Makarov, AA TI Thermodynamics of denaturation of complexes of barnase and binase with barstar SO BIOPHYSICAL CHEMISTRY LA English DT Article DE barnase; binase; barstar; protein-protein complex; electrostatic interactions; thermal stability ID BACTERIAL RIBONUCLEASE; HEAT DENATURATION; INHIBITOR; STABILITY AB Differential scanning calorimetry was used to study the thermodynamics of denaturation of protein complexes for which the free energy stabilizing the complexes varied between -8 and -16 kcal/mol. The proteins studied were the ribonucleases barnase and binase, their inhibitor barstar and mutants thereof, and complexes between the two. The results are in good agreement with the model developed by Brandts and Lin for studying the thermodynamics of denaturation for tight complexes between two proteins which undergo two-state thermal unfolding transitions. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Texas A&M Univ, Dept Med Biochem & Genet, College Stn, TX 77843 USA. Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117871, Russia. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Pace, CN (reprint author), Texas A&M Univ, Dept Med Biochem & Genet, College Stn, TX 77843 USA. RI Makarov, Alexander/P-5279-2016 FU FIC NIH HHS [TW01058]; NIGMS NIH HHS [GM37039] NR 15 TC 16 Z9 16 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD SEP PY 2003 VL 105 IS 2-3 BP 383 EP 390 DI 10.1016/S0301-4622(03)00103-0 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 725LV UT WOS:000185545400025 PM 14499906 ER PT J AU Mittal, A Leikina, E Chernomordik, LV Bentz, J AF Mittal, A Leikina, E Chernomordik, LV Bentz, J TI Kinetically differentiating influenza hemagglutinin fusion and hemifusion machines SO BIOPHYSICAL JOURNAL LA English DT Article ID MEDIATED MEMBRANE-FUSION; PORE FORMATION; STALK MODEL; TRANSITION; ACTIVATION; TRIMERS; DOMAIN AB Membrane fusion mediated by influenza virus hemagglutinin (HA) yields different phenotypes depending on the surface density of activated HAs. A key question is whether different phenotypes arise from different fusion machines or whether different numbers of identical fusion machines yield different probabilistic outcomes. If fusion were simply a less probable event than hemifusion, requiring a larger number of identical fusion machines to occur first, then two predictions can be made. First, fusion should have a shorter average delay time than hemifusion, since there are more machines. Second, fusion should have a longer execution time of lipid mixing after it begins than hemifusion, since the full event cannot be faster than the partial event. Using a new automated video microscopy technique, we simultaneously monitored many HA-expressing cells fusing with erythrocytes and identified individual cell pairs with either full or only partial redistribution of fluorescent lipids. The full lipid mixing phenotype also showed contents mixing, i.e., fusion. Kinetic screening of the digitized fluorescence data showed that the execution of lipid mixing after the onset is faster for fusion than hemifusion. We found no correlation between the delay times before the onset of lipid mixing and the final fusion phenotype. We also found that the execution time for fusion was faster than that for hemifusion. Thus, we provide the first experimental evidence for fusion and hemifusion arising from different machines. C1 Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Bentz, J (reprint author), Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. RI Mittal, Aditya/E-3087-2010 OI Mittal, Aditya/0000-0002-4030-0951 NR 33 TC 27 Z9 27 U1 1 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2003 VL 85 IS 3 BP 1713 EP 1724 DI 10.1016/S0006-3495(03)74601-3 PG 12 WC Biophysics SC Biophysics GA 716BX UT WOS:000185009900033 PM 12944286 ER PT J AU Frolov, VA Dunina-Barkovskaya, AY Samsonov, AV Zimmerberg, J AF Frolov, VA Dunina-Barkovskaya, AY Samsonov, AV Zimmerberg, J TI Membrane permeability changes at early stages of influenza hemagglutinin-mediated fusion SO BIOPHYSICAL JOURNAL LA English DT Article ID BROWNIAN DYNAMICS SIMULATION; VIRAL ENVELOPE PROTEIN; CELL-CELL FUSION; PORE FORMATION; STALK MODEL; MAST-CELLS; VIRUS; HEMIFUSION; EXOCYTOSIS; EVENTS AB While biological membrane fusion is classically defined as the leak-free merger of membranes and contents, leakage is a finding in both experimental and theoretical studies. The fusion stages, if any, that allow membrane permeation are uncharted. In this study we monitored membrane ionic permeability at early stages of fusion mediated by the fusogenic protein influenza hemagglutinin (HA). HAb2 cells, expressing HA on their plasma membrane, fused with human red blood cells, cultured liver cells PLC/PRF/5, or planar phospholipid bilayer membranes. With a probability that depended upon the target membrane, an increase of the electrical conductance of the fusing membranes (leakage) by up to several nS was generally detected. This leakage was recorded at the initial stages of fusion, when fusion pores formed. This leakage usually accompanied the "flickering'' stage of the early fusion pore development. As the pore widened, the leakage reduced; concomitantly, the lipid exchange between the fusing membranes accelerated. We conclude that during fusion pore formation, HA locally and temporarily increases the permeability of fusing membranes. Subsequent rearrangement in the fusion complex leads to the resealing of the leaky membranes and enlargement of the pore. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, AN Frumkin Inst Electrochem, Moscow, Russia. Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow, Russia. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, 10-10D14,10 Ctr Dr,SC 1855, Bethesda, MD 20892 USA. OI Frolov, Vadim/0000-0002-0653-5669 NR 50 TC 51 Z9 51 U1 2 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2003 VL 85 IS 3 BP 1725 EP 1733 DI 10.1016/S0006-3495(03)74602-5 PG 9 WC Biophysics SC Biophysics GA 716BX UT WOS:000185009900034 PM 12944287 ER PT J AU Gaede, HC Gawrisch, K AF Gaede, HC Gawrisch, K TI Lateral diffusion rates of lipid, water, and a hydrophobic drug in a multilamellar liposome SO BIOPHYSICAL JOURNAL LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; NOESY CROSS-RELAXATION; GRADIENT-SPIN-ECHO; TRANSLATIONAL DIFFUSION; LIQUID-CRYSTALS; MODEL MEMBRANES; LAMELLAR PHASE; NMR; BILAYER; PHOSPHOLIPIDS AB The lateral diffusion constants of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine ( POPC), water, and ibuprofen were measured in multilamellar liposomes using pulsed field gradient magic-angle spinning (PFG-MAS) H-1 NMR. The analysis of diffusion data obtained in powder samples and a method for liposome curvature correction are presented. At 322 K POPC has a diffusion constant of (8.6 +/- 0.2) x 10(-12) m(2)/s when dehydrated (8.2 waters/lipid) and (1.9 +/- 0.1) x 10(-11) m(2)/s in excess water. The diffusion constant of water in dehydrated POPC was found to be (4.7 +/- 0.1) x 10(-10) m(2)/s. The radius of curvature is 21 +/- 2 mum for the dehydrated sample and 4.5 +/- 0.5 mum for POPC sample containing excess water. The activation energies of diffusion are 40.6 +/- 0.4 kJ/mole for dehydrated POPC, 30.7 +/- 0.9 kJ/mole for POPC with excess water, and 28.6 +/- 1.5 kJ/mole for water in dehydrated POPC. The diffusion constants and activation energies for a sample of POPC/ibuprofen/water (1:0.56:15) were also measured. The ibuprofen, which locates in the lipid-water interface, diffuses faster than POPC but has a slightly higher activation energy of lateral diffusion. Within certain restrictions, PFG-MAS NMR provides a useful method for characterizing membrane organization and mobility. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Rm 150, Rockville, MD 20852 USA. RI Gaede, Holly/B-7392-2015 OI Gaede, Holly/0000-0003-4444-4394 NR 32 TC 105 Z9 111 U1 1 U2 31 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2003 VL 85 IS 3 BP 1734 EP 1740 DI 10.1016/S0006-3495(03)74603-7 PG 7 WC Biophysics SC Biophysics GA 716BX UT WOS:000185009900035 PM 12944288 ER PT J AU Cai, HX Richter, CP Chadwick, RS AF Cai, HX Richter, CP Chadwick, RS TI Motion analysis in the hemicochlea SO BIOPHYSICAL JOURNAL LA English DT Article ID TECTORIAL MEMBRANE; OPTICAL-FLOW; MODEL; ORGAN; CORTI AB Optical flow techniques are often used to estimate velocity fields to represent motion in successive video images. Usually the method is mathematically ill-posed, because the single scalar equation representing the conservation of local intensity contains more than one unknown velocity component. Instead of regularizing the problem using optimization techniques, we formulate a well-posed problem for the gerbil hemicochlea preparation by introducing an in-plane incompressibility constraint, and then show that local brightness is also conserved. We solve the resulting system using a Lagrangian description of the conservation equations. With this approach, the displacement of isointensity contours on sequential images determines the normal component of velocity of an area element, while the tangential component is computed from the local constant area constraint. We have validated our method using pairs of images generated from our calculations of the vibrational deformation in a cross section of the organ of Corti and tectorial membrane in the mammalian cochlea, and quantified the superior performance of our method when complex artificial motion is applied to a noisy image obtained from the hemicochlea preparation. The micromechanics of the organ of Corti and the tectorial membrane is then analyzed by our new method. C1 NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Dept Otolaryngol, Chicago, IL 60611 USA. RP Chadwick, RS (reprint author), NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. RI Richter, Claus-Peter/B-4641-2012 NR 26 TC 17 Z9 18 U1 1 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 2003 VL 85 IS 3 BP 1929 EP 1937 DI 10.1016/S0006-3495(03)74620-7 PG 9 WC Biophysics SC Biophysics GA 716BX UT WOS:000185009900052 PM 12944305 ER PT J AU Hausmann, M Winkler, R Hildenbrand, G Finsterle, J Weisel, A Rapp, A Schmitt, E Janz, S Cremer, C AF Hausmann, M Winkler, R Hildenbrand, G Finsterle, J Weisel, A Rapp, A Schmitt, E Janz, S Cremer, C TI COMBO-FISH: specific labeling of nondenatured chromatin targets by computer-selected DNA oligonucleotide probe combinations SO BIOTECHNIQUES LA English DT Article ID TRIPLE-HELIX FORMATION; IN-SITU HYBRIDIZATION; MONOCLONAL-ANTIBODY; GENE ACTIVITY; LIVING CELLS; SEQUENCE; CHROMOSOMES; MICROSCOPY; NUCLEI; VISUALIZATION AB Here we present the principle of fluorescence in situ hybridization (FISH) with combinatorial oligonucleotide (COMBO) probes as a new approach for the specific labeling of genomic sites. COMBO-FISH takes advantage of homopurine/homopyrimidine oligonucleotides that form triple helices with intact duplex genomic DNA, without the need for prior denaturation of the target sequence that is usually applied for probe binding in standard FISH protocols. An analysis of human genome databases has shown that homopurine/homopyrimidine sequences longer than 14 by are nearly homogeneously distributed over the genome, and they represent from 1% to 2% of the entire genome. Because the observation volume in a confocal laser-scanning microscope equipped with a high numerical aperture lens typically corresponds to an approximate 250-kb chromatin domain in a normal mammalian cell nucleus, this volume should contain 150-200 homopurine/homopyrimidine stretches. Using DNA database information, one can configure a set of distinct, uniformly labeled oligonucleotide probes from, these stretches that is expected to exclusively co-localize within a 250-kb chromatin domain. Due to the diffraction-limited resolution of a microscope, the fluorescence signals of the configured oligonucleotide probe set merge into a typical, nearly homogeneous FISH spot. Using a set of 32 homopyrimidine probes, we performed experiments in the Abelson murine leukemia region of human chromosome 9 as some of the very first proofs-of-principle of COMBO-FISH. Although the experimental protocol currently contains several steps that are incompatible with living cell conditions, the theoretical approach may be the first methodological advance toward the long-term but still elusive goal of carrying out specific FISH in high-resolution fluorescence microscopy of vital cells. C1 Univ Heidelberg, Kirchhoff Inst Phys, Heidelberg, Germany. Inst Mol Biotechnol, Jena, Germany. NIH, Bethesda, MD USA. Univ Hosp Freiburg, Inst Pathol, Freiberg, Germany. RP Hausmann, M (reprint author), Inst Pathol, Albertstr 19, D-79104 Freiberg, Germany. RI Rapp, Alexander/F-5327-2012 OI Rapp, Alexander/0000-0001-9108-3929 NR 52 TC 32 Z9 32 U1 2 U2 7 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2003 VL 35 IS 3 BP 564 EP + PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 721UR UT WOS:000185337300020 PM 14513562 ER PT J AU Jia, WT Yu, CR Rahmani, M Krystal, G Sausville, EA Dent, P Grant, S AF Jia, WT Yu, CR Rahmani, M Krystal, G Sausville, EA Dent, P Grant, S TI Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways SO BLOOD LA English DT Article ID PROTEIN-KINASE-C; HUMAN LEUKEMIA-CELLS; GLYCOGEN-SYNTHASE KINASE-3; BREAST-CANCER CELLS; SELECTIVE INHIBITOR; SIGNAL-TRANSDUCTION; ANTITUMOR-ACTIVITY; INDUCED APOPTOSIS; PHARMACOLOGICAL INHIBITORS; MITOCHONDRIAL DYSFUNCTION AB Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis. Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (le, loss of mitochondrial membrane potential [DeltaPsi(m)]; cytosolic release of cytochrome c), caspase activation, and apoptosis. Synergistic induction of apoptosis was also observed in other human leukemia cell types (eg, Jurkat, NB4). Coexposure of human leukemia cells to 17-AAG and the PKC inhibitor bisindolyl-maleimide (GFX) did not result in enhanced lethality, arguing against the possibility that the PKC 1 inhibitory actions of UCN-01 are responsible for synergistic interactions. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation. of Raf-1, MEK1/2, and mitogen-activated protein kinase (MAP K). Coadministration of 17-AAG and UCN-01 did not modify expression of Hsp90, Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further p34(cdc2) dephosphorylation and diminished expression of Bcl-2, Mcl-1, and XIAP. In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality. Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon. C1 Virginia Commonwealth Univ, Med Coll Virginia, Div Hematol Oncol, Dept Med, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Grant, S (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Div Hematol Oncol, Dept Med, MCV Stn Box 230, Richmond, VA 23298 USA. FU NCI NIH HHS [CA 63753, CA 93738] NR 60 TC 77 Z9 79 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2003 VL 102 IS 5 BP 1824 EP 1832 DI 10.1182/blood-2002-12-3785 PG 9 WC Hematology SC Hematology GA 714ZH UT WOS:000184945200048 PM 12738674 ER PT J AU Westervelt, P Lane, AA Pollock, JL Oldfather, K Holt, MS Zimonjic, DB Popescu, NC DiPersio, JF Ley, TJ AF Westervelt, P Lane, AA Pollock, JL Oldfather, K Holt, MS Zimonjic, DB Popescu, NC DiPersio, JF Ley, TJ TI High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RAR alpha expression SO BLOOD LA English DT Article ID CATHEPSIN-G GENE; TRANSGENIC MICE; FUSION PROTEIN; PML/RAR-ALPHA; CHROMOSOMAL-ABNORMALITIES; GLOBIN GENE; CELLS; PATHOGENESIS; DIFFERENTIATION; APL AB Transgenic mice expressing PML-RARalpha in early myeloid cells under control of human cathepsin G regulatory sequences all develop a myeloproliferative syndrome, but only 15% to 20% develop acute promyelocytic leukemia (APL) after a latent period of 6 to 14 months. However, this transgene is expressed at very low levels in the bone marrow cells of transgenic mice. Because the transgene includes only 6 kb of regulatory sequences from the human cathepsin G locus, we hypothesized that sequences required for high-level expression of the transgene might be located elsewhere in the cathepsin G locus and that a knock-in model might yield much higher expression levels and higher penetrance of disease. We, therefore, targeted a human PML-RARalpha cDNA to the 5' untranslated region of the murine cathepsin G gene, using homologous recombination in embryonic stem cells. This model produced a high-penetrance APL phenotype, with more than 90% of knock-in mice developing APL between 6 and 16 months of age. The latent period and phenotype of APL (including a low frequency of an interstitial deletion of chromosome 2) was similar to that of the previous transgenic model. Remarkably, however, the expression level of PML-RARalpha in bone marrow cells or APL cells was less than 3% of that measured in the low-penetrance transgenic model. Although the explanation for this result is not yet clear, one hypothesis suggests that very low levels of PML-RARalpha expression in early myeloid cells may be optimal for the development of APL in mice. C1 Washington Univ, Sch Med, Dept Med, Div Oncol,Siteman Canc Ctr, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Genet, Siteman Canc Ctr, St Louis, MO 63110 USA. NCI, Mol Cytogenet Sect, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Ley, TJ (reprint author), Washington Univ, Sch Med, Dept Med, Div Oncol,Siteman Canc Ctr, 660 S Euclid Ave,Campus Box 8007, St Louis, MO 63110 USA. FU NCI NIH HHS [CA83962]; NHLBI NIH HHS [HL0399102, T32 HLO 7088] NR 33 TC 97 Z9 100 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 SEP 1 PY 2003 VL 102 IS 5 BP 1857 EP 1865 DI 10.1182/blood-2002-12-3779 PG 9 WC Hematology SC Hematology GA 714ZH UT WOS:000184945200052 PM 12750176 ER PT J AU Bourdon, E Kang, DK Ghosh, MC Drake, SK Wey, J Levine, RL Rouault, TA AF Bourdon, E Kang, DK Ghosh, MC Drake, SK Wey, J Levine, RL Rouault, TA TI The role of endogenous heme synthesis and degradation domain cysteines in cellular iron-dependent degradation of IRP2 SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article ID REGULATORY PROTEIN-2; NITRIC-OXIDE; FERRITIN SYNTHESIS; BINDING PROTEIN; METABOLISM; TISSUE; ALPHA; MICE AB Iron regulatory protein 2 (IRP2) is a mammalian cytosolic iron-sensing protein that regulates expression of iron metabolism proteins, including ferritin and transferrin receptor 1. IRP2 is ubiquitinated and degraded by the proteasome in iron-replete cells but is relatively stable in iron-depleted cells. Recent work has shown that IRP2 contains a unique 73-amino-acid domain that binds iron in vitro and undergoes iron-dependent oxidation and cleavage (J. Biol. Chem. 278 (2003), 14857). Several cysteines in the 73-amino-acid domain function as an in vitro iron-binding site. To assess the role of these cysteines in cellular iron- dependent degradation of IRP2, we mutagenized these cysteines in various combinations in the context of full-length protein and generated cell lines in which recombinant IRP2 expression was inducible. Iron-dependent degradation of IRP2 mutagenized at any or all of the cysteines of the putative degradation domain in cells was comparable to wild-type (WT). Both WT and cysteine mutant protein were stabilized in 3% oxygen. Treatment with sodium nitroprusside (SNP), an NO+ donor, caused a decrease in cellular IRP2 concentrations, but the SNP effect was abrogated by simultaneous addition of the iron chelator desferal and was not affected by cysteine mutations. Inhibition of endogenous heme synthesis with succinylacetone significantly inhibited iron- dependent degradation of IRP2. Addition of cobalt chloride inhibited degradation of both WT and mutagenized IRP2. Thus, we could not discern a role for the recently defined in vitro cysteine-dependent iron-binding site of IRP2 in cellular physiology. The early molecular events in iron-dependent degradation of IRP2 remain to be elucidated. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD USA. NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 24 TC 40 Z9 42 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD SEP-OCT PY 2003 VL 31 IS 2 BP 247 EP 255 DI 10.1016/S1079-9796(03)00161-X PG 9 WC Hematology SC Hematology GA 723RF UT WOS:000185444800014 PM 12972033 ER PT J AU Riminucci, A Kuznetsov, SA Cherman, N Corsi, A Bianco, P Robey, PG AF Riminucci, A Kuznetsov, SA Cherman, N Corsi, A Bianco, P Robey, PG TI Osteoclastogenesis in fibrous dysplasia of bone: in situ and in vitro analysis of IL-6 expression SO BONE LA English DT Article DE bone disease; bone histology; cAMP; osteoclasts; stromal cells ID MCCUNE-ALBRIGHT SYNDROME; STIMULATORY G-PROTEIN; PARATHYROID-HORMONE; PAGETS-DISEASE; INTRAVENOUS PAMIDRONATE; ACTIVATING MUTATIONS; MESSENGER-RNA; INTERLEUKIN-6; RESORPTION; CELLS AB Fibrous dysplasia of bone (FD) is caused by somatic mutations of the GNAS1 gene, which lead to constitutive activation of adenylyl cyclase and overproduction of cAMP in osteogenic cells. Previous in vitro studies using nonclonal, heterogeneous strains of FD-derived cells suggested that IL-6 might play a critical role in promoting excess osteoclastogenesis in FD. In this study, we investigated IL-6 expression in FD in situ and its relationship to the actual patterns of osteoclastogenesis within the abnormal tissue. We found that osteoclastogenesis is not spatially restricted to bone surfaces in FD but occurs to a large extent ectopicly in the fibrous tissue, where stromal cells diffusely express IL-6 mRNA and exhibit a characteristic cell morphology. We also observed specific expression of IL-6 mRNA in a proportion of osteoclasts, suggesting that an autocrine/paracrine loop may contribute to osteoclastogenesis in vivo in FD, as in some other bone diseases, including Paget's disease. We also generated homogeneous, clonally derived strains of wild-type and GNAS1-mutated stromal cells from the same individual, parent FD lesions. In this way, we could show that mutated stromal cells produce IL-6 at a basal magnitude and rate that are significantly higher than in the cognate wild-type cells. Conversely, wild-type cells respond to db-cAMP with a severalfold increase in magnitude and rate of IL-6 production, whereas mutant strains remain essentially unresponsive. Our data establish a direct link between GNAS1 mutations in stromal cells and IL-6 production but also define the complexity of the role of IL-6 in regulating osteoclastogenesis in FD in vivo. Here, patterns of osteoclastogenesis and bone resorption reflect not only the cell-autonomous effects of GNAS1 mutations in osteogenic cells (including IL-6 production) but also the local and systemic context to which non-osteogenic cells, local proportions of wild-type vs mutated cells, and systemic hormones contribute. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIDCR, CSDB, NIH, DHHS, Bethesda, MD 20892 USA. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Parco Sci Biomed San Raffaele, I-00100 Rome, Italy. Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. RP Robey, PG (reprint author), NIDCR, CSDB, NIH, DHHS, 30 Convent Dr MSC 4320, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Fondazione Telethon NR 29 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2003 VL 33 IS 3 BP 434 EP 442 DI 10.1016/S8756-3282(03)00064-4 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 725MA UT WOS:000185545900023 ER PT J AU Catani, M Jones, DK Donato, R ffytche, DH AF Catani, M Jones, DK Donato, R ffytche, DH TI Occipito-temporal connections in the human brain SO BRAIN LA English DT Article DE tractography; inferior longitudinal fasciculus; occipito-temporal connections ID DIFFUSION-TENSOR MRI; AUTOMATED IMAGE REGISTRATION; TEMPORAL-LOBE; VISUAL HYPOEMOTIONALITY; DISCONNEXION SYNDROMES; MACACA-FASCICULARIS; AXONAL PROJECTIONS; HUMAN AMYGDALA; PATHWAYS; CORTEX AB Diffusion tensor MRI (DT-MRI) provides information about the structural organization and orientation of white matter fibres and, through the technique of 'tractography', reveals the trajectories of cerebral white matter tracts. We used tractography in the living human brain to address the disputed issue of the nature of occipital and temporal connections. Classical anatomical studies described direct fibre connections between occipital and anterior temporal cortex in a bundle labelled the inferior longitudinal fasciculus (ILF). However, their presence has been challenged by more recent evidence suggesting that connections between the two regions are entirely indirect, conveyed by the occipito-temporal projection system-a chain of U-shaped association fibres. DT-MRI data were collected from 11 right-handed healthy subjects (mean age 33.3 +/- 4.7 years). Each data set was co-registered with a standard MRI brain template, and a group-averaged DT-MRI data set was created. 'Virtual' in vivo dissection of occipito-temporal connections was performed in the group-averaged data. Further detailed virtual dissection was performed on the single brain data sets. Our results suggest that in addition to the indirect connections of the occipito-temporal projection system: (i) a major associative connection between the occipital and anterior temporal lobe is provided by a fibre bundle whose origin, course and termination are consistent with classical descriptions of the ILF in man and with monkey visual anatomy; (ii) the tractography-defined ILF is structurally distinct from fibres of the optic radiation and from U-shaped fibres connecting adjacent gyri; (iii) it arises in extrastriate visual 'association' areas; and (iv) it projects to lateral and medial anterior temporal regions. While the function of the direct ILF pathway is unclear, it appears to mediate the fast transfer of visual signals to anterior temporal regions and neuromodulatory back-projections from the amygdala to early visual areas. Future tractography studies of patients with occipito-temporal disconnection syndromes may help define the functional roles of the direct and indirect occipito-temporal pathways. C1 Inst Psychiat, London SE5 8AF, England. NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Perugia, Dept Expt Med & Biochem Sci, Sect Anat, I-06100 Perugia, Italy. RP Catani, M (reprint author), Inst Psychiat, De Crespigny Pk, London SE5 8AF, England. RI Jones, Derek/D-1460-2009; Catani, Marco/H-7801-2012; OI Catani, Marco/0000-0002-5488-6463; ffytche, Dominic/0000-0002-4214-9642; Jones, Derek/0000-0003-4409-8049 NR 66 TC 445 Z9 457 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2003 VL 126 BP 2093 EP 2107 DI 10.1093/brain/awg203 PN 9 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 718LJ UT WOS:000185147400023 PM 12821517 ER PT J AU Winterer, G Goldman, D AF Winterer, G Goldman, D TI Genetics of human prefrontal function SO BRAIN RESEARCH REVIEWS LA English DT Review DE genetics; COMT; intelligence; prefrontal function; endophenotype ID FRAGILE-X-SYNDROME; CATECHOL-O-METHYLTRANSFERASE; APOLIPOPROTEIN-E POLYMORPHISM; MENTAL-RETARDATION PROTEIN; GENERAL COGNITIVE-ABILITY; TO-NOISE RATIO; HUMAN INTELLIGENCE DIFFERENCES; EVENT-RELATED POTENTIALS; TEST-RETEST RELIABILITY; MONOAMINE-OXIDASE-A AB Evolution of the prefrontal cortex was an essential precursor to civilization. During the past decade, it became increasingly obvious that human prefrontal function is under substantial genetic control. In particular, heritability studies of frontal lobe-related neuropsychological function, electrophysiology and neuroimaging have greatly improved our insight. Moreover, the first genes that are relevant for prefrontal function such as catechol-O-methyltransferase (COMT) are currently discovered. In this review, we summarize the present knowledge on the genetics of human prefrontal function. For historical reasons, we discuss the genetics of prefrontal function within the broader concept of general cognitive ability (intelligence). Special emphasis is also given to methodological concerns that need to be addressed when conducting research on the genetics of prefrontal function in humans. Published by Elsevier B.V. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Winterer, G (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4s229A MSC 1379, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 374 TC 85 Z9 88 U1 12 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD SEP PY 2003 VL 43 IS 1 BP 134 EP 163 DI 10.1016/S0165-0173(03)00205-4 PG 30 WC Neurosciences SC Neurosciences & Neurology GA 738ZE UT WOS:000186317100009 PM 14499466 ER PT J AU Zujewski, JA Eng-Wong, J O'Shaughnessy, J Venzon, D Chow, C Danforth, D Kohler, DR Cusack, G Riseberg, D Cowan, KH AF Zujewski, JA Eng-Wong, J O'Shaughnessy, J Venzon, D Chow, C Danforth, D Kohler, DR Cusack, G Riseberg, D Cowan, KH TI A pilot study of dose intense doxorubicin and cyclophosphamide followed by infusional paclitaxel in high-risk primary breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; dose dense chemotherapy; neoadjuvant chemotherapy ID COLONY-STIMULATING FACTOR; SURGICAL ADJUVANT BREAST; STAGE-II; PHASE-II; CHEMOTHERAPY; THERAPY; TRIAL; INTENSIFICATION; ESCALATION; CARCINOMA AB We conducted a pilot study of dose dense doxorubicin and cyclophosphamide (AC) combination chemotherapy followed by infusional paclitaxel ( T) in primary breast cancer to determine its safety and feasibility. Twenty-two subjects (10 with stage II and greater than or equal to4 positive lymph nodes, and 12 with stage III disease) were treated with AC (A 60 mg/m(2) and C 2000 mg/m(2)) with filgrastim every 14 days for three cycles followed by infusional paclitaxel (140 mg/m(2) over 96 h) every 14 days for three cycles. Mean overall cycle length was 15.3 days and mean duration of therapy was 92 days. Dose reductions of C or T were required in 7/132 (5.3%) cycles for mucositis, diarrhea, or failure to recover platelets by day 15. Ninety-five percent of subjects had grade 4 neutropenia and 1 subject had a platelet nadir of < 20,000. Actual delivered dose intensity (DI) over six cycles was: A 27 mg/m(2) per week; C 892 mg/m(2) per week; T 64 mg/m(2) per week (90.6, 89.2, and 91.4% of planned DI, respectively). Average total dose administered was: A 180 mg/m(2); C 5880 mg/m(2); T 403 mg/m(2) (100, 98, and 96% of planned total doses, respectively). Clinical response rate in 10 subjects receiving neoadjuvant therapy was 100% (4 complete response, 6 partial response). Four subjects had a pathologic complete response ( three subjects without evidence of malignancy and one subject with ductal carcinoma in situ.) Administration of dose dense AC followed by infusional paclitaxel in 14-day cycles is feasible and this regimen is active in breast cancer. C1 NCI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Zujewski, JA (reprint author), NCI, 10-12N214,10 Ctr Dr, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 35 TC 4 Z9 4 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2003 VL 81 IS 1 BP 41 EP 51 DI 10.1023/A:1025421416674 PG 11 WC Oncology SC Oncology GA 714KV UT WOS:000184913800005 PM 14531496 ER PT J AU Geller, BM Kerlikowske, K Carney, PA Abraham, LA Yankaskas, BC Taplin, SH Ballard-Barbash, R Dignan, MB Rosenberg, R Urban, N Barlow, WE AF Geller, BM Kerlikowske, K Carney, PA Abraham, LA Yankaskas, BC Taplin, SH Ballard-Barbash, R Dignan, MB Rosenberg, R Urban, N Barlow, WE TI Mammography surveillance following breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; mammography; recurrence; screening; surveillance ID CONSERVATIVE SURGERY; LOCAL RECURRENCE; TIME-COURSE; STAGE; LUMPECTOMY; RADIATION; THERAPY; RADIOTHERAPY; IRRADIATION; MASTECTOMY AB Background. To describe when women diagnosed with breast cancer return for their first mammography, and to identify factors predictive of women returning for mammographic surveillance. Methods. Women who underwent mammography at facilities participating in the National Cancer Institute's Breast Cancer Surveillance Consortium (BCSC) during 1996 and who were subsequently diagnosed with ductal carcinoma in situ or invasive breast cancer were included in this study. Data from seven mammography registries were linked to population-based cancer and pathology registries. Kaplan-Meier curves were used to depict the number of months from the breast cancer diagnosis to the first mammogram within the defined follow-up period. Demographic, disease and treatment variables were included in univariate and multivariate analyses to identify factors predictive of women returning for mammography. Results. Of the 2503 women diagnosed with breast cancer, 78.1% returned for mammography examination between 7 and 30 months following the diagnosis. Mammography facilities indicated that 66.8% of mammography examinations were classified as screening. Multivariate analyses found that women were most likely to undergo surveillance mammography if they were diagnosed at ages 60-69 with Stage 0, I or II breast cancer and had received radiation therapy in addition to surgery. Conclusions. While the majority of women return for mammographic surveillance following breast cancer, some important subgroups of women at higher risk for recurrence are less likely to return. Research is needed to determine why some women are not undergoing mammography surveillance after a breast cancer diagnosis and whether surveillance increases the chance of detecting tumors with a good prognosis. C1 Univ Vermont, Off Hlth Promot Res, Coll Med, Burlington, VT 05401 USA. Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Dartmouth Coll Sch Med, Dept Community & Family Med, Norris Cotton Canc Ctr, Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. NCI, Appl Res Branch, CSRP, DCCPS, Bethesda, MD 20892 USA. Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Geller, BM (reprint author), Univ Vermont, Off Hlth Promot Res, Coll Med, 1 S Prospect St, Burlington, VT 05401 USA. FU NCI NIH HHS [UO1CA70040, UO1CA86076, UO1CA86082, UO1CA70013, R01CA63146, UO1CA63740, UO1CA63731, UO1CA69976, UO1CA63736] NR 26 TC 34 Z9 35 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD SEP PY 2003 VL 81 IS 2 BP 107 EP 115 DI 10.1023/A:1025794629878 PG 9 WC Oncology SC Oncology GA 722YX UT WOS:000185406600002 PM 14572153 ER PT J AU Tobin, E Rohwedder, A Holland, SM Philips, B Carlson, JA AF Tobin, E Rohwedder, A Holland, SM Philips, B Carlson, JA TI Recurrent 'sterile' verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE cyst abscess; epidermodysplasia verruciformis; human papillomavirus; idiopathic CD4 lymphopenia; nuclear factor kB essential modulator; verrucous cyst ID HUMAN-PAPILLOMAVIRUS DNA; RENAL-TRANSPLANT RECIPIENTS; IMMUNODEFICIENCY-VIRUS-INFECTION; EPIDERMOID CYST; ALLOGRAFT RECIPIENTS; SKIN CANCERS; TYPE-5 DNA; HPV TYPES; PATIENT; WARTS AB Rupture of follicular ( epidermoid) cysts is believed to be the consequence of bacterial infection. We report a 24-year-old man with idiopathic CD4 lymphopenia and chronic Mycobacterium avium intracellulare infection who developed multiple, recurring painful abscesses over the distal extremities that increased in number and severity when systemic steroid and interferon-gamma treatment was instituted for interstitial lung disease. Cultures were consistently negative for microorganisms, but pathological examination revealed ruptured epidermoid cyst walls with human papillomavirus (HPV) viropathic changes (keratinocytes with perinuclear halos and abundant basophilic keratohyaline granules). Cutaneous examination showed numerous, widespread flat-topped papules and achromic macules over the extremities, head and neck. Nested polymerase chain reaction analysis for HPV DNA revealed that the abscess-related cyst walls harboured epidermodysplasia verruciformis (EV)-associated HPV types 20, 24, alb-7 (AY013872) and 80. His cutaneous lesions harboured HPV types 3, 8 and 80. Similar to past reports, our patient developed an EV-like eruption in the setting of immunodeficiency. In this instance, EV-associated HPV infection of the follicular infundibular epithelium or pre-existing cysts in the setting of immunodeficiency may have led to cystic growth, rupture and subsequent painful inflammation. C1 Albany Med Coll, Div Dermatol, Albany, NY 12208 USA. Upstate Infect Dis, Albany, NY 12208 USA. Ruhr Univ Bochum, Dept Microbiol & Virol, D-44801 Bochum, Germany. NIAID, Immunopathogenesis Unit, Clin Pathophysiol Sect, Lab Host Def,NIH, Bethesda, MD 20892 USA. Albany Med Coll, Div Dermatopathol, Albany, NY 12208 USA. RP Carlson, JA (reprint author), Albany Med Coll, Div Dermatol, MC-81, Albany, NY 12208 USA. OI Carlson, John Andrew/0000-0002-6866-6314 NR 77 TC 21 Z9 22 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD SEP PY 2003 VL 149 IS 3 BP 627 EP 633 DI 10.1046/j.1365-2133.2003.05543.x PG 7 WC Dermatology SC Dermatology GA 725GC UT WOS:000185534600028 PM 14511000 ER PT J AU Valent, P Akin, C Sperr, WR Horny, HP Arock, M Lechner, K Bennett, JM Metcalfe, DD AF Valent, P Akin, C Sperr, WR Horny, HP Arock, M Lechner, K Bennett, JM Metcalfe, DD TI Diagnosis and treatment of systemic mastocytosis: State of the art SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review ID MAST-CELL DISEASE; BLOOD MONONUCLEAR-CELLS; UMBILICAL-CORD BLOOD; COLONY-FORMING CELL; C-KIT MUTATIONS; BONE-MARROW; URTICARIA PIGMENTOSA; GENERALIZED MASTOCYTOSIS; CUTANEOUS-MASTOCYTOSIS; MEDIATOR RELEASE C1 Univ Vienna, Dept Internal Med 1, Div Haematol, A-1010 Vienna, Austria. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Med Univ Lubeck, Inst Pathol, Lubeck, Germany. Fac Pharm, Lab Hematol Cellulaire & Mol, Paris, France. Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Med Oncol Div, Rochester, NY 14642 USA. RP Valent, P (reprint author), Univ Vienna, Dept Internal Med 1, Div Haematol & Haemostaseol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. NR 169 TC 114 Z9 118 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2003 VL 122 IS 5 BP 695 EP 717 DI 10.1046/j.1365-2141.2003.04575.x PG 23 WC Hematology SC Hematology GA 717TG UT WOS:000185106000001 PM 12930381 ER PT J AU Bahceci, E Epperson, D Douek, DC Melenhorst, JJ Childs, RC Barrett, AJ AF Bahceci, E Epperson, D Douek, DC Melenhorst, JJ Childs, RC Barrett, AJ TI Early reconstitution of the T-cell repertoire after non-myeloablative peripheral blood stem cell transplantation is from post-thymic T-cell expansion and is unaffected by graft-versus-host disease or mixed chimaerism SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE bone marrow transplantation immunology; T cells; T-cell receptor; graft-versus-host disease; stem cell transplantation ID BONE-MARROW TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; IMMUNE RECONSTITUTION; THYMIC FUNCTION; LATE INFECTIONS; LYMPHOCYTES-T; DONOR; REGENERATION; RECIPIENTS; AGE AB To study immune recovery after non-myeloablative, reduced-intensity stem cell allografts (NST) and T-cell-depleted myeloablative transplants (TCD), we measured T-cell subset recovery by flow cytometry, T-cell repertoire by spectratyping and thymic T-cell output using a T-cell receptor excision circle (TREC) assay. We found a rapid and comparable increase in lymphocyte numbers in both NST and TCD, supporting the presence of a powerful drive for lymphocyte recovery after transplant. Spectratyping on d 45 and 100 revealed almost complete normalization of the T-cell repertoire in NST patients by d 45, whereas TCD patients demonstrated marked skewing of the repertoire, persisting to d 100. After NST, there was a significantly higher number of TREC-positive CD4(+) and CD8(+) cells ( P = 0.02 and P = 0.01 respectively). However, in both NST and TCD, early T-cell recovery after transplant appeared to result entirely from post-thymic T cells, the expansion pattern of which is most influenced by the starting T-cell dose, but not markedly by graft-versus-host disease (GVHD) or mixed chimaerism. These results define important qualitative differences in the T-cell repertoire according to the type of transplant schedule used. C1 NHLBI, Bone Marrow Transplant Unit, Hematol Branch, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bahceci, E (reprint author), Yale Univ, Sch Med, Sect Med Oncol, NIH, 333 Cedar St,POB 208032, New Haven, CT 06520 USA. NR 46 TC 36 Z9 40 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2003 VL 122 IS 6 BP 934 EP 943 DI 10.1046/j.1365-2141.2003.04522.x PG 10 WC Hematology SC Hematology GA 719HC UT WOS:000185196700008 PM 12956764 ER PT J AU Lee, DK Augustin, W Buggage, RR Suhler, EB AF Lee, DK Augustin, W Buggage, RR Suhler, EB TI Serpiginous choroidopathy presenting as choroidal neovascularisation SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID UVEITIS C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Maryland Gen Hosp, Dept Ophthalmol, Jonas Friendenwald Ophthalm Inst, Baltimore, MD USA. RP Buggage, RR (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 7 TC 10 Z9 10 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD SEP PY 2003 VL 87 IS 9 BP 1184 EP 1185 DI 10.1136/bjo.87.9.1184 PG 2 WC Ophthalmology SC Ophthalmology GA 713EB UT WOS:000184842500029 PM 12928294 ER PT J AU Buggage, RR Shen, DF Chan, CC Callanan, DG AF Buggage, RR Shen, DF Chan, CC Callanan, DG TI Propionibacterium acnes endophthalmitis diagnosed by microdissection and PCR SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Texas Retina Associates, Arlington, TX USA. RP Buggage, RR (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 7 TC 8 Z9 10 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD SEP PY 2003 VL 87 IS 9 BP 1190 EP 1191 DI 10.1136/bjo.87.9.1190 PG 2 WC Ophthalmology SC Ophthalmology GA 713EB UT WOS:000184842500035 PM 12928300 ER PT J AU de Coupade, C Solito, E Levine, JD AF de Coupade, C Solito, E Levine, JD TI Dexamethasone enhances interaction of endogenous Annexin 1 with L-selectin and triggers shedding of L-selectin in the monocytic cell line U-937 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE Annexin 1; L-selectin; shedding; monocytes; inflammation ID U937 CELLS; IN-VIVO; PHORBOL ESTER; NEUTROPHIL ADHESION; MEDIATED REGULATION; BINDING PROTEINS; BIOLOGICAL ROLE; MESSENGER-RNA; LIPOCORTIN 1; N-TERMINUS AB 1 L-selectin, constitutively expressed by leukocytes, is involved in the initial binding of leukocytes to activated endothelium. Anti-inflammatory drugs like glucocorticoids can induce shedding of L-selectin, but the mechanism is still unknown. Annexin 1, a protein whose synthesis and externalization/secretion are induced during the inflammatory response, has been proposed as a mediator of the anti-inflammatory actions of glucocorticoids. 2 The monocytic cell line U-937 strongly expresses Annexin 1 after 24 h of phorbol 12-myristate 13-acetate (PMA, 1 nM) treatment and externalizes/releases the protein after additional 16 h of dexamethasone (1 muM) treatment. 3 This study investigated the possible regulation of cell surface L-selectin shedding by endogenous Annexin 1, and its role in glucocorticoid-induced L-selectin shedding in the U-937 cell line. 4 PMA- and dexamethasone treatment-induced L-selectin shedding was potentially mediated by Annexin 1, since neutralizing antibodies against Annexin 1 reduced dexamethasone- and Annexin 1-induced shedding. 5 Immunoprecipitation and binding assays provided support for the suggestion that this effect could be mediated by an interaction between externalized Annexin I and L-selectin. Such interaction involved the N-terminal domain of Annexin 1 and was calcium-dependent. Confocal microscopy studies demonstrated increased colocalization of Annexin 1 and L-selectin on the cell surface. 6 Overall, our study provides new insights into the potential role of endogenous ANXA1 as a mediator of dexamethasone-induced L-selectin shedding, which may contribute to the antiinflammatory activity of glucocorticoids. C1 Univ Calif San Francisco, Dept Med & Oral & Maxillofacial Surg, NIH Pain Ctr, San Francisco, CA 94143 USA. Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Neuroendocrinol, London W12 ONN, England. RP Levine, JD (reprint author), Univ Calif San Francisco, Dept Med & Oral & Maxillofacial Surg, NIH Pain Ctr, Box 0440,521 Parnassus Ave, San Francisco, CA 94143 USA. FU NIADDK NIH HHS [AM 32634] NR 77 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2003 VL 140 IS 1 BP 133 EP 145 DI 10.1038/sj.bjp.0705413 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 721NB UT WOS:000185321500016 PM 12967943 ER PT J AU Stanford, SJ San, H Nabel, EG Hislop, AA Haworth, SG Mitchell, JA AF Stanford, SJ San, H Nabel, EG Hislop, AA Haworth, SG Mitchell, JA TI Induction of heme oxygenase-1 in the murine lung afterbirth does not influence vascular remodelling SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract CT Meeting of the British-Pharmacological-Society CY JUN 25-27, 2003 CL UNIV SURREY, GUILDFORD, ENGLAND SP British Pharmacolog Soc HO UNIV SURREY C1 Univ London Imperial Coll Sci Technol & Med, Royal Brompton, Crit Care Unit, London SW3 6NP, England. Inst Child Hlth, Dev Vasc Biol & Pharmacol Unit, London WC1N 1EH, England. NHLBI, Vasc Biol Branch, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2003 VL 140 SU S MA 12P PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 730AJ UT WOS:000185806800013 ER PT J AU Brown, JK Byers, T Doyle, C Coumeya, KS Demark-Wahnefried, W Kushi, LH McTiernan, A Rock, CL Aziz, N Bloch, AS Eldridge, B Hamilton, K Katzin, C Koonce, A Main, J Mobley, C Morra, ME Pierce, MS Sawyer, KA AF Brown, JK Byers, T Doyle, C Coumeya, KS Demark-Wahnefried, W Kushi, LH McTiernan, A Rock, CL Aziz, N Bloch, AS Eldridge, B Hamilton, K Katzin, C Koonce, A Main, J Mobley, C Morra, ME Pierce, MS Sawyer, KA TI Nutrition and physical activity during and after cancer treatment: An American Cancer Society guide for informed choices SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review ID CELL LUNG-CANCER; RECEIVING ADJUVANT CHEMOTHERAPY; RANDOMIZED CONTROLLED TRIAL; QUALITY-OF-LIFE; BREAST-CANCER; PROSTATE-CANCER; BETA-CAROTENE; DIETARY-FAT; POSTMENOPAUSAL WOMEN; POOLED ANALYSIS AB Cancer survivors are often highly motivated to seek information about food choices, physical activity, dietary supplement use, and complementary nutritional therapies to improve their treatment outcomes, quality of life, and survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information on which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity issues during the phases of cancer treatment and recovery, living after recovery from treatment, and living with advanced cancer; selected nutritional and physical activity issues such as body weight, food choices, and complementary and alternative nutritional options; and selected issues related to breast, colorectal, lung, prostate, head and neck, and upper gastrointestinal cancers. In addition, handouts containing commonly asked questions and answers and a resource list are provided for survivors and families. Tables that grade the scientific evidence for benefit versus harm related to nutrition and physical activity for breast, colorectal, lung, and prostate cancers are also included for this growing, body of knowledge to provide guidance for informed decision making and to identify areas for future research. (CA Cancer J Clin 2003,53:268-291.) (C) American Cancer Society, 2003. C1 SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Amer Canc Soc, Atlanta, GA 30329 USA. Univ Alberta, Fac Phys Educ, Edmonton, AB, Canada. Duke Univ, Med Ctr, Durham, NC USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Calif San Diego, Dept Family & Prevent Med, Canc Prevent & Control Program, La Jolla, CA 92093 USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. St Alphonsus Canc Treatment Ctr, Boise, ID USA. Carol G Simon Canc Ctr, Morristown, NJ USA. St Johns Hlth Ctr, Ctr Hlth Enhancement, Santa Monica, CA USA. Ctr Dis Control & Prevent, Program Serv Branch, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. Santa Barbara Athlet Club, Santa Barbara, CA USA. WellFit Program, Santa Barbara, CA USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Morra Commun, Milford, CT USA. Univ Tennessee, Coll Nursing, Knoxville, TN USA. RP Brown, JK (reprint author), SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. OI Kushi, Lawrence/0000-0001-9136-1175 NR 147 TC 178 Z9 180 U1 3 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD SEP-OCT PY 2003 VL 53 IS 5 BP 268 EP 291 PG 24 WC Oncology SC Oncology GA 731DT UT WOS:000185869800002 PM 14570227 ER PT J AU Riminucci, M Corsi, A Peris, K Fisher, LW Chimenti, S Bianco, P AF Riminucci, M Corsi, A Peris, K Fisher, LW Chimenti, S Bianco, P TI Coexpression of bone sialoprotein (BSP) and the pivotal transcriptional regulator of osteogenesis, Cbfa1/Runx2, in malignant melanoma SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE bone sialoprotein; cancer; melanoma; Cbfa1; immunohistology; mRNA; cell lines ID HUMAN BREAST-CANCER; MATRIX METALLOPROTEINASE-2 MMP-2; NASAL MUCOSAL MELANOMA; OSTEOBLAST DIFFERENTIATION; INTEGRIN ALPHA(V)BETA(3); CLEIDOCRANIAL DYSPLASIA; FUNCTIONAL-ANALYSIS; CELL ATTACHMENT; PROSTATE-CANCER; LUNG-CANCER AB Bone sialoprotein (BSP) is a member of the SIBLINGS family. normally restricted to the skeleton, but it has been shown to be ectopically expressed in some human invasive carcinomas. BSP expression in human cancer was initially associated with the ability of BSP-expressing tumors to metastasize to bone, although the rnechanism whereby BSP expression should facilitate homing of cancer cells to the bone marrow environment has remained unexplained. More recently, clinical and experimental data have converged in highlighting a potential link between BSP expression and tumor invasiveness in general. We show here that human malignant melanoma cells express BSP in vivo as a function of extent of local invasion, and that expression of BSP mRNA and protein in melanoma cells is associated with the expression of the transcriptional regulator of osteogenic cell differentiation, Cbfal/Runx2. It has been well established that expression of Cbfal/Runx2 in the mouse is normally restricted to bone-forming cells. In the mouse, Cbfal/Runx2 dictates osteogenic differentiation of mesodermal cells by regulating bone-specific genes. Since it also regulates expression of at least two matrix metalloproteases implicated in tumor invasion and metastasis (collagenase 3, membrane type 1 matrix metalloprotemase), we propose that the relationship between BSP expression and an invasive behavior in human epithelial cancer cells may be rooted in a common transcriptional control exerted by Cbfal. C1 Parco Sci Biomed San Raffaele, Rome, Italy. Univ Aquila, Pathol Lab, Dept Expt Med, I-67100 Laquila, Italy. Univ Aquila, Div Dermatol, Dept Biomed Sci, I-67100 Laquila, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Natl Inst Hlth, Bethesda, MD USA. Univ Roma Tor Vergata, Dept Dermatol, Rome, Italy. Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy. RP Bianco, P (reprint author), Parco Sci Biomed San Raffaele, Rome, Italy. OI Peris, Ketty/0000-0002-5237-0463 NR 65 TC 28 Z9 30 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD SEP PY 2003 VL 73 IS 3 BP 281 EP 289 DI 10.1007/s00223-002-2134-y PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 721BD UT WOS:000185296400012 PM 14667142 ER PT J AU Henson, DE Chu, KC Levine, PH AF Henson, DE Chu, KC Levine, PH TI Histologic grade, stage, and survival in breast carcinoma SO CANCER LA English DT Article DE breast carcinoma; race; survival; histologic grade; stage; tumor size; African American women; Caucasian women ID SURGICAL ADJUVANT BREAST; CANCER PATIENTS; RACIAL-DIFFERENCES; PROGNOSTIC FACTORS; BLACK; WHITE; RACE; WOMEN AB BACKGROUND. African American women have lower breast carcinoma survival rates than do Caucasian women. African American women often present with advanced-stage disease and more aggressive tumors as shown by histologic and laboratory-based prognostic factors. Aggressive tumor behavior may be responsible, at least in part, for the advanced stage and reduced survival rates. METHODS. The authors investigated the correlation between survival and histologic grade, stage of disease, and tumor size for both African American and Caucasian women who were younger than age 50 years and age 50 years and older. The authors also investigated the distribution of grade within each stage group and the distribution of grade by tumor size. African American and Caucasian women were matched by stage, tumor size, and histologic grade. Survival was represented by 6-year breast carcinoma-specific survival rates. RESULTS. Compared with Caucasian women, African American women, regardless of age, had proportionally more Grade III tumors and fewer Grade I and II tumors for all stages combined and for each individual stage group. Similarly, matched for tumor size, African American women had more Grade III tumors and fewer Grade I and II tumors compared with Caucasian women, except for tumors smaller than 1.0 cm. For nearly all combinations of stage and grade regardless of age, the 6-year breast carcinoma-specific survival rate was lower for African American women than for Caucasian women, although it did not always reach statistical significance. CONCLUSIONS. Compared with Caucasian women, African American women, regardless of age, presented with proportionally more aggressive tumors for each stage of disease and for each tumor size above 1.0 cm as revealed by the histologic grade. Higher histologic grade may be a significant contributing factor to survival disadvantage for African American women. Published 2003 by the American Cancer Society. C1 George Washington Univ, Inst Canc, Ctr Med, Off Canc Prevent & Control,Dept Pathol, Washington, DC 20037 USA. Natl Canc Inst, Ctr Reduce Canc Hlth Dispar, Bethesda, MD USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. RP Henson, DE (reprint author), George Washington Univ, Inst Canc, Ctr Med, Off Canc Prevent & Control,Dept Pathol, Ross Hall,Room 502,2300 St,NW, Washington, DC 20037 USA. NR 27 TC 64 Z9 65 U1 2 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 1 PY 2003 VL 98 IS 5 BP 908 EP 917 DI 10.1002/cncr.11558 PG 10 WC Oncology SC Oncology GA 714RV UT WOS:000184928000005 PM 12942556 ER PT J AU Romano, MF Festa, M Petrella, A Rosati, A Pascale, M Bisogni, R Poggi, V Kohn, EC Venuta, S Turco, MC Leone, A AF Romano, MF Festa, M Petrella, A Rosati, A Pascale, M Bisogni, R Poggi, V Kohn, EC Venuta, S Turco, MC Leone, A TI BAG3 protein regulates cell survival in childhood acute lymphoblastic leukemia cells SO CANCER BIOLOGY & THERAPY LA English DT Letter ID CHRONIC LYMPHOCYTIC-LEUKEMIA; IN-VITRO; BCL-2; APOPTOSIS; EXPRESSION; FAMILY; CORTICOSENSITIVITY; HSP70/HSC70; DEATH C1 Univ Salerno, DIFARMA, I-84084 Salerno, Italy. Univ Naples Federico II, DBBM, Naples, Italy. Pausilipon Hosp, Dept Pediat Oncohematol, Naples, Italy. NCI, Mol Signaling Sect, Pathol Lab, Bethesda, MD 20892 USA. Univ Catanzaro, DMCS, Catanzaro, Italy. RP Turco, MC (reprint author), Univ Salerno, DIFARMA, Via Ponte don Melillo, I-84084 Salerno, Italy. EM mcturco@unisa.it RI Pascale, Maria/B-4273-2012; Petrella, Antonello/E-7708-2012; OI PETRELLA, Antonello/0000-0002-6945-5295 NR 19 TC 42 Z9 45 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP-OCT PY 2003 VL 2 IS 5 BP 508 EP 510 PG 3 WC Oncology SC Oncology GA 751PN UT WOS:000187076300006 PM 14614315 ER PT J AU Zhang, H Merchant, MS Chua, KS Khanna, C Helman, LJ Telford, B Ward, Y Summers, J Toretsky, J Thomas, EK June, CH Mackall, CL AF Zhang, H Merchant, MS Chua, KS Khanna, C Helman, LJ Telford, B Ward, Y Summers, J Toretsky, J Thomas, EK June, CH Mackall, CL TI Tumor expression of 4-1BB ligand sustains tumor lytic T cells SO CANCER BIOLOGY & THERAPY LA English DT Article DE 4-1BB; 4-1BBL; Ewing's sarcoma; adoptive immunotherapy; T cell co-stimulation ID BONE-MARROW-TRANSPLANTATION; MELANOMA PATIENTS; DENDRITIC CELLS; COSTIMULATORY MOLECULES; IMMUNE SURVEILLANCE; IN-VITRO; LYMPHOCYTES; ANTIGEN; CD28; RECEPTOR AB Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3(+)CD8(+) subset and are CD28(-)/4-1BB(+). Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer. C1 NCI, Immunol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Oncol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Immunex Inc, Div Extramural Res, Seattle, WA USA. Univ Penn, Ctr Canc, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Mackall, CL (reprint author), NCI, Immunol Sect, Pediat Oncol Branch, Bldg 10,Rm 13C240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov NR 47 TC 28 Z9 31 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP-OCT PY 2003 VL 2 IS 5 BP 579 EP 586 PG 8 WC Oncology SC Oncology GA 751PN UT WOS:000187076300022 PM 14614331 ER PT J AU Teitelbaum, SL Britton, JA Gammon, MD Schoenberg, JB Brogan, DJ Coates, RJ Daling, JR Malone, KE Swanson, CA Brinton, LA AF Teitelbaum, SL Britton, JA Gammon, MD Schoenberg, JB Brogan, DJ Coates, RJ Daling, JR Malone, KE Swanson, CA Brinton, LA TI Occupation and breast cancer in women 20-44 years of age (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; case-control studies; occupations; risk factors ID RISK-FACTORS; ELECTROMAGNETIC-FIELDS; PHYSICAL-ACTIVITY; YOUNGER WOMEN; EARLY-ONSET; POPULATION; EXPOSURES; MORTALITY; PATTERNS AB Objective: To examine the relation between breast cancer risk and job history among women 20 - 44 years of age who participated in a multi-center, population-based, case - control study. Methods: Participants consisted of women newly diagnosed with breast cancer ( 1642) and controls identified by random-digit dialing ( 1494). Details about the three longest jobs were collected and coded by an industrial hygienist. Odds ratios and 95% confidence intervals were calculated and adjusted for age, study site, and other breast cancer risk factors. Results: Several occupational and industrial categories were found to influence breast cancer risk. Strati. cation of the study population by parity revealed differences in breast cancer risk between the two groups for several occupational categories, including teachers, librarians or counselors ( increased risk only among parous women) and natural scientists and mathematicians ( decreased risk only among nulliparous women). Conclusions: This is among the first population-based case - control studies to examine occupational history and breast cancer risk in young women, with the ability to consider a wide array of potential confounders, including reproductive characteristics. This study provides further evidence of an increased breast cancer risk for several occupations and industries. Other findings were not as strongly supported by previous investigations. C1 CUNY Mt Sinai Sch Med, Dept Community & Prevent Med, Div Environm Hlth Sci, New York, NY 10029 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Ctr Dis Control, Div Canc Prevent & Control, Atlanta, GA 30333 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Teitelbaum, SL (reprint author), CUNY Mt Sinai Sch Med, Dept Community & Prevent Med, Div Environm Hlth Sci, 1 Gustave L Levy Pl,Box 1043, New York, NY 10029 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 40 TC 14 Z9 15 U1 2 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2003 VL 14 IS 7 BP 627 EP 637 DI 10.1023/A:1025682810900 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 720LB UT WOS:000185261300004 PM 14575360 ER PT J AU Abnet, CC Qiao, YL Dawsey, SM Buckman, DW Yang, CS Blot, WJ Dong, ZW Taylor, PR Mark, SD AF Abnet, CC Qiao, YL Dawsey, SM Buckman, DW Yang, CS Blot, WJ Dong, ZW Taylor, PR Mark, SD TI Prospective study of serum retinol, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin and esophageal and gastric cancers in China SO CANCER CAUSES & CONTROL LA English DT Article DE beta-carotene; beta-cryptoxanthin; esophageal cancer; gastric cancer; lutein; retinol; zeaxanthin ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; HELICOBACTER-PYLORI; ALPHA-TOCOPHEROL; RISK-FACTORS; LUNG-CANCER; CASE-COHORT; LINXIAN; SUPPLEMENTATION; SEROPOSITIVITY AB Objective: This study examined the relationship between pretrial serum concentrations of retinol, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin and the subsequent risk of developing esophageal squamous cell carcinoma and gastric cardia or non-cardia adenocarcinoma in subjects selected from a randomized nutritional intervention trial in Linxian, China, a region with epidemic rates of esophageal and gastric cardia cancer. Methods: We used a stratified case - cohort design to select cohort members for inclusion in this study. In all we measured serum concentrations of the above vitamins in 590 esophageal, 395 gastric cardia, and 87 gastric noncardia case subjects as well as in 1053 control subjects. Relative risks ( RRs) were estimated using Cox proportional hazards models. Results: Median values in our cohort were low for serum retinol (33.6 mug/dl), beta-carotene (4.3 mug/dl), and beta-cryptoxanthin (3.5 mug/dl), but were high for lutein/zeaxanthin (40.0 mug/dl). Gastric cardia cancer incidence fell 10% for each quartile increase in serum retinol (RR = 0.90, 95% CI = 0.83 - 0.99). For esophageal cancer, an inverse association with retinol levels was found only in male non-smokers ( RR = 0.79 per quartile increase, 95% CI = 0.63 - 0.99). For gastric non-cardia cancer, an inverse association was limited to subjects 50 years old or younger ( RR = 0.58 per quartile, 95% CI = 0.31 - 0.96). For beta-cryptoxanthin there was a borderline significant protective association for gastric non-cardia cancer ( RR = 0.88 per quartile, 95% CI = 0.76 - 1.0). In contrast, we found the incidence of gastric non-cardia cancer increased ( RR = 1.2 per quartile, 95% CI = 1.0 - 1.3) with increasing concentration of serum lutein/zeaxanthin. Conclusions: In this population, we found that low retinol and high lutein/zeaxanthin concentrations increased the risks of gastric cardia and gastric non-cardia cancer respectively. We found that there were no strong associations between any of the other analytes and any of the cancer sites. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Canc, Dept Epidemiol, Beijing 100021, Peoples R China. Informat Management Serv Inc, Rockville, MD USA. Rutgers State Univ, Coll Pharm, Canc Res Lab, Piscataway, NJ 08855 USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Abnet, CC (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, 6116 Execut Blvd,Room 705, Bethesda, MD 20892 USA. RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 NR 36 TC 36 Z9 39 U1 0 U2 6 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2003 VL 14 IS 7 BP 645 EP 655 DI 10.1023/A:1025619608851 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 720LB UT WOS:000185261300006 PM 14575362 ER PT J AU Howe, HL Edwards, BK Young, JL Shen, TF West, DW Hutton, M Correa, CN AF Howe, HL Edwards, BK Young, JL Shen, TF West, DW Hutton, M Correa, CN TI A vision for cancer incidence surveillance in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE cancer surveillance; epidemiology; neoplasms; public health; surveillance ID PROSTATE-CANCER; REGISTRY DATA; RATES; US; HEALTH; AGE; MORTALITY; OUTCOMES; TRENDS; NATION AB A comprehensive framework for cancer surveillance should span the entire lifespan and be capable of providing information on risk, burden, disparity, cost, cancer care, survival, and death. Cancer incidence, the point in the continuum when an individual is diagnosed with cancer, has a strong, well-developed system to produce information about newly diagnosed cancer cases. However, in the future, this system must be enhanced and integrated with other cancer surveillance networks and other systems to provide timely information on the burden of newly diagnosed patients with respect to various cross-cutting population characteristics ( e. g., social, economic, race/ethnic, urbanicity, or access to care) to define, monitor, and reduce incidence and various disparities noted among population groups. Collaboration in data collection, standard setting, surveillance activities, research, education and training, data use, and advocacy among all registries and national programs will be important to the continued success of the cancer incidence surveillance system. The cancer registry is an integral part of the infrastructure to reduce the burden of cancer, including the numbers of newly diagnosed cases. C1 NAACCR Inc, Springfield, IL 62704 USA. NCI, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. Illinois Dept Publ Hlth, Springfield, IL 62761 USA. No Calif Canc Ctr, Union City, CA USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Louisiana Tumor Registry, New Orleans, LA USA. RP Howe, HL (reprint author), NAACCR Inc, 2121 W White Oaks Dr, Springfield, IL 62704 USA. NR 48 TC 19 Z9 19 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2003 VL 14 IS 7 BP 663 EP 672 DI 10.1023/A:1025667524781 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 720LB UT WOS:000185261300008 PM 14575364 ER PT J AU Morton, LM Holford, TR Leaderer, B Zhang, YW Zahm, SH Boyle, P Flynn, S Tallini, G Owens, PH Zhang, B Zheng, TZ AF Morton, LM Holford, TR Leaderer, B Zhang, YW Zahm, SH Boyle, P Flynn, S Tallini, G Owens, PH Zhang, B Zheng, TZ TI Alcohol use and risk of non-Hodgkin's lymphoma among Connecticut women (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE alcohol consumption; case-control studies; lymphoma; non-Hodgkin; women ID CHEMOPREVENTIVE AGENT RESVERATROL; CONSUMPTION; CANCER; EPIDEMIOLOGY; DRINKING; TOBACCO; GRAPES; CELLS; DIET; MEN AB Objective: Incidence rates of non-Hodgkin's lymphoma (NHL) have risen dramatically over the past several decades; however, the etiology of NHL remains largely unknown. Previous studies of the relationship between alcohol consumption and NHL have yielded conflicting results. Data from a population-based case - control study among women in Connecticut were analyzed to determine the potential impact of alcohol consumption on risk of NHL. Methods: The study included 601 histologically confirmed, incident cases of NHL and 718 population-based controls. In-person interviews were administered using standardized, structured questionnaires to collect data on history of consumption for beer, wine, and liquor. Results: When compared to non-drinkers, women who reported consumption of at least 12 drinks per year of any type of alcohol experienced slightly reduced risk of NHL ( OR: 0.82; 95% CI: 0.65 - 1.04). Further strati. cation by alcohol type revealed that the inverse association was mainly limited to wine consumption ( OR: 0.75; 95% CI: 0.59 - 0.96), with no clear association for beer or liquor consumption. Risk of NHL was further reduced with increasing duration of wine consumption ( p for linear trend = 0.02). Consumption of wine for greater than 40 years was associated with approximately 40% reduction in risk ( OR: 0.63; 95% CI: 0.44 - 0.91). Conclusion: Our results are consistent with several recent epidemiologic studies that have also suggested an inverse association between wine consumption and risk of NHL. The reduction in risk of NHL associated with increased duration of wine consumption warrants further investigation in other populations. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. European Inst Oncol, Dept Epidemiol & Biostat, I-20141 Milan, Italy. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3A 1A2, Canada. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; OI Boyle, Peter/0000-0001-6251-0610; Morton, Lindsay/0000-0001-9767-2310; Tallini, Giovanni/0000-0003-0113-6682 FU NCI NIH HHS [CA62006-05] NR 22 TC 35 Z9 38 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2003 VL 14 IS 7 BP 687 EP 694 DI 10.1023/A:1025626208861 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 720LB UT WOS:000185261300011 PM 14575367 ER PT J AU Meuwissen, R Linn, SC Linnoila, RI Zevenhoven, J Mooi, WJ Berns, A AF Meuwissen, R Linn, SC Linnoila, RI Zevenhoven, J Mooi, WJ Berns, A TI Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model SO CANCER CELL LA English DT Article ID RETINOBLASTOMA TUMOR-SUPPRESSOR; NEUROENDOCRINE TUMORS; MOLECULAR-GENETICS; TRANSGENIC MICE; G(1) CONTROL; K-RAS; DIFFERENTIATION; EXPRESSION; MARKER; P53 AB Small cell lung cancer (SCLC) is a highly aggressive human tumor with a more than 95% mortality rate. Its ontogeny and molecular pathogenesis remains poorly understood. We established a mouse model for neuroendocrine (NE) lung tumors by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. Mice carrying conditional alleles for both Rb1 and Trp53 developed with high incidence aggressive lung tumors with striking morphologic and immunophenotypic similarities to SCLC. Most of these tumors, which we designate MSCLC (murine small cell lung carcinoma), diffusely spread through the lung and gave rise to extrapulmonary metastases. In our model, inactivation of both Rb1 and p53 was a prerequisite for the pathogenesis of SCLC. C1 Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Ctr Biomed Genet, NL-1066 CX Amsterdam, Netherlands. Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Med Oncol, NL-1066 CX Amsterdam, Netherlands. Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Pathol, NL-1066 CX Amsterdam, Netherlands. NCI, Cell & Canc Biol Dept, Ctr Canc Res, Rockville, MD 20850 USA. RP Berns, A (reprint author), Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. NR 47 TC 225 Z9 232 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP PY 2003 VL 4 IS 3 BP 181 EP 189 DI 10.1016/S1535-6108(03)00220-4 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 726JB UT WOS:000185595000005 PM 14522252 ER PT J AU Kanovsky, M Michl, J Botzolaki, G Morin, J Kovac, C Chung, DL Chie, L Friedman, FK Pincus, MR AF Kanovsky, M Michl, J Botzolaki, G Morin, J Kovac, C Chung, DL Chie, L Friedman, FK Pincus, MR TI Peptides designed from molecular modeling studies of the ras-p21 protein induce phenotypic reversion of a pancreatic carcinoma cell line but have no effect on normal pancreatic acinar cell growth SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE ras-p21 peptides; molecular modeling; phenotypic reversion; pancreatic cancer ID NUCLEOTIDE EXCHANGE PROTEIN; ONCOGENIC RAS-P21; OOCYTE MATURATION; SIGNAL-TRANSDUCTION; TERMINAL KINASE; RAS PROTEINS; WILD-TYPE; INHIBITION; IDENTIFICATION; EXPRESSION AB Purpose: From molecular modeling studies we found that two ras-p2l peptides, corresponding to p2l residues 35-47 (PNC-7) and 96-110 (PNC-2), selectively block oncogenic (Val 12-p2l), but not insulin-activated wild-type, p2l-induced oocyte maturation. Our purpose was to determine if these peptides block the growth of mammalian cancer cells but not their normal counterpart cells. Methods: Since oncogenic ras has been implicated as a causative factor in over 90% of human pancreatic cancers, we have established a normal pancreatic acinar cell line (BMRPA1) and the corresponding ras-transformed pancreatic cancer cell line (TUC-3). We treated both cell fines with PNC-7 and PNC-2 and the unrelated negative control peptide, X13, attached to the penetratin sequence that allows membrane penetration and also transfected these cell lines with plasmids encoding all three peptides. Results: Treatment of TUC-3 cells with each peptide resulted in their complete phenotypic reversion to the untransformed phenotype as revealed by the lack of tumor formation of these revertant cells implanted in the peritoneal cavities of nude mice. In contrast, treatment with X13-leader resulted in no inhibition of cell growth. Identical results were obtained when TUC-3 cells were transfected with plasmids expressing PNC-2, PNC-7 and X 13. None of these peptides affected the normal growth of BMRPA1 cells. Conclusions: PNC-2 and PNC-7 peptides induce phenotypic reversion of ras-induced pancreatic cancer cells and have no effect on normal pancreatic cell growth. Since the plasmid encoding PNC-2 without penetratin also had the same effect on the TUC-3 cell line, we conclude that the penetratin sequence has no effect on the activity of this peptide. Since X 13 attached to penetratin bad no effect on TUC-3 cells, the effect is specific for PNC-2 and PNC-7 and further confirms that the effect is not caused by the penetratin sequence. PNC-2- and PNIZ-7-penetratin may therefore be useful in the treatment of ras-induced pancreatic carcinomas. C1 SUNY Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USA. New York Harbor VA Med Ctr, Dept Pathol & Lab Med, Brooklyn, NY 11209 USA. Long Isl Univ, Dept Biol, Brooklyn, NY 11201 USA. Long Isl Univ, Dept Chem, Brooklyn, NY 11201 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Pincus, MR (reprint author), SUNY Downstate Med Ctr, Dept Pathol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. RI Friedman, Fred/D-4208-2016 FU NCI NIH HHS [R01 CA 42500] NR 25 TC 14 Z9 14 U1 0 U2 1 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 SEP PY 2003 VL 52 IS 3 BP 202 EP 208 DI 10.1007/s00280-003-0639-3 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 715QT UT WOS:000184984300004 PM 12783204 ER PT J AU Ferreccio, C Bratti, MC Sherman, ME Herrero, R Wacholder, S Hildesheim, A Burk, RD Hutchinson, M Alfaro, M Greenberg, MD Morales, J Rodriguez, AC Schussler, J Eklund, C Marshall, G Schiffman, M AF Ferreccio, C Bratti, MC Sherman, ME Herrero, R Wacholder, S Hildesheim, A Burk, RD Hutchinson, M Alfaro, M Greenberg, MD Morales, J Rodriguez, AC Schussler, J Eklund, C Marshall, G Schiffman, M TI A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; COSTA-RICA; PAPANICOLAOU SMEAR; POPULATION; WOMEN; CERVICOGRAPHY; ABNORMALITIES; METAANALYSIS; SPECIFICITY; SENSITIVITY AB Increased understanding of human papillomavirus (HPV) infection as the central cause of cervical cancer has permitted the development of improved screening techniques. To evaluate their usefulness, we evaluated the performance of multiple screening methods concurrently in a large population-based cohort of >8500 nonvirginal women without hysterectomies, whom we followed prospectively in a high-risk region of Latin America. Using Youden's index as a measure of the trade-off between sensitivity and specificity, we estimated the performances of a visual screening method (cervicography), conventional cytology, liquid-based cytology (ThinPrep), and DNA testing for 13 oncogenic HPV types. The reference standard of disease was neoplasia greater than or equal to cervical intraepithelial neoplasia grade 3 (CIN 3), defined as histologically confirmed CIN 3 detected within 2 years of enrollment (n = 90) or invasive cancer detected within 7 years (n = 20). We analyzed each technique alone and in paired combinations (n = 112 possible strategies), and evaluated the significance of differences between strategies using a paired Z test that equally weighted sensitivity and specificity. As a single test, either liquid-based cytology or HPV DNA testing was significantly more accurate than conventional cytology or cervicography. Paired tests incorporating either liquid-based cytology or HPV DNA testing were not substantially more accurate than either of those two test strategies alone. However, a possibly useful synergy was observed between the conventional smear and cervicography. Consideration of age or behavioral risk profiles did not alter any of these conclusions. Overall, we conclude that highly accurate screening for cervical cancer and CIN 3 is now technically feasible. The remaining vital issue is to extend improved cervical cancer prevention programs to resource-poor regions. C1 Catholic Univ Chile, Dept Salud Publ, Santiago, Chile. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. Albert Einstein Coll Med, New York, NY 10461 USA. Brown Univ, Women & Infants Hosp, Providence, RI 02905 USA. US Hlth Connect, Blue Bell, PA 19034 USA. Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol, NIH, Dept Hlth & Human Serv, Room 7066,6120 Execut Blvd, Rockville, MD 20852 USA. RI Marshall, Guillermo/F-2302-2011 FU NCI NIH HHS [CA78527] NR 37 TC 45 Z9 49 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 SEP PY 2003 VL 12 IS 9 BP 815 EP 823 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 724BX UT WOS:000185467900001 PM 14504189 ER PT J AU Terry, PD Lagergren, J Wolk, A Steineck, G Nyren, O AF Terry, PD Lagergren, J Wolk, A Steineck, G Nyren, O TI Dietary intake of heterocyclic amines and cancers of the esophagus and gastric cardia SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CYTOCHROME-P450 EXPRESSION; MEAT; METABOLISM; CARCINOGENICITY; ETIOLOGY; COOKING; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; MUTAGENICITY; CARCINOMAS; INDUCTION AB The results of two epidemiological studies suggest that high intake of heterocyclic amines, which are formed on the surface of meats cooked at high temperatures, might be associated with increased risk of esophageal or cardia cancers. Our aim was to further investigate heterocyclic amine intake and risk of these cancers. We examined data from a nationwide, population-based, case-control study of risk factors for adenocarcinoma of the esophagus and gastric cardia and squamous cell carcinoma of the esophagus in Sweden, with 185, 258, and 165 cases, respectively, and 815 controls. Heterocyclic amine intake was estimated based on the frequency of consumption and degree of surface browning of commonly fried meats, and the consumption of pan juices. Statistically nonsignificant 50-70% higher risks of esophageal squamous cell carcinoma were observed among individuals in the highest quartile levels of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, and 2-amino-1methyl-6-phenylimidazo[4,5-b]pyridine relative to those in the lowest. Dose-risk trends Were evident. Subjects reporting high intake of all three heterocyclic amines had an odds ratio of 2.4 (95% confidence interval, 1.2-4.8) relative to those with low intake of all three substances. In contrast, no association was found with risk of adenocarcinoma of the esophagus or gastric cardia. Heterocyclic amine intake might be associated with an increase in risk of squamous cell carcinoma of the esophagus. Given the dearth of epidemiological data regarding these cancers and the lack of established biological mechanisms, confirmatory data are needed. C1 Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Karolinska Inst, Div Nutrit Epidemiol, Dept Environm Med, Stockholm, Sweden. Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden. Karolinska Hosp, Dept Surg, S-10401 Stockholm, Sweden. RP Terry, PD (reprint author), NIEHS, Epidemiol Branch, POB 12233 MD A3-05, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [R01 CA57947-03] NR 38 TC 36 Z9 36 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 SEP PY 2003 VL 12 IS 9 BP 940 EP 944 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 724BX UT WOS:000185467900021 PM 14504209 ER PT J AU Shao, JY Lee, SB Guo, BHP Evers, M Sheng, HM AF Shao, JY Lee, SB Guo, BHP Evers, M Sheng, HM TI Prostaglandin E-2 stimulates the growth of colon cancer cells via induction of amphiregulin SO CANCER RESEARCH LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; CARCINOMA CELLS; PROTEIN; KINASE; EXPRESSION; RECEPTOR; TRANSFORMATION; CYCLOOXYGENASE-2; MODULATION; INHIBITION AB Prostaglandin E-2 (PGE(2)), a major product of cyclooxygenase enzymes, is implicated in colorectal carcinogenesis and has been shown to stimulate the growth of human colorectal carcinoma cells. Here, we show that PGE2 activated the cyclic AMP/protein kinase A pathway, which induced the expression of amphiregulin (AR), an epidermal growth factor family member, through activation of a cyclic AMP-responsive element in the AR promoter. AR exerted a mitogenic effect on LS-174 cells and partially mediated the PGE(2)-induced growth stimulation. In addition, PGE(2), in collaboration with transforming growth factor-alpha or K-Ras oncogene, synergistically induced AR expression and activated receptor tyrosine kinase-dependent signaling pathways. Our results provide novel mechanisms for cyclooxygenase-2 pro-oncogenic activity and suggest that PGE2 may act with major oncogenic pathways in a synergistic fashion to activate the epidermal growth factor receptor signaling system through a ligand-dependent autocrine pathway. C1 Univ Texas, Med Branch, Dept Surg, Galveston, TX 77555 USA. Univ Texas, Med Branch, Sealy Ctr Canc Cell Biol, Galveston, TX 77555 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Sheng, HM (reprint author), Univ Texas, Med Branch, Dept Surg, Galveston, TX 77555 USA. NR 22 TC 125 Z9 140 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 SEP 1 PY 2003 VL 63 IS 17 BP 5218 EP 5223 PG 6 WC Oncology SC Oncology GA 722XD UT WOS:000185402600009 PM 14500348 ER PT J AU Nishizuka, S Chen, ST Gwadry, FG Alexander, J Major, SM Scherf, U Reinhold, WC Waltham, M Charboneau, L Young, L Bussey, KJ Kim, SY Lababidi, S Lee, JK Pittaluga, S Scudiero, DA Sausville, EA Munson, PJ Petricoin, EF Liotta, LA Hewitt, SM Raffeld, M Weinstein, JN AF Nishizuka, S Chen, ST Gwadry, FG Alexander, J Major, SM Scherf, U Reinhold, WC Waltham, M Charboneau, L Young, L Bussey, KJ Kim, SY Lababidi, S Lee, JK Pittaluga, S Scudiero, DA Sausville, EA Munson, PJ Petricoin, EF Liotta, LA Hewitt, SM Raffeld, M Weinstein, JN TI Diagnostic markers that distinguish colon and ovarian adenocarcinomas: identification by genomic, proteomic, and tissue array profiling SO CANCER RESEARCH LA English DT Article ID UNKNOWN PRIMARY SITE; NATIONAL-CANCER-INSTITUTE; TUMOR-CELL-LINES; MOLECULAR PHARMACOLOGY; EXPRESSION DATABASE; DRUG DISCOVERY; VILLIN; PROTEIN; GENE; CARCINOMA AB Colon and ovarian cancers can be difficult to distinguish in the abdomen, and the distinction is important because it determines which drugs will be used for therapy. To identify molecular markers for that differential diagnosis, we developed a multistep protocol starting with the 60 human cancer cell lines used by the National Cancer Institute to screen for new anticancer agents. The steps included: (a) identification of candidate markers using cDNA microarrays; (b) verification of clone identities by resequencing; (e) corroboration of transcript levels using Affymetrix oligonucleotide chips; (d) quantitation of protein expression by "reverse-phase" protein microarray; and (e) prospective validation of candidate markers on clinical tumor sections in tissue microarrays. The two best candidates identified were villin for colon cancer cells and moesin for ovarian cancer cells. Because moesin stained stromal elements in both types of cancer, it would probably not have been identified as a marker if we had started with mRNA or protein profiling of bulk tumors. Villin appears at least as useful as the currently used colon cancer marker cytokeratin 20, and moesin also appears to have utility. The multistep process introduced here has the potential to produce additional markers for cancer diagnosis, prognosis, and therapy. C1 NCI, Lab Mol Pharmacol, Genom & Bioinformat Grp, NIH, Bethesda, MD 20892 USA. Ctr Informat Technol, Math & Stat Comp Lab, Analyt Biostat Sect, NCI, Bethesda, MD 20814 USA. Dev Therapeut Program, Div Canc Treatment & Diagnosis, Bethesda, MD 20814 USA. Sci Applicat Int Corp, NCI, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Food & Drug Adm, Ctr Biol Evaluat & Res, Tissue Proteom Unit, Div Therapeut Prot, Bethesda, MD 20814 USA. RP Weinstein, JN (reprint author), NCI, Lab Mol Pharmacol, Genom & Bioinformat Grp, NIH, Bldg 37,Rm 5056, Bethesda, MD 20892 USA. RI Waltham, Mark/A-1728-2009; OI Hewitt, Stephen/0000-0001-8283-1788; Kim, Sohyoung/0000-0002-6140-7918 NR 47 TC 150 Z9 155 U1 1 U2 8 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 SEP 1 PY 2003 VL 63 IS 17 BP 5243 EP 5250 PG 8 WC Oncology SC Oncology GA 722XD UT WOS:000185402600015 PM 14500354 ER PT J AU Hansen, LA Brown, D Virador, V Tanaka, T Andreola, F Strain, K Dancheck, B Riley, R Arbeit, JM De Luca, LM Kogan, S Yuspa, SH AF Hansen, LA Brown, D Virador, V Tanaka, T Andreola, F Strain, K Dancheck, B Riley, R Arbeit, JM De Luca, LM Kogan, S Yuspa, SH TI A PMLRARA transgene results in a retinoid-deficient phenotype associated with enhanced susceptibility to skin tumorigenesis SO CANCER RESEARCH LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PML-RAR-ALPHA; ACID RECEPTOR-ALPHA; FEMALE SENCAR MICE; MOUSE SKIN; VITAMIN-A; HISTONE DEACETYLASE; TUMOR SUPPRESSION; ONCOGENE; CARCINOGENESIS AB The construction of transgenic FVB/N mice targeting the PMLRARA fusion gene under the control of a human MRP8 promoter recapitulated the phenotype of acute promyelocytic leukemia but had the unexpected result of multiple squamous papillomas of the skin (Brown et al., Proc. Natl. Acad. Sci. USA, 94:2551-2556, 1997). In addition, transgenic MRP8-PMLRARA mice exhibited a skin phenotype characteristic of vitamin A deficiency. The severity of the skin phenotype and spontaneous papilloma development correlated with the level of transgene expression. Papilloma formation was preceded by follicular hyperplasia and the expression of epidermal differentiation markers in the follicular epithelium. Mutations in the Ha or Ki alleles of ras were not detected in papillomas that developed on transgenic skin, and papilloma formation was accentuated on the C57/B16 background, unlike the usual resistance of this strain to skin tumor induction. Analysis of liver extracts from transgenic mice indicated a deficiency in the production of retinoic acid. Furthermore, affected transgenic epidermis had reduced levels of retinoic acid receptoralpha (RARalpha) and retinoic X receptor (RXRalpha), and supplementation with exogenous retinoic acid prevented the skin phenotype. When transgenic keratinocytes were grafted to nude mice, the resulting integument was normal, and conversely, when transgenic bone marrow was grafted to normal mice, a skin phenotype did not develop. Together these results suggest that local interruption of PML and RARalpha signaling in the skin, together with a systemic retinoid deficiency, initiates a tumor induction pathway that is independent of ras activation. C1 NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. Creighton Univ, Dept Biomed Sci, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Yuspa, SH (reprint author), NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. RI Strain, Kenneth/D-5236-2011 OI Strain, Kenneth/0000-0002-2066-5355 FU NIEHS NIH HHS [K22 ES000365] NR 52 TC 13 Z9 13 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 SEP 1 PY 2003 VL 63 IS 17 BP 5257 EP 5265 PG 9 WC Oncology SC Oncology GA 722XD UT WOS:000185402600017 PM 14500356 ER PT J AU Ying, H Suzuki, H Zhao, L Willingham, MC Meltzer, P Cheng, SY AF Ying, H Suzuki, H Zhao, L Willingham, MC Meltzer, P Cheng, SY TI Mutant thyroid hormone receptor beta represses the expression and transcriptional activity of peroxisome proliferator-activated receptor gamma during thyroid carcinogenesis SO CANCER RESEARCH LA English DT Article ID GENERALIZED RESISTANCE; PAPILLARY CARCINOMAS; LIPOPROTEIN-LIPASE; NUCLEAR RECEPTORS; RET/PTC1 ONCOGENE; LIGAND-BINDING; PPAR-GAMMA; GENE; GROWTH; MICE AB The molecular genetics underlying thyroid carcinogenesis is not clear. Recent identification of a PAX8-peroxisome proliferator-activated receptor gamma (PPAR-gamma) fusion gene in human thyroid follicular carcinoma suggests a tumor suppressor role of PPARgamma in thyroid carcinogenesis. Mice harboring a knockin mutant thyroid hormone beta receptor (TRbetaPV) spontaneously develop thyroid follicular carcinoma through pathological progression of hyperplasia, capsular invasion, vascular invasion, anaplasia, and eventually, distant organ metastasis. This mutant mouse (TRbeta(PV/PV) mouse) provides an unusual opportunity to ascertain the role of PPARgamma in thyroid carcinogenesis. Here, we show that the expression of PPARgamma mRNA was repressed in the thyroid gland of mutant mice during carcinogenesis. In addition, TRbetaPV acted to abolish the ligand (troglitazone)-mediated transcriptional activity of PPARgamma. These results indicate that repression of PPARgamma expression and its transcriptional activity are associated with thyroid carcinogenesis and raise the possibility that PPARgamma could be tested as a therapeutic target in thyroid follicular carcinoma. C1 NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Rm 5128, Bethesda, MD 20892 USA. NR 34 TC 53 Z9 55 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 SEP 1 PY 2003 VL 63 IS 17 BP 5274 EP 5280 PG 7 WC Oncology SC Oncology GA 722XD UT WOS:000185402600019 PM 14500358 ER PT J AU Bertherat, J Groussin, L Sandrini, F Matyakhina, L Bei, T Stergiopoulos, S Papageorgiou, T Bourdeau, I Kirschner, LS Vincent-Dejean, C Perlemoine, K Gicquel, C Bertagna, X Stratakis, CA AF Bertherat, J Groussin, L Sandrini, F Matyakhina, L Bei, T Stergiopoulos, S Papageorgiou, T Bourdeau, I Kirschner, LS Vincent-Dejean, C Perlemoine, K Gicquel, C Bertagna, X Stratakis, CA TI Molecular and functional analysis of PRKARIA and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; SPOTTY SKIN PIGMENTATION; SCHWANNOMAS CARNEY COMPLEX; ALPHA REGULATORY SUBUNIT; ELEMENT-BINDING PROTEIN; CYCLIC-AMP; ENDOCRINE OVERACTIVITY; I-ALPHA; THYROID-CANCER; CELL-LINE AB Germ-line protein kinase A (PKA) regulatory-subunit type-Ialpha (RIalpha; PRKAR1A)-inactivating mutations and loss-of-heterozygosity (LOH) of its 17q22-24 locus have been found in Cushing syndrome (CS) caused by primary pigmented nodular adrenocortical disease (PPNAD). We examined whether somatic 17q22-24, PRKAR1A, or PKA changes are present in 44 sporadic adrenocortical tumors (29 adenomas and 15 cancers); 26 of these tumors were responsible for CS. A probe containing the PRKAR1A gene-mapped by fluorescent in situ hybridization to 17q22-24-and corresponding microsatellite markers were used to study allelic losses; PRKAR1A was sequenced in all samples. 17q22-24 losses were seen in 23 and 53% of adenomas and cancers, respectively. In three tumors, somatic, PRKAR1A -inactivating mutations were identified: (a) a nonsense mutation in exon 6 (A751G); (b) a splicing mutation (9IVS-1G/A); and (c) a transition (1050T>C) followed by a 22-bp deletion, also in exon 9; all predicted premature RIalpha protein terminations. Quantitative message and protein studies showed RIalpha down-regulation in tumors with genetic changes; their cortisol secretion pattern was similar to that of PPNAD, and they had higher PKA activity by enzymatic studies. We conclude that somatic allelic losses of the 17q22-24 region, PRKAR1A -inactivating mutations or down-regulation, and corresponding PKA activity changes are present in at least some sporadic adrenocortical tumors, especially those with a PPNAD-like clinical presentation of CS. C1 NICHD, DEB, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. Univ Paris 05, Hop Cochin, INSERM, U567,CNRS,UMR 8104, F-75014 Paris, France. COMETE Network, F-75012 Paris, France. Hop Trousseau, Lab Explorat Fonctionelles Endocriniennes, F-75012 Paris, France. RP Stratakis, CA (reprint author), NICHD, DEB, Sect Endocrinol & Genet, NIH, Bldg 10,Rm 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. RI Levesque, Isabelle/A-1899-2012 NR 65 TC 153 Z9 158 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 SEP 1 PY 2003 VL 63 IS 17 BP 5308 EP 5319 PG 12 WC Oncology SC Oncology GA 722XD UT WOS:000185402600023 PM 14500362 ER PT J AU Ma, WB Tessarollo, L Hong, SB Baba, M Southon, E Back, TC Spence, S Lobe, CG Sharma, N Maher, GW Pack, S Vortmeyer, AO Guo, CF Zbar, B Schmidt, LS AF Ma, WB Tessarollo, L Hong, SB Baba, M Southon, E Back, TC Spence, S Lobe, CG Sharma, N Maher, GW Pack, S Vortmeyer, AO Guo, CF Zbar, B Schmidt, LS TI Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene SO CANCER RESEARCH LA English DT Article ID HIPPEL-LINDAU-DISEASE; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; CENTRAL-NERVOUS-SYSTEM; SUPPRESSOR GENE; EMBRYONIC LETHALITY; GERMLINE MUTATIONS; UBIQUITIN LIGASE; TSC2 MUTATION; PROTEIN; EXPRESSION AB von Hippel-Lindau (VHL) disease is a multisystem inherited cancer syndrome characterized by the development of highly vascular tumors including hemangioblastomas of the retina and central nervous system, pheochromocytomas, and clear cell renal carcinoma, which result from somatic inactivation of the wild-type VHL allele in cells harboring a germ-line VHL mutation. Homozygous inactivation of the VHL gene in mice resulted in embryonic lethality. To produce a mouse model that closely mimics human VHL disease and avoids embryonic lethality, we used Cre/lox site-specific recombination technology. We generated mice carrying conditional VHL alleles and a cre transgene under the control of the human beta-actin promoter, which directs cre expression in a mosaic pattern in multiple organs. VHLf/d/Cre mice developed multiple, hepatic hemangiomas that led to premature death, as well as angiectasis and angiogenesis in multiple organs. Interestingly, testes of male VHLf/d/Cre mice were unusually small with severely reduced sperm count resulting in infertility. Loss of pVHL function in this VHL conditional knockout mouse model results in an extensive abnormal vascular phenotype in multiple mouse organs, which will provide a useful animal model for testing potential antiangiogenic therapies for VHL disease treatment. Importantly, the phenotypic defects in sperm development observed in these mice support a novel role for VHL in spermatogenesis. This VHL conditional knockout mouse model will provide an in vivo system for studying the functional requirement of the VHL gene in reproductive biology. C1 NCI, Ctr Canc Res, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Lab Anim Sci, Frederick, MD 21702 USA. NCI, Basic Res Program, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. Yokohama City Univ, Sch Med, Dept Urol, Yokohama, Kanagawa 236, Japan. Sunnybrook & Womens Coll, Ctr Hlth, Toronto, ON M4N 3M5, Canada. Natl Inst Neurol Dis Blindness & Stroke, Surg Neurol Branch, Bethesda, MD 20894 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21210 USA. RP Schmidt, LS (reprint author), NCI, Ctr Canc Res, Immunobiol Lab, Bldg 560,Room 12-69, Frederick, MD 21702 USA. RI Baba, Masaya/L-7490-2013; Pack, Svetlana/C-2020-2014 OI Baba, Masaya/0000-0002-5308-6683; FU PHS HHS [N01-C0-12400] NR 56 TC 80 Z9 84 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 SEP 1 PY 2003 VL 63 IS 17 BP 5320 EP 5328 PG 9 WC Oncology SC Oncology GA 722XD UT WOS:000185402600024 PM 14500363 ER PT J AU Bishop, AJR Hollander, MC Kosaras, B Sidman, RL Fornace, AJ Schiestl, RH AF Bishop, AJR Hollander, MC Kosaras, B Sidman, RL Fornace, AJ Schiestl, RH TI Atm-, p53-, and Gadd45a-deficient mice show an increased frequency of homologous recombination at different stages during development SO CANCER RESEARCH LA English DT Article ID EYED UNSTABLE MUTATION; RETINAL-PIGMENT EPITHELIUM; CELL-CYCLE CHECKPOINT; ATAXIA-TELANGIECTASIA; DNA-DAMAGE; IONIZING-RADIATION; P53 PROTEIN; X-RAYS; INTRACHROMOSOMAL RECOMBINATION; DEPENDENT PHOSPHORYLATION AB Atm, p53, and Gadd45a form part of a DNA-damage cellular response pathway; the absence of any one of these components results in increased genomic instability. We conducted an in vivo examination of the frequency of spontaneous homologous recombination in Atm-, p53-, or Gadd45a-deficient mice. In the absence of p53, we observed the greatest increase in events, a lesser increase in the absence of Atm, and only a modest increase in the absence of Gadd45a. The striking observation was the difference in the time at which the spontaneous events occurred in atm and trp53 mutant mice. The frequency of homologous recombination in atm mutant mice was increased later during development. In contrast, p53 appears to have a role in suppressing homologous recombination early during development, when p53 is known to spontaneously promote p21 activity. The timing of the increased spontaneous recombination was similar in the Gadd45a- and p53-deficient mice. This temporal resolution suggests that Atm and p53 can act to maintain genomic integrity by different mechanisms in certain in vivo contexts. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Inst Med, Dept Neurol, Boston, MA 02115 USA. Univ Calif Los Angeles, Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. RP Schiestl, RH (reprint author), Harvard Univ, Sch Med, Dept Genet, 200 Longwood Ave, Boston, MA 02115 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NIEHS NIH HHS [KO2 ES00299, R01 ES09519]; NIGMS NIH HHS [F32GM19147] NR 72 TC 44 Z9 49 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2003 VL 63 IS 17 BP 5335 EP 5343 PG 9 WC Oncology SC Oncology GA 722XD UT WOS:000185402600026 PM 14500365 ER PT J AU Clair, T Aoki, J Koh, E Bandle, RW Nam, SW Ptaszynska, MM Mills, GB Schiffmann, E Liotta, LA Stracke, ML AF Clair, T Aoki, J Koh, E Bandle, RW Nam, SW Ptaszynska, MM Mills, GB Schiffmann, E Liotta, LA Stracke, ML TI Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate SO CANCER RESEARCH LA English DT Article ID SMOOTH-MUSCLE CELLS; LYSOPHOSPHATIDIC ACID RECEPTOR; MOTILITY-STIMULATING PROTEIN; SPHINGOSINE 1-PHOSPHATE; DIFFERENTIAL REGULATION; HAPTOTACTIC MOTILITY; LYSOPHOSPHOLIPASE-D; ENDOTHELIAL-CELLS; PHOSPHOLIPASE-D; MELANOMA-CELLS AB Autotaxin (ATX) is an exoenzyme that potently induces tumor cell motility, and enhances experimental metastasis and angiogenesis. ATX was shown recently to be identical to serum lysophospholipase D activity, producing lysophosphatidic acid (LPA) from lyso-glycerophospholipids. LPA, itself a strong chemoattractant for tumor cells, may mediate the actions of ATX. We now extend the substrate specificity to sphingo-sylphosphorylcholine (SPC), which ATX hydrolyzes to sphingosine-1-phosphate (SIP). Under migration assay conditions, this novel reaction for the production of SIP has a substrate (SPC) K-m = 0.23 +/- 0.07 mm. In our responder cell lines (NIH3T3 clone7 and A2058), S1P exerts maximal biological effects at concentrations of 10-100 nm and is mimicked in its biological effects by ATX plus SPC. These effects include inhibition of ATX- and LPA-stimulated motility, and elevation of activated Rho. In NIH3T3 clone7 cells stimulated with platelet-derived growth factor and treated with 10-25 nm S1P, motility is not inhibited and activation of Rho is unaffected, indicating that S1P possesses specificity in its effects. The exoenzyme ATX can potentially regulate diverse processes such as motility and angiogenesis via the S1P family of receptors. Because ATX hydrolyzes nucleotides, lyso-glycerophospholipids, and phosphosphingo-lipids into bioactive products, it possesses the ability, depending on the availability of substrates, to act as positive or negative regulator of receptor-mediated activity in the cellular microenvironment. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 113, Japan. MD Anderson Canc Ctr, Dept Mol Therapeut, Houston, TX 77030 USA. RP Clair, T (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Aoki, Junken/0000-0001-9435-1896 NR 51 TC 163 Z9 168 U1 0 U2 8 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 SEP 1 PY 2003 VL 63 IS 17 BP 5446 EP 5453 PG 8 WC Oncology SC Oncology GA 722XD UT WOS:000185402600041 PM 14500380 ER PT J AU Ying, H Suzuki, H Furumoto, H Walker, R Meltzer, P Willingham, MC Cheng, SY AF Ying, H Suzuki, H Furumoto, H Walker, R Meltzer, P Willingham, MC Cheng, SY TI Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR-BETA; NECROSIS-FACTOR-ALPHA; HORMONE NUCLEAR RECEPTORS; TRANSFORMING GENE PTTG; TRANSGENIC MICE; CYCLIN D1; CELL-LINE; PAPILLARY CARCINOMAS; LIPOPROTEIN-LIPASE; RET/PTC1 ONCOGENE AB The molecular genetics underlying thyroid carcinogenesis is not well understood. We have recently created a mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse). TRbeta(PV/PV) mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia and eventually metastasis to distant organs. TRbeta(PV/PV) mice provide an unusual opportunity to study the alterations in gene regulation that occur during thyroid carcinogenesis. To this end, we profiled the genomic changes in the thyroids of TRbeta(PV/PV) mice at 6 months of age, at which time metastasis had begun. From arrays of 20 000 mouse cDNAs, 185 genes were up-regulated (2-17-fold) and 92 were down-regulated (2-20-fold). Functional clustering of named genes with reported functions (100 genes) indicated that similar to39% of these genes were tumor-, metastasis/invasion- and cell-cycle-related. Among the activated tumor-related genes identified, cyclin D1, pituitary tumor transforming gene-1, cathespin D and transforming growth factor alpha were also found to over-express in human thyroid cancers. Analyses of the gene profiles suggested that the signaling pathways mediated by thyrotropin, peptide growth factors, transforming growth factor-beta, tumor necrosis factor-alpha and nuclear factor-kappaB were activated, whereas pathways mediated by peroxisome proliferation activated receptor gamma were repressed. These results indicate that complex alterations of multiple signaling pathways contribute to thyroid carcinogenesis. The critical genes associated with thyroid follicular carcinogenesis uncovered in the present study could serve as signature genes for diagnostic purposes, as well as for possible therapeutic targets. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. NR 70 TC 56 Z9 57 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 SEP PY 2003 VL 24 IS 9 BP 1467 EP 1479 DI 10.1093/carcin/bgg111 PG 13 WC Oncology SC Oncology GA 721HB UT WOS:000185310000006 PM 12869418 ER PT J AU Balansky, RM Izzotti, A D'Agostini, F Camoirano, A Bagnasco, M Lubet, RA De Flora, S AF Balansky, RM Izzotti, A D'Agostini, F Camoirano, A Bagnasco, M Lubet, RA De Flora, S TI Systemic genotoxic effects produced by light, and synergism with cigarette smoke in the respiratory tract of hairless mice SO CARCINOGENESIS LA English DT Article ID EPIDERMOID CARCINOMA-CELLS; INDUCED DNA-DAMAGE; HALOGEN LAMPS; HUMAN-LYMPHOCYTES; UV-RADIATION; IN-VITRO; 8-HYDROXY-2'-DEOXYGUANOSINE; ULTRAVIOLET; SUNLIGHT; CARCINOGENESIS AB No information is available on the interaction between cigarette smoke, the most important man-made carcinogen, and light, the most widespread natural carcinogen. In order to clarify this issue, SKH-1 hairless mice were exposed to environmental smoke and/or to the light emitted by sunlight-simulating halogen quartz bulbs. After 28 days, intermediate biomarkers were evaluated in skin, respiratory tract, bone marrow and peripheral blood. The results showed that, individually, the light produced extensive alterations not only in the skin but even at a systemic level, as shown by formation of bulky DNA adducts in both lung and bone marrow and induction of cytogenetic damage in bone marrow and peripheral blood erythrocytes. Smoke damaged the respiratory tract and produced significant alterations in the skin as well as an evident cytogenetic damage in both bone marrow and peripheral blood. Interestingly, as compared with exposure to smoke only, alternate daily cycles of exposure to both light and smoke significantly increased malondialdehyde concentrations and DNA adduct levels in lung and the frequency of micronuclei in pulmonary alveolar macrophages. The oral administration of sulindac, a non-steroidal anti-inflammatory drug, attenuated several biomarker alterations due to the combined exposure of mice to light and smoke. In conclusion, the light induces a systemic genotoxic damage, which is presumably due to the UV-mediated formation in the skin of long-lived derivatives, such as aldehydes. This damage may mechanistically be involved in light-related hematopoietic malignancies. In addition, the light displayed an insofar unsuspected synergism with smoke in the induction of DNA damage in the respiratory tract. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Bethesda, MD 20892 USA. Natl Oncol Ctr, Sofia 1756, Bulgaria. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. OI izzotti, alberto/0000-0002-8588-0347 FU NCI NIH HHS [N01-CN-75008] NR 47 TC 35 Z9 35 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2003 VL 24 IS 9 BP 1525 EP 1532 DI 10.1093/carcin/bgg108 PG 8 WC Oncology SC Oncology GA 721HB UT WOS:000185310000012 PM 12844483 ER PT J AU Cachau, RE Gonzalez-Sapienza, G Burt, SK Ventura, ON AF Cachau, RE Gonzalez-Sapienza, G Burt, SK Ventura, ON TI A new addition to the structural bioinformatics toolbox: 3D models of short bioactive peptides from multiple sequences using feedback restrained molecular dynamics (FRMD) SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Article DE epitope mapping; monoclonal antibodies; peptidomimetics; restraint; model; SAR; FRMD; mimotope; bioinformatics; structure ID GRANULOSUS ANTIGEN-B; ECHINOCOCCUS-GRANULOSUS; PROTEIN HORMONE AB Modem molecular biology techniques allow the use of new approaches for the 3D mapping of 1D information. Molecular biology techniques are capable of producing large amounts of 1D information (sequences) from a number of different sources (phage displays, ESTs etc.). In this work, we present a technique that takes advantage of large sets of 1D information and increasingly available computer power to create 3D models. For the purpose of validation the technique is first applied to the modeling of an erythropoietin analog of known 3D structure from 1D information only. The technique is then used to model the immunoreactive region of echinococcus granulosus AgB based on phage raised mimotopes for which there is no previous structural information. The technique here presented is of general application to similar problems where 1D information is available and structure activity relationships (SAR) is needed. C1 SAIC Frederick Inc, Natl Canc Inst, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. Univ Republica, Fac Quim, Catedra Inmunol, Montevideo 11600, Uruguay. UDELAR, Fac Quim, CCPG, DEQUIFIM, Montevideo 11800, Uruguay. RP Cachau, RE (reprint author), SAIC Frederick Inc, Natl Canc Inst, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. FU FIC NIH HHS [D43 TW005718]; NCI NIH HHS [N01-CO-12400] NR 15 TC 1 Z9 3 U1 0 U2 0 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD SEP PY 2003 VL 49 IS 6 BP 973 EP 983 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 749PK UT WOS:000186929000013 PM 14656056 ER PT J AU Steiner, TJ Scher, AI Stewart, WF Kolodner, K Liberman, J Lipton, RB AF Steiner, TJ Scher, AI Stewart, WF Kolodner, K Liberman, J Lipton, RB TI The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity SO CEPHALALGIA LA English DT Article DE epidemiology; migraine; prevalence; sociodemographic; United Kingdom ID POPULATION-BASED SURVEY; TENSION-TYPE HEADACHE; GENERAL-POPULATION; NATIONWIDE SURVEY; CLINICAL-FEATURES; EPIDEMIOLOGY; IMPACT; RACE; AURA AB This study estimates the 1-year prevalence of migraine in adults in England in relation to the major demographic variables of age, gender and ethnicity, and describes some of its features, including aspects of consequential disability. A telephone survey was conducted of a random sample (n = 4007) of the population aged 16-65 years of mainland England using a previously validated diagnostic interview. The response rate was 76.5%. Overall, 7.6% of males and 18.3% of females reported migraine with or without aura within the last year meeting diagnostic criteria closely approximate to those of the International Headache Society. Prevalence of migraine varied with age, rising through early adult life and declining in the late 40s and early 50s. Prevalence was higher in Caucasians than in other races. Attack rates were greater than or equal to1/month in most migraineurs, and most experienced interference with daily activities in greater than or equal to50% of their attacks. On average, an estimated 5.7 working days were lost per year for every working or student migraineur, although the most disabled 10% accounted for 85% of the total. Results were in keeping with those from surveys in other countries. If these findings in mainland England are projected to the entire UK population, we estimate that 5.85 million people aged 16-65 years experience 190 000 migraine attacks every day and lose 25 million days from work or school each year because of them. Migraine is an important public health problem in the UK, associated with very substantial costs. C1 Univ London Imperial Coll Sci Technol & Med, Div Neurosci, London W6 8RP, England. NINDS, Neuroepidemiol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. Innovat Med Res, Towson, MD USA. Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. RP Steiner, TJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Neurosci, Charing Cross Campus,St Dunstans Rd, London W6 8RP, England. NR 42 TC 190 Z9 194 U1 1 U2 11 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD SEP PY 2003 VL 23 IS 7 BP 519 EP 527 DI 10.1046/j.1468-2982.2003.00568.x PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 717XA UT WOS:000185115000007 PM 12950377 ER PT J AU Merikangas, KR AF Merikangas, KR TI Genetic epidemiologic approaches to understanding patterns of migraine comorbidity SO CEPHALALGIA LA English DT Meeting Abstract CT 11th Congress of the International-Headache-Society CY SEP 12-16, 2003 CL ROME, ITALY SP Int Headache Soc C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD SEP PY 2003 VL 23 IS 7 BP 567 EP 567 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 717XA UT WOS:000185115000021 ER PT J AU Shenton, JM Teranishi, M Abu-Asab, MS Yager, JA Uetrecht, JP AF Shenton, JM Teranishi, M Abu-Asab, MS Yager, JA Uetrecht, JP TI Characterization of a potential animal model of an idiosyncratic drug reaction: Nevirapine-induced skin rash in the rat SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TOXIC EPIDERMAL NECROLYSIS; IMMUNODEFICIENCY-VIRUS INFECTION; PENICILLAMINE-INDUCED AUTOIMMUNITY; STEVENS-JOHNSON-SYNDROME; BROWN-NORWAY RATS; POSTEXPOSURE PROPHYLAXIS; GUINEA-PIGS; T-CELLS; HEPATOTOXICITY; KERATINOCYTES AB Idiosyncratic drug reactions are difficult to study in humans due to their unpredictability. Unfortunately, this characteristic also hinders the development of animal models needed for mechanistic studies. Nevirapine, used to treat human immunodeficiency virus (HIV) infections, results in a severe idiosyncratic skin rash in some patients. We found that nevirapine can also cause a significant rash in some strains of rats. At a dose of 150 mg/kg/day, the incidence in female Sprague-Dawley rats was 6/28 (21%), in female Brown Norway rats 32/32 (100%), and in female Lewis rats 0/6 (0%) while no male Sprague-Dawley or Brown Norway rats developed a rash. Female SJL mice 0/7 also did not develop nevirapine-induced skin lesions. The first sign of a reaction in Brown Norway rats was red ears at days 7-10 followed by a rash with scabbing mainly on the back; this was a shorter time to onset than in Sprague-Dawley rats. Light microscopy of the skin revealed a primarily mononuclear inflammatory infiltrate and lesions typical of self-trauma. Immunohistochemistry results suggest that the infiltrate was composed of CD4 and CD8 T cells as well as macrophages. A lower dose of either 40 or 75 mg/kg/day did not lead to a rash and, in fact, 2 weeks of the lower doses induced tolerance to the 150 mg/kg/day dose in female Brown Norway rats. A dose of 100 mg/kg/day resulted in rash in 2/4 (50%) of female Brown Norway rats. Rechallenge of Brown Norway rats that had been allowed to recuperate after a nevirapine-induced rash led to red ears in less than 24 h followed by hair loss and occasional skin lesions. Although the skin rash was less evident on rechallenge, microscopically, the cellular infiltrate was more prominent, especially surrounding the hair follicles. Moreover, there were lesions of interface dermatitis with apoptosis and satellitosis, indicative of a cell-mediated immune attack on the epidermis. While systemic signs of illness did not accompany the rash on primary exposure, on rechallenge, the animals appeared generally unwell and this forced sacrifice after 2 weeks or less of treatment. Importantly, splenocytes isolated from rechallenged animals were able to transfer susceptibility to nevirapine-induced skin rash to naive female Brown Norway recipients, which was illustrated by a faster time to onset of rash in the recipients. The characteristics of this adverse reaction are similar to that seen in humans; that is, it is idiosyncratic in that it only occurs in some strains of animals, is delayed in onset, is more common in females, is dose-dependent, and appears to be immune-mediated. Therefore, it may represent a good animal model for the study of idiosyncratic drug reactions. C1 Univ Toronto, Fac Pharm, Toronto, ON, Canada. NIH, Bethesda, MD 20892 USA. Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. Univ Toronto, Fac Med, Toronto, ON, Canada. RP Uetrecht, JP (reprint author), Univ Toronto, Fac Pharm, 19 Russell St, Toronto, ON, Canada. OI Abu-Asab, Mones/0000-0002-4047-1232 NR 30 TC 67 Z9 70 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2003 VL 16 IS 9 BP 1078 EP 1089 DI 10.1021/tx034064+ PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 723AR UT WOS:000185410700006 PM 12971795 ER PT J AU Lamb, ME Sternberg, KJ Orbach, Y Hershkowitz, I Horowitz, D AF Lamb, ME Sternberg, KJ Orbach, Y Hershkowitz, I Horowitz, D TI Differences between accounts provided by witnesses and alleged victims of child sexual abuse SO CHILD ABUSE & NEGLECT LA English DT Article DE child sexual abuse; witness accounts; alleged victims' accounts ID INVESTIGATIVE UTTERANCE TYPES; ANATOMICALLY DETAILED DOLLS; EYEWITNESS MEMORY; FORENSIC INTERVIEWS/; QUESTION TYPE; EVENT; PARTICIPATION; TESTIMONY; SUGGESTIBILITY; EXPERIENCE AB Objectives: To determine whether child witnesses of sexual abuse were more or less informative about the alleged incidents than alleged victims when interviewed similarly. Method: Twenty-six alleged victims of child sexual abuse (aged 5 to 14 years; M = 9.8 years) and 26 children who had witnessed but not experienced similar events were interviewed by experienced youth investigators about the alleged abuse. Children in the two groups were matched with respect to their age, relationships with the alleged perpetrator, and seriousness of the alleged offenses. All children were interviewed using the NICHD investigative interview protocol. Results: Witnesses and victims provided similar amounts of information about the incidents of abuse. Interviewers used more open-ended invitations and elicited more information using open-ended prompts from witnesses than from victims, whereas they used more risky (including suggestive) prompts when interviewing victims. Discussion: These results confirm that young children can be informative witnesses about events that they have either experienced or witnessed. Published by Elsevier Ltd. C1 NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Univ Haifa, Sch Social Work, IL-31999 Haifa, Israel. Minist Labor & Social Affairs, Jerusalem, Israel. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Dept Hlth & Human Serv,NIH, Suite 8048,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 57 TC 9 Z9 9 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD SEP PY 2003 VL 27 IS 9 BP 1019 EP 1031 DI 10.1016/S0145-2134(03)00167-4 PG 13 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 732LP UT WOS:000185947500005 PM 14550329 ER PT J AU Johnson, DJ Jaeger, E Randolph, SM Cauce, AM Ward, J AF Johnson, DJ Jaeger, E Randolph, SM Cauce, AM Ward, J CA Natl Inst Child Hlth Human Dev Early Child Care Res Network TI Studying the effects of early child care experiences on the development of children of color in the United States: Toward a more inclusive research agenda SO CHILD DEVELOPMENT LA English DT Review ID NATIONAL LONGITUDINAL SURVEY; EARLY MATERNAL EMPLOYMENT; BLACK EXTENDED FAMILY; AFRICAN-AMERICAN; COGNITIVE-DEVELOPMENT; ACADEMIC-ACHIEVEMENT; RACIAL SOCIALIZATION; ETHNIC SOCIALIZATION; BEHAVIORAL OUTCOMES; MINORITY CHILDREN AB Evidence is presented of the different cultural and ecological contexts affecting early child care for families of color. It is argued that improvements on previous research require a fundamental shift in how race, ethnicity, and culture as psychological variables are examined. Furthermore, to avoid the pitfalls and failures of previous research, new research must incorporate expanded models of child care and development in childhood. The integrative model of development for children of color proposed by Garcia Coll et al. (1996) is presented as a basis for developing more specific ecological models relevant to addressing child care issues in ethnic minority families. Finally, priority areas for future research are recommended to stimulate and enable child care researchers to adopt a more inclusive view of child care and its effects. C1 NICHD, Early Child Care Res Network, CRMC, Rockville, MD 20852 USA. Michigan State Univ, E Lansing, MI 48824 USA. St Josephs Univ, Philadelphia, PA 19131 USA. Univ Maryland, College Pk, MD 20742 USA. Univ Washington, Seattle, WA 98195 USA. Harvard Univ, Cambridge, MA 02138 USA. RP Johnson, DJ (reprint author), NICHD, Early Child Care Res Network, CRMC, 6100 Execut Blvd,4B05, Rockville, MD 20852 USA. NR 129 TC 46 Z9 46 U1 5 U2 7 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD SEP-OCT PY 2003 VL 74 IS 5 BP 1227 EP 1244 DI 10.1111/1467-8624.00604 PG 18 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 725HF UT WOS:000185537600001 PM 14552395 ER PT J AU Duncan, GJ Allhusen, V Belsky, J Booth, CL Bradley, R Brownell, CA Caldwell, B Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Johnson, DJ Kelly, JF McCartney, K Marshall, N O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Robeson, W Spieker, S Vandell, DL Weinraub, M AF Duncan, GJ Allhusen, V Belsky, J Booth, CL Bradley, R Brownell, CA Caldwell, B Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Johnson, DJ Kelly, JF McCartney, K Marshall, N O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Robeson, W Spieker, S Vandell, DL Weinraub, M CA Natl Istituto Child Hlth Human Dev TI Modeling the impacts of child care quality on children's preschool cognitive development SO CHILD DEVELOPMENT LA English DT Article; Proceedings Paper CT Biennial Meeting of the Society-for-Research-in-Child-Development CY APR, 2001 CL MINNEAPOLIS, MN SP Soc Res Child Dev ID LANGUAGE-DEVELOPMENT; MATERNAL EMPLOYMENT; SOCIAL-DEVELOPMENT; OUTCOMES; EXPERIENCES; PROGRAMS; FAMILY; ENVIRONMENT; VOCABULARY; INFANTS AB The National Institute of Child Health and Human Development (NICHD) Study of Early Child Care compared 3 statistical methods that adjust for family selection bias to test whether child care type and quality relate to cognitive and academic skills. The methods included: multiple regression models of 54-month outcomes, change models of differences in 24- and 54-month outcomes, and residualized change models of 54-month outcomes adjusting for the 24-month outcome. The study was unable to establish empirically which model best adjusted for selection and omitted-variable bias. Nevertheless, results suggested that child care quality predicted cognitive outcomes at 54 months, with effect sizes of .04 to .08 for both infant and preschool ages. Center care during preschool years also predicted outcomes across all models. C1 NICHD, Early Child Care Res Network, OEP, Off Director, Rockville, MD 20852 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Univ London Birkbeck Coll, London WC1E 7HX, England. Univ Washington, Seattle, WA 98195 USA. Univ Arkansas, Little Rock, AR 72204 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Michigan State Univ, E Lansing, MI 48824 USA. Harvard Univ, Cambridge, MA 02138 USA. Univ Kansas, Lawrence, KS 66045 USA. Univ Texas, Dallas, TX 75230 USA. Univ N Carolina, Greensboro, NC 27412 USA. Georgetown Univ, Washington, DC 20057 USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Maryland, College Pk, MD 20742 USA. Wellesley Coll, Wellesley, MA 02181 USA. Univ Wisconsin, Madison, WI USA. Temple Univ, Philadelphia, PA 19122 USA. RP Duncan, GJ (reprint author), NICHD, Early Child Care Res Network, OEP, Off Director, 6100 Execut Blvd,4A01, Rockville, MD 20852 USA. RI Marshall, Nancy/C-3428-2012 NR 89 TC 251 Z9 255 U1 13 U2 37 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD SEP-OCT PY 2003 VL 74 IS 5 BP 1454 EP 1475 PG 22 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 725HF UT WOS:000185537600014 PM 14552408 ER PT J AU Wilson, JJ Pine, DS Cargan, A Goldstein, RB Nunes, EV Weissman, MM AF Wilson, JJ Pine, DS Cargan, A Goldstein, RB Nunes, EV Weissman, MM TI Neurological soft signs and disruptive behavior among children of opiate dependent parents SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE children of substance dependent parents; neurological soft signs; behavior disorders ID NEUROPSYCHIATRIC DISORDERS; MAJOR DEPRESSION; COCAINE EXPOSURE; BASAL GANGLIA; BOYS; FAMILY; INTELLIGENCE; IMPAIRMENT; ATTENTION; DEFICITS AB The present study investigates the relationship between neurological soft signs and psychiatric symptoms among children of opiate dependent parents. A consecutive series of 102 children of opiate dependent parents received standardized psychiatric and neurological assessments. Symptoms of externalizing but not internalizing disorders associated with poor performance on the soft sign exam, controlling for age, intelligence, and socioeconomic status. Given the importance of externalizing disorders in the development of substance use disorders, studies of children at high risk for substance use disorder should also consider screening and assessment of children for soft neurological signs. C1 Columbia Univ Coll Phys & Surg, Unit 66, New York, NY 10032 USA. NIMH, Bethesda, MD 20892 USA. RP Wilson, JJ (reprint author), Columbia Univ Coll Phys & Surg, Unit 66, 1051 Riverside Dr, New York, NY 10032 USA. OI Weissman, Myrna/0000-0003-3490-3075; Goldstein, Rise/0000-0002-9603-9473 FU NIDA NIH HHS [K02 DA00288, DA07210, DA14572]; NIMH NIH HHS [MH01391, MH43878] NR 60 TC 3 Z9 3 U1 3 U2 4 PU KLUWER ACADEMIC-HUMAN SCIENCES PRESS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0009-398X J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD FAL PY 2003 VL 34 IS 1 BP 19 EP 34 DI 10.1023/A:1025397824785 PG 16 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 722GV UT WOS:000185367800002 PM 14518621 ER PT J AU Meadows, BJ AF Meadows, BJ TI Eliciting remote data entry system requirements for the collection of cancer clinical trial data SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Article DE clinical trials; clinical nursing research; controlled vocabulary; data collection; information systems ID INFORMATION-SYSTEMS; REFERENCE-STANDARDS; PERFORMANCE AB Information regarding the clinical course of a patient in a clinical trial is critical for cancer research. Nurses and clinical research associates must locate data stored in many formats and transfer data to paper case report forms. These forms are associated with a unique protocol document that specifies the set of data to be collected. This paper-based process involves a series of abstractions that pose a significant potential for error, Remote data entry has been advocated to facilitate and streamline the collection of clinical trial data. A systematic process to elicit system requirements from end-users is described as an approach to integrate computer technology with cancer research. Nurses and clinical research associates, as end-users of remote data entry, can provide invaluable input into the requirements necessary to develop an efficient and practical system. By incorporating this input, remote data entry can offer a potential benefit for preserving data integrity. C1 NCI, Rockville, MD 20852 USA. RP Meadows, BJ (reprint author), NCI, 6130 Execut Blvd,Room 7042, Rockville, MD 20852 USA. EM meadowsb@ctep.nci.nih.gov NR 39 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1538-2931 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD SEP-OCT PY 2003 VL 21 IS 5 BP 234 EP 240 DI 10.1097/00024665-200309000-00010 PG 7 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA 804BN UT WOS:000220274300002 PM 14504599 ER PT J AU Fogarty, PF Rick, ME Zeng, W Risitano, AM Dunbar, CE Bussel, JB AF Fogarty, PF Rick, ME Zeng, W Risitano, AM Dunbar, CE Bussel, JB TI T cell receptor VB repertoire diversity in patients with immune thrombocytopenia following splenectomy SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE autoimmune disease; immune thrombocytopenia; platelets; splenectomy; T cells ID RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; BONE-MARROW; PURPURA; AUTOANTIBODIES; GLYCOPROTEINS; ACCUMULATION; LYMPHOCYTES; CLONOTYPES AB In recent years, a pathophysiological role for T cells in immune thrombocytopenia (ITP) has been established. We applied cDNA size distribution analysis of the T cell receptor (TCR) beta-variable (VB) complementarity-determining region 3 (CDR3) in order to investigate T cell repertoire diversity among immune thrombocytopenia patients who had either responded or not responded to splenectomy, and compared them to normal controls. ITP patients who had had a durable platelet response to splenectomy showed a mean 2.8 +/- 2.1 abnormal CDR3 size patterns per patient, similar to healthy volunteers (2.9 +/- 2.0 abnormal CDR3 size patterns). In contrast, patients unresponsive to splenectomy demonstrated evidence of significantly more clonal T cell expansions than patients who had responded to splenectomy or controls (11.3 +/- 3.3 abnormal CDR3 size patterns per patient; P < 0.001). Of the VB subfamilies analysed, VB3 and VB15 correlated with response or non-response to splenectomy, each demonstrating oligoclonality in non-responding patients (P < 0.05). These findings suggest that removal of the spleen may lead directly or indirectly to reductions in T cell clonal expansions in responders, or that the extent of T cell clonality impacts responsiveness to splenectomy in patients with ITP. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, New York, NY USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,10 Ctr Dr,MSC 1652, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 34 TC 14 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD SEP PY 2003 VL 133 IS 3 BP 461 EP 466 DI 10.1046/j.1365-2249.2003.02239.x PG 6 WC Immunology SC Immunology GA 717AL UT WOS:000185063400023 PM 12930375 ER PT J AU Gerber, LH Furst, G Yarboro, C El-Gabalawy, H AF Gerber, LH Furst, G Yarboro, C El-Gabalawy, H TI Number of active joints, not diagnosis, is the primary determinant of function and performance in early synovitis SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE arthritis; function ID RECENT-ONSET ARTHRITIS; BONE-MINERAL DENSITY; RHEUMATOID-ARTHRITIS; MUSCLE STRENGTH; DISABILITY; DISEASE; CAPACITY AB Objective. A substudy within a larger study of patients with inflammatory arthritis of less than one year to analyze baseline measures or joint counts, laboratory values, patient questionnaires and ARA diagnostic criteria for rheumatoid arthritis, as predictors of one year performance and functional status. Methods. 229 patients with synovitis of less than one year were enrolled and evaluated at baseline and one year. Measures included the number of swollen or tender joints [active joint counts]; biological indices of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]; and patient questionnaire measures of pain [Wisconsin Brief Pain Inventory], fatigue [multi-dimensional assessment of fatigue], depression [Center for Epidemiologic Studies - Depression Scale], sleep [Sleep Quality Index], performance [Human Activity Profile], and function [Sickness Impact Profile ambulation subscale and Health Assessment Questionnaire]. Correlations between these measures were evaluated using the Spearman rank order correlation. Patients were classified according to whether the-v met ARA criteria for RA, had high (> 7) or low (less than or equal to 7) numbers of affected joints; and high, intermediate, or low levels of performance; and were compared using the Kruskal-Wallis test. Results. At baseline, an active joint count of > 7 versus less than or equal to 7 was associated significantly with higher age, rheumatoid factor positivity, a diagnosis a rheumatoid arthritis versus spondyloarthropathy or undifferentiated arthritis, and receiving a disease modifying antirheumatic drug (DMARD), but not with sex, race, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), or receiving prednisone. Furthermore, high baseline active joint counts were associated significantly with patient questionnaire scores for maximum activity, fatigue and depression, but differences were not significant for sleep, ambulation and pain scores. A comparison of patients who met or did not meet criteria for RA indicated significant differences only according to the fatigue scores, but none of the other questionnaire measures. Correlations of baseline measures with one-year performance were highest for the baseline active joint count compared to laboratory and questionnaire variables. The maximum activity score at one year was predicted significantly by the baseline maximum activity score, active joint count, and age, but not by laboratory tests at whether the patient met criteria for RA. Conclusion. The active joint count predicts subsequent performance and function for patients with recent onset, inflammatory synovitis more effectively than whether patients met ARA criteria for RA. C1 NIH, Dept Rehabil Med, US Dept HHS, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gerber, LH (reprint author), NIH, Dept Rehabil Med, US Dept HHS, Warren G Magnuson Clin Ctr, Bldg 10,Room 6S235,MSC 1604, Bethesda, MD 20892 USA. NR 26 TC 16 Z9 17 U1 0 U2 2 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2003 VL 21 IS 5 SU 31 BP S65 EP S70 PG 6 WC Rheumatology SC Rheumatology GA 732XD UT WOS:000185970100012 PM 14969053 ER PT J AU Goldbach-Mansky, R Mahadevan, V Yao, L Lipsky, PE AF Goldbach-Mansky, R Mahadevan, V Yao, L Lipsky, PE TI The evaluation of bone damage in rheumatoid arthritis with magnetic resonance imaging SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE magnetic resonance imaging; bone erosions; rheumatoid arthritis ID FINGER JOINTS; INTERNATIONAL MULTICENTER; INFLAMMATORY ARTHRITIS; MRI; WRIST; EROSIONS; KNEE; LESIONS; EDEMA AB Magnetic resonance imaging (MRA) greatly improves the early detection and visualization of osseous and non-osseous joint changes over conventional x-rays of involved joints in patients with rheumatoid arthritis (RA). However the "pathophysiological correlate" of these MR imaging changes remains Poorly defined. Careful validation of MRI findings and the evaluation of MRI as a tool to follow the effect of therapy remain to be performed before MRI may be used as a clinical tool to follow therapy or as a surrogate for evaluating osseous changes over time. C1 NIAMSD, Off Clin Director, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Goldbach-Mansky, R (reprint author), NIAMSD, Off Clin Director, Bldg 10,Room 9S205,10 Ctr Dr, Bethesda, MD 20892 USA. NR 29 TC 7 Z9 7 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2003 VL 21 IS 5 SU 31 BP S50 EP S53 PG 4 WC Rheumatology SC Rheumatology GA 732XD UT WOS:000185970100009 PM 14969050 ER PT J AU Tofilon, PJ Saxman, S Coleman, CN AF Tofilon, PJ Saxman, S Coleman, CN TI Molecular targets for radiation therapy: Bringing preclinical data into clinical trials SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID ZD1839 IRESSA; RADIOTHERAPY; MODULATION; SINGLE C1 NCI, Mol Radiat Therapeut Branch, Radiat Res Program,NIH, Radiat Oncol Sci Program,Div Canc Treatment & Dia, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, Mol Radiat Therapeut Branch, Radiat Res Program,NIH, Radiat Oncol Sci Program,Div Canc Treatment & Dia, Bethesda, MD 20892 USA. NR 16 TC 6 Z9 7 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 SEP 1 PY 2003 VL 9 IS 10 BP 3518 EP 3520 PN 1 PG 3 WC Oncology SC Oncology GA 725NB UT WOS:000185548300001 PM 14506136 ER PT J AU Dong, SM Sun, DI Benoit, NE Kuzmin, I Lerman, MI Sidransky, D AF Dong, SM Sun, DI Benoit, NE Kuzmin, I Lerman, MI Sidransky, D TI Epigenetic inactivation of RASSF1A in head and neck cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; SQUAMOUS-CELL CARCINOMA; 3P ALLELE LOSS; HUMAN-CHROMOSOME 3P21.3; PROMOTER HYPERMETHYLATION; HUMAN-PAPILLOMAVIRUS; REGION 3P21.3; NASOPHARYNGEAL CARCINOMA; BREAST CANCERS; LUNG-CANCER AB Purpose: RASSF1A, a recently identified candidate tumor suppressor gene, was found to be inactivated in lung cancer and other tumor types. We sought to understand the role of RASSF1A in head and neck cancer. Experimental Design: We analyzed the status of RASSF1A and presence of high-risk human papilloma virus (HPV) in head and neck cancer squamous cell carcinoma (HNSCC) cell lines and primary tumors. We used methylation-specific PCR to detect promoter hypermethylation and direct sequence analysis to detect point mutations in primary tumors and cell lines. 5-aza-2-deoxycytidine was used to demethylate the RASSF1A promoter in cell lines. Results: Promoter methylation of RASSF1A was detected in 42.9% (3 of 7) cell lines and 15% (7 of 46) primary tumors but not in the normal control DNA. Direct sequence analysis revealed a point mutation in a cell line and another in a primary HNSCC. After treatment with 5-aza-2-deoxycytidine, re-expression and demethylation of RASSF1A gene were detected in cell tines with promoter hypermethylation. HPV DNA was detected in 34.7% (16 of 46) primary HNSCC. We found a significant inverse correlation between RASSF1A promoter methylation and HPV infection (P 0.038). Conclusions: Our results suggest that RASSF1A is inactivated in a subset of HNSCC primary tumors. Moreover, an inverse correlation between RASSF1A and HPV supports a biological mechanism in which both RASSF1A promoter methylation and HPV infection abrogate the same pathway in tumorigenesis. C1 Johns Hopkins Univ, Sch Med, Div Head & Neck Surg, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. NCI, Immunobiol Lab, Frederick, MD 21702 USA. Catholic Univ Korea, Dept Otolaryngol Head & Neck Surg, Coll Med, Seoul, South Korea. RP Sidransky, D (reprint author), Johns Hopkins Univ, Sch Med, Div Head & Neck Surg, Dept Otolaryngol Head & Neck Surg, 818 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. FU NCI NIH HHS [N01-CO-12400]; NIDCR NIH HHS [R01-DE012588] NR 40 TC 55 Z9 58 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 SEP 1 PY 2003 VL 9 IS 10 BP 3635 EP 3640 PN 1 PG 6 WC Oncology SC Oncology GA 725NB UT WOS:000185548300016 PM 14506151 ER PT J AU Russell, JS Burgan, W Oswald, KA Camphausen, K Tofilon, PJ AF Russell, JS Burgan, W Oswald, KA Camphausen, K Tofilon, PJ TI Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin: A multitarget approach to radiosensitization SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; PROSTATE-CANCER; SIGNAL-TRANSDUCTION; HSP90; APOPTOSIS; RECEPTOR; PATHWAY; GROWTH; RADIORESISTANCE; GELDANAMYCIN AB Purpose: Current strategies for tumor cell radiosensitization focus on a target-based approach. However, the radioresponse of a tumor cell is influenced by a wide variety of signaling molecules existing in a number of different survival pathways. Therefore, in an attempt to increase the probability and/or degree of radiosensitization, we have begun to investigate a multitarget approach using the heat shock protein 90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17AAG). Experimental Design: The effect of 17AAG on the levels of three proteins (Raf-1, ErbB2, and Akt) previously implicated in the regulation of radiosensitivity was determined in four human tumor cell lines. Tumor cell survival. after exposure to corresponding concentrations of 17AAG combined with clinically relevant doses of X-rays was then evaluated using a clonogenic assay. The radiosensitivity of a nonimmortalized, normal fibroblast cell line was also determined after exposure to 17AAG. Results: Exposure to nanomolar concentrations of 17AAG reduced the levels of the three radiosensitivity-associated proteins in a cell type manner. Using corresponding concentrations, 17AAG enhanced the radiosensitivity of each of the tumor cell lines with enhancement factors ranging from 1.3 to 1.7. The enhancement appeared to be related to the number of radioresponse-regulatory proteins affected. In contrast to the tumor cell lines, 17AAG had no effect on the radiosensitivity of a normal, nonimmortalized human fibroblast cell line. Conclusions: These data suggest that heat shock protein 90 may be an appropriate target for selectively enhancing the radiosensitivity of tumor cells over normal cells. Furthermore, they illustrate the potential of a multitarget approach to radiosensitization. C1 NCI, Mol Radiat Therapeut Branch, Radiat Oncol Sci Program, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, Mol Radiat Therapeut Branch, Radiat Oncol Sci Program, EPN-6015A,6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. NR 25 TC 84 Z9 91 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2003 VL 9 IS 10 BP 3749 EP 3755 PN 1 PG 7 WC Oncology SC Oncology GA 725NB UT WOS:000185548300032 PM 14506167 ER PT J AU Mamede, M Saga, T Kobayashi, H Ishimori, T Higashi, T Sato, N Brechbiel, MW Konishi, J AF Mamede, M Saga, T Kobayashi, H Ishimori, T Higashi, T Sato, N Brechbiel, MW Konishi, J TI Radiolabeling of avidin with very high specific activity for internal radiation therapy of intraperitoneally disseminated tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID ELECTRON-EMITTING RADIONUCLIDES; NEUTRON-CAPTURE THERAPY; GROUP NO 6; MONOCLONAL-ANTIBODY; AUGER-ELECTRON; ANTISENSE OLIGONUCLEOTIDES; STARBURST DENDRIMERS; PAMAM DENDRIMERS; CELLS-INVITRO; COLON-CANCER AB Purpose: For the effective internal radiation therapy of i.p. disseminated tumors, we developed avidin (Av)-dendrimer-chelate complex, which can be labeled with indium-111, emitting Auger and conversion electrons, with very high specific activity, and we studied its internalization, biodistribution, and therapeutic effect in nude mice with i.p. tumors. Experimental Design: Generation 4 dendrimer (G4) was biotinylated and conjugated with 52 1B4M chelates. In-111-G4-bt was mixed with Av to form In-111-G4-Av complex. In-111-G4-Av was incubated with ovarian cancer cells (SHIN-3), and the rate of internalization of the radiolabel into SHIN-3 cells was followed. In-111-G4-Av was i.p. injected into nude mice that had i.p. disseminated SHIN-3 tumors, and the biodistribution was determined. Nude mice bearing i.p. disseminated tumors received i.p. injection of In-111-G4-Av (9.25 or 18.5 MBq x 2, with a 1-week interval) and were followed for the formation of malignant ascites. Results: Av could be labeled with In-111 with specific activity as high as 37 GBq/mg. More than 75% of the radioactivity was internalized 24 It after binding to cancer cells. In-111-G4-Av accumulated rapidly and highly in the i.p. tumors (128.20% injected dose/gram of tissue at 2 h, 114.91% injected dose/gram of tissue at 24 h for unsaturated compound) with high tumor:background ratios. Treatment with a high dose of In-111-G4-bt-Av was tolerable and showed dose-dependent therapeutic effect. Conclusions: G4-Av complex, which could be labeled with In-111 with very high specific activity and showed efficient internalization into cancer cells and high accumulation to i.p. tumors, appears to be suitable for the internal radiation therapy of i.p. disseminated tumors using metallic radionuclides emitting Auger and conversion electrons. C1 Kyoto Univ, Grad Sch Med, Dept Nucl Med & Diagnost Imaging, Sakyo Ku, Kyoto 6068507, Japan. NCI, NIH, Bethesda, MD 20892 USA. RP Saga, T (reprint author), Kyoto Univ, Grad Sch Med, Dept Nucl Med & Diagnost Imaging, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. RI Mamede, Marcelo/A-1751-2014 OI Mamede, Marcelo/0000-0001-5818-0954 NR 43 TC 16 Z9 16 U1 1 U2 5 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 SEP 1 PY 2003 VL 9 IS 10 BP 3756 EP 3762 PN 1 PG 7 WC Oncology SC Oncology GA 725NB UT WOS:000185548300033 PM 14506168 ER PT J AU Ouatas, T Halverson, D Steeg, PS AF Ouatas, T Halverson, D Steeg, PS TI Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: New uses for old compounds SO CLINICAL CANCER RESEARCH LA English DT Article ID NM23/NUCLEOSIDE DIPHOSPHATE KINASE; NERVE GROWTH-FACTOR; CANCER-CELLS; MELANOMA-CELLS; ADENOCARCINOMA CELLS; NEUROBLASTOMA-CELLS; SIGNAL-TRANSDUCTION; BASEMENT-MEMBRANE; ALPHA-ISOFORM; PC12 CELLS AB Purpose: Long-term elevation of metastasis suppressor gene expression in micrometastases represents a novel therapeutic strategy for breast and other cancers. We searched for well-tolerated compounds that could elevate Nm23 metastasis suppressor expression in metastatic human breast cancer cell lines. Experimental Design: MDA-MB-435 and MDA-MB-231 human breast carcinoma cells were treated with dexamethasone or medroxyprogesterone acetate (MPA) in cultures containing either charcoal-stripped serum or FCS. Aspects of nm23 expression and function were determined. Results: Previous investigation of the nm23-H10 promoter suggested that glucocorticoids may contribute to the elevation of Nm23-H1 expression. Dexamethasone elevated Nm23-H1 and Nm23-H2 protein levels in two metastatic human breast carcinoma cell lines 2-3-fold over a 4-day time course when cultured in steroid-free culture medium, with high-dose inhibition, via a traditional transcriptional mechanism. Elevation of Nm23-H1 expression was not observed using FCS-containing culture medium, which contains endogenous levels of corticosteroids, limiting the potential in vivo use of dexamethasone. MPA was investigated as a glucocorticoid receptor agonist. MPA elevated breast carcinoma Nm23-H1 protein expression 3-fold over a 10 nM to 1 muM dose range when cultured in steroid-free or FCS-containing medium, with a shorter time course. Elevation of Nm23-H1 expression in the presence of endogenous corticosteroids found in FCS involved a distinct, glucocorticoid receptor-dependent, posttranscriptional mechanism of action. KPA had no effect on proliferation in vitro but reduced the soft agar colonization of metastatic breast cancer cell lines by similar to50%. Conclusions: MPA represents a first generation lead agent for the elevation of Nm23-H1 metastasis suppressor expression and the inhibition of metastatic colonization. C1 NCI, Womens Canc Sect, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NIH, Bldg 10,Room 2A33, Bethesda, MD 20892 USA. NR 72 TC 59 Z9 64 U1 1 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 SEP 1 PY 2003 VL 9 IS 10 BP 3763 EP 3772 PN 1 PG 10 WC Oncology SC Oncology GA 725NB UT WOS:000185548300034 PM 14506169 ER PT J AU Kokkinakis, DM Ahmed, MM Chendil, D Moschel, RC Pegg, AE AF Kokkinakis, DM Ahmed, MM Chendil, D Moschel, RC Pegg, AE TI Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O-6-methylguanine-DNA methyltransferase with O-6-benzylguanine or O-6-benzyl-2 '-deoxyguanosine SO CLINICAL CANCER RESEARCH LA English DT Article ID LONG-TERM SURVIVAL; DUCTAL ADENOCARCINOMA; ALKYLATING-AGENTS; CANCER; DNA; CARCINOMA; TRIAL; PHASE; STREPTOZOTOCIN; 5-FLUOROURACIL AB Adenocarcinoma of the pancreas is refractory to chemotherapeutic agents, including BCNU and streptozotocin. We have previously shown that drugs, which adduct the O-6-position of guanine, are ineffective against pancreatic tumor cell lines because of high expression of O-6-methylguanine-DNA methyltransferase (MGMT). The effect of MGMT inactivation on the resistance of pancreatic tumors to carmustine (BCNU) and to temozolomide (TMZ) was examined in five human pancreatic tumor xenografts in athymic mice. Tumor-bearing mice were treated: (a) with a single i.p. injection of BCNU or TMZ at the maximum-tolerated doses of 75 and 340 mg/m(2), respectively; and (b) with O-6-benzyl-guanine (BG) or O-6-benzyl-2'-deoxyguanosine (dBG) in combination with BCNU or TMZ. Pretreatment with the MGMT inactivators BG or dBG reduced the maximum-tolerated doses of BCNU and TMZ to 35 and 170 mg/m(2), respectively. MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 having MGMT levels of 890, 1680, 680, 900, and 330 fmol/mg protein, respectively, were unresponsive to BCNU. MIA PaCa-2 and CFPAC-1 were also unresponsive to TMZ, whereas CAPAN-2 responded with a tumor delay of 32 days. BG or dBG sensitized all tumors to both BCNU and TMZ. BG plus BCNU treatment of MIA PaCa-2, CF-PAC-1, PANC-1, CAPAN-2, and BxPC-3 induced tumor delays of 18, 16, 12, 14, and 16 days, respectively. In comparison, dBG plus BCNU at doses that were equitoxic to BCNU plus BG yielded tumor delays of 30, 19, 16, 21, and 22 days, respectively. The pancreatic tumors tested displayed functional mismatch repair that, however, may not be always sufficiently restrictive to prevent mutations under alkylation stress. Treatments with either BCNU or TMZ resulted in some degree of mutation in recurring tumors with the exception of CAPAN-2, the only wt-p53 xenograft. dBG, a weak MGMT inactivator in vitro as compared with BG, was markedly more effective than the latter in enhancing the efficacy of BCNU against pancreatic tumor xenografts. Both BG and dBG also enhanced the efficacy of TMZ against pancreatic tumors, possibly because of the repression of MGMT, which cannot be achieved with TMZ treatments alone. These results suggest that pancreatic tumors, which are resistant to DNA alkylating agents, may be sensitized to such agents when pretreated with MGMT inactivators. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Hillman Canc Ctr, Canc Inst Res Pavil, Dept Pathol, Pittsburgh, PA 15213 USA. Univ Kentucky, Dept Radiat Med, Lexington, KY 40536 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. Penn State Univ Hosp, Sch Med, MS Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. RP Kokkinakis, DM (reprint author), Univ Pittsburgh, Hillman Canc Ctr, Canc Inst Res Pavil, Dept Pathol, 5117 Ctr Ave,Suite G12B, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [CA 57725, CA 78561] NR 34 TC 22 Z9 24 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 SEP 1 PY 2003 VL 9 IS 10 BP 3801 EP 3807 PN 1 PG 7 WC Oncology SC Oncology GA 725NB UT WOS:000185548300039 PM 14506174 ER PT J AU Swain, SM Yang, XW AF Swain, SM Yang, XW TI Commentary re: N. J. McCarthy et al., microvessel density, expression of estrogen receptor alpha, MIB-1, p53 and c-erbB-2 in inflammatory breast cancer. Clin. Cancer Res., 8 : 3857-3862, 2002 - Reply SO CLINICAL CANCER RESEARCH LA English DT Letter C1 NCI, Ctr Canc Res, Canc Therapeut Branch, Bethesda, MD 20889 USA. RP Swain, SM (reprint author), NCI, Ctr Canc Res, Canc Therapeut Branch, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 1 TC 0 Z9 0 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 SEP 1 PY 2003 VL 9 IS 10 BP 3816 EP 3816 PN 1 PG 1 WC Oncology SC Oncology GA 725NB UT WOS:000185548300042 ER PT J AU Sausville, EA AF Sausville, EA TI Concluding remarks: Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Dev Therapeut Program, NIH, Rockville, MD 20852 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, NIH, 6130 Execut Blvd,Room 8018, Rockville, MD 20852 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 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2003 VL 9 IS 10 SU 2 BP 4022S EP 4023A PN 2 PG 2 WC Oncology SC Oncology GA 726MQ UT WOS:000185603200027 ER PT J AU Kim, I Barnes, AJ Schepers, R Moolchan, ET Wilson, L Cooper, G Reid, C Hand, C Huestis, MA AF Kim, I Barnes, AJ Schepers, R Moolchan, ET Wilson, L Cooper, G Reid, C Hand, C Huestis, MA TI Sensitivity and specificity of the Cozart Microplate EIA Cocaine Oral Fluid at proposed screening and confirmation cutoffs SO CLINICAL CHEMISTRY LA English DT Article ID GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; HUMAN VOLUNTEERS; SALIVA; PLASMA; METHAMPHETAMINE; METABOLITES; URINE; COCAETHYLENE; HUMANS AB Background: Oral fluid is currently being evaluated as an alternative matrix for monitoring illicit drugs in federally mandated workplace drug testing, for addiction treatment programs, and for driving under the influence testing. The sensitivity, specificity, and efficiency of the Cozart(R) Microplate EIA Cocaine Oral Fluid Kit (COC ELISA) were determined by comparison with gas chromatography-mass spectrometry (GC/MS) results at screening and. confirmation cutoffs proposed in the US and UK. Method: Oral fluid was collected by expectoration after citric acid candy stimulation or with Salivette(R) neutral cotton swabs or Salivette citric acid-treated cotton swabs before and after cocaine (COC) administration. Specimens (n = 1468) were analyzed with the COC ELISA for screening and with solid-phase extraction followed by GC/MS for confirmation.. Three screening cutoffs (10, 20, and 30 mug/L) and four GC/MS cutoffs (2.5, 8, 10, and 15 mug/L COC, benzoylecgonine, and/or ecgonine methyl ester) were evaluated. GC/MS limit of quantification was 2.5 mug/L for all analytes. Results: COC ELISA interassay imprecision (CV; n 19) was 16% at 16.7 mug/L and 12% at 81.8 mug/L. With the 2.5, 8, 10, and 15 mug/L GC/MS cutoffs, 59.0%, 54.7%, 52.7%, and 48.7% of the oral fluid specimens were positive, respectively. Sensitivity, specificity, and efficiency were 92.2%, 84.7%, and 88.8%, respectively, for the suggested Substance Abuse and Mental Health Services Administration (SAMHSA) cutoffs and 90.2%, 89.2%, and 89.7% for cutoffs currently, used in the UK. Conclusions: COC ELISA had suitable sensitivity, specificity, and efficiency for identifying COC exposure at both the proposed SAMHSA and UK cutoffs. Sensitivity, specificity, and efficiency were >84% for both cutoffs, but 92 additional. true-positive samples were identified with the SAMHSA cutoffs. (C) 2003 American Association for Clinical Chemistry. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Cozart Biosci Ltd, Abingdon OX14 4RU, Oxon, England. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 29 TC 14 Z9 15 U1 1 U2 10 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 SEP PY 2003 VL 49 IS 9 BP 1498 EP 1503 DI 10.1373/49.9.1498 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 714DC UT WOS:000184896200012 PM 12928231 ER PT J AU Feerick, MM Prinz, RJ AF Feerick, MM Prinz, RJ TI Special issue: Children exposed to domestic violence: Current status and research directions - Introduction SO CLINICAL CHILD AND FAMILY PSYCHOLOGY REVIEW LA English DT Editorial Material DE domestic violence; children; children exposed to violence; research needs AB This issue of Clinical Child and Family Psychology Review, "Children Exposed to Domestic Violence: Current Status and Research Directions," addresses the current status of our knowledge as well as critical research needs in the area of children exposed to domestic violence. Although much has been learned in recent years about children exposed to violence, significant research gaps remain, the identification of which may help to build a more complete and rigorous science base in this area. This journal issue represents the distillation of a 3-day workshop on children exposed to violence, held in July of 2002, that identified what is known about children exposed to violence and what this information tells us about future research directions. Although many federal agencies have supported some research in this area, there is a need for more targeted attention on the topic, particularly with regard to measurement, sampling, and interventions/services. The papers in this issue were selected with these themes in mind. Although no single issue could cover the entire field, we intend to offer a representative sample of where we are and where we need to go with the hope of stimulating additional thought, collaboration, and research in this important area. C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. RP Feerick, MM (reprint author), NICHHD, Child Dev & Behav Branch, Room 4B05,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1096-4037 J9 CLIN CHILD FAM PSYCH JI Clin. Child Fam. Psychol. Rev. PD SEP PY 2003 VL 6 IS 3 BP 147 EP 149 DI 10.1023/A:1024926331185 PG 3 WC Psychology, Clinical SC Psychology GA 704UD UT WOS:000184358100001 ER PT J AU Prinz, RJ Feerick, MM AF Prinz, RJ Feerick, MM TI Next steps in research on children exposed to domestic violence SO CLINICAL CHILD AND FAMILY PSYCHOLOGY REVIEW LA English DT Article; Proceedings Paper CT Workshop on Children Exposed to Violence CY JUL, 2002 CL WASHINGTON, D.C. DE domestic violence; children; effects on children; children exposed to violence AB The papers in this special issue of Clinical Child and Family Psychology Review provided an overview of what is known about children's exposure to domestic violence, and include indications of gaps in extant research. These gaps and research needs are summarized in this conclusion. Specifically, there is need for further research in several broad areas: definition and measurement of children's exposure to domestic violence; development of research methods and statistical designs that provide detailed information and provide for evidence of intervention effectiveness; impact of domestic violence on parenting and family functioning; the role of child factors and exposure to violence factors in predicting developmental risk and resilience; medical and health consequences of exposure to violence; and the nature of child-system interaction in response to domestic violence. Research needs in these areas are discussed in greater detail, and specific questions are raised for further development. C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. RP Feerick, MM (reprint author), NICHHD, Child Dev & Behav Branch, Room 4B05,6100 Ececut Blvd,MSC 7510, Bethesda, MD 20892 USA. NR 0 TC 17 Z9 17 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1096-4037 J9 CLIN CHILD FAM PSYCH JI Clin. Child Fam. Psychol. Rev. PD SEP PY 2003 VL 6 IS 3 BP 215 EP 219 DI 10.1023/A:1024966501143 PG 5 WC Psychology, Clinical SC Psychology GA 704UD UT WOS:000184358100007 PM 14620581 ER PT J AU Khalsa, JH Genser, S Coates, P Francis, H AF Khalsa, JH Genser, S Coates, P Francis, H TI Interventions for metabolic and endocrine complications of human immunodeficiency virus/acquired immune deficiency syndrome and illicit drug use SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIV/AIDS AB Illicit drug use and concurrent infection with human immunodeficiency virus (HIV) are associated with metabolic and endocrine complications that may include lipid, carbohydrate, and endocrine metabolism disorders and nutritional deficiencies. Interventions for these metabolic and endocrine complications range from micronutrient supplementation to hormone-replacement therapy. We present the current strategies for the management of metabolic and endocrine disorders of HIV/acquired immunodeficiency virus and drug use. In addition, the panel members (contributing authors of the present supplement) recommend further research to determine the nature and extent of problems and to design better and effective therapies. C1 NIDA, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, Bethesda, MD 20892 USA. NIH, Off Dietary Supplements, Off Director, Bethesda, MD 20892 USA. RP Khalsa, JH (reprint author), NIDA, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 5 TC 4 Z9 4 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2003 VL 37 SU 2 BP S37 EP S42 DI 10.1086/375890 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 715YJ UT WOS:000185001800001 PM 12942372 ER PT J AU Grillon, C Baas, J AF Grillon, C Baas, J TI A review of the modulation of the startle reflex by affective states and its application in psychiatry SO CLINICAL NEUROPHYSIOLOGY LA English DT Review DE startle reflex; psychiatry; emotion; anxiety; fear; psychophysiology ID FEAR-POTENTIATED STARTLE; POSTTRAUMATIC-STRESS-DISORDER; GULF-WAR VETERANS; BASE-LINE STARTLE; ACOUSTIC STARTLE; PREPULSE INHIBITION; CONDITIONED-FEAR; ANXIETY DISORDERS; VIETNAM VETERANS; AFFECTIVE REACTIVITY AB Objective: To provide an overview of startle reflex methodologies applied to the examination of emotional and motivational states in humans and to review the findings in different forms of psychopathology. Methods: Pertinent articles were searched mostly via MEDLINE and PsycINFO. Results: The startle reflex is a non-invasive translational tool of research that bridges the gap between animal and human investigations. Startle is used to study fear and anxiety, affective disturbances, sensitization, motivational states, and homeostasis. Conclusions: The startle reflex is highly sensitive to various factors that are of interest in the studies of emotional disorders and has promoted new areas of investigations in psychiatry. However, research in psychiatry is still in its infancy and most findings await replication. Future progress will benefit from the development of innovative and powerful designs tailored to investigate specific disorders. Significance: The startle reflex has utility as a research tool to examine trauma-related disorders, fear learning, drug addiction, and to contrast affective states and emotional processing across diagnostic groups, but its usefulness as a diagnostic tool is limited. (C) 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 NIMH, DHHS, Mood & Anxiety Disorders Program, Bethesda, MD 20895 USA. RP Grillon, C (reprint author), NIMH, DHHS, Mood & Anxiety Disorders Program, 15K N Dr,Bldg 15K,MSC 2670, Bethesda, MD 20895 USA. OI Baas, Johanna/0000-0001-6267-8712 NR 225 TC 293 Z9 296 U1 22 U2 47 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 SEP PY 2003 VL 114 IS 9 BP 1557 EP 1579 DI 10.1016/S1388-2457(03)00202-5 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 722XJ UT WOS:000185403100001 PM 12948786 ER PT J AU Garvey, MA Ziemann, U Bartko, JJ Denckla, MB Barker, CA Wassermann, EM AF Garvey, MA Ziemann, U Bartko, JJ Denckla, MB Barker, CA Wassermann, EM TI Cortical correlates of neuromotor development in healthy children SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE contralateral and ipsilateral silent period; motor threshold; human physiologic maturation; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; MOTOR EVOKED-POTENTIALS; TRANSCALLOSAL INHIBITION; SILENT PERIOD; HUMAN HANDEDNESS; CORTEX; MOVEMENTS; MATURATION; SYSTEM; AGE AB Objective: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. Methods: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. Results: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. Conclusions: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. Significance: TMS can provide important insights into certain functional aspects of neurodevelopment in children. (C) 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 NINDS, Pediat Movement Disorders Unit, Human Motor Control Sect, Motor Neurol Branch,NIH, Bethesda, MD 20892 USA. Univ Frankfurt, Neurol Clin, D-60590 Frankfurt, Germany. Kennedy Krieger Inst, Baltimore, MD USA. NINDS, Brain Stimulat Unit, Bethesda, MD 20892 USA. RP Garvey, MA (reprint author), NINDS, Pediat Movement Disorders Unit, Human Motor Control Sect, Motor Neurol Branch,NIH, 10 Ctr Dr,5N226,MSC 1428, Bethesda, MD 20892 USA. RI Barker, Christopher/I-9477-2012 NR 49 TC 71 Z9 72 U1 1 U2 9 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 SEP PY 2003 VL 114 IS 9 BP 1662 EP 1670 DI 10.1016/S1388-2457(03)00130-5 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 722XJ UT WOS:000185403100010 PM 12948795 ER PT J AU Rogawski, MA Wenk, GL AF Rogawski, MA Wenk, GL TI The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease SO CNS DRUG REVIEWS LA English DT Review DE Alzheimer's disease; amantadine; channel block; dementia; 5-HT3 receptor; memantine; nicotinic receptor; NMDA receptor; uncompetitive antagonist ID METHYL-D-ASPARTATE; NMDA RECEPTOR ANTAGONISTS; LONG-TERM POTENTIATION; CHANNEL BLOCKER MEMANTINE; CULTURED CORTICAL-NEURONS; STRONG VOLTAGE-DEPENDENCY; AMINO-ALKYL-CYCLOHEXANES; LOW-AFFINITY; PARKINSONS-DISEASE; NUCLEUS BASALIS AB Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits AD production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate - an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity - while sparing synaptic responses required for normal behavioral functioning, cognition and memory. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. Univ Arizona, Div Neural Syst Memory & Aging, Tucson, AZ USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, 49 Convent Dr,MSC 4457, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 169 TC 194 Z9 212 U1 3 U2 37 PU NEVA PRESS PI BRANFORD PA P O BOX 347, BRANFORD, CT 06405 USA SN 1080-563X J9 CNS DRUG REV JI CNS Drug Rev. PD FAL PY 2003 VL 9 IS 3 BP 275 EP 308 PG 34 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 729AH UT WOS:000185748200004 PM 14530799 ER PT J AU Rasmusson, AM Vythilingam, M Morgan, CA AF Rasmusson, AM Vythilingam, M Morgan, CA TI The neuroendocrinology of posttraumatic stress disorders: New directions SO CNS SPECTRUMS LA English DT Review ID CORTICOTROPIN-RELEASING HORMONE; URINARY CORTISOL EXCRETION; PITUITARY-ADRENAL AXIS; DEHYDROEPIANDROSTERONE-SULFATE DHEAS; DEXAMETHASONE SUPPRESSION TEST; NEUROPEPTIDE-Y; 21-HYDROXYLASE DEFICIENCY; ANTIDEPRESSANT DRUGS; PREMENOPAUSAL WOMEN; HOLOCAUST SURVIVORS AB Studies of the hypothalamic-pituitary-adrenal (HPA) axis in persons with posttraumatic stress disorder (PTSD) have produced variable findings. This review focuses on the factors likely to have affected the outcome of these studies, including population characteristics and experimental design. Also discussed is a possible role for the adrenal neurosteroid dehydroepiandrosterone (DHEA) as a mediator of HPA axis adaptation to extreme stress and the psychiatric symptoms associated with PTSD. The antiglucocorticoid properties of DHEA may contribute to an upregulation of HPA axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in some PTSD subpopulations. The neuromodulatory effects of DHEA and its metabolite DHEAS at gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the brain may contribute to psychiatric symptoms associated with PTSD. The possible importance of other neurohormone systems in modulating HPA axis and symptom responses to traumatic stress is also discussed. Understanding the complex interactions of these stress-responsive neurosteroid and peptide systems may help explain the variability in patterns of HPA axis adaptation, brain changes, and psychiatric symptoms observed in PTSD and lead to better targeting of preventive and therapeutic interventions. C1 Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare Serv, Clin Neurosci Div, Vet Affairs Natl Ctr PTSD, West Haven, CT USA. NIMH, Mood & Anxiety Disorders Program, Anxiety Disorders Clin, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. RP Rasmusson, AM (reprint author), Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. FU NIDA NIH HHS [1K12DA14038-01] NR 92 TC 87 Z9 90 U1 3 U2 7 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTR JI CNS Spectr. PD SEP PY 2003 VL 8 IS 9 BP 651 EP + PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 724QX UT WOS:000185499200006 PM 15079139 ER PT J AU Wang, YQ Crawford, MA Chen, JS Li, JY Ghebremeskel, K Campbell, TC Fan, WX Parker, R Leyton, J AF Wang, YQ Crawford, MA Chen, JS Li, JY Ghebremeskel, K Campbell, TC Fan, WX Parker, R Leyton, J TI Fish consumption, blood docosahexaenoic acid and chronic diseases in Chinese rural populations SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY LA English DT Review DE cardiovascular disease; chronic disease; coronary heart disease; DHA; docosahexaenoic; fish consumption ID CORONARY-HEART-DISEASE; N-3 FATTY-ACIDS; SMOOTH-MUSCLE-CELLS; MEDITERRANEAN DIET; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; EICOSAPENTAENOIC ACID; PLASMA-LIPIDS; RAT-BRAIN; MORTALITY AB The Chinese traditional diet is low in fat. However, there is regional variability in the amount, type of fat consumed and the pattern of chronic diseases. An epidemiological survey of 65 rural counties in China (6500 subjects) was conducted in the 1980s. We have re-examined the red blood cell fatty acid and antioxidant composition, with fish consumption. Fish consumption correlated significantly with the levels of docosahexaenoic acid (DHA) in red blood cells (RBC) (r=0.640, P<0.001), selenium (r=0.467, P<0.001) and glutathione peroxidase (r=0.333, P<0.01) in plasma. The proportion of DHA in RBC was inversely associated with total plasma triglyceride concentrations. A strong inverse correlation between DHA in RBC and cardiovascular disease (CVD) was found. The strongest correlation was the combination of DHA and oleic acid. RBC docosahexaenoic acid itself also correlated negatively and significantly with most chronic diseases and appeared to be more protective than either eicosapentacnoic or the omega3 docosapenataenoic acids. These results demonstrate the protective nature of fish consumption and DHA, found in high fat Western diets, operates at a low level of fat. This finding suggests the protective effect of fish consumption as validated by red cell DHA is universal. The protective effect is, therefore, most likely to be due to the fundamental properties of docosahexaenoic acid in cell function. (C) 2003 Elsevier Science Inc. All rights reserved. C1 London Metropolitan Univ, Inst Brain Chem & Human Nutr, London N7 8DB, England. Chinese Acad Prevent Med, Beijing, Peoples R China. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. Natl Canc Inst, Med Branch, Rockville, MD USA. RP Crawford, MA (reprint author), London Metropolitan Univ, Inst Brain Chem & Human Nutr, N Campus,166-222 Holloway Rd, London N7 8DB, England. OI Wang, Yiqun/0000-0003-4225-3033 NR 67 TC 15 Z9 18 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1095-6433 J9 COMP BIOCHEM PHYS A JI Comp. Biochem. Physiol. A-Mol. Integr. Physiol. PD SEP PY 2003 VL 136 IS 1 BP 127 EP 140 DI 10.1016/S1095-6433(03)00016-3 PG 14 WC Biochemistry & Molecular Biology; Physiology; Zoology SC Biochemistry & Molecular Biology; Physiology; Zoology GA 730EU UT WOS:000185816900012 PM 14527635 ER PT J AU Awasthi, PR French, CF Sztein, J Bedigian, R Sharp, JJ Lloyd, KCK AF Awasthi, PR French, CF Sztein, J Bedigian, R Sharp, JJ Lloyd, KCK TI Frozen sperm as an alternative to shipping live mice SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID MOUSE SPERMATOZOA; TRANSPORT; CRYOPRESERVATION; EMBRYOS; FERTILIZATION AB Dissemination of live mice by air and/or ground shipping is costly and can result in spread of disease between senders' and recipients' colonies. Transporting cryopreserved sperm that can be recovered and used for deriving live mice by using assisted reproductive techniques may be a more economical, efficient, and safer alternative to shipping live animals. In this study, we tested the hypothesis that sperm cryopreserved at one location and then transported transcontinentally via a common package delivery service using both air and ground transport to a second location could be recovered for in vitro fertilization (IVF) to successfully derive liveborn offspring at the second location. Split aliquots of sperm from individual mice were tested at both senders' and recipients' locations by using similar cryopreservation and IVF procedures, in order to control for differences in handling procedures. At both senders' locations, fertilization rates using cryopreserved sperm were lower than those using fresh sperm. However, fertilization rates using sperm recovered after cryopreservation at the senders' locations Were not significantly different than those obtained when the same cryopreserved sperm was recovered and used at the recipients' locations. At the one location where tested, the numbers of pups born and subsequently weaned after IVF using either shipped or nonshipped cryopreserved sperm were similar. We conclude that cryopreserved sperm can be transported between different facilities and used for IVF to successfully derive liveborn mice. C1 NCI, Sci Applicat Int Corp, Lab 124, Ft Detrick, Frederick, MD 21702 USA. Univ Calif Davis, Ctr Comparat Med, Mouse Biol Program, Murine Targeted Genom Lab, Davis, CA 95616 USA. RP Lloyd, KCK (reprint author), NCI, Sci Applicat Int Corp, Lab 124, Ft Detrick, Bldg 567,POB B, Frederick, MD 21702 USA. RI Sztein, Jorge/B-7165-2012 FU NCRR NIH HHS [U42-RR-14905] NR 11 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD SEP PY 2003 VL 42 IS 5 BP 8 EP 11 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 728CU UT WOS:000185698300002 PM 14510517 ER PT J AU Weed, JL Wagner, PO Byrum, R Parrish, S Knezevich, M Powell, DA AF Weed, JL Wagner, PO Byrum, R Parrish, S Knezevich, M Powell, DA TI Treatment of persistent self-injurious behavior in rhesus monkeys through socialization: A preliminary report SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID VASECTOMY; MARMOSET AB This paper is a retrospective report describing outcomes for six male rhesus monkeys, each with a history of persistent self-injurious behavior (SIB), after their social introduction to female rhesus monkeys. Pairing procedures for five of the six male primates were implemented after surgical vasectomy. One male had previous pairing experience with a female prior to vasectomy resulting in an unplanned pregnancy. This male was re-socialized with his former female partner after surgery. The SIB-related medical histories of the males before and after the pairings are presented. One goal for promoting pair-housing of chronic SIB male monkeys with female monkeys was to determine whether this intervention would function to reduce or eliminate the expression of SIB and thus provide enhanced socialization opportunities for previously singly housed animals. C1 NIH, Vet Resources Program, Off Res Serv, Poolesville, MD 20837 USA. NICHHD, Comparat Ethol Lab, Poolesville, MD 20837 USA. BIOQUAL Inc, Rockville, MD 20850 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. RP Weed, JL (reprint author), NIH, Vet Resources Program, Off Res Serv, Box 56,Bldg 102, Poolesville, MD 20837 USA. NR 27 TC 29 Z9 29 U1 0 U2 3 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD SEP PY 2003 VL 42 IS 5 BP 21 EP 23 PG 3 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 728CU UT WOS:000185698300004 PM 14510519 ER PT J AU Soderlund, H Nyberg, L Adolfsson, R Nilsson, LG Launer, LJ AF Soderlund, H Nyberg, L Adolfsson, R Nilsson, LG Launer, LJ TI High prevalence of white matter hyperintensities in normal aging: Relation to blood pressure and cognition SO CORTEX LA English DT Article DE MRI; white matter hyperintensities; aging; cognition ID ALZHEIMERS-DISEASE; RISK-FACTORS; LESIONS; DEMENTIA; ROTTERDAM; MEMORY; BRAIN; HEALTH; AGE; MRI AB The occurrence of cerebral white matter hyperintensities (WMHs), and their associations with blood pressure, episodic memory, and other cognitive tasks, were examined in a population-based sample of 123 individuals between 64 and 74 years old. Magnetic Resonance Imaging (MRI) detected subcortical and periventricular hyperintensities in 90% and 67% of the cases, respectively. Subcortical WMHs were related to elevated diastolic blood pressure measured ten years earlier, and periventricular WMHs were related to elevated diastolic blood pressure measured five and ten years earlier. Subcortical hyperintensities were weakly associated with impaired motor speed, but this association was not significant. Periventricular WMHs had a negative effect on episodic memory, although the relation was not linear. Collectively, the notion that white matter hyperintensities impair cognitive function got weak support in this Swedish sample. C1 Univ Stockholm, Dept Psychol, S-10691 Stockholm, Sweden. Umea Univ, Dept Psychol, S-90187 Umea, Sweden. Umea Univ, Dept Psychiat, S-90187 Umea, Sweden. NIA, Epidemiol Demog Biometry Program, Bethesda, MD 20892 USA. RP Soderlund, H (reprint author), Univ Stockholm, Dept Psychol, S-10691 Stockholm, Sweden. RI Nyberg, Lars/C-2514-2009; Soderlund, Hedvig/B-4060-2013 OI Nyberg, Lars/0000-0002-3367-1746; NR 44 TC 67 Z9 68 U1 0 U2 5 PU MASSON DIVISIONE PERIODICI PI MILAN PA VIA FRATELLI BRESSAN 2, 20126 MILAN, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD SEP-DEC PY 2003 VL 39 IS 4-5 BP 1093 EP 1105 DI 10.1016/S0010-9452(08)70879-7 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 752MX UT WOS:000187166200026 PM 14584568 ER PT J AU Clarke, EB Curtis, JR Luce, JM Levy, M Danis, M Nelson, J Solomon, MZ AF Clarke, EB Curtis, JR Luce, JM Levy, M Danis, M Nelson, J Solomon, MZ TI Quality indicators for end-of-life care in the intensive care unit SO CRITICAL CARE MEDICINE LA English DT Article DE terminal care; palliative care; intensive care; critical care; quality indicators; health care; total quality management ID CRITICALLY ILL PATIENTS; PALLIATIVE CARE; PATIENTS PERSPECTIVES; FAMILY MEMBERS; DYING PATIENTS; NEEDS; PHYSICIANS; RELATIVES; EXPERIENCE; CHALLENGES AB Objective: The primary goal of this study was to address the documented deficiencies in end-of-life care (EOLC) in intensive care unit settings by identifying key EOLC domains and related quality indicators for use in the intensive care unit through a consensus process. A second goal was to propose specific clinician and organizational behaviors and interventions that might be used to improve these EOLC quality indicators. Participants: Participants were the 36 members of the Robert Wood Johnson Foundation (RWJF) Critical Care End-of-Life Peer Workgroup and 15 nurse-physician teams from 15 intensive care units affiliated with the work group members. Fourteen adult medical, surgical, and mixed intensive care units from 13 states and the District of Columbia in the United States and one mixed intensive care unit in Canada were represented. Methods: An in-depth literature review was conducted to identify articles that assessed the domains of quality of EOLC in the intensive care unit and general health care. Consensus regarding the key EOLC domains in the intensive care unit and quality performance indicators within each domain was established based on the review of the literature and an iterative process involving the authors and members of the RWJF Critical Care End-of-Life Peer Workgroup. Specific clinician and organizational behaviors and interventions to address the proposed EOLC quality indicators within the domains were identified through a collaborative process with the nurse-physician teams in 15 intensive care units. Measurements and Main Results: Seven EOLC domains were identified for use in the intensive care unit: a) patient- and family-centered decision making; b) communication; c) continuity of care; d) emotional and practical support; e) symptom management and comfort care; f) spiritual support; and g) emotional and organizational support for intensive care unit clinicians. Fifty-three EOLC quality indicators within the seven domains were proposed. More than 100 examples of clinician and organizational behaviors and interventions that could address the EOLC quality indicators in the intensive care unit setting were identified. Conclusions: These EOLC domains and the associated quality indicators, developed through a consensus process, provide clinicians and researchers with a framework for understanding quality of EOLC in the intensive care unit. Once validated, these indicators might be used to improve the quality of EOLC by serving as the components of an internal or external audit evaluating EOLC continuous quality improvement efforts in intensive care unit settings. C1 Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care, Seattle, WA 98104 USA. Ctr Appl Eth & Profess Practice, Newton, MA USA. Educ Dev Ctr, Newton, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco Gen Hosp, Div Pulm & Crit Care Med, San Francisco, CA 94110 USA. Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Div Pulm & Crit Care Med, New York, NY USA. RP Clarke, EB (reprint author), Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care, 325 9Th Ave,Box 359762, Seattle, WA 98104 USA. NR 64 TC 152 Z9 154 U1 2 U2 13 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 SEP PY 2003 VL 31 IS 9 BP 2255 EP 2262 DI 10.1097/01.CCM.0000084849.96385.85 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 721BL UT WOS:000185297100001 PM 14501954 ER PT J AU Puck, JA Zhu, SG AF Puck, JA Zhu, SG TI Immune disorders caused by defects in the caspase cascade SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; INTERLEUKIN-1-BETA CONVERTING-ENZYME; FAS GENE-MUTATIONS; LYMPHOCYTE APOPTOSIS; CYTOCHROME-C; ACTIVATION; DEATH; MICE; PROTEASE; CLONING AB In the immune system, lymphocyte activation by antigen is followed by cell proliferation and induction of effector functions. Subsequently, physiologic cell-death signals are induced, resulting in removal of expanded effector-cell populations to maintain homeostasis. Caspases are intracellular participants in both activation responses and cell death by apoptosis. Targets of caspases include inflammatory activators and also other members of the caspase family that mediate apoptosis. Caspase-8 and caspase-10 participate in the protease cascade following cell surface CD95 engagement by its ligand. Humans with defects in these caspases were initially evaluated for the autoimmune lympho-proliferative syndrome because of their spleen and lymph node enlargement. Although both caspase-8- and caspase-10-deficient individuals had impaired apoptosis, those with caspase-8 deficiency, who also had immunodeficiency, had additional defects in activation of lymphocytes and natural killer cells. These disorders help to define the importance and specificity of the caspase proteases in intracellular signaling pathways. C1 NHGRI, Genet & Mol Biol Branch, NIH, NHGRI NIH Bldg 49,Rm 4AI4,49 Convent Dr, Bethesda, MD 20892 USA. RP Puck, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, NHGRI NIH Bldg 49,Rm 4AI4,49 Convent Dr, Bethesda, MD 20892 USA. NR 32 TC 2 Z9 3 U1 1 U2 1 PU CURRENT SCIENCE INC PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD SEP PY 2003 VL 3 IS 5 BP 378 EP 384 DI 10.1007/s11882-003-0070-1 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 716XX UT WOS:000185055900003 PM 12906772 ER PT J AU Kelly, J Leonard, WJ AF Kelly, J Leonard, WJ TI Immune deficiencies due to defects in cytokine signaling SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; INTERFERON-GAMMA-RECEPTOR; BACILLE CALMETTE-GUERIN; T-CELL-ACTIVATION; GENE-THERAPY; MYCOBACTERIAL INFECTION; TARGETED DISRUPTION; NATURAL-KILLER; VIRAL DISEASE; MICE AB Severe combined immunodeficiency (SCID) represents a syndrome comprising the most severe forms of inherited immunodeficiencies. Defects in cytokine signaling pathways can result in impaired development of lymphoid cells and/or defective functioning of these cells, and most cases of SCID result from defective signaling through the common cytokine receptor gamma chain (gamma(c)) or associated molecules and signaling pathways. Studies of these patients and the analysis of gene-targeted mice provide insight into the underlying signaling defects in humans with SCID provides the basis for future therapies for these patients. More subtle deficiencies in cytokine signaling have also been found as causes of other forms of immunodeficiency, and the knowledge learned could lead to novel approaches to antimicrobial therapy. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kelly, J (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 57 TC 2 Z9 2 U1 0 U2 0 PU CURRENT SCIENCE INC PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD SEP PY 2003 VL 3 IS 5 BP 396 EP 401 DI 10.1007/s11882-003-0073-y PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 716XX UT WOS:000185055900006 PM 12906775 ER PT J AU Praetorius, HA Spring, KR AF Praetorius, HA Spring, KR TI The renal cell primary cilium functions as a flow sensor SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review ID POLYCYSTIC KIDNEY-DISEASE; SMOOTH-MUSCLE CELLS; INTRAFLAGELLAR TRANSPORT; MDCK CELLS; C-ELEGANS; GENE; LOCALIZES; PATHWAY; POLARIS; PROTEIN AB Purpose of review To discuss recent reports on the function and importance of the renal primary cilium, a widely distributed organelle. Recent findings Most epithelial cells, including those in the kidney, express a solitary primary cilium. The primary cilium functions as a flow sensor in cultured renal epithelial cells (MDCK and mouse collecting tubule) mediating a large increase in intracellular calcium concentration. Flow sensing is shown to reside in the cilium itself and to involve the proteins polycystin 1 and 2, defects in which are associated with the majority of cases of human polycystic kidney disease. The role of the cilium in flow-dependent potassium secretion by the collecting tubule and in sensing of chemical components of the luminal fluid are also described. Summary The primary cilium is mechanically sensitive and serves as a flow sensor in cultured renal epithelia. Bending the cilium by mechanical means or flow causes a large, prolonged transient increase in intracellular calcium. The mechanically sensitive protein in the cilium is a polycystin. C1 Univ Aarhus, Inst Expt Clin Res, Ctr Water & Salt Res, DK-8200 Aarhus C, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Praetorius, HA (reprint author), Univ Aarhus, Inst Expt Clin Res, Ctr Water & Salt Res, Brendstrupgaardsvej 1, DK-8200 Aarhus C, Denmark. NR 26 TC 152 Z9 158 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD SEP PY 2003 VL 12 IS 5 BP 517 EP 520 DI 10.1097/01.mnh.0000088730.87142.d1 PG 4 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 719FZ UT WOS:000185194100006 PM 12920399 ER PT J AU Hansen, A Lipsky, PE Dorner, T AF Hansen, A Lipsky, PE Dorner, T TI New concepts in the pathogenesis of Sjogren syndrome: many questions, fewer answers SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE Sjogren syndrome; predisposing factors; lymphocytes; autoantigens; lymphoma ID GLAND EPITHELIAL-CELLS; LYMPHOID-TISSUE LYMPHOMA; MINOR SALIVARY-GLANDS; PERIPHERAL-BLOOD; B-CELLS; AUTOIMMUNE EXOCRINOPATHY; CLASSIFICATION CRITERIA; PAROTID-GLAND; DRY EYE; KERATOCONJUNCTIVITIS SICCA AB Although a modified European-American consensus classification of Sjogren syndrome has been introduced during the last year, the etiopathogenesis of this disease characterized by chronic lymphocytic inflammation, impaired function, and, finally, destruction of the salivary and lacrimal glands as well as systemic manifestations remains to be elucidated. Recent insights into the pathogenesis of Sjogren syndrome resulting from immunogenetic, hormonal, and epidemiologic evaluations as well as animal and in vitro studies are highlighted by this review. Evidence confirms that lymphocytic disturbances, including ectopic germinal center formation and aberrations of cellular signaling play a significant role in Sjogren syndrome. Although some of these features are unique to Sjogren syndrome, others are also found in a number of systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. The underlying cause of Sjogren syndrome remains largely enigmatic. However, distinct characteristics may provide the basis for the classification of the disease entities. Finally, an enhanced risk of lymphomagenesis is a well-known hallmark of primary Sjogren syndrome, indicating the central role of derangement of lymphocyte regulation. As demonstrated by the introduction of the new targeted therapeutic approaches in rheumatoid arthritis, solid insights into the pathogenesis of Sjogren syndrome may pave the way toward new therapeutic approaches. C1 Univ Hosp Charite, Dept Med, Outpatients Dept, D-10098 Berlin, Germany. NIAMSD, NIAMS, NIH, Bethesda, MD USA. RP Hansen, A (reprint author), Univ Hosp Charite, Dept Med, Outpatients Dept, Schumannstr 20-21, D-10098 Berlin, Germany. NR 102 TC 45 Z9 49 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI CURR. OPIN. RHEUMATOL. PD SEP PY 2003 VL 15 IS 5 BP 563 EP 570 DI 10.1097/00002281-200309000-00007 PG 8 WC Rheumatology SC Rheumatology GA 715PB UT WOS:000184980000007 PM 12960481 ER PT J AU Nie, ZZ Boehm, M Boja, ES Vass, WC Bonifacino, JS Fales, HM Randazzo, PA AF Nie, ZZ Boehm, M Boja, ES Vass, WC Bonifacino, JS Fales, HM Randazzo, PA TI Specific regulation of the adaptor protein complex AP-3 by the Arf GAP AGAP1 SO DEVELOPMENTAL CELL LA English DT Article ID GTPASE-ACTIVATING PROTEIN; SYNAPTIC VESICLE FORMATION; HERMANSKY-PUDLAK-SYNDROME; INTRACELLULAR-TRANSPORT; ACTIN CYTOSKELETON; IDENTIFICATION; LOCALIZATION; FAMILY; ASAP1; CELL AB Arf1 regulates membrane trafficking at several membrane sites by interacting with at least seven different vesicle coat proteins. Here, we test the hypothesis that Arf1-dependent coats are independently regulated by specific interaction with Arf GAPs. We find that the Arf GAP AGAP1 directly associates with and colocalizes with AP-3, a coat protein complex involved in trafficking in the endosomal-lysosomal system. Binding is mediated by the PH domain of AGAP1 and the delta and sigma3 subunits of AP-3. Overexpression of AGAP1 changes the cellular distribution of AP-3, and reduced expression of AGAP1 renders AP-3 resistant to brefeldin A. AGAP1 overexpression does not affect the distribution of other coat proteins, and AP-3 distribution is not affected by overexpression of other Arf GAPs. Cells overexpressing AGAP1 also exhibit increased LAMP1 trafficking via the plasma membrane. Taken together, these results support the hypothesis that AGAP1 directly and specifically regulates AP-3-dependent trafficking. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Room 4118, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 40 TC 53 Z9 59 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD SEP PY 2003 VL 5 IS 3 BP 513 EP 521 DI 10.1016/S1534-5807(03)00234-X PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 721GX UT WOS:000185309600018 PM 12967569 ER PT J AU Lindsay, RS Funahashi, T Krakoff, J Matsuzawa, Y Tanaka, S Kobes, S Bennett, PH Tataranni, PA Knowler, WC Hanson, RL AF Lindsay, RS Funahashi, T Krakoff, J Matsuzawa, Y Tanaka, S Kobes, S Bennett, PH Tataranni, PA Knowler, WC Hanson, RL TI Genome-wide linkage analysis of serum adiponectin in the Pima Indian population SO DIABETES LA English DT Article ID INSULIN-RESISTANCE SYNDROME; ADIPOSE-SPECIFIC PROTEIN; QUANTITATIVE-TRAIT LOCI; LIPOPROTEIN-CHOLESTEROL; PLASMA-CONCENTRATIONS; DIABETES-MELLITUS; MEXICAN-AMERICANS; GENE-EXPRESSION; VLDL RECEPTOR; KAPPA-B AB Adiponectin is a circulating protein secreted by adipocytes and is thought to have insulin-sensitizing effects. We present genetic analysis of adiponectin levels in 517 Pima Indians without diabetes (from 162 families, 750 sib-pairs). Adiponectin concentrations were heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences in this population. In genome-wide linkage analyses, suggestive linkage (logarithm of odds [LOD] = 3.0) of adiponectin adjusted for age and sex was found on chromosome 9p at 18 cM. Linkage was also present after inclusion of adiponectin concentrations of siblings with type 2 diabetes not treated pharmacologically (total siblings 582, 182 families, 860 sib-pairs: LOD = 3.5). Tentative evidence of linkage was also found on chromosomes 2 (LOD = 1.7 at 89 cM), 3 (LOD = 1.9 at 124 cM), and 10 (LOD = 1.7 at 70 cM), offering some support to findings of a previous genome-wide scan of adiponectin. Our data suggest that quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in the Pima population. C1 NIDDK, NIH, Phoenix, AZ 85014 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Osaka, Japan. RP Hanson, RL (reprint author), NIDDK, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 50 TC 74 Z9 79 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2003 VL 52 IS 9 BP 2419 EP 2425 DI 10.2337/diabetes.52.9.2419 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716KP UT WOS:000185027600029 PM 12941784 ER PT J AU Bunt, JC Salbe, AD Harper, IT Hanson, RL Tataranni, PA AF Bunt, JC Salbe, AD Harper, IT Hanson, RL Tataranni, PA TI Weight, adiposity, and physical activity as determinants of an insulin sensitivity index in Pima Indian children SO DIABETES CARE LA English DT Article ID ASSESSING RISK-FACTORS; DOUBLY LABELED WATER; BETA-CELL FUNCTION; ENERGY-EXPENDITURE; PREPUBERTAL CHILDREN; RESISTANCE SYNDROME; CAUCASIAN CHILDREN; BODY-COMPOSITION; OBESE CHILDREN; MINIMAL MODEL AB OBJECTIVE - To determine whether measures of physical activity are related to an insulin sensitivity index ([ISI] 10(4)/fasting insulin X glucose) independent of weight or adiposity in children. RESEARCH DESIGN AND METHODS - We conducted a longitudinal study of 90 Pima Indian children (39 boys and 51 girls) at 5 and 10 years of age measuring adiposity (dual-energy X-ray absorptiometry), physical activity behavior (questionnaire: number of activities per week [ACT], average hours per week [TIMED, and energy expenditure (doubly labeled water: physical activity level [PALI). RESULTS - in cross-sectional analyses, ACT was correlated with ISI at 5 years of age (r = 0.24, P = 0.02) and at 10 years of age (r = 0.21, P = 0.05), but these relationship's were not independent of weight or adiposity. PAL was correlated with ISI at 10 years of age (r = 0.39, P = 0.03) but was not independent of weight or adiposity. Longitudinally, ISI decreased I. Tom 5 to 10 years of age, and increases in weight and adiposity were associated with decreases in ISI (r = 0.51 and -0.41, respectively; both P < 0.0001). ACT decreased from 5 to 10 years of age, but children who had smaller decreases in ACT had smaller decreases in 151, independent of increases in weight or adiposity (partial r = 0.22, P = 0.04 adjusted for either weight or adiposity). CONCLUSIONS - These data suggest that early establishment and maintenance of. an active lifestyle can have a beneficial effect on ISI that is partially independent of changes in weight or adiposity. This is particularly relevant considering the current epidemics of both obesity and type 2 diabetes in children. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. RP Bunt, JC (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, Dept Hlth & Human Serv, 4212 N 16th St,Room 541-A, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 42 TC 27 Z9 29 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2003 VL 26 IS 9 BP 2524 EP 2530 DI 10.2337/diacare.26.9.2524 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720AU UT WOS:000185239000006 PM 12941713 ER PT J AU Tulloch-Reid, MK Williams, DE Looker, HC Hanson, RL Knowler, WC AF Tulloch-Reid, MK Williams, DE Looker, HC Hanson, RL Knowler, WC TI Do measures of body fat distribution provide information on the risk of type 2 diabetes in addition to measures of general obesity? Comparison of anthropometric predictors of type 2 diabetes in Pima Indians SO DIABETES CARE LA English DT Article ID MELLITUS; WOMEN; ADIPOSITY; NIDDM; MEN AB OBJECTIVE - To investigate which anthropometric measurements of obesity best predict type 2 diabetes in a population of Pima Indians and whether additional information on diabetes risk could, be obtained by combining measures of general obesity with measures of body fat distribution. RESEARCH DESIGN AND METHODS - We conducted a prospective study of 624 men and 990 nonpregnant women > 18 years of age without diabetes. Subjects were followed a mean of 5.25 years for the development of type 2 diabetes (using 1997 American Diabetes Association criteria). RESULTS - A total of 322, new cases of type 2 diabetes (107 men, and 215 women) were diagnosed during follow-up. Baseline obesity measurements were highly correlated and predicted diabetes in proportional hazards models adjusted for age. BMI had the highest hazard ratio in men and women, with age-adjusted hazard ratios per SD of 1.73 (95% Cl 1.44-2.07) and 1.67 (1.45-1.91), respectively. According to receiver-operating characteristic analysis, BMI and waist-to-height ratio were the best predictors of diabetes in men, while in women BMI, waist-to-height ratio, waist circumference, and waist-to-thigh ratio were the best predictors. The predictive abilities of models containing BMI were not significantly improved by including other measures of general obesity or measures of the body fat distribution. CONCLUSIONS - Throughout its range, BMI was an excellent predictor of type 2 diabetes risk in Pima Indians and was not significantly improved by combining it with other measures of general adiposity or body fat distribution. C1 NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix Epidemiol Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Tulloch-Reid, MK (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Tulloch-Reid, Marshall/E-4383-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 13 TC 91 Z9 91 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2003 VL 26 IS 9 BP 2556 EP 2561 DI 10.2337/diacare.26.9.2556 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720AU UT WOS:000185239000011 PM 12941718 ER PT J AU Garfield, SA Malozowski, S Chin, MH Narayan, KMV Glasgow, RE Green, LW Hiss, RG Krumholz, HM AF Garfield, SA Malozowski, S Chin, MH Narayan, KMV Glasgow, RE Green, LW Hiss, RG Krumholz, HM CA Diabet Mellitus Interagency Coordi TI Considerations for diabetes translational research in real-world settings SO DIABETES CARE LA English DT Editorial Material ID BEHAVIORAL-SCIENCE RESEARCH; COMMUNITY SETTINGS; PHYSICAL-ACTIVITY; GLYCEMIC CONTROL; CHRONIC DISEASE; UNITED-STATES; PUBLIC-HEALTH; CARE; MANAGEMENT; COMPLICATIONS C1 NIDDKD, Div Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. Kaiser Permanente, Clin Res Unit, Canon City, CO USA. Univ Michigan, Dept Med Educ, Ann Arbor, MI 48109 USA. Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. RP Garfield, SA (reprint author), NIDDKD, Div Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RI Narayan, K.M. Venkat /J-9819-2012 OI Narayan, K.M. Venkat /0000-0001-8621-5405 NR 44 TC 93 Z9 94 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2003 VL 26 IS 9 BP 2670 EP 2674 DI 10.2337/diacare.26.9.2670 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720AU UT WOS:000185239000029 PM 12941736 ER PT J AU LeRoith, D Smith, DO AF LeRoith, D Smith, DO TI Loss of glucose homoeostasis: implications of basal glycaemia in type 2 diabetes SO DIABETES OBESITY & METABOLISM LA English DT Review DE glucose homoeostasis; glycaemic control; insulin glargine; insulin; type 2 diabetes ID FASTING PLASMA-GLUCOSE; LONG-TERM INSTABILITY; INSULIN-SECRETION; POSTPRANDIAL HYPERGLYCEMIA; CARDIOVASCULAR-DISEASE; NONDIABETIC SUBJECTS; ORAL-AGENTS; NPH INSULIN; MELLITUS; NIDDM C1 NIH, Diabet Branch, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Inst Diabet, Serv Endocrinol, Washington, DC 20307 USA. RP LeRoith, D (reprint author), NIH, Diabet Branch, NIH MSC 1758,Room 8D12,Bldg 10, Bethesda, MD 20892 USA. NR 77 TC 1 Z9 1 U1 0 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-8902 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD SEP PY 2003 VL 5 IS 5 BP 285 EP 294 DI 10.1046/j.1463-1326.2003.00278.x PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 717WB UT WOS:000185112800004 PM 12940865 ER PT J AU Einat, H Manji, HK Gould, TD Du, J Chen, G AF Einat, H Manji, HK Gould, TD Du, J Chen, G TI Possible involvement of the ERK signaling cascade in bipolar disorder: Behavioral leads from the study of mutant mice SO DRUG NEWS & PERSPECTIVES LA English DT Article ID ACTIVATED PROTEIN-KINASE; LONG-TERM POTENTIATION; MOOD-STABILIZING AGENTS; MAP KINASE; SYNAPTIC PLASTICITY; NEUROTROPHIC FACTOR; MAJOR DEPRESSION; NEURONAL PLASTICITY; EMERGENT PROPERTIES; LOCOMOTOR-ACTIVITY AB Despite the devastating impact that bipolar disorder has on the lives of millions worldwide, little is known for certain about its etiology or pathophysiology. Whereas research has traditionally focused on biogenic amines, it is becoming increasingly more apparent that intracellular pathways are involved in the etiology and treatment of the disease and that a true understanding of the pathophysiology of bipolar disorder must address its neurobiology at different physiological levels, that is, molecular, cellular, systems and behavioral levels. There is now considerable biochemical evidence that the antimanic agents lithium and valproate robustly activate the ERK signaling cascade in therapeutically relevant paradigms. This raises the possibility that this pathway may play a role in the antimanic effects of these agents. The present paper reviews behavioral studies that may shed light on the involvement of the ERK pathway in affective-like behaviors in animals. The available literature suggests that genetic manipulations of the brain-derived neurotrophic factor (BDNF)-ERK kinase pathway produces a variety of changes in affective-like behaviors, with most changes consistent with manic-like behavior. Thus, overall, mice with targeted mutation of the BDNF gene exhibited increased spontaneous locomotion and increased response to acute amphetamine, altered response to chronic cocaine, increased aggression, increase in risk-taking behavior, as demonstrated by time spent in the center of an open field, and changes in eating patterns. Although it has to be acknowledged that the currently available behavioral data from the BDNF-ERK pathway mutants is less than ideal to offer real substantiation relating this pathway to bipolar disorder, the data still supports the possibility that this pathway modulates manic-like behavior in animals, and perhaps mania in humans. (C) 2003 Prous Science. All rights reserved. C1 NIMH, Mol Pathophysiol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RI Einat, Haim/A-7203-2009; Chen, Guang/A-2570-2017 NR 91 TC 31 Z9 31 U1 0 U2 1 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0214-0934 J9 DRUG NEWS PERSPECT JI Drug News Perspect. PD SEP PY 2003 VL 16 IS 7 BP 453 EP 463 DI 10.1358/dnp.2003.16.7.829357 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 743QM UT WOS:000186585100008 PM 14668941 ER PT J AU Riedlinger, G Kridel, S Al-Housseini, AM Brow, JM Bugge, TH Leppla, SH Duesbery, N Vande Woulde, G Frankel, A AF Riedlinger, G Kridel, S Al-Housseini, AM Brow, JM Bugge, TH Leppla, SH Duesbery, N Vande Woulde, G Frankel, A TI Metastatic melanoma and matrix metalloproteinases SO DRUGS OF THE FUTURE LA English DT Review ID PROTEIN-KINASE KINASE; CELLS IN-VITRO; MALIGNANT-MELANOMA; TUMOR-GROWTH; ANIMAL-MODELS; ANTHRAX TOXIN; NUDE-MICE; BIOLOGICAL PROPERTIES; VASCULOGENIC MIMICRY; INVASIVE MELANOMA AB Metastatic melanoma is a rapidly progressive incurable malignancy for which both novel therapies are needed. Analysis of the biology of melanoma cells reveals a dependency upon several critical pathways, with matrix metalloproteinases (MMPs) essential for tumor spread and dissemination. We describe a growing number of protein therapeutics which target melanoma cells by requiring activation by MMPs. These agents should have distinct side affects and may be useful in combinations with standard cytoxic chemotherapy or immunotherapies. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. Van Andel Res Inst, Labs Dev Cell Biol & Mol Oncol, Grand Rapids, MI 49503 USA. RP Frankel, A (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI DUESBERY, NICK/0000-0002-4258-5655 NR 82 TC 2 Z9 2 U1 0 U2 1 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD SEP PY 2003 VL 28 IS 9 BP 897 EP 904 DI 10.1358/dof.2003.028.09.857377 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 771XB UT WOS:000188810400006 ER PT J AU Klein, W Suk, W Goldstein, B AF Klein, W Suk, W Goldstein, B TI SGOMSEC 15 - Methodologies for assessing exposures to metals: Speciation, bioaccessibility, and bioavailability in the environment, food, and feed - Introduction SO ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY LA English DT Editorial Material C1 Fraunhofer Inst Umweltchem & Okotoxikol, D-57377 Schmallenberg, Germany. NIEHS, Off Program Dev, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. RP Klein, W (reprint author), Fraunhofer Inst Umweltchem & Okotoxikol, D-57377 Schmallenberg, Germany. NR 0 TC 1 Z9 1 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0147-6513 J9 ECOTOX ENVIRON SAFE JI Ecotox. Environ. Safe. PD SEP PY 2003 VL 56 IS 1 BP 3 EP 5 DI 10.1016/S0147-6513(03)00044-7 PG 3 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 715NR UT WOS:000184979100002 PM 12915135 ER PT J AU Arnoult, D Gaume, B Karbowski, M Sharpe, JC Cecconi, F Youle, RJ AF Arnoult, D Gaume, B Karbowski, M Sharpe, JC Cecconi, F Youle, RJ TI Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization SO EMBO JOURNAL LA English DT Article DE AIF; cytochrome c; EndoG; HtrA2; Omi; Smac; Diablo ID CYTOCHROME-C RELEASE; PROGRAMMED CELL-DEATH; APOPTOSIS-INDUCING FACTOR; ENDONUCLEASE-G; SERINE-PROTEASE; CAENORHABDITIS-ELEGANS; BAX OLIGOMERIZATION; OUTER-MEMBRANE; PROTEINS; DNA AB Mitochondrial outer-membrane permeabilization by pro-apoptotic Bcl-2 family members plays a crucial role in apoptosis induction. However, whether this directly causes the release of the different mitochondrial apoptogenic factors simultaneously is currently unknown. Here we report that in cells or with isolated mitochondria, pro-apoptotic Bcl-2 proteins cause the release of cytochrome c, Smac/Diablo and HtrA2/Omi but not endonuclease G (EndoG) and apoptosis-inducing factor (AIF). In cells treated with Bax/Bak-dependent pro-apoptotic drugs, neither the caspase inhibitor zVAD-fmk nor loss of Apaf-1 affected the efflux of cytochrome c, Smac/Diablo and HtrA2/Omi, but both prevented the release of EndoG and AIF. Our findings identify the mitochondrial response to pro-apoptotic stimuli as a selective process leading to a hierarchical ordering of the effectors involved in cell death induction. Moreover, as in Caenorhabditis elegans, EndoG and AIF act downstream of caspase activation. Thus EndoG and AIF seem to define a 'caspase-dependent' mitochondria-initiated apoptotic DNA degradation pathway that is conserved between mammals and nematodes. C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 52 TC 286 Z9 299 U1 0 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 SEP 1 PY 2003 VL 22 IS 17 BP 4385 EP 4399 DI 10.1093/emboj/cdg423 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 718LP UT WOS:000185147900006 PM 12941691 ER PT J AU Muller, J Ritt, DA Copeland, TD Morrison, DK AF Muller, J Ritt, DA Copeland, TD Morrison, DK TI Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate SO EMBO JOURNAL LA English DT Article DE 14-3-3; C-TAK1; phosphorylation motif; protein kinase; subcellular protein localization ID PHOSPHORYLATES HUMAN CDC25C; 14-3-3 PROTEIN-BINDING; DESMOSOMAL PLAQUE; STRUCTURAL BASIS; NUCLEAR EXPORT; MAPK SCAFFOLD; KINASE; LOCALIZATION; SERINE-216; CHK1 AB Cdc25C-associated kinase 1 (C-TAK1) has been implicated in cell cycle regulation and Ras signaling through its interactions with two putative substrates, the Cdc25C phosphatase and the MAPK scaffold KSR1. Here, we identify sequence motifs required for stable C-TAK1 association and substrate phosphorylation. Using a mutational approach to disrupt binding of C-TAK1 to KSR1 and Cdc25C, we demonstrate that C-TAK1 contributes to the regulation of these proteins in vivo through the generation of 14-3-3-binding sites. KSR1 proteins defective in C-TAK1 binding had severely reduced phosphorylation at the 14-3-3-binding site in vivo, were constitutively localized to the plasma membrane and had increased biological activity. Disruption of the Cdc25C-C-TAK1 interaction resulted in reduced 14-3-3-binding site phosphorylation and nuclear accumulation of Cdc25C in interphase cells. Finally, utilizing the acquired C-TAK1 binding and substrate phosphorylation data, we identify plakophilin 2 (PKP2) as a novel C-TAK1 substrate. Phosphorylation of PKP2 by C-TAK1 also generates a 14-3-3-binding site that influences PKP2 localization. These findings underscore the importance of C-TAK1 as a regulator of 14-3-3 binding and protein localization. C1 NCI, Regulat Cell Growth Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP NCI, Regulat Cell Growth Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM dmorrison@ncifcrf.gov NR 36 TC 41 Z9 41 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD SEP 1 PY 2003 VL 22 IS 17 BP 4431 EP 4442 DI 10.1093/emboj/cdg426 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 718LP UT WOS:000185147900010 PM 12941695 ER PT J AU Felici, A Wurthner, JU Parks, WT Giam, LR Reiss, M Karpova, TS McNally, JG Roberts, AB AF Felici, A Wurthner, JU Parks, WT Giam, LR Reiss, M Karpova, TS McNally, JG Roberts, AB TI TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling SO EMBO JOURNAL LA English DT Article DE Smad proteins; TGF-beta signaling; TRAP-1; TGF-beta receptors ID GROWTH-FACTOR-BETA; FYVE DOMAIN PROTEIN; EARLY ENDOSOMES; FUNCTIONAL-CHARACTERIZATION; SMAD PATHWAY; RECEPTOR; CLATHRIN; SARA; TRANSCRIPTION; ACTIVATION AB Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine signaling to the nucleus through cell surface transmembrane receptor serine/threonine kinases and cytoplasmic effectors, including Smad proteins. We describe a novel modulator of this pathway, TLP (TRAP-1-like protein), which is 25% identical to the previously described Smad4 chaperone, TRAP-1, and shows identical expression patterns in human tissues. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. Overexpression of TLP represses the ability of TGF-beta to induce transcription from SBE-Luc, a Smad3/4-specific reporter, while it potentiates transcription from ARE-Luc, a Smad2/4-specific reporter. Consistent with this, TLP inhibits the formation of Smad3/4 complexes in the absence of effects on phosphorylation of Smad3, while it affects neither Smad2 phosphorylation nor hetero-oligomerization. We propose that TLP might regulate the balance of Smad2 and Smad3 signaling by localizing Smad4 intracellularly, thus contributing to cellular specificity of TGF-beta transcriptional responses in both normal and pathophysiology. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Internal Med,Canc Inst New Jersey, Div Med Oncol, New Brunswick, NJ 08903 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RI Reiss, Michael/A-8314-2009 NR 53 TC 58 Z9 67 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 1 PY 2003 VL 22 IS 17 BP 4465 EP 4477 DI 10.1093/emboj/cdg428 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 718LP UT WOS:000185147900013 PM 12941698 ER PT J AU Schwan, TG Policastro, PF Miller, Z Thompson, RL Damrow, T Keirans, JE AF Schwan, TG Policastro, PF Miller, Z Thompson, RL Damrow, T Keirans, JE TI Tick-borne relapsing fever caused by Borrelia hermsii, Montana SO EMERGING INFECTIOUS DISEASES LA English DT Article ID MONOCLONAL-ANTIBODY; INTERSTATE OUTBREAK; ARGASIDAE; UTAH AB Five persons contracted tick-borne relapsing fever after staying in a cabin in western Montana. Borrelia hermsii was isolated from the blood of two patients, and Ornithodoros hermsi ticks were collected from the cabin, the first demonstration of this bacterium and tick in Montana. Relapsing fever should be considered when patients who reside or have vacationed in western Montana exhibit a recurring febrile illness. C1 NIAID, Rocky Mt Labs, NIH, Lab Human Bacterial Pathogenesis, Hamilton, MT USA. Grp Hlth Cooperat Puget Sound, Seattle, WA USA. Dept Publ Hlth, Helena, MT USA. Georgia So Univ, Statesboro, GA 30460 USA. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, NIH, Lab Human Bacterial Pathogenesis, 903 S 4th St, Hamilton, MT USA. FU NIAID NIH HHS [R01 AI040729, AI-40729] NR 20 TC 41 Z9 42 U1 0 U2 0 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2003 VL 9 IS 9 BP 1151 EP 1154 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 717QM UT WOS:000185100900019 PM 14519254 ER PT J AU Eisenhofer, G Goldstein, DS Kopin, IJ Crout, JR AF Eisenhofer, G Goldstein, DS Kopin, IJ Crout, JR TI Pheochromocytoma: Rediscovery as a catecholamine-metabolizing tumor SO ENDOCRINE PATHOLOGY LA English DT Review DE pheochromocytoma; paraganglioma; chromaffin cells; adrenal glands; hypertension; catecholamines; norepinephrine; epinephrine; normetanephrine; metanephrine; synthesis; metabolism; secretion ID PLASMA-FREE METANEPHRINES; BIOCHEMICAL-DIAGNOSIS; LIQUID-CHROMATOGRAPHY; 4-HYDROXY-3-METHOXYMANDELIC ACID; NOREPINEPHRINE METABOLISM; ADRENAL INCIDENTALOMA; O-METHYLTRANSFERASE; MONOAMINE OXIDASE; DOPAMINE SULFATE; URINARY AB Catecholamine-producing tumors are rare neoplasms derived mainly from chromaffin cells of the adrenal medulla (pheochromocytomas)or, in about 10% of cases, from paraganglia (paragangliomas). Diagnosis of these tumors relies heavily on measurements of urinary or plasma catecholamines or catecholamine metabolites. The metabolites are usually thought to be produced after release of catecholamines into the bloodstream. This, however, ignores observations of over 40 yr ago that catecholamines are metabolized within pheochromocytoma tumor cells. Development of improved methods for measurement of catecholamine metabolites, in particular, plasma concentrations of free normetanephrine and metanephrine, has reestablished the importance of intratumoral catecholamine metabolism. In patients with pheochromocytoma, over 90% of the elevations in plasma free normetanephrine and metanephrine result from metabolism of catecholamines within pheochromocytoma tumor cells. This process occurs continuously and independently of variations in catecholamine release. As a consequence, measurements of plasma concentrations and urinary outputs of normetanephrine and metanephrine provide more reliable methods for diagnosis of pheochromocytoma than measurements of the parent amines. Rediscovery of the importance of intratumoral catecholamine metabolism is leading to a reevaluation of the procedures used to diagnose pheochromocytoma. This review provides an update on the diagnosis of pheochromocytoma, with emphasis on identifying and correcting relevant misconceptions about catecholamine metabolism. C1 Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. RP Eisenhofer, G (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. NR 92 TC 27 Z9 28 U1 4 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD FAL PY 2003 VL 14 IS 3 BP 193 EP 212 DI 10.1007/s12022-003-0012-4 PG 20 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 738YD UT WOS:000186314700002 PM 14586065 ER PT J AU Smith, RE Good, BC AF Smith, RE Good, BC TI Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others SO ENDOCRINE-RELATED CANCER LA English DT Review ID ONCOLOGY TECHNOLOGY-ASSESSMENT; ESTROGEN-RECEPTOR; TAMOXIFEN THERAPY; POSTMENOPAUSAL WOMEN; RANDOMIZED TRIAL; CLINICAL-TRIAL; CONTRALATERAL BREAST; AROMATASE INHIBITORS; PREVENTION TRIALS; RISK REDUCTION AB The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents. C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. RP Smith, RE (reprint author), Natl Surg Adjuvant Breast & Bowel Project, 4 Allegheny Ctr,5th Floor, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10-CA-37377, U10-CA-69974] NR 54 TC 14 Z9 16 U1 0 U2 2 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD SEP PY 2003 VL 10 IS 3 BP 347 EP 357 DI 10.1677/erc.0.0100347 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 730UV UT WOS:000185849300001 PM 14503912 ER PT J AU Esaki, T Suzuki, H Cook, M Shimoji, K Cheng, SY Sokoloff, L Nunez, J AF Esaki, T Suzuki, H Cook, M Shimoji, K Cheng, SY Sokoloff, L Nunez, J TI Functional activation of cerebral metabolism in mice with mutated thyroid hormone nuclear receptors SO ENDOCRINOLOGY LA English DT Article ID GLUCOSE-UTILIZATION; TARGETED MUTATION; BRAIN-DEVELOPMENT; ALPHA-ISOFORM; RAT-BRAIN; GENE; HYPOTHYROIDISM; CEREBELLUM; ADULT; EXPRESSION AB Neonatal hypothyroidism impairs structural maturation in the brain and results in diminished electrical activities and energy metabolism. We recently found that glucose utilization (CMRglc) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor alpha1 (TRalpha1), but not TRbeta. Previous studies had shown that CMRglc increases linearly with spike frequency in the afferent pathways to synapse-rich regions in neuropil, but not in neuronal cell bodies. To determine whether the decreased CMRglc in mutant TRalpha1(PV/+) mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMRglc bilaterally in four stations of the whisker-to-barrel cortex pathway. Baseline CMRglc (unstimulated side) was markedly lower in all four stations in the TRalpha1(PV/+) mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na+,K+-adenosine triphosphatase expression and neuronal differentiation. Despite the lower baseline CMRglc, however, vibrissal stimulation evoked percent increases in CMRglc in the TRalpha1(PV/+) mutants that were as great as those in wild-type mice. These results indicate that in the TRalpha1(PV/+) mutants there it is a reduction in synaptic density that is responsible for the decrease in CMRglc, but functionality of existing synapses is retained. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. NCI, Positron Emiss Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36,Room 1A-07,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 30 TC 21 Z9 21 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 SEP 1 PY 2003 VL 144 IS 9 BP 4117 EP 4122 DI 10.1210/en.2003-0414 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 713XN UT WOS:000184883400048 PM 12933686 ER PT J AU Kamiya, Y Zhang, XY Ying, H Kato, Y Willingham, MC Xu, JM O'Malley, BW Cheng, SY AF Kamiya, Y Zhang, XY Ying, H Kato, Y Willingham, MC Xu, JM O'Malley, BW Cheng, SY TI Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone SO ENDOCRINOLOGY LA English DT Article ID HISTONE DEACETYLASE; MESSENGER-RNA; BETA-RECEPTOR; TR-BETA; MICE; GENE; EXPRESSION; REPRESSION; MUTATION; ISOFORMS AB Mutations in the thyroid hormone receptor-beta gene (TRbeta) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TRbetaPV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TRbeta(PV/+) mice but not in TRbeta(PV/PV) mice. In TRbeta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TRbeta(PV/+) or TRbeta(PV/PV) mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T-3 target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TRbeta mutants in a tissue-dependent manner. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Pathol, Sch Med, Winston Salem, NC 27157 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD07857] NR 21 TC 25 Z9 27 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 SEP 1 PY 2003 VL 144 IS 9 BP 4144 EP 4153 DI 10.1210/en.2003-0239 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 713XN UT WOS:000184883400051 PM 12933689 ER PT J AU Nelson, LM Bakalov, VK AF Nelson, LM Bakalov, VK TI Mechanisms of follicular dysfunction in 46,XX spontaneous premature ovarian failure SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Review ID STIMULATING-HORMONE RECEPTOR; XX GONADAL-DYSGENESIS; HUMAN GRANULOSA-CELLS; ELEVATED SERUM LEVELS; AUTOIMMUNE OOPHORITIS; YOUNG-WOMEN; HYPERGONADOTROPIC HYPOGONADISM; LUTEINIZING-HORMONE; MENSTRUAL-CYCLE; INACTIVATING MUTATIONS AB Previously, "premature menopause" was the term used to describe 46,XX spontaneous premature ovarian failure. For young women desiring pregnancy, this term implies absolute and irreversible infertility-finality caused by follicular depletion. This is clearly not the case. Pregnancy can occur after this diagnosis. Insights into the pathophysiology of this disorder make it clear that approximately one half of young women who have 46,XX spontaneous premature ovarian failure have follicles remaining in the ovary. Ongoing research is uncovering the mechanisms of follicular dysfunction in these women. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 114 TC 10 Z9 10 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 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD SEP PY 2003 VL 32 IS 3 BP 613 EP + DI 10.1016/S0889-8529(03)00043-4 PG 26 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 727DL UT WOS:000185641300005 PM 14560890 ER PT J AU Kanno, J Onyon, L Peddada, S Ashby, J Jacob, E Owens, W AF Kanno, J Onyon, L Peddada, S Ashby, J Jacob, E Owens, W TI The OECD program to validate the rat uterotrophic bioassay. Phase 2: Dose-response studies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE endocrine disruption; estrogen; rat uterus; uterotrophic ID SPRAGUE-DAWLEY RATS; BISPHENOL-A; REPRODUCTIVE TOXICITY; ESTROGEN-RECEPTOR; GENISTEIN; PHYTOESTROGENS; 4-NONYLPHENOL; 2-GENERATION; METHOXYCHLOR AB The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. The purpose of the validation program was to demonstrate the performance of two versions of the uterotrophic bioassay, the immature female rat and the adult ovariectomized rat, in four standardized protocols. This article reports the dose-response studies of the validation program; the coded single-dose studies are reported in an accompanying paper. The dose-response study design used five selected weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p'-DDT. These weak agonists were administered in a prescribed series of doses to measure the performance and reproducibility of the protocols among the participating laboratories. All protocols successfully detected increases in uterine weights when the weak agonists were administered. Within each protocol, there was good agreement and reproducibility of the dose response among laboratories with each substance. Substance-specific variations were observed in the influence of the route of administration on the uterine response, the potency as related to the dose producing the first statistically significant increase in uterine weights, and the maximum increase in uterine weight. Substantive performance differences were not observed between the uterotrophic bioassay versions or among the standardized protocols, and these were judged to be qualitatively equivalent. It is noteworthy that these results were reproducible under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age), indicating that the bioassay's performance as a screen is robust. In conclusion, both the intact, immature, and adult OVX versions, and all protocols appear to be reproducible and transferable across laboratories and are able to detect weak estrogen agonists. C1 Natl Inst Hlth Sci, Tokyo 158, Japan. Org Econ Cooperat & Dev, Environm Hlth & Safety Div, Paris, France. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Syngenta Cent Toxicol Lab, Macclesfield, Cheshire, England. BASF AG, Aktiengesell, D-6700 Ludwigshafen, Germany. Procter & Gamble Co, Cincinnati, OH USA. RP Owens, W (reprint author), OECD, Environm Hlth & Safety Div, OECD Programme, 2 Rue Andre Pascal, F-75775 Paris 16, France. RI Peddada, Shyamal/D-1278-2012 NR 24 TC 90 Z9 92 U1 2 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2003 VL 111 IS 12 BP 1530 EP 1549 DI 10.1289/ehp.5780 PG 20 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 733HZ UT WOS:000185995500036 PM 12948896 ER PT J AU Kanno, J Onyon, L Peddada, S Ashby, J Jacob, E Owens, W AF Kanno, J Onyon, L Peddada, S Ashby, J Jacob, E Owens, W TI The OECD program to validate the rat uterotrophic bioassay. Phase 2: Coded single-dose studies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE endocrine disruption; estrogen; rat uterus; uterotrophic ID DI(N-BUTYL) PHTHALATE; REPRODUCTIVE-SYSTEM; LATE PREGNANCY AB The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. This portion of phase 2 assessed the reproducibility of the assay with a battery of positive and negative test substances. Positive agonists of the estrogen receptor included the potent reference estrogen 17alpha-ethinyl estradiol (EE), and the weak estrogen agonists bisphenol A, genistein, methoxychlor, nonylphenol, and o,p'-DDT. The negative test substance or nonagonist was n-dibutylphthalate. The test substances were coded, and prescribed doses of each test substance were administered in 16 laboratories. Two versions of the uterotrophic assay, the intact immature and the adult ovariectomized female rat, were tested and compared using four standardized protocols covering both sc and po administration. Assay reproducibility was compared using a) EE doses identical to those used in phase 1 and in parallel dose-response studies, b) single doses of the weak agonists identical to one of five doses from the dose-response studies, and c) a single dose of the negative test substance. The results were reproducible and in agreement both within individual laboratories and across the participating laboratories for the same test substance and protocol. The few exceptions are examined in detail. The reproducibility was achieved despite a variety of different experimental conditions (e.g., variations in animal strain, diet, housing protocol, bedding, vehicle, animal age). In conclusion, both versions of the uterotrophic bioassay and all protocols appear robust, reproducible, and transferable across laboratories and able to detect weak estrogen agonists. These results will be submitted along with other data for independent peer review to provide support for the validation of the uterotrophic bioassay. C1 Procter & Gamble Co, Cent Prod Safety, Cincinnati, OH 45252 USA. Natl Inst Hlth Sci, Tokyo 158, Japan. Org Econ Cooperat & Dev, Environm Hlth & Safety Div, Paris, France. NIEHS, Res Triangle Pk, NC 27709 USA. Syngenta Cent Toxicol Lab, Macclesfield, Cheshire, England. BASF AG, Aktiengesell, D-6700 Ludwigshafen, Germany. RP Owens, W (reprint author), Procter & Gamble Co, Cent Prod Safety, 11810 E Miami River Rd, Cincinnati, OH 45252 USA. RI Peddada, Shyamal/D-1278-2012 NR 14 TC 66 Z9 66 U1 1 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2003 VL 111 IS 12 BP 1550 EP 1558 DI 10.1289/ehp.5870 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 733HZ UT WOS:000185995500037 PM 12948897 ER PT J AU Cook, PM Robbins, JA Endicott, DD Lodge, KB Guiney, PD Walker, MK Zabel, EW Peterson, RE AF Cook, PM Robbins, JA Endicott, DD Lodge, KB Guiney, PD Walker, MK Zabel, EW Peterson, RE TI Effects of aryl hydrocarbon receptor-mediated early life stage toxicity on lake trout populations in Lake Ontario during the 20th century SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID DIBENZO-P-DIOXIN; POLYCHLORINATED BIPHENYL CONGENERS; EQUIVALENCY FACTORS TEFS; GREAT-LAKES; CHLORINATED HYDROCARBONS; SALVELINUS-NAMAYCUSH; SAC FRY; ONCORHYNCHUS-MYKISS; DIETARY EXPOSURE; NIAGARA RIVER AB Lake trout embryos and sac fry are very sensitive to toxicity associated with maternal exposures to 2,3,7,8-tetra chlorodibenzo-p-dioxin (TCDD) and structurally related chemicals that act through a common aryl hydrocarbon receptor (AHR)-mediated mechanism of action. The loading of large amounts of these chemicals into Lake Ontario during the middle of the 20th century coincided with a population decline that culminated in extirpation of this species around 1960. Prediction of past TCDD toxicity equivalence concentrations in lake trout eggs (TEC(egg)s) relative to recent conditions required fine resolution of radionuclide-dated contaminant profiles in two sediment cores; reference core specific biota-sediment accumulation factors (BSAFs) for TCDD-like chemicals in lake trout eggs; adjustment of the BSAFs for the effect of temporal changes in the chemical distributions between water and sediments; and toxicity equivalence factors based on trout early life stage mortality. When compared to the dose-response relationship for overt early life stage toxicity of TCDD to lake trout, the resulting TEC(egg)s predict an extended period during which lake trout sac fry survival was negligible. By 1940, following more than a decade of population decline attributable to reduced fry stocking and loss of adult lake trout to commercial fishing, the predicted sac fry mortality due to AHR-mediated toxicity alone explains the subsequent loss of the species. Reduced fry survival, associated with lethal and sublethal adverse effects and possibly complicated by other environmental factors, occurred after 1980 and contributed to a lack of reproductive success of stocked trout despite gradually declining TEC(egg)s. Present exposures are close to the most probable no observable adverse effect level (NOAEL TEC(egg) = 5 pg TCDD toxicity equivalence/g egg). The toxicity predictions are very consistent with the available historical data for lake trout population levels in Lake Ontario, stocking programs, and evidence for recent improvement in natural reproduction concomitant with declining levels of persistent bioaccumulative chemicals in sediments and biota. C1 US EPA, Mid Continent Ecol Div, Natl Hlth & Environm Effects Res Lab, Duluth, MN 55804 USA. NOAA, Great Lakes Environm Res Lab, Ann Arbor, MI 48105 USA. Univ Minnesota, Dept Chem Engn, Duluth, MN 55812 USA. Univ Wisconsin, NIEHS, Marine & Freshwater Biomed Sci Ctr, Milwaukee, WI 53204 USA. Univ Wisconsin, Mol & Environm Toxicol Ctr, Madison, WI 53726 USA. Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA. RP Cook, PM (reprint author), US EPA, Mid Continent Ecol Div, Natl Hlth & Environm Effects Res Lab, 6201 Congdon Blvd, Duluth, MN 55804 USA. EM cook.philip@epa.gov NR 98 TC 77 Z9 87 U1 2 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD SEP 1 PY 2003 VL 37 IS 17 BP 3864 EP 3877 DI 10.1021/es034045m PG 14 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 716YL UT WOS:000185057500037 PM 12967107 ER PT J AU Sandler, DP Comstock, GW AF Sandler, DP Comstock, GW TI A conversation with George W. Comstock SO EPIDEMIOLOGY LA English DT Editorial Material C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, Mail Drop A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. NR 6 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 BP 623 EP 627 DI 10.1097/01.ede.0000081990.82964.1f PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 718EV UT WOS:000185132900018 PM 14501279 ER PT J AU Alavanja, M Lee, WJ Rusiecki, J Dosemeci, M Hoppin, JF Sandler, D Blair, A AF Alavanja, M Lee, WJ Rusiecki, J Dosemeci, M Hoppin, JF Sandler, D Blair, A TI Cancer incidence among pesticide applicators exposed to alachlor or atrazine in the agricultural health study SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 NIEHS, Res Triangle Pk, NC 27709 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S57 EP S57 DI 10.1097/00001648-200309001-00124 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600125 ER PT J AU Bates, M Rey, O Biggs, ML Hopenhayn, C Moore, LF Kalman, D Steinmaus, C Smith, A AF Bates, M Rey, O Biggs, ML Hopenhayn, C Moore, LF Kalman, D Steinmaus, C Smith, A TI Arsenic in drinking water and bladder cancer in Argentina: Results of a case-control study. SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Univ Catolica Cordoba, Cordoba, Argentina. Univ Washington, Seattle, WA 98195 USA. Univ Kentucky, Lexington, KY USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S123 EP S123 DI 10.1097/00001648-200309001-00301 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600302 ER PT J AU Buck, G Weiner, J Greizerstein, H Whitcomb, B Scisterman, E Kostyniak, P Lobdell, D Crickard, K Sperrazza, R AF Buck, G Weiner, J Greizerstein, H Whitcomb, B Scisterman, E Kostyniak, P Lobdell, D Crickard, K Sperrazza, R TI Environmental PCB and pesticide exposure and risk of endometriosis SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 NICHHD, Dept Hlth & Human Serv, Bethesda, MD USA. SUNY Buffalo, Buffalo, NY USA. Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. US EPA, Washington, DC 20460 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S43 EP S43 DI 10.1097/00001648-200309001-00086 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600087 ER PT J AU Cantor, K Baris, D Inskip, P AF Cantor, K Baris, D Inskip, P TI Mortality among radio amateur operators SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S83 EP S83 DI 10.1097/00001648-200309001-00193 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600194 ER PT J AU Longnecker, MP Klebanoff, MA Brock, JW AF Longnecker, MP Klebanoff, MA Brock, JW TI In utero: Exposure to organochlorines in relation to reproductive and developmental outcomes in the collaborative perinatal project SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 NIEHS, DHHS, NIH, Res Triangle Pk, NC 27709 USA. NICHHD, Rockville, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S139 EP S139 DI 10.1097/00001648-200309001-00346 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600347 ER PT J AU Ward, MH Giglierano, J Wolter, C Miller, RS Nuckols, JR Hartge, P AF Ward, MH Giglierano, J Wolter, C Miller, RS Nuckols, JR Hartge, P TI How accurately does geocoding determine residential locations in rural and urban areas? SO EPIDEMIOLOGY LA English DT Meeting Abstract CT 15th Conference of the International-Society-for-Environment-Epidemiology CY SEP 23-26, 2003 CL PERTH, AUSTRALIA SP Int Soc Environm Epidemiol, CommonWealth Dept Hlth & Aged Care, US EPA C1 NCI, Div Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Iowa Geol Survey, Iowa City, IA USA. Colorado State Univ, Dept Environm & Radiol Hlth Sci, Colorado Springs, CO USA. RI Miller, Ryan/G-6356-2010 NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2003 VL 14 IS 5 SU 1 BP S102 EP S103 DI 10.1097/00001648-200309001-00246 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 724LG UT WOS:000185488600247 ER PT J AU Hendler, RW Bose, S AF Hendler, RW Bose, S TI Interconversions among four M-intermediates in the bacteriorhodopsin photocycle SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE enzyme control; lipid protein interactions; membrane proteins; proton pumps ID CYTOPLASMIC SURFACE; PURPLE MEMBRANE; ANGSTROM RESOLUTION; NATIVE LIPIDS; PROTON PUMP; HIGH PH; KINETICS; PROTEIN; MODEL; COMPLEX AB Halobacterium salinarum displays four distinct kinetic forms of M-intermediate in its bacteriorhodopsin photocycle. In wild-type, there are mainly two species with time constants near 2 and 5 ms. Under various kinds of stress, two other species arise with time constants near 10 and 70 ms. We show that these four species are interconvertible. Increases in membrane hydrophobicity convert the slower to faster forms. Perturbations caused by Triton X-100 or mutations convert faster to slower forms. The fastest form requires a hydrophobic membrane environment near a ring of four charged aspartate residues in the trimer, namely Asp36, Asp38, Asp102, and Asp104 in the cytoplasmic loop regions. Interconversions of the 2-ms and 5-ms species of the wildtype are accomplished by pH-changes. The potential significance of these findings is discussed. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hendler, RW (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 27 TC 9 Z9 9 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD SEP PY 2003 VL 270 IS 17 BP 3518 EP 3524 DI 10.1046/j.1432-1033.2003.03731.x PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 722HU UT WOS:000185370000005 PM 12919316 ER PT J AU Cruz-Monserrate, Z Mullaney, JT Harran, PG Pettit, GR Hamel, E AF Cruz-Monserrate, Z Mullaney, JT Harran, PG Pettit, GR Hamel, E TI Dolastatin 15 binds in the vinca domain of tubulin as demonstrated by Hummel-Dreyer chromatography SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE cemadotin; dolastatin 10; cryptophycin 1; dolastatin 15; tubulin ID ANTINEOPLASTIC AGENTS; CELLULAR MICROTUBULES; INHIBITION; MECHANISM; PEPTIDE; POLYMERIZATION; ALKALOIDS; DISTINCT; COMBRETASTATIN-A-4; CRYPTOPHYCIN-1 AB The antimitotic depsipeptide dolastatin 15 was radiolabeled with tritium in its amino-terminal dolavaline residue. Dolastatin 15, although potently cytotoxic, is a relatively weak inhibitor of tubulin assembly and does not inhibit the binding of any other ligand to tubulin. The only methodology found to demonstrate an interaction between the depsipeptide and tubulin was Hummel-Dreyer equilibrium chromatography on Sephadex G-50 superfine. The average apparent K-d value obtained in these studies was about 30 muM, with no difference observed when column size or tubulin concentration was varied. This relatively high dissociation constant is consistent with the apparent weak interaction of dolastatin 15 with tubulin demonstrated indirectly in the assembly assay. We attempted to gain insight into the binding site for dolastatin 15 on tubulin by studying inhibitory effects of other drugs when the gel filtration column was equilibrated with both [H-3] dolastatin 15 and a second, nonradiolabeled drug. No inhibition was detected with either the colchicine site agent combretastatin A-4 or with an analog of the antimitotic marine peptide diazonamide A (both the analog and diazonamide A are potent inhibitors of tubulin assembly). Weak inhibition was observed with cemadotin, a structural analog of dolastatin 15, and with the depsipeptide cryptophycin 1. Moderate inhibition occurred with vinblastine and vincristine, and strong inhibition with maytansine, halichondrin B, and the peptides dolastatin 10 and phomopsin A. These observations suggest that the binding site(s) for peptide and depsipeptide antimitotic drugs may consist of a series of overlapping domains rather than a well-defined locus on the surface of beta-tubulin. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ USA. Arizona State Univ, Canc Res Inst, Tempe, AZ USA. Univ Texas, SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75235 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bldg 469 Room 104, Frederick, MD 21702 USA. RI Cruz-Monserrate, Zobeida/H-2290-2013; Cruz, Zobeida/J-2714-2013 NR 33 TC 35 Z9 38 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD SEP PY 2003 VL 270 IS 18 BP 3822 EP 3828 DI 10.1046/j.1432-1033.2003.03776.x PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 740EM UT WOS:000186390000018 PM 12950266 ER PT J AU Difilippantonio, S Chen, Y Pietas, A Schluns, K Pacyna-Gengelbach, M Deutschmann, N Padilla-Nash, HM Ried, T Petersen, I AF Difilippantonio, S Chen, Y Pietas, A Schluns, K Pacyna-Gengelbach, M Deutschmann, N Padilla-Nash, HM Ried, T Petersen, I TI Gene expression profiles in human non-small and small-cell lung cancers SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE gene expression profile; suppression subtractive hybridisation; human non-small cell lung cancer; small-cell lung cancer; sequencing; gene mapping and full-length cDNA ID CARCINOMAS; DIFFERENTIATION; INVASION; GROWTH; ADENOCARCINOMA; TRANSFORMATION; PROGNOSIS; PATTERNS; ARRAYS; HEAD AB Suppression subtractive hybridisation (SSH) was performed comparing normal bronchial epithelial cells with a lung squamous cell carcinoma (SCC) and a metastatic small-cell lung carcinoma (SCLC). The sequence analysis of four cDNA libraries revealed 869 individual sequences. Of these, 342 were tested using northern blots of lung cancer cell lines representing the three major subtypes (SCC, adenocarcinoma, SCLC) which confirmed the differential expression of 236 cDNAs. The extended analysis of 31 randomly chosen fragments confirmed the validity of the approach to identify genes associated with lung cancer development. Additionally, five novel full-length cDNA were isolated encoding the microtubule-associated proteins 1A/1B light chain 3, the epithelial V-like antigen 1 (EVA1), the GTP-binding protein SAR1, a new member of the S100-type calcium binding protein family and a new homeobox-containing gene. (C) 2003 Published by Elsevier Science Ltd. C1 Univ Hosp Charite, Inst Pathol, D-10098 Berlin, Germany. NCI, Dept Genet, NIH, Bethesda, MD 20892 USA. RP Petersen, I (reprint author), Univ Hosp Charite, Inst Pathol, Schumannsrt 20-21, D-10098 Berlin, Germany. NR 30 TC 47 Z9 52 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2003 VL 39 IS 13 BP 1936 EP 1947 DI 10.1016/S0959-8049(03)00419-2 PG 12 WC Oncology SC Oncology GA 721QQ UT WOS:000185327400018 PM 12932674 ER PT J AU Sanchez, A Nagy, P Thorgeirsson, SS AF Sanchez, A Nagy, P Thorgeirsson, SS TI STAT-3 activity in chemically-induced hepatocellular carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE STAT-3; liver tumour; dexamethasone; c-myc ID TRANSCRIPTIONAL ACTIVATION; LIVER-REGENERATION; TRANSGENIC MICE; FACTOR RECEPTOR; KAPPA-B; GROWTH; CANCER; CELLS; PROTEIN; ALPHA AB The signal transducer and activator of transcription (STAT)-3 regulates basic biological processes and it has been reported to be constitutively active in different types of malignant tumours. STAT-3 is active during the regenerative growth of the liver, but there are hardly any data about its presence in liver tumours. We investigated and found a high activity of STAT-3 using an electrophoretic mobility shift assay (EMSA) in chemically-induced rat hepatocellular carcinomas (HCCs). Dexamethasone treatment downregulated both STAT-3 activity and cell proliferation in the tumours. Therefore, the activity of the STAT-3 signal transduction pathway seems to be required for the growth of HCCs and could be a potential new target for therapeutic trials of this tumour type. (C) 2003 Elsevier Ltd. All rights reserved. C1 Semmelweis Univ, Inst Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Nagy, P (reprint author), Semmelweis Univ, Inst Pathol & Expt Canc Res 1, Ulloi Ut 26, H-1085 Budapest, Hungary. EM nagy@korb1.sote.hu RI Sanchez, Aranzazu/H-7810-2015 OI Sanchez, Aranzazu/0000-0001-9145-6633 NR 30 TC 25 Z9 28 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2003 VL 39 IS 14 BP 2093 EP 2098 DI 10.1016/S0959-8049(03)00393-9 PG 6 WC Oncology SC Oncology GA 724WV UT WOS:000185510400025 PM 12957465 ER PT J AU Vamecq, J Maurois, P Bac, P Bailly, F Bernier, JL Stables, JP Husson, I Gressens, P AF Vamecq, J Maurois, P Bac, P Bailly, F Bernier, JL Stables, JP Husson, I Gressens, P TI Potent mammalian cerebroprotection and neuronal cell death inhibition are afforded by a synthetic antioxidant analogue of marine invertebrate cell protectant ovothiols SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE developing brain; ovothiol; oxidative stress; recycling mechanisms; thioredoxin ID SUPEROXIDE-DISMUTASE; GLUTATHIONE-PEROXIDASE; MAGNESIUM-DEFICIENCY; DEVELOPING BRAIN; NEUROPROTECTION; STRESS; 4-MERCAPTOIMIDAZOLES; ANTICONVULSANT; APOPTOSIS; TOLERANCE AB Implicit strategies for neuroprotection in the adult brain include GABA(A) receptor activation, N-methyl-D-aspartate receptor and sodium voltage-gated channel inhibition. Ironically, these same targets may be harmful to the immature or developing brain. Protection has been demonstrated for both immature and mature brain with the use of a synthetic ovothiol analogue. The following beneficial effects have been demonstrated in mice: protection against audiogenic seizures, brain structures with clear-cut delineation of ibotenate-challenged white and grey matter lesions along with exceptional early and delayed protections, and potent cerebral cell death inhibition. The compound lacks both GABAergic activity and sodium channel blocker properties, which may help explain the lack of toxicity normally expressed in an immature brain utilizing these agents [J.W. Olney (2002) Neurotoxicology, 93, 1-10]. The oxidized form of the compound is virtually devoid of antioxidant activity. In vivo it exhibits cerebroprotective properties similar to those of reduced compounds endowed with antioxidant properties. This unexpected finding has prompted an extensive in vitro exploration of underlying molecular mechanisms that have led to the identification of several recycling mechanisms consistent with non rate-limiting conversion of oxidized to reduced compound forms. Taken as a whole, this work offers an unique combined in vitro and in vivo support that: (i) antioxidant therapy, here engineered from marine invertebrate egg protectants, may be a valuable strategy in protecting both mammalian adult and developing brain; and (ii) recycling (thiol-disulphide exchange) properties of the oxidized form of an antioxidant compound are as important as the antioxidant potential exhibited by a bioactive reduced antioxidant in certain neuroprotective processes. C1 CHRU, Salengro Univ Hosp, Neuropaediat Dept Professor Louis Vallee, INSERM,UNIV 045131, F-59037 Lille, France. Univ Lille 2, Fac Med, Dept Pharmacol, EA 1046, F-59045 Lille, France. Fac Pharm Chatenay Malabry, Neuropharmacol Lab, Chatenay Malabry, France. UST Lille 1, CNRS, UMR 8009, Lab Chim Organ& Macromol, Lille, France. NINDS, Preclin Pharmacol Sect, Epilepsy Branch, DCDND,NINDS, Bethesda, MD USA. Hop Robert Debre, INSERM E9935, Neuropaediat Dept Professor Philippe Evrard, F-75019 Paris, France. RP Vamecq, J (reprint author), CHRU, Salengro Univ Hosp, Neuropaediat Dept Professor Louis Vallee, INSERM,UNIV 045131, F-59037 Lille, France. EM lvallee@chru-lille.fr OI Gressens, Pierre/0000-0002-0909-4221 NR 40 TC 13 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 2003 VL 18 IS 5 BP 1110 EP 1120 DI 10.1046/j.1460-9568.2003.02846.x PG 11 WC Neurosciences SC Neurosciences & Neurology GA 719EK UT WOS:000185190500010 PM 12956711 ER PT J AU Law, AJ Weickert, CS Webster, MJ Herman, MM Kleinman, JE Harrison, PJ AF Law, AJ Weickert, CS Webster, MJ Herman, MM Kleinman, JE Harrison, PJ TI Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate receptor; hippocampus; in situ hybridization; neonate; ontogeny ID D-ASPARTATE RECEPTOR; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; POSTNATAL-DEVELOPMENT; DIFFERENTIAL EXPRESSION; MOLECULAR-CLONING; SYNAPTIC CURRENTS; TEMPORAL CORTEX; LEAD-EXPOSURE; GLUTAMATE AB The N-methyl-D-aspartate receptor plays a critical role in the formation and maintenance of synapses during brain development. In the rodent, changes in subunit expression and assembly of the heteromeric receptor complex accompany these maturational processes. However, little is known about N-methyl-D-aspartate receptor subunit expression during human brain development. We used in situ hybridization to examine the distribution and relative abundance of NR1, NR2A and NR2B subunit messenger ribonucleic acids in the hippocampal formation and adjacent cortex of 34 human subjects at five stages of life (neonate, infant, adolescent, young adult and adult). At all ages, the three messenger ribonucleic acids were expressed in all subfields, predominantly by pyramidal neurons, granule cells and polymorphic hilar cells. However, their abundance varied across ontogeny. Levels of NR1 messenger ribonucleic acid in CA4, CA3 and CA2 subfields were significantly lower in the neonate than all other age groups. In the dentate gyrus, subiculum and parahippocampal gyrus, NR2B messenger ribonucleic acid levels were higher in the neonate than in older age groups. NR2A messenger ribonucleic acid levels remained constant, leading to an age-related increase in NR2A/2B transcript ratio. We conclude that N-methyl-D-aspartate receptor subunit messenger ribonucleic acids are differentially expressed during postnatal development of the human hippocampus, with a pattern similar but not identical to that seen in the rodent. Changes in subunit composition may thus contribute to maturational differences in human hippocampal N-methyl-D-aspartate receptor function, and to their role in the pathophysiology of schizophrenia and other neurodevelopmental disorders. C1 Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Stanley Lab Brain Res, Bethesda, MD 20814 USA. RP Law, AJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, England. RI Shannon Weickert, Cynthia/G-3171-2011; Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 NR 77 TC 56 Z9 60 U1 0 U2 10 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 2003 VL 18 IS 5 BP 1197 EP 1205 DI 10.1046/j.1460-9568.2003.02850.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 719EK UT WOS:000185190500017 PM 12956718 ER PT J AU De Weerd, P Desimone, R Ungerleider, LG AF De Weerd, P Desimone, R Ungerleider, LG TI Generalized deficits in visual selective attention after V4 and TEO lesions in macaques SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Review DE extrastriate cortex; perception; rhesus monkey; ventral stream; vision; visual cortex ID EXTRASTRIATE AREA V4; INFERIOR TEMPORAL CORTEX; KINETICALLY DEFINED BOUNDARIES; CORTICAL AREAS; INFEROTEMPORAL LESIONS; SPATIAL ATTENTION; NEURAL MECHANISMS; FUNCTIONAL-ORGANIZATION; CONTEXTUAL INFLUENCES; DIRECTED ATTENTION AB To test the role of areas V4 and TEO in the attentional filtering of distracting information, we studied the effects of lesions in these areas, in monkeys discriminating target stimuli surrounded by irrelevant distracters. The lesions were restricted, such that a single visual field quadrant was affected by a V4 lesion alone, a TEO lesion alone, or a combined lesion in V4 and TEO, while one quadrant served as a normal control. The monkeys fixated a spot while discriminating the orientation, colour or motion of target stimuli presented extrafoveally in each quadrant. When the target was presented alone, discrimination deficits in the quadrants affected by the lesions were generally small. However, these deficits were substantially increased by surrounding the target with luminance, colour or motion distracters. The discrimination of target orientation was more impaired than the discrimination of target colour or motion, irrespective of distracter type. The discrimination of target motion was strongly affected only by motion distracters. The magnitude of the impairments increased with distracter strength and with the extent to which the distracters conveyed information conflicting with the target. Deficits in the quadrant affected by combined V4 and TEO lesions were twice as large as those in quadrants affected by V4 or TEO lesions alone. The results suggest that in the absence of V4 and TEO, information from both relevant and irrelevant stimuli is 'averaged' together across several different feature domains, impairing the discrimination of the relevant target features. The results suggest a broad role of V4 and TEO in visual selective attention. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP De Weerd, P (reprint author), Univ Arizona, Dept Psychol, Coll Social & Behav Sci, Bldg 68,1503 E Univ Blvd,POB 210068, Tucson, AZ 85721 USA. FU NIMH NIH HHS [R01 MH61972-03] NR 101 TC 18 Z9 18 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 2003 VL 18 IS 6 BP 1671 EP 1691 DI 10.1046/j.1460-9568.2003.02862.x PG 21 WC Neurosciences SC Neurosciences & Neurology GA 725GP UT WOS:000185535700032 PM 14511346 ER PT J AU Elkashef, A Vocci, F AF Elkashef, A Vocci, F TI Medications in development to treat stimulants addiction: Update from NIDA/DTRD SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Nat Inst Drug Abuse, Div Treatment Re s& Dev, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S415 EP S415 DI 10.1016/S0924-977X(03)92266-8 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300672 ER PT J AU Fuxe, K Ferre, S Woods, A Lluis, C Franco, R Agnati, L AF Fuxe, K Ferre, S Woods, A Lluis, C Franco, R Agnati, L TI Novel strategies for treatment of schizophrenia and Parkinson's disease. Focus on receptor - Receptor interactions in the basal ganglia SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol ID MGLU5 RECEPTORS C1 Karolinska Inst, Dept Neurosci, Stockholm, Sweden. NIH, Nat Inst Intramural Res Prog, Baltimore, MD USA. Univ Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain. Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. RI Franco, Rafael/C-3694-2015 OI Franco, Rafael/0000-0003-2549-4919 NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S93 EP S94 DI 10.1016/S0924-977X(03)91596-3 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300002 ER PT J AU Konstantinidis, A Ptak-Butta, J Stastny, J Winkler, D Pjrek, E Barnas, C Neumeister, A Kasper, S AF Konstantinidis, A Ptak-Butta, J Stastny, J Winkler, D Pjrek, E Barnas, C Neumeister, A Kasper, S TI Follow-up of patients with major depression treated with intravenous mirtazapine SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Univ Hosp Psychiat, Dept Gen Psychiat, Vienna, Austria. NIMH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S259 EP S259 DI 10.1016/S0924-977X(03)91908-0 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300314 ER PT J AU Le Foll, B Diaz, J Schwartz, JC Sokoloff, P AF Le Foll, B Diaz, J Schwartz, JC Sokoloff, P TI Nicotine and dopamine D3 receptor: Implications in drug addiction and Parkinson's disease SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol ID D-3 RECEPTOR C1 NIDA, Preclin Pharmacol Sect, Baltimore, MD USA. Physiol Lab, Fac Pharm, Paris, France. INSERM, U573, Paris, France. RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S170 EP S170 DI 10.1016/S0924-977X(03)91706-8 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300112 ER PT J AU Levine, L Landbloom, RP Schoepp, DD Tizzano, JP Grillon, C AF Levine, L Landbloom, RP Schoepp, DD Tizzano, JP Grillon, C TI Activity in the fear-potentiated startle (FPS) in rodents and healthy subjects with LY354740, a novel mGlu2/3 receptor agonist SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Lilly Res Labs, Indianapolis, IN USA. DOV Pharmaceut, Hackensack, NJ USA. NIMH, NIH, DHHS, Mood & Anxiety Disorder Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S364 EP S365 DI 10.1016/S0924-977X(03)92147-X PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300553 ER PT J AU Lipska, B AF Lipska, B TI Modeling schizophrenia in animals SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S158 EP S159 DI 10.1016/S0924-977X(03)91690-7 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300096 ER PT J AU Manji, HK AF Manji, HK TI The molecular and cellular neurobiology of bipolar disorder SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S145 EP S145 DI 10.1016/S0924-977X(03)91670-1 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300076 ER PT J AU Rapoport, JL AF Rapoport, JL TI Drug discovery and mood and anxiety disorders of childhood SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S146 EP S146 DI 10.1016/S0924-977X(03)91672-5 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300078 ER PT J AU Rasmusson, A Guidotti, A Charney, D Vojvoda, D Lipschitz, D Weisman, D Krystal, J AF Rasmusson, A Guidotti, A Charney, D Vojvoda, D Lipschitz, D Weisman, D Krystal, J TI Adrenal & CSF neurosteroids as mediators of HPA axis upregulation and symptom production in premenopausal women with PTSD SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Yale Univ, Sch Med, West Haven, CT 06516 USA. Univ Illinois, Chicago, IL 60680 USA. NIMH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S151 EP S152 DI 10.1016/S0924-977X(03)91680-4 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300086 ER PT J AU Schwarcz, R Pereira, EFR Alkondon, M Almeida, LEF Fawcett, WP Randall, WR Guidetti, P Sapko, MT Yu, P Tagle, DA Albuquerque, EX AF Schwarcz, R Pereira, EFR Alkondon, M Almeida, LEF Fawcett, WP Randall, WR Guidetti, P Sapko, MT Yu, P Tagle, DA Albuquerque, EX TI Physiological regulation of alpha 7 nicotinic receptor activity by endogenous levels of the brain metabolite kynurenic acid: Clinical implications SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NIH, Bethesda, MD 20892 USA. Fed Univ Rio De Janeiro, ICB, CCS, Rio De Janeiro, Brazil. Univ Maryland, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S128 EP S128 DI 10.1016/S0924-977X(03)91647-6 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300053 ER PT J AU Winkler, D Pjrek, E Pezawas, L Konstantinidis, A Presslich, O Tauscher, J Kasper, S AF Winkler, D Pjrek, E Pezawas, L Konstantinidis, A Presslich, O Tauscher, J Kasper, S TI Influence of psychopharmacologic treatment on short-term actigraphic measurements SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 16th Congress of the European-College-of-Neuropsychopharmacology CY SEP 20-24, 2003 CL PRAGUE, CZECH REPUBLIC SP European Coll Neuropsychopharmacol C1 Univ Vienna, Dept Gen Psychiat, A-1010 Vienna, Austria. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2003 VL 13 SU 4 BP S451 EP S451 DI 10.1016/S0924-977X(03)92358-3 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 723BJ UT WOS:000185412300764 ER PT J AU Sakai, K Kitaguchi, K Hikosaka, O AF Sakai, K Kitaguchi, K Hikosaka, O TI Chunking during human visuomotor sequence learning SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE motor learning; sequence; chunk ID PRESUPPLEMENTARY MOTOR AREA; MEDIAL FRONTAL-CORTEX; LEFT-HEMISPHERE; SPATIAL MEMORY; BASAL GANGLIA; MONKEY; SKILL; MOVEMENT; PIGEON; ACQUISITION AB Motor sequence learning is a process whereby a series of elementary movements is re-coded into an efficient representation for the entire sequence. Here we show that human subjects learn a visuomotor sequence by spontaneously chunking the elementary movements, while each chunk acts as a single memory unit. The subjects learned to press a sequence of 10 sets of two buttons through trial and error. By examining the temporal patterns with which subjects performed a visuomotor sequence, we found that the subjects performed the 10 sets as several clusters of sets, which were separated by long time gaps. While the overall performance time decreased by repeating the same sequence, the clusters became clearer and more consistent. The cluster pattern was uncorrelated with the distance of hand movements and was different across subjects who learned the same sequence. We then split a learned sequence into three segments, while preserving or destroying the clusters in the learned sequence, and shuffled the segments. The performance on the shuffled sequence was more accurate and quicker when the clusters in the original sequence were preserved than when they were destroyed. The results suggest that each cluster is processed as a single memory unit, a chunk, and is necessary for efficient sequence processing. A learned visuomotor sequence is hierarchically represented as chunks that contain several elementary movements. We also found that the temporal patterns of sequence performance transferred from the nondominant to dominant hand, but not vice versa. This may suggest a role of the dominant hemisphere in storage of learned chunks. Together with our previous unit-recording and imaging studies that used the same learning paradigm, we predict specific roles of the dominant parietal area, basal ganglia, and presupplementary motor area in the chunking. C1 Inst Neurol, Wellcome Dept Cognit Neurol, London WC1N 3BG, England. Mukogawa Womens Univ, Sch Letters, Dept Educ, Nishinomiya, Hyogo 6638558, Japan. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sakai, K (reprint author), Inst Neurol, Wellcome Dept Cognit Neurol, 12 Queen Sq, London WC1N 3BG, England. NR 48 TC 127 Z9 128 U1 0 U2 18 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 SEP PY 2003 VL 152 IS 2 BP 229 EP 242 DI 10.1007/s00221-003-1548-8 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 727NT UT WOS:000185665500010 PM 12879170 ER PT J AU Harvey, BK Chang, CF Chiang, YH Bowers, WJ Morales, M Hoffer, BJ Wang, Y Federoff, HJ AF Harvey, BK Chang, CF Chiang, YH Bowers, WJ Morales, M Hoffer, BJ Wang, Y Federoff, HJ TI HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE ischemia; stroke; herpes simplex; amplicon; GDNF; gene therapy ID MIDDLE CEREBRAL-ARTERY; TRANSIENT GLOBAL-ISCHEMIA; MEDIATED GENE-TRANSFER; FOREBRAIN ISCHEMIA; FACTOR PROTECTS; NEURONAL DEATH; BRAIN INJURY; EXPRESSION; VECTORS; RAT AB Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary cortical cultures HSVgdnf reduced oxidant-induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex 4 days prior to, or 3 days, after a 60-min unilateral occlusion of the middle cerebral artery. Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed 1 month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein and the apoptotic marker caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Rochester, Ctr Aging & Dev Biol, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Neurobiol & Anat, Rochester, NY 14642 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. Natl Def Med Ctr, Tri Serv Gen Hosp, Taipei, Taiwan. Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY USA. Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. RP Federoff, HJ (reprint author), Univ Rochester, Ctr Aging & Dev Biol, 601 Elmwood Ave, Rochester, NY 14642 USA. RI Harvey, Brandon/A-5559-2010 NR 31 TC 42 Z9 44 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2003 VL 183 IS 1 BP 47 EP 55 DI 10.1016/S0014-4886(03)00080-3 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 718VG UT WOS:000185166700007 PM 12957487 ER PT J AU Hill, JM Ades, AM McCune, SK Sahir, N Moody, EM Abebe, DT Crnic, LS Brenneman, DE AF Hill, JM Ades, AM McCune, SK Sahir, N Moody, EM Abebe, DT Crnic, LS Brenneman, DE TI Vasoactive intestinal peptide in the brain of a mouse model for Down syndrome SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Down syndrome; Ts65Dn segmental trisomy; vasoactive intestinal peptide; VIP binding sites; VIP mRNA; immunocytochemistry; GTP-insensitive binding ID EMBRYONIC GROWTH; TS65DN MICE; NEURONAL DEATH; BINDING-SITES; RAT-BRAIN; VIP; POLYPEPTIDE; EXPRESSION; RECEPTORS; BLOCKADE AB The most common genetic cause of mental retardation is Down syndrome, trisomy of chromosome 21, which is accompanied by small stature, developmental delays, and mental retardation. In the Ts65Dn segmental trisomy mouse model of Down syndrome, the section of mouse chromosome 16 most homologous to human chromosome 21 is trisomic. This model exhibits aspects of Down syndrome including growth restriction, delay in achieving developmental milestones, and cognitive dysfunction. Recent data link vasoactive intestinal peptide malfunction with developmental delays and cognitive deficits. Blockage of vasoactive intestinal peptide during rodent development results in growth and developmental delays, neuronal dystrophy, and, in adults, cognitive dysfunction. Also, vasoactive intestinal peptide is elevated in the blood of newborn children with autism and Down syndrome. In the current experiments, vasoactive intestinal peptide binding sites were significantly increased in several brain areas of the segmental trisomy mouse, including the olfactory bulb, hippocampus, cortex, caudate/putamen, and cerebellum, compared with wild-type littermates. In situ hybridization for VIP mRNA revealed significantly more dense vasoactive intestinal peptide mRNA in the hippocampus, cortex, raphe nuclei, and vestibular nuclei in the segmental trisomy mouse compared with wild-type littermates. In the segmental trisomy mouse cortex and hippocampus, over three times as many vasoactive intestinal peptide-immunopositive cells were visible than in wild-type mouse cortex. These abnormalities in vasoactive intestinal peptide parameters in the segmental trisomy model of Down syndrome suggest that vasoactive intestinal peptide may have a role in the neuropathology of Down-like cognitive dysfunction. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NICHD, Sect Dev & Mol Pharmacol, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. Univ Colorado, Sch Med, Dept Pediat, Denver, CO 80262 USA. Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. RP Hill, JM (reprint author), NICHD, Sect Dev & Mol Pharmacol, NIH, Bldg 49,Rm 5A38,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 62 TC 24 Z9 25 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2003 VL 183 IS 1 BP 56 EP 65 DI 10.1016/S0014-4886(03)00164-X PG 10 WC Neurosciences SC Neurosciences & Neurology GA 718VG UT WOS:000185166700008 PM 12957488 ER PT J AU Simon, R AF Simon, R TI Using DNA microarrays for diagnostic and prognostic prediction SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE diagnostic classification; gene expression profiling; microarray; pharmacogenomics; prognostic classification ID GENE-EXPRESSION PROFILES; B-CELL LYMPHOMA; BREAST-CANCER; MOLECULAR CLASSIFICATION; SURVIVAL; ALGORITHMS; MELANOMA; SETS AB DNA microarrays are a potentially powerful technology for improving diagnostic classification, treatment selection and prognostic assessment. There are, however, many potential pitfalls in the use of microarrays; that result in false leads and erroneous conclusions. Effective use of this technology requires new levels of interdisciplinary collaboration with statistical and computational scientists. This paper provides a review of the key features to be observed in developing diagnostic and prognostic classification systems based upon gene expression profiling. It also attempts to outline some of the steps needed to develop initial microarray research findings into classification systems suitable for broad clinical application. C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@nih.gov NR 30 TC 23 Z9 29 U1 0 U2 2 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEYY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD SEP PY 2003 VL 3 IS 5 BP 587 EP 595 DI 10.1586/14737159.3.5.587 PG 9 WC Pathology SC Pathology GA 767KD UT WOS:000188438000006 PM 14510179 ER PT J AU Philp, D Huff, T Gho, YS Hannappel, E Kleinman, HK AF Philp, D Huff, T Gho, YS Hannappel, E Kleinman, HK TI The actin binding site on thymosin beta(4) promotes angiogenesis SO FASEB JOURNAL LA English DT Article DE beta-thymosin; angiogenic activity; 5 kDa polypeptide; G-actin ID DEOXYNUCLEOTIDYL TRANSFERASE-ACTIVITY; ENDOTHELIAL-CELLS; IN-VIVO; PEPTIDE; EXPRESSION; TRANSGLUTAMINASE; METASTASIS; MOTILITY; CANCER; LINES AB Thymosin beta(4) is a ubiquitous 43 amino acid, 5 kDa polypeptide that is an important mediator of cell proliferation, migration, and differentiation. It is the most abundant member of the beta-thymosin family in mammalian tissue and is regarded as the main G-actin sequestering peptide. Thymosin beta(4) is angiogenic and can promote endothelial cell migration and adhesion, tubule formation, aortic ring sprouting, and angiogenesis. It also accelerates wound healing and reduces inflammation when applied in dermal wound-healing assays. Using naturally occurring thymosin beta(4), proteolytic fragments, and synthetic peptides, we find that a seven amino acid actin binding motif of thymosin beta(4) is essential for its angiogenic activity. Migration assays with human umbilical vein endothelial cells and vessel sprouting assays using chick aortic arches show that thymosin beta(4) and the actin-binding motif of the peptide display near-identical activity at similar to50 nM, whereas peptides lacking any portion of the actin motif were inactive. Furthermore, adhesion to thymosin beta(4) was blocked by this seven amino acid peptide demonstrating it as the major thymosin beta(4) cell binding site on the molecule. The adhesion and sprouting activity of thymosin beta(4) was inhibited with the addition of 5-50 nM soluble actin. These results demonstrate that the actin binding motif of thymosin beta(4) is an essential site for its angiogenic activity. C1 NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Inst Biochem, Erlangen, Germany. Kyung Hee Univ, Grad Sch E W Med Sci, Yongin, South Korea. RP Kleinman, HK (reprint author), NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, 30-433 30 Convent Dr,MSC-4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 40 TC 88 Z9 98 U1 1 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2003 VL 17 IS 12 BP 2103 EP + DI 10.1096/fj.03-0121fje PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 732DG UT WOS:000185925100014 PM 14500546 ER PT J AU Jung, YJ Isaacs, JS Lee, SM Trepel, J Neckers, L AF Jung, YJ Isaacs, JS Lee, SM Trepel, J Neckers, L TI IL-1 beta mediated up-regulation of HIF-1 alpha via an NFkB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis SO FASEB JOURNAL LA English DT Article DE hypoxia-inducible factor-1 alpha; inflammation-induced cancer ID NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; TUMOR-NECROSIS-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; DNA-BINDING; PHOSPHATIDYLINOSITOL 3-KINASE; STABILIZE HIF-1-ALPHA; PROLYL HYDROXYLATION; SYNOVIAL FIBROBLASTS; SIGNAL-TRANSDUCTION AB Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL- 1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor ( VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL- 1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E-2 (PGE(2)), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF- 1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways. C1 NCI, Cell & Canc Biol Branch, CCR, Rockville, MD 20850 USA. NCI, Med Oncol Clin Res Unit, CCR, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Cell & Canc Biol Branch, CCR, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. EM len@helix.nih.gov NR 76 TC 377 Z9 405 U1 2 U2 24 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2003 VL 17 IS 12 BP 2115 EP + DI 10.1096/fj.03-0329fje PG 22 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 732DG UT WOS:000185925100023 PM 12958148 ER PT J AU Rouzaud, F Annereau, JP Valencia, JC Costin, GE Hearing, VJ AF Rouzaud, F Annereau, JP Valencia, JC Costin, GE Hearing, VJ TI Regulation of melanocortin 1 receptor expression at the mRNA and protein levels by its natural agonist and antagonist SO FASEB JOURNAL LA English DT Article DE promoter; 5 ' untranslated region (5 ' UTR); melanocyte; translation ID MELANOCYTE-STIMULATING-HORMONE; AGOUTI-RELATED PROTEIN; TRANSLATIONAL CONTROL; ALPHA-MELANOTROPIN; SIGNALING PROTEIN; INDUCED ANOREXIA; POINT MUTATIONS; NEUROPEPTIDE-Y; MSH RECEPTORS; IN-VITRO AB Five melanocortin receptors, which form a subfamily of G protein-coupled receptors, are expressed in mammalian tissues and regulate such diverse physiological processes as pigmentation, adrenal function, energy homeostasis, feeding efficiency, and sebaceous gland lipid production, as well as immune and sexual function. Pigmentation in mammals is stimulated by alpha-melanocyte stimulating hormone (MSH), which binds to the melanocortin 1 receptor (Mclr) and induces an activation of melanogenic enzymes through stimulation of adenylate cyclase and protein kinase A. The antagonist agouti signal protein (ASP) interacts with the Mclr and blocks its stimulation by MSH. We examined the influence of ASP or MSH on Mclr gene expression, and we report that both ligands influence the Mclr 5' promoter structure in distinct manners. Our study further shows that MSH regulates Mclr function at both the mRNA and protein levels, whereas ASP acts only on its translation. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1B25, Bethesda, MD 20892 USA. EM hearingv@nih.gov NR 52 TC 32 Z9 33 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2003 VL 17 IS 12 BP 2154 EP + DI 10.1096/fj.03-0206fje PG 21 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 732DG UT WOS:000185925100010 PM 14500544 ER PT J AU Delany, PJ Fletcher, BW Shields, JJ AF Delany, PJ Fletcher, BW Shields, JJ TI Reorganizing care for the substance using offender - The case for collaboration SO FEDERAL PROBATION LA English DT Article C1 NIDA, Bethesda, MD 20892 USA. Catholic Univ Amer, Washington, DC 20064 USA. RP Delany, PJ (reprint author), NIDA, Bethesda, MD 20892 USA. NR 27 TC 3 Z9 3 U1 3 U2 3 PU US COURTS PI WASHINGTON PA ADMIN OFFICE SUPREME COURT BLDG, WASHINGTON, DC 20544 USA SN 0014-9128 J9 FED PROBAT JI Fed. Probat. PD SEP PY 2003 VL 67 IS 2 BP 64 EP 68 PG 5 WC Criminology & Penology; Law SC Criminology & Penology; Government & Law GA 734YU UT WOS:000186086200011 ER PT J AU Alvero, RJ McKeeby, J Segars, J Miller, BT Nieman, L Armstrong, AY AF Alvero, RJ McKeeby, J Segars, J Miller, BT Nieman, L Armstrong, AY TI Reducing the risk and economic impact of High Order Multiple (HOM) gestations by the use of blastocysts at the time of embryo transfer. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NIH, Bethesda, MD 20892 USA. Reprod Assoc New Jersey, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P176 BP S180 EP S181 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400487 ER PT J AU Brinton, LA Lamb, EJ Moghissi, KS Scoccia, H Westhoff, C Althuis, M AF Brinton, LA Lamb, EJ Moghissi, KS Scoccia, H Westhoff, C Althuis, M TI Causes of infertility and ovarian cancer risk. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NCI, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. Wayne State Univ, Detroit, MI 48202 USA. Univ Illinois, Chicago, IL 60680 USA. Columbia Univ, New York, NY 10027 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O234 BP S90 EP S90 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400235 ER PT J AU Catherino, WH Stenmark, MH Leppert, PC Tsibris, JCM Niemann, LK Segars, JH AF Catherino, WH Stenmark, MH Leppert, PC Tsibris, JCM Niemann, LK Segars, JH TI Promoters of leiomyoma: Dermatopontin expression in leiomyoma suggests an association between fibroids and keloids. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 Univ S Florida, Tampa, FL 33620 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P392 BP S251 EP S251 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400696 ER PT J AU Catherino, WH Leppert, PC Payson, M Potlog-Nahari, C Nieman, LK Segars, JH AF Catherino, WH Leppert, PC Payson, M Potlog-Nahari, C Nieman, LK Segars, JH TI Initiators of leiomyoma: Differential proto-oncogene expression in small versus large fibroids identified by microarray analysis. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P390 BP S250 EP S251 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400694 ER PT J AU Catherino, WH Klipstein, S McKeeby, J Segars, JH AF Catherino, WH Klipstein, S McKeeby, J Segars, JH TI Clomid citrate challenge test identifies more poor responders than day 3 FSH in patients over 35 years. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. Walter Reed Army Med Ctr, ART Program, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P111 BP S158 EP S158 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400421 ER PT J AU Larsen, FW DiAugistine, R Walmer, DK Klotz, DM AF Larsen, FW DiAugistine, R Walmer, DK Klotz, DM TI Insulin-like growth factor-1 regulates VEGF expression in primary human uterine epithelial cells. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 Duke Univ, Med Ctr, Durham, NC 27706 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P453 BP S269 EP S270 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400754 ER PT J AU Luterzo, J Parker, J Armstrong, A Alvero, R AF Luterzo, J Parker, J Armstrong, A Alvero, R TI A curriculum and performance assessment tool for saline sonohysterography. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 Walter Reed Army Med Ctr, Washington, DC 20307 USA. NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O218 BP S83 EP S84 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400219 ER PT J AU Neithardt, AB Segars, J Alvero, R Armstrong, A AF Neithardt, AB Segars, J Alvero, R Armstrong, A TI The current and future role of fallopian tube anastomosis: A survey of current Reproductive Endocrinology fellows and practitioners. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. Univ Colorado, Ctr Hlth Sci, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P548 BP S302 EP S302 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400846 ER PT J AU Neithardt, AB Murdock, CM Segars, JH McKeeby, JL AF Neithardt, AB Murdock, CM Segars, JH McKeeby, JL TI Pre-embryo transfer sham at the time of embryo transfer improves clinical pregnancy rates. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O249 BP S95 EP S95 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400250 ER PT J AU Neithardt, AB Catherino, WH Murdock, CM Segars, JH AF Neithardt, AB Catherino, WH Murdock, CM Segars, JH TI Cost analysis for ART using a model of the effect of age and FSH levels upon pregnancy rates: The concept of a minimally acceptable pregnancy rate. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O188 BP S71 EP S72 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400189 ER PT J AU Parker, JD Leondires, MP Segars, JH McKeeby, JL AF Parker, JD Leondires, MP Segars, JH McKeeby, JL TI Ovarian suppression with oral contraceptive pills prior to ART: Can you get too much of a "good" thing? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 Walter Reed Army Med Ctr, Washington, DC 20307 USA. Ctr Adv Reprod Med, Norwalk, CT USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O286 BP S110 EP S110 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400287 ER PT J AU Payson, MD Catherino, W Tsibris, J Segars, J AF Payson, MD Catherino, W Tsibris, J Segars, J TI Connective tissue growth factor expression in uterine leiomyomas. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. Univ S Florida, Tampa, FL 33620 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P397 BP S253 EP S253 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400701 ER PT J AU Potlog-Nahari, C Catherino, W Catherino, H Wesley, R Nieman, LK Segars, JH McKeeby, J AF Potlog-Nahari, C Catherino, W Catherino, H Wesley, R Nieman, LK Segars, JH McKeeby, J TI Pregnancy rates of blastocyst-staged embryos are reduced if transferred to an endometrium classified as grade B by transvaginal ultrasound. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA O38 BP S14 EP S15 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400039 ER PT J AU Stratton, P Sinaii, N Segars, J Potlog-Nahari, C Nieman, LNK Winkel, CA AF Stratton, P Sinaii, N Segars, J Potlog-Nahari, C Nieman, LNK Winkel, CA TI Surgical findings of endometriosis and their correlation to pelvic pain. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TEXAS SP Amer Soc Reprod Med C1 NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2003 VL 80 SU 3 MA P299 BP S221 EP S221 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 727RM UT WOS:000185672400604 ER PT J AU Kuznetsov, VA AF Kuznetsov, VA TI Hypergeometric model of evolution of conserved protein coding sequences in the proteomes SO FLUCTUATION AND NOISE LETTERS LA English DT Article DE protein domains; motifs; conserved sequences; evolution dynamics; birth-death stochastic processes; Kolmogorov-Waring distribution; Yule distribution; generalized hypergeometric series ID GENE-EXPRESSION; NETWORKS; DISTRIBUTIONS; FAMILY; ORGANIZATION; PREDICTIONS; STATISTICS; DOMAINS; NUMBER; YEAST AB The diversity of protein sequences that exists today has probably evolved from antecedent evolutionarily- conserved domain-like sequences (i.e. motifs, repeats, structural domains) encoded by short ancient genes. We have studied the statistical distributions of the occurrences of the domain-like families within proteins in the proteomes. A generalized hypergeometric stochastic process is introduced in order to model the evolution dynamics of these conserved sequences. We found that the limiting probability function associated with this process fits the empirical distributions for the 90 fully-sequence bacterial, archaeal and eukaryotic organisms. For eukaryotes, our limiting distribution is reduced to Waring's distribution. However, for many archaeal and bacterial organisms the empirical distributions degenerate to the Yule-like distribution. Comparison of all of these distributions implies critical evolutionary events, which lead to the proportional growth of the number of new protein-coding genes and proteome complexity in the eukaryotic organisms and suggest that evolution of many archaeal and bacterial organisms are subject to external global (ecological) forces. Best-fit model data predicts that (1) there are only similar to 5500 or so of the distinct InterPro domains in a given higher eukaryotic organism and that (2) a general trend in eukaryotic proteome evolution is described by the increase in frequency of multi-domain proteins composed of already-existing (older) distinct domains as oppose to creating new ones. Our model can be applicable for analysis of the evolution of word distributions in the texts and be used in other large-scale evolutional systems like the Internet, the economy and the universe. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Kuznetsov, VA (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, 13 South Dr, Bethesda, MD 20892 USA. EM vk28u@nih.gov NR 36 TC 8 Z9 9 U1 0 U2 1 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA JOURNAL DEPT PO BOX 128 FARRER ROAD, SINGAPORE 912805, SINGAPORE SN 0219-4775 J9 FLUCT NOISE LETT JI Fluct. Noise Lett. PD SEP PY 2003 VL 3 IS 3 BP L295 EP L324 DI 10.1142/S0219477503001397 PG 30 WC Mathematics, Interdisciplinary Applications; Physics, Applied SC Mathematics; Physics GA 808TB UT WOS:000220590300006 ER PT J AU Hoffmann, SC Pearl, JP Blair, PJ Kirk, AD AF Hoffmann, SC Pearl, JP Blair, PJ Kirk, AD TI Immune profiling: Molecular monitoring in renal transplantation SO FRONTIERS IN BIOSCIENCE LA English DT Article DE kidney; urinary tract; immunity; immune system; transplantation; RT-PCR; gene expression; flow cytometry; review ID BLOOD MONONUCLEAR-CELLS; QUANTITATIVE RT-PCR; CHRONIC ALLOGRAFT NEPHROPATHY; CYTOKINE GENE POLYMORPHISM; NECROSIS-FACTOR-ALPHA; KIDNEY-TRANSPLANT; FLOW-CYTOMETRY; SUBCLINICAL REJECTION; MESSENGER-RNA; TNF-ALPHA AB Molecular techniques have become a mainstay for most biomedical research. In particular, sensitive methods for gene transcript detection and advanced flow cytometry have been crucial in fostering our understanding of the basic mechanisms promoting allosensitization and adaptive immune regulation. These technologies have been validated in vitro, and in pre-clinical settings, and as such their clinical application is now clearly appropriate. It is becoming increasingly clear that these robust techniques hold much promise to better elucidate human transplant biology, and more importantly, guide clinical decision making with mechanistically-based information. This article will discuss our laboratory's use of several novel technologies, including gene polymorphism analysis, real-time polymerase chain reaction transcript quantification, and multi-color flow cytometry in clinical human renal transplantation. Specific technical methodology will be presented outlining keys for effective clinical application. Clinical correlations will be presented as examples of how these techniques may have clinical relevance. Suggestions for the adaptation of these methods for therapeutic intervention will be given. We propose that clinical transplantation should proceed in close step with modern molecular diagnostics. C1 NIDDKD, Transplantat Sect, Transplantat & Autoimmunity Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Dept Surg, Bethesda, MD 20889 USA. Naval Med Res Ctr, Bethesda, MD 20889 USA. RP Kirk, AD (reprint author), Room 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM allank@intra.niddk.nih.gov RI Kirk, Allan/B-6905-2012 NR 83 TC 16 Z9 16 U1 0 U2 0 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD SEP PY 2003 VL 8 BP E444 EP E462 DI 10.2741/1167 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 719VX UT WOS:000185226700020 PM 12957862 ER PT J AU Wagner, M Fickert, P Zollner, G Fuchsbichler, A Silbert, D Tsybrovskyy, O Zatloukal, K Guo, GL Schuetz, JD Gonzalez, FJ Marschall, HU Denk, H Trauner, M AF Wagner, M Fickert, P Zollner, G Fuchsbichler, A Silbert, D Tsybrovskyy, O Zatloukal, K Guo, GL Schuetz, JD Gonzalez, FJ Marschall, HU Denk, H Trauner, M TI Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice SO GASTROENTEROLOGY LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; RESISTANCE-ASSOCIATED PROTEIN-3; ORGANIC ANION TRANSPORTER; ORPHAN NUCLEAR RECEPTORS; SALT EXPORT PUMP; RAT-LIVER; OBSTRUCTIVE CHOLESTASIS; TIGHT JUNCTION; INDUCED APOPTOSIS; URSODEOXYCHOLIC ACID AB Background & Aims: Cholestasis induces changes in hepatic adenosine triphosphate-binding cassette (ABC) transporter expression. We aimed to investigate the role of the nuclear bile acid receptor (farnesoid X receptor [FXR]) in mediating changes in ABC transporter expression and in determining liver injury. Metho : Hepatic ABC transporter (multidrug resistance-associated proteins [Mrp] 2-4 and bile salt export pump [Bsep]) expression and localization were studied in common bile duct-ligated (CBDL) FXR knockout (FXR-/-), wild-type (FXR+/+), and sham-operated mice. Serum alanine aminotransferase, alkaline phosphatase, bilirubin and bile acid levels, hepatic bile acid composition, and liver histology were investigated. Cholangiomanometry and bile duct morphometry were performed. Results: CBDL induced expression of Mrp 3 and Mrp 4 in FXR+/+ and even more in FXR-/-, whereas Mrp 2 expression remained unchanged. Bsep expression was maintained in CBDL FXR+/+ but remained undetectable in CBDL FXR-/-. Alanine aminotransferase levels and mortality rates did not differ between CBDL FXR+/+ and FXR-/-. CBDL increased billary pressure and induced bile ductular proliferation and bile infarcts in FXR+/+, whereas FXR-/- had lower biliary pressures, less ductular proliferation, and developed disseminated liver cell necroses. Conclusions: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis. Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype. Lack of bile infarcts in CBDL FXR-/- suggests that development of bile infarcts is related to bile acid-dependent bile flow and biliary pressure. This information is relevant for the potential use of FXR modulators in the treatment of cholestatic liver diseases. C1 Karl Franzens Univ Graz, Dept Med, Div Gastroenterol & Hepatol, A-8036 Graz, Austria. Karl Franzens Univ Graz, Dept Pathol, A-8036 Graz, Austria. St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. NCI, Bethesda, MD 20892 USA. Huddinge Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden. RP Trauner, M (reprint author), Karl Franzens Univ Graz, Dept Med, Div Gastroenterol & Hepatol, Auenbruggerpl 15, A-8036 Graz, Austria. EM michael.trauner@uni-graz.at OI Zollner, Gernot/0000-0002-8117-6061; Fickert, Peter/0000-0003-0906-4636 FU NIGMS NIH HHS [GM60904] NR 65 TC 172 Z9 174 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD SEP PY 2003 VL 125 IS 3 BP 825 EP 838 DI 10.1016/S0016-5085(03)01068-0 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 718XT UT WOS:000185172300023 PM 12949728 ER PT J AU Bakowska, JC Di Maria, MV Camp, SM Wang, Y Allen, PD Breakefield, XO AF Bakowska, JC Di Maria, MV Camp, SM Wang, Y Allen, PD Breakefield, XO TI Targeted transgene integration into transgenic mouse fibroblasts carrying the full-length human AAVS1 locus mediated by HSV/AAV rep(+) hybrid amplicon vector SO GENE THERAPY LA English DT Article DE AAV; AAVS1; transgenic mice; amplicon ID SITE-SPECIFIC INTEGRATION; ADENOASSOCIATED VIRUS AAV; TERMINAL REPEAT; HELPER VIRUS; IN-VIVO; MAMMALIAN-CELLS; GENE-EXPRESSION; DNA-SEQUENCES; RECOMBINATION; GENOME AB Herpes simplex virus type 1/adeno-associated virus (HSV/AAV) rep(+) hybrid amplicon vectors containing AAV inverted terminal repeats (ITRs) and rep gene sequences can mediate site-specific integration into the human genome. In this study, we have generated and characterized the first transgenic mice that bear the full-length (8.2 kb) human AAVS1 locus. Immortalized mouse embryonic fibroblasts from this mouse line were transduced with the rep(+), rep (containing only ITRs flanking the transgene) hybrid amplicon vectors, and the standard amplicon vector to determine stable integration frequency and the site of integration. Transduction of transgenic fibroblasts resulted in a 10-fold higher stable integration frequency with rep(+) hybrid amplicon vector than with rep or standard amplicon vectors. Southern blot analysis of genomic DNA from transgenic cells stably transduced with the rep(+) hybrid amplicon vector revealed site-specific integration of transgenes at the AAVS1 locus in 50% of clones. Some site-specific and random integration events were limited to the ITR-flanked transgene cassette. In contrast, transduction of transgenic mouse cells with the rep or standard amplicon vectors resulted in random integrations of the entire rep hybrid amplicon or amplicon DNA that were incorporated into the host genome as a concatenate of various sizes. These results demonstrate for the first time that the genome of transgenic mice bearing the human AAVS1 locus serves as a platform for site-specific integration of AAV ITR-flanked transgene cassettes within the hybrid amplicon vector in the presence of Rep. C1 Massachusetts Gen Hosp, Mol Neurogenet Unit, Dept Neurol, Charlestown, MA 02129 USA. NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. Albany Med Sch, Albany, NY USA. Johns Hopkins Sch Med, Div Pulm & Crit Care, Ctr Asthma & Allergy, Baltimore, MD USA. Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. Harvard Med Sch, Program Neurosci, Boston, MA USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Dept Neurol, CNY 6205,Bldg 149,13th St, Charlestown, MA 02129 USA. OI Di Maria, Michael/0000-0003-0346-8517 FU NCI NIH HHS [CA69346]; NINDS NIH HHS [NS24279] NR 48 TC 33 Z9 34 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD SEP PY 2003 VL 10 IS 19 BP 1691 EP 1702 DI 10.1038/sj.gt.3302061 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 712KF UT WOS:000184796300008 PM 12923568 ER PT J AU Nagorsen, D Panelli, M Dudley, ME Finkelstein, SE Rosenberg, SA Marincola, FM AF Nagorsen, D Panelli, M Dudley, ME Finkelstein, SE Rosenberg, SA Marincola, FM TI Biased epitope selection by recombinant vaccinia-virus (rVV)-infected mature or immature dendritic cells SO GENE THERAPY LA English DT Article DE antigen; CTL; dendritic cells; epitopes; MHC; vaccinia virus ID CD8(+) T-CELLS; MELANOMA ANTIGEN GP100; METASTATIC MELANOMA; CLASS-I; EXPRESSION ANALYSIS; MULTIPLE EPITOPES; TUMOR-REGRESSION; FINE SPECIFICITY; IMMUNE EVASION; PEPTIDE AB Recombinant expression vectors represent a powerful way to deliver whole antigens (Ags) for immunization. Sustained Ag expression in vector-infected dendritic cells (DC) combines Ag-specific stimulation with powerful costimulation and, simultaneously, through 'self-selection' of ad hoc epitopes broadens the scope of immunization beyond restrictions posed by individual patients' human leukocyte antigen (HLA) phenotype. In this study, therefore, we evaluated the efficiency of a recombinant vaccinia virus encoding the gp100/PMel17 melanoma Ag (rVV-gp100) to infect immature (iDC) or mature dendritic cells (mDC) derived from circulating mononuclear cells and the effect of infection on their status of maturation. In addition, we tested the ability of rVV-gp100-infected iDC and mDC to present the HLA-A*0201-associated gp100:209-217 epitope (g209). Irrespective of status of maturation, rVV-gp100 infection induced gp100 expression while only partially reversing the expression of some maturation markers. However, endogenous presentation of the wild-type g209 epitope was inefficient. The low efficiency was epitope-specific since infection of DC with rVV encoding a gp100 construct containing the modified gp100:209-217 (210M) (g209-2M) epitope characterized by high binding affinity for HLA-A*0201 restored efficient Ag presentation. Presentation of an HLA-class II-associated epitope and cytokine release by DC was not altered by rVV infection. Thus, Ag expression driven by rVV may be an efficient strategy for whole Ag delivery. However, since the effectiveness of Ag processing and presentation is subject to stringent HLA/epitope pairing, and for other yet undefined rules, the assumption that whole Ag delivery may circumvent HLA restriction is incorrect and recombinant expression vectors encoding well-characterized polyepitopic constructs may prove more effective. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Free Univ Berlin, UKBF, Med Klin 3, Home Inst, D-1000 Berlin, Germany. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-32] NR 63 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD SEP PY 2003 VL 10 IS 20 BP 1754 EP 1765 DI 10.1038/sj.gt.3302066 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 717FL UT WOS:000185076000005 PM 12939642 ER PT J AU Roberts, BT Wickner, RB AF Roberts, BT Wickner, RB TI Heritable activity: a prion that propagates by covalent autoactivation SO GENES & DEVELOPMENT LA English DT Article DE pion; protease; vacuole; epigenctics; yeast ID YEAST SACCHAROMYCES-CEREVISIAE; SARCOMA-ASSOCIATED HERPESVIRUS; PROTEIN-DEGRADATION; AUTO-ACTIVATION; IN-VITRO; GENE; VACUOLE; MUTATIONS; SCRAPIE; DOMAIN AB Known prions (infectious proteins) are self-propagating amyloids or conformationally altered proteins, but in theory an enzyme necessary for its own activation could also be a prion (or a gene composed of protein). We show that yeast protease B is such a prion, called [beta]. [beta] is infectious, reversibly curable, and its de novo generation is induced by overexpression of the pro-protease. Present in normal cells but masked by the functionally redundant protease A, [beta] is advantageous during starvation and necessary for sporulation. We propose that other enzymes whose active, modified, form is necessary for their maturation might also be prions. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 38 TC 65 Z9 70 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD SEP 1 PY 2003 VL 17 IS 17 BP 2083 EP 2087 DI 10.1101/gad.1115803 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 717UN UT WOS:000185109300002 PM 12923060 ER PT J AU Miura, S Mishina, Y AF Miura, S Mishina, Y TI Whole-embryo culture of E5.5 mouse embryos: Development to the gastrulation stage SO GENESIS LA English DT Article DE whole embryo culture; gastrulation; extraembryonic tissues; prestreak stage; mesoderm formation ID PRIMORDIAL GERM-CELLS; ANTERIOR NEURAL PLATE; VISCERAL ENDODERM; PRIMITIVE STREAK; NODAL EXPRESSION; LAYER FORMATION; CLONAL ANALYSIS; SPECIFICATION; FATE; GENE AB This study reports establishment of an in vitro culture system for E5.5 mouse embryos that supports development to the gastrulation stage and allows the use of experimental approaches to study gastrulation during mouse embryogenesis. Recent experiments suggest that the extraembryonic tissues may play a critical role for gastrulation from as early as E5.5. To apply whole embryo culture to E5.5 embryos and analyze gastrulation, it is essential to optimize the conditions so that most of the embryos develop to the gastrulation stage in culture. For this purpose, we established a protocol in which embryos were isolated using micromanipulator and cultured with 50-75% rat serum. Although cultured embryos tended to grow a larger extraembryonic portion, more than 80% of them developed the primitive streak and induce mesoderm, which corresponds to the mid-streak stage. (C) 2003 Wiley-Liss, Inc. C1 Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Mol Dev Biol Sect, Res Triangle Pk, NC 27709 USA. RP Mishina, Y (reprint author), Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Mol Dev Biol Sect, 111 TW Alexander Dr,POB 12233,MD C4-10,C458, Res Triangle Pk, NC 27709 USA. NR 41 TC 8 Z9 9 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD SEP PY 2003 VL 37 IS 1 BP 38 EP 43 DI 10.1002/gene.10229 PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 729VH UT WOS:000185795400007 PM 14502576 ER PT J AU Pfeiffer, RM Gail, MH AF Pfeiffer, RM Gail, MH TI Sample size calculations for population- and family-based case-control association studies on marker genotypes SO GENETIC EPIDEMIOLOGY LA English DT Article DE case-control study; family-based case-control study; trend test; correlated binary data; power calculations; linkage disequilibrium ID COMPLEX HUMAN-DISEASES; LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; POWER CALCULATIONS; GENERAL-CLASS; TESTS; FREQUENCIES; DESIGNS; LOCUS; SIBS AB Most previous sample size calculations for case-control studies to detect genetic associations with disease assumed that the disease gene locus is known, whereas, in fact, markers are used. We calculated sample sizes for unmatched case-control and sibling case-control studies to detect an association between a biallelic marker and a disease governed by a putative biallelic disease locus. Required sample sizes increase with increasing discrepancy between the marker and disease allele frequencies, and with less-than-maximal linkage disequilibrium between the marker and disease alleles. Qualitatively similar results were found for studies of parent offspring triads based on the transmission disequilibrium test (Abel and Muller-Myhsok, 1998, Am. J. Hum. Genet. 63:664-667; Tu and Whittemore, 1999, Am. J. Hum. Genet. 64:641-649). We also studied other factors affecting required sample size, including attributable risk for the disease allele, inheritance mechanism, disease prevalence, and for sibling case-control designs, extragenetic familial aggregation of disease and recombination. The large sample-size requirements Published 2003 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pfeiffer, RM (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8030, Bethesda, MD 20892 USA. RI Pfeiffer, Ruth /F-4748-2011 NR 29 TC 32 Z9 33 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 SEP PY 2003 VL 25 IS 2 BP 136 EP 148 DI 10.1002/gepi.10245 PG 13 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 718FA UT WOS:000185133400005 PM 12916022 ER PT J AU Garfinkel, DJ Nyswaner, K Wang, J Cho, JY AF Garfinkel, DJ Nyswaner, K Wang, J Cho, JY TI Post-transcriptional cosuppression of Ty1 retrotransposition SO GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE GENOME; SHORT-SEQUENCE RECOMBINATION; ECTOPIC RECOMBINATION; TRANSPOSABLE ELEMENTS; REVERSE-TRANSCRIPTASE; GENE-EXPRESSION; RIBOSOMAL DNA; COPY NUMBER; YEAST; TRANSPOSITION AB To determine whether homology-dependent gene silencing or cosuppression mechanisms underlie copy number control (CNC) of Ty1 retrotransposition, we introduced an active Ty1 element into a naive strain. Single Ty1 element retrotransposition was elevated in a Ty1-less background, but decreased dramatically when additional elements were present. Transcription from the suppressing Ty1 elements enhanced CNC but translation or reverse transcription was not required. Ty1 CNC occurred with a transcriptionally active Ty2 element, but not with Ty3 or Ty5 elements. CNC also occurred when the suppressing Ty1 elements were transcriptionally silenced, fused to the constitutive PGK1 promoter, or contained a minimal segment of mostly TYA1-gag sequence. Ty1 transcription of a multicopy element expressed from the GAL1 promoter abolished CNC, even when the suppressing element was defective for transposition. Although Ty1 RNA and TyA1-gag protein levels increased with the copy number of expressible elements, a given element's transcript level varied less than twofold regardless of whether the suppressing elements were transcriptionally active or repressed. Furthermore, a decrease in the synthesis of Ty1 cDNA is strongly associated with Ty1 CNC. Together our results suggest that Ty1 cosuppression can occur post-transcriptionally, either prior to or during reverse transcription. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Garfinkel, DJ (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, POB B, Frederick, MD 21702 USA. EM garfinke@ncifcrf.gov NR 69 TC 33 Z9 34 U1 0 U2 1 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD SEP PY 2003 VL 165 IS 1 BP 83 EP 99 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 726UG UT WOS:000185618200007 PM 14504219 ER PT J AU Klar, AJS AF Klar, AJS TI Human handedness and scalp hair-whorl direction develop from a common genetic mechanism SO GENETICS LA English DT Article ID TWINS; LATERALIZATION; LANGUAGE; MODELS; SCHIZOPHRENIA; INHERITANCE; PSYCHOSIS; ASYMMETRY; FAMILIES; ORIGINS AB Theories concerning the cause of right- or left-hand preference in humans vary from purely learned behavior, to solely genetics, to a combination of the two mechanisms. The cause of handedness and its relation to the biologically specified scalp hair-whorl rotation is determined here. The general public, consisting of mostly right-handers (RH), shows counterclockwise whorl rotation infrequently in 8.4% of individuals. Interestingly, non-right-handers (NRH, i.e., left-handers and ambidextrous) display a random mixture of clockwise and counterclockwise swirling patterns. Confirming this finding, in another independent sample of individuals chosen because of their counterclockwise rotation, one-half of them are NRH. These findings of coupling in RH and uncoupling in NRH unequivocally establish that these traits develop from a common genetic mechanism. Another result concerning handedness of the progeny of discordant monozygotic twins suggests that lefties are one gene apart from righties. Together, these results suggest. (1) that a single gene controls handedness, whorl orientation, and twin concordance and discordance and (2) that neuronal and visceral (internal organs) forms of bilateral asymmetry arc coded by separate sets of genetic pathways. The sociological impact of the study is discussed. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, POB B,7th St,Bldg 539, Frederick, MD 21702 USA. NR 40 TC 62 Z9 65 U1 1 U2 11 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD SEP PY 2003 VL 165 IS 1 BP 269 EP 276 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 726UG UT WOS:000185618200022 PM 14504234 ER PT J AU Bowen, NJ Jordan, IK Epstein, JA Wood, V Levin, HL AF Bowen, NJ Jordan, IK Epstein, JA Wood, V Levin, HL TI Retrotransposons and their recognition of pol II promoters: A comprehensive survey of the transposable elements from the complete genome sequence of Schizosaccharomyces pombe SO GENOME RESEARCH LA English DT Article ID FISSION YEAST; SACCHAROMYCES-CEREVISIAE; REVERSE TRANSCRIPTION; SILENT CHROMATIN; EVOLUTIONARY HISTORY; LTR RETROTRANSPOSONS; DNA INTEGRATION; FAMILIES; GENES; TY5 AB The complete DNA sequence of the genome of Schizosaccharomyces pombe provides the opportunity to investigate the entire complement of transposable elements (TEs), their association with specific sequences, their chromosomal distribution, and their evolution. Using homology-based sequence identification, we found that the sequenced strain of S. pombe contained only one family of full-length transposons. This family, Tf2, consisted of 13 full-length copies of a long terminal repeat (LTR) retrotransposon. We found that LTR-LTR recombination of previously existing transposons had resulted in extensive populations of solo LTRs. These included 35 solo LTRs of Tf2, as well as 139 solo LTRs from other Tf families. Phylogenetic analysis of solo Tf LTRs reveals that Tf1 and Tf2 were the most recently active elements within the genome. The solo LTRs also served as footprints for previous insertion events by the Tf retrotransposons. Analysis of 186 genomic insertion events revealed a close association with RNA polymerase II promoters. These insertions Clustered in the promoter-proximal regions of genes, upstream of protein coding regions by 100 to 400 nucleotides. The association of Tf insertions with pol II promoters was very similar to the preference previously observed for Tf1 integration. We found that the recently active Tf elements were absent from centromeres and pericentromeric regions of the genome containing tandem tRNA gene clusters. In addition, Our analysis revealed that chromosome III has twice the density of insertion events compared to the other two chromosomes. Finally we describe a novel repetitive sequence, wtf, which was also preferentially located oil chromosome III, and was often located near solo LTRs of Tf elements. C1 NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NICHD, Unit Biol Computat, NIH, Bethesda, MD 20892 USA. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Levin, HL (reprint author), NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM henry_levin@nih.gov RI Bowen, Nathan/F-3132-2010; OI Bowen, Nathan/0000-0002-1609-6698; Wood, Valerie/0000-0001-6330-7526 NR 53 TC 80 Z9 94 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD SEP PY 2003 VL 13 IS 9 BP 1984 EP 1997 DI 10.1101/gr.1191603 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 717JL UT WOS:000185085300002 PM 12952871 ER PT J AU Kurima, K Yang, YD Sorber, K Griffith, AJ AF Kurima, K Yang, YD Sorber, K Griffith, AJ TI Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis SO GENOMICS LA English DT Article DE deafness; epidermodysplasia verruciformis; EVER1; EVER2; hearing; ion channel; papillomavirus; receptor; TMC domain; transmembrane ID HUMAN-PAPILLOMAVIRUS; DEAFNESS; POLYCYSTIN-2; MUTATIONS; MOUSE; MAPS; MICE; MECHANOSENSATION; LYMPHOCYTES; DOMINANT AB Mutations of TMC1 cause deafness in humans and mice. TMC1 and a related gene, TMC2, are the founding members of a novel gene family. Here we describe six additional TMC paralogs (TMC3 to TMC8) in humans and mice, as well as homologs in other species. cDNAs spanning the full length of the predicted open reading frames of the mammalian genes were cloned and sequenced. All are strongly predicted to encode proteins with 6 to 10 transmembrane domains and a novel conserved 120-amino-acid sequence that we termed the TMC domain. TMC1, TMC2, and TMC3 comprise a distinct subfamily expressed at low levels, whereas TMC4 to TMC8 are expressed at higher levels in multiple tissues. TMC6 and TMC8 are identical to the EVER1 and EVER2 genes implicated in epidermodysplasia verruciformis, a recessive disorder comprising susceptibility to cutaneous human papilloma virus infections and associated nonmelanoma skin cancers, providing additional genetic and tissue systems in which to study the TMC gene family. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. OI Lontok, Katherine/0000-0001-7127-340X FU NIDCD NIH HHS [1-Z01-DC-000060-02] NR 27 TC 69 Z9 84 U1 1 U2 7 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 SEP PY 2003 VL 82 IS 3 BP 300 EP 308 DI 10.1016/S0888-7543(03)00154-X PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 713AT UT WOS:000184833100006 PM 12906855 ER PT J AU Geller, HM Wang, H Katagiri, Y AF Geller, HM Wang, H Katagiri, Y TI Neuronal guidance by astrocyte extracellular matrix SO GLIA LA English DT Meeting Abstract CT 6th European Meeting on Glial Cell Function in Health and Disease CY SEP 03-06, 2003 CL BERLIN, GERMANY C1 NHLBI, Neurobiol Grp, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0894-1491 J9 GLIA JI Glia PD SEP PY 2003 SU 2 BP 10 EP 10 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 714XB UT WOS:000184938300038 ER PT J AU Hudson, LD Lovas, G AF Hudson, LD Lovas, G TI What neuronal cues direct oligodendrocytes to remyelinate? SO GLIA LA English DT Meeting Abstract CT 6th European Meeting on Glial Cell Function in Health and Disease CY SEP 03-06, 2003 CL BERLIN, GERMANY C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD USA. Jahn Ferenc Hosp, Dept Neurol, Budapest, Hungary. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0894-1491 J9 GLIA JI Glia PD SEP PY 2003 SU 2 BP 13 EP 13 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 714XB UT WOS:000184938300050 ER PT J AU Ochel, HJ Gademann, G Trepel, J Neckers, L AF Ochel, HJ Gademann, G Trepel, J Neckers, L TI Modulation of prion protein structural integrity by geldanamycin SO GLYCOBIOLOGY LA English DT Article DE conformation; geldanamycin; glycosylation; Hsp90/prion ID SCRAPIE PRP 27-30; VARIANT CJD; BSE AGENT; IN-VIVO; MICE; GLYCOSYLATION; CONFORMATION; DISEASE; HSP90; CELLS AB The cellular prion protein PrPc is of crucial importance for the development of neurodegenerative diseases called transmissible spongiform encephalopathies. We investigated if the function of members of the HSP90 family is required for the integrity of the normal, nonpathogenic prion protein called PrPc. ukaryotic cells were treated with the structurally unrelated HSP90-inhibitors geldanamycin (GA) or radicicol (RC). In either case the cellular prion protein was induced and exhibited faster migrating bands on western blot analysis, whereas geldampicin (GE), an analog of GA known not to bind to HSP90, had no effect. Ongoing protein and messenger RNA synthesis during treatment were found to be necessary for the appearance of these bands. Cotreatment with tunicamycin abrogated any effect of HSP90 inhibitors on the cellular prion protein. Finally, enzymatic deglycosylation with peptide:N-glycosidase F of the normal prion protein as well as the variant induced by benzoquinone ansamycins resulted in very similar band patterns. These experiments indicate that either altered glycosylation, or a change in conformation, or both are involved in the induction of faster migrating bands by HSP90 inhibitors. Thus the inhibition of the function of members of the HSP90 family of molecular chaperones results in profound changes in the physicochemical properties of PrPc. C1 Otto von Guericke Univ, Fac Med, Clin Radiat Therapy, Radiobiol Lab, D-39120 Magdeburg, Germany. NCI, NIH, Med Branch, Tumor Cell Biol Sect, Rockville, MD 20850 USA. RP Ochel, HJ (reprint author), Otto von Guericke Univ, Fac Med, Clin Radiat Therapy, Radiobiol Lab, Leipziger Str 44, D-39120 Magdeburg, Germany. NR 44 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD SEP PY 2003 VL 13 IS 9 BP 655 EP 660 DI 10.1093/glycob/cwg081 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 720JZ UT WOS:000185258800009 PM 12773477 ER PT J AU Gerhard, DS Nguyen, LT Zhang, ZY Borecki, IB Coleman, BI Rader, JS AF Gerhard, DS Nguyen, LT Zhang, ZY Borecki, IB Coleman, BI Rader, JS TI A relationship between methylenetetrahydrofolate reductase variants and the development of invasive cervical cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article ID HUMAN PAPILLOMAVIRUS INFECTION; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; LINKAGE DISEQUILIBRIUM; INTRAEPITHELIAL NEOPLASIA; CHINESE POPULATION; COLORECTAL-CANCER; COMMON MUTATION; RISK FACTOR; POLYMORPHISMS; GENE AB Objective. Low red blood cell folate levels have been associated with hypomethylation of DNA in dysplastic tissue and an increased risk for cervical intraepithelial neoplasia in human papillomavirus (HPV)-infected women. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine, the important components of DNA synthesis and methylation. Two common genetic polymorphisms, causing reduced MTHFR activity, have been identified. Therefore, the goal of this study was to evaluate these MTHFR variations as risk factors for invasive cervical cancer. Methods. To overcome the failure to properly match cases and controls that can cause false-positive inferences due to population stratification and unrecognized variables in a traditional case-control study, a family-based transmission/disequilibrium. test (TDT) was used. We obtained samples from nuclear families of 102 women with invasive cervical cancer (ICC). One polymorphism was typed by a PCR-RFLP method, while a template-directed dye-terminator assay was developed for the other. Results and conclusions. We were unable to confirm a strong association of MTHFR polymorphisms and ICC using family-based controls and a transmission/disequilibrium test. The overall results of the TDT showed chi(2) (1 df) of 0.28 (P = 0.60) for exon 4, chi(2) (1 df) of 0.81(P = 0.37) for exon 7, and chi(2) (3 df) of 2.56 (P = 0.46) for the haplotype, meaning that there was no transmission of those alleles significantly in excess of Mendelian expectations to affected women. In addition, there was no effect of these variants with increased parity or infection with high-fisk-type human papillomavirus. (C) 2003 Elsevier Inc. All rights reserved. C1 Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Biostat, St Louis, MO 63110 USA. RP Gerhard, DS (reprint author), NCI, Off Canc Genom, Bldg 31,Room 10A07, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA094141]; NIGMS NIH HHS [GM28719] NR 42 TC 33 Z9 34 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2003 VL 90 IS 3 BP 560 EP 565 DI 10.1016/S0090-8258(03)00368-8 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 725AT UT WOS:000185521000009 PM 13678724 ER PT J AU Schieke, SM AF Schieke, SM TI Photoageing and infrared radiation. Novel aspects of molecular mechanisms SO HAUTARZT LA German DT Article DE photoaging; IR response; MMP-1; MAPK ID A RADIATION; COMBINATION; HEAT AB Human skin is exposed to infrared (IR) radiation (760nm - 1mm) from natural and artificial sources. In particular, the use of IR for cosmetic and "wellness" purposes has become increasingly popular and viewed as completely safe. However, epidemiological data and clinical observations indicate that IR radiation cannot be considered as totally innocuous to human skin. In particular, IR radiation, just as UV radiation, seems to be involved in photoageing and potentially also in photocarcinogenesis. In recent studies the molecular mechanisms involved in this process such as cellular signal transduction and gene expression have been characterised. IR radiation induces the synthesis of matrix metalloproteinase-1 via the mitogen-activated protein kinase signalling pathway. Since this mechanism is a major pathophysiologic factor in UV-induced skin ageing, its activation by IR radiation points to a role of IR in premature skin ageing and indicates the potential need for protection against unwanted IR effects. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Univ Dusseldorf gGmbH, IUF, Dusseldorf, Germany. Univ Klinikum Dusseldorf, Hautklin, Dusseldorf, Germany. RP Schieke, SM (reprint author), NHLBI, Cardiovasc Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 3 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0017-8470 J9 HAUTARZT JI Hautarzt PD SEP PY 2003 VL 54 IS 9 BP 822 EP 824 DI 10.1007/s00105-003-0577-3 PG 3 WC Dermatology SC Dermatology GA 725NT UT WOS:000185549800005 PM 12955258 ER PT J AU Boscoe, FP McLaughlin, C Schymura, MJ Kielb, CL AF Boscoe, FP McLaughlin, C Schymura, MJ Kielb, CL TI Visualization of the spatial scan statistic using nested circles SO HEALTH & PLACE LA English DT Article DE cluster detection; spatial scan statistics; prostate cancer; visualization ID PROSTATE-CANCER MORTALITY; BREAST-CANCER; RADICAL PROSTATECTOMY; DEMOGRAPHIC VARIATION; UNITED-STATES; NEW-YORK; DISEASE; CLUSTERS; PATTERNS; TRENDS AB We propose a technique for the display of results of Kulldorff's spatial scan statistic and related cluster detection methods that provides a greater degree of informational content. By simultaneously considering likelihood ratio and relative risk, it is possible to identify focused sub-clusters of higher (or lower) relative risk among broader regional excesses or deficits. The result is a map with a nested or contoured appearance. Here the technique is applied to prostate cancer mortality data in counties within the contiguous United States during the period 1970-1994. The resulting map shows both broad and localized patterns of excess and deficit, which complements a choropleth map of the same data. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 New York State Dept Hlth, State Canc Registry, Albany, NY 12237 USA. NCI, SEER Program, Bethesda, MD 20892 USA. Ctr Environm Hlth, Dept Hlth, Troy, NY USA. RP Schymura, MJ (reprint author), New York State Dept Hlth, State Canc Registry, Corning Tower Room 536,Empire State Plaza, Albany, NY 12237 USA. NR 35 TC 41 Z9 47 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1353-8292 J9 HEALTH PLACE JI Health Place PD SEP PY 2003 VL 9 IS 3 BP 273 EP 277 DI 10.1016/S1353-8292(02)00060-6 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 709DE UT WOS:000184608800010 PM 12810334 ER PT J AU Haas, DW Wilkinson, GR Kuritzkes, DR Richman, DD Nicotera, J Mahon, LF Sutcliffe, C Siminski, S Andersen, J Coughlin, K Clayton, EW Haines, J Marshak, A Saag, M Lawrence, J Gustavson, J Bennett, JA Christensen, R Matula, MA Wood, AJJ AF Haas, DW Wilkinson, GR Kuritzkes, DR Richman, DD Nicotera, J Mahon, LF Sutcliffe, C Siminski, S Andersen, J Coughlin, K Clayton, EW Haines, J Marshak, A Saag, M Lawrence, J Gustavson, J Bennett, JA Christensen, R Matula, MA Wood, AJJ CA Adult AIDS Clinical Trials Grp TI A multi-investigator/institutional DNA bank for AIDS-related human genetic studies: AACTG Protocol A5128 SO HIV CLINICAL TRIALS LA English DT Article DE DNA banking; ethics; pharmacogenomics ID ANTIRETROVIRAL THERAPY; HUMAN GENOME; PHARMACOGENETICS; EPIDEMIOLOGY; ASSOCIATION; HYPERSENSITIVITY; DISCRIMINATION; POLYMORPHISMS; SEQUENCE; ABACAVIR AB An understanding of the relationships among allelic variability and clinical outcomes will be critical if HIV-infected patients are to benefit from the explosion in knowledge in human genomics. Human DNA banks must allow future analyses while addressing confidentiality, ethical, and regulatory issues. Method: A multidisciplinary group of clinical investigators, ethicists, data managers, regulatory specialists, and community representatives developed Adult AIDS Clinical Trials Group (AACTG) Protocol A5128. Participants in past or present AACTG clinical trials may contribute DNA. Extraction from whole blood is performed at a central laboratory, where participants' unique identifiers are replaced by randomly assigned identifiers prior to DNA storage. To identify genotype-phenotype relationships, genetic assay results can be temporarily linked to clinical trials data. Results: Institutional review boards in 21 states and Puerto Rico have approved Protocol A5128, and accrual is ongoing. Of the first 4,247 enrollees, 82% are male, 56% are white, 26% are African American, and 15% are Hispanic. Because participants may participate in multiple AACTG protocols, these represent 11,424 cases in 324 different AACTG studies and substudies, with at least 100 participants from 24 different studies. Studies exploring specific genotype-phenotype relationships are underway. Conclusion: The AACTG DNA bank will be an important resource for genomic discovery relevant to HIV therapy. C1 Vanderbilt Univ, Sch Med, Div Infect Dis, Nashville, TN 37203 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. VA San Diego Healthcare Syst, San Diego, CA USA. AACTG Operat Ctr, Silver Spring, MD USA. Frontier Sci Tech Res Fdn, Amherst, NY USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Beth Israel Med Ctr, New York, NY 10003 USA. Univ Alabama, Birmingham, AL USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Community Constituency Grp, San Francisco, CA USA. Community Constituency Grp, New York, NY USA. Community Constituency Grp, Seattle, WA USA. NIAID, Div Aids, Bethesda, MD 20892 USA. RP Haas, DW (reprint author), Vanderbilt Univ, Sch Med, Div Infect Dis, 345 24th Ave N,Suite 105, Nashville, TN 37203 USA. RI Haines, Jonathan/C-3374-2012 FU NIAID NIH HHS [U01AI027659, U01AI027663, U01AI027670, U01AI032775, U01AI046339, U01AI38858, U01AI46370] NR 40 TC 43 Z9 44 U1 1 U2 2 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD SEP-OCT PY 2003 VL 4 IS 5 BP 287 EP 300 PG 14 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 735KV UT WOS:000186113400001 PM 14583845 ER PT J AU Lederhendler, II AF Lederhendler, II TI Aggression and violence: perspectives on integrating animal and human research approaches SO HORMONES AND BEHAVIOR LA English DT Article; Proceedings Paper CT Workshop on Comtemporary Issues in Aggressive Behavior CY 2002 CL AMHERST, MA ID MONOGAMOUS VOLE; BEHAVIOR; ACTIVATION; RECEPTOR; AMYGDALA; MICE; VASOPRESSIN; EMOTION; SEPARATION; ATTENTION AB Aggression and violence are concerns that engage us across society as moral and cultural issues. They are also critical issues for mental health research-both for survivors and for understanding how such behaviors occur. Interpersonal violence often explodes in deliberate acts of physical force leaving survivors behind with a diminished sense of control that is often shadowed by persistent fear and anxiety. The treatment of the victims is a clear and immediate concern; from their perspectives the medical consequences require effective attention whether they suffered as a result of acts of nature, mental disease, ideology, or combinations of these. At the same time preventing violent behavior from happening in the first place is a compelling challenge for public health research. (C) 2003 Elsevier Inc. All rights reserved. C1 NIMH, NIH, DHHS, Bethesda, MD 20892 USA. RP Lederhendler, II (reprint author), NIMH, NIH, DHHS, 6001 Execut Blvd,7170 MSC 9637, Bethesda, MD 20892 USA. EM ilederhe@mail.nih.gov NR 52 TC 5 Z9 5 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X J9 HORM BEHAV JI Horm. Behav. PD SEP PY 2003 VL 44 IS 3 BP 156 EP 160 DI 10.1016/S0018-506X(03)00136-3 PG 5 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 742HA UT WOS:000186510300002 PM 14609537 ER PT J AU Mulligan, CJ Robin, RW Osier, MV Sambuughin, N Goldfarb, LG Kittles, RA Hesselbrock, D Goldman, D Long, JC AF Mulligan, CJ Robin, RW Osier, MV Sambuughin, N Goldfarb, LG Kittles, RA Hesselbrock, D Goldman, D Long, JC TI Allelic variation at alcohol metabolism genes (ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population SO HUMAN GENETICS LA English DT Article ID MITOCHONDRIAL ALDEHYDE DEHYDROGENASE; LINKAGE DISEQUILIBRIUM; ADH2-ASTERISK-2 ALLELE; RACIAL-DIFFERENCES; CLADISTIC-ANALYSIS; DRINKING BEHAVIOR; NATIVE-AMERICANS; DIVERSITY; GENOME; GENOTYPES AB Enzymes encoded by two gene families, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B (previously ADH2), ADH1C (previously ADH3), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe (n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study. C1 Univ Florida, Dept Anthropol, Gainesville, FL 32611 USA. NIAAA, Neurogenet Lab, NIH, Sitka, AK USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ USA. NINDS, NIH, Bethesda, MD 20892 USA. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Washington Univ, Dept Surg, St Louis, MO USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI USA. RP Mulligan, CJ (reprint author), Univ Florida, Dept Anthropol, POB 117305, Gainesville, FL 32611 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NCRR NIH HHS [1 P41 RR03655]; NIAAA NIH HHS [R03 AA12906, AA09379] NR 54 TC 73 Z9 78 U1 1 U2 18 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2003 VL 113 IS 4 BP 325 EP 336 DI 10.1007/s00439-003-0971-z PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 713EL UT WOS:000184843900005 PM 12884000 ER PT J AU Thameem, F Yang, XL Permana, PA Wolford, JK Bogardus, C Prochazka, M AF Thameem, F Yang, XL Permana, PA Wolford, JK Bogardus, C Prochazka, M TI Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians SO HUMAN GENETICS LA English DT Article ID OXIDATIVE STRESS; INDEPENDENT REPLICATION; MELLITUS; INSULIN; SEARCH; SCAN; IDENTIFICATION; EXPRESSION; PROMOTER AB Elevation of plasma glucose concentration may induce generation of oxygen-free radicals, which can play an important role in the progression of diabetes and/or development of its complications. Various glutathione transferases utilize the availability of reduced glutathione for the cellular defense against oxygen-free radicals. One such enzyme is microsomal glutathione S-transferase 3 encoded by MGST3, which maps to chromosome 1q23, a region linked to Type 2 diabetes mellitus (T2DM) in Pima Indians, Caucasian, and Chinese populations. We investigated the MGST3 gene as a potential susceptibility gene for T2DM by screening this locus for single nucleotide polymorphisms (SNPs) in diabetic and non-diabetic Pima Indians. We also measured the skeletal muscle MGST3 mRNA level by Real-Time (RT) PCR and its relationship with insulin action in non-diabetic individuals. We identified 25 diallelic variants, most of which, based on their genotypic concordance, could be divided into three distinct linkage disequilibrium (LD) groups. We genotyped unique representative SNPs in selected diabetic and non-diabetic Pima Indians and found no evidence for association with T2DM. Furthermore, inter-individual variation of skeletal muscle MGST3 mRNA was not correlated with differences in insulin action in non-diabetic subjects. We conclude that alterations of MGST3 are unlikely to contribute to T2DM or differences in insulin sensitivity in the Pima Indians. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Thameem, F (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 25 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2003 VL 113 IS 4 BP 353 EP 358 DI 10.1007/s00439-003-0980-y PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 713EL UT WOS:000184843900008 PM 12898215 ER PT J AU Yang, YP Swaminathan, S Martin, BK Sharan, SK AF Yang, YP Swaminathan, S Martin, BK Sharan, SK TI Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model SO HUMAN MOLECULAR GENETICS LA English DT Article ID DNA-DAMAGE RESPONSE; OVARIAN-CANCER; EMBRYONIC LETHALITY; ESCHERICHIA-COLI; HUMAN-DISEASE; GENE; BREAST; ENHANCER; PHOSPHORYLATION; NONSENSE AB Numerous missense mutations in human BRCA1 gene have been linked to predisposition to breast cancer. However, the functional significance of the majority of these mutations remains unknown. We have examined the molecular basis for three such cancer-causing mutations. The first mutation, a TAG transversion in codon 64, is predicted to change a conserved cysteine residue to glycine in the RING finger domain of the 1863 amino acid BRCA1 protein. Using a humanized mouse model we demonstrate that this missense mutation actually results in a functionally null protein. This striking result occurs because the single base alteration generates a new 5' splice site in exon 5 and also disrupts a putative exonic splicing enhancer motif. Consequently, the normal splice donor site is disrupted and an internal cryptic splice site is activated. This results in a 22-nucleotide deletion and the aberrant transcript is predicted to encode a severely truncated protein consisting of only 63 amino acids. To identify other missense mutations in BRCA1 that may result in aberrant splicing, we screened various mutations using the Genscan program. We demonstrate that at least two other missense mutations in codons 1495 and 1823 result in aberrant splicing due to the possible disruption of cis-acting splicing regulatory elements. In conclusion, our study demonstrates for the first time the application of a humanized mouse model for functional analysis of human mutations in mice and also shows the need for a careful examination of the functional consequences of single base alterations and single nucleotide polymorphisms identified in human disease-causing genes. C1 NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, 1050 Boyles St, Frederick, MD 21702 USA. NR 43 TC 44 Z9 46 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 SEP 1 PY 2003 VL 12 IS 17 BP 2121 EP 2131 DI 10.1093/hmg/ddg222 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 721MZ UT WOS:000185321300004 PM 12915465 ER PT J AU Bomprezzi, R Ringner, M Kim, S Bittner, ML Khan, J Chen, YD Elkahloun, A Yu, AM Bielekova, B Meltzer, PS Martin, R McFarland, HF Trent, JM AF Bomprezzi, R Ringner, M Kim, S Bittner, ML Khan, J Chen, YD Elkahloun, A Yu, AM Bielekova, B Meltzer, PS Martin, R McFarland, HF Trent, JM TI Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; NECROSIS-FACTOR-ALPHA; T-CELL; CLASSIFICATION; CYCLE; ACTIVATION; PSORIASIS; PROMOTER; IMMUNITY; PROTEIN AB Multiple sclerosis (MS) and other T cell-mediated autoimmune diseases develop in individuals carrying a complex susceptibility trait, probably following exposure to various environmental triggers. Owing to the presumed weak influence of single genes on disease predisposition and the recognized genetic heterogeneity of autoimmune disorders in humans, candidate gene searches in MS have been difficult. In an attempt to identify molecular markers indicative of disease status rather than susceptibility genes for MS, we show that gene expression profiling of peripheral blood mononuclear cells by cDNA microarrays can distinguish MS patients from healthy controls. Our findings support the concept that the activation of autoreactive T cells is of primary importance for this complex organ-specific disorder and prompt further investigations on gene expression in peripheral blood cells aimed at characterizing disease phenotypes. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Theoret Phys, SE-22362 Lund, Sweden. Translat Genom Res Inst, Phoenix, AZ 85004 USA. NCI, Ctr Adv Technol, NIH, Gaithersburg, MD 20877 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Bomprezzi, R (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Bldg 50,Room 5150, Bethesda, MD 20892 USA. RI Ringner, Markus/G-3641-2011; Khan, Javed/P-9157-2014 OI Ringner, Markus/0000-0001-5469-8940; Khan, Javed/0000-0002-5858-0488 NR 48 TC 141 Z9 144 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2003 VL 12 IS 17 BP 2191 EP 2199 DI 10.1093/hmg/ddg221 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 721MZ UT WOS:000185321300010 PM 12915464 ER PT J AU Berman, JJ Henson, DE AF Berman, JJ Henson, DE TI The precancers: Waiting for a classification SO HUMAN PATHOLOGY LA English DT Editorial Material ID CANCER; LESIONS; GROWTH C1 NCI, Canc Diag Program, Rockville, MD USA. George Washington Univ, Inst Canc, Dept Pathol, Washington, DC USA. George Washington Univ, Inst Canc, Off Canc Prevent & Control, Washington, DC USA. RP Berman, JJ (reprint author), NCI, Canc Diag Program, Rockville, MD USA. NR 15 TC 4 Z9 4 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 SEP PY 2003 VL 34 IS 9 BP 833 EP 834 DI 10.1053/S0046-8177(03)00440-4 PG 2 WC Pathology SC Pathology GA 726UB UT WOS:000185617500001 PM 14562276 ER PT J AU Passaro, MD Piquion, J Mullen, N Sutherland, D Zhai, SP Figg, WD Blye, R Nieman, LK AF Passaro, MD Piquion, J Mullen, N Sutherland, D Zhai, SP Figg, WD Blye, R Nieman, LK TI Luteal phase dose-response relationships of the antiprogestin CDB-2914 in normally cycling women SO HUMAN REPRODUCTION LA English DT Article DE CDB-2914; menses; normally cycling women; progesterone receptor modulator ID GLUCOCORTICOID ANTAGONIST RU-486; LONG-TERM; MIFEPRISTONE RU-486; MENSTRUAL-CYCLE; CUSHINGS-SYNDROME; BREAST-CANCER; RU486; RADIOIMMUNOASSAY; PROGESTERONE; MENINGIOMAS AB BACKGROUND: Progesterone receptor modulators have potential therapeutic use in progesterone-dependent conditions such as endometriosis, fibroids and induction of labour. The synthetic steroid CDB-2914 binds to the progesterone and glucocorticoid receptors. In animals it has antiprogestational activity at doses 50-fold less than those required for antiglucocorticoid effects. METHODS AND RESULTS: We evaluated the biological activity, blood levels and safety of CDB-2914 at escalating single doses, in 36 normally cycling women at mid-luteal phase. CDB-2914 at doses of 1-100 mg did not change luteal phase length, but after 200 mg, all women had early endometrial bleeding. Four women with early menses had concurrent functional luteolysis (one at 10, 50, 100 and 200 mg). There were no biochemical or clinical signs of toxicity, and no effect on urinary cortisol or circulating thyroxine, prolactin, adrenocorticotrophic hormone or renin levels. Higher serum equivalents of CDB-2914 were observed by radioimmunoassay than by high performance liquid chromatography detection, indicating a considerable contribution of metabolites. CONCLUSIONS: Mid-luteal administration of CDB-2914 antagonizes progesterone action on the endometrium, in a dose-dependent fashion, without apparent antiglucocorticoid effects. Further study of CDB-2914 is needed to determine its clinical role. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 46 TC 20 Z9 20 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 2003 VL 18 IS 9 BP 1820 EP 1827 DI 10.1093/humrep/deg342 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 721NA UT WOS:000185321400011 PM 12923133 ER PT J AU Alvero, R Hearns-Stokes, RM Catherino, WH Leondires, MP Segars, JH AF Alvero, R Hearns-Stokes, RM Catherino, WH Leondires, MP Segars, JH TI The presence of blood in the transfer catheter negatively influences outcome at embryo transfer SO HUMAN REPRODUCTION LA English DT Article DE blood; embryo transfer technique; implantation; pregnancy rate; retained embryos ID IN-VITRO FERTILIZATION; ASSISTED-REPRODUCTIVE-TECHNOLOGY; PREGNANCY RATES; INVITRO FERTILIZATION; ULTRASOUND GUIDANCE; MULTIPLE ATTEMPTS; MORPHOLOGY; PROGRAM; TRIAL AB BACKGROUND: Embryo transfer (ET) influences pregnancy rates in patients undergoing assisted reproduction. Data are conflicting as to which variables affect ET success. This study examines variables that may affect outcome after ET in assisted reproductive technology patients who had high-quality embryos transferred. METHODS: Over a 23 month period, 669 consecutive cycles were examined. Only patients having grade I and grade II embryos, or blastocyst transfers, were included in this retrospective analysis. A total of 584 consecutive cycles met study criteria. At the time of ET, the following variables were recorded: aborted first attempt at ET; presence of blood and/or mucus in or on the transfer catheter after ET; ease of ET as judged by provider; need for mock embryo transfer immediately before the actual transfer and retention of embryos in the transfer catheter. These variables were retrospectively analysed for their impact on implantation rate (IR) and clinical pregnancy rate (CPR). RESULTS: There were 290 gestations (49.7% CPR). Multiple attempts at ET, subjective difficulty of ET, performance of a sham pass immediately prior to embryo transfer, and presence of mucus on or in the catheter did not affect the CPR or IR. No difference was noted in the mean age of patients having or lacking any of these factors. There was a significant association between the presence of blood on or in the catheter and decreased IR (P = 0.015) and CPR (P = 0.004). Retained embryos also decreased IR (P = 0.03). Multivariable analysis confirmed that the presence of blood on the transfer catheter was the most important of these transfer characteristics in predicting IR (P = 0.042) and CPR (P = 0.018). CONCLUSIONS: These results suggest that when only high-grade embryos or blastocysts are transferred, the presence of blood on the catheter is associated with decreased IR and CPR in assisted reproduction. C1 Univ Colorado, Hlth Sci Ctr, Aurora, CO 80010 USA. Walter Reed Army Med Ctr, Washington, DC 20003 USA. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Alvero, R (reprint author), Univ Colorado, Hlth Sci Ctr, Anschutz Outpatient Pavil,1635 N Ursula St,Mail S, Aurora, CO 80010 USA. NR 29 TC 36 Z9 37 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 2003 VL 18 IS 9 BP 1848 EP 1852 DI 10.1093/humrep/deg359 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 721NA UT WOS:000185321400015 PM 12923137 ER PT J AU Harville, EW Wilcox, AJ Baird, DD Weinberg, CR AF Harville, EW Wilcox, AJ Baird, DD Weinberg, CR TI Vaginal bleeding in very early pregnancy SO HUMAN REPRODUCTION LA English DT Article DE bleeding; first trimester; implantation; spontaneous abortion ID OVULATION AB Introduction: Little is known about the occurrence and patterns of vaginal bleeding during the earliest stages of pregnancy. We explore this in a prospective study of early pregnancy. Methods: A total of 221 healthy women kept daily diaries and provided daily urine samples while trying to become pregnant. Of these, 151 women became clinically pregnant [i.e. pregnancy that lasted greater than or equal to6 weeks beyond last menstrual period (LMP)] during the study. Diaries provided information on days with vaginal bleeding and sexual intercourse. Urine hormone assays were used to identify ovulation and implantation. Women were interviewed about their medical histories and lifestyle factors. Results: A total of 14 women (9%) recorded at least 1 day of vaginal bleeding during the first 8 weeks of pregnancy. Twelve of these 14 pregnancies continued to a live birth. Bleeding tended to occur around the time when women would expect their periods, although rarely on the day of implantation. Bleeding was not associated with intercourse. Conclusions: Early bleeding in clinical pregnancies is generally light, and not likely to be mistaken for LMP. Thus, early bleeding is unlikely to contribute to errors in LMP-based gestational age. We found no support for the hypothesis that implantation can produce vaginal bleeding. Similarly, intercourse did not cause bleeding. Nearly all women with bleeding went on to have successful pregnancies. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Harville, EW (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. OI Wilcox, Allen/0000-0002-3376-1311; Baird, Donna/0000-0002-5544-2653 NR 13 TC 25 Z9 25 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 2003 VL 18 IS 9 BP 1944 EP 1947 DI 10.1093/humrep/deg379 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 721NA UT WOS:000185321400032 PM 12923154 ER PT J AU Verlander, JW Hassell, KA Royaux, IE Glapion, DM Wang, ME Everett, LA Green, ED Wall, SM AF Verlander, JW Hassell, KA Royaux, IE Glapion, DM Wang, ME Everett, LA Green, ED Wall, SM TI Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney - Role of pendrin in mineralocorticoid-induced hypertension SO HYPERTENSION LA English DT Article DE acid-base equilibrium; hypertension, mineralocorticoid; anions; mice; ion transport ID CORTICAL COLLECTING DUCTS; INTERCALATED CELL SUBTYPES; RAT-KIDNEY; BICARBONATE TRANSPORT; SYNDROME GENE; ACID; ALDOSTERONE; EXPRESSION; SECRETION; AMMONIA AB Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus, Pds (Slc26a4) is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion exchange - mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether Pds mRNA and protein expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice, Pds mRNA increased 60%, whereas pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B intercalated cells and increased 6-fold in type B cells. Because pendrin transports HCO3- and Cl-, we tested whether DOCP treatment unmasks abnormalities in acid-base or NaCl balance in Pds (-/-) mice. In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in Pds (-/-) and Pds (-/-) mice. After DOCP treatment, weight gain and hypertension were observed in Pds (+/+) but not in Pds (-/-) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in Pds (-/-) than Pds (+/+) mice. We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis. C1 Emory Univ, Dept Med, Div Renal, Atlanta, GA 30322 USA. Univ Florida, Coll Med, Dept Med, Gainesville, FL USA. Univ Texas, Sch Med, Dept Med, Houston, TX 77030 USA. Univ Texas, Sch Med, Dept Surg, Houston, TX USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Wellcome Trust Sanger Inst, Cambridge, England. RP Wall, SM (reprint author), Emory Univ, Dept Med, Div Renal, WMRB Rm 338,1639 Pierce Dr NE, Atlanta, GA 30322 USA. RI Verlander, Jill/I-5991-2015 FU NIDDK NIH HHS [DK 52935] NR 34 TC 121 Z9 122 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 BP 356 EP 362 DI 10.1161/01.HYP.0000088321.67254.B7 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500021 PM 12925556 ER PT J AU Barkley, RA Chakravarti, A Hunt, S Province, MA Weder, AB Boerwinkle, E AF Barkley, RA Chakravarti, A Hunt, S Province, MA Weder, AB Boerwinkle, E TI Positional identification of hypertension genes on chromosome 2 SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Univ Utah, Salt Lake City, UT USA. Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. Univ Michigan, Div Hypertens, Ann Arbor, MI 48109 USA. NHLBI, Family Blood Pressure Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA 21 BP 391 EP 391 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500053 ER PT J AU Turban, S Wang, XY Knepper, MA AF Turban, S Wang, XY Knepper, MA TI Regulation of NHE3 and NKCC2 abundance in kidney during aldosterone-escape: Role of NO SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA 19 BP 391 EP 391 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500051 ER PT J AU Spinetti, G Wang, MY Monticone, R Zhang, J Zhao, D Lakatta, EG AF Spinetti, G Wang, MY Monticone, R Zhang, J Zhao, D Lakatta, EG TI MCP-1 and its receptor CCR2 in age-associated arterial remodeling SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA 64 BP 400 EP 400 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500096 ER PT J AU Fedorova, OV Agalakova, NI Zhuravin, IA Talan, MI Lakatta, EG Bagrov, AY AF Fedorova, OV Agalakova, NI Zhuravin, IA Talan, MI Lakatta, EG Bagrov, AY TI Brain ouabain stimulates marinobufagenin via AT sensitive pathway in NaCl loaded Dahl-S rats SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P126 BP 428 EP 428 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500243 ER PT J AU Fenton, RA Chou, CL Ageloff, S Brandt, W Stokes, JB Knepper, MA AF Fenton, RA Chou, CL Ageloff, S Brandt, W Stokes, JB Knepper, MA TI Elevation of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) and urea transporter abundance in inner medullary collecting duct of Dahl salt-sensitive rat SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NHLBI, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P132 BP 429 EP 429 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500249 ER PT J AU Wang, XY Turban, S Knepper, MA AF Wang, XY Turban, S Knepper, MA TI Cyclooxygenase inhibition increases ENaC subunit abundances in rat kidney SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P131 BP 429 EP 429 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500248 ER PT J AU Song, J Shi, M Knepper, MA Ecelbarger, CA AF Song, J Shi, M Knepper, MA Ecelbarger, CA TI Regulation of major renal sodium transport proteins and blood pressure in rats fed fructose with normal or high NaCl SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 Georgetown Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P133 BP 430 EP 430 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500250 ER PT J AU Wang, MY Zhang, J Spinetti, G Montoicone, R Zhao, D Cheng, L Krawczyk, M Talan, M Lakatta, E AF Wang, MY Zhang, J Spinetti, G Montoicone, R Zhao, D Cheng, L Krawczyk, M Talan, M Lakatta, E TI Angiotensin II induces arterial and circulatory gelatinases activity SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NIA, GRC, NIH, Baltimore, MD 21224 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P160 BP 435 EP 435 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500277 ER PT J AU Appel, LJ Harsha, DW Sacks, FM Svetkey, LP Obarzanek, E Bray, GA Aickin, M Conlin, PR Miller, ER AF Appel, LJ Harsha, DW Sacks, FM Svetkey, LP Obarzanek, E Bray, GA Aickin, M Conlin, PR Miller, ER TI Moderate sodium reduction has no effect on blood lipids: Results of the DASH-sodium trial SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Harvard Univ, Sch Med, Boston, MA USA. Duke Univ, Durham, NC USA. NHLBI, Baltimore, MD USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 MA P215 BP 446 EP 446 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500331 ER PT J AU Vupputuri, S Batuman, V He, J AF Vupputuri, S Batuman, V He, J TI Hypertension and low-level lead exposure: A scientific issue or a matter of faith? Response SO HYPERTENSION LA English DT Letter ID BLOOD-PRESSURE C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. RP Vupputuri, S (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2003 VL 42 IS 3 BP E9 EP E9 DI 10.1161/01.HYP.0000085859.22259.42 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 718FY UT WOS:000185135500031 ER PT J AU Kuo, CK Tuan, RS AF Kuo, CK Tuan, RS TI Tissue engineering with mesenchymal stem cells SO IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE LA English DT Article ID MARROW STROMAL CELLS; BONE-MARROW; BIODEGRADABLE POLYMER; PART 1; CARTILAGE; SCAFFOLDS; REPAIR; DEFECTS; DESIGN; 21ST-CENTURY C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Room 1503,MSC 8022, Bethesda, MD 20892 USA. NR 31 TC 35 Z9 54 U1 1 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0739-5175 J9 IEEE ENG MED BIOL JI IEEE Eng. Med. Biol. Mag. PD SEP-OCT PY 2003 VL 22 IS 5 BP 51 EP 56 DI 10.1109/MEMB.2003.1256272 PG 6 WC Engineering, Biomedical; Medical Informatics SC Engineering; Medical Informatics GA 755WT UT WOS:000187435000014 PM 14699936 ER PT J AU Miranda, PC Hallett, M Basser, PJ AF Miranda, PC Hallett, M Basser, PJ TI The electric field induced in the brain by magnetic stimulation: A 3-D finite-element analysis of the effect of tissue heterogeneity and anisotropy SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE anisotropic media; brain; conductivity; current density; eddy currents; electric fields; electromagnetic induction; finite element methods; magnetic stimulation; nonhomogeneous media ID HUMAN MOTOR CORTEX; PERIPHERAL-NERVE; DIFFUSION TENSOR; VOLUME CONDUCTOR; CEREBRAL-CORTEX; ELECTROMAGNETIC INDUCTION; THEORETICAL CALCULATION; INDUCED CURRENTS; EDDY-CURRENTS; EXCITATION AB We investigate the effect of tissue heterogeneity and anisotropy on the electric field and current density distribution induced in the brain during magnetic stimulation. Validation of the finite-element (FE) calculations in a homogeneous isotropic sphere showed that the magnitude of the total electric field can be calculated to within an error of approximately 5% in the region of interest, even in the presence of a significant surface charge contribution. We used a high conductivity inclusion within a sphere of lower conductivity to simulate a lesion due to an infarct. Its effect is to increase the electric field induced in the surrounding low, conductivity region. This boost is greatest in the vicinity of interfaces that lie perpendicular to the current flow. For physiological values of the conductivity distribution, it can reach a factor of 1.6 and extend many millimeters from the interface. We also show that anisotropy can significantly alter the electric field and current density distributions. Either heterogeneity or anisotropy can introduce a radial electric field component, not present in a homogeneous isotropic conductor. Heterogeneity and anisotropy are predicted to significantly affect the distribution of the electric field induced in the brain. It is, therefore, expected that anatomically faithful FE models of individual brains which incorporate conductivity tensor data derived from diffusion tensor measurements, will provide a better understanding of the location of possible stimulation sites in the brain. C1 Univ Lisbon, Fac Sci, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. NINDS, Human Motor Control Sect, MNB, NIH, Bethesda, MD 20892 USA. NICHD, Sect Tissue Biophys & Biomimet, LIMB, NIH, Bethesda, MD 20892 USA. RP Miranda, PC (reprint author), Univ Lisbon, Fac Sci, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. EM pmcm@fc.ul.pt RI Miranda, Pedro/A-5643-2013; Basser, Peter/H-5477-2011 OI Miranda, Pedro/0000-0002-6793-8111; NR 53 TC 108 Z9 113 U1 2 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD SEP PY 2003 VL 50 IS 9 BP 1074 EP 1085 DI 10.1109/TBME.2003.816079 PG 12 WC Engineering, Biomedical SC Engineering GA 711QD UT WOS:000184751800004 PM 12943275 ER PT J AU Brooks, DG Hamer, DH Arlen, PA Gao, LY Bristol, G Kitchen, CMR Berger, EA Zack, JA AF Brooks, DG Hamer, DH Arlen, PA Gao, LY Bristol, G Kitchen, CMR Berger, EA Zack, JA TI Molecular characterization, reactivation, and depletion of latent HIV SO IMMUNITY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; SCID-HU MOUSE; HUMAN HEMATOLYMPHOID DIFFERENTIATION; IN-VIVO; HIV-1-INFECTED PATIENTS; ENVELOPE GLYCOPROTEIN; INFECTED INDIVIDUALS; COMBINATION THERAPY AB Antiretroviral therapy is unable to eliminate HIV infection in a small, long-lived population of latently infected T cells, providing a source for renewed viral replication following cessation of therapy. Analysis of individual latently infected cells generated in the SCID-hu (Thy/Liv) mouse demonstrated no functional viral RNA produced in the latent state. Following reactivation viral expression was dramatically increased, rendering the infected cells susceptible to an anti-HIV immunotoxin. Treatment with the immunotoxin in conjunction with agents that activate virus expression without inducing cell division (IL-7 or the non-tumor-promoting phorbol ester prostratin) depleted the bulk of the latent reservoir and left uninfected cells able to respond to subsequent costimulation. We demonstrate that activation of latent virus is required for targeting by antiviral agents and provide the basis for future therapeutic strategies to eradicate the latent reservoir. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, AIDS Inst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Zack, JA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [AI36059, AI36554] NR 51 TC 134 Z9 137 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP PY 2003 VL 19 IS 3 BP 413 EP 423 DI 10.1016/S1074-7613(03)00236-X PG 11 WC Immunology SC Immunology GA 724RD UT WOS:000185499800012 PM 14499116 ER PT J AU Chang, YC Miller, GF Kwon-Chung, KJ AF Chang, YC Miller, GF Kwon-Chung, KJ TI Importance of a developmentally regulated pheromone receptor of Cryptococcus neoformans for virulence SO INFECTION AND IMMUNITY LA English DT Article ID MATING-TYPE LOCUS; SACCHAROMYCES-CEREVISIAE; SIGNAL TRANSDUCTION; GENE; ALPHA; FILOBASIDIELLA; HOMOLOG; PATHWAY; YEAST AB Cryptococcus neoformans is the etiologic agent of cryptococcosis. Two mating types exist in this fungus, MATalpha and MATa. The CPRa gene of C. neoformans is a MATa strain-specific gene and encodes a putative seven-transmembrane domain pheromone receptor. Unlike the other reported fungal pheromone receptors, CPRa shows functional diversity. Deletion of CPRa drastically affects mating efficiency but does not abolish mating. CPRa expression is developmentally regulated and is not affected by deletion of the transcriptional regulator STE12a. The expression of CPRa is markedly increased by shifting cultures from liquid to solid media. CPRa also plays a significant role in virulence. Deltacpra cells produce smaller capsules in the brains of mice than the wild-type cells, and the mice infected with Deltacpra survive significantly longer than those receiving the wild-type strain. Our results suggest that the MATa pheromone receptor of C neoformans is not only required for mating but also important for survival and growth of the fungus in host tissue. C1 NIAID, LCI, NIH, Bethesda, MD 20892 USA. NIH, Off Director, Vet Resources Program, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, LCI, NIH, Bldg 10,Room 11C304, Bethesda, MD 20892 USA. NR 30 TC 37 Z9 38 U1 0 U2 1 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 SEP PY 2003 VL 71 IS 9 BP 4953 EP 4960 DI 10.1128/IAI.71.9.4953-4960.