FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Evans, DL Charney, DS AF Evans, DL Charney, DS TI Mood disorders and medical illness: A major public health problem SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DEPRESSION; DISEASE; CANCER; WOMEN; RISK C1 Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. RP Evans, DL (reprint author), Univ Penn, Dept Psychiat, 3 Blockley Hall,423 Guardian Hall, Philadelphia, PA 19104 USA. NR 22 TC 78 Z9 80 U1 3 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 AUG 1 PY 2003 VL 54 IS 3 BP 177 EP 180 DI 10.1016/S0006-3323(03)00639-5 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 706KA UT WOS:000184451800001 PM 12893090 ER PT J AU Stover, E Fenton, W Rosenfeld, A Insel, TR AF Stover, E Fenton, W Rosenfeld, A Insel, TR TI Depression and comorbid medical illness: The National Institute of Mental Health Perspective SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID PSYCHOPATHOLOGY C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Stover, E (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 6217,MSC 9621, Bethesda, MD 20892 USA. NR 15 TC 17 Z9 17 U1 0 U2 1 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 AUG 1 PY 2003 VL 54 IS 3 BP 184 EP 186 DI 10.1016/S0006-3223(03)00272-5 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 706KA UT WOS:000184451800003 PM 12893092 ER PT J AU Kaufmann, PG AF Kaufmann, PG TI Depression in cardiovascular disease: Can the risk be reduced? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; PREVENTION PROJECT; CARDIAC MORTALITY; RANDOMIZED-TRIAL; MAJOR DEPRESSION; SYMPTOMS; STROKE; RECOVERY; HEALTH C1 NHLBI, Rockledge Ctr 2, NIH, Bethesda, MD 20892 USA. RP Kaufmann, PG (reprint author), NHLBI, Rockledge Ctr 2, NIH, 6701 Rockledge Dr,Room 8118, Bethesda, MD 20892 USA. NR 44 TC 4 Z9 4 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2003 VL 54 IS 3 BP 187 EP 190 DI 10.1016/S0006-3223(03)00545-6 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 706KA UT WOS:000184451800004 PM 12893093 ER PT J AU Croyle, RT Rowland, JH AF Croyle, RT Rowland, JH TI Mood disorders and cancer: A national cancer institute perspective SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID RISK C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,6138, Bethesda, MD 20892 USA. NR 11 TC 11 Z9 13 U1 0 U2 0 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 AUG 1 PY 2003 VL 54 IS 3 BP 191 EP 194 DI 10.1016/S006-3223(03)00427-X PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 706KA UT WOS:000184451800005 PM 12893094 ER PT J AU Weisdorf, DJ Hurd, D Carter, S Howe, C Jensen, LA Wagner, J Stablein, D Thompson, J Kernan, NA AF Weisdorf, DJ Hurd, D Carter, S Howe, C Jensen, LA Wagner, J Stablein, D Thompson, J Kernan, NA TI Prospective grading of graft-versus-host disease after unrelated donor marrow transplantation: A grading algorithm versus blinded expert panel review SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE graft-versus-host disease; bone marrow transplantation; grading; biopsy ID IBMTR SEVERITY INDEX; HEPATIC GRAFT; DIAGNOSIS; BIOPSY; SKIN; METHOTREXATE; CYCLOSPORINE; PROPHYLAXIS; RECIPIENTS; THERAPY AB In conjunction with a randomized trial of T-cell depletion versus conventional graft-versus-host disease (GVHD) prophylaxis, we assessed GVHD grading by comparing the transplant center 100-day score, a clinically calculated algorithm, and a blinded expert panel review (PR). Weekly skin, gut, and liver clinical staging; clinically verified differential diagnosis; biopsy information; cyclosporine levels; and initiation of treatment were reviewed and graded according to the consensus GVHD grading method modified by a prospectively determined grading algorithm that specified liver and gut downstaging if a differential diagnosis in that organ was identified. Transplant center (TC) determination of maximum grade was compared with the algorithm-calculated grade and the final expert PR. Of 404 patients reviewed, the TC grade concurred with the calculated algorithm grade in 72% (the algorithm upgraded 18% and downgraded 10%), whereas the TC grade agreed with the PR in 77% (the PR upgraded 12% and downgraded 11%). The calculated algorithm grade was nearly fully (92%) concordant with the final PR grade (the PR upgraded 0.7% and downgraded 7%). Blinded, duplicate reviews for quality control (n = 108) agreed with the initial review in 89% of cases. Algorithm and/or PR review reduced the TC-reported incidence of grade II (28% to 23%) and increased grade III (11% to 20%), whereas grade 0 (41% to 42%), grade I (13% to 12%), and grade IV (7% to 6%) were invariant. Recalculation of the algorithm grading without differential diagnosis downstaging reduced agreement with the TC to a small extent. The original algorithm changed 51 (13%) of 404 from grade 0 to II into grade III or IV or vice versa; calculation without the downgrade modified 44 cases (11%). Maximum acute GVHD grade had a major effect on 2-year disease-free survival, but assignment by TC, calculated algorithm, or final PR grade had little effect on survival within grades or grade categories 0 through II versus III or IV. We conclude that detailed and expert PR yields GVHD scoring that is internally consistent and reproducible with 89% concordance. Weekly recording of GVHD stage along with a calculated grading algorithm acknowledging differential diagnoses results in a final and maximum grade nearly fully concordant with the expert blinded PR. Multicenter prospective GVHD scoring using all available weekly staging and differential diagnosis data can be reliably assessed with a clinically relevant algorithm. This approach can thereby reduce investigator bias, facilitate comparison between centers, and perhaps eliminate the need for an expert PR. This technique should be used in future prospective studies of GVHD prophylaxis. (C) 2003 American Society for Blood and Marrow Transplantation. C1 Univ Minnesota, Minneapolis, MN 55455 USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. EMMES Corp, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. Univ Kentucky, Lexington, KY USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Mayo Mail Code 480,420 Delaware St SE, Minneapolis, MN 55455 USA. OI Kernan, Nancy/0000-0003-1417-1823 NR 28 TC 32 Z9 32 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2003 VL 9 IS 8 BP 512 EP 518 DI 10.1016/S1083-8791(03)00162-9 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 718VP UT WOS:000185167400005 PM 12931120 ER PT J AU Krieg, RC Paweletz, CP Liotta, LA Petricoin, EF AF Krieg, RC Paweletz, CP Liotta, LA Petricoin, EF TI Dilution of protein gel stain results in retention of staining capacity SO BIOTECHNIQUES LA English DT Article ID POLYACRYLAMIDE-GELS; ELECTROPHORESIS C1 NCI, Clin Proteom Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. RP Krieg, RC (reprint author), NCI, Clin Proteom Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 9 TC 9 Z9 11 U1 0 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2003 VL 35 IS 2 BP 376 EP + PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 711VV UT WOS:000184762500018 PM 12951779 ER PT J AU Woo, JH Neville, DM AF Woo, JH Neville, DM TI Separation of bivalent anti-T cell immunotoxin from Pichia pastoris glycoproteins by borate anion exchange SO BIOTECHNIQUES LA English DT Article ID SINGLE-CHAIN IMMUNOTOXIN; CAPILLARY-ELECTROPHORESIS; AFFINITY-CHROMATOGRAPHY; PAPER-ELECTROPHORESIS; GLYCOPEPTIDES; ACID; GLYCOASPARAGINES; PURIFICATION; CULTURES; BINDING AB A major problem encountered in the large-scale purification of the bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(G4S), from Pichia pastoris supernatants was the presence of host glycoproteins exhibiting similar charge, size, and hydrophobicity characteristics. We overcame this problem by employing borate anion exchange chromatography. The borate anion has an affinity for carbohydrates and imparts negative charges to these structures. We found that at a concentration of sodium borate between 50 and 100 mM, the nonglycosylated immunotoxin did not bind to Poros 50 HQ anion exchanger resin, but glycoproteins, including aggregates related to the immunotoxin, did. By using this property of the immunotoxin in the presence of sodium borate, we successfully developed a 3-step purification procedure: (i) Butyl-650M hydrophobic interaction chromatography, (ii) Poros 50 HQ anion exchange chromatography in the presence of borate, and (iii) HiTrap(TM) Q anion exchange chromatography. The final preparation exhibited a purity of greater than 98% and a yield of greater than 50% from the supernatant. Previously, boronic acid resins have been used to separate glycoproteins from proteins. However combining borate anion with conventional anion exchange resins accomplishes the separation of the immunotoxin from glycoproteins and eliminates the need to evaluate nonstandard resins with respect to good manufacturing practice guidelines. C1 NIMH, LMB, Bethesda, MD 20892 USA. RP Woo, JH (reprint author), NIMH, LMB, Bldg 36,Rm 1 B08,36 Convent Dr, Bethesda, MD 20892 USA. NR 21 TC 14 Z9 14 U1 1 U2 3 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2003 VL 35 IS 2 BP 392 EP 398 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 711VV UT WOS:000184762500021 PM 12951782 ER PT J AU McCauslin, CS Wine, J Cheng, LZ Klarmann, KD Candotti, F Clausen, PA Spence, SE Keller, JR AF McCauslin, CS Wine, J Cheng, LZ Klarmann, KD Candotti, F Clausen, PA Spence, SE Keller, JR TI In vivo retroviral gene transfer by direct intrafemoral injection results in correction of the SCID phenotype in Jak3 knock-out animals SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SEVERE COMBINED IMMUNODEFICIENCY; EX-VIVO; PROGENITOR CELLS; LYMPHOID-CELLS; JAK3-DEFICIENT MICE; MURINE MODEL; MARROW-CELLS; EXPRESSION; EFFICIENT AB Efficient retroviral gene transfer to pluripotential hematopoietic stem cells (PHSCs) requires ex vivo culture in multiple hematopoietic growth factors (HGFs) to promote cell division. While treatment of PHSCs with HGF can render stem cells viable targets for retroviral infection, HGFs can promote differentiation, loss of self-renewal potential, and affect the homing/engraftment capacity of PHSCs. To avoid the negative impacts observed with ex vivo transduction protocols, we developed a murine model for in vivo retroviral infection by direct intrafemoral injection (DII), thus abolishing the need for removal of cells from their native microenvironment and the signals necessary to maintain their unique physiology. Using this approach we have demonstrated in vivo retroviral gene transfer to colony-forming units-c (CFU-c), short-term reconstituting cells, and PHSCs. Moreover, direct intrafemoral injection of Jak3 knock-out mice with retroviral particles encoding the Jak3 gene resulted in reconstitution of normally deficient lymphocyte populations concomitant with improved immune function. In addition, DII can be used to target the delivery of other gene therapy vectors including adenoviral vectors to bone marrow cells in vivo. Taken together, these results demonstrate that in vivo retroviral gene transfer by direct intrafemoral injection may be a viable alternative to current ex vivo gene transfer approaches. C1 NCI, Basic Res Program, SAIC Frederick,Lab Expt Immunol, Lab Mol Immunoregulat,Ctr Canc Res, Frederick, MD 21702 USA. Johns Hopkins Univ, Sch Med, Div Immunol & Hematopoiesis, Baltimore, MD USA. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Marligen Biosci, Ijamsville, MD USA. RP Spence, SE (reprint author), NCI, Mouse Canc Genet Program, Bldg 549,Rm 219,POB B, Frederick, MD 21702 USA. NR 37 TC 20 Z9 22 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2003 VL 102 IS 3 BP 843 EP 848 DI 10.1182/blood-2002-12-3859 PG 6 WC Hematology SC Hematology GA 705LD UT WOS:000184395800025 PM 12689938 ER PT J AU Hinds, KA Hill, JM Shapiro, EM Laukkanen, MO Silva, AC Combs, CA Varney, TR Balaban, RS Koretsky, AP Dunbar, CE AF Hinds, KA Hill, JM Shapiro, EM Laukkanen, MO Silva, AC Combs, CA Varney, TR Balaban, RS Koretsky, AP Dunbar, CE TI Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells SO BLOOD LA English DT Article ID IN-VIVO TRACKING; MARROW-CELLS; CONTRAST AGENTS; MAMMALIAN-CELLS; T-CELLS; MIGRATION; MICE; RAT; DIFFERENTIATE; TRAFFICKING AB Tracking transplanted stem cells using magnetic resonance imaging (MRI) could offer biologic insight into homing and engraftment. Ultrasmall dextran-coated iron oxide particles have previously been developed for uptake into cells to allow MRI tracking. We describe a new application of much larger, micron-scale, iron oxide magnetic particles with enhanced MR susceptibility, which enables detection of single cells at resolutions that can be achieved in vivo. In addition, these larger particles possess a fluorophore for histologic confirmation of cell distribution. We demonstrate highly efficient, nontoxic, endosomal uptake of these particles into hematopoietic CD34(+) cells and mesenchymal stem cells documented by confocal and electron microscopy. Labeled cells retain biologic activity with preservation of colony-forming ability and differentiation capacity. MRI studies could detect labeled CD34(+) cells and mesenchymal stem cells (MSCs) at single cell resolution. This appears to be a promising tool for serial noninvasive monitoring of in vivo cell homing and localization using MRI. C1 NHLBI, Hematol Branch, Mol Biol Lab, Lab Cardiac Energet,NIH, Bethesda, MD 20892 USA. NHLBI, Light Microscopy core Facil, NIH, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Osiris Therapeut, Baltimore, MD USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Silva, Afonso/A-7129-2009; Balaban, Robert/A-7459-2009; Koretsky, Alan/C-7940-2015 OI Balaban, Robert/0000-0003-4086-0948; Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01] NR 31 TC 295 Z9 311 U1 4 U2 24 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 AUG 1 PY 2003 VL 102 IS 3 BP 867 EP 872 DI 10.1182/blood-2002-12-3669 PG 6 WC Hematology SC Hematology GA 705LD UT WOS:000184395800028 PM 12676779 ER PT J AU Yamaguchi, H Baerlocher, GM Lansdorp, PM Chanock, SJ Nunez, O Sloand, E Young, NS AF Yamaguchi, H Baerlocher, GM Lansdorp, PM Chanock, SJ Nunez, O Sloand, E Young, NS TI Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome SO BLOOD LA English DT Article ID LINKED DYSKERATOSIS-CONGENITA; FLOW-CYTOMETRY; LENGTH; DISEASE; SUBPOPULATIONS; COMPONENT AB Mutations in the. human telomerase RNA (TERC) occur in autosomal dominant dyskeratosis congenita (DKC). Because of the possibility that TERC mutations might underlie seemingly acquired forms of bone marrow failure, we examined blood samples from a large number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS). Only 3 of 210 cases showed heterozygous TERC mutations: both nucleotide 305 (n305) (G>A) and n322 (G>A) were within the conserved region (CR) 4-CR5 domain; n450 (G>A) was localized to the boxH/ACA domain. However, only one patient (with a mutation at n305 [G>A]) had clinical characteristics suggesting DKC; her blood cells contained short telomeres and her sister also suffered from bone marrow failure. Another 21 patients with short telomeres did not show TERC mutations. Our results suggest that cryptic DKC, at least secondary to mutations in the TERC gene, is an improbable diagnosis in patients with otherwise typical AA, PNH, and MDS. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. British Columbia Canc Res Ctr, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Univ British Columbia, Dept Med, Vancouver, BC, Canada. NCI, Sect Genom Variat, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,MSC 1652, Bethesda, MD 20892 USA. NR 25 TC 164 Z9 174 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 AUG 1 PY 2003 VL 102 IS 3 BP 916 EP 918 DI 10.1182/blood-2003-01-0335 PG 3 WC Hematology SC Hematology GA 705LD UT WOS:000184395800034 PM 12676774 ER PT J AU Chen, L Li, D Li, CL Engel, A Deng, CX AF Chen, L Li, D Li, CL Engel, A Deng, CX TI A Ser250Trp substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis SO BONE LA English DT Article DE Fgfr2; intramembraneous ossification; coronal suture; proliferation; apoptosis; Apert syndrome ID APERT-SYNDROME; OSTEOBLAST DIFFERENTIATION; CLEIDOCRANIAL DYSPLASIA; LIMB DEVELOPMENT; MUTATIONS; CBFA1; MICE; ACHONDROPLASIA; PROLIFERATION; CALVARIA AB Apert syndrome (AS) is one of the most severe craniosynostoses and is characterized by premature fusion of craniofacial sutures. Mutations of either Ser252Trp or Pro253Arg in fibroblast growth factor receptor 2 (FGFR2) are responsible for nearly all known cases of AS. Here we show that mutant mice carrying the activation mutation, Ser250Trp, which corresponds to Ser252Trp in human FGFR2, have malformations mimicking the skull abnormalities found in AS patients. Mutant mice (Fgfr2(250/+)) are smaller in body size with brachycephaly and exhibit distorted skulls with widely spaced eyes. Unexpectedly, the premature closure of the coronal suture is accompanied by decreased, rather than increased, bone formation. We demonstrate that the Fgfr2-Ser250Trp mutation does not cause obvious alterations in cell proliferation and differentiation; however, it results in increased Bax expression and apoptosis of osteogenic cells in mutant coronal suture. The accelerated cell death possibly reduces the space between osteogenic fronts of flat bones and results in the physical contact of these bones. Thus, our data reveal that dysregulated apoptosis plays an important role in the pathogenesis of AS related phenotypes. (C) 2003 Elsevier Inc. All rights reserved. C1 NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 56 TC 82 Z9 97 U1 0 U2 3 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 AUG PY 2003 VL 33 IS 2 BP 169 EP 178 DI 10.1016/S8756-3282(02)00222-9 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 726VC UT WOS:000185621000001 PM 14499350 ER PT J AU Fujiwara, H Sconocchia, G Melenhorst, J Eniafe, R Nakamura, R Hensel, N Barrett, AJ AF Fujiwara, H Sconocchia, G Melenhorst, J Eniafe, R Nakamura, R Hensel, N Barrett, AJ TI Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator-responder pairs SO BONE MARROW TRANSPLANTATION LA English DT Article DE leukemia-restriction; cytotoxic T-lymphocytes; HLA-mismatched; stem cell transplant ID BONE-MARROW TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; GRAFT-VERSUS-HOST; CLASS-I MOLECULES; IMMUNE RECONSTITUTION; IDENTICAL SIBLINGS; RELAPSED LEUKEMIA; PROGENITOR CELLS; LYMPHOCYTES; ANTIGENS AB Exploiting the graft-versus-leukemia (GVL) effect in mismatched transplants requires its separation from graft-versus-host disease (GVHD). We generated leukemia-specific cytotoxic T lymphocytes (CTL) in three haplotype-mismatched, two class I-mismatched and two single HLA-A locus-matched stimulator-responder pairs. Six patients with chronic myelogenous leukemia and one patient with acute myeloid leukemia transformed from MDS were studied. CTL generated after 10 days stimulation with unselected leukemic peripheral blood mononuclear cells inhibited leukemic CFU-GM colony growth (>85% at 10:1 effector:target ratio) with no third-party colony inhibition. In five pairs, responders were cultured separately with leukemia cells, PHA-B or LCL from the stimulator. After 2-4 restimulations, the T cell repertoire was examined by flow analysis using Vbeta-specific antibodies. Test cultures (but not controls) showed preferential expansion of 1-4 Vbeta families either common to two or more stimulators or unique to a particular stimulator. Notably, we elicited leukemia-specific TCR Vbeta expansions on four out of five occasions. In two pairs, responder cells selected for the appropriate leukemia-specific Vbeta family were shown to have leukemia-specific cytotoxicity. These leukemia-restricted T-cells were CD8+ or CD4+ and CD25+ or CD57+. The results support the development of strategies to selectively deplete GVHD and conserve GVL reactivity in mismatched transplants. C1 NHLBI, Allogene Stem Cell Transplant Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Allogene Stem Cell Transplant Sect, Hematol Branch, NIH, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 9 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2003 VL 32 IS 4 BP 371 EP 378 DI 10.1038/sj.bmt.1704142 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 708DB UT WOS:000184550900004 PM 12900773 ER PT J AU Moore, JJ Snowden, J Pavletic, S Barr, W Burt, R AF Moore, JJ Snowden, J Pavletic, S Barr, W Burt, R TI Hematopoietic stem cell transplantation for severe rheumatoid arthritis SO BONE MARROW TRANSPLANTATION LA English DT Article; Proceedings Paper CT Conference on Stem Cells for Tolerance and Tissue Regeneration CY JUN 06-08, 2002 CL SNOWBIRD, UTAH DE rheumatoid arthritis; hematopoietic stem cell transplantation ID BONE-MARROW-TRANSPLANTATION; COLONY-STIMULATING FACTOR; HIGH-DOSE CHEMOTHERAPY; AUTOIMMUNE-DISEASE; MOBILIZATION; EFFICACY; BLOOD; CYCLOPHOSPHAMIDE; ESCALATION; PLACEBO AB The substantial morbidity and mortality associated with rheumatoid arthritis (RA), while not widely appreciated, provide adequate justification for consideration of high-dose immunoablative therapy followed by hematopoietic stem cell transplantation. While some patients with RA follow a benign course, selected subsets of patients have been identified with 5-year survival rates of 40-70%. A number of factors that can be easily determined serve as useful prognostic indicators for poor outcome. These include the presence of many involved joints (total joint count), the degree of functional disability as measured by the health assessment questionnaire and the presence of rheumatoid factor. This article summarises the present status of hematopoietic stem cell transplantation for rheumatoid arthritis and proposes future directions for research. C1 St Vincents Hosp, Dept Haematol, Sydney, NSW 2010, Australia. Royal Hallamshire Hosp, Sheffield S10 2JF, S Yorkshire, England. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Med Ctr, Chicago, IL 60611 USA. RP Moore, JJ (reprint author), St Vincents Hosp, Dept Haematol, Sydney, NSW 2010, Australia. NR 23 TC 6 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2003 VL 32 SU 1 BP S53 EP S56 DI 10.1038/sj.bmt.1703944 PG 4 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 724XR UT WOS:000185514000014 PM 12931243 ER PT J AU Muraro, PA Martin, R AF Muraro, PA Martin, R TI Immunological questions on hematopoietic stem cell transplantation for multiple sclerosis SO BONE MARROW TRANSPLANTATION LA English DT Article; Proceedings Paper CT Conference on Stem Cells for Tolerance and Tissue Regeneration CY JUN 06-08, 2002 CL SNOWBIRD, UTAH DE multiple sclerosis; stem cells; hematopoietic stem cell transplantation ID BASIC-PROTEIN PEPTIDE; MRI ACTIVITY; BONE-MARROW; DISEASE; MS; LESIONS; NEURONS; BLOOD; REPERTOIRE AB Multiple sclerosis (MS) is considered an inflammatory autoimmune disorder. Approved immunotherapies are only moderately effective in reducing disease exacerbations and brain inflammation in a subset of patients. Autologous hematopoietic stem cell transplantation (HSCT) has emerged in recent years as the first opportunity to offer to patients a radical, potentially curative treatment. Here, we will summarize key immunopathological aspects of MS and discuss important questions that need to be addressed to clarify the therapeutic role and mechanism of action of HSCT in this disorder. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Muraro, PA (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr MSC1400, Bethesda, MD 20892 USA. OI Muraro, Paolo/0000-0002-3822-1218 NR 24 TC 6 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2003 VL 32 SU 1 BP S41 EP S44 DI 10.1038/sj.bmt.1704096 PG 4 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 724XR UT WOS:000185514000011 PM 12931240 ER PT J AU Bagnato, F Jeffries, N Richert, ND Stone, RD Ohayon, JM McFarland, HF Frank, JA AF Bagnato, F Jeffries, N Richert, ND Stone, RD Ohayon, JM McFarland, HF Frank, JA TI Evolution of T-1 black holes in patients with multiple sclerosis imaged monthly for 4 years SO BRAIN LA English DT Article DE axonal loss; black holes; inflammatory activity; MRI; multiple sclerosis ID MAGNETIC-RESONANCE SPECTROSCOPY; SECONDARY PROGRESSIVE MS; T1-WEIGHTED SPIN-ECHO; HYPOINTENSE LESIONS; DISEASE-ACTIVITY; CLINICAL-TRIALS; ENHANCING LESIONS; CEREBRAL ATROPHY; IMAGING LESIONS; TRANSFER MR AB T-1 black holes (BHs) on MRIs may represent either areas of oedema or axonal loss in patients with multiple sclerosis. BHs begin as contrast enhancing lesions (CELs) and evolve differently from patient to patient, and within the same patient over time. We analysed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated multiple sclerosis patients were evaluated for numbers of CELs and BHs. A BH was defined as a hypointense lesion on a T-1 pre-constrast image that coincided with a region of high signal intensity on the T-2-weighted images. A BH was considered as acute (ABH) when it occurred coincidently with the presence of enhancement and as persisting (PBH) when present after the cessation of enhancement. The present study aimed to analyse: (i) the incidence of CELs and new PBHs, and the accumulation of PBHs; (ii) the relationship between the quantity of the CELs in a given month and the likelihood of accumulating PBHs in the subsequent month; and (iii) the relationship between the duration of CELs and PBHs. Pitman's correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs, while a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model. The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an isointense lesion was analysed using Kaplan-Meier survival models. PBHs accumulated (P<0.001) in all patients, but the formation of new PBHs increased in four patients (Pless than or equal to0.007) in conjunction with an increase in either the quantity of CELs (P<0.001, for two patients) or the proportion of CELs turning into PBHs (Pless than or equal to0.02, for two patients). Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH. The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P<0.002) than those preceded by CELs visible on greater than or equal to2 monthly MRIs. The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement. C1 Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr MSC 1400, Bethesda, MD 20892 USA. NR 36 TC 94 Z9 94 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2003 VL 126 BP 1782 EP 1789 DI 10.1093/brain/awg182 PN 8 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 705GB UT WOS:000184386400007 PM 12821527 ER PT J AU Schmidt, J Metselaar, JM Wauben, MHM Toyka, KV Storm, G Gold, R AF Schmidt, J Metselaar, JM Wauben, MHM Toyka, KV Storm, G Gold, R TI Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis SO BRAIN LA English DT Article DE autoimmunity; neuroinflammatory diseases; long-circulating steroid liposomes; glucocorticosteroid pulse therapy; experimental autoimmune encephalomyelitis ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; STERICALLY STABILIZED LIPOSOMES; SCINTIGRAPHIC DETECTION; IN-SITU; METHYLPREDNISOLONE; INFLAMMATION; APOPTOSIS; LOCALIZATION; ACCUMULATION AB High-dose glucocorticosteroid hormones are a mainstay in the treatment of relapses in multiple sclerosis. We searched for a way to deliver ultra high doses of glucocorticosteroids to the CNS of rats with experimental autoimmune encephalomyelitis (EAE) using a novel formulation of polyethylene glycol (PEG)-coated long-circulating liposomes encapsulating prednisolone (prednisolone liposomes, PL). H-3-labelled PL showed selective targeting to the inflamed CNS, where up to 4.5-fold higher radioactivity was achieved than in healthy control animals. HPLC revealed much higher and more persistent levels of prednisolone in spinal cord after PL compared with an equal dose of free prednisolone. Gold-labelled liposomes could be detected in the target tissue, mostly taken up by macrophages (Mphi), microglial cells and astrocytes. Blood-brain barrier disruption was greatly reduced by 10 mg/kg PL, which was superior to a 5-fold higher dose of free methylprednisolone (MP). PL was also superior to MP in diminishing T-cell infiltration by induction of T-cell apoptosis in spinal cord. Mphi infiltration was clearly decreased only by PL. The percentage of tumour necrosis factor-alpha (TNF-alpha)-positive T cells or Mphi was greatly reduced by PL and by MP. No adverse effects on glial cells were detected. A single injection of PL clearly ameliorated the course of adoptive transfer EAE and EAE induced by immunization. In conclusion, PL is a highly effective drug in treatment of EAE, and is superior to a 5-fold higher dose of free MP, possibly by means of drug targeting. These findings may have implications for future therapy of autoimmune disorders such as multiple sclerosis. C1 Univ Wurzburg, Dept Neurol, Clin Res Grp Multiple Sclerosis, D-8700 Wurzburg, Germany. Univ Utrecht, Fac Vet Med, Dept Pharmaceut, Utrecht, Netherlands. Univ Utrecht, Fac Vet Med, Dept Immunol & Infect Dis, Div Immunol, Utrecht, Netherlands. RP Schmidt, J (reprint author), NINDS, NIH, Neuromuscular Dis Sect, Bldg 10,Room 4N 248,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. RI Schmidt, Jens/B-5791-2013; Storm, Gert/O-8696-2016 NR 31 TC 116 Z9 120 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2003 VL 126 BP 1895 EP 1904 DI 10.1093/brain/awg176 PN 8 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 705GB UT WOS:000184386400018 PM 12805101 ER PT J AU Hirose, S Mohney, RP Okada, M Kaneko, S Mitsudome, A AF Hirose, S Mohney, RP Okada, M Kaneko, S Mitsudome, A TI The genetics of febrile seizures and related epilepsy syndromes SO BRAIN & DEVELOPMENT LA English DT Review DE autosomal dominant epilepsy with febrile seizures plus; generalized epilepsy with febrile seizures plus; ion channel; genetics; channelopathy; epilepsy ID FRONTAL-LOBE EPILEPSY; FAMILIAL NEONATAL CONVULSIONS; SEVERE MYOCLONIC EPILEPSY; RECEPTOR ALPHA-4 SUBUNIT; NEURONAL SODIUM-CHANNEL; GENERALIZED EPILEPSY; ACETYLCHOLINE-RECEPTOR; HUMAN BRAIN; HIPPOCAMPAL-NEURONS; HEMIPLEGIC MIGRAINE AB Febrile seizures (FS) may represent the most common seizure disorder in childhood and are known to be associated with putative genetic predispositions. Nevertheless, molecular genetic approaches toward understanding FS have been just initiated this decade. Recently, several genetic loci for FS have been mapped thereby assuring the genetic heterogeneity of FS. However, the exact molecular mechanisms of FS are yet to be elucidated. Genetic defects have been recently identified in autosomal dominant epilepsy with FS plus or generalized epilepsy with FS plus. The underlying mutations were found in genes encoding several Na+ channel subunits and the gamma2 subunit of gamma amino-butyric acid (GABA)A receptors in the brain. Furthermore, both channels are also associated with severe myoclonic epilepsy in infancy, where the seizure attacks often begin with prolonged FS and are precipitated by fever even afterwards. Na+ channels are associated with other temperature-sensitive disorders, and GABA(A) receptors are known to play an important role in the pathogenesis of FS. These lines of evidence suggest the involvement of various Na+ channels, GABA(A) receptors and additional auxiliary proteins in the pathogenesis of frequent FS and even in simple FS. This hypothesis may facilitate our understanding of the genetic background of FS. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Fukuoka Univ, Sch Med, Dept Pediat, Jonan Ku, Fukuoka 8140180, Japan. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Hirosaki Univ, Sch Med, Dept Neuropsychiat, Hirosaki, Aomori 0368562, Japan. RP Hirose, S (reprint author), Fukuoka Univ, Sch Med, Dept Pediat, Jonan Ku, 45-1,7-Chome Nanakuma, Fukuoka 8140180, Japan. NR 77 TC 29 Z9 34 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0387-7604 J9 BRAIN DEV-JPN JI Brain Dev. PD AUG PY 2003 VL 25 IS 5 BP 304 EP 312 DI 10.1016/S0387-7604(03)00026-3 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 703YE UT WOS:000184309900003 PM 12850508 ER PT J AU Qu, Y Chang, L Klaff, J Seeman, R Balbo, A Rapoport, SI AF Qu, Y Chang, L Klaff, J Seeman, R Balbo, A Rapoport, SI TI Imaging of brain serotonergic neurotransmission involving phospholipase A(2) activation and arachidonic acid release in unanesthetized rats SO BRAIN RESEARCH PROTOCOLS LA English DT Article DE phospholipase A(2); serotonin; arachidonic; imaging; quantitative autoradiography; signal transduction ID POSITRON-EMISSION-TOMOGRAPHY; SIGNAL-TRANSDUCTION; CHOLINERGIC STIMULATION; AWAKE RATS; RECEPTOR; TURNOVER AB In vitro studies have shown that 5-HT2 receptors can be coupled via G-proteins to phospholipase A(2) (PLA(2)) activation, releasing arachidonic acid from phospholipids. To examine this signaling pathway in brain, we developed an in vivo method to image regional brain PLA(2) activation in unanesthetized rats given different types of serotonergic drugs. Increased arachidonate incorporation from plasma, in response to drug-induced PLA(2)-activation, can be quantified with autoradiography, following the intravenous injection of radiolabeled arachidonate. For example, a 5-HT2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane, produced widespread increases in incorporation of labeled arachidonate by directly binding to 5-HT2A/2C receptors. Fluoxetine, a selective serotonin reuptake inhibitor, selectively increased incorporation of arachidonic acid by increasing 5-HT availability in the synaptic cleft and thus indirectly activating phospholipase A(2) The detailed method is described. (C) 2003 Elsevier B.V. All rights reserved. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Qu, Y (reprint author), Johnson & Johnson Pharmaceut Res & Dev, 3210 Merryfield Row, San Diego, CA 92130 USA. NR 18 TC 6 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1385-299X J9 BRAIN RES PROTOC JI Brain Res. Protoc. PD AUG PY 2003 VL 12 IS 1 BP 16 EP 25 DI 10.1016/S1385-299X(03)00057-6 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 724RV UT WOS:000185501300003 PM 12928041 ER PT J AU Yamada, KM Pankov, R Cukierman, E AF Yamada, KM Pankov, R Cukierman, E TI Dimensions and dynamics in integrin function SO BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH LA English DT Article; Proceedings Paper CT International Symposium on Extracellular Matrix (SIMEC 2002) CY OCT 07-10, 2002 CL ANGRA REIS, BRAZIL DE extracellular matrix; cell adhesion; integrin fibronectin; signal transductlon; migration ID CELL-MATRIX ADHESIONS; GREEN FLUORESCENT PROTEIN; EXTRACELLULAR-MATRIX; FIBRONECTIN MATRIX; COLLAGENASE-3 MMP-13; SIGNAL-TRANSDUCTION; GROWTH; FIBROBLASTS; CONTRACTION; EXPRESSION AB Integrins play crucial roles in cell adhesion, migration, and signaling by providing transmembrane links between the extracellular matrix and the cytoskeleton. Integrins cluster in macromolecular complexes to generate cell-matrix adhesions such as focal adhesions. In this mini-review, we compare certain integrin-based biological responses and signaling during cell interactions with standard 2D cell culture versus 3D matrices. Besides responding to the composition of the matrix, cells sense and react to physical properties that include three-dimensionality and rigidity. In routine cell culture, fibroblasts and mesenchymal cells appear to use focal adhesions as anchors. They then use intracellular actomyosin contractility and dynamic, directional integrin movements to stretch cell-surface fibronectin and to generate characteristic long fibrils of fibronectin in "fibrillar adhesions". Some cells in culture proceed to produce dense, three-dimensional matrices similar to in vivo matrix, as opposed to the flat, rigid, two-dimensional surfaces habitually used for cell culture. Cells within such more natural 3D matrices form a distinctive class of adhesion termed "3D-matrix adhesions". These 3D adhesions show distinctive morphology and molecular composition. Their formation is heavily dependent on interactions between integrin alpha(5)beta(1), and fibronectin. Cells adhere much more rapidly to 3D matrices. They also show more rapid morphological changes, migration, and proliferation compared to most 2D matrices or 3D collagen gels. Particularly notable are low levels of tyrosine phosphorylation of focal adhesion kinase and moderate increases in activated mitogen-activated protein kinase. These findings underscore the importance of the dimensionality and dynamics of matrix substrates in cellular responses to the extracellular matrix. C1 NIDCR, CDBRB, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA USA. RP Yamada, KM (reprint author), NIDCR, CDBRB, NIH, Bldg 30,Rm 421,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. RI Pankov, Roumen/B-3284-2014; OI Pankov, Roumen/0000-0002-3157-3659; Yamada, Kenneth/0000-0003-1512-6805 NR 59 TC 115 Z9 117 U1 2 U2 16 PU ASSOC BRAS DIVULG CIENTIFICA PI SAO PAULO PA FACULDADE MEDICINA, SALA 21, 14049 RIBEIRAO PRETO, SAO PAULO, BRAZIL SN 0100-879X J9 BRAZ J MED BIOL RES JI Brazilian J. Med. Biol. Res. PD AUG PY 2003 VL 36 IS 8 BP 959 EP 966 PG 8 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA 716DE UT WOS:000185012900002 PM 12886449 ER PT J AU Lalonde, FM Myslobodsky, M AF Lalonde, FM Myslobodsky, M TI Are dopamine antagonists a risk factor for breast cancer? An answer from Parkinson's disease SO BREAST LA English DT Article DE breast cancer; Parkinson's disease; prolactin; malignancies; depression; epidemiology; dopamine antagonists ID DEPRESSED MOOD; PROLACTIN; GROWTH; HYPERPROLACTINEMIA; STRESS AB Women undergoing chemotherapy for breast cancer are often administered dopamine antagonist adjuvant medications that may increase levels of prolactin potentially increasing the risk of cancer. Using nationwide computerized registers of death data for the years 1991 through 1996 we examined 12,430,473 deaths of persons over 40 years of age and extracted 144,364 cases with Parkinson's disease (PD), a dopamine deficient population. Patients with PD had lower rates of breast and other types of malignancies, even in the presence of depression and suicide. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Myslobodsky, M (reprint author), NIMH, Geriatr Psychiat Branch, NIH, 10 Ctr Dr 4S-235,MSC 1379, Bethesda, MD 20892 USA. NR 21 TC 10 Z9 11 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD AUG PY 2003 VL 12 IS 4 BP 280 EP 282 DI 10.1016/S0960-9776(03)00061-4 PG 3 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 707KC UT WOS:000184509000008 PM 14659314 ER PT J AU Fruehauf, S Seggewiss, R AF Fruehauf, S Seggewiss, R TI It's moving day: Factors affecting peripheral blood stem mobilization and strategies for improvement SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE peripheral blood stem cells; mobilization; transplantation; new agents; AMD-3100 ID COLONY-STIMULATING FACTOR; HEMATOPOIETIC PROGENITOR CELLS; NON-HODGKINS-LYMPHOMA; RECOMBINANT HUMAN GRANULOCYTE; STEADY-STATE HEMATOPOIESIS; MULTIPLE-MYELOMA PATIENTS; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; CSF-SUPPORTED CHEMOTHERAPY; HIGH-DOSE CYCLOPHOSPHAMIDE; FACTOR RHG-CSF C1 Univ Heidelberg, Dept Internal Med 5, D-69115 Heidelberg, Germany. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Fruehauf, S (reprint author), Univ Heidelberg, Dept Internal Med 5, Hosp Str 3, D-69115 Heidelberg, Germany. NR 161 TC 60 Z9 64 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 AUG PY 2003 VL 122 IS 3 BP 360 EP 375 DI 10.1046/j.1365-2141.2003.04483.x PG 16 WC Hematology SC Hematology GA 704NP UT WOS:000184346000002 PM 12877663 ER PT J AU Byrne, KM Leitman, SF Schechter, AN Stroncek, DF AF Byrne, KM Leitman, SF Schechter, AN Stroncek, DF TI Increasing oxygen tension improves filtration of sickle trait donor blood SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell trait; red blood cells; leucocyte-reduced red blood cells; Hb oxygen saturation ID CELL-DISEASE; POLYMERIZATION; COMPONENTS; REDUCTION AB A major cause of filter failure of red cell (RBC) components from donors with sickle cell trait (HbAS) is the polymerization of haemoglobin. The oxygen saturation (sO(2) ) of blood stored in various plastics and different volumes of air was assessed. Blood from 10 HbAS donors was collected and divided into two bags, one with air added, one without. Bags with added air had increased sO(2) levels (from 49 +/- 10% to 76 +/- 6%). Filtration was successful for nine of 10 components with air, and one of 10 without air. Successful filtration of RBC components occurs when sO(2) is increased. C1 NIDDKD, Dept Transfus Med, NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Byrne, KM (reprint author), NIDDKD, Dept Transfus Med, NIH, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711,10 Ctr Dr,MSC-1184, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 11 TC 7 Z9 7 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 AUG PY 2003 VL 122 IS 4 BP 678 EP 681 DI 10.1046/j.1365-2141.2003.04464.x PG 4 WC Hematology SC Hematology GA 708NC UT WOS:000184573300017 PM 12899724 ER PT J AU Ciulla, TA Criswell, MH Danis, RP Fronheiser, M Yuan, P Cox, TA Csaky, KG Robinson, MR AF Ciulla, TA Criswell, MH Danis, RP Fronheiser, M Yuan, P Cox, TA Csaky, KG Robinson, MR TI Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; EXUDATIVE MACULAR DEGENERATION; INTRAVITREAL TRIAMCINOLONE; MESSENGER-RNA; EXPRESSION; STEROIDS AB Aim: To determine if intravitreal microimplants containing triamcinolone acetonide ( TAAC) inhibit experimental fibrovascular proliferation ( FVP) induced by laser trauma in a rat as a model of choroidal neovascular membranes (CNVMs). Methods: 20 anaesthetised male Brown Norway rats received a series of eight krypton red laser lesions per eye (647 nm, 0.05 s, 50 mum, 150 mW). Three types of sterilised TAAC microimplant designs were evaluated: implant A consisting of 8.62% TAAC/20% polyvinyl alcohol (PVA) matrix ( by dry weight); implant B consisting of 3.62% TAAC/20% PVA matrix; and implant C consisting of a dual 8.62% TAAC/20% PVA matrix design combined with a central core (0.5 mm) of compressed TAAC to extend the implant release time. For each animal studied, one eye received one of the three aforementioned TAAC implant designs, while the fellow eye received a control implant consisting of PVA but without TAAC. The animals were sacrificed at day 35 and ocular tissues were processed for histological analysis. Serial histological specimens were methodically assessed in a masked fashion to analyse each laser lesion for the presence or absence of FVP; maximum FVP thickness for each lesion was measured from the choriocapillaris. Results: All three types of TAAC implants inhibited FVP relative to controls in a statistically significant fashion. In the eyes that received implant A (n = 8), the mean thickness of the recovered lesions ( n = 36) measured 32 (SD 22) mum, compared to 52 ( 30) mum ( p < 0.005) for the recovered lesions ( n = 40) from the fellow control eyes. In the eyes that received implant B ( n = 6), the mean thickness of the recovered lesions ( n = 31) measured 28 ( 15) μm, compared to 50 ( 29) μm ( p < 0.001) for the lesions ( n = 19) recovered from the fellow control eyes. In the eyes that received implant C ( n = 6), the mean thickness of the recovered lesions ( n = 21) measured 39 ( 24) mum, compared to 65 ( 30) mum ( p < 0.001) for the lesions ( n = 39) recovered from the fellow control eyes. Conclusions: All three of the tested TAAC microimplant designs produced potent inhibition of FVP in a rat model of CNVMs. There were no differences in inhibition of FVP between the three different types of implants evaluated. This study provides evidence that: ( 1) corroborates previous investigations that propose TAAC as a potential treatment for CNVMs in humans, and ( 2) demonstrates TAAC can be effectively delivered via long acting sustained release intraocular microimplants. It should be noted, however, that the FVP observed in this rat laser trauma may not reflect the CNVM observed in human with exudative age related macular degeneration (AMD). C1 Indiana Univ, Dept Ophthalmol, Sch Med, Retina Serv,Res Labs, Indianapolis, IN 46260 USA. NIH, Bioengn & Phys Sci Div, ORS, Bethesda, MD 20892 USA. NIH, Dept Pharm, Ctr Clin, Bethesda, MD USA. NEI, NIH, Bethesda, MD 20892 USA. RP Ciulla, TA (reprint author), Indiana Univ, Dept Ophthalmol, Sch Med, Retina Serv,Res Labs, 702 Rotary Circle, Indianapolis, IN 46260 USA. NR 31 TC 52 Z9 61 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 AUG PY 2003 VL 87 IS 8 BP 1032 EP 1037 DI 10.1136/bjo.87.8.1032 PG 6 WC Ophthalmology SC Ophthalmology GA 704NU UT WOS:000184346400026 PM 12881350 ER PT J AU Barbieri, M Bregola, G Buzzi, A Marino, S Zucchini, S Stables, JP Bergamaschi, M Pietra, C Villetti, G Simonato, M AF Barbieri, M Bregola, G Buzzi, A Marino, S Zucchini, S Stables, JP Bergamaschi, M Pietra, C Villetti, G Simonato, M TI Mechanisms of action of CHF3381 in the forebrain SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE CHF3381; N-methyl-D-aspartate (NMDA); NA(+) channel; glutamate; hippocampus; cortex ID FOS MESSENGER-RNA; ANTICONVULSANT DRUGS DIPHENYLHYDANTOIN; SENSITIVE SODIUM-CHANNELS; CENTRAL-NERVOUS-SYSTEM; NEURO-BLASTOMA CELLS; C-FOS; PATCH-CLAMP; RAT-BRAIN; EXPRESSION; NMDA AB 1 Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. 2 CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly -80% of the NMDA-evoked current, with EC50 of approximately 5 muM. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. 3 CHF3381 also inhibited voltage-gated Na+ currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 muM). 4 Consistent with the mild effects on voltage-gated Na+ channels, CHF3381 (100 muM) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anticonvulsant agent and Na+ channel blocker lamotrigine (100 muM) inhibited stimulation-evoked glutamate overflow by approximately 50%. 5 CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. 6 The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation. C1 Univ Ferrara, Dept Clin & Expt Med, Pharmacol Sect, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Neurosci, I-44100 Ferrara, Italy. NINDS, Epilepsy Branch, Preclin Pharmacol Serv, Bethesda, MD 20892 USA. Chiesi Farmaceutici Spa, R&D Dept, I-43100 Parma, Italy. RP Simonato, M (reprint author), Univ Ferrara, Dipartimento Med Clin & Sperimentale, Sez Farmacol, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. NR 27 TC 7 Z9 7 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 AUG PY 2003 VL 139 IS 7 BP 1333 EP 1341 DI 10.1038/sj.bjp.0705381 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 708EB UT WOS:000184553200012 PM 12890713 ER PT J AU Inskip, PD AF Inskip, PD TI Multiple primary tumors involving cancer of the brain and central nervous system as the first or subsequent cancer SO CANCER LA English DT Article DE brain cancer; multiple primary tumors; radiotherapy; epidemiology; Surveillance; Epidemiology, and End Results (SEER) registries ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CUTANEOUS MALIGNANT-MELANOMA; SALIVARY-GLAND TUMORS; THYROID-CANCER; 2ND PRIMARY; COLORECTAL-CANCER; POOLED ANALYSIS; RADIATION; CHILDHOOD; NEOPLASMS AB BACKGROUND. This study was undertaken to determine whether cancer of the brain and central nervous system (CNS) occurs together with other types of cancer more often or less often than would be expected due to chance. METHODS. The study was based on data collected by the Surveillance, Epidemiology, and End Results (SEER) Program for cancers diagnosed in the U.S. between 1973 and 1998. The standardized incidence ratio (SIR) for new malignancies was estimated as the number of patients diagnosed with a particular type of cancer (observed), divided by the number of diagnoses expected based on person-years of follow-up and incidence rates for SEER cancer registries. RESULTS. Among patients who were diagnosed first with cancer of the brain or CNS, statistically significant excesses were observed for cancers of bone (SIR = 14.4), soft tissue (SIR = 4.6), brain and CNS (SIR = 5.9), salivary gland (SIR 5.1), and thyroid gland (SIR = 2.7) in addition to acute myelocytic leukemia (SIR 4.1) and melanoma of the skin (SIR = 1.7). Excess risk of new malignancies was markedly greater after first cancers of the brain or CNS diagnosed in childhood compared with similar diagnoses in adulthood. In reverse associations, significant excesses of cancer of the brain and CNS were observed only after diagnoses of acute lymphocytic leukemia (SIR = 7.4) and cancer of the testis (SIR = 1.8) or the thyroid gland (SIR = 1.7). CONCLUSIONS. Cancer treatment appears to have been the major factor underlying most of the positive associations between brain cancer and primary cancers of other types, with a probable lesser contribution from shared genetic susceptibility. Results provide little or no evidence that brain cancer shares important etiologic factors with the common cancers of adulthood. Published 2003 by the American Cancer Society.*. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Inskip, PD (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Execut Plaza S,Room 7052, Bethesda, MD 20892 USA. NR 48 TC 18 Z9 20 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2003 VL 98 IS 3 BP 562 EP 570 DI 10.1002/cncr.11554 PG 9 WC Oncology SC Oncology GA 702VU UT WOS:000184246000015 PM 12879474 ER PT J AU Woodson, K Tangrea, JA Lehman, TA Modali, R Taylor, KM Snyder, K Taylor, PR Virtamo, J Albanes, D AF Woodson, K Tangrea, JA Lehman, TA Modali, R Taylor, KM Snyder, K Taylor, PR Virtamo, J Albanes, D TI Manganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland) SO CANCER CAUSES & CONTROL LA English DT Article DE antioxidants; ATBC Study; manganese superoxide dismutase; prostate cancer; alpha-tocopherol ID BREAST-CANCER; RADICAL PROSTATECTOMY; EXPRESSION; CELLS; OVEREXPRESSION; PROGRESSION; METABOLISM; MALIGNANCY; DISEASE AB Objective: Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that plays a key role in protecting the cell from oxidative damage. A polymorphism in the mitochondrial targeting sequence (a valine to alanine substitution), thought to alter transport of the enzyme into mitochondria, has been associated with increased risk for breast cancer with a more pronounced association among women with low intake of dietary antioxidants. We examined the role of MnSOD in the development of prostate cancer in a large, randomized cancer prevention trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We hypothesized that MnSOD may be associated with prostate cancer and that long-term antioxidant supplementation (alpha-tocopherol 50 mg/day for five to eight years) could modify the effect on risk. Methods: Logistic regression was used to estimate these associations among 197 cases and 190 controls genotyped and matched for age, intervention group, and clinic. Results: Men homozygous for the MnSOD ala allele had a 70% increase in risk over men homozygous for the val allele (odds ratio, OR = 1.72, 95% confidence interval, CI = 0.96-3.08, p = 0.07). Supplementation with alpha-tocopherol had no impact on the MnSOD-prostate cancer association. Although there was no difference in the association with disease stage, men homozygous for MnSOD ala (compared to MnSOD val/val or val/ala) showed a three-fold risk increase for high-grade tumors (OR = 2.72, 95% CI: 1.15-6.40, p = 0.02). Conclusion: These data suggest an effect of the MnSOD ala/ala genotype on the development of prostate cancer. Our observation of a stronger association with high-grade tumors may have prognostic implications that should also be pursued. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. BioServe Biotechnol, Laurel, MD USA. Management Informat Serv Inc, Silver Spring, MD USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Woodson, K (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, 6116 Execut Blvd,MSC 8314, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01 CN 45165] NR 25 TC 85 Z9 89 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 AUG PY 2003 VL 14 IS 6 BP 513 EP 518 DI 10.1023/A:1024840823328 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703LF UT WOS:000184280300002 PM 12948282 ER PT J AU Colbert, LH Lacey, JV Schairer, C Albert, P Schatzkin, A Albanes, D AF Colbert, LH Lacey, JV Schairer, C Albert, P Schatzkin, A Albanes, D TI Physical activity and risk of endometrial cancer in a prospective cohort study (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE activity; cohort studies; endometrial cancer; exercise; physical fitness ID PROGESTIN REPLACEMENT THERAPY; MENOPAUSAL ESTROGEN; BREAST-CANCER; LIFE-STYLE; WOMEN; EXERCISE; SWEDEN AB Objective: To examine the physical activity and endometrial cancer relationship in a prospective study of US women enrolled in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-up Study. Methods: We assessed past-year physical activity of all types in 23,369 women who returned the baseline questionnaire (1987-1989) and had no prior hysterectomy and/or endometrial cancer. Cox proportional hazards models were used to estimate age, education, and parity-adjusted rate ratios (RR) and 95% confidence intervals (CI) for the 253 confirmed endometrial cancer cases identified during an average 8.2 years of follow-up (ending 1995 1998). Results: There were no dose-response relationships with either total or vigorous physical activity; however, compared to the lowest total activity quartile, the higher four quartiles had a non-significantly lower risk (RR = 0.8, CI = 0.6-1.0). The association with moderate activity varied with follow-up time: RRs (CI) for a 1 h increase in daily moderate activity within 2-year intervals of follow-up (less than or equal to2, 2.1-4.9, 5.0-8.0, > 8 years) were 1.1 (1.0, 1.2), 1.0 (0.9, 1.1), 1.0 (0.9, 1.1), 1.0 (0.9, 1.1), and 0.8 (0.7, 1.0), respectively. Conclusion: These data suggest that recent physical activity is not strongly related to the risk of endometrial cancer, and that prolonged exposure and longer follow-up may be necessary. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagn, Bethesda, MD 20892 USA. RP Colbert, LH (reprint author), Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave,MSC, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 24 TC 34 Z9 37 U1 1 U2 3 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 AUG PY 2003 VL 14 IS 6 BP 559 EP 567 DI 10.1023/A:1024866827775 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703LF UT WOS:000184280300007 PM 12948287 ER PT J AU Travier, N Gridley, G Blair, A Dosemeci, M Boffetta, P AF Travier, N Gridley, G Blair, A Dosemeci, M Boffetta, P TI Cancer incidence among male Swedish veterinarians and other workers of the veterinary industry: a record-linkage study SO CANCER CAUSES & CONTROL LA English DT Article DE cancer incidence; epidemiology; occupational exposure; veterinarians ID UNITED-STATES VETERINARIANS; CALIFORNIA VETERINARIANS; SMOKING CHARACTERISTICS; MORTALITY; SWEDEN; DEATH; OCCUPATIONS; ETIOLOGY; PLANTS; RISK AB Objective: To investigate the risk of cancer among veterinarians in a large record-linkage study from Sweden. Methods: We used the nationwide, Swedish Cancer Environment Registry III, which links the Cancer Register data for 1971-1989 to the national population censuses from 1960 and 1970, to compare the incidence of cancer among male veterinarians to that of the remaining part of the active population using multivariable Poisson regression models and standardized incidence ratios. One thousand one hundred and seventy eight men classified as veterinarians or workers in the veterinary industry at either census were identified. Results: Veterinarians in the veterinary industry experienced increased risk of esophageal (relative risk (RR) 3.78, 95% confidence interval (CI) 1.42-10.09), colon (RR: 2.36, 95% CI: 1.42-3.91), pancreatic (RR: 2.10, 95% CI: 0.94-4.68) and brain (RR: 2.51, 95% CI: 1.04-6.03) cancers as well as melanoma of the skin (RR: 2.77, 95% CI: 1.24-6.17). Similar excess risks were observed when veterinarians were compared with individuals of similar socioeconomic status. Conclusion: The increased risks of esophageal, colon, pancreatic and brain cancers as well as melanoma observed among veterinarians did not seem to be explained by the high socio-economic status of this occupational group. Therefore, it is possible that some of these results reflect the carcinogenicity of occupational exposures, including animal viruses, solar or ionizing radiations and anesthetics. C1 Int Agcy Res Canc, Unit Environm Canc Epidemiol, F-69008 Lyon, France. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Boffetta, P (reprint author), Int Agcy Res Canc, Unit Environm Canc Epidemiol, 150 Cours Albert Thomas, F-69008 Lyon, France. NR 29 TC 12 Z9 13 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2003 VL 14 IS 6 BP 587 EP 593 DI 10.1023/A:1024834927738 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 703LF UT WOS:000184280300010 PM 12948290 ER PT J AU Holmbeck, K Bianco, P Birkedal-Hansen, H AF Holmbeck, K Bianco, P Birkedal-Hansen, H TI MT1-MMP: A collagenase essential for tumor cell invasive growth SO CANCER CELL LA English DT Article ID MATRIX METALLOPROTEINASES; CANCER; MICE AB The manuscript discussed in this preview describes that reconstituted three-dimensional extracellular matrices such as fibrillar collagen and fibrin exert stringent territorial growth control on cells. The authors show that tumor cells are able to escape the matrix-enforced growth control effect (entrapment) by pericellular proteolysis mediated by MT1-MMP, a membrane bound matrix metalloproteinase capable of directly cleaving both type I collagen and fibrin but not by other, soluble matrix metalloprotinases. These data convincingly demonstrate one way that tumor cells orchestrate proteolysis to invade surrounding tissues. C1 Natl Inst Dent & Craniofacial Res, Matrix Metalloproteinase Unit, NIH, Bethesda, MD 20892 USA. Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Rome, Italy. RP Holmbeck, K (reprint author), Natl Inst Dent & Craniofacial Res, Matrix Metalloproteinase Unit, NIH, Bethesda, MD 20892 USA. NR 8 TC 12 Z9 13 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2003 VL 4 IS 2 BP 83 EP 84 DI 10.1016/S1535-6108(03)00196-X PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 716ZH UT WOS:000185060000002 PM 12957281 ER PT J AU Musser, SM Egorin, MJ Zuhowski, EG Hamburger, DR Parise, RA Covey, JM White, KD Eiseman, JL AF Musser, SM Egorin, MJ Zuhowski, EG Hamburger, DR Parise, RA Covey, JM White, KD Eiseman, JL TI Biliary excretion of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) and metabolites by Fischer 344 rats SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE geldanamycin; ansamycin; HSP90; biliary excretion ID GLUCOCORTICOID RECEPTOR FUNCTION; GENE-PRODUCT P185; BENZOQUINOID ANSAMYCINS; ANTITUMOR AGENT; ANTIPROLIFERATIVE ACTIVITY; GELDANAMYCIN DERIVATIVES; TISSUE DISTRIBUTION; TYROSINE KINASES; CELL-LINES; IN-VIVO AB Purpose. 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), an analogue of the benzoquinone ansamycin geldanamycin, has been extensively studied preclinically and is being evaluated clinically. Studies were performed to define the biliary excretion of 17AAG after i.v. delivery to rats, and to characterize the metabolites of 17AAG observed in rat bile. Materials and methods. In vivo studies were performed in bile-duct-cannulated Fischer 344 rats given a 10 mg/kg i.v. bolus dose of 17AAG. In vitro studies were performed with cloned human CYPs and microsomal epoxide hydrolase. Biliary excretion of 17AAG and metabolites was quantified by HPLC and followed for 4 h after drug delivery. 17AAG metabolites in bile and in in vitro reaction mixtures were identified with LC/MS/MS.Results. By 15 min after i.v. delivery of 17AAG, bile contained at least 15 biotransformation products with absorbance spectra similar to that of 17AAG. Of these, metabolites eluting at 2.7, 2.9, and 8.6 min were present in sufficient concentrations to be quantified, although the lack of authentic standards resulted in their being expressed as 17AAG equivalents. Within the first 4 h after drug delivery, biliary excretion accounted for 28.9+/-6.1% of the 10-mg/kg 17AAG dose. 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) accounted for 4.1+/-1.0% of the delivered dose, with 17AAG accounting for 2.0+/-0.5% and 17AG accounting for 2.1+/-0.5%. The metabolites eluting at 2.7, 2.9, and 8.6 min accounted for 10.6+/-2.0%, 9.8+/-1.2%, and 1.0+/-0.2%, respectively, of the administered dose. LC/MS/MS analysis of bile demonstrated major metabolites with molecular weights of 545 and 619, corresponding to 17AG and the diol previously described as resulting from metabolism of 17AAG by CYP3A and microsomal epoxide hydrolase. Of the remaining proposed metabolites, ten had a mass and MS/MS spectrum consistent with mono-oxygenated 17AAG metabolites. One of these metabolites has been identified as the epoxide previously described as resulting from CYP3A oxidation of the allyl double bond. Two other proposed metabolites had a mass and MS/MS spectrum consistent with demethylated 17AAG metabolites, and one had a mass and MS/MS spectrum consistent with a di-demethylated 17AAG metabolite. An analogous series of demethylated and oxidized metabolites was also observed for the 17AG metabolite. Conclusions. Biliary excretion of 17AAG represents a major route of elimination, although most of the material excreted is in the form of metabolites. Bile of rats dosed with 17AAG contained a number of metabolites not previously identified in the plasma or urine of mice treated with 17AAG, but analogous to metabolites described in bile of rats treated with 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG, NSC 707545), another geldanamycin analogue undergoing preclinical evaluation in preparation for subsequent clinical trials. C1 US FDA, Instrumentat & Biophys Branch, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Div Hematol Oncol, Dept Med, Sch Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Pharmacol, Sch Med, Pittsburgh, PA 15213 USA. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Daig, Bethesda, MD 20892 USA. RP Egorin, MJ (reprint author), Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Room G27E,Hillman Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [N01-CM07106, 2P30CA47904] NR 44 TC 8 Z9 8 U1 0 U2 2 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 AUG PY 2003 VL 52 IS 2 BP 139 EP 146 DI 10.1007/s00280-003-0630-z PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 703TV UT WOS:000184297800008 PM 12761648 ER PT J AU Best, A Hiatt, RA Cameron, R Rimer, BK Abrams, DB AF Best, A Hiatt, RA Cameron, R Rimer, BK Abrams, DB TI The evolution of cancer control research: An international perspective from Canada and the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SMOKING CESSATION; INTERVENTION; COMMUNITY; HEALTH; TRIAL AB Four phases in the evolution of cancer control frameworks are reviewed, highlighting how national Canadian and United States planning and implementation activities have built on each other's work to define and guide cancer control research. Hallmarks have come to be: (a) coordination of the cycle that applies research to practice and policy decisions; (b) synthesis of knowledge at each phase of cancer control framework; (c) a focus on populations and public health with feedback loops between fundamental and applied research; and (d) interdisciplinary integration of the biological, behavioral, social, and other population sciences. Current research priorities and initiatives based on the research framework now common to both Canada and the United States are described. We conclude by calling for an international forum for the systematic advancement of cancer control research, and closer ties between the cancer control communities in North America. C1 Vancouver Gen Hosp, Ctr Clin Epidemiol & Evaluat, Vancouver, BC V5Z 1L8, Canada. Univ British Columbia, Dept Hlth Care & Epidemiol, Vancouver, BC V5Z 1L8, Canada. NCI, Div Canc Control & Populat Sci, US Dept HHS, Bethesda, MD 20892 USA. Natl Canc Inst Canada, Ctr Behav Res & Program Evaluat, Waterloo, ON N2L 3G1, Canada. Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. Miriam Hosp, Brown Med Sch, Ctr Behav, Providence, RI 02903 USA. Miriam Hosp, Brown Med Sch, Ctr Prevent Med, Providence, RI 02903 USA. RP Best, A (reprint author), Vancouver Hosp & Hlth Sci Ctr, Ctr Clin Epidemiol & Evaluat, Room 718,828 W 10th Ave, Vancouver, BC V5Z 1L8, Canada. NR 21 TC 23 Z9 23 U1 0 U2 1 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 AUG PY 2003 VL 12 IS 8 BP 705 EP 712 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 711UD UT WOS:000184758700003 PM 12917200 ER PT J AU Glebov, OK Rodriguez, LM Nakahara, K Jenkins, J Cliatt, J Humbyrd, CJ DeNobile, J Soballe, P Simon, R Wright, G Lynch, P Patterson, S Lynch, H Gallinger, S Buchbinder, A Gordon, G Hawk, E Kirsch, IR AF Glebov, OK Rodriguez, LM Nakahara, K Jenkins, J Cliatt, J Humbyrd, CJ DeNobile, J Soballe, P Simon, R Wright, G Lynch, P Patterson, S Lynch, H Gallinger, S Buchbinder, A Gordon, G Hawk, E Kirsch, IR TI Distinguishing right from left colon by the pattern of gene expression SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN GASTROINTESTINAL-TRACT; GROWTH-FACTOR RECEPTOR; COLORECTAL-CANCER; DNA; ADENOCARCINOMA; CARCINOGENESIS; CARCINOMAS; HEREDITARY; PROFILES; TISSUE AB Distinct epidemiological and clinicopathological characteristics of colorectal carcinomas (CRCs) based on their anatomical location suggest different risk factors and pathways of transformation associated with proximal and distal colon carcinogenesis. These differences may reflect distinct biological characteristics of proximal and distal colonic mucosa, acquired in embryonic or postnatal development, that determine a differential response to uniformly distributed environmental factors. Alternatively, the differences in the epidemiology of proximal and distal CRCs could result from the presence of different procarcinogenic factors in the ascending versus descending colon, acting on cells with either similar or distinct biological characteristics. We applied cDNA microarray technology to explore the possibility that mucosal epithelium from adult proximal and distal colon can be distinguished by their pattern of gene expression. In addition, gene expression was studied in fetal (17-24 weeks gestation) proximal and distal colon. More than 1000 genes were expressed differentially in adult ascending versus descending colon, with 165 genes showing >2-fold and 49 genes showing >3-fold differences in expression. With almost complete concordance, biopsies of adult colonic epithelium can be correctly classified as proximal or distal by gene expression profile. Only 87 genes were expressed differently in ascending and descending fetal colon, indicating that, although anatomically relevant differences are already established in embryonic colon, additional changes in gene expression occur in postnatal development. C1 NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Dept Surg, Bethesda, MD 20889 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Oncol, Houston, TX 77030 USA. Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA. Univ Toronto, Toronto, ON M5G 1X5, Canada. Pharmacia, Clin Oncol Res & Dev, Peapack, NJ 07977 USA. Ovat Pharma, Lincolnshire, IL 60015 USA. RP Kirsch, IR (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kirschi@exchange.nih.gov RI Gallinger, Steven/E-4575-2013 NR 29 TC 117 Z9 124 U1 0 U2 2 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 AUG PY 2003 VL 12 IS 8 BP 755 EP 762 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 711UD UT WOS:000184758700010 PM 12917207 ER PT J AU Seifried, HE McDonald, SS Anderson, DE Greenwald, P Milner, JA AF Seifried, HE McDonald, SS Anderson, DE Greenwald, P Milner, JA TI The antioxidant conundrum in cancer SO CANCER RESEARCH LA English DT Review ID MANGANESE SUPEROXIDE-DISMUTASE; TUMOR-CELL GROWTH; VITAMIN-E; OXIDATIVE STRESS; DNA-DAMAGE; SELENIUM-COMPOUNDS; BREAST-CANCER; DISEASE; LYCOPENE; INTERVENTION AB The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. However, any health-related effects of interactions between dietary antioxidants and ROS likely depend on the health status of an individual and may also be influenced by genetic susceptibilities. Clinical studies of antioxidant supplementation and changes in either oxidative status, disease risk, or disease outcome have been carried out in healthy individuals, populations at risk for certain diseases, and patients undergoing disease therapy. The use of antioxidants during cancer therapy is currently a topic of heated debate because of an overall lack of clear research findings. Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS. and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment. C1 NCI, Div Canc Prevent, NIH, Rockville, MD 20852 USA. Sci Consulting Grp Inc, Gaithersburg, MD USA. RP Seifried, HE (reprint author), NCI, Div Canc Prevent, NIH, 6130 Execut Blvd,Suite 3160, Rockville, MD 20852 USA. NR 50 TC 118 Z9 128 U1 2 U2 13 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 AUG 1 PY 2003 VL 63 IS 15 BP 4295 EP 4298 PG 4 WC Oncology SC Oncology GA 708JB UT WOS:000184562500001 PM 12907593 ER PT J AU Wu, YP Cui, K Miyoshi, K Hennighausen, L Green, JE Setser, J LeRoith, D Yakar, S AF Wu, YP Cui, K Miyoshi, K Hennighausen, L Green, JE Setser, J LeRoith, D Yakar, S TI Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors SO CANCER RESEARCH LA English DT Article ID ESTROGEN-RECEPTOR STATUS; HORMONE TRANSGENIC MICE; PROSTATE-CANCER RISK; BREAST-CANCER; FACTOR-BINDING; PLASMA-LEVELS; CATHEPSIN-D; CELLS; EXPRESSION; PROTEIN-3 AB Insulin-like growth factors (IGFs) play a crucial role in regulating cell proliferation and differentiation. The aim of this study was to examine the potential relationship between serum IGF-I levels and breast cancer risk. To do this, we studied liver-specific IGF-I gene-deleted (LID) mice, in which circulating IGF-I levels are 25% of that in control mice. Mammary tumors were induced in two ways: (a) by exposing mice to the carcinogen 7,12-dimethybenz (a)anthracene; and (b) by crossing LID mice with C3(1)/SV40 large T-antigen transgenic mice. In both models, LID mice exhibited a delayed latency period of mammary tumor development. In the 7,12-dimethybenz (a)anthracene-induced mammary tumor model, the incidence of palpable mammary tumors was significantly lower in LID mice (26% versus 56% in controls), and the onset of the tumors was delayed (74 +/- 1.2 days in LID mice versus 59.5 +/- 1.1 days in controls). Histological analysis showed extensive squamous metaplasia in late-stage mammary tumors of control mice, whereas late-stage tumors from LID mice exhibited extensive hyperplasia, but little metaplasia. In control mice, the onset of C3(1)/SV40- large T-antigen-induced mammary tumors occurred at 21.6 +/- 1.8 weeks of age, whereas in LID mice the average age of onset was 30.2 +/- 1.7 weeks. In addition, 60% of the mice in the control group developed two or more mammary tumors per mouse, whereas in the LID mice only 30% developed more than one mammary tumor per mouse. Our data demonstrate that circulating IGF-I levels play a significant role as a risk factor in the onset and development of mammary tumors in two well-established animal models of breast cancer. C1 NIDDKD, Sect Cellular & Mol Physiol, Diabet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Yakar, S (reprint author), NIDDKD, Sect Cellular & Mol Physiol, Diabet Branch, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 142 Z9 151 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 AUG 1 PY 2003 VL 63 IS 15 BP 4384 EP 4388 PG 5 WC Oncology SC Oncology GA 708JB UT WOS:000184562500016 PM 12907608 ER PT J AU Wang, Y Zhang, ZQ Kastens, E Lubet, RA You, M AF Wang, Y Zhang, ZQ Kastens, E Lubet, RA You, M TI Mice with alterations in both p53 and Ink4a/Arf display a striking increase in lung tumor multiplicity and progression: Differential chemopreventive effect of budesonide in wild-type and mutant A/J mice SO CANCER RESEARCH LA English DT Article ID MURINE BONE-MARROW; NON-SMALL-CELL; PULMONARY CARCINOGENESIS; RAS PROTOONCOGENE; AEROSOLIZED BUDESONIDE; LIGASE ACTIVITY; GENE-PRODUCT; B-LINEAGE; CANCER; MOUSE AB p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with similar to4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). In addition, most of the lung tumors (similar to80%) from mice with a p53 mutation and deletion of Ink4A/Arf were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in <10% of the lung tumors from the wildtype mice and &SIM;50% of the lung tumors from Ink4a/Arf heterozygous-deficient or p53 mutant mice. These results indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression (P < 0.01). The usefulness of this new mouse model in lung cancer chemoprevention was examined. The chemopreventive efficacy of budesonide was examined in wild-type mice, mice with Ink4A/Arf heterozygous deficiency, mice with a mutation in the p53 gene, or mice with both a mutation in the p53 gene and deletion in the Ink4A/Arf locus. Mice treated with budesonide displayed an average of 90% inhibition of lung tumor progression in a standard 18-week chemoprevention assay, regardless of p53 and/or Ink4A/Arf status. However, the efficacy of budesonide against lung tumor progression decreased from 94 to 77% (P = 0.07) in mice with alterations in both p53 and Ink4A/Arf in a 40-week chemoprevention assay. Similarly, when mice bearing established lung adenomas were treated with budesonide, genotype-dependent differential effects of budesonide in wild-type and mutant mice were clearly revealed with a 82, 64, 45, and 33% decrease in tumor volume in wild-type mice, p53(+/+)Ink4a/Arf(+/-) mice, p53(+/-)Ink4a/Arf(+/+) mice, and p53(+/-)Ink4a/Arf(+/-), respectively. Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effectiveness of chernopreventive agents on the mutant A/J mice containing alterations with p53 and Ink4a/Arf is the best preclinical estimate of their efficacy in humans. Thus, the mutant A/J mouse model should prove useful for chemoprevention studies. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Ccampus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. FU NCI NIH HHS [R01 CA 78797, R01 CA 58554] NR 47 TC 50 Z9 51 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 AUG 1 PY 2003 VL 63 IS 15 BP 4389 EP 4395 PG 7 WC Oncology SC Oncology GA 708JB UT WOS:000184562500017 PM 12907609 ER PT J AU Shibutani, S Suzuki, N Laxmi, YRS Schild, LJ Divi, RL Grollman, AP Poirier, MC AF Shibutani, S Suzuki, N Laxmi, YRS Schild, LJ Divi, RL Grollman, AP Poirier, MC TI Identification of tamoxifen-DNA adducts in monkeys treated with tamoxifen SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER PATIENTS; ALPHA-ACETOXYTAMOXIFEN; ENDOMETRIAL CANCER; RAT-BRAIN; LIVER DNA; SULFOTRANSFERASE; HYDROXYTAMOXIFEN; ANALOGS; CELLS; RISK AB The risk of developing endometrial cancer is increased in breast cancer patients treated with tamoxifen (TAM) and in healthy women undergoing TAM chemoprevention. We have detected previously TAM-DNA adducts in the endometrium of women receiving TAM (Shibutani et al., Carcinogenesis, 21: 1461-1467, 2000). To investigate the genotoxic damage induced by TAM in the uterus and other tissues of primates, we gave adult female cynomolgus monkeys six times the human-equivalent dose of TAM (2 mg/kg body weight/day) for 30 days. DNA samples were prepared from the uterus, ovary, liver, kidney, and brain cortex of three TAM-exposed monkeys and one control monkey and were analyzed as coded specimens. To identify the TAM-DNA adducts, we established a new high-performance liquid chromatography gradient system for P-32-postlabeling/high-performance liquid chromatography analysis, which can resolve the trans- and cis-diastereoisomers of alpha-(N-2-deoxyguanosinyl)TAM (dG-N-2-TAM), alpha-(N-2-deoxyguanosinyl)-N-desmethylTAM, and alpha-(N-2-deoxyguanosinyl)tamoxifen N-oxide. Trans-forms of dG-N-2-TAM and dG-N-2-N-desTAM adducts were detected in the livers of all three TAM-fed monkeys at levels of 2.7 adducts/10(8) nucleotides and 1.7 adducts/10(8) nucleotides, respectively. The levels of dG-N-2-TAM adducts observed in the uterus of one monkey and in the ovaries of two monkeys were similar to10-fold lower than those observed in the livers. TAM exposure also induced dG-N-2-TAM adduct in the brain cortex of all three monkeys with a value of 1.5 adducts/10(8) nucleotides. No TAM-DNA adducts were detected in the kidneys or in any tissues obtained from the unexposed monkey. Our results suggest that women receiving TAM may form genotoxic damage in many organs, including the reproductive organs. C1 SUNY Stony Brook, Dept Pharmacol Sci, Biol Chem Lab, Stony Brook, NY 11794 USA. NCI, Carcinogen DNA Interact Sect, NIH, Bethesda, MD 20892 USA. RP Shibutani, S (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Biol Chem Lab, Stony Brook, NY 11794 USA. FU NIEHS NIH HHS [ES 09418] NR 33 TC 36 Z9 36 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 AUG 1 PY 2003 VL 63 IS 15 BP 4402 EP 4406 PG 5 WC Oncology SC Oncology GA 708JB UT WOS:000184562500019 PM 12907611 ER PT J AU Shivakrupa, R Bernstein, A Watring, N Linnekin, D AF Shivakrupa, R Bernstein, A Watring, N Linnekin, D TI Phosphatidylinositol 3 '-kinase is required for growth of mast cells expressing the Kit catalytic domain mutant SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASE; CONSTITUTIVELY ACTIVATING MUTATIONS; GASTROINTESTINAL STROMAL TUMOR; CHRONIC MYELOID-LEUKEMIA; BLOOD MONONUCLEAR-CELLS; PROTOONCOGENE C-KIT; SRC FAMILY KINASES; HEMATOPOIETIC-CELLS; POINT MUTATION; IN-VIVO AB The Kit receptor tyrosine kinase is critical for the growth and development of hematopoietic cells, germ cells, and the interstitial cells of Cajal. Gain-of-function mutations in codon 816 of the catalytic domain of human Kit [codon 814 of murine Kit (mKit)] are found in patients with mastocytosis, leukemia, and germ cell tumors. There are no drugs that inhibit the activity of Kit catalytic domain mutants to a greater extent than wild-type Kit. The objective of this study Was to understand the biochemical mechanisms mediating mast cell transformation by this Kit mutant to identify molecular targets for pharmacological intervention. To this end, we examined signaling pathways activated in the murine mast cell line IC2 infected with either wild-type (IC2-mKit) or mutant mKit (IC2-mKit(D814Y)). In this study, we show that mKit(D814Y) is constitutively phosphorylated on tyrosine 719, and this likely results in constitutive association with activated phosphatidylinositol 3'-kinase (PI3K). In vitro growth of IC2-mKit(D814Y) cells is more sensitive to inhibition of PI3K than SCF-induced growth of IC2-mKit cells. s.c. injection of IC2-mKit(D814Y) in syngeneic mice results in mast cell tumors. To determine whether inhibition of PI3K could reduce mKit(D814Y)-mediated tumorigenicity, mice were treated with 1.5 mg/kg wortmannin three times a week. Five weeks after injection of tumor cells, a 75% reduction in tumor weight was observed when wortmannin treatments were initiated 2 days after inoculation with tumor cells. A 66% reduction occurred when treatment was initiated 2 weeks after inoculation. Treatment with wortmannin increased necrosis in the tumors, and this was associated with apoptosis. Interestingly, there was no effect on tumor vasculature. Thus, PI3K is required for survival and growth of the IC2-mKit(D814Y) mast cell line both in vitro and in vivo. These findings may provide insight into designing strategies for treatment of mastocytosis and other diseases associated with mutations in the Kit catalytic domain. C1 NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ottawa, ON, Canada. Univ Toronto, Canadian Inst Hlth Res, Ottawa, ON, Canada. RP Shivakrupa, R (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Bldg 567,Room 226, Frederick, MD 21702 USA. NR 62 TC 36 Z9 36 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 AUG 1 PY 2003 VL 63 IS 15 BP 4412 EP 4419 PG 8 WC Oncology SC Oncology GA 708JB UT WOS:000184562500021 PM 12907613 ER PT J AU McGlynn, KA Hunter, K LeVoyer, T Roush, J Wise, P Michielli, RA Shen, FM Evans, AA London, WT Buetow, KH AF McGlynn, KA Hunter, K LeVoyer, T Roush, J Wise, P Michielli, RA Shen, FM Evans, AA London, WT Buetow, KH TI Susceptibility to aflatoxin B-1-related primary hepatocellular carcinoma in mice and humans SO CANCER RESEARCH LA English DT Article ID MICROSOMAL EPOXIDE HYDROLASE; S-TRANSFERASE M1; HEPATITIS-B CARRIERS; GENETIC POLYMORPHISMS; VIRUS-INFECTION; NULL GENOTYPES; LIVER-CANCER; RISK-FACTORS; HAIMEN-CITY; FOLLOW-UP AB The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B-1 (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the, two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA USA. Fudan Med Univ, Shanghai, Peoples R China. RP McGlynn, KA (reprint author), NCI, DCEG, EEB, EPS-7060,6120 Execut Blvd, Bethesda, MD 20852 USA. NR 44 TC 58 Z9 63 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 AUG 1 PY 2003 VL 63 IS 15 BP 4594 EP 4601 PG 8 WC Oncology SC Oncology GA 708JB UT WOS:000184562500045 PM 12907637 ER PT J AU Maxwell, PJ Longley, DB Latif, T Boyer, J Allen, W Lynch, M McDermott, U Harkin, DP Allegra, CJ Johnston, PG AF Maxwell, PJ Longley, DB Latif, T Boyer, J Allen, W Lynch, M McDermott, U Harkin, DP Allegra, CJ Johnston, PG TI Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling SO CANCER RESEARCH LA English DT Article ID EXPRESSION PROFILES; COLORECTAL-CANCER; THYMOSIN BETA-10; BREAST-CANCER; CELLS; CHEMOTHERAPY; SENSITIVITY; OXALIPLATIN; CORRELATE; TUMORS AB The fluoropyrimidine 5-Fluorouracil (5-FU) is widely used in the treatment of cancer. To identify novel downstream mediators of tumor cell response to 5-FU, we used DNA microarray technology to identify genes that are transcriptionally activated by 5-FU treatment in the MCF-7 breast cancer cell line. Of 2400 genes analyzed, 619 were up-regulated by >3-fold. Highly up-regulated genes (>6-fold) with signal intensities of >3000 were analyzed by Northern blot. Genes that were consistently found to be up-regulated were spermine/spermidine acetyl transferase (SSAT), annexin II, thymosin-beta-10, chaperonin-10, and MAT-8. Treatment of MCF-7 cells with the antifolate tomudex and DNA-damaging agent oxaliplatin also resulted in up-regulation of each of these targets. The 5-FU-induced activation of MAT-8, thymosin-beta-10, and chaperonin-10 was abrogated by inactivation of p53 in MCF-7 cells, whereas induction of SSAT and annexin II was significantly reduced in the absence of p53. Moreover, each of these genes contained more than one potential p53-binding site, suggesting that p53 may play an important regulatory role in 5-FU-induced expression of these genes. In addition, we found that basal expression levels of SSAT, annexin II, thymosin beta-10, and chaperonin-10 were increased (by similar to2-3-fold), and MAT-8 expression dramatically increased (by similar to10-fold) in a 5-FU-resistant colorectal cancer cell line (H630-R10) compared with the parental H630 cell line, suggesting these genes may be useful biomarkers of resistance. These results demonstrate the potential of DNA microarrays to identify novel genes involved in mediating the response of tumor cells to chemotherapy. C1 Queens Univ Belfast, Canc Res Ctr, Dept Oncol, Belfast BT9 7AB, Antrim, North Ireland. NCI, Ctr Canc Res, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Johnston, PG (reprint author), Queens Univ Belfast, Belfast City Hosp, Canc Res Ctr, Dept Oncol, Univ Floor,Lisburn Rd, Belfast BT9 7AB, Antrim, North Ireland. NR 20 TC 102 Z9 108 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 AUG 1 PY 2003 VL 63 IS 15 BP 4602 EP 4606 PG 5 WC Oncology SC Oncology GA 708JB UT WOS:000184562500046 PM 12907638 ER PT J AU Fan, T Yan, QS Huang, JQ Austin, S Cho, E Ferris, D Muegge, K AF Fan, T Yan, QS Huang, JQ Austin, S Cho, E Ferris, D Muegge, K TI Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis SO CANCER RESEARCH LA English DT Article ID SNF2 FAMILY MEMBER; DNA METHYLATION; CENTROSOME AMPLIFICATION; TETRAPLOIDY CHECKPOINT; GENE-EXPRESSION; CELL-CYCLE; CANCER; HYPOMETHYLATION; SUPPRESSION; PROTEIN AB Genomic hypomethylation and chromosomal instability are frequent characteristics of human cancer cells. Targeted deletion of Lsh leads to a global defect in genomic methylation, and Lsh-deficient mice die at birth with a reduced body weight. Here, we examine the growth pattern of embryonal fibroblasts derived from Lsh(-/-) mice. The absence of Lsh leads to a severe proliferative defect of fibroblasts with lower saturation density, early signs of senescence, and a lower frequency of immortalization. The impaired growth rate in vitro may be in part responsible for the small size of Lsh-deficient mice. In addition, Lsh(-/-) fibroblasts accumulated high centrosome numbers, formed multipolar spindles, displayed micronuclei formation, and elevated nuclear DNA content. A similar increase in centrosome abnormalities was observed when wild-type fibroblasts were treated with a DNA-demethylating agent, suggesting that genomic hypomethylation plays an important role in mitotic defects of Lsh(-/-) murine embryonal fibroblasts, possibly by altering chromatin structure. Because supernumerary centrosomes are a common feature in cancer cells, this Lsh-dependent pathway has the potential to contribute to genetic instability and chromosomal aberrations during tumor progression. C1 NCI, Mol Immunoregulat Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. NCI, Lab Leukocyte Biol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. NCI, Image Anal Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, Mol Immunoregulat Lab, Basic Res Program, SAIC Frederick, Bldg 469,Room 243, Frederick, MD 21701 USA. FU NCI NIH HHS [N01 CO 12400] NR 34 TC 30 Z9 35 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 AUG 1 PY 2003 VL 63 IS 15 BP 4677 EP 4683 PG 7 WC Oncology SC Oncology GA 708JB UT WOS:000184562500057 PM 12907649 ER PT J AU Leonard, GD McCaffrey, JA Maher, M AF Leonard, GD McCaffrey, JA Maher, M TI Optimal therapy for oesophageal cancer SO CANCER TREATMENT REVIEWS LA English DT Review ID SQUAMOUS-CELL CARCINOMA; LYMPH-NODE DISSECTION; ADVANCED ESOPHAGOGASTRIC CANCER; PROTRACTED VENOUS-INFUSION; COMBINED-MODALITY THERAPY; LONG-TERM SURVIVAL; PHASE-II TRIAL; RANDOMIZED TRIAL; RADIATION-THERAPY; PREOPERATIVE CHEMORADIOTHERAPY AB Oesophageal carcinoma is one of the commonest cancers in the world and has an increasing incidence in Western civilisation. As the epidemiology of the disease has changed so too has our treatment strategies. The present standard of care is surgery but this is associated with disappointing survival figures. The role of chemotherapy and radiation is now established in inoperable disease. How best to deliver these modes of therapy has yet to be defined. Extrapolation of data from previous trials is difficult as these trials have many deficiencies and do not account for recent advances in therapeutics or techniques of delivery. The role of chemo-radiotherapy in operable disease is even more controversial. A number of prospective randomised trials of trimodality therapy versus surgery alone suggests a benefit for multimodal therapy. These trials also reveal evidence to support the use of chemo-radiotherapy alone in a subset of patients with resectable disease. The appropriate application of these varied therapeutic interventions remains unanswered. Further progress in diagnostic techniques and predictive markers may allow us to stratify patients into different treatment groups. Continued investigation is required to keep pace with the evolution of oesophageal cancer and its therapy. This will facilitate a better understanding of the disease and optimise the treatment offered to patients. Published by Elsevier Science Ltd. C1 NCI, Natl Naval Med Ctr, Med Oncol Clin Res Unit, Bethesda, MD 20889 USA. Mater Misericordiae Hosp, Dept Med & Radiat Oncol, Dublin 7, Ireland. RP Leonard, GD (reprint author), NCI, Natl Naval Med Ctr, Med Oncol Clin Res Unit, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 59 TC 16 Z9 16 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0305-7372 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD AUG PY 2003 VL 29 IS 4 BP 275 EP 282 DI 10.1016/S0305-7372(02)00131-7 PG 8 WC Oncology SC Oncology GA 716ZK UT WOS:000185060200003 PM 12927567 ER PT J AU Karbowski, M Youle, RJ AF Karbowski, M Youle, RJ TI Dynamics of mitochondrial morphology in healthy cells and during apoptosis SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE Bax; fission; fusion; fragmentation; Drp1; Fzo1 ID OUTER-MEMBRANE PROTEIN; DOMINANT OPTIC ATROPHY; CYTOCHROME-C RELEASE; WD REPEAT PROTEIN; ENDOPLASMIC-RETICULUM; SACCHAROMYCES-CEREVISIAE; SUBCELLULAR-LOCALIZATION; PROAPOPTOTIC BAX; MAMMALIAN-CELLS; YEAST REQUIRES AB Mitochondria exist as dynamic networks that often change shape and subcellular distribution. The number and morphology of mitochondria within a cell are controlled by precisely regulated rates of organelle fusion and fission. Recent reports have described dramatic alterations in mitochondrial morphology during the early stages of apoptotic cell death, a fragmentation of the network and the remodeling of the cristae. Surprisingly, proteins discovered to control mitochondrial morphology appear to also participate in apoptosis and proteins associated with the regulation of apoptosis have been shown to affect mitochondrial ultrastructure. In this review the recent progress in understanding the mechanisms governing mitochondrial morphology and the latest advances connecting the regulation of mitochondrial morphology with programmed cell death are discussed. C1 NINDS, Biochem Sect, SNB, Nihon Univ, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, SNB, Nihon Univ, Bldg 10,Room 5D-37,10 Ctr Dr, Bethesda, MD 20892 USA. NR 99 TC 396 Z9 413 U1 6 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 2003 VL 10 IS 8 BP 870 EP 880 DI 10.1038/sj.cdd.4401260 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 702KY UT WOS:000184224100003 PM 12867994 ER PT J AU Chong, HJ Bouton, LA Bailey, DP Wright, H Ramirez, C Gharse, A Oskeritzian, C Xia, HZ Zhu, JF Paul, WE Kepley, C Schwartz, LB Ryan, JJ AF Chong, HJ Bouton, LA Bailey, DP Wright, H Ramirez, C Gharse, A Oskeritzian, C Xia, HZ Zhu, JF Paul, WE Kepley, C Schwartz, LB Ryan, JJ TI IL-4 selectively enhances Fc gamma RIII expression and signaling on mouse mast cells SO CELLULAR IMMUNOLOGY LA English DT Article DE mast cell; Fc gamma R; IL-4; CD16 ID DEFICIENT MICE; SYSTEMIC-ANAPHYLAXIS; NEGATIVE REGULATION; RECEPTOR IIB; EPSILON-RI; IGE; MODULATION; RESPONSES; DISEASE; STAT6 AB Fc receptors for IgG (FcgammaR) are widely expressed in the hematopoietic system and mediate a variety of inflammatory responses. There are two functional classes of FcgammaR, activation and inhibitory receptors. Since IgG immune complexes (IgG IC) bind each class with similar affinity, co-expression of these receptors leads to their co-ligation. Thus, expression levels of this antagonistic pair play a critical role in determining the cellular response. Murine mast cells co-express the activation receptor FcgammaRIII and the inhibitory receptor FcgammaRIIb and can be activated by IgG IC. Mast cell activation contributes to allergic and other inflammatory diseases-particularly those in which IgG IC may play important roles. Using mouse bone marrow-derived mast cells, we report that IL-4 selectively increases FcgammaRIII expression without altering FcgammaRIIb. This enhanced expression could be induced by Stat6 activation alone, and appeared to be mediated in part by increased FcgammaRIIIalpha protein synthesis without significant changes in transcription. The increase in FcgammaRIII expression was functionally significant, as it was matched by enhanced FcgammaR-mediated degranulation and cytokine production. Selective regulation of mast cell FcgammaR by interleukin-4 could alter inflammatory IgG responses and subsequently disease severity and progression. (C) 2003 Elsevier Inc. All rights reserved. C1 Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23284 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. RI Zhu, Jinfang/B-7574-2012 FU NIAID NIH HHS [1R01AI27517, 1R01AI43433] NR 34 TC 15 Z9 15 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 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG PY 2003 VL 224 IS 2 BP 65 EP 73 DI 10.1016/j.cellimm.2003.08.004 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 743WN UT WOS:000186596700001 PM 14609572 ER PT J AU Gelderman, MP Charukamnoetkanok, P Brady, JP Hung, L Zigler, JS Wawrousek, EE Vistica, BP Fortin, E Chan, CC Gery, I AF Gelderman, MP Charukamnoetkanok, P Brady, JP Hung, L Zigler, JS Wawrousek, EE Vistica, BP Fortin, E Chan, CC Gery, I TI A novel inflammatory eye disease induced by lymphocytes from knockout mice sensitized against the deleted ocular antigen SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE lens-associated uveitis; alpha-crystallin; inflammation; autoimmunity; knockout mice ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; DOUBLE-TRANSGENIC MICE; PROGRAMMED CELL-DEATH; ALPHA-B-CRYSTALLIN; NEO-SELF-ANTIGEN; IMMUNE-RESPONSES; T-CELL; PHACOANAPHYLACTIC ENDOPHTHALMITIS; LENS; PEPTIDES AB Lens-associated uveitis (LAU), a severe inflammatory eye disease, is thought to be mediated by autoimmunity against lens crystallins. Previously described animal models for this disease are antibody-mediated, since no cellular response to self crystallins could be induced in experimental animals. Here, we describe a new model for LAU, in which lymphocytes from knockout mice deficient in alphaB-crystallin are sensitized against the deleted protein and induce severe ocular inflammation when adoptively transferred into wild type recipients. Similar to LAU, the experimental disease developed only following rupture of the lens capsule, produced in this study by capsulotomy; no disease was detected in recipient eyes with no capsulotomy, or in those treated with cautery, or in eyes affected by systemic treatment with sodium iodate, lipopolysaccharide or X-irradiation. The ocular changes in affected eyes included heavy cellular infiltration and proteinaceous exudate in both the anterior and posterior segments of the eye, that reached their peak on day 4 following cell transfer and subsided quite rapidly thereafter. C1 NEI, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Gery, I (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. RI Wawrousek, Eric/A-4547-2008 NR 33 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD AUG PY 2003 VL 133 IS 2 BP 177 EP 181 DI 10.1046/j.1365-2249.2003.02218.x PG 5 WC Immunology SC Immunology GA 706TZ UT WOS:000184472300006 PM 12869022 ER PT J AU ten Tije, AJ Verweij, J Sparreboom, A van der Gaast, A Fowst, C Fiorentini, F Tursi, J Antonellini, A Mantel, M Hartman, CM Stoter, G Planting, AST de Jonge, MJA AF ten Tije, AJ Verweij, J Sparreboom, A van der Gaast, A Fowst, C Fiorentini, F Tursi, J Antonellini, A Mantel, M Hartman, CM Stoter, G Planting, AST de Jonge, MJA TI Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 12-15, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Clin Oncol ID TALLIMUSTINE; GLUTATHIONE; BINDING AB Purpose: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients. Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection. Results: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor. Conclusion: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2). C1 Erasmus MC, Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. NCI, Med Oncol Clin Res Unit, Pharmacol Res Core, Bethesda, MD 20892 USA. Pharmacia Corp, Milan, Italy. RP ten Tije, AJ (reprint author), Erasmus MC, Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands. RI Sparreboom, Alex/B-3247-2008 NR 22 TC 18 Z9 18 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 AUG 1 PY 2003 VL 9 IS 8 BP 2957 EP 2964 PG 8 WC Oncology SC Oncology GA 710KW UT WOS:000184680200013 PM 12912942 ER PT J AU Rosenberg, SA Yang, JC Schwartzentruber, DJ Hwu, P Topalian, SL Sherry, RM Restifo, NP Wunderlich, JR Seipp, CA Rogers-Freezer, L Morton, KE Mavroukakis, SA Gritz, L Panicali, DL White, DE AF Rosenberg, SA Yang, JC Schwartzentruber, DJ Hwu, P Topalian, SL Sherry, RM Restifo, NP Wunderlich, JR Seipp, CA Rogers-Freezer, L Morton, KE Mavroukakis, SA Gritz, L Panicali, DL White, DE TI Recombinant Fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID IN-VIVO; LYMPHOCYTES; EPITOPES; IDENTIFICATION; IMMUNIZATION; PEPTIDE; CTL; INTERLEUKIN-2; IMMUNOTHERAPY; INDUCTION AB Purpose: The purpose of this study was to, evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma. Experimental Design: In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/ melanocyte-associated antigen, gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma. Results: Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fow1pox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)w-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression. Conclusions: These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2. C1 NCI, Canc Res Ctr, Surg Branch, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MA USA. RP Rosenberg, SA (reprint author), NCI, Canc Res Ctr, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 20 TC 67 Z9 70 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 AUG 1 PY 2003 VL 9 IS 8 BP 2973 EP 2980 PG 8 WC Oncology SC Oncology GA 710KW UT WOS:000184680200015 PM 12912944 ER PT J AU Worrillow, LJ Travis, LB Smith, AG Rollinson, S Smith, AJ Wild, CP Holowaty, EJ Kohler, BA Wiklund, T Pukkala, E Roman, E Morgan, GJ Allan, JM AF Worrillow, LJ Travis, LB Smith, AG Rollinson, S Smith, AJ Wild, CP Holowaty, EJ Kohler, BA Wiklund, T Pukkala, E Roman, E Morgan, GJ Allan, JM TI An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents SO CLINICAL CANCER RESEARCH LA English DT Article ID DNA-MISMATCH REPAIR; MICROSATELLITE INSTABILITY OCCURS; 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; P53 MUTATIONS; MYELODYSPLASTIC SYNDROME; OVARIAN-CANCER; TUMOR-CELLS; COLORECTAL CANCERS; MUTATOR PHENOTYPE AB Purpose: We sought to determine whether the -6 exon -13 T > C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O-6 -guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair. Experimental Design: Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26. Results: Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the-variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O-6-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40-11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were hornozygous for the variant (C) allele, a frequency substantially higher than in the control population. Conclusions: Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O-6-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model. C1 Univ Leeds, Sch Med, Leukaemia Res Fund Epidemiol & Genet Unit, Leeds LS2 9JT, W Yorkshire, England. Univ Leeds, Sch Med, Mol Epidemiol Unit, Acad Unit Epidemiol & Hlth Serv Res, Leeds LS2 9JT, W Yorkshire, England. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Canc Care Ontario, Toronto, ON, Canada. New Jersey Dept Hlth & Senior Serv, Trenton, NJ USA. Univ Helsinki, Cent Hosp, Helsinki, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. RP Allan, JM (reprint author), Univ Leeds, Sch Med, Leukaemia Res Fund Epidemiol & Genet Unit, Algernon Firth Bldg, Leeds LS2 9JT, W Yorkshire, England. RI Allan, James/B-4448-2009 NR 51 TC 55 Z9 60 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 AUG 1 PY 2003 VL 9 IS 8 BP 3012 EP 3020 PG 9 WC Oncology SC Oncology GA 710KW UT WOS:000184680200021 PM 12912950 ER PT J AU Chen, X Beutler, JA McCloud, TG Loehfelm, A Yang, L Dong, HF Chertov, OY Salcedo, R Oppenheim, JJ Howard, OMZ AF Chen, X Beutler, JA McCloud, TG Loehfelm, A Yang, L Dong, HF Chertov, OY Salcedo, R Oppenheim, JJ Howard, OMZ TI Tannic acid is an inhibitor of CXCL12 (SDF-1 alpha)/CXCR4 with antiangiogenic activity SO CLINICAL CANCER RESEARCH LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; DRUG FORSYTHIAE FRUCTUS; GREEN TEA POLYPHENOLS; ENDOTHELIAL-CELLS; HYDROLYZABLE TANNINS; CANCER METASTASIS; PLANT POLYPHENOLS; SUSPENSA VAHL; EXPRESSION; APOPTOSIS AB Purpose: Increasing evidence suggests that interaction between the chemoattractant CXCL12/stromal cell-derived factor-la and its receptor CXCR4 plays a pivotal role in the metastasis of various tumors. Our previous studies showed that multi-component Chinese herbal medicines inhibited the effects of CXCL12/CXCR4. As a result of sequential chromatographic fractionation of one herbal medicine ingredient, Lianqiao (fruit of Forsythia suspensa), we observed that tannins were, at least in part, responsible for this activity. The aim of this study was to assess the anti-CXCL12/CXCR4 activity of a commercial tannic acid and evaluate its potential to inhibit tumor cell migration and angiogenesis in vitro. Experimental Design: The inhibitory effect of tannic acid on CXCL12/CXCR4 was measured by chemotaxis assay, ligand binding assay, and fluorescence-activated cell sorter analysis. The antiangiogenic effect of tannic acid was assessed by in vitro endothelial cell tube formation. Results: Tannic acid, at nontoxic concentrations, specifically inhibited CXCL12-induced human monocyte migration (IC50, 7.5 mug/ml) but did not inhibit CCL2-, CCL3-, CCL5-, formylmethionylleucylphenylalanine (fMLP)-, or C5a-induced migration. The compound markedly blocked CXCL12 binding to THP-1 cells (IC50, 0.36 mug/ml). Tannic acid also inhibited CXCL12-induced, but not epidermal growth factor-induced, migration of MDA 231 breast tumor cells. Additionally, 0.5 mug/ml of tannic acid selectively inhibited CXCL12-mediated, but not basic fibroblast growth factor- or endothelial cell growth supplement-mediated, bovine aorta endothelial cell capillary tube formation. Conclusion: These studies indicate that tannic acid is a novel selective CXCL12/CXCR4 antagonist and consequently may provide a mechanistic basis for the reported antitumor and anti-inflammatory properties of tannic acid. C1 Natl Canc Inst, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. Natl Canc Inst, Basic Res Program, Ctr Canc Res, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. Natl Canc Inst, Mol Targets Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. TherImmune Res Corp, Gaithersburg, MD 20879 USA. RP Howard, OMZ (reprint author), Natl Canc Inst, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012; Beutler, John/B-1141-2009; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Beutler, John/0000-0002-4646-1924; Chen, Xin/0000-0002-2628-4027 FU NCI NIH HHS [N01-CO-12400, U01 CA91269-01] NR 45 TC 43 Z9 48 U1 0 U2 7 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 AUG 1 PY 2003 VL 9 IS 8 BP 3115 EP 3123 PG 9 WC Oncology SC Oncology GA 710KW UT WOS:000184680200034 PM 12912963 ER PT J AU Palayoor, ST Tofilon, PJ Coleman, CN AF Palayoor, ST Tofilon, PJ Coleman, CN TI Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha in prostate cancer cells SO CLINICAL CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; UBIQUITIN-PROTEASOME PATHWAY; FACTOR 1-ALPHA HIF-1-ALPHA; TUMOR ANGIOGENESIS; IN-VIVO; CYCLOOXYGENASE-2 INHIBITOR; HIF-ALPHA; GROWTH; EXPRESSION; FACTOR-1-ALPHA AB Purpose: Hypoxia-inducible factors HIF-1alpha and HIF-2alpha are considered to be potential targets for antineoplastic therapy because they regulate the expression of genes that contribute to tumor cell survival, aggressiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) have gained considerable interest as anticancer agents because of their cytotoxic and antiangiogenic properties. The aim of this study was to investigate whether NSAIDs inhibit HIFs and HIF-regulated gene expression in prostate cancer cells. Experimental Design: PC3 and DU-145 cells were treated with ibuprofen (Ibu) and other NSAIDs under normoxic and hypoxic (95% N-2, 5% CO2; <10 ppm O-2) conditions. The effect of NSAIDs on HIF proteins was analyzed by Western blot analysis. HIF-regulated proteins, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1), were analyzed by ELISA and Western blot analysis, respectively. Results: Exposure of PC3 and DU-145 cells to hypoxic condition up-regulated HIF-1alpha and HIF-2alpha proteins. Treatment with Ibu under normoxic and hypoxic conditions reduced the level of HIF-1alpha and HIF-2alpha. Ibu-mediated down-regulation of HIFs was associated with down-regulation of HIF-regulated proteins VEGF and Glut-1 in cells exposed to hypoxia. Other nonspecific NSAIDs, diclofenac and ketorolac, also inhibited HIF-1alpha and HIF-2alpha. The reduction in HIFs was observed in PC3 cells that expressed cyclooxygenase-2 (COX-2) protein as well as in DU-145 cells, which did not express COX-2 protein. COX-2-specific inhibitor NS-398 did not inhibit HIF-1alpha or VEGF and GLUT-1. Conclusions: These data indicate that one of the effects of NSAIDs-is to reduce HIF protein levels. The inhibition of HIFs by NSAIDs was COX-2 independent. C1 NCI, Radiat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Mol Radiat Therapeut Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Palayoor, ST (reprint author), NCI, Radiat Oncol Branch, CCR, NIH, Bldg 10,Room B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 63 TC 60 Z9 65 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2003 VL 9 IS 8 BP 3150 EP 3157 PG 8 WC Oncology SC Oncology GA 710KW UT WOS:000184680200038 PM 12912967 ER PT J AU Petricoin, E Liotta, LA AF Petricoin, E Liotta, LA TI Counterpoint - The vision for a new diagnostic paradigm SO CLINICAL CHEMISTRY LA English DT Editorial Material ID PROTEOMIC PATTERNS; PROSTATE-CANCER; OVARIAN-CANCER; SERUM; BIOMARKER; IDENTIFICATION C1 NCI, NCI FDA Clin Proteom Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, FDA Clin Proteom Program, Off Direct, Ctr Biol Evaluat & Res Food & Drug Adm, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, NCI FDA Clin Proteom Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 12 TC 59 Z9 61 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2003 VL 49 IS 8 BP 1276 EP 1278 DI 10.1373/49.8.1276 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 705CR UT WOS:000184378900007 PM 12881442 ER PT J AU Wright, GL Morrison, R Fultz, ME Wright, G McCumbee, W Wehner, P Studeny, M AF Wright, GL Morrison, R Fultz, ME Wright, G McCumbee, W Wehner, P Studeny, M TI Effect of fasting on vascular contractility in lean and obese Zucker rats SO CLINICAL NUTRITION LA English DT Article ID INSULIN-RESISTANCE; OBESITY/INSULIN RESISTANCE; FATTY RAT; HYPERTENSION; VASODILATATION; ATTENUATION; METABOLISM; AORTA AB We compared the effects of fasting (36 h) on blood pressure and aortic contractile responsiveness in lean and obese Zucker rats. Fasting of lean animals resulted in a significant loss in body weight (-9.1+/-0.1 %) and reduction in systolic blood pressure (-11.4+/-1.9 mmHg). Fasting plasma triacylglycerols (-76%) and beta-hydroxybutryic acid (beta-HBA) (+ 218%) were significantly decreased and increased, respectively. The fasting plasma concentrations of insulin (-72%) were significantly decreased, whereas glucose and epinephrine (Epi) were not changed in lean rats. The fasting of obese rats also resulted in weight loss (-5.6+/-1.3%) but did not cause a significant reduction of blood pressure. The plasma total cholesterol (+18%) was increased, triacylglycerols (-42%) were decreased and beta-HBA levels were unchanged in fasted obese rats. Similar to lean animals, the insulin levels of fasted obese rats were significantly decreased (-85%), whereas glucose and Epi concentrations were not significantly changed. Fasting of lean animals had no effect on the maximal contractile response of aortae to high K+ and phorbol 12,13 dibutyrate (PDBu) but significantly reduced the response to norepinephrine (NE) (% reference: fed, 61.1 + 11.0; fasted, 45.6+/-4.5). In addition, the concentration for half-maximal response (ED50) to NE was increased in fasted lean rats (fed, 1.8+/-0.2 x 10(-8) M; fasted, 3.0+/-0.3 x 10(-8) M). By comparison, fasting of obese rats had no significant effect on the contractile response to K+, NE, or PDBu. The results show that short-term food withdrawal induces significant changes in vascular contractile properties of lean but not obese rats. Because fasting-induced changes were variable depending on the agonist, the results further suggest that the mechanism did not involve a general loss or enhancement in functional status. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Marshall Univ, Joan Edwards Sch Med, Dept Physiol, Huntington, WV 24704 USA. Natl Inst Environm & Hlth Safety, Res Triangle Pk, NC USA. Marshall Univ, Joan Edwards Sch Med, Dept Cardiol, Huntington, WV USA. RP Wright, GL (reprint author), Marshall Univ, Joan Edwards Sch Med, Dept Physiol, 1542 Spring Valley Dr, Huntington, WV 24704 USA. NR 25 TC 5 Z9 5 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 J9 CLIN NUTR JI Clin. Nutr. PD AUG PY 2003 VL 22 IS 4 BP 359 EP 363 DI 10.1016/S0261-5614(03)00030-X PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 718AE UT WOS:000185122300004 PM 12880602 ER PT J AU Wakefield, LM Thordarson, G Nieto, AI Shyamala, G Galvez, JJ Anver, MR Cardiff, RD AF Wakefield, LM Thordarson, G Nieto, AI Shyamala, G Galvez, JJ Anver, MR Cardiff, RD TI Spontaneous pituitary abnormalities and mammary hyperplasia in FVB/NCr mice: Implications for mouse modeling SO COMPARATIVE MEDICINE LA English DT Article ID GLAND DEVELOPMENT; PLASMA-PROLACTIN; TRANSGENIC MICE; BREAST-CANCER; GROWTH; TUMORIGENESIS; RECEPTOR AB The FVB/N mouse strain is widely used in the generation of transgenic mouse models. We have observed that mammary glands of wild-type virgin female FVB/NCr mice frequently have the morphologic and histologic appearance of a gland during pregnancy. By 13 months of age, the mammary glands of more than 40% of the mice examined had lobuloalveolar hyperplasia that was characterized by the presence of secretory alveoli and distended ducts apparently containing secretory material. The prevalence of this phenotype further increased with age. The mammary phenotype was highly correlated with the presence of proliferative, prolactin-secreting lesions in the pituitary gland. In mice aged 18 to 23 months, hyperplasia of the pars distalis was seen in 11 of 21 mice (52%), and a further 4 of 21 mice (19%) had pituitary adenomas. Pituitary hyperplasia was already evident in some mice as young as nine months. The pituitary phenotype was also associated with high prevalence (4/6 mice) of spontaneous mammary tumors in aged multiparous, but not virgin FVB/NCr mice. This high prevalence of pituitary abnormalities and their effects on the mammary gland have important consequences for the interpretation of new phenotypes generated in transgenic models using this mouse substrain. C1 Univ Calif Davis, Dept Med Pathol, Davis, CA 95616 USA. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Univ Calif Santa Cruz, Sinsheimer Labs, Santa Cruz, CA 95064 USA. Univ Complutense Madrid, Fac Vet, Dept Patol Anim 2, E-28040 Madrid, Spain. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. NCI, Sci Applicat Int Corp, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Cardiff, RD (reprint author), Univ Calif Davis, Dept Med Pathol, 98 Cty Rd & Hutchison Dr, Davis, CA 95616 USA. FU PHS HHS [N01-C0-12400] NR 24 TC 25 Z9 26 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD AUG PY 2003 VL 53 IS 4 BP 424 EP 432 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 721FD UT WOS:000185305600012 PM 14524419 ER PT J AU Nieto, AI Shyamala, G Galvez, JJ Thordarson, G Wakefield, LM Cardiff, RD AF Nieto, AI Shyamala, G Galvez, JJ Thordarson, G Wakefield, LM Cardiff, RD TI Persistent mammary hyperplasia in FVB/N mice SO COMPARATIVE MEDICINE LA English DT Article ID GLAND INVOLUTION; CELL-DEATH; MOUSE AB The inbred FVB/N mouse strain is widely used for creating transgenic mice. Over the past decade, persistent mammary hyperplasia has been detected in many multiparous FVB/N female mice sent to the University of California, Davis (UCD) Mutant Mouse Pathology Laboratory (MMPL) by a number of different laboratories. However, the experimental details concerning most specimens were not always available. To confirm these empiric findings, experiments were carried out to evaluate the mammary glands of FVB/N mice under controlled conditions. Persistent mammary hyperplasia that related to parity was found. Weeks after their first to fourth pregnancy, 10 FVB/N female mice from the Lawrence Berkeley National Laboratory (LBNL) colony were studied and the mammary glands were evaluated. The percentage of fat pad filled was estimated, using image analysis. Serum samples and the pituitary gland from other FVB/N mice from the LBNL were assayed for prolactin concentration. Multiparous FVB/N females consistently had persistent mammary hyperplasia. Four of seven females in the LBNL colony had hyperplasia after three pregnancies. A few foci of squamous nodules and sporadic carcinomas also were observed. Thus, some FVB/N females may have persistent mammary hyperplasia after three pregnancies without detectable pituitary abnormalities. Mammary carcinomas also may develop sporadically. These background phenotypes must be considered when interpreting the effect of genetic manipulation in FVB/N mice. C1 Univ Calif Davis, Dept Med Pathol, Davis, CA 95616 USA. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. Univ Complutense Madrid, Fac Vet, Dept Patol Anim 2, E-28040 Madrid, Spain. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. Univ Calif Santa Cruz, Sinsheimer Labs, Santa Cruz, CA 95064 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Cardiff, RD (reprint author), Univ Calif Davis, Dept Med Pathol, 98 Cty Rd & Hutchison Dr, Davis, CA 95616 USA. FU NCI NIH HHS [CA 66541]; NCRR NIH HHS [U42-RR14905]; PHS HHS [N01-C0-12400] NR 12 TC 19 Z9 20 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD AUG PY 2003 VL 53 IS 4 BP 433 EP 438 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 721FD UT WOS:000185305600013 PM 14524420 ER PT J AU Uphyrkina, O O'Brien, SJ AF Uphyrkina, O O'Brien, SJ TI Applying molecular genetic tools to the conservation and action plan for the critically endangered Far Eastern leopard (Panthera pardus orientalis) SO COMPTES RENDUS BIOLOGIES LA English DT Article; Proceedings Paper CT International Congress on Biodiversity Conservation and Management CY JUL 04-07, 2002 CL VOUZIERS, FRANCE DE endangered species; conservation genetics; Panthera pardus; reintroduction ID CONSEQUENCES AB A role for molecular genetic approaches in conservation of endangered taxa is now commonly recognized. Because conservation genetic analyses provide essential insights on taxonomic status, recent evolutionary history and current health of endangered taxa, they are considered in nearly all conservation programs. Genetic analyses of the critically endangered Far Eastern, or Amur leopard, Panthera pardus orientalis, have been done recently to address all of these questions and develop strategies for survival of the leopard in the wild. The genetic status and implication for conservation management of the Far Eastern leopard subspecies are discussed. (C) 2003 Academie des sciences. Published by Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 NCI, Lab Genome Divers, Frederick, MD 21702 USA. Russian Acad Sci, Inst Biol & Soil Sci, Lab Evolut Zool & Genet, Vladivostok 690022, Russia. RP O'Brien, SJ (reprint author), NCI, Lab Genome Divers, Frederick, MD 21702 USA. NR 14 TC 2 Z9 2 U1 6 U2 68 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1631-0691 J9 CR BIOL JI C. R. Biol. PD AUG PY 2003 VL 326 SU 1 BP S93 EP S97 DI 10.1016/S1631-0691(03)00044-1 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 728ZH UT WOS:000185745900016 PM 14558456 ER PT J AU Joshi, BH Leland, P Puri, RK AF Joshi, BH Leland, P Puri, RK TI Identification and characterization of interleukin-13 receptor in human medulloblastoma and targeting these receptors with interleukin-13-pseudomonas exotoxin fusion protein SO CROATIAN MEDICAL JOURNAL LA English DT Article; Proceedings Paper CT Mayo Clinic Course in Advanced Cellular and Molecular Medicine CY SEP 01-05, 2003 CL ZAGREB, CROATIA DE bacterial toxins; fluorescent antibody technique; interleukin-13; medulloblastoma; pseudomonas aeruginosa; receptors; interleukin; reverse transcriptase polymerase chain reaction ID CELL CARCINOMA-CELLS; CIRCULARLY PERMUTED INTERLEUKIN-4; HIGH-AFFINITY INTERLEUKIN-4; COMMON GAMMA-CHAIN; HUMAN GLIOMA-CELLS; PSEUDOMONAS EXOTOXIN; IL-13 RECEPTOR; CHIMERIC PROTEIN; SIGNAL-TRANSDUCTION; BRAIN-TUMORS AB Aim. To identify and characterize the subunit structure of interleukin-13 receptor (IL-13R) in human medulloblastoma cell lines and target them with a chimeric fusion protein consisting of interleukin-13 and Pseudomonas exotoxin (termed as IL-13 cytotoxin). Methods. Five human medulloblastoma cell lines were examined for the expression of IL-13R subunits at the mRNA and protein levels by reverse transcriptase-polymerase chain reaction (RT-PCR) and indirect immunofluorescence studies, respectively. In addition, IL-13 cytotoxin-induced cytotoxicity was examined in these medulloblastoma cell lines by measuring protein synthesis inhibition. Results. All five medulloblastoma cell lines expressed mRNA and proteins for IL-4Ralpha and IL-13Ralpha1 chains, whereas three of the cell lines also showed the presence of IL-13Ralpha2. mRNA or protein for IL-2gammac chain was not detected in any of the cell lines. Consistent with the expression of IL-13Ralpha2 chain, IL-13 cytotoxin was highly and specifically cytotoxic to three of five medulloblastoma cell lines. The sensitivity of medulloblastoma cell lines to IL-13 cytotoxin could be completely eliminated by concurrent incubation with excess of IL-13, but not with IL-2 or IL-4. Conclusion. These studies establish IL-13R, in particular IL-13Ralpha2, as a medulloblastoma-associated target for IL-13 cytotoxin therapy. IL-13 cytotoxin may be useful for medulloblastoma therapy. Alternatively, IL-13Ralpha2 may serve as a tumor-specific antigen for active immunotherapy. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Puri, RK (reprint author), NIH Bldg 29B,Room 2NN10,29 Lincoln Dr, Bethesda, MD 20892 USA. NR 62 TC 16 Z9 18 U1 0 U2 0 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD AUG PY 2003 VL 44 IS 4 BP 455 EP 462 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 718HB UT WOS:000185138100012 PM 12950150 ER PT J AU Higgins, RD Yan, Y Geng, YX Sharma, J Barr, SM AF Higgins, RD Yan, Y Geng, YX Sharma, J Barr, SM TI Captopril and vascular endothelial growth factor in a mouse model of retinopathy SO CURRENT EYE RESEARCH LA English DT Article DE oxygen; angiogenesis; angiotensin; retina; mouse ID PROLIFERATIVE DIABETIC-RETINOPATHY; RETINAL NEOVASCULARIZATION; ANGIOTENSIN-II; MURINE MODEL; EXPRESSION; ANGIOGENESIS; PREMATURITY; BLOCKADE; HYPOXIA; OXYGEN AB Purpose. Angiotensin converting enzyme (ACE) inhibition has been shown in animal models of retinopathy and in patients with diabetes to improve retinal neovascularization. The mechanism is not clearly identified, but could potentially be mediated via vascular endothelial growth factor modification. The objective of this study was to determine the effect of captopril, an angiotensin converting enzyme (ACE) inhibitor, on retinal VEGF, VEGF-R1, and VEGF-R2 expression in a mouse model of oxygen induced retinopathy (OIR). Methods. A mouse model of OIR was used and retinal tissue was obtained at P7, prior to oxygen exposure, at P12, just after oxygen exposure, and at P17, the time of maximal retinal neovascularization for VEGF, VEGF-R1 and VEGF-R2 assessment. A group of animals were treated with captopril (0.5 mg/kg/d SC from P7 for five days). Results. Captopril plus OIR treated animals had higher levels of retinal VEGF mRNA and protein at P12 (p<0.05) and lower levels at P17 (p<0.05) than OIR animals. VEGF-R1 mRNA expression increased 16 fold from P7 to P17 (p<0.05) in room air reared animals. VEGF-R1 mRNA expression was unaffected by OIR and/or captopril treatment. VEGF-R2 mRNA expression decreased from P7 to P17 by 1.5-fold in room air reared animals (p=0.001). Retinal VEGF-R2 mRNA and protein expression were significantly higher at P12 in OIR plus captopril treated animals than OIR animals (p=0.01). Conclusions. In summary, captopril maintains VEGF and increases VEGF-R2 expression during the period of hyperoxia when VEGF expression is normally suppressed. Captopril treatment during oxygen exposure is associated with a reduction in the angiogenic response at day 17 as manifested by decreased VEGF and VEGF-R2 expression in retinal tissue. Angiotensin converting enzyme inhibition is associated with changes in expression of VEGF and VEGF-R2 in the evolution of retinal neovascularization in the mouse model of retinopathy. C1 Georgetown Univ, Childrens Med Ctr, Dept Pediat, Div Neonatol, Washington, DC 20007 USA. RP Higgins, RD (reprint author), NICHD, Pregnancy & Perinatol Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. NR 19 TC 11 Z9 13 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD AUG PY 2003 VL 27 IS 2 BP 123 EP 129 DI 10.1076/ceyr.27.2.123.15955 PG 7 WC Ophthalmology SC Ophthalmology GA 719WD UT WOS:000185227300009 PM 14632165 ER PT J AU Lehrmann, E Hyde, TM Vawter, MP Becker, KG Kleinman, JE Freed, WJ AF Lehrmann, E Hyde, TM Vawter, MP Becker, KG Kleinman, JE Freed, WJ TI The use of microarrays to characterize neuropsychiatric disorders: Postmortem studies of substance abuse and schizophrenia SO CURRENT MOLECULAR MEDICINE LA English DT Review DE mRNA quality; cDNA microarray; transcriptional profile; cocaine abuse; human brain; prefrontal cortex; MAPK pathway ID SIGNAL-REGULATED KINASE; GENE-EXPRESSION DIFFERENCES; MESSENGER-RNA; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; CLUSTER-ANALYSIS; HUMAN-BRAIN; FUNCTIONAL GENOMICS; SYNAPTIC PLASTICITY; VULNERABILITY GENES AB Neuropsychiatric disorders are generally diagnosed based on a classification of behavioral and, in some cases, specific neurological deficits. The lack of distinct quantitative and qualitative biological descriptors at the anatomical and cellular level complicates the search for and understanding of the. neurobiology of these disorders. The advent of microarray technology has enabled large-scale profiling of transcriptional activity, allowing a comprehensive characterization of transcriptional patterns relating to the pathophysiology of neuropsychiatric disorders. We review some of the unique methodological constraints related to the use of human postmortem brain tissue in addition to the generally applicable requirements for microarray experiments. Microarray studies undertaken in neuropsychiatric disorders such as schizophrenia and substance abuse by the use of postmortem brain tissue indicate that transcriptional changes relating to synaptic function and plasticity, cytoskeletal function, energy metabolism, oligodendrocytes, and distinct intracellular signaling pathways are generally present. These have been supported by microarray studies in experimental models, and have produced multiple avenues to be explored at the functional level. The quality and specificity of information obtained from human postmortem tissue is rapidly increasing with the maturation and refinement of array-related methodologies and analysis tools, and with the use of focused cell populations. The development of experimental models of gene regulation in these disorders will serve as the initial step towards a comprehensive genome-linked analysis of the brain and associated disorders, and help characterize the integration and coordinate regulation of complex functions within the CNS. C1 Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, DHHS, NIH, Baltimore, MD 21224 USA. Univ Calif Irvine, Irvine, CA 92697 USA. NIA, DNA Array Unit, Res Resources Branch, DHHS,NIH, Baltimore, MD 21224 USA. NIMH, Clin Brain Disorders Branch, IRP, DHHS,NIH, Bethesda, MD 20892 USA. RP Lehrmann, E (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, DHHS, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 99 TC 16 Z9 17 U1 1 U2 2 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2003 VL 3 IS 5 BP 437 EP 446 DI 10.2174/1566524033479690 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 711NV UT WOS:000184748700006 PM 12942997 ER PT J AU Nie, ZZ Hirsch, DS Randazzo, PA AF Nie, ZZ Hirsch, DS Randazzo, PA TI Arf and its many interactors SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID ADP-RIBOSYLATION-FACTOR; GUANINE-NUCLEOTIDE-EXCHANGE; GTPASE-ACTIVATING PROTEINS; TRANS-GOLGI NETWORK; VESICULAR TRANSPORT; BINDING PROTEINS; STRUCTURAL BASIS; TARGET PROTEIN; COPI VESICLES; SEC7 DOMAIN AB Arf GTP-binding proteins regulate membrane traffic and actin remodeling. Similar to other GTP-binding proteins, a complex of Arf-GTP with an effector protein mediates Arf function. Arf interacts with at least three qualitatively different types of effectors. First, it interacts with structural proteins, the vesicle coat proteins. The second type of effector is lipid-metabolizing enzymes, and the third comprises those proteins that bind to Arf-GTP but whose biochemical or biological functions are not yet clearly defined. Arf interacts with two other families of proteins, the exchange factors and the GTPase-activating proteins. Recent work examining the functional relationships among the diverse Arf interactors has led to reconsideration of the prevailing paradigms for Arf action. C1 NCI, Cellular Oncol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Nie, ZZ (reprint author), NCI, Cellular Oncol Lab, Canc Res Ctr, Bldg 37,Room 4118, Bethesda, MD 20892 USA. NR 96 TC 167 Z9 169 U1 3 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD AUG PY 2003 VL 15 IS 4 BP 396 EP 404 DI 10.1016/S0955-0674(03)00071-1 PG 9 WC Cell Biology SC Cell Biology GA 709TV UT WOS:000184641200005 PM 12892779 ER PT J AU Austin, CP AF Austin, CP TI The completed human genome: implications for chemical biology SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID SMALL-MOLECULE; DRUG DISCOVERY; GENE-EXPRESSION; RECEPTOR; IDENTIFICATION; PROJECT; MICROARRAYS; COMPENDIUM; INHIBITORS; DROSOPHILA AB The recently completed human genome sequence represents an enormous opportunity to understand biology and accelerate the development of new therapeutics. However, it also presents equally large logistical, scientific and paradigmatic challenges to efficiently translate the enormous cache of sequence data into functional information that will be the precursor of new drug development. Small-molecule chemical biology applied on a genomic scale promises to speed this translation to novel therapeutics. C1 NHGRI, Bethesda, MD 20892 USA. RP Austin, CP (reprint author), NHGRI, Natl Inst Hlth Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov NR 50 TC 27 Z9 28 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD AUG PY 2003 VL 7 IS 4 BP 511 EP 515 DI 10.1016/S1367-5931(03)00083-8 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 718UW UT WOS:000185165700012 PM 12941427 ER PT J AU Germain, RN AF Germain, RN TI Immunological techniques - Editorial overview SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material ID CD4 T-CELLS; IN-VIVO; WHOLE-BODY; VISUALIZATION; SENSITIVITY; POLARITY; MOTILITY; ANTIGEN; MRI C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2003 VL 15 IS 4 BP 363 EP 365 DI 10.1016/S0952-7915(03)00081-5 PG 3 WC Immunology SC Immunology GA 709TU UT WOS:000184641100001 ER PT J AU Sher, A Pearce, E Kaye, P AF Sher, A Pearce, E Kaye, P TI Shaping the immune response to parasites: role of dendritic cells SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID TOXOPLASMA-GONDII INFECTION; TOLL-LIKE RECEPTOR-2; IL-12 PRODUCTION; CUTTING EDGE; IN-VITRO; T-CELLS; VISCERAL LEISHMANIASIS; PROTECTIVE IMMUNITY; TH2 RESPONSES; INDUCE TH1 AB Parasites represent a diverse group of pathogens that often trigger highly polarized immune responses that become tightly regulated during chronic infection. Recent studies have implicated the parasite-dendritic-cell interaction as a key determinant of the host response to these eukaryotic invaders. Dendritic cells appear to be pivotal in the initiation of cellular immunity against parasites as well as in directing Th1/Th2 effector choice. Moreover, there is increasing evidence that parasites regulate dendritic-cell function for the purposes of evading host immunity. This regulation also benefits parasites by protecting their host niche from the potentially lethal consequences of an uncontrolled inflammatory response. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA. Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England. RP Sher, A (reprint author), NIAID, Parasit Dis Lab, Bldg 50,Room 6140, Bethesda, MD 20892 USA. NR 54 TC 76 Z9 86 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2003 VL 15 IS 4 BP 421 EP 429 DI 10.1016/S0952-7915(03)00072-4 PG 9 WC Immunology SC Immunology GA 709TU UT WOS:000184641100011 PM 12900274 ER PT J AU Kirman, JR Seder, RA AF Kirman, JR Seder, RA TI DNA vaccination: the answer to stable, protective T-cell memory? SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID PRIME-BOOST IMMUNIZATION; RAISED IMMUNE-RESPONSES; CD8-T-CELL MEMORY; CD4-T-CELL HELP; PLASMID DNA; CPG MOTIFS; CLASS-II; IN-VIVO; CD8(+); CD4(+) AB Distinct populations of both CD4(+) and CD8(+) memory T cells have been identified on the basis of their location (lymphoid versus non-lymphoid tissues) and function. There have been several recent advances in our understanding of the factors that govern the generation and maintenance of T-cell memory in vivo. Utilising this knowledge could contribute to the refinement of DNA vaccine technology to induce more robust and longer-lasting protective T-cell based immunity. C1 Malaghan Inst Med Res, Wellington, New Zealand. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kirman, JR (reprint author), Malaghan Inst Med Res, POB 7060, Wellington, New Zealand. NR 47 TC 27 Z9 29 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2003 VL 15 IS 4 BP 471 EP 476 DI 10.1016/S0952-7915(03)00068-2 PG 6 WC Immunology SC Immunology GA 709TU UT WOS:000184641100018 PM 12900281 ER PT J AU Murphy, DD Ravina, B AF Murphy, DD Ravina, B TI Brain banking for neurodegenerative diseases SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE brain banking; neurodegeneration; neuropathology ID PROGRESSIVE SUPRANUCLEAR PALSY; PARKINSONS-DISEASE; LEWY BODIES; CLINICAL-DIAGNOSIS; ALPHA-SYNUCLEIN; DEMENTIA; PATHOLOGY; MUTATIONS; FAMILY; BODY AB Purpose of review Brain banking remains a necessity for the study of neurodegenerative diseases. While the characterization of pathology observed at autopsy confirms clinical diagnosis, the structure and contents of pathological hallmarks are the starting point from which disease pathogenesis may be elucidated. Traditional neuropathology has served to define, characterize, and diagnose neurodegenerative diseases, accompanied by clinical presentation. The pathological substrates are then studied for their role in how they cause dysfunction in disease, or how their accumulation is presumably damaging. Recent findings New genetic findings have revolutionized these studies and have prompted a reexamination of traditional pathological definitions of disease. Many familial genetic mutations have been found, encoding proteins such as synuclein, parkin, tau, and others, creating genetic ways to define neurodegenerative diseases. Many of these proteins are components of aggregates, thus the ability to label these proteins has revealed new pathological characteristics that must be standardized. More complicating is that many proteins genetically linked to clinically distinct diseases are involved in overlapping neuropathology of what now appears to be a spectrum of diseases: 'synucleinopathies', 'tauopathies', and so on. Moreover, as genetic discoveries fuel molecular experiments on brain tissue, banking methods must now accommodate these techniques. Lastly, DNA screening involves ethical issues beyond those which were previously considered with postmortem tissue banking. Summary As more proteins are linked to disease, more is revealed about the underlying causative mechanisms, exposing points for interventions. To achieve this end, characterization for neurodegenerative disease in the post genomic era must include genotype, phenotype and clinical characterization, and postmortem brain banking data which includes these. C1 Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Murphy, DD (reprint author), NSC Rm 2223,6001 Execut Blvd, Rockville, MD 20852 USA. NR 42 TC 10 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 2003 VL 16 IS 4 BP 459 EP 463 DI 10.1097/01.wco.0000084222.82329.f2 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 710KF UT WOS:000184678800003 PM 12869803 ER PT J AU Hermesz, E Williams-Simons, L Mahon, KA AF Hermesz, E Williams-Simons, L Mahon, KA TI A novel inducible element, activated by contact with Rathke's pouch, is present in the regulatory region of the Rpx/Hesx1 homeobox gene SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Rpx; Rathke's pouch; pituitary; hypothalamic development; transgenic mice; gastrulation; prechordal plate; induction; Hesx1 ID ANTERIOR NEURAL PLATE; BUFO-JAPONICUS; MOUSE EMBRYOS; PITUITARY; MESENCHYME; CELLS; PRIMORDIUM; HYPOPHYSIS; INDUCTION; DIFFERENTIATION AB Reciprocal inductive interactions are postulated to play a role in the determination and differentiation of the pituitary gland and the ventral hypothalamus. The homeobox gene Rpx/Hesxl is expressed during gastrulation in the anterior endoderm, prechordal plate, and the prospective cephalic neural plate, and at later stages of development in Rathke's pouch, the primordium of the pituitary. We have defined the regulatory elements necessary for proper spatial and temporal expression during development in transgenic mice using lacZ reporter genes. Proper spatial and temporal expression in the anterior endoderm prechordal plate and anterior neural plate can be recapitulated with as little as 568 bp of upstream sequence and intragenic, sequence containing the first exon and intron. Late-stage expression in Ratlike's pouch requires additional negative and positive regulatory elements. Interestingly, deletion analysis uncovered an element that directs transgene expression to a region of the hypothalamus that lies in direct contact with Rathke's pouch. In vitro tissue recombination experiments have established that this expression is induced by contact With the pouch. We propose that this element may be present in other genes that normally respond to signals emanating from the pouch during the development of the hypothalamic-pituitary axis. The Rpx-lacZ transgenic mice provide a novel model system for the molecular dissection of inductive cell signaling during pituitary development. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Hermesz, E (reprint author), Univ Szeged, Fac Sci, Dept Biochem, POB 533, H-6701 Szeged, Hungary. NR 49 TC 17 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2003 VL 260 IS 1 BP 68 EP 78 DI 10.1016/S0012-1606(03)00218-5 PG 11 WC Developmental Biology SC Developmental Biology GA 710KH UT WOS:000184679000006 PM 12885556 ER PT J AU Mi, QS Ly, D Lamhamedi-Cherradi, SE Salojin, KV Zhou, L Grattan, M Meagher, C Zucker, P Chen, YH Nagle, J Taub, D Delovitch, TL AF Mi, QS Ly, D Lamhamedi-Cherradi, SE Salojin, KV Zhou, L Grattan, M Meagher, C Zucker, P Chen, YH Nagle, J Taub, D Delovitch, TL TI Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice SO DIABETES LA English DT Article ID T-CELLS; DENDRITIC CELLS; IN-VIVO; DEFICIENT MICE; DEATH DOMAIN; APO2 LIGAND; TNF-ALPHA; KAPPA-B; TRAIL; EXPRESSION AB Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet beta-cells activated by TNF-alpha + interferon-gamma. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD.Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27(kip1). Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes. C1 John P Robarts Res Inst, Autoimmun Diabet Grp, London, ON N6G 2V4, Canada. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. John P Robarts Res Inst, Neurosignaling Grp, London, ON N6G 2V4, Canada. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5C1, Canada. RP Delovitch, TL (reprint author), John P Robarts Res Inst, Autoimmun Diabet Grp, 1400 Western Rd, London, ON N6G 2V4, Canada. NR 47 TC 64 Z9 74 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2003 VL 52 IS 8 BP 1967 EP 1975 DI 10.2337/diabetes.52.8.1967 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 705UT UT WOS:000184414200012 PM 12882912 ER PT J AU Ryan, AS Berman, DM Nicklas, BJ Sinha, M Gingerich, RL Meneilly, GS Egan, JM Elahi, D AF Ryan, AS Berman, DM Nicklas, BJ Sinha, M Gingerich, RL Meneilly, GS Egan, JM Elahi, D TI Plasma adiponectin and leptin levels, body composition, and glucose utilization in adult women with wide ranges of age and obesity SO DIABETES CARE LA English DT Article ID ADIPOSE-SPECIFIC PROTEIN; INSULIN-RESISTANCE; FAT; SENSITIVITY; WEIGHT; GENE; HYPERINSULINEMIA; POLYMORPHISM; ASSOCIATION; EXPRESSION AB OBJECTIVE - The purpose of this study was to determine the relationships between plasma adiponectin and leptin levels, total and central obesity, and glucose utilization across the adult age span. RESEARCH DESIGN AND METHODS - We studied 148 women aged 18 - 81 years with a BMI range of 17.2-44.3 kg/m(2). Total percent body fat was determined by dual-energy X-ray absorptiometry and abdominal fat by computed tomography. Glucose tolerance in non-type 2 diabetic volunteers was determined with an oral glucose tolerance test. Glucose Utilization M was measured during the last 60 min of hyperinsulinemic-euglycemic clamps (240 pmol.m(-2).min(-1)). Plasma adiponectin levels were measured by radioimmunoassay. The women were separated into three age-groups: young, middle, and old (<40, 40-59, and 60 years, respectively), as well as by glucose tolerance status. RESULTS - Adiponectin concentrations did not differ by age-groups. There were significant age effects for BMI, percent body fat, visceral fat, subcutaneous abdominal fat, VO2max, and M. Adiponectin levels were lower in the prediabetic women (n = 18) than in the normal glucose-tolerant women (n = 108) and the women with type 2 diabetes (n = 22) (both P < 0.05). Univariate correlations revealed significant negative relationships between plasma adiponectin levels and MAL percent body fat, visceral fat, subcutaneous abdominal fat, fasting leptin, and fasting insulin and positive relationship with M (all P < 0.05). In a multiple stepwise regression model to predict adiponectin, only M remained in the model at P < 0.001. Multivariate analyses revealed a significant relation for M as a function of adiponectin, insulin, and VO2max. CONCLUSIONS - The data suggest that plasma adiponectin does not change with age but levels are negatively associated with percent body fat, visceral fat, subcutaneous abdominal fat 0 1 insulin, and leptin levels in women. Adiponectin is positively associated With M across the age span in women. C1 Univ Maryland, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. VA Maryland Hlth Care Syst, Baltimore Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. Linco Res, St Charles, MO USA. Univ British Columbia, Dept Med, Vancouver, BC, Canada. NIA, Baltimore, MD 21224 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Ryan, AS (reprint author), Baltimore Vet Affairs Med Ctr, Div Gerontol, BT-18-GR,10 N Greene St, Baltimore, MD 21201 USA. FU NIA NIH HHS [K01-AG00685, K01-AG00747]; PHS HHS [R29-A614066] NR 25 TC 173 Z9 179 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 AUG PY 2003 VL 26 IS 8 BP 2383 EP 2388 DI 10.2337/diacare.26.8.2383 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720AQ UT WOS:000185238700026 PM 12882866 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 insulin sensitivity in Pima Indian children. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIDDK, DHHS, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 771 BP A267 EP A267 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100770 ER PT J AU DelParigi, A Beach, TG Page, GP Allison, DB Tataranni, A AF DelParigi, A Beach, TG Page, GP Allison, DB Tataranni, A TI Differential gene expression in the hypothalamus of obese and lean humans: a preliminary report. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIH, Clin Diabet & Nutr Sect, Phoenix, AZ USA. Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA. Sun Hlth Res Inst, Brain Bank, Sun City, AZ USA. Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 657 BP A227 EP A228 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100657 ER PT J AU Haluzik, M Gavrilova, O LeRoith, D AF Haluzik, M Gavrilova, O LeRoith, D TI The effect of peroxisome proliferator-activated receptor alpha (PPAR-alpha) knockout on insulin sensitivity as studied by the hyperinsulinemic-euglycemic clamp technique SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 Charles Univ, Fac Med 1, Dept Med 3, CR-11636 Prague 1, Czech Republic. NIDDK, Diabet Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 587 BP A204 EP A204 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100587 ER PT J AU Hoogwerf, BJ Chew, EY Cusick, M Ferris, FL Agron, E AF Hoogwerf, BJ Chew, EY Cusick, M Ferris, FL Agron, E TI Risk factors for nephropathy in the Early Treatment Diabetic Retinopathy Study (ETDRS). SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NEI, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NIH, ETDRS Res Grp, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 960 BP A332 EP A332 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100959 ER PT J AU Kovacs, P Harper, I Kobes, S Hanson, R Bogardus, C Baier, LJ Tataranni, PA AF Kovacs, P Harper, I Kobes, S Hanson, R Bogardus, C Baier, LJ Tataranni, PA TI A novel missense mutation (Val1481Ile) in the fatty acid synthase gene (FAS) is associated with percentage of body fat and lipid oxidation rates in Pima Indians. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 381 BP A135 EP A135 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100381 ER PT J AU Oknianska, A Zmuda, E Holst, LS Manganiello, V Degerman, E AF Oknianska, A Zmuda, E Holst, LS Manganiello, V Degerman, E TI The role of protein kinase B in the regulation of lipid metabolism in adipocytes. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 Lund Univ, Dept Cell & Mol Biol, S-22100 Lund, Sweden. NIH, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 49 BP A20 EP A20 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100050 ER PT J AU Pavkov, ME Bennett, PH Sievers, ML Knowler, WC Nelson, RG AF Pavkov, ME Bennett, PH Sievers, ML Knowler, WC Nelson, RG TI Effects of chronic kidney disease and end stage renal failure on mortality in Pima Indians with Type 2 diabetes. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIDDK, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 944 BP A326 EP A326 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100943 ER PT J AU Stefan, N Kovacs, P Stumvoll, M Hanson, RL Lehn-Stefan, A Permana, PA Baier, LJ Tataranni, PA Silver, K Bogardus, C AF Stefan, N Kovacs, P Stumvoll, M Hanson, RL Lehn-Stefan, A Permana, PA Baier, LJ Tataranni, PA Silver, K Bogardus, C TI Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIDDK, NIH, Phoenix, AZ USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 374 BP A132 EP A132 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100374 ER PT J AU Stumvoll, M Tataranni, PA Bogardus, C AF Stumvoll, M Tataranni, PA Bogardus, C TI Glucose allostasis. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 563 BP A196 EP A196 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100563 ER PT J AU Vozarova, B Weyer, C Stefan, N Del Parigi, A Havel, P Hanson, R Bogardus, C Tataranni, A AF Vozarova, B Weyer, C Stefan, N Del Parigi, A Havel, P Hanson, R Bogardus, C Tataranni, A TI Parasympathetic blockade attenuates differences in pancreatic polypeptide but not insulin secretion in Pima Indians versus Caucasians SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 NIH, Phoenix, AZ USA. Univ Calif Davis, Davis, CA 95616 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 479 BP A169 EP A169 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100479 ER PT J AU Williams, K Ferrannini, E Bogardus, C DeFronzo, RA Hunt, KJ Garvey, W Reaven, GM Stern, MP AF Williams, K Ferrannini, E Bogardus, C DeFronzo, RA Hunt, KJ Garvey, W Reaven, GM Stern, MP TI A model to identify individuals likely to be insulin resistant. SO DIABETOLOGIA LA English DT Meeting Abstract CT 18th Congress of the International-Diabetes-Federation CY AUG 24-29, 2003 CL PARIS, FRANCE SP Int Diabetes Fed C1 Univ Texas, Hlth Sci Ctr, Dept Med Clin Epidemiol, San Antonio, TX USA. CNR, Inst Clin Physiol, I-56100 Pisa, Italy. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. Univ Texas, Hlth Sci Ctr, Dept Med Diabet, San Antonio, TX USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. Stanford Univ, Sch Med, San Francisco, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2003 VL 46 SU 2 MA 555 BP A193 EP A194 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 720BX UT WOS:000185242100555 ER PT J AU Corleto, VD Goebel, SU Panzuto, F Jensen, RT Delle Fave, G Annibale, B AF Corleto, VD Goebel, SU Panzuto, F Jensen, RT Delle Fave, G Annibale, B TI Co-existence of hyperparathyroidism, hypergastrinaemia and multiple gastric carcinoids is not always due to incomplete expression of the MEN-1 syndrome SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE gastric carcinoid; hypergastrinaemia; hyperparathyroidism; multiple endocrine neoplasia type 1 ID ENDOCRINE NEOPLASIA TYPE-1; ATROPHIC BODY GASTRITIS; ZOLLINGER-ELLISON-SYNDROME; NEUROENDOCRINE TUMORS; DUODENAL-ULCER; GENE; CLASSIFICATION; HETEROZYGOSITY; PREVALENCE; MUTATIONS AB Until recently, the association of primary hyperparathyroidism and gastric carcinoid, with or without hypergastrinaemia, had been considered an incomplete form of multiple endocrine neoplasia type 1. This is because it seemed unlikely that the rare joint appearance of these diseases could occur only by chance. It is now possible to evaluate the pathogenetic involvement of the Multiple endocrine neoplasia type 1 gene in many, apparently sporadic, clinical conditions. This is a case report of a female mimicking multiple endocrine neoplasia type 1 due to the presence of hyperparathyroidism, gastric carcinoid, and hypergastrinaemia. However, involvement of the MEN-1 gene (exons 2-10) was not detected, whereas hypergastrinaemia was attributed to a chronic atrophic gastritis. (C) 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 Univ Roma La Sapienza, Sch Med 2, Gastroenterol & Hepatol Unit, Rome, Italy. NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Corleto, VD (reprint author), Univ Roma La Sapienza, Sch Med 2, Gastroenterol & Hepatol Unit, Rome, Italy. OI Panzuto, Francesco/0000-0003-2789-4289 NR 25 TC 4 Z9 4 U1 0 U2 0 PU PACINI EDITORE PI PISA PA VIA DELLA GHERARDESCA-ZONA INDUSTRIALE OSPEDALETTO, 56121 PISA, ITALY SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD AUG PY 2003 VL 35 IS 8 BP 585 EP 589 DI 10.1016/S1590-8658(03)00278-0 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 717TM UT WOS:000185106500012 PM 14567464 ER PT J AU Fisher, ER Colangelo, L Wieand, S Fisher, B Wolmark, N AF Fisher, ER Colangelo, L Wieand, S Fisher, B Wolmark, N TI Lack of influence of cytokeratin-positive mini micrometastases in "negative node" patients with colorectal cancer: Findings from the national surgical adjuvant breast and bowel projects protocols R-01 and C-01 SO DISEASES OF THE COLON & RECTUM LA English DT Article DE occult nodal metastases; nodal mini micrometastases; Dukes A and B colorectal cancer ID LYMPH-NODES; CHEMOTHERAPY; IDENTIFICATION; METASTASIS; CARCINOMA; SURVIVAL AB Purpose: Results of the few extant reports concerning the clinical significance of so-called "occult micrometastases" of lymph nodes of patients with Dukes A and B colorectal cancer have been variable. We examined the presumably negative nodes of a larger cohort of such patients who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trials R-01 and C-01 for the influence of what we preferably designate as nodal mini micrometastases on parameters of survival. Methods: Mini micrometastases were detected by immunohistochemical staining of the original lymph node sections with anticytokeratin A1/A3 in a total of 241 Dukes A and B patients with rectal and 158 with colonic cancers. Their frequency, as well as that of nuclear and histologic grades, and an estimation of their relationship to relative risks were correlated with overall and recurrence-free survival by univariate and multivariate analyses. Results: Nodal mini micrometastases were detected in 73 of 399 (18.3 percent) patients of this cohort. They failed to exhibit any significant relationship to overall or recurrence-free survival. No association between the assessments of tumor differentiation and mini micrometastases was found. Nuclear and histologic grades also failed to further discriminate overall or recurrence-free survival in patients with A or B stages of colonic or rectal cancers in this cohort. Conclusion: The immunohistochemical demonstration of nodal mini micrometastases failed to discriminate high- and low-risk groups of patients with colorectal cancer who were designated as being node-negative after routine pathologic examination. C1 NSABP, Pathol Ctr, Pittsburgh, PA USA. NSABP, Ctr Biostat, Pittsburgh, PA USA. NSABP, Headquarter Ctr, Pittsburgh, PA USA. RP Fisher, ER (reprint author), Allegheny Gen Hosp, 5th Floor,320 East North Ave, Pittsburgh, PA 15212 USA. NR 15 TC 36 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD AUG PY 2003 VL 46 IS 8 BP 1021 EP 1025 DI 10.1097/01.DCR.0000080144.15633.15 PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 711NX UT WOS:000184748900004 PM 12907892 ER PT J AU Morin, PJ AF Morin, PJ TI Drug resistance and the microenvironment: nature and nurture SO DRUG RESISTANCE UPDATES LA English DT Review DE chemoresistance; extracellular matrix; collagen IV; collagen VI; cisplatin ID CELL LUNG-CANCER; NF-KAPPA-B; EXTRACELLULAR-MATRIX; MYELOMA CELLS; CONSTITUTIVE ACTIVATION; CONFERS RESISTANCE; INDUCED APOPTOSIS; ANTICANCER DRUGS; MULTIPLE-MYELOMA; GROWTH-FACTOR AB Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have an important impact on the success of chemotherapy. Indeed, cell-cell and cell-matrix interactions can influence the cancer cells sensitivity to apoptosis and affect drug resistance. A model is proposed in which the tumor cells may actively reorganize their environment to maximize their survival in the presence of anticancer agents. Published by Elsevier Ltd. C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21224 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 89 Z9 91 U1 1 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD AUG PY 2003 VL 6 IS 4 BP 169 EP 172 DI 10.1016/S1368-7646(03)00059-1 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 724TQ UT WOS:000185503100002 PM 12962682 ER PT J AU Battey, JF AF Battey, JF TI Using genetics to understand auditory function and improve diagnosis SO EAR AND HEARING LA English DT Article ID HEREDITARY HEARING-LOSS; OUTER HAIR-CELLS; UNCONVENTIONAL MYOSIN; DEAFNESS; MUTATION; PROTEIN; PRESTIN; MOUSE; GENES; MICE C1 Natl Inst Deafness & Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), Natl Inst Deafness & Commun Disorders, NIH, Bldg 31,Room 3C02,31 Convent Dr,MSC 2320, Bethesda, MD 20892 USA. NR 24 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD AUG PY 2003 VL 24 IS 4 BP 266 EP 269 DI 10.1097/01.AUD.0000079807.44293.DE PG 4 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 747CH UT WOS:000186787300003 PM 12923417 ER PT J AU Friedman, TB Schultz, JM Ben-Yosef, T Pryor, SP Lagziel, A Fisher, RA Wilcox, ER Riazuddin, S Ahmed, ZM Belyantseva, IA Griffith, AJ AF Friedman, TB Schultz, JM Ben-Yosef, T Pryor, SP Lagziel, A Fisher, RA Wilcox, ER Riazuddin, S Ahmed, ZM Belyantseva, IA Griffith, AJ TI Recent advances in the understanding of syndromic forms of hearing loss SO EAR AND HEARING LA English DT Article ID WAARDENBURG-HIRSCHSPRUNG-DISEASE; SYNDROME-TYPE-I; AUTOSOMAL RECESSIVE DEAFNESS; JACKSON SHAKER MICE; SYNDROME TYPE 1D; USHER-SYNDROME; PENDRED-SYNDROME; INNER-EAR; PROTOCADHERIN GENE; MISSENSE MUTATION C1 Natl Inst Deafness Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, Rockville, MD 20850 USA. Natl Inst Deafness Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. Natl Inst Deafness Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. RP Friedman, TB (reprint author), Natl Inst Deafness Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, 5 Res Court,Room 2A-19, Rockville, MD 20850 USA. NR 66 TC 11 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD AUG PY 2003 VL 24 IS 4 BP 289 EP 302 DI 10.1097/01.AUD.0000079804.00047.CE PG 14 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 747CH UT WOS:000186787300006 PM 12923420 ER PT J AU Chen, A Rogan, WJ AF Chen, A Rogan, WJ TI Nonmalarial infant deaths and DDT use for malaria control SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CHILD-MORTALITY; DICHLORODIPHENYL DICHLOROETHENE; POLYCHLORINATED-BIPHENYLS; INFECTIOUS-DISEASES; PERINATAL-MORTALITY; NONHUMAN-PRIMATES; RURAL MALAWI; BREAST-MILK; PRETERM; METABOLITES AB Although dichlorodiphenyl trichloroethane (DDT) is being banned worldwide, countries in sub-Saharan Africa have sought exemptions for malaria control. Few studies show illness in children from the use of DDT and the possibility of risks to them from DDT use has been minimized. However, plausible if inconclusive studies associate DDT with more preterm births and shorter duration of lactation, which raise the possibility that DDT does indeed have such toxicity. Assuming that these associations are causal, we estimated the increase in infant deaths that might result from DDT spraying. The estimated increases are of the same order of magnitude as the decreases from effective malaria control. Unintended consequences of DDT use need to be part of the discussion of modern vector control policy. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 44 TC 22 Z9 22 U1 1 U2 5 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2003 VL 9 IS 8 BP 960 EP 964 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 707FP UT WOS:000184500100010 PM 12967494 ER PT J AU Factor, SH Levine, OS Schwartz, B Harrison, LH Farley, MM McGeer, A Schuchat, A AF Factor, SH Levine, OS Schwartz, B Harrison, LH Farley, MM McGeer, A Schuchat, A TI Invasive group A streptococcal disease: Risk factors for adults SO EMERGING INFECTIOUS DISEASES LA English DT Article ID NECROTIZING FASCIITIS; PRIMARY VARICELLA; INFECTIONS; CHILDREN; CARRIAGE AB We conducted a case-control study to identify risk factors for invasive group A streptococcal (GAS) infections, which can be fatal. Case-patients were identified when Streptococcus pyogenes was isolated from a normally sterile site and control subjects (two or more) were identified and matched to case-patients by using sequential-digit telephone dialing. All participants were non institutionalized surveillance area residents, >18 years of age. Conditional logistic regression identified the risk factors for invasive GAS infection: in adults 18 to 44 years of age, exposure to one or more children with sore throats (relative risk [RR]=4.93, p=0.02), HIV infection (RR=15.01, p=0.04), and history of injecting drug use (RR=14.71, p=0.003); in adults >45 years of age, number of persons in the home (RR=2.68, p=0.004), diabetes (RR=2.27, p=0.03), cardiac disease (RR=3.24, p=0.006), cancer (RR=3.54, p=0.006), and corticosteroid use (RR=5.18, p=0.03). Thus, host and environmental factors increased the risk for invasive GAS disease. C1 Ctr Dis Control & Prevent, Atlanta, GA USA. New York Acad Med, New York, NY USA. NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Emory Univ, Atlanta, GA 30322 USA. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. RP Factor, SH (reprint author), New York City Dept Hlth & Mental Hyg, Dept Dis Intervent, 125 Worth St, New York, NY 10013 USA. RI mcgeer, allison /H-7747-2014 OI mcgeer, allison /0000-0001-5647-6137 NR 19 TC 52 Z9 52 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 AUG PY 2003 VL 9 IS 8 BP 970 EP 977 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 707FP UT WOS:000184500100012 PM 12967496 ER PT J AU Hochberg, Z Pacak, K Chrousos, GP AF Hochberg, Z Pacak, K Chrousos, GP TI Endocrine withdrawal syndromes SO ENDOCRINE REVIEWS LA English DT Review ID CORTICOTROPIN-RELEASING HORMONE; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; ANABOLIC-STEROID WITHDRAWAL; MESSENGER-RIBONUCLEIC-ACID; MESOLIMBIC DOPAMINE SYSTEM; IDIOPATHIC SHORT STATURE; IN-VIVO MICRODIALYSIS; DISCRETE BRAIN NUCLEI; HUMAN GROWTH-HORMONE; PREMENSTRUAL-SYNDROME AB Hypersecretion of endogenous hormones or chronic administration of high doses of the same hormones induces varying degrees of tolerance and dependence. Elimination of hormone hypersecretion or discontinuation of hormone therapy may result in a mixed picture of two syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome. Thus, hormones with completely different physiological effects may produce similar withdrawal syndromes, with symptoms and signs reminiscent of those observed with drugs of abuse, suggesting shared mechanisms. This review postulates a unified endocrine withdrawal syndrome, with changes in the hypothalamic-pituitary-adrenal axis and the central opioid peptide, in which noradrenergic and dopaminergic systems of the brain act as common links in its pathogenesis. Long-term adaptations to hormones may involve relatively persistent changes in molecular switches, including common intracellular signaling systems, from membrane receptors to transcription factors. The goals of therapy are to ease withdrawal symptoms and to expedite weaning of the patient from the hormonal excess state. Clinicians should resort to the fundamentals of tapering hormones down over time, even in the case of abrupt removal of a hormone-producing tumor. In addition, the prevention of stress and concurrent administration of antidepressants may ameliorate symptoms and signs of an endocrine withdrawal syndrome. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Meyer Childrens Hosp, Div Endocrinol, IL-31096 Haifa, Israel. RP Chrousos, GP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. NR 167 TC 62 Z9 64 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD AUG PY 2003 VL 24 IS 4 BP 523 EP 538 DI 10.1210/er.2001-0014 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 712PU UT WOS:000184806700005 PM 12920153 ER PT J AU Cheng, WS Giandomenico, V Pastan, I Essand, M AF Cheng, WS Giandomenico, V Pastan, I Essand, M TI Characterization of the androgen-regulated prostate-specific T cell receptor gamma-chain alternate reading frame protein (TARP) promoter SO ENDOCRINOLOGY LA English DT Article ID UPSTREAM ENHANCER; RESPONSE ELEMENT; GENE-EXPRESSION; ANTIGEN GENE; CANCER; ADENOVIRUS; IDENTIFICATION; CONSTRUCTION; COACTIVATOR; INTERACTS AB TARP (T cell receptor gamma-chain alternate reading frame protein) is uniquely expressed in males in prostate epithelial cells and prostate cancer cells. Here we demonstrate that TARP expression is regulated by testosterone at the transcriptional level through specific binding of androgen receptor to an androgen response element in the proximal TARP promoter. We further demonstrate that the promoter specifically initiates reporter gene expression in TARP-positive prostate cancer cell lines. To develop a regulatory sequence for prostate-specific gene expression, we constructed a chimeric sequence consisting of the TARP promoter and the prostate-specific antigen (PSA) enhancer. We found that in the prostatic adenocarcinoma cell line LNCaP, the transcriptional activity of the regulatory sequence consisting of a TARP promoter and PSA enhancer is 20 times higher than the activity of a regulatory sequence consisting of the PSA promoter and PSA enhancer. Thus, our studies define a regulatory sequence that may be used to restrict expression of therapeutic genes to prostate cancer cells and may therefore play a role in prostate cancer gene therapy. C1 Uppsala Univ, Rudbeck Lab, SE-75185 Uppsala, Sweden. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Essand, M (reprint author), Uppsala Univ, Rudbeck Lab, SE-75185 Uppsala, Sweden. NR 25 TC 21 Z9 22 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 AUG PY 2003 VL 144 IS 8 BP 3433 EP 3440 DI 10.1210/en.2003-0121 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 703AW UT WOS:000184258700022 PM 12865322 ER PT J AU Osornio-Vargas, AR Bonner, JC Alfaro-Moreno, E Martinez, L Garcia-Cuellar, C Rosales, SPD Miranda, J Rosas, I AF Osornio-Vargas, AR Bonner, JC Alfaro-Moreno, E Martinez, L Garcia-Cuellar, C Rosales, SPD Miranda, J Rosas, I TI Proinflammatory and cytotoxic effects of Mexico City air pollution particulate matter in vitro are dependent on particle size and composition SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE apoptosis; cytotoxicity; endotoxin; IL-6; interleukin-6; J774A.1 cells; Mexico City; particle composition; particulate matter; PM10; PM2.5; TNF-alpha; tumor necrosis factor-alpha ID COARSE PARTICLES; FINE PM2.5; MORTALITY; APOPTOSIS; INDUCTION; CELLS AB Exposure to urban airborne particulate matter (PM) is associated with adverse health effects. We previously reported that the cytotoxic and proinflammatory effects of Mexico City PM10 (less than or equal to 10 mum mean aerodynamic diameter) are determined by transition metals and endotoxins associated with these particles. However, PM2.5 (less than or equal to 2.5 mum mean aerodynamic diameter) could be more important as a human health risk because this smaller PM has the potential to reach the distal lung after inhalation. In this study, we compared the cytotoxic and proinflammatory effects of Mexico City PM 10 with those of PM2.5 using the routine monocytic J774A.1 cell line in vitro. PMs were collected from the northern zone or the southeastern zone of Mexico City. Elemental composition and bacterial endotoxin on PMs were measured. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production by J774A. 1 cells was measured in the presence or absence of recombinant endotoxin-neutralizing protein (rENP). Both northern and southeastern PMs contained endotoxin and a variety of transition metals. Southeastern PM10 contained the highest endotoxin levels, 2-fold higher than that in northern PM10. Northern and southeastern PM2.5 contained the lowest endotoxin levels. Accordingly, southeastern PM10 was the most potent in causing secretion of the proinflammatory cytokines TNF-alpha and IL-6. All PM2.5 and PM10 samples caused cytotoxicity, but northern F`Ms were the most toxic. Cytokine secretion induced by southeastern PM10 was reduced 50-75% by rENP. These results indicate major differences in PM10 and PM2.5 PM2.5 induces cytotoxicity in vitro through an endotoxin-independent mechanism that is likely mediated by transition metals. In contrast, PM10 with relatively high levels of endotoxin induces proinflammatory cytokine release via an endotoxin-dependent mechanism. C1 Inst Nacl Cancerol, Div Invest Basica, Mexico City 14080, DF, Mexico. Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. Univ Nacl Autonoma Mexico, Fac Med, Mexico City 04510, DF, Mexico. Univ Nacl Autonoma Mexico, Ctr Ciencias Atmosfera, Mexico City 04510, DF, Mexico. Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. Univ Nacl Autonoma Mexico, Inst Fis, Mexico City 04510, DF, Mexico. RP Osornio-Vargas, AR (reprint author), Inst Nacl Cancerol, Div Invest Basica, Av San Fernando 22,Tlalpan, Mexico City 14080, DF, Mexico. RI Osornio Vargas, Alvaro/D-4012-2009; Osornio Vargas, Alvaro/B-4645-2010; OI Osornio Vargas, Alvaro/0000-0001-8287-7102; Alfaro-Moreno, Ernesto/0000-0003-1132-7992 NR 27 TC 127 Z9 129 U1 3 U2 23 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 AUG PY 2003 VL 111 IS 10 BP 1289 EP 1293 DI 10.1289/ehp.5913 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 711MX UT WOS:000184746600029 PM 12896848 ER PT J AU Koken, PJM Piver, WT Ye, F Elixhauser, A Olsen, LM Portier, CJ AF Koken, PJM Piver, WT Ye, F Elixhauser, A Olsen, LM Portier, CJ TI Temperature, air pollution, and hospitalization for cardiovascular diseases among elderly people in Denver SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE acute myocardial infarction; air pollution; cardiac dysrhythmias; cardiovascular diseases; CO; congestive heart failure; coronary atherosclerosis; generalized estimating equations; NO2; O-3; PM10; Poisson regression; pulmonary heart disease; SO2; temperature ID CONGESTIVE-HEART-FAILURE; TIME-SERIES ANALYSIS; CARBON-MONOXIDE; US CITIES; ADMISSIONS; MORTALITY; ASSOCIATION; WEATHER; HEALTH; ARRHYTHMIA AB Daily measures of maximum temperature, particulate matter! 10 Put in aerodynamic diameter (PM10), and gaseous pollution (ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide) were collected in Denver, Colorado, in July and August between 1993 and 1997. We then compared these exposures with concurrent data on the number of daily hospital admissions for cardiovascular diseases in men and women > 65 years of age. Generalized linear models, assuming a Poisson error structure for the selected cardiovascular disease hospital admissions, were constructed to evaluate the associations with air pollution and temperature. After adjusting the admission data for yearly trends, day of-week effects, ambient maximum temperature, and dew point temperature, we studied the associations of the pollutants in single-pollutant models with lag times of 0-4 days. The results suggest that O-3 is associated with an increase in the risk of hospitalization for acute myocardial infarction, coronary atherosclerosis, and pulmonary heart disease. SO2 appears to be related to increased hospital stays for cardiac dysrhythmias, and CO is significantly associated with congestive heart failure. No association was found between particulate matter or NO2 and any of the health outcomes. Males tend to have higher numbers of hospital admissions than do females for all of the selected cardiovascular diseases, except for congestive heart failure. Higher temperatures appear to be an important factor in increasing the frequency of hospitalization for acute myocardial infarction and congestive heart failure, and are associated with a decrease in the frequency of visits for coronary atherosclerosis and pulmonary heart disease. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Agcy Healthcare Res & Qual, Rockville, MD USA. NASA, Greenbelt, MD USA. RP Koken, PJM (reprint author), NIEHS, MD A3-06,POB 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 46 TC 136 Z9 142 U1 6 U2 22 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 AUG PY 2003 VL 111 IS 10 BP 1312 EP 1317 DI 10.1289/ehp.5957 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 711MX UT WOS:000184746600033 PM 12896852 ER PT J AU Kamel, F Umbach, DM Lehman, TA Park, LP Munsat, TL Shefner, JM Sandler, DP Hu, H Taylor, JA AF Kamel, F Umbach, DM Lehman, TA Park, LP Munsat, TL Shefner, JM Sandler, DP Hu, H Taylor, JA TI Amyotrophic lateral sclerosis, lead, and genetic susceptibility: Polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE delta-aminolevulinic acid dehydratase; amyotrophic lateral sclerosis; genetic susceptibility; lead; vitamin D receptor ID BLOOD LEAD; BONE LEAD; DIMERCAPTOSUCCINIC ACID; ALAD POLYMORPHISM; SMELTER WORKERS; EXPOSED WORKERS; GENOTYPE; ASSOCIATIONS; TOXICITY; DENSITY AB Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDA may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of AlS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% Cl), 0.60-6.31. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 IVS2 + 299G >A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Bioserve Biotechnol, Rockville, MD USA. WESTAT Corp, Durham, NC USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. SUNY Upstate Med Univ, Syracuse, NY USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, Box 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI Kamel, Freya/0000-0001-5052-6615; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 NR 37 TC 43 Z9 47 U1 0 U2 3 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 AUG PY 2003 VL 111 IS 10 BP 1335 EP 1339 DI 10.1289/ehp.6109 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 711MX UT WOS:000184746600036 PM 12896855 ER PT J AU Suk, WA Ruchirawat, KM Balakrishnan, K Berger, M Carpenter, D Damstra, T de Garbino, JP Koh, D Landrigan, PJ Makalinao, I Sly, PD Xu, Y Zheng, BS AF Suk, WA Ruchirawat, KM Balakrishnan, K Berger, M Carpenter, D Damstra, T de Garbino, JP Koh, D Landrigan, PJ Makalinao, I Sly, PD Xu, Y Zheng, BS TI Environmental threats to children's health in Southeast Asia and the Western Pacific SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE Bangkok; children's environmental health; exposure; lead; mercury; risk; Southeast Asia; Western Pacific AB The Southeast Asia and Western Pacific regions contain half of the world's children and are among the most rapidly industrializing regions of the globe. Environmental threats to children's health are widespread and are multiplying as nations in the area undergo industrial development and pass through the epidemiologic transition. These environmental hazards range from traditional threats such as bacterial contamination of drinking water and wood smoke in poorly ventilated dwellings to more recently introduced chemical threats such as asbestos construction materials; arsenic in groundwater; methyl isocyanate in Bhopal, India; untreated manufacturing wastes released to landfills; chlorinated hydrocarbon and organophosphorous pesticides; and atmospheric lead emissions from the combustion of leaded gasoline. To address these problems, pediatricians, environmental health scientists, and public health workers throughout Southeast Asia and the Western Pacific have begun to build local and national research and prevention programs in children's environmental health. Successes have been achieved as a result of these efforts: A cost-effective system for producing safe drinking water at the village level has been devised in India; many nations have launched aggressive antismoking campaigns; and Thailand, the Philippines, India, and Pakistan have all begun to reduce their use of lead in gasoline, with resultant declines in children's blood lead levels. The International Conference on Environmental Threats to the Health of Children, held in Bangkok, Thailand, in March 2002, brought together more than 300 representatives from 35 countries and organizations to increase awareness on environmental health hazards affecting children in these regions and throughout the world. The conference, a direct result of the Environmental Threats to the Health of Children meeting held in Manila in April 2000, provided participants with the latest scientific data on children's vulnerability to environmental hazards and models for future policy and public health discussions on ways to improve children's health. The Bangkok Statement, a pledge resulting from the conference proceedings, is an important first step in creating a global alliance committed to developing active and innovative national and international networks to promote and protect children's environmental health. C1 NIEHS, Ctr Risk & Integrated Sci, Res Triangle Pk, NC 27709 USA. Chulabhorn Res Inst, Bangkok, Thailand. Sri Ramachandra Med Coll & Res Inst, Madras, Tamil Nadu, India. US EPA, Off Childrens Hlth Protect, Washington, DC 20460 USA. SUNY Albany, Sch Publ Hlth, Rensselaer, NY USA. WHO, Int Programme Chem Safety, Res Triangle Pk, NC USA. WHO, Int Programme Chem Safety, CH-1211 Geneva, Switzerland. Natl Univ Singapore, Dept Community Occupat & Family Med, Singapore 117548, Singapore. Mt Sinai Sch Med, Ctr Childrens Hlth & Environm, Dept Community & Prevent Med, New York, NY USA. Univ Philippines, Coll Med, Dept Pharmacol & Toxicol, Manila, Philippines. Princess Margaret Hosp Children, Subiaco, WA USA. Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China. Chinese Acad Sci, Inst Geochem, Guiyang, Peoples R China. RP Suk, WA (reprint author), NIEHS, Ctr Risk & Integrated Sci, 79 TW Alexander Dr,4401 Bldg,Mail Drop EC-27, Res Triangle Pk, NC 27709 USA. EM suk@niehs.nih.gov RI Sly, Peter/F-1486-2010; Balakrishnan, Kalpana/B-6653-2015 OI Sly, Peter/0000-0001-6305-2201; Balakrishnan, Kalpana/0000-0002-5905-1801 NR 34 TC 42 Z9 48 U1 3 U2 28 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 AUG PY 2003 VL 111 IS 10 BP 1340 EP 1347 DI 10.1289/ehp.6059 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 711MX UT WOS:000184746600037 PM 12896856 ER PT J AU Lee, CR Zeldin, DC AF Lee, CR Zeldin, DC TI The reality of pharmacogenomics: Optimizing therapeutic decision making SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 Univ N Carolina, Expt Therapeut Program, Chapel Hill, NC 27514 USA. NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. RP Lee, CR (reprint author), Univ N Carolina, Expt Therapeut Program, Chapel Hill, NC 27514 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2003 VL 111 IS 11 BP A566 EP A567 DI 10.1289/ehp.111-a566 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 716FZ UT WOS:000185019300001 PM 12928152 ER PT J AU Strand, MK Stuart, GR Longley, MJ Graziewicz, MA Dominick, OC Copeland, WC AF Strand, MK Stuart, GR Longley, MJ Graziewicz, MA Dominick, OC Copeland, WC TI POS5 gene of Saccharomyces cerevisiae encodes a mitochondrial NADH kinase required for stability of mitochondrial DNA SO EUKARYOTIC CELL LA English DT Article ID POLYMERASE-GAMMA; OXIDATIVE DAMAGE; GLUTATHIONE DEPLETION; MULTIPLE DELETIONS; HYDROGEN-PEROXIDE; RADICAL FORMATION; NITRIC-OXIDE; NUCLEAR-DNA; IN-VITRO; YEAST AB In a search for nuclear genes that affect mutagenesis of mitochondrial DNA in Saccharomyces cerevisiae, an ATP-NAD (NADH) kinase, encoded by POS5, that functions exclusively in mitochondria was identified. The POS5 gene product was overproduced in Escherichia coli and purified without a mitochondrial targeting sequence. A direct biochemical assay demonstrated that the POS5 gene product utilizes ATP to phosphorylate both NADH and NAD(+), with a twofold preference for NADH. Disruption of POS5 increased minus-one frame-shift mutations in mitochondrial DNA 50-fold, as measured by the arg8(m) reversion assay, with no increase in nuclear mutations. Also, a dramatic increase in petite colony formation and slow growth on glycerol or limited glucose were observed. POS5 was previously described as a gene required for resistance to hydrogen peroxide. Consistent with a role in the mitochondrial response to oxidative stress, a pos5 deletion exhibited a 28-fold increase in oxidative damage to mitochondrial proteins and hypersensitivity to exogenous copper. Furthermore, disruption of POS5 induced mitochondrial biogenesis as a response to mitochondrial dysfunction. Thus, the POS5 NADH kinase is required for mitochondrial DNA stability with a critical role in detoxification of reactive oxygen species. These results predict a role for NADH kinase in human mitochondrial diseases. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP NIEHS, Mol Genet Lab, POB 12233,MD E3-01, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov NR 84 TC 61 Z9 71 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD AUG PY 2003 VL 2 IS 4 BP 809 EP 820 DI 10.1128/EC.2.4.809-820.2003 PG 12 WC Microbiology; Mycology SC Microbiology; Mycology GA 712ND UT WOS:000184803000017 PM 12912900 ER PT J AU Sorger, JM Despres, D McVeigh, ER Hill, JM AF Sorger, JM Despres, D McVeigh, ER Hill, JM TI Stem cell homing in myocardial infarction SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology CY AUG 30-SEP 03, 2003 CL VIENNA, AUSTRIA SP European Soc Cardiol C1 NHLBI, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2003 VL 24 SU S BP 120 EP 120 DI 10.1016/S0195-668X(03)94103-0 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 727CM UT WOS:000185638800452 ER PT J AU Kidd, LR Woodson, K Taylor, PR Albanes, D Virtamo, J Tangrea, JA AF Kidd, LR Woodson, K Taylor, PR Albanes, D Virtamo, J Tangrea, JA TI Polymorphisms in glutathione-S-transferase genes (GST-M1, GST-T1 and GST-P1) and susceptibility to prostate cancer among male smokers of the ATBC cancer prevention study SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE genetic polymorphism; glutathione-S-transferase; prostate cancer ID POLYCYCLIC AROMATIC-HYDROCARBONS; BETA-CAROTENE SUPPLEMENTS; ENVIRONMENT INTERACTIONS; ALPHA-TOCOPHEROL; DIOL EPOXIDES; RISK; GENOTYPES; MU; ASSOCIATION; ETIOLOGY AB Glutathione-S-transferase (GST) genes encode a family of detoxification enzymes that offer protection against endogenous and exogenous sources of reactive oxygen species (ROS). Germline variations in GST genes may alter the catalytic efficiency of GST isoenzymes leading to a potential increase in susceptibility to the genotoxic effects of ROS and electrophilic substances. A nested case-control study design was used to examine the association between the polymorphic GST genes and prostate cancer risk among Finnish male smokers of the ATBC Cancer Prevention Study. A case-case analysis was used to determine the association between these genetic polymorphisms and prostate cancer progression. Germline DNA was obtained from 206 prostate cancer cases and 194 controls frequency matched on age, intervention group and study clinic. Cases and controls were genotyped for three GST genes using MALDI-TOF mass spectrometry or multiplex polymerase chain reaction (PCR). Relative to the wild-type genotype, we observed a 36% reduction in prostate cancer risk associated with the GST-M1-null genotype (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.43, 0.95). Unlike GST-M1, GST-T1-null (OR 0.74, 95% Cl 0.42,1.33) and GST-P1*B (OR 1.10, 95% CI 0.72,1.69) were not strongly associated with prostate cancer risk. We did not observe any significant associations between the selected polymorphic GST genes and tumour grade or stage. In conclusion, we did not observe a direct association between polymorphic GST-T1 or GST-P1 and prostate cancer risk. Our observation of a relatively strong inverse association between the GST-M1-null genotype and prostate cancer risk needs to be confirmed in larger association studies. (C) 2003 Lippincott Williams Wilkins. C1 NCI, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. RP Kidd, LR (reprint author), NCI, Canc Res Ctr, Canc Prevent Studies Branch, 6116 Execut Blvd,Suite 705,MSC 8314, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [R01 CA034627, N01 CN45035, N01 CN45165, R03 CA128028] NR 26 TC 38 Z9 43 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD AUG PY 2003 VL 12 IS 4 BP 317 EP 320 DI 10.1097/01.cej.0000082922.97406.3e PG 4 WC Oncology SC Oncology GA 712NM UT WOS:000184803800012 PM 12883385 ER PT J AU Joe, B Garrett, MR Dene, H Remmers, EF Meng, H AF Joe, B Garrett, MR Dene, H Remmers, EF Meng, H TI Genetic susceptibility to carrageenan-induced innate inflammatory response in inbred strains of rats SO EUROPEAN JOURNAL OF IMMUNOGENETICS LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; QUANTITATIVE TRAIT LOCI; ADJUVANT-INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; REGULATORY LOCUS; IDENTIFICATION; IMMUNITY; SEVERITY; HYPERTENSION AB Rat models are useful for the genetic dissection of the biology of innate immunity. Inbred rat strains were evaluated for carrageenan-induced innate inflammatory responses. Results indicated that the genetic control of innate immune responses is polygenic and influenced by gender, and may not necessarily be consistent with the genetics of experimental arthritis. The newly identified susceptible strains, in order of decreasing susceptibility, include Dahl salt-sensitive (S), Dahl salt-resistant (R), Milan normotensive strain (MNS) and Wistar Kyoto (WKY) rats. Similarly, the newly identified relatively resistant strains, in decreasing order of resistance, include DA rats, spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats. Linkage analyses using combinations of these susceptible and resistant strains are proposed. C1 Med Coll Ohio, Dept Physiol & Mol Med, Toledo, OH 43614 USA. NIAMSD, Complex Dis Genet Unit, Genom Sect, NIH, Bethesda, MD 20892 USA. RP Joe, B (reprint author), Med Coll Ohio, Dept Physiol & Mol Med, 3035 Arlington Ave, Toledo, OH 43614 USA. NR 31 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7420 J9 EUR J IMMUNOGENET JI Eur. J. Immunogenet. PD AUG PY 2003 VL 30 IS 4 BP 243 EP 247 DI 10.1046/j.1365-2370.2003.00402.x PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 711LY UT WOS:000184744100002 PM 12919284 ER PT J AU Frossi, B De Carli, M Daniel, KC Rivera, J Pucillo, C AF Frossi, B De Carli, M Daniel, KC Rivera, J Pucillo, C TI Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE mast cell; inflammation; Fc epsilon receptor; cytokine ID DNA-BINDING ACTIVITY; GENE-EXPRESSION; SCHISTOSOMA-MANSONI; INNATE IMMUNITY; IGE RECEPTOR; PROTEIN; TRANSCRIPTION; ACTIVATION; REPAIR; REF-1 AB Mast cells are exposed to an oxidative environment in the course of allergic and inflammatory reactions. We have examined the effects of H2O2 stimulation in a primary rat basophilic leukemia cell line (RBL-2H3) and compared with IgE-dependent stimulation. Like IgE stimulation, H2O2 up-regulates IL-4 and IL-6 gene expression and cytokine secretion, shows a little effect on IL-5 but does not induce IL-10 gene expression. Simultaneous H2O2 treatment and FcepsilonRI triggering of mast cells has additive effects on IL-4 expression. In addition, we show that both stimuli induce the nuclear translocation of APE/Ref-1, a bifunctional enzyme that stimulates the DNA-binding activity of several transcription factors through the reduction of highly reactive cysteines. Conditional inactivation of APE/Ref-1 expression abolishes H2O2-induced IL-4 and IL-6 gene expression but does not affect that induced by FcepsilonRI stimulation. Our findings indicate that oxidative stress activates the gene expression of a specific cytokine pattern in mast cells through an APE/Ref-1-dependent pathway, which is distinct from the one that is activated by FcepsilonRI stimulation. Nonetheless, H2O2 and FcepsilonRI signalings are additive in augmenting IL-4 production. Most importantly, oxidative stress can induce a pro-type 2 inflammatory response from mast cells that is independent of FcepsilonRI stimulation. C1 Univ Udine, Dipartimento Sci & Tecnol Biomed, I-33100 Udine, Italy. Univ Udine, Ctr Excellence, MATI, I-33100 Udine, Italy. Azienda Osped S Maria Misericordia, SOC Med 2, Udine, Italy. Rayne Inst, London, England. NIAMS, Mol Inflammat Sect MIIB, NIH, Bethesda, MD USA. RP Pucillo, C (reprint author), Univ Udine, Dipartimento Sci & Tecnol Biomed, P M Kolbe 4, I-33100 Udine, Italy. RI Pucillo, Carlo/A-5515-2008; OI Pucillo, Carlo/0000-0002-4872-6156 NR 41 TC 54 Z9 56 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2003 VL 33 IS 8 BP 2168 EP 2177 DI 10.1002/eji.200323995 PG 10 WC Immunology SC Immunology GA 709WC UT WOS:000184648700013 PM 12884291 ER PT J AU Hoffman, AF Riegel, AC Lupica, CR AF Hoffman, AF Riegel, AC Lupica, CR TI Functional localization of cannabinoid receptors and endogenous cannabinoid production in distinct neuron populations of the hippocampus SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE electrophysiology; GABA; glutamate; interneurons; marijuana; rat ID POLYPEPTIDE-IMMUNOREACTIVE INTERNEURONS; LONG-TERM POTENTIATION; RAT HIPPOCAMPUS; SYNAPTIC TRANSMISSION; PYRAMIDAL CELLS; GABA RELEASE; GABAERGIC INTERNEURONS; PRESYNAPTIC TERMINALS; NUCLEUS-ACCUMBENS; CA1 AB The possible localization of cannabinoid (CB) receptors to glutamatergic and GABAergic synaptic terminals impinging upon GABAergic interneurons in the CA1 region of the rat hippocampus was examined using the electrophysiological measurement of neurotransmitter release in brain slices. Whereas activation of cannabinoid receptors via the application of the cannabinoid agonist WIN55,212-2 significantly and dose-dependently reduced evoked IPSCs recorded from interneurons possessing somata located in the stratum radiatum (S.R.) and stratum oriens (S.O.) lamellae, evoked glutamatergic EPSCs were unaffected in both neuronal populations. However, in agreement with previous reports, WIN55,212-2 significantly reduced EPSCs recorded from CA1 pyramidal neurons. Additional experiments confirmed that the effects of WIN55,212-2 on IPSCs were presynaptic and that they could be blocked by the CB1 receptor antagonist SR141716A. The involvement of endogenous cannabinoids in the presynaptic inhibition of GABA release was also examined in the interneurons and pyramidal cells using a depolarization-induced suppression of inhibition (DSI) paradigm. DSI was observed in CA1 pyramidal neurons under control conditions, and its incidence was greatly increased by the cholinergic agonist carbachol. However, DSI was not observed in the S.R. or S.O. interneuron populations, in either the presence or absence of carbachol. Whereas DSI was not present in these interneurons, the inhibitory inputs to these cells were modulated by the synthetic cannabinoid WIN55,212-2. These data support the hypothesis that cannabinoid receptors are located on inhibitory, but not excitatory, axon terminals impinging upon hippocampal interneurons, and that CA1 pyramidal neurons, and not interneurons, are capable of generating endogenous cannabinoids during prolonged states of depolarization. C1 NIDA, Cellular Neurobiol Res Branch, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIDA, Cellular Neurophysiol Unit, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, Cellular Neurobiol Res Branch, NIH, US Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU NIDA NIH HHS [DA14263] NR 57 TC 44 Z9 46 U1 0 U2 1 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 AUG PY 2003 VL 18 IS 3 BP 524 EP 534 DI 10.1046/j.1460-9568.2003.02773.x PG 11 WC Neurosciences SC Neurosciences & Neurology GA 711CE UT WOS:000184720400006 PM 12911748 ER PT J AU Thiruchelvam, M McCormack, A Richfield, EK Baggs, RB Tank, AW Di Monte, DA Cory-Slechta, DA AF Thiruchelvam, M McCormack, A Richfield, EK Baggs, RB Tank, AW Di Monte, DA Cory-Slechta, DA TI Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE locomotor activity; mouse; striatum; substantia nigra; tyrosine hydroxylase ID ENVIRONMENTAL RISK-FACTORS; SUBSTANTIA-NIGRA NEURONS; BLOOD-BRAIN-BARRIER; TYROSINE-HYDROXYLASE; MONOAMINE-OXIDASE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP; HERBICIDE PARAQUAT; STRIATAL DOPAMINE; ALPHA-SYNUCLEIN; ADRENAL-GLAND AB While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity. C1 Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. Parkinsons Inst, Sunnyvale, CA 94089 USA. Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, NIEHS, Environm Hlth Sci Ctr, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Div Lab Anim Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Physiol & Pharmacol, Rochester, NY 14642 USA. RP Cory-Slechta, DA (reprint author), Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. FU NIDA NIH HHS [DA05014]; NIEHS NIH HHS [ES05903, ES01247, ES05017, ES10442, ES10806]; NINDS NIH HHS [NS39415] NR 53 TC 162 Z9 170 U1 0 U2 7 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 AUG PY 2003 VL 18 IS 3 BP 589 EP 600 DI 10.1046/j.1460-9568.2003.02781.