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 715WR UT WOS:000184996600016 PM 12933837 ER PT J AU Jin, ZG Chu, CY Robbins, JB Schneerson, R AF Jin, ZG Chu, CY Robbins, JB Schneerson, R TI Preparation and characterization of group A meningococcal capsular polysaccharide conjugates and evaluation of their immunogenicity in mice SO INFECTION AND IMMUNITY LA English DT Article ID INFLUENZAE TYPE-B; MENINGITIDIS SEROGROUP-A; SUB-SAHARAN AFRICA; NEISSERIA-MENINGITIDIS; ROUTINE IMMUNIZATION; ANTIBODY-RESPONSE; VACCINES; PROTEIN; TOXIN; VACCINATION AB Epidemic and endemic meningitis caused by group A Neisseria meningitidis remains a problem in sub-Saharan Africa. Although group A meningococcal capsular polysaccharide (GAMP) vaccine confers immunity at all ages, the improved immunogenicity of a conjugate and its compatibility with the World Health Organization's Extended Program on Immunization offers advantages over GAMP alone. Conjugates of GAMP bound to bovine serum albumin (BSA) were synthesized, characterized, and evaluated for their immunogenicities in mice. Two methods, involving adipic acid dihydrazide (ADH) as a linker, were used. First, ADH was bound to GAMP activated with cyanogen bromide (CNBr) or with 1-cyano-4(dimethylamino)-pyridinium tetrafluoroborate (CDAP) to form GAMP(CNBr)AH and GAMP(CDAP)AH. These derivatives were bound to BSA by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form GAMP(CNBr)AH-BSA and GAMP(CDAP)AH-BSA. Second, ADH was bound to BSA with EDC to form AHBSA. AHBSA was bound to activated GAMP to form GAMP(CNBr)-AHBSA and GAMP(CDAP)-AHBSA. The yield of GAMP(CDAP)-AHBSA (35 to 40%) was higher than those of the other conjugates (5 to 20%). GAMP conjugates elicited immunoglobulin G (IgG) anti-GAMP in all mice after three injections of 2.5 or 5.0 mug of GAMP: the geometric mean (GM) was highest in recipients of GAMP(CDAP)-AHBSA (11.40 enzyme-linked immunosorbent assay units). Although the difference was not statistically significant, the 5.0-mug dose elicited a higher GM IgG anti-GAMP than the 2.5-mug dose. Low levels of anti-GAMP were elicited by GAMP alone. GAMP(CDAP)-AHBSA elicited bactericidal activity roughly proportional to the level of IgG anti-GAMP. C1 NICHD, NIH, Lab Dev & Mol Immun, Bethesda, MD 20892 USA. RP Jin, ZG (reprint author), NICHD, NIH, Lab Dev & Mol Immun, Bldg 6,Rm 424, Bethesda, MD 20892 USA. NR 47 TC 14 Z9 19 U1 1 U2 6 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 SEP PY 2003 VL 71 IS 9 BP 5115 EP 5120 DI 10.1128/IAI.71.9.5115-5120.2003 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 715WR UT WOS:000184996600033 PM 12933854 ER PT J AU Mendez, S Tabbara, K Belkaid, Y Bertholet, S Verthelyi, D Klinman, D Seder, RA Sacks, DL AF Mendez, S Tabbara, K Belkaid, Y Bertholet, S Verthelyi, D Klinman, D Seder, RA Sacks, DL TI Coinjection with CpG-containing immunostimulatory oligodeoxynucleotides reduces the pathogenicity of a live vaccine against cutaneous leishmaniasis but maintains its potency and durability SO INFECTION AND IMMUNITY LA English DT Article ID SUSCEPTIBLE BALB/C MICE; CD8(+) T-CELLS; PROTECTIVE IMMUNITY; MAJOR INFECTION; INTERFERON-GAMMA; CONTROLLED TRIAL; DNA VACCINATION; NATURAL MODEL; DOUBLE-BLIND; PLUS BCG AB The inoculation of live, nonattenuated Leishmania major to produce a lesion in a selected site that heals, referred to as leishmanization, is to date the only vaccine against leishmaniasis that has proven to be effective in humans. Its use has been restricted or abandoned entirely, however, due to safety concerns. In an attempt to develop a leishmanization protocol that minimizes pathology while maintaining long-term protection, live parasites were coinjected with CpG-containing immunostimulatory oligodeoxynucleotides (CpG ODNs) alone or in combination with whole-cell lysates of heat-killed L. major promastigotes bound to alum (ALM). C57BL/6 mice infected intradermally by using L. major plus CpG ODN with or without ALM developed few or no dermal lesions and showed an early containment of parasite growth, while mice infected with L. major with or without ALM developed sizable dermal lesions that required up to 10 weeks to heal. The CpG ODNs provoked a transient inflammation that included an early recruitment and accumulation of gamma interferon-producing CD4(+) lymphocytes in the site. Attenuation of the live vaccine did not compromise its ability to confer long-term immunity, as mice receiving L. major and CpG ODN plus ALM were totally protected against reinfection with L. major for up to 6 months. By comparison, the immunity elicited by two efficient nonlive vaccines began to wane by 6 months. Our results suggest that immune modulation using CpG ODNs might be a practical approach to improving the safety of a highly effective live vaccine that has already been widely applied. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Cellular Immunol Sect, Sect Retroviral Immunol, Bethesda, MD 20892 USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, Bldg 4,Rm 126,Ctr Dr MSC 0425, Bethesda, MD 20892 USA. NR 52 TC 55 Z9 56 U1 0 U2 3 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 SEP PY 2003 VL 71 IS 9 BP 5121 EP 5129 DI 10.1128/IAI.71.9.5121-5129.2003 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 715WR UT WOS:000184996600034 PM 12933855 ER PT J AU Su, Z Tam, MF Jankovic, D Stevenson, MM AF Su, Z Tam, MF Jankovic, D Stevenson, MM TI Vaccination with novel immunostimulatory adjuvants against blood-stage malaria in mice SO INFECTION AND IMMUNITY LA English DT Article ID PLASMODIUM-CHABAUDI-CHABAUDI; T-CELL SUBSETS; GAMMA-INTERFERON; IMMUNE-RESPONSES; IFN-GAMMA; PROTECTIVE IMMUNITY; DEFICIENT MICE; EFFECTOR MECHANISMS; SCHISTOSOMA-MANSONI; CYTOKINE PRODUCTION AB An important aspect of malaria vaccine development is the identification of an appropriate adjuvant which is both capable of stimulating a protective immune response and safe for use by humans. Here, we investigated the feasibility of using novel immunostimulatory molecules as adjuvants combined with a crude antigen preparation and coadsorbed to aluminum hydroxide (alum) as a vaccine against blood-stage Plasmodium chabaudi AS malaria. Prior to challenge infection, immunization of genetically susceptible A/J mice with the combination of malaria antigen plus recombinant interleukin-12 (IL-12) in alum induced a Th1 immune response with production of high levels of gamma interferon (IFN-gamma) and diminished IL-4 levels by spleen cells stimulated in vitro with parasite antigen compared to mice immunized with antigen alone, antigen in alum, or antigen plus IL-12. Mice immunized with malaria antigen plus recombinant IL-12 in alum had high levels of total malaria-specific antibody and immunoglobulin G2a. Compared to unimmunized mice, immunization with antigen plus IL-12 in alum induced the highest level of protective immunity against challenge infection with P. chabaudi AS, which was evident as a significantly decreased peak parasitemia level and 100% survival. Protective immunity was dependent on CD4(+) T cells, IFN-gamma, and B cells and was long-lasting. Replacement of IL-12 as an adjuvant by synthetic oligodeoxynucleotides (ODN) containing CpG motifs induced a similar level of vaccine-induced protection against challenge infection with P. chabaudi AS. These results illustrate that it is possible to enhance the potency of a crude malaria antigen preparation delivered in alum by inclusion of immunostimulatory molecules, such as IL-12 or CpG-ODN. C1 NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD USA. RP Stevenson, MM (reprint author), Montreal Gen Hosp, Res Inst, Rm L11-409,1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. NR 49 TC 48 Z9 52 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 SEP PY 2003 VL 71 IS 9 BP 5178 EP 5187 DI 10.1128/IAI.71.9.5178-5187.2003 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 715WR UT WOS:000184996600041 PM 12933862 ER PT J AU Ribeiro, JMC AF Ribeiro, JMC TI A catalogue of Anopheles gambiae transcripts significantly more or less expressed following a blood meal SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE mosquito; genome; hematophagy; gene expression; gene regulation ID MALARIA VECTOR; AEDES-AEGYPTI; DROSOPHILA-MELANOGASTER; PROPHENOLOXIDASE CDNA; MOLECULAR-CLONING; SALIVARY-GLAND; TRYPSIN GENES; MOSQUITO; PROTEIN; SEQUENCE AB The recent assembly of the Anopheles gambiae genome included the sequencing of similar to80,000 EST from blood fed (BF) and nonblood fed (NBF) adult female mosquitoes to help find the exons and introns in the mosquito genome. These two EST libraries provided an insight into the differential gene expression resulting from the metabolically intense task of converting the massive blood meal into eggs. Previously, 168 genes have been identified to be either significantly more or significantly less transcribed after the blood meal [Science 298 (2002) 129]. Presently, 435 transcripts are described; these are grouped in supplemental tables by probable function to facilitate public access to these data and to help in designing postgenome experiments in the biology of Anopheles gambiae. The electronic tables and supplemental material are available at http://www.nebi.nim.nih.gov/ projects/Mosquito/Ag-ESTs. Published by Elsevier Ltd. C1 NIAID, Lab Malaria & Vector Res, Med Entomol Sect, NIH, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, Med Entomol Sect, NIH, Room 4-126,Ctr Dr, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 40 TC 55 Z9 55 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD SEP PY 2003 VL 33 IS 9 BP 865 EP 882 DI 10.1016/S0965-1748(03)00080-8 PG 18 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 718QH UT WOS:000185157600002 PM 12915178 ER PT J AU Dostalova, I Pacak, K Nedvidkova, J AF Dostalova, I Pacak, K Nedvidkova, J TI Application of in vivo microdialysis to measure leptin concentrations in adipose tissue SO INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES LA English DT Article DE leptin; microdialysis; adipose tissue ID HUMAN SKELETAL-MUSCLE; EXPRESSION; RECEPTOR AB Microdialysis is a relatively new in vivo sampling technique, which allows repeated collecting of interstitial fluid and infusion of effector molecules into the tissue without influencing whole body function. The possibility of using microdialysis catheter with a large-pore size dialysis membrane (100 kDa) to measure concentrations of the adipocyte-derived peptide hormone leptin in interstitial fluid of adipose tissue was explored. Krebs-Henseleit buffer with 40 g/l dextran-70 was used to prevent perfusion fluid loss across the dialysis membrane. The relative recovery of leptin in vitro was determined using CMA/65 microdialysis catheter (100 kDa cut-off, membrane length 30 mm; CMA, Stockholm, Sweden) and four perfusion rates were tested (0.5, 1.0, 2.0,5.0 mul/min). Furthermore, the microdialysis catheter CMA/65 was inserted into subcutaneous abdominal adipose tissue of 11 healthy human subjects and leptin concentrations in the interstitial fluid of adipose tissue in vivo were measured. The present findings are the first documentation on the use of microdialysis to study local leptin concentrations in the interstitial fluid of adipose tissue. (C) 2003 Elsevier B.V. All rights reserved. C1 Inst Endocrinol, Prague 11694, Czech Republic. Charles Univ, Fac Sci, Prague 11694, Czech Republic. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD USA. RP Nedvidkova, J (reprint author), Inst Endocrinol, Narodni Trida 8, Prague 11694, Czech Republic. NR 11 TC 21 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0141-8130 J9 INT J BIOL MACROMOL JI Int. J. Biol. Macromol. PD SEP PY 2003 VL 32 IS 3-5 BP 205 EP 208 DI 10.1016/S0141-8130(03)00055-2 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 724QA UT WOS:000185497200018 PM 12957318 ER PT J AU Yamamoto, A Kumakura, S Uchida, M Barrett, JC Tsutsui, T AF Yamamoto, A Kumakura, S Uchida, M Barrett, JC Tsutsui, T TI Immortalization of normal human embryonic fibroblasts by introduction of either the human papillomavirus type 16 E6 or E7 gene alone SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human fibroblasts; immortalization; HPV-16 E6 or E7 ID HUMAN-DIPLOID FIBROBLASTS; HUMAN EPITHELIAL-CELLS; WILD-TYPE P53; CYCLE CONTROL; ASSOCIATION; EXPRESSION; TELOMERASE; PROTEIN; KERATINOCYTES; AMPLIFICATION AB The ability of the human papillomavirus type 16 (HPV-16) E6 or E7 gene to induce immortalization of normal human embryonic fibroblast WHE-7 cells was examined. WHE-7 cells at 9 population doublings (PD) were infected with retrovirus vectors encoding either HPV-16 E6 or E7 alone or both E6 and E7 (E6/E7). One of 4 isolated clones carrying E6 alone became immortal and is currently at >445 PD. Four of 4 isolated clones carrying E7 alone escaped from crisis and are currently at >330 PD. Three of 5 isolated clones carrying E6/E7 were also immortalized and are currently at >268 PD. The immortal clone carrying E6 only and 2 of the 3 immortal clones carrying E6/E7 expressed a high level of E6 protein, and all the immortal clones carrying E7 alone and the other immortal clone carrying E6/E7 expressed a high level of E7 protein when compared to their mortal or precrisis clones. The immortal clones expressing a high level of E6 or E7 protein were positive for telomerase activity or an alternative mechanism of telomere maintenance, respectively, known as ALT (alternative lengthening of telomeres). All the mortal or precrisis clones were negative for both phenotypes. All the immortal clones exhibited abrogation of G I arrest after DNA damage by X-ray irradiation. The expression of INK4a protein (p16(INK4),) was undetectable in the E6-infected mortal and immortal clones, whereas Rb protein (pRb) was hyperphosphorylated only in the immortal clone. p16(INK4a) was overexpressed in all the E7-infected immortal clones and their clones in the pre-crisis period as well as all the E6/E7-infected mortal and immortal clones, but the pRb expression was downregulated in all of these clones. These results demonstrate for the first time to our knowledge that HPV-16 E6 or E7 alone can induce immortalization of normal human embryonic fibroblasts. Inactivation of p16(INK4a)/pRb pathways in combination with activation of a telomere maintenance mechanism is suggested to be necessary for immortalization of normal human embryonic fibroblasts by these viral oncogenes. The susceptibility of human cells to immortalization may be related to the state of differentiation of the cells. (C) 2003 Wiley-Liss, Inc. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Nippon Dent Univ Tokyo, Dept Oral & Maxillofacial Surg, Tokyo, Japan. Nippon Dent Univ Tokyo, Dept Pharmacol, Tokyo, Japan. NCI, Lab Biosyst & Canc, Canc & Aging Sect, Bethesda, MD USA. RP Barrett, JC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 25 Z9 27 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 1 PY 2003 VL 106 IS 3 BP 301 EP 309 DI 10.1002/ijc.11219 PG 9 WC Oncology SC Oncology GA 703KA UT WOS:000184277500001 PM 12845665 ER PT J AU Shum, L Wang, XB Kane, AA Nuckolls, GH AF Shum, L Wang, XB Kane, AA Nuckolls, GH TI BMP4 promotes chondrocyte proliferation and hypertrophy in the endochondral cranial base SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY LA English DT Article DE bone morphogenetic proteins; cranial base; synchondrosis; endochondral ossification; chondrocyte hypertrophy ID HORMONE-RELATED PEPTIDE; BONE MORPHOGENETIC PROTEINS; TRANSCRIPTION FACTOR SOX9; INDIAN-HEDGEHOG; GROWTH-PLATE; SKELETAL DEVELOPMENT; II COLLAGEN; CARTILAGE; DIFFERENTIATION; CHONDROGENESIS AB Defects in the growth and development of the endochondral bones that comprise the cranial base contribute to several craniofacial dysmorphic syndromes. Since Bone Morphogenetic Protein (BMP) signaling regulates chondrocyte differentiation and endochondral ossification in developing long bones, we have tested the hypothesis that BMP signaling also participates in regulating development of the cranial base. During in vivo developmental progression of the cranial base in mice, a burst of skeletal growth and chondrocyte maturation was identified in the perinatal period. Using a novel serum-free organ culture system, cranial base structures were cultured as explants in the presence of BMP4 or noggin, and analyzed for morphological and molecular changes. Growth of perinatal cranial base explants was inhibited by treatment with noggin, a BMP inhibitor. Exogenous BMP4 promoted cartilage growth, matrix deposition and chondrocyte proliferation in a dose dependent manner. Correspondingly, expression level of the cartilage markers Sox9 and collagen type II were also increased. Alkaline phosphatase and collagen type X expression were up-regulated and expressed in ectopic hypertrophic chondrocytes after treatment of the cultures with 100 ng/ml BMP4 for seven days. This increase in chondrocyte hypertrophy was accompanied by increased indian hedgehog (Ihh) and parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) receptor (PPR) expression, but not increased PTHrP expression. We conclude that endogenous BMPs are required to maintain cartilage growth, and exogenous BMP4 can enhance cartilage maturation and induce ectopic chondrocyte hypertrophy in the cranial base. Therefore, appropriate levels of BMP signaling are important for normal cranial base development. C1 NIAMSD, US Dept HHS, Dev Biol Sect,Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Dept Plast & Reconstruct Surg, St Louis, MO USA. RP Nuckolls, GH (reprint author), NIAMSD, US Dept HHS, Dev Biol Sect,Cartilage Biol & Orthopaed Branch, NIH, 1 Democracy Plaza,Suite 800,6701 Democracy Blvd,M, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [Z01-AR41114] NR 48 TC 45 Z9 48 U1 0 U2 0 PU U B C PRESS PI BILBAO PA UNIV BASQUE COUNTRY, EDITORIAL SERVICES, PO BOX 1397, E-48080 BILBAO, SPAIN SN 0214-6282 J9 INT J DEV BIOL JI Int. J. Dev. Biol. PD SEP PY 2003 VL 47 IS 6 BP 423 EP 431 PG 9 WC Developmental Biology SC Developmental Biology GA 736FA UT WOS:000186159700005 PM 14598792 ER PT J AU Agid, R Levin, T Gomori, JM Lerer, B Bonne, O AF Agid, R Levin, T Gomori, JM Lerer, B Bonne, O TI T2-weighted image hyperintensities in major depression: focus on the basal ganglia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE basal ganglia; magnetic resonance imaging (MRI); major depression; T2-weighted image hyperintensities (T2-WIH) ID WHITE-MATTER LESIONS; LATE-LIFE DEPRESSION; CEREBRAL BLOOD-FLOW; DEFINED VASCULAR DEPRESSION; MULTIPLE-SCLEROSIS; MOOD DISORDERS; SIGNAL HYPERINTENSITIES; GERIATRIC DEPRESSION; ALZHEIMERS-DISEASE; ELDERLY SUBJECTS AB A major focus of attention in structural brain-imaging research in major depression is the increased prevalence of T2-weighted image 'hyperintensities' (T2-WIH). Our aims in this study were to characterize the distribution and magnetic resonance imaging (MRI) presentation of brain hyperintensities in major depression patients compared to healthy control subjects and to explore the association between the presence of T2-WIH and measures of clinical and cognitive state. Thirty-seven patients suffering from major depression and 27 age- and sex-matched healthy controls underwent brain MRI and were evaluated by the Hamilton Rating Scale for Depression, the Mini Mental State Examination and the Haschinsky Ischaemia Index. T2-WIH (at least one) were found in 26 out of 37 major depression patients and 7 out of 27 controls (p = 0.0001). The number of brain T2-WIH was significantly and positively correlated with age in depressed (p = 0.001) but not in healthy subjects. Mean volume of T2-WIH was significantly greater (p = 0.004) in depressed subjects. In the control group T2-WIH were exclusively located in the supratentorial hemispheral white matter while in the depressed group T2-WIH were also found in basal ganglia, temporal lobe, cerebellum and brainstem. More (52 vs. 20%; p = 0.018) T2-WIH were demonstrable on T1 in depressed subjects. Depressed patients with T2-WIH in basal ganglia were clearly the most severely depressed and cognitively impaired subjects, and may constitute a clinically distinct subgroup within major depression. C1 Long Isl Jewish Med Ctr, Dept Oncol, New Hyde Pk, NY 11040 USA. Eitanim Mental Hlth Ctr, Jerusalem, Israel. Hadassah Univ Hosp, Dept Psychiat, IL-91120 Jerusalem, Israel. Hadassah Univ Hosp, Dept Radiol, IL-91120 Jerusalem, Israel. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 200, Bethesda, MD 20892 USA. RI Levin, Tomer/D-2997-2016 OI Levin, Tomer/0000-0001-5054-5103 NR 92 TC 12 Z9 13 U1 3 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD SEP PY 2003 VL 6 IS 3 BP 215 EP 224 DI 10.1017/S146114570300347X PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 739GJ UT WOS:000186336500003 PM 12974987 ER PT J AU Friedl, J Turner, E Alexander, HR AF Friedl, J Turner, E Alexander, HR TI Augmentation of endothelial cell monolayer permeability by hyperthermia but not tumor necrosis factor: Evidence for disruption of vascular integrity via VE-cadherin down-regulation SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE vascular biology; hyperthermia; tumor necrosis factor; permeability; regional perfusion ID ISOLATED LIMB PERFUSION; FACTOR CACHECTIN; MALIGNANT-MELANOMA; ALPHA-CATENIN; RTNF-ALPHA; SARCOMA; GAMMA; TNF AB Following isolated limb perfusion (ILP) with hyperthermia (HT), TNF and melphalan, there is immediate tumor softening secondary to augmentation of capillary leak in the tumor neovasculature. TNF can induce vascular permeability but is always used with HT during ILP and the contribution of the latter on permeability is not known. This study characterizes the effects of HT and TNF on vascular permeability in vitro. Permeability across confluent human umbilical vein endothelial cells exposed to HT (40degreesC) with or without 0.1-1000 ng/ml TNF was assessed by quantitating flux of albumin bound Evan's Blue dye from the upper to lower chamber. Immunofluorescent staining for VE-cadherin and F-actin was performed after human umbilical vein endothelial cells (hUVECs) were exposed to these conditions. HT induced a significant and reversible increase in permeability compared to untreated hUVECs (p<0.001) whereas barrier function was not altered by TNF. Untreated hUVECs had uniform cell surface staining for VE-cadherin, the primary endothelial intercellular adhesion molecule, with colocalization of F-actin cytoskeletal elements. HT resulted in a marked decrease in VE-cadherin staining and contraction of F-actin at sites of endothelial cell-cell separation. These data demonstrate that under conditions relevant to those used in ILP, HT but not TNF contributes to a rapid and reversible change in endothelial cell permeability in association with a down regulation of VE-cadherin. These data support the use of HT in isolation perfusion and demonstrate a novel mechanism for alterations in microvascular permeability by HT. C1 Univ Vienna, Gen Hosp Vienna, Dept Gen Surg, A-1090 Vienna, Austria. NCI, Surg Metab Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Friedl, J (reprint author), Univ Vienna, Gen Hosp Vienna, Dept Gen Surg, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 26 TC 23 Z9 23 U1 2 U2 2 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 SEP PY 2003 VL 23 IS 3 BP 611 EP 616 PG 6 WC Oncology SC Oncology GA 709XM UT WOS:000184651900009 PM 12888895 ER PT J AU Morikawa, J Li, H Kim, S Nishii, K Ueno, S Suh, E Dougherty, E Shmulevich, I Shiku, H Zhang, W Kobayashi, T AF Morikawa, J Li, H Kim, S Nishii, K Ueno, S Suh, E Dougherty, E Shmulevich, I Shiku, H Zhang, W Kobayashi, T TI Identification of signature genes by microarray for acute myeloid leukemia without maturation and acute promyelocytic leukemia with t(15;17)(q22;q12)(PML/RAR alpha) SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE acute myeloid leukemia without maturation; acute promyelocytic leukemia with t(15;17)(q22;q12)(PML/RARa); cDNA microarray; gene expression profiling ID TRANS-RETINOIC ACID; ABL TYROSINE KINASE; RECEPTOR-TYPE-BETA; BCR-ABL; CDNA MICROARRAYS; INTENSIVE CHEMOTHERAPY; GEMTUZUMAB OZOGAMICIN; MYELOGENOUS LEUKEMIA; EXPRESSION PROFILES; FUSION PROTEIN AB Acute myeloid leukemia (AML) has distinct subgroups characterized by different maturation and specific chromosomal translocation. In order to gain insight into the gene expression activities in AML, we carried out a gene C expression profiling study with 21 AML samples using cDNA microarrays. focusing on acute promyelocytic leukemia with specific translocation t(15;17)(q22;q12) [French-American-British or FAB-M3 with t(15; 17)] and AML without maturation (FAB-M1) characterized by morphologically and phenotypically immature AML blasts and no recurrent chromosomal abnormalities. Using a multivariate sigma-classifier algorithm, we identified 33 strong feature genes that distinguish FAB-M3 with t(15; 17) from other AML samples, and 24 strong feature genes that classify FAB-M1. A direct comparison between FAB-M3 with t(15;17) and FAB-M1 led to selection of 13 strong feature Genes. Those Genes include some known to be related to leukemogenesis and cell differentiation. RIN1, a Gene in the ras pathway, was up-regulated in FAB-M3 with t(15;17). Growth factor-binding protein 2 gene was downregulated in FAB-M1. Huntingtin gene was up-regulated in FAB-M1. Others include syndecan 4, interleukin-2 receptor beta, folate receptor beta, low affinity immunoglobulin gamma, Fc receptor IIC precursor, insulin-like growth factor binding protein 2, and myeloperoxidase, which are involved in cell differentiation. Overexpression of myeloperoxidase in FAB-M3 cells with t(15;17) compared to FAB-M1 cells is consistent with the conventional cytochemical staining pattern. Thus, the study revealed that a morphologically-defined FAB-M1 subtype has a distinct gene expression signature that contributes to its cell differentiation and proliferation as well as FAB-M3 with a recurrent cytogenetic abnormality t(15;17)(q22;q12). C1 Mie Univ, Sch Med, Dept Internal Med 2, Tsu, Mie 5148507, Japan. NIH, Div Computat Biol, Ctr Informat Technol, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Canc Genom Core Lab, Houston, TX 77030 USA. RP Kobayashi, T (reprint author), Mie Univ, Sch Med, Dept Internal Med 2, 2-174 Edobashi, Tsu, Mie 5148507, Japan. NR 49 TC 19 Z9 19 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 SEP PY 2003 VL 23 IS 3 BP 617 EP 625 PG 9 WC Oncology SC Oncology GA 709XM UT WOS:000184651900010 PM 12888896 ER PT J AU Naidoo, KS Raghunandan, A Mashige, KP Govender, P Holden, BA Pokharel, GP Ellwein, LB AF Naidoo, KS Raghunandan, A Mashige, KP Govender, P Holden, BA Pokharel, GP Ellwein, LB TI Refractive error and visual impairment in African children in South Africa SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SHUNYI DISTRICT; POPULATION; CHINA AB PURPOSE. To assess the prevalence of refractive error and visual impairment in school-aged African children in South Africa. METHODS. Random selection of geographically defined clusters was used to identify a sample of children 5 to 15 years of age in the Durban area. From January to August 2002, children in 35 clusters were enumerated through a door-to-door survey and examined in temporary facilities. The examination included visual acuity measurements, ocular motility evaluation, retinoscopy and autorefraction under cycloplegia, and examination of the anterior segment, media, and fundus. In nine clusters, children with reduced vision and a sample of those with normal vision underwent independent replicate examinations for quality assurance. RESULTS. A total of 5599 children living in 2712 households were enumerated, and 4890 (87.3%) were examined. The prevalence of uncorrected, presenting, and best-corrected visual acuity of 20/40 or worse in the better eye was 1.4%, 1.2%, and 0.32%, respectively. Refractive error was the cause in 63.6% of the 191 eyes with reduced vision, amblyopia in 7.3%, retinal disorders in 9.9%, corneal opacity in 3.7%, other causes in 3.1%, and unexplained causes in the remaining 12.0%. Exterior and anterior segment abnormalities were observed in 528 (10.8%) children, mainly corneal and conjunctival. Myopia (at least -0.50 D) in one or both eyes was present in 2.9% of children when measured with retinoscopy and in 4.0% measured with autorefraction. Beginning with an upward trend at age 14, myopia prevalence with autorefraction reached 9.6% at age 15. Myopia was also associated with increased parental education. Hyperopia (+2.00 D or more) in at least one eye was present in 1.8% of children when measured with retinoscopy and in 2.6% measured with autorefraction, with no significant predictors of hyperopia risk. CONCLUSIONS. The prevalence of reduced vision is low in school-age African children, most of it because of uncorrected refractive error. The high prevalence of corneal and other anterior segment abnormalities is a reflection of the inadequacy of primary eye care services in this area. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ KwaZulu Natal, Dept Optometry, ZA-4000 Durban, South Africa. Int Ctr Eyecare Educ, Sydney, NSW, Australia. Univ Houston, Coll Optometry, Houston, TX USA. WHO, Prevent Blindness & Deafness, CH-1211 Geneva, Switzerland. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM ellweinl@nei.nih.gov OI Govender, Pirindhavellie/0000-0002-9136-4111 FU NEI NIH HHS [N01-EY02103] NR 17 TC 159 Z9 169 U1 4 U2 21 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2003 VL 44 IS 9 BP 3764 EP 3770 DI 10.1167/iovs.03-0283 PG 7 WC Ophthalmology SC Ophthalmology GA 715WC UT WOS:000184994900007 PM 12939289 ER PT J AU Ochrietor, JD Moroz, TP van Ekeris, L Clamp, MF Jefferson, SC deCarvalho, AC Fadool, JM Wistow, G Muramatsu, T Linser, PJ AF Ochrietor, JD Moroz, TP van Ekeris, L Clamp, MF Jefferson, SC deCarvalho, AC Fadool, JM Wistow, G Muramatsu, T Linser, PJ TI Retina-specific expression of 5A11/Basigin-2, a member of the immunoglobulin gene superfamily SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SEQUENCE TAG ANALYSIS; NEURAL RETINA; MOUSE BASIGIN; PIGMENT EPITHELIUM; NEIBANK PROJECT; IG SUPERFAMILY; ANTIGEN; CELL; CD147; MOLECULE AB PURPOSE. 5A11/Basigin has recently been identified as a critical glycoprotein for full maturity and function of the mouse retina. However, the biological function of 5A11/Basigin has yet to be determined. Previous reports indicate the presence of multiple 5A11/Basigin polypeptides within the retina. Therefore, in an effort to determine the function of 5A11/Basigin, the molecular diversity of its expression was evaluated. METHODS. Northern blot and immunoblot techniques were used to evaluate the number of forms of 5A11/Basigin in the mouse retina. cDNA cloning, using a mouse retina library or RT-PCR from rat, chicken, zebrafish, and human retina, was performed to determine the sequence of 5A11/Basigin transcripts. A peptide was generated, based on the deduced amino acid sequence, for subsequent antibody production. Localization of 5A11/Basigin expression was evaluated by immunoblot, immunohistochemistry, and real-time RT-PCR. RESULTS. Two 5A11/Basigin transcripts of similar to1.5 kb and similar to1.8 kb which correspond to glycosylated proteins of similar to45 and similar to5 kDa, respectively, were identified in mouse retina. The shorter form was previously cloned. However, the longer form, a splice variant of mouse 5A11/Basigin, is a member of the immunoglobulin gene superfamily and has been named 5A11/Basigin-2. Homologous transcripts were also cloned from rat, chicken, zebrafish, and human retina. 5A11/Basigin-2 expression was limited to the retina, specifically to photoreceptor cells, where it appeared to be most concentrated in the inner segments. CONCLUSIONS. The specific and limited expression of 5A11/Basigin-2 explicitly within photoreceptor cells implies that this glycoprotein plays a fundamental role within the retina. However, its role remains to be determined. C1 Univ Florida, Whitney Lab, St Augustine, FL 32080 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Sch Med, Dept Biochem, Nagoya, Aichi 466, Japan. RP Ochrietor, JD (reprint author), Univ Florida, Whitney Lab, 9505 Ocean Shore Blvd, St Augustine, FL 32080 USA. EM jdo@whitney.ufl.edu OI deCarvalho, Ana C/0000-0003-1183-4548 FU NEI NIH HHS [EY13020, F32EY13918] NR 38 TC 35 Z9 40 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2003 VL 44 IS 9 BP 4086 EP 4096 DI 10.1167/iovs.02-0995 PG 11 WC Ophthalmology SC Ophthalmology GA 715WC UT WOS:000184994900050 PM 12939332 ER PT J AU Hermoso, M Cidlowski, J AF Hermoso, M Cidlowski, J TI Putting the brake on inflammatory responses: the role of glucocorticoids SO IUBMB LIFE LA English DT Review DE glucocorticoids (GC); glucocorticoid receptor (GR); nuclear factor kappa B (NF kappa B); activator protein-1 (AP-1); Toll-like receptors (TLRs) ID NF-KAPPA-B; TRANSCRIPTION FACTOR AP-1; NECROSIS-FACTOR-ALPHA; DNA-BINDING; CELL-PROLIFERATION; MAP KINASE; TARGETED DISRUPTION; MEDIATED INHIBITION; GENE-EXPRESSION; BETA ISOFORM AB Glucocorticoids are among the most widely used agents for the treatment of inflammatory diseases. The primary mechanism of glucocorticoid action is via the glucocorticoid receptor (GR), which blocks the expression of proinflammatory cytokines and adhesion molecules. Repression of many pro-inflammatory genes occurs by inhibition of transcription factors including nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1). In this article, we discuss the physiological and molecular interaction that occurs between GR and proinflammatory cytokines signaling pathways. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cidlowski, J (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. NR 60 TC 26 Z9 27 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD SEP PY 2003 VL 55 IS 9 BP 497 EP 504 DI 10.1080/15216540310001642072 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 740FY UT WOS:000186393400001 PM 14658755 ER PT J AU Frank, I Santos, JJ Mehlhop, E Villamide-Herrera, L Santisteban, C Gettie, A Ignatius, R Lifson, JD Pope, M AF Frank, I Santos, JJ Mehlhop, E Villamide-Herrera, L Santisteban, C Gettie, A Ignatius, R Lifson, JD Pope, M TI Presentation of exogenous whole inactivated simian immunodeficiency virus by mature dendritic cells induces CD4(+) and CD8(+) T-Cell responses SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE simian immunodeficiency virus; immune response; whole inactivated virus; dendritic cells ID CLASS-II TRANSPORT; ENVELOPE GLYCOPROTEIN; RHESUS MACAQUES; VIRAL REPLICATION; LYMPH-NODES; VACCINE; HIV-1; SIV; TYPE-1; MATURATION AB Interactions between HIV-1 and dendritic cells (DCs) play an important role in the initial establishment and spread of infection and development of antiviral immunity. We used chemically inactivated aldrithiol-2 (AT-2) simian immunodeficiency virus (SIV) with functional envelope glycoproteins to study virus interactions with DCs and developed an in vitro system to evaluate the quality of SIV antigen (Ag) presentation by DCs to T cells. AT-2 SIV interacts authentically with T cells and DCs and thus allows assessment of natural SIV-specific responses. CD4(+) and CD8(+) T cells from blood or lymph nodes of SIV-infected macaques released interferon-gamma (IFNgamma) and proliferated in response to a variety of AT-2 SIV isolates. Responses did not vary significantly as a function of the quantitative envelope glycoprotein content of the virions. Presentation of Ags derived from AT-2 SIV by DCs was more potent than presentation by comparably Ag-loaded monocytes. Interestingly, SIV-pulsed mature DCs stimulated both CD4(+) and CD8(+) T-cell responses, whereas immature DCs primarily stimulated CD4(+) T cells. Further studies using AT-2 inactivated virus may help to define better the details of the virus-DC interactions critical for infection versus induction of antiviral immune responses. C1 Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Aaron Diamond AIDS Res Ctr, New York, NY USA. Free Univ Berlin, Benjamin Franklin Med Ctr, Dept Med Microbiol & Immunol Infect, D-1000 Berlin, Germany. NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [RR00164]; NIAID NIH HHS [AI47681, AI52060] NR 59 TC 35 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2003 VL 34 IS 1 BP 7 EP 19 DI 10.1097/00126334-200309010-00002 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 719YL UT WOS:000185232600002 PM 14501788 ER PT J AU Royaux, IE Belyantseva, IA Wu, T Kachar, B Everett, LA Marcus, DC Green, ED AF Royaux, IE Belyantseva, IA Wu, T Kachar, B Everett, LA Marcus, DC Green, ED TI Localization and functional studies of pendrin in the mouse inner ear provide insight about the etiology of deafness in pendred syndrome SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE pendred syndrome; pendrin; anion transporter; cochlea; knockout mouse; endocochlear potential ID SULCUS EPITHELIAL-CELLS; SYNDROME GENE PDS; ENDOLYMPHATIC SAC; ULTRASTRUCTURAL ANALYSIS; CATION ABSORPTION; NA+/I-SYMPORTER; EXPRESSION; COCHLEA; RAT; TISSUES AB Immunolocalization studies of mouse cochlea and vestibular end-organ were performed to study the expression pattern of pendrin, the protein encoded by the Pendred syndrome gene (PDS), in the inner ear. The protein was restricted to the areas composed of specialized epithelial cells thought to play a key role in regulating the composition and resorption of endolymph. In the cochlea, pendrin was abundant in the apical membrane of cells in the spiral prominence and outer sulcus cells (along with their root processes). In the vestibular end-organ, pendrin was found in the transitional cells of the cristae ampullaris, utriculi, and sacculi as well as in the apical membrane of cells in the endolymphatic sac. Pds-knockout (Pds(-/-)) mice were found to lack pendrin immunoreactivity in all of these locations. Histological studies revealed that the stria vascularis in Pds(-/-) mice was only two-thirds the thickness seen in wildtype mice, with the strial marginal cells showing irregular shapes and sizes. Functional studies were also performed to examine the role of pendrin in endolymph homeostasis. Using double-barreled electrodes placed in both the cochlea and the utricle, the endocochlear potential and endolymph potassium concentration were measured in wild-type and Pds(-/-) mice. Consistent with the altered strial morphology, the endocochlear potential in Pds(-/-) mice was near zero and did not change during anoxia. On the other hand, the endolymphatic potassium concentration in Pds(-/-) mice was near normal in the cochlea and utricle. Together, these results suggest that pendrin serves a key role in the functioning of the basal and/or intermediate cells of the stria vascularis to maintain the enclocochlear potential, but not in the potassium secretory function of the marginal cells. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, 50 S Dr,Bld50, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [R01-DC00212, R01 DC000212] NR 45 TC 75 Z9 78 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1525-3961 J9 JARO JI JARO PD SEP PY 2003 VL 4 IS 3 BP 394 EP 404 DI 10.1007/s10162-002-3052-4 PG 11 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 726XD UT WOS:000185626100009 PM 14690057 ER PT J AU Preston, KL Epstein, DH Davoudzadeh, D Huestis, MA AF Preston, KL Epstein, DH Davoudzadeh, D Huestis, MA TI Methadone and metabolite urine concentrations in patients maintained on methadone SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID STEADY-STATE PHARMACOKINETICS; ALPHA-ACETYLMETHADOL LAAM; N-DEMETHYLATION; MAINTENANCE TREATMENT; EXCRETION; EDDP; INVOLVEMENT; WITHDRAWAL; CLEARANCE; PROGRAMS C1 Natl Inst Drug Abuse, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD 21224 USA. Microgen Corp, Fremont, CA 94538 USA. RP Preston, KL (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 24 TC 17 Z9 18 U1 3 U2 5 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD SEP PY 2003 VL 27 IS 6 BP 332 EP 341 PG 10 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 717UG UT WOS:000185108700002 PM 14516485 ER PT J AU Wagner, B Galey, WR AF Wagner, B Galey, WR TI Kinetic analysis of hexose transport to determine the mechanism of amygdalin and prunasin absorption in the intestine SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE amygdalin; prunasin/D-mandelonitrile beta-D-glucoside; phloridzin; rat; monosaccharide transport; everted sac; glycoside transport; small intestine; absorption; D-[C-14]-glucose ID ACTIVE-TRANSPORT; RAT INTESTINE; DOSAGE FORMS; LAETRILE; INVITRO; METABOLISM; TOXICITY; SYSTEM; MEXICO; CANCER AB Evidence is accumulating that glucose-conjugated compounds may be carried across the gut mucosa via the epithelial sodium-dependent monosaccharide transporter SGLT1. A modification of the everted intestinal sac technique was utilized to study the transport of the cyanogenic glycoside amygdalin (D-mandelonitrile beta-D-gentiobioside) and its metabolite D-mandelontrile P-D-glucoside (prunasin). Everted sacs of rat jejunum and ileum were bathed in isotonic oxygenated sodium chloride-potassium phosphate buffer containing 2.8 muCi D-[H-3]-mannose and 0.187 muCi D-[C-14]-glucose. For treatment groups, buffers contained phloridzin, galactose, amygdalin or prunasin. The rate constant (k) for the transport process was calculated. Compared with the control (n = 33), phloridzin (n = 25) significantly reduced the rate constants of both D-[C-14]-glucose and D-[H-3]-mannose. Substitution of sodium with choline and incremental galactose treatments similarly reduced D-[C-14]-glucose influx, indicating that a fraction of the transport is carrier-mediated. Treatment with amygdalin did not significantly affect the rate constants Of D- [C-14]-glucose or D- [H-3]-mannose transport. However, treatment with 1 mM prunasin (a = 16) did reduce the influx of D-[C-14]-glucose without affecting D-[H-3]-mannose values. This is consistent with the reports finding that glycoside absorption may be mediated by SGLT1. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol,S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. Howard Hughes Med Inst, HHMI NIH Med Scholars Program, Chevy Chase, MD 20815 USA. RP Wagner, B (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol,S Texas Vet Hlth Care Syst, 7703 Floyd Curl Dr,MC 7882, San Antonio, TX 78229 USA. OI Wagner, Brent/0000-0002-7063-0142 NR 38 TC 4 Z9 4 U1 1 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0260-437X J9 J APPL TOXICOL JI J. Appl. Toxicol. PD SEP-OCT PY 2003 VL 23 IS 5 BP 371 EP 375 DI 10.1002/jat.934 PG 5 WC Toxicology SC Toxicology GA 724LX UT WOS:000185490000010 PM 12975776 ER PT J AU Reddy, PT Prasad, CR Reddy, PH Reeder, D McKenney, K Jaffe, H Dimitrova, MN Ginsburg, A Peterkofsky, A Murthy, PS AF Reddy, PT Prasad, CR Reddy, PH Reeder, D McKenney, K Jaffe, H Dimitrova, MN Ginsburg, A Peterkofsky, A Murthy, PS TI Cloning and expression of the gene for a novel protein from Mycobacterium smegmatis with functional similarity to eukaryotic calmodulin SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CALCIUM-BINDING PROTEIN; ESCHERICHIA-COLI; ADENYLATE-CYCLASE; BACILLUS-SUBTILIS; PURIFICATION; PHOSPHOLIPIDS; TUBERCULOSIS; SEQUENCE; PHLEI; CELLS AB A calmodulin-like protein (CAMLP) from Mycobacterium smegmatis was purified to homogeneity and partially sequenced; these data were used to produce a full-length clone, whose DNA sequence contained a 55-amino-acid open reading frame. M. smegmatis CAMLP, expressed in Escherichia coli, exhibited properties characteristic of eukaryotic calmodulin: calcium-dependent stimulation of eukaryotic phosphodiesterase, which was inhibited by the calmodulin antagonist trifluoperazine, and reaction with anti-bovine brain calmodulin antibodies. Consistent with the presence of nine acidic amino acids (16%) in M. smegmatis CAMLP, there is one putative calcium-binding domain in this CAMLP, compared to four such domains for eukaryotic calmodulin, reflecting the smaller molecular size (approximately 6 kDa) of M. smegmatis CAMLP. Ultracentrifugation and mass spectral studies excluded the possibility that calcium promotes oligomerization of purified M. smegmatis CAMLP. C1 Natl Inst Stand & Technol, Chem Sci & Technol Lab, Div Biotechnol, Bioproc Engn Grp, Gaithersburg, MD 20899 USA. NINDS, LCN, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Coll Med Sci, Dept Biochem, Delhi 110095, India. GTB Hosp, Delhi 110095, India. Univ Delhi, Sri Venkateswara Coll, Dept Biochem, New Delhi 110021, India. NR 42 TC 8 Z9 8 U1 0 U2 0 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 SEP PY 2003 VL 185 IS 17 BP 5263 EP 5268 DI 10.1128/JB.185.17.5263-5268.2003 PG 6 WC Microbiology SC Microbiology GA 713KK UT WOS:000184856600025 PM 12923099 ER PT J AU Xu, DQ Thompson, J Cisar, JO AF Xu, DQ Thompson, J Cisar, JO TI Genetic loci for coaggregation receptor polysaccharide biosynthesis in Streptococcus gordonii 38 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CELL-SURFACE POLYSACCHARIDE; VIRIDANS GROUP STREPTOCOCCI; DTDP-RHAMNOSE SYNTHESIS; GLCNAC C4 EPIMERASE; CAPSULAR POLYSACCHARIDE; FUNCTIONAL-ANALYSIS; ORAL STREPTOCOCCI; BIOCHEMICAL-CHARACTERIZATION; PNEUMONIAE SEROTYPE-14; ACTINOMYCES-VISCOSUS AB The cell wall polysaccharide of Streptococcus gordonii 38 functions as a coaggregation receptor for surface adhesins on other members of the oral biofilm community. The structure of this receptor polysaccharide (RPS) is defined by a heptasaccharide repeat that includes a GalNAcbeta1-->3Gal-containing recognition motif. The same R-PS has now been identified from S. gordonii AT, a partially sequenced strain. PCR primers designed from sequences in the genomic database of strain AT were used to identify and partially characterize the S. gordonii 38 RPS gene cluster. This cluster includes genes for seven putative glycosyltransferases, a polysaccharide polymerase (Wzy), an oligosaccharide repeating unit transporter (Wzx), and a galactofuranose mutase, the enzyme that promotes synthesis of UDP-Galf, one of five predicted RPS precursors. Genes outside this region were identified for the other four nucleotide-linked sugar precursors of RPS biosynthesis, namely, those for formation of UDP-Glc, UDP-Gal, UDP-GalNAc, and dTDP-Rha. Two genes for putative galactose 4-epimerases were identified. The first, designated galE1, was identified as a pseudogene in the galactose operon, and the second, designated galE2, was transcribed with three of the four genes for dTDP-Rha biosynthesis (i.e., rmlA, rmlC, and rmlB). Insertional inactivation of galE2 abolished (i) RPS production, (ii) growth on galactose, and (iii) both UDP-Gal and UDP-GalNAc 4-epimerase activities in cell extracts. Repair of the galE1 pseudogene in this galE2 mutant restored growth on galactose but not RPS production. Cell extracts containing functional GalE1 but not GalE2 contained UDP-Gal 4-epimerase but not UDP-GalNAc 4-epimerase activity. Thus, provision of both UDP-Gal and UDP-GalNAc for RPS production by S. gordonii 38 depends on the dual specificity of the epimerase encoded by galE2. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Cisar, JO (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 532,30 Convent Dr, Bethesda, MD 20892 USA. NR 56 TC 28 Z9 29 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2003 VL 185 IS 18 BP 5419 EP 5430 DI 10.1128/JB.185.18.5419-5430.2003 PG 12 WC Microbiology SC Microbiology GA 719AR UT WOS:000185181500011 PM 12949094 ER PT J AU Karev, GP Berezovskaya, FS AF Karev, GP Berezovskaya, FS TI Mathematical models for the "Schmalhgausent law" SO JOURNAL OF BIOLOGICAL SYSTEMS LA English DT Article DE power growth; self-similarity; Leslie-type model; self-thinning AB The empirical formula of growth (decrease) of biological objects, corresponding to polygonal line in double logarithmic scale is discussed. Leslie-type models producing solutions similar to some specific cases of this formula (including logistic-like curve) are studied. As an example, a model of tree stand self-thinning is derived and investigated; the model allows fitting empirical data with high accuracy. C1 Natl Inst Hlth, Bethesda, MD 20894 USA. Howard Univ, Dept Math, Washington, DC 20059 USA. RP Karev, GP (reprint author), Natl Inst Hlth, Bethesda, MD 20894 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA JOURNAL DEPT PO BOX 128 FARRER ROAD, SINGAPORE 912805, SINGAPORE SN 0218-3390 J9 J BIOL SYST JI J. Biol. Syst. PD SEP PY 2003 VL 11 IS 3 BP 245 EP 264 DI 10.1142/S0218339003000865 PG 20 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 732ZM UT WOS:000185975500003 ER PT J AU Cadet, ER Gafni, RI McCarthy, EF McCray, DR Bacher, JD Barnes, KM Baron, J AF Cadet, ER Gafni, RI McCarthy, EF McCray, DR Bacher, JD Barnes, KM Baron, J TI Mechanisms responsible for longitudinal growth of the cortex: Coalescence of trabecular bone into cortical bone SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID CULTURED PERIOSTEAL CELLS; OSTEOGENIC CAPACITY; IN-VITRO; DIFFERENTIATION; RABBITS; TISSUE; HISTOMORPHOMETRY; CHONDROGENESIS; EXPRESSION; AUTOGRAFTS AB Background: The purpose of the present study was to determine whether longitudinal growth of the cortex occurs through intramembranous bone formation involving the periosteum or through endochondral bone formation involving the growth plate and to explore the cellular and biochemical mechanisms responsible for this process. Methods: Cortical bone formation was studied in the metaphyses of growing New Zealand White rabbits by means of (1) oxytetracycline labeling and fluorescence microscopy, (2) computer-assisted histomorphometry, (3) osteoblast culture and [H-3]-thymidine incorporation in the presence of periosteum or periosteum-conditioned medium, and (4) surgical insertion of membranes between the periosteum and the underlying spongiosa. Results: Within the metaphyseal cortex, oxytetracycline labeling produced fluorescent closed curves outlining enlarging trabeculae derived from coalescing endochondral trabecular bone. In this region of coalescing trabeculae close to the periosteum, osteoblast surface was increased compared with trabeculae farther from the periosteum (p < 0.001). The osteoclast surface did not differ. In vitro, osteoblast proliferation was increased in the presence of periosteum (p < 0.001) or periosteum-conditioned medium (p < 0.001). Surgical insertion of permeable or impermeable membranes between the periosteum and the spongiosa did not prevent cortex formation. Conclusions: These observations demonstrate that metaphyseal cortical bone is formed by coalescence of endochondral trabecular bone. This coalescence is associated with increased osteoblast surface in the peripheral spongiosa. The increased osteoblast surface could be due to inductive effects of periosteum; in the present study, periosteum stimulated osteoblast proliferation in vitro but was not required for metaphyseal cortical bone formation in vivo. Clinical Relevance: Understanding metaphyseal cortical growth may help to elucidate the pathophysiology of osseous growth disorders in children. C1 New York Presbyterian Hosp, Columbia Presbyterian Med Ctr, Dept Orthopaed Surg, New York, NY 10032 USA. NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Ctr, Dept Pathol, Baltimore, MD 21231 USA. NICHHD, Unit Growth & Dev, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bone Histomorphometry Lab, Baltimore, MD USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Cadet, ER (reprint author), New York Presbyterian Hosp, Columbia Presbyterian Med Ctr, Dept Orthopaed Surg, 622 W 168th St,PH-11, New York, NY 10032 USA. NR 31 TC 38 Z9 38 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD SEP PY 2003 VL 85A IS 9 BP 1739 EP 1748 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 722XN UT WOS:000185403500013 PM 12954833 ER PT J AU Barsony, J Prufer, K AF Barsony, J Prufer, K TI Export of TR3 orphan nuclear receptor mediates rapid mitochondrial effects of vitamin D receptor Agonists and antagonists. 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