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 711CE UT WOS:000184720400013 PM 12911755 ER PT J AU Floel, A Ellger, T Breitenstein, C Knecht, S AF Floel, A Ellger, T Breitenstein, C Knecht, S TI Language perception activates the hand motor cortex: implications for motor theories of speech perception SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE gesture; mirror neurons; motor system; motor theory of speech perception; transcranial magnetic stimulation ID MAGNETIC STIMULATION; EXCITABILITY; HUMANS; COMMUNICATION; HANDEDNESS; EXECUTION; PREMOTOR; BRAIN AB The precise mechanisms of how speech may have developed are still unknown to a large extent. Gestures have proven a powerful concept for explaining how planning and analysing of motor acts could have evolved into verbal communication. According to this concept, development of an action-perception network allowed for coding and decoding of communicative gestures. These were manual or manual/articulatory in the beginning and then became increasingly elaborate in the articulatory mode. The theory predicts that listening to the 'gestures' that compose spoken language should activate an extended articulatory and manual action-perception network. To examine this hypothesis, we assessed the effects of language on cortical excitability of the hand muscle representation by transcranial magnetic stimulation. We found the hand motor system to be activated by linguistic tasks, most notably pure linguistic perception, but not by auditory or visuospatial processing. The amount of motor system activation was comparable in both hemispheres. Our data support the theory that language may have evolved within a general and bilateral action-perception network. C1 Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Munster, Dept Neurol, D-4400 Munster, Germany. RP Floel, A (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. RI Floel, Agnes/A-9426-2017; OI Knecht, Stefan/0000-0003-1056-9228 NR 28 TC 70 Z9 72 U1 1 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 AUG PY 2003 VL 18 IS 3 BP 704 EP 708 DI 10.1046/j.1460-9568.2003.02774.x PG 5 WC Neurosciences SC Neurosciences & Neurology GA 711CE UT WOS:000184720400025 PM 12911767 ER PT J AU Moody, TW Leyton, J Garcia-Marin, L Jensen, RT AF Moody, TW Leyton, J Garcia-Marin, L Jensen, RT TI Nonpeptide gastrin releasing peptide receptor antagonists inhibit the proliferation of lung cancer cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE PD176252; gastrin releasing peptide receptor; antagonist; lung cancer; proliferation ID BOMBESIN-LIKE PEPTIDES; NEUROMEDIN-B; HIGH-AFFINITY; CYTOSOLIC CALCIUM; GROWTH-FACTORS; CLONING; RAT; STIMULATION; ANALOGS; KINASE AB The ability of nonpeptide antagonists to interact with gastrin releasing peptide receptors on lung cancer cells was investigated. PD 176252 (3-(1H-Indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(4-nitro-phenyl)-ureido]-propionamide) and PD168368 (3-(1H-Indol-3-yl)-2-methyl-2-[3(4-nitro-phenyl)-ureido]-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide) inhibited specific I-125-gastrin releasing peptide binding to NCI-H1299 cells with IC50 values of 20 and 1500 nM, respectively. Similar binding results were obtained using NCI-H157, H345 and N592 human lung cancer cells. PD176252 inhibited the ability of I nM bombesin to cause elevation of cytosolic calcium in Fura-2 loaded NCI-H345 or H1299 cells, whereas it had no effect on basal cytosolic calcium. PD 176252 antagonized the ability of 10 nM bombesin to cause elevation of c-fos mRNA in NCI-H1299 cells. Also, PD 176252 inhibited the ability of 100 nM bombesin to cause tyrosine phosphorylation of focal adhesion kinase in NCI-H1299 cells. Using a [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, PD176252 was more potent than PD168368 at inhibiting NCI-H1299 proliferation. Also, 1 muM PD176252 significantly inhibited lung cancer colony number in vitro. PD 176252 in a dose-dependent manner inhibited NCI-H1299 xenograft growth in nude mice in vivo. These results indicate that PD 176252 is a gastrin releasing peptide receptor antagonist, which inhibits the proliferation of lung cancer cells. (C) 2003 Elsevier B.V. All rights reserved. C1 NCI, Off Director, Dept Hlth & Human Serv, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. NIDDKD, Digest Dis Branch, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, Off Director, Dept Hlth & Human Serv, NIH,Ctr Canc Res, Bldg 31,Room 3A34,31 Ctr Dr, Bethesda, MD 20892 USA. RI Garcia-Marin, Luis /L-4680-2014 OI Garcia-Marin, Luis /0000-0002-1795-7381 NR 46 TC 28 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD AUG 1 PY 2003 VL 474 IS 1 BP 21 EP 29 DI 10.1016/S0014-2999(03)01996-4 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 712VL UT WOS:000184819000004 PM 12909192 ER PT J AU Varnas, K Halldin, C Pike, VW Hall, H AF Varnas, K Halldin, C Pike, VW Hall, H TI Distribution of 5-HT4 receptors in the postmortem human brain - an autoradiographic study using [I-125]SB 207710 SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE [I-125]SB 207710; 5-HT4 receptors; human brain; whole hemisphere autoradiography ID IN-SITU HYBRIDIZATION; BINDING-SITES; RAT-BRAIN; SEROTONIN 5-HT4; MESSENGER-RNA; H-3 GR113808; GUINEA-PIG; LOCALIZATION; PHARMACOLOGY; RADIOLIGAND AB The autoradiographic distribution of the 5-HT4 receptor was described using human postmortem brain sections and the selective radioligand [I-125]SB 207710 [(1-n-butyl-4-piperidinyl)methy1-8-amino-7-[I-125]iodo-1,4-benzodioxane-5-carboxylatel. The specific binding was highest in regions of the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus and substantia nigra) and the hippocampal formation (CA1 and subiculum). In the neocortex, the binding showed a distinct lamination pattern with high levels in superficial layers and a band displaying lower levels in deep cortical layers. The results confirm previous studies on the distribution of 5-HT4 receptors in the human brain in vitro and provide high-resolution correlates for in vivo imaging studies using the radioligand recently developed for single photon emission tomography (SPET), [I-123]SB 207710. (C) 2003 Elsevier B.V./ECNP. All rights reserved. C1 Karolinska Hosp, Psychiat Sect, Dept Clin Neurosci, Karolinska Inst, S-17176 Stockholm, Sweden. NIMH, Mol Imaging Branch, Rockville, MD 20850 USA. RP Hall, H (reprint author), Karolinska Hosp, Psychiat Sect, Dept Clin Neurosci, Karolinska Inst, S-17176 Stockholm, Sweden. FU NIMH NIH HHS [MH 44814] NR 20 TC 41 Z9 41 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD AUG PY 2003 VL 13 IS 4 BP 228 EP 234 DI 10.1016/S0924-977X(03)00009-9 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 711MU UT WOS:000184746300002 PM 12888181 ER PT J AU Compton, WM Glantz, M Delany, P AF Compton, WM Glantz, M Delany, P TI Addiction as a chronic illness - putting the concept into action SO EVALUATION AND PROGRAM PLANNING LA English DT Article C1 NIDA, Div Epidemiol, Serv & Prevent Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Compton, WM (reprint author), NIDA, Div Epidemiol, Serv & Prevent Res, NIH,Dept Hlth & Human Serv, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. NR 4 TC 14 Z9 14 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7189 J9 EVAL PROGRAM PLANN JI Eval. Program Plan. PD AUG PY 2003 VL 26 IS 3 BP 353 EP 354 DI 10.1016/S0149-7189(03)00038-7 PG 2 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 710ER UT WOS:000184668300013 ER PT J AU Schroeder, JR Gupman, AE Epstein, DH Umbricht, A Preston, KL AF Schroeder, JR Gupman, AE Epstein, DH Umbricht, A Preston, KL TI Do noncontingent vouchers increase drug use? SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID COCAINE ABSTINENCE; CONTINGENCY MANAGEMENT; METHADONE-MAINTENANCE; BEHAVIORAL-APPROACH; FOLLOW-UP; REINFORCEMENT; ADDICTS; DEPENDENCE; VALIDITY; THERAPY AB Data from 2 contingency management trials, targeting opiate or cocaine use, were used to investigate whether noncontingent vouchers inadvertently reinforce drug use. The control group in each trial received noncontingent vouchers matched in value and frequency to those received by experimental groups, but independent of urinalysis. Vouchers were offered thrice weekly for 8 weeks (opiates) or 12 weeks (cocaine). Both dose-response and temporal associations of noncontingent voucher receipt with drug-positive urines were assessed. Drug use was unrelated to frequency of noncontingent voucher delivery and noncontingent voucher receipt when being drug positive was unassociated with risk of subsequent drug use, with one exception: cocaine use in the cocaine study (relative risk = 1.05, 95% confidence interval: 1.01-1.09). Overall, results do not indicate a causal relationship between noncontingent voucher receipt and increased drug use. C1 Natl Inst Drug Abuse, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. RP Schroeder, JR (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Dept Hlth & Human Serv, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 26 TC 5 Z9 5 U1 2 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD AUG PY 2003 VL 11 IS 3 BP 195 EP 201 DI 10.1037/1064-1297.11.3.195 PG 7 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 710BM UT WOS:000184661000001 PM 12940498 ER PT J AU Xu, LX Yang, LH Moitra, PK Hashimoto, K Rallabhandi, P Kaul, S Meroni, G Jensen, JP Weissman, AM D'Arpa, P AF Xu, LX Yang, LH Moitra, PK Hashimoto, K Rallabhandi, P Kaul, S Meroni, G Jensen, JP Weissman, AM D'Arpa, P TI BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5 delta SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE BTBD1; BTBD2; TRIM5; tripartite domain; RBCC domain; cytoplasmic bodies; BTB/POZ ID ACUTE PROMYELOCYTIC LEUKEMIA; FAMILIAL MEDITERRANEAN FEVER; RING FINGER PROTEINS; COILED-COIL DOMAIN; ART. NO. 1; B-BOX; UBIQUITIN LIGASE; TRIPARTITE MOTIF; SYNAPTIC GROWTH; FACTOR-RECEPTOR AB We previously identified BTBD1 and BTBD2 as novel topoisomerase I-interacting proteins that share 80% amino acid identity. Here we report the characterization of their subcellular localization. In a number of mouse and human cells, BTBD1 and BTBD2 (BTBD1/2) colocalized to punctate or elongated cytoplasmic bodies (< 5 mum long and several per cell) that were larger and more elongated in cancer cell lines than in fibroblasts and myoblasts. A search for potential colocalizing proteins identified TRIM family members that localize to morphologically similar cytoplasmic bodies, which were then tested for colocalization with BTBD1/2. TRIM5delta, expressed as a GFP fusion, colocalized with BTBD1/2 immunostaining and appeared to serve as a scaffold for the assembly of endogenous BTBD1/2 proteins. TRIM family members contain a RING domain, B-box(es), and coiled-coil regions, which have a characteristic order and spacing (RBCC domain). RING-dependent ubiquitin ligase activity and multimerization via the coiled-coil region may be defining properties of the RBCC/TRIM protein family. We found that TRIM5delta with a deleted coiled-coil region or a mutated RING domain failed to colocalize with BTBD1/2. Additionally, TRIM5delta ubiquitylated itself in a RING finger- and UbcH5B-dependent manner. BTBD1/2 each contain a PHR-similarity region, repeated twice on the putative ubiquitin ligases PAM, highwire and RPM-1, which also contain a RING and B-box. Thus, four protein modules found on each of these putative ubiquitin ligases, a RING, a B-box and two PHR repeats, are present on BTBD1/2 and TRIM5delta that are colocalized to cytoplasmic bodies. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. TIGEM, CNR, I-80131 Naples, Italy. NCI, Regulat Prot Funct Lab, Canc Res Ctr, Frederick, MD 21702 USA. RP D'Arpa, P (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Biochem & Mol Biol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU Telethon [TGM00P14, TGM06S01] NR 47 TC 88 Z9 93 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 1 PY 2003 VL 288 IS 1 BP 84 EP 93 DI 10.1016/S0014-4827(03)00187-3 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 705YA UT WOS:000184423800008 PM 12878161 ER PT J AU Sweeney, MHJ Garland, DL Truscott, RJW AF Sweeney, MHJ Garland, DL Truscott, RJW TI Movement of cysteine in intact monkey lenses: the major site of entry is the germinative region SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE lens; diffusion; glutathione; cataract; modelling; transport ID GLUTATHIONE SYNTHESIS ENZYMES; CATARACTOUS HUMAN LENSES; NUCLEAR CATARACT; FIBER CELLS; RAT LENS; AGE; TRANSPORT; COMMUNICATION; PERMEABILITY; DIFFUSION AB Monkey lenses were incubated with S-35-L-cysteine for various times and the movement of label within the lens followed by autoradiography. Cysteine appeared to enter primarily at the germinative region of the lens. No evidence was found for major transport through either the anterior or posterior faces of the lens. The movement of cysteine within different parts of the lens was followed over time. The data suggest that, for cysteine, the major pathway for transport within the lens involves entry at the germinative region followed by movement along the fibre cells. The data were consistent with orthogonal movement across the fibres in the equatorial plane but little or no movement across the fibres at the anterior pole or posterior faces of the lens. Such a scenario is in accord with the distribution of connexons, indicating that this pattern of entry may also be observed for other small molecules. The finding of high permeability at the lens germinative region is in accord with the anatomy of the eye, since this is the lens surface in contact with the posterior chamber. Thus, cysteine secreted by the ciliary body into the aqueous humor would come into contact initially with the region of the lens best able to absorb this amino acid. Although this aspect was not addressed in the current study, the same phenomenon may also be observed with other lens nutrients. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Wollongong, Australian Cataract Res Fdn, Dept Chem, Wollongong, NSW 2522, Australia. Univ Sydney, Save Sight Inst, Sydney, NSW 2006, Australia. NEI, NIH, Bethesda, MD 20892 USA. RP Truscott, RJW (reprint author), Univ Wollongong, Australian Cataract Res Fdn, Dept Chem, Northfields Ave, Wollongong, NSW 2522, Australia. FU NEI NIH HHS [EY13570-02] NR 41 TC 18 Z9 18 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD AUG PY 2003 VL 77 IS 2 BP 245 EP 251 DI 10.1016/S0014-4835(03)00110-6 PG 7 WC Ophthalmology SC Ophthalmology GA 709UE UT WOS:000184642100015 PM 12873456 ER PT J AU Akin, C Brockow, K D'Ambrosio, C Kirshenbaum, AS Ma, YS Longley, BJ Metcalfe, DD AF Akin, C Brockow, K D'Ambrosio, C Kirshenbaum, AS Ma, YS Longley, BJ Metcalfe, DD TI Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; BCR-ABL; ACTIVATING MUTATION; HUMAN MASTOCYTOSIS; CATALYTIC DOMAIN; PROGENITOR-CELL; IN-VITRO; GROWTH; GENE; PROLIFERATION AB Objective. STI571 is a tyrosine kinase inhibitor which inhibits the kinase activity of kit, the receptor for stem cell factor (SCF). Because activating mutations of c-kit affecting codon 816 are associated with human mast cell neoplasms, we determined whether STI571 exerted a similar cytotoxic effect on neoplastic and normal human mast cells. Methods. We investigated the effect of addition of STI571 in increasing concentrations (0.01 to 10 micromolar) to two HMC-1 human mast cell leukemia cell lines carrying two different activating c-kit mutations in codons 816 or 560, as well as the effect of the drug on short-term bone marrow cultures obtained from patients who carry a mutated codon 816 or wild-type c-kit. Results. STI571 failed to inhibit the growth of HMC-1(560,816) cells bearing a codon 816 mutation but effectively suppressed the proliferation of HMC-1560 carrying c-kit with the wild-type codon 816. STI571 did not induce preferential killing of neoplastic bone marrow mast cells in short-term cultures from patients bearing a codon 816 c-kit mutation. In contrast, STI571 caused a dramatic reduction in mast cells in patients without codon 816 c-kit mutations. Conclusion. These results suggest that STI571, while effectively killing mast cells with wildtype c-kit, did not show preferential cytotoxicity to neoplastic human mast cells and thus may not be effective in the treatment of human systemic mastocytosis associated with codon 816 c-kit mutations. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. RP Akin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. OI Akin, Cem/0000-0001-6301-4520 NR 27 TC 158 Z9 164 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2003 VL 31 IS 8 BP 686 EP 692 DI 10.1016/S0301-472X(03)00112-7 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 713PB UT WOS:000184866200004 PM 12901973 ER PT J AU Barbiero, L Benussi, L Ghidoni, R Alberici, A Russo, C Schettini, G Pagano, SF Parati, EA Mazzoli, F Nicosia, F Signorini, S Feudatari, E Binetti, G AF Barbiero, L Benussi, L Ghidoni, R Alberici, A Russo, C Schettini, G Pagano, SF Parati, EA Mazzoli, F Nicosia, F Signorini, S Feudatari, E Binetti, G TI BACE-2 is overexpressed in Down's syndrome SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Down's syndrome; BACE-2; amyloid precursor protein; APP processing; beta-secretase; overexpression; fibroblasts; fetal brain; embryonic neural stem cells; Alzheimer disease ID AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; BETA-SECRETASE; NEUROPATHOLOGICAL CHANGES; ASPARTYL PROTEASE; DEMENTIA; PLAQUES; REGION; AGE; EXPRESSION AB Brain deposition of the amyloid-beta protein (Abeta) is a frequent complication of Down's syndrome (DS) patients. Abeta peptide is generated by endoproteolytic processing of Abeta precursor protein by gamma and beta secretases. Recently a transmembrane aspartyl protease, BACE, has been identified as the beta-secretase, and its homologous BACE-2 has also been described. BACE-2 gene resides on chromosome 21 in the obligate DS region. It cleaves Abeta precursor protein at its beta site and more efficiently at a different site within Abeta. In the present study we characterized the BACE-2 gene and protein expression in the DS patients and healthy control. We analyzed, by using a nonradioactive ribonuclease protection assay, the levels of BACE-2 mRNA expression in primary skin fibroblasts. The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group. Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment. In the medium conditioned by fibroblast, we revealed an evident secretion of BACE-2 protein, represented by two different molecular weights, remarkably increased in DS fibroblasts. BACE-2 overexpression was also confirmed in the DS fetal brains and human neural embryonic DS stem cells in which conditioned media BACE-2 was secreted. These data highlight the importance of the extracellular compartment where BACE-2 overexpression could play a role in plaque formation in DS patients. (C) 2003 Elsevier Science (USA). All rights reserved. C1 IRCCS, Ctr S Giovanni Dio Fatebenefratelli, Neurobiol Lab, Memory Clin, I-25123 Brescia, Italy. Univ Genoa, Adv Biotechnol Ctr, Natl Canc Inst, Sect Pharmacol & Neurosci, Genoa, Italy. Natl Neurol Inst C, Neuropharmacol Lab, Milan, Italy. RP Binetti, G (reprint author), IRCCS, Ctr S Giovanni Dio Fatebenefratelli, Neurobiol Lab, Memory Clin, Via Pilastroni 4, I-25123 Brescia, Italy. RI Parati, Eugenio/G-8765-2011; BENUSSI, LUISA/K-4409-2016; Ghidoni, Roberta/K-4507-2016; Binetti, Giuliano/K-4519-2016; OI BENUSSI, LUISA/0000-0003-2836-8141; Ghidoni, Roberta/0000-0002-7691-1957; Binetti, Giuliano/0000-0003-2759-5844; russo, claudio/0000-0002-2520-2958 NR 37 TC 32 Z9 35 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2003 VL 182 IS 2 BP 335 EP 345 DI 10.1016/S0014-4886(03)00049-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 707RY UT WOS:000184524700008 PM 12895444 ER PT J AU Teichner, A Ovadia, H Lavie, G Leker, RR AF Teichner, A Ovadia, H Lavie, G Leker, RR TI Combination of dexanabinol and tempol in focal cerebral ischemia: is there a ceiling effect? SO EXPERIMENTAL NEUROLOGY LA English DT Article DE stroke; dexanabinol; tempol; neuroprotection; exitotoxicity; free radicals; nitroxide; nitric oxide synthase ID NECROSIS-FACTOR-ALPHA; CLOSED-HEAD INJURY; BRAIN INJURY; NMDA ANTAGONIST; RT-PA; HU-211; RAT; MODEL; STROKE; NEUROPROTECTANT AB Because ischemic neuronal death is triggered by several parallel mechanisms, a combination of drugs active against individual death-promoting mechanisms may have synergistic effects. Dexanabinol is a noncompetitive NMDA antagonist with anti-inflammatory effects and tempol is a nitroxide antioxidant. Therefore, we explored whether their combined use results in smaller infarct volumes as compared with their individual administration. Rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given vehicle, dexanabinol alone, tempol alone, or a combination of dexanabinol and tempol (n = 13 per group) 1 h later. Five animals in each group were evaluated with a motor rating scale 24 h after PMCAO and the infarct volumes were then measured. The remaining animals were examined with motor and behavioral scales up to 30 days after PMCAO and their infarct volumes were then determined. Motor disability and water maze latencies at all time points examined and infarct volumes at days 1 and 30 were significantly reduced in all active treatment groups when compared with vehicle. However, no significant differences were observed between the active treatment groups. In conclusions, combination therapy with dexanabinol and tempol does not appear to have additional neuroprotective effects compared to those conferred by each agent alone even when administered at optimal timing and dosing. Therefore, a ceiling neuroprotective effect that is impossible to overcome may exist. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Hebrew Univ Jerusalem, Hadassah Univ Hosp, Hadassah Med Sch, Dept Neurol, Jerusalem, Israel. RP Leker, RR (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Room 3c12,36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. NR 34 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2003 VL 182 IS 2 BP 353 EP 360 DI 10.1016/S0014-4886(03)00083-9 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 707RY UT WOS:000184524700010 PM 12895446 ER PT J AU Mancuso, M Filosto, M Bosetti, F Ceravolo, R Rocchi, A Tognoni, G Manca, ML Solaini, G Siciliano, G Murri, L AF Mancuso, M Filosto, M Bosetti, F Ceravolo, R Rocchi, A Tognoni, G Manca, ML Solaini, G Siciliano, G Murri, L TI Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Alzheimer's disease; lactate; mitochondria; cytochrome c oxidase; platelets; exercise ID OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; FUNCTIONAL ALTERATIONS; HIPPOCAMPAL-FORMATION; HUNTINGTONS-DISEASE; ANAEROBIC THRESHOLD; CEREBROSPINAL-FLUID; ENZYME-ACTIVITIES; ATP SYNTHASE; CELL-DEATH AB Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimer's disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 +/- 11.4 vs 48.4 +/- 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = -0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Pisa, Dept Neurosci, Neurol Clin, I-56126 Pisa, Italy. Univ Verona, Sect Clin Neurol, Dept Neurol Sci & Vis, Verona, Italy. Univ Perfezionamento S Anna, Scuola Super Studi, Pisa, Italy. Natl Inst Aging, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Mancuso, M (reprint author), Univ Pisa, Dept Neurosci, Neurol Clin, Via Roma 67, I-56126 Pisa, Italy. RI Siciliano, Gabriele/K-7259-2016; ceravolo, roberto/K-6831-2016; OI Siciliano, Gabriele/0000-0002-6142-2384; ceravolo, roberto/0000-0003-1412-9406; SOLAINI, GIANCARLO/0000-0001-7825-0446; Filosto, Massimiliano/0000-0002-2852-7512 FU Telethon [1179C] NR 49 TC 51 Z9 52 U1 2 U2 14 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 AUG PY 2003 VL 182 IS 2 BP 421 EP 426 DI 10.1016/S0014-4886(03)00092-X PG 6 WC Neurosciences SC Neurosciences & Neurology GA 707RY UT WOS:000184524700016 PM 12895452 ER PT J AU Liu, SH Schubert, RL Bugge, TH Leppla, SH AF Liu, SH Schubert, RL Bugge, TH Leppla, SH TI Anthrax toxin: structures,, functions and tumour targeting SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE anthrax toxin; cancer therapy; immunotoxin; lethal factor; matrix metalloprotease; protective antigen; tumour cell surface; urokinase plasminogen activator; urokinase plasminogen activator receptor ID RECEPTOR-BOUND UROKINASE; PLASMINOGEN-ACTIVATOR SYSTEM; PROTEIN-KINASE KINASE; PHASE-I TRIAL; PROTECTIVE ANTIGEN; LETHAL FACTOR; BACILLUS-ANTHRACIS; MATRIX METALLOPROTEINASES; EXTRACELLULAR-MATRIX; MAMMALIAN-CELLS AB Anthrax toxin, the major virulence factor of Bacillus anthracis, consists of three polypeptides: protective antigen (PrAg), lethal factor (LF) and oedema factor (EF). To intoxicate mammalian cells, PrAg binds to its cellular receptors and is subsequently activated via proteolysis, yielding a carboxyl-terminal fragment which coordinately assembles to form heptamers that bind and translocate LF and EF into the cytosol to exert their cytotoxic effects. Substantial progress has been made in recent years towards the characterisation of the structure and function of anthrax toxin, and this has greatly facilitated rational drug design of antianthrax agents. There is also emerging evidence that toxins can be manipulated for cancer therapy. LF can efficiently inactivate several mitogen-activated protein kinase kinases (MAPKKs) via cleavage of their amino-terminal sequences. Consequently, antitumour effects of wild type lethal toxin were observed after treatment of mitogen-activated protein kinase (MAPK)-dependent tumours such as human melanomas. Modification of the toxin's proteolytic activation site limits its cytotoxicity to certain cell types and creates a versatile method of treatment. One approach that has successfully achieved specific tumour targeting is the alteration of the furin cleavage of PrAg so that it is not activated by furin, but, alternatively, by proteases that are highly expressed by tumour tissues, including matrix metalloproteases and urokinase. C1 NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Liu, SH (reprint author), NIAID, Microbial Pathogenesis Sect, NIH, 30 Convent Dr,Bldg 30,Room 303,MSC 4350, Bethesda, MD 20892 USA. NR 104 TC 36 Z9 42 U1 1 U2 3 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD AUG PY 2003 VL 3 IS 5 BP 843 EP 853 DI 10.1517/14712598.3.5.843 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 708BB UT WOS:000184545600014 PM 12880383 ER PT J AU Druey, KM AF Druey, KM TI Regulators of G protein signalling: potential targets for treatment of allergic inflammatory diseases such as asthma SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE allergy; asthma; chemokines; G proteins; RGS proteins ID AIRWAY SMOOTH-MUSCLE; GTPASE-ACTIVATING PROTEINS; COUPLED RECEPTOR KINASE; RECTIFIER K+ CHANNELS; NECROSIS-FACTOR-ALPHA; CD4(+) T-CELLS; RGS PROTEINS; B-LYMPHOCYTES; MAST-CELL; IN-VIVO AB Asthma, a disease that affects nearly 15% of the world's population, is characterised by lung inflammation and reversible airway obstruction, which leads to wheezing and dyspnoea. Asthma is a prototype for allergic processes initiated by tissue inflammatory leukocytes, such as mast cells, whose secreted mediators recruit lymphocytes and eosinophils to the lung parenchyma. Signals transmitted through G-protein-coupled receptors (GPCRs) contribute to both the development and perpetuation of allergic processes, and pharmacological agents that block or stimulate GPCR action have been a mainstay of allergic disease therapy. Despite the widespread use of GPCR-targeted agents, little is understood about intracellular regulation of G protein pathways in immune cells. Regulators of G protein signalling (RGS proteins) enhance G protein deactivation and may contribute to the specificity and precision characteristic of GPCR signalling pathways. This review discusses the emerging functions of RGS proteins in immune processes and inflammatory states such as asthma, and their potential value as therapeutic targets for the treatment of allergic disease. C1 NIAID, Lab Allerg Dis, Mol Signal Transduct Sect, NIH, Rockville, MD 20852 USA. RP Druey, KM (reprint author), NIAID, Lab Allerg Dis, Mol Signal Transduct Sect, NIH, 2441 Parklawn Dr, Rockville, MD 20852 USA. NR 110 TC 13 Z9 14 U1 2 U2 2 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD AUG PY 2003 VL 7 IS 4 BP 475 EP 484 DI 10.1517/14728222.7.4.475 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 715NQ UT WOS:000184979000002 PM 12885267 ER PT J AU Laurent, M Martinerie, C Thibout, H Hoffman, MP Verrecchia, F Le Bouc, Y Mauviel, A Kleinman, HK AF Laurent, M Martinerie, C Thibout, H Hoffman, MP Verrecchia, F Le Bouc, Y Mauviel, A Kleinman, HK TI NOVH increases MMP3 expression and cell migration in glioblastoma cells via a PDGFR-alpha-dependent mechanism SO FASEB JOURNAL LA English DT Article DE CCN family; macroarray; metalloprotease; PDGF receptors ID TISSUE GROWTH-FACTOR; IMMEDIATE-EARLY GENE; SMOOTH-MUSCLE-CELLS; MATRIX METALLOPROTEINASES; ENDOTHELIAL-CELLS; WILMS-TUMORS; FACTOR-BETA; PRODUCT; FAMILY; DOMAIN AB Nephroblastoma overexpressed gene (NOV) is highly expressed in the nervous system. We investigated its biological activity by expressing the human NOV gene ( NOVH) in a human glioblastoma cell line that is negative for NOVH and by analyzing four clones with different levels of NOVH expression. There was no difference in cell proliferation between the NOVH-expressing cell lines, but there was increased cell adhesion and migration that correlated with increasing NOVH expression. Gene expression profiling was used to investigate the mechanisms by which NOVH expression regulated cell activity. We identified two induced genes in NOVH-expressing cells that are involved in cell migration: matrix metalloprotease (MMP) 3 and platelet-derived growth factor receptor (PDGFR)-alpha. Our studies show that PDGFR-alpha induced MMP3 gene expression and increased cell proliferation and cell migration upon stimulation by platelet-derived growth factor (PDGF)-AA. We also show that the induction of MMP3 in cells expressing NOVH is potentiated by either cell density, serum, or PDGF-BB. Thus, expression of NOVH in glioblastoma cells triggers a cascade of gene expression resulting in increased cell adhesion and migration. C1 Hop St Antoine, INSERM,U515, Proliferat Differenciat & Proc Tumoraux Batim, F-75012 Paris, France. NIDCR, NIH, Bethesda, MD 20814 USA. Hop St Louis, INSERM, U32, F-75010 Paris, France. RP Laurent, M (reprint author), Hop St Antoine, INSERM,U515, Proliferat Differenciat & Proc Tumoraux Batim, 184 Rue Fbg St Antoine,Batiment Kourilsky, F-75012 Paris, France. EM laurent@st-antoine.inserm.fr RI MAUVIEL, Alain/F-6251-2013 NR 45 TC 33 Z9 36 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2003 VL 17 IS 11 BP 1919 EP + DI 10.1096/fj.02-1023fje PG 23 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 721YB UT WOS:000185345100013 PM 14519668 ER PT J AU Bornstein, SR Yoshida-Hiroi, M Sotiriou, S Levine, M Hartwig, HG Nussbaum, RL Eisenhofer, G AF Bornstein, SR Yoshida-Hiroi, M Sotiriou, S Levine, M Hartwig, HG Nussbaum, RL Eisenhofer, G TI Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2) SO FASEB JOURNAL LA English DT Article DE SVCT2; ascorbic acid; catecholamines; norepinephrine; epinephrine; dopamine; adrenal gland; sympathetic nervous system ID CORTICOTROPIN-RELEASING HORMONE; VITAMIN-C TRANSPORT; CHROMAFFIN CELLS; BIOSYNTHESIS; SECRETION; GLAND AB Ascorbic acid ( vitamin C) is a cofactor required in catecholamine synthesis for conversion of dopamine to norepinephrine by dopamine beta-hydroxylase. Mutant mice lacking the plasma membrane ascorbic acid transporter (SVCT2) have severely reduced tissue levels of ascorbic acid and die after birth. We therefore investigated whether these mice might have impaired synthesis of catecholamines. Levels of catecholamines in brain were unaffected by SVCT2 deficiency. In heart, the only evidence for impaired dopamine beta-hydroxylase activity was a twofold increase in tissue dopamine. An influence of the deficiency on tissue catecholamines was most prominent in the adrenals where norepinephrine was decreased by 50% and epinephrine, by 81%. On the ultrastructural level, adrenal chromaffin cells in SVCT2 null mice showed depletion of catecholamine storage vesicles, increased amounts of rough endoplasmic reticulum, signs of apoptosis, and increased glycogen storage. Decreased plasma levels of corticosterone indicated additional effects of the deficiency on adrenal cortical function. These data show that deranged catecholamine system function in SVCT2 null mice is largely restricted to the adrenal medulla and cannot account for the lethality in these animals. The data, however, establish a crucial role for ascorbic acid in adrenal chromaffin cell function. C1 Univ Dusseldorf, Dept Endocrinol, D-40225 Dusseldorf, Germany. Univ Dusseldorf, Dept Anat, D-40225 Dusseldorf, Germany. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), Univ Dusseldorf, Dept Endocrinol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM stefan.bornstein@uni-duesseldorf.de NR 30 TC 33 Z9 37 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2003 VL 17 IS 11 BP 1928 EP + DI 10.1096/fj.02-1167fje PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 721YB UT WOS:000185345100019 PM 12897061 ER PT J AU El-Agnaf, OMA Salem, SA Paleologou, KE Cooper, LJ Fullwood, NJ Gibson, MJ Curran, MD Court, JA Mann, DMA Ikeda, S Cookson, MR Hardy, J Allsop, D AF El-Agnaf, OMA Salem, SA Paleologou, KE Cooper, LJ Fullwood, NJ Gibson, MJ Curran, MD Court, JA Mann, DMA Ikeda, S Cookson, MR Hardy, J Allsop, D TI alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma SO FASEB JOURNAL LA English DT Article DE amyloid; dementia with Lewy bodies; neurodegeneration ID MULTIPLE-SYSTEM ATROPHY; ALZHEIMERS-DISEASE; LEWY BODIES; HUMAN BRAIN; CEREBROSPINAL-FLUID; MESSENGER-RNA; MOUSE MODEL; FATTY-ACIDS; PROTEIN; MUTATIONS AB Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fibrillar aggregates of alpha-synuclein protein (alpha-syn) inside brain cells. It is likely that the formation of alpha-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, because two different mutations in the gene encoding alpha-syn have been found in inherited forms of PD. alpha-Syn is mainly expressed by neuronal cells and is generally considered to exist as a cytoplasmic protein. Here, we report the unexpected identification of alpha-syn in conditioned culture media from untransfected and alpha-syn-transfected human neuroblastoma cells, as well as in human cerebrospinal fluid and blood plasma. The method used was immunocapture by using anti-alpha-syn antibodies coupled to magnetic beads, followed by detection on Western blots. In all cases, alpha-syn was identified as a single 15 kDa band, which co-migrated with a recombinant form of the protein and reacted with five different antibodies to alpha-syn. Our findings suggest that cells normally secrete alpha-syn into their surrounding media, both in vitro and in vivo. The detection of extracellular alpha-syn and/or its modified forms in body fluids, particularly in human plasma, offers new opportunities for the development of diagnostic tests for PD and related diseases. C1 Univ Lancaster, Div Biol Sci, Lancaster LA1 4YQ, England. Belfast City Hosp, Movement Disorders Clin, Belfast BT9 7AD, Antrim, North Ireland. Belfast City Hosp, No Ireland Reg Histocompatibil & Immunogenet Lab, Belfast BT9 7AD, Antrim, North Ireland. Newcastle Gen Hosp, Joint MRC Newcastle Univ Dev Clin Brain Ageing, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. Hope Hosp, Clin Neurosci Res Grp, Greater Manchester Neurosci Ctr, Salford M6 8HD, Lancs, England. Shinshu Univ, Sch Med, Nagano, Japan. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP El-Agnaf, OMA (reprint author), Univ Lancaster, Div Biol Sci, Lancaster LA1 4YQ, England. EM o.el-agnaf@lancaster.ac.uk RI Allsop, David/B-9725-2008; Hardy, John/C-2451-2009 OI Allsop, David/0000-0002-0513-5575; NR 44 TC 282 Z9 287 U1 2 U2 12 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2003 VL 17 IS 11 BP 1945 EP + DI 10.1096/fj.03-0098fje PG 16 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 721YB UT WOS:000185345100012 PM 14519670 ER PT J AU Gao, HM Liu, B Zhang, WQ Hong, JS AF Gao, HM Liu, B Zhang, WQ Hong, JS TI Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson's disease SO FASEB JOURNAL LA English DT Article DE microglia; microgliosis; neurodegeneration; reactive oxygen species; astroglia ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; NIGRAL DOPAMINERGIC-NEURONS; NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE; NEURODEGENERATIVE DISEASES; ACTIVATED MICROGLIA; INTRANIGRAL INJECTION; GLIAL-CELLS; BRAIN; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AB 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons as seen in Parkinson's disease. Although increasing evidence suggests an involvement of glia in MPTP neurotoxicity, the nature of this involvement remains unclear. Exploiting the advantage of cell culture systems, we demonstrated that microglia, but not astroglia, significantly enhanced the progression of MPTP-induced dopaminergic neurodegeneration. Characterization of the temporal relationship between neurodegeneration and microglial activation demonstrates that reactive microgliosis resulting from MPTP-initiated neuronal injury, but not direct activation, underlies the microglia-enhanced MPTP neurotoxicity. Mechanistically, through the release of NADPH oxidase-derived reactive oxygen species, microglia contribute to the progressive neuronal damage. Among the factors measured, the production of extracellular superoxide was the most prominent. NADPH oxidase inhibitor, apocynin, attenuated MPTP-induced dopaminergic neurodegeneration only in the presence of glia. More importantly, dopaminergic neurons from mice lacking NADPH oxidase, a key enzyme for superoxide production in immune cells, are significantly more resistant to MPTP neurotoxicity than those from wild-type controls, and microglia dictate the resistance. This study demonstrates that reactive microgliosis triggered by MPTP-induced neuronal injury and NADPH oxidase-mediated superoxide production in microglia constitute an integral component of MPTP neurotoxicity. This study also suggests that NADPH oxidase may be a promising target for therapeutic interventions in Parkinson's disease. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Liu, B (reprint author), Univ Florida, Coll Pharm, Dept Pharmacodynam, POB 100487 HSC, Gainesville, FL 32610 USA. EM liu@cop.ufl.edu RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 54 TC 193 Z9 202 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2003 VL 17 IS 11 BP 1954 EP + DI 10.1096/fj.03-0109fje PG 22 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 721YB UT WOS:000185345100026 PM 12897068 ER PT J AU Gao, HM Liu, B Zhang, WQ Hong, JS AF Gao, HM Liu, B Zhang, WQ Hong, JS TI Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease SO FASEB JOURNAL LA English DT Article DE inflammation; microglia; NADPH oxidase; synergistic neurotoxicity ID NITRIC-OXIDE SYNTHASE; ENVIRONMENTAL RISK-FACTORS; SUBSTANTIA-NIGRA; NADPH OXIDASE; GLIAL-CELLS; MICROGLIAL ACTIVATION; INTRANIGRAL INJECTION; INFLAMMATORY REACTION; ALZHEIMERS-DISEASE; PESTICIDE EXPOSURE AB Parkinson's disease (PD) is a profound movement disorder resulting from progressive degeneration of the nigrostriatal dopaminergic pathway. Although its etiology remains unknown, increasing evidence suggests the involvement of multiple factors such as environmental toxins and genetic susceptibilities in the pathogenesis of PD. In this study using mesencephalic neuronglia cultures as an in vitro PD model, we demonstrated that the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP, 0.1-0.5 muM) and an inflammogen lipopolysaccharide (LPS, 0.5 ng/ml) synergistically induced a progressive and selective degeneration of dopaminergic neurons. The synergistic neurotoxicity was observed when both agents were applied either simultaneously or in tandem. The synergistic neurotoxicity was more prominent when lower doses of both agents were applied for a longer period of time. Mechanistically, microglial NADPH oxidase-mediated generation of reactive oxygen species played a pivotal role in the synergistic neurotoxicity: MPTP and LPS synergistically stimulated the NADPH oxidase-mediated release of superoxide free radical; pharmacological inhibition and genetic inactivation of NADPH oxidase prevented superoxide production and the synergistic neurotoxicity. Additionally, inhibition of nitric oxide synthase afforded significant neuroprotection, suggesting the involvement of nitric oxide in the synergistic neurotoxicity. This study lends strong support for a multifactorial etiology of PD and provides clues for therapeutic interventions. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233,F1-01, Res Triangle Pk, NC 27709 USA. EM gao@niehs.nih.gov RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 67 TC 110 Z9 113 U1 1 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2003 VL 17 IS 11 BP 1957 EP + DI 10.1096/fj.03-0203fje PG 25 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 721YB UT WOS:000185345100007 PM 12923073 ER PT J AU Tsibris, JCM Segars, J Enkemann, S Coppola, D Wilbanks, GD O'Brien, WF Spellacy, WN AF Tsibris, JCM Segars, J Enkemann, S Coppola, D Wilbanks, GD O'Brien, WF Spellacy, WN TI New and old regulators of uterine leiomyoma growth from screening with DNA arrays SO FERTILITY AND STERILITY LA English DT Article ID RETINOIC ACID C1 Univ S Florida, Dept Obstet & Gynecol, Tampa, FL 33606 USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Univ S Florida, Dept Pathol, Tampa, FL 33620 USA. H Lee Moffit Canc Ctr & Res Inst, Dept Interdisciplinary Oncol & Microarray Core Fa, Tampa, FL USA. RP Tsibris, JCM (reprint author), Univ S Florida, Dept Obstet & Gynecol, 4 Columbia Dr,Rm 524, Tampa, FL 33606 USA. NR 6 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2003 VL 80 IS 2 BP 279 EP 281 DI 10.1016/S0015-0282(03)00728-3 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 709PZ UT WOS:000184634700009 PM 12909486 ER PT J AU Catherino, WH Prupas, C Tsibris, JCM Leppert, PC Payson, M Nieman, LK Segars, JH AF Catherino, WH Prupas, C Tsibris, JCM Leppert, PC Payson, M Nieman, LK Segars, JH TI Strategy for elucidating differentially expressed genes in leiomyomata identified by microarray technology SO FERTILITY AND STERILITY LA English DT Article DE fibroid; microarray; PCR; Dlk; Frizzled-2; CD-24 ID COMPLEMENTARY-DNA MICROARRAY; UTERINE LEIOMYOMATA; PROTEIN; CELLS; CD24; ANTIGEN; ARRAYS; RECEPTOR; PROFILES; FAMILY AB Objective: cDNA microarray technology identifies genes that are differentially expressed between tissues. Our previous study identified several genes that might contribute to the fibroid phenotype. We therefore sought to confirm genes involved in three distinct signal transduction pathways. Design: Evaluation of differential mRNA and protein expression of D1k, Frizzled-2, and CD-24 in fibroids compared with adjacent myometrium. Setting: University hospital. Patient(s): Five women undergoing medically indicated hysterectomy for symptomatic fibroids. Intervention(s): Microarray analysis of up to 33,000 genes, reverse transcriptase-polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, and immunohistochemistry. Main Outcome Measure(s): Expression of mRNA transcripts and protein in fibroid compared with myometrium. Result(s): A more extensive microarray confirmed differential expression of Frizzled-2 and CD-24 but did not confirm Dlk overexpression. RT-PCR and real-time PCR demonstrated equivalent Dlk mRNA expression between fibroid and myometrium (ratio, 1.02), a slight Frizzled-2 overexpression (ratio, 2.09), and robust CD-24 overexpression in fibroids (ratio, 1-2.35). Western blot and immunohistochemistry confirmed Frizzled-2 overexpression, but did not confirm Dlk overexpression. Conclusion(s): Microarray technology is the first phase of tissue evaluation, but changes in gene expression must be confirmed. Confirmed genes can then be used to generate hypotheses testing their involvement in fibroid development. (C) 2003 by American Society for Reproductive Medicine. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Combined Fed Program Reprod Endocrinol, Bethesda, MD USA. Univ S Florida, Tampa, FL USA. RP Segars, JH (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D-42, Bethesda, MD 20892 USA. NR 25 TC 43 Z9 44 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 AUG PY 2003 VL 80 IS 2 BP 282 EP 290 DI 10.1016/S0015-0282(03)00953-1 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 709PZ UT WOS:000184634700010 PM 12909487 ER PT J AU Catherino, WH Segars, JH AF Catherino, WH Segars, JH TI Microarray analysis in fibroids: which gene list is the correct list? SO FERTILITY AND STERILITY LA English DT Article C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Combined Fed Program Reprod Endocrinol, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Segars, JH (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D-42, Bethesda, MD 20892 USA. NR 5 TC 14 Z9 14 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 AUG PY 2003 VL 80 IS 2 BP 293 EP 294 DI 10.1016/S0015-0282(03)00958-0 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 709PZ UT WOS:000184634700012 PM 12909489 ER PT J AU Tscharke, RL Lazera, M Chang, YC Wickes, BL Kwon-Chung, KJ AF Tscharke, RL Lazera, M Chang, YC Wickes, BL Kwon-Chung, KJ TI Haploid fruiting in Cryptococcus neoformans is not mating type alpha-specific SO FUNGAL GENETICS AND BIOLOGY LA English DT Article ID STE12 HOMOLOG; FILOBASIDIELLA-NEOFORMANS; BODY PRODUCTION; VIRULENCE; FILAMENTATION; ASSOCIATION; GENETICS; MARKER; STATE AB Under appropriate conditions, haploid Cryptococcus neoformans cells can undergo a morphological switch from a budding yeast form to develop hyphae and viable basidiospores, which resemble those produced by mating. This process, known as haploid fruiting, was previously thought to occur only in MATalpha strains. We identified two new strains of C neoformans var. neoformans serotype D that are MATa type and are able to haploid fruit. Further, a MATa reference strain, B-3502, also produced hyphae and fruited after prolonged incubation on filament agar. Over-expression of STE12a dramatically enhanced the ability of all MATa strains tested to filament. Segregation analysis of haploid fruiting ability confirmed that haploid fruiting is not MATalpha-specific. Our results indicate that MATa cells are intrinsically able to haploid fruit and previous observations that they do not were probably biased by the examination of a small number of genetically related isolates that have been maintained in the laboratory for many years. Published by Elsevier Science (USA). C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Ctr Pesquisa Hosp, Rio De Janeiro, Brazil. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R29AI43522] NR 23 TC 47 Z9 50 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1087-1845 J9 FUNGAL GENET BIOL JI Fungal Genet. Biol. PD AUG PY 2003 VL 39 IS 3 BP 230 EP 237 DI 10.1016/S1087-1845(03)00046-X PG 8 WC Genetics & Heredity; Mycology SC Genetics & Heredity; Mycology GA 710EP UT WOS:000184668100005 PM 12892636 ER PT J AU Claudel, T Inoue, Y Barbier, O Duran-Sandoval, D Kosykh, V Fruchart, J Fruchart, JC Gonzalez, FJ Staels, B AF Claudel, T Inoue, Y Barbier, O Duran-Sandoval, D Kosykh, V Fruchart, J Fruchart, JC Gonzalez, FJ Staels, B TI Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression SO GASTROENTEROLOGY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; TRIGLYCERIDE-RICH LIPOPROTEINS; LOW-DENSITY-LIPOPROTEIN; NEGATIVE FEEDBACK-REGULATION; BILE-ACID SYNTHESIS; SALT EXPORT PUMP; C-III GENE; ACTIVATED RECEPTOR; RAT HEPATOCYTES; TRANSGENIC MICE AB Background & Aims: Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression. Methods: The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells. Results. In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the 14 footprint between nucleotides -739 and -704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4alpha from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4alpha-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR. Conclusions. We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists. C1 Inst Pasteur, INSERM, UR545, Dept Atheroscierose, F-59019 Lille, France. Univ Lille 2, Fac Pharm, Lille, France. NIH, Lab Metab, Div Basic Sci, Bethesda, MD 20892 USA. Russian Cardiol Complex, Inst Expt Cardiol, Moscow, Russia. RP Staels, B (reprint author), Inst Pasteur, INSERM, UR545, Dept Atheroscierose, 1 Rue Pr Calmette,BP245, F-59019 Lille, France. NR 71 TC 142 Z9 146 U1 0 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2003 VL 125 IS 2 BP 544 EP 555 DI 10.1016/S0016-5085(03)00896-5 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 707VU UT WOS:000184531200034 PM 12891557 ER PT J AU Bordi, C Delle Fave, G Jensen, RT AF Bordi, C Delle Fave, G Jensen, RT TI Discussion on the effect of chronic hypergastrinemia on human enterochromaffin-like cells: Insights from patients with sporadic gastrinomas - Reply SO GASTROENTEROLOGY LA English DT Letter ID ENDOCRINE-CELLS; GASTRITIS C1 Univ Parma, Dept Pathol & Lab Med, Sect Anat Pathol, I-43100 Parma, Italy. Univ Roma La Sapienza, Div Digest & Liver Dis, Sch Med 2, Rome, Italy. NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Bordi, C (reprint author), Univ Parma, Dept Pathol & Lab Med, Sect Anat Pathol, I-43100 Parma, Italy. NR 6 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2003 VL 125 IS 2 BP 627 EP 628 DI 10.1016/S0016-5085(03)00971-5 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 707VU UT WOS:000184531200051 ER PT J AU Silva, JC Shabalina, SA Harris, DG Spouge, JL Kondrashov, AS AF Silva, JC Shabalina, SA Harris, DG Spouge, JL Kondrashov, AS TI Conserved fragments of transposable elements in intergenic regions: evidence for widespread recruitment of MIR- and L2-derived sequences within the mouse and human genomes SO GENETICS RESEARCH LA English DT Article ID INTERSPERSED REPEATS; REPETITIVE SEQUENCES; REGULATORY ELEMENTS; MOBILE ELEMENTS; ALU FUNCTION; EVOLUTION; GENES; DNA; DIVERGENCE; MAMMALS AB We analysed the distribution of transposable elements (TEs) in 100 aligned pairs of orthologous intergenic regions from the mouse and human genomes. Within these regions, conserved segments of high similarity between the two species alternate with segments of low similarity. Identifiable TEs comprise 40-60 % of segments of low similarity. Within such segments, a particular copy of a TE found in one species has no orthologue in the other. Overall, TEs comprise only approximately 20 % of conserved segments. However, TEs from two families, MIR and L2, are rather common within conserved segments. Statistical analysis of the distributions of TEs suggests that a majority of the MIR and L2 elements present in murine intergenic regions have human orthologues. These elements must have been present in the common ancestor of human and mouse and have remained under substantial negative selection that prevented their divergence beyond recognition. If so, recruitment of MIR- and L2-derived sequences to perform a function that increases host fitness is rather common, with at least two such events per host gene. The central part of the MIR consensus sequence is over-represented in conserved segments given its background frequency in the genome, suggesting that it is under the strongest selective constraint. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. Natl Secur Agcy, Ft George G Meade, MD 20755 USA. RP Silva, JC (reprint author), Inst Genom Res, 9712 Med Ctr Dr, Rockville, MD 20850 USA. EM jsilva@tigr.org RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 NR 48 TC 46 Z9 49 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0016-6723 J9 GENET RES JI Genet. Res. PD AUG PY 2003 VL 82 IS 1 BP 1 EP 18 DI 10.1017/S0016672303006268 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 727ZR UT WOS:000185691200001 PM 14621267 ER PT J AU Lo, HS Wang, ZN Hu, Y Yang, HH Gere, S Buetow, KH Lee, MP AF Lo, HS Wang, ZN Hu, Y Yang, HH Gere, S Buetow, KH Lee, MP TI Allelic variation in gene expression is common in the human genome SO GENOME RESEARCH LA English DT Article ID CHROMOSOME; TISSUE; WT1 AB Variations in gene sequence and expression underlie much Of human variability. Despite the known biological roles of differential allelic gene expression resulting from X-chromosome inactivation and genomic imprinting, a large-scale analysis of allelic gene expression in human is lacking. We examined allele-specific gene expression of 1063 transcribed single-nucleotide polymorphisms (SNPs) by using Affymetrix HuSNP oligo arrays. Among the 602 genes that were heterozygous and expressed in kidney or liver tissues from seven individuals, 326 (54%) showed preferential expression of one allele in at least one individual, and 170 of those showed greater than fourfold difference between the two alleles. The allelic variation has been confirmed by real-time quantitative PCR experiments. Some of these 170 genes are known to be imprinted, such as SNRPN, IPW, HTR2A, and PEG3. Most of the differentially expressed genes are not in known imprinting domains but instead are distributed throughout the genome. Our Studies demonstrate that variation of gene expression between alleles is common, and this variation may contribute to human variability. C1 NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Lee, MP (reprint author), NCI, Lab Populat Genet, Bethesda, MD 20892 USA. NR 8 TC 320 Z9 333 U1 0 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2003 VL 13 IS 8 BP 1855 EP 1862 DI 10.1101/gr.1006603 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 707VQ UT WOS:000184530900007 PM 12902379 ER PT J AU Murphy, WJ Fronicke, L O'Brien, SJ Stanyon, R AF Murphy, WJ Fronicke, L O'Brien, SJ Stanyon, R TI The origin of human chromosome 1 and its homologs in placental mammals SO GENOME RESEARCH LA English DT Article ID RADIATION HYBRID MAP; CHROMOSOME EVOLUTION; GENOME ORGANIZATION; ANCESTRAL KARYOTYPE; CONSERVED SYNTENY; ZOO-FISH; SEQUENCE; CAT; PHYLOGENETICS; PRIMATES AB Developing ordered gene maps from multiple mammalian species coupled with chromosome-painting data provide a powerful resource for resolving the evolutionary history of chromosomes and whole genomes. In this work, we recapitulate the evolutionary history of human chromosome I and its homologs in placental mammals, putatively the largest physical unit in the ancestral placental genome. Precise definition of translocation exchange breakpoints in human, carnivore, cetartiodactyl, and rodent-ordered gene maps demonstrate that chromosome breakpoints, previously considered as equivalent, actually represent distinct chromosome positions and exchange events. Multidirectional chromosome painting, using probes from homologs to chromosome I in seven mammal species from six orders of placental mammals, confirm the gene-mapping results and indicate that the multiple human chromosome I homologs in these species are derived from independent fissions of a single ancestral chromosome. Chromosome painting using human chromosome I probes identifies a single human chromosome I homolog in phylogenetically distant taxa, the two-toed sloth, cetaceans, and higher primates. The diverse phylogenetic occurrence of a single Hsal synteny among the major clades of placental mammals suggests that human chromosome I represents an intact ancestral chromosome, which was variously fissioned in the majority of placental species. We find that the number of human chromosome I fissions in a specific lineage reflects its general rate of genomic evolution. Further, historic chromosome exchange appears to have been disproportionately clustered in two breakpoint hotspots on the long arm. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Genet Branch, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM murphywi@mail.ncifcrf.gov OI Stanyon, Roscoe/0000-0002-7229-1092 NR 39 TC 45 Z9 47 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 AUG PY 2003 VL 13 IS 8 BP 1880 EP 1888 DI 10.1101/gr.1022303 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 707VQ UT WOS:000184530900010 PM 12869576 ER PT J AU Sood, R Makalowska, I Galdzicki, M Hu, P Eddings, E Robbins, CM Moses, T Namkoong, J Chen, SZ Trent, JM AF Sood, R Makalowska, I Galdzicki, M Hu, P Eddings, E Robbins, CM Moses, T Namkoong, J Chen, SZ Trent, JM TI Cloning and characterization of a novel gene, SHPRH, encoding a conserved putative protein with SNF2/helicase and PHD-finger domains from the 6q24 region SO GENOMICS LA English DT Article DE SHPRH; 6q24; tumor suppressor; SNF2 domain; PHD-finger domain; RING-finger domain; linker histone domain; DNA/RNA helicases ID TRANSCRIPTIONAL REGULATION; TRANSGENIC MICE; CELL-LINES; LONG ARM; CHROMOSOME-6; CANCER; MELANOMA; HETEROZYGOSITY; TUMORIGENICITY; CHROMATIN AB Here we report the identification of a novel transcript containing SNF2, PHD-finger, RING-finger, helicase, and linker histone domains mapping to the q24 band region of human chromosome 6. These domains are characteristic of several DNA repair proteins, transcription factors, and helicases. We have cloned both human and mouse homologs of this novel gene using interexon PCR and RACE technologies. The human cDNA. termed SHPRH, is 6018 bp and codes for a putative protein of 1683 amino acids. The mouse cDNA, termed Shprh, is 7225 bp and codes for a putative protein of 1616 amino acids. The deduced amino acid sequences of the two proteins share 86% identity. Both genes are expressed ubiquitously. with a transcript size of similar to7.5 kb. Mapping of this gene to 6q24, a region reported to contain a tumor suppressor locus, prompted us to evaluate SHPRH by mutation analysis in tumor cell lines. We have identified one truncating and three missense mutations. thus suggesting SHPRH as a possible candidate for the tumor suppressor gene. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Rutgers State Univ, Susan Lehman Cullman Lab Canc Res, Dept Biol Chem, Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA. RP Sood, R (reprint author), NHGRI, Canc Genet Branch, NIH, Bldg 50,Room 5343,900 Rockville Pike, Bethesda, MD 20892 USA. RI Galdzicki, Michal/F-5682-2010 OI Galdzicki, Michal/0000-0002-8392-8183 NR 37 TC 26 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 0888-7543 J9 GENOMICS JI Genomics PD AUG PY 2003 VL 82 IS 2 BP 153 EP 161 DI 10.1016/S0888-7543(03)00121-6 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 699GQ UT WOS:000184049200006 PM 12837266 ER PT J AU Stanyon, R Stone, G Garcia, M Froenicke, L AF Stanyon, R Stone, G Garcia, M Froenicke, L TI Reciprocal chromosome painting shows that squirrels, unlike murid rodents, have a highly conserved genome organization SO GENOMICS LA English DT Article DE chromosomal homology; Zoo-FISH; synteny; phylogeny; sciurids ID MOUSE; HYBRIDIZATION; RESOLUTION; EVOLUTION; HOMOLOGY; SEGMENTS; HUMANS; FISH; MAPS; RAT AB We present the first report of reciprocal chromosome painting between humans and a rodent. Gene mapping and sequencing data lead to the generalization that rodent genomes are highly rearranged. In contrast, our results show a surprising conservation of genome structure between humans and squirrels. The synteny of 12 human chromosomes was entirely conserved (5, 6, 9, 11, 13-15, 17, 18, 20, 21, and X). Of the 12 syntenic associations of human chromosomes present in the squirrel, six are well-known ancestral eutherian associations (3/21, 4/8, 7/16, 12/22, 14/15, 16/19). Apparently, few derived translocations characterize the evolutionary origin of the rodents. One association (10p/1qter) may be a cladistic marker for the cohort Glires, linking rodents and lagomorphs. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Comparat Mol Cytogenet Core, Genet Branch, Frederick, MD 21702 USA. Univ Autonoma Barcelona, Dept Biol Cellular Fisiol & Immunol, E-08193 Barcelona, Spain. RP Stanyon, R (reprint author), NCI, Comparat Mol Cytogenet Core, Genet Branch, Bldg 560,Room 11-74A, Frederick, MD 21702 USA. OI Stanyon, Roscoe/0000-0002-7229-1092 NR 18 TC 47 Z9 49 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 0888-7543 J9 GENOMICS JI Genomics PD AUG PY 2003 VL 82 IS 2 BP 245 EP 249 DI 10.1016/S0888-7543(03)00109-5 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 699GQ UT WOS:000184049200014 PM 12837274 ER PT J AU Burke, TW Walker, CL AF Burke, TW Walker, CL TI Arzoxifene as therapy for endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE arzoxifene; endometrial cancer; hormonal therapy; third-generation SERM ID ESTROGEN-RECEPTOR MODULATORS; GYNECOLOGIC-ONCOLOGY-GROUP; POLYCYSTIC-OVARY-SYNDROME; SURGICAL-ADJUVANT-BREAST; PROGESTERONE-RECEPTOR; PHASE-II; POSTMENOPAUSAL WOMEN; TAMOXIFEN THERAPY; SERUM-CHOLESTEROL; RANDOMIZED TRIAL AB Objective. Arzoxifene, an orally active third-generation selective estrogen-receptor modulator (SERM), opposes the action of estrogen on the breast and endometrium but exerts an estrogen-agonist effect on bone and the lipid profile. Since this is an appealing combination for hormonal therapy of estrogen-related cancers, we initiated testing the potential of arzoxifene in women with treatment-refractory endometrial cancer. Methods. Two phase I studies were conducted to evaluate the safety and pharmacokinetics of single and multiple doses of arzoxifene. In addition, two multi-institutional phase II trials have been completed on 100 women with metastatic or recurrent endometrial cancer. Results. No serious adverse events were observed in the single-dose phase I study, the principal side effect being hot flashes in 5115 healthy volunteers. In the second phase I study, conducted in 32 women with metastatic breast cancer, one patient had a serious, possibly drug-related adverse reaction (pulmonary embolism). The two multi-institutional trials demonstrated significant activity at 20 mg/day in patients with metastatic or recurrent endometrial cancer. Observed clinical response rates were 25 and 31%, with a median response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilized in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related. Conclusions. Further investigation is warranted to verify these preliminary response rates and the clinical significance of the stable disease cases, to compare clinical outcomes with those in progestin-treated women, and to elucidate the mechanisms of SERM action in this disease. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. NIEHS, Ctr Res Environm Dis, Dept Carcinogenesis Mol Genet & Environm Carcinog, Smithville, TX 78957 USA. RP Burke, TW (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd,Box 440, Houston, TX 77030 USA. NR 55 TC 18 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2003 VL 90 IS 2 SU S BP S40 EP S46 DI 10.1016/S0090-8258(03)00343-3 PN 2 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 717CP UT WOS:000185068300007 PM 12928005 ER PT J AU Copeland, LJ Bookman, M Trimble, E AF Copeland, LJ Bookman, M Trimble, E TI Clinical trials of newer regimens for treating ovarian cancer: the rationale for Gynecologic Oncology Group Protocol GOG 182-ICON5 SO GYNECOLOGIC ONCOLOGY LA English DT Article DE ovarian cancer; platinum; taxane; gemcitabine; PEG-liposomal doxorubicin; topotecan; study protocol; Gynecologic Oncology Group ID RANDOMIZED TRIAL; STAGE-III; PHASE-II; IN-VITRO; CISPLATIN; CYCLOPHOSPHAMIDE; PACLITAXEL; TOPOTECAN; DOXORUBICIN; WOMEN AB Objectives. The current standard of chemotherapy for previously untreated patients with stage III/IV ovarian cancer who have undergone optimal or suboptimal cytoreductive surgery leaves room for improvement in terms of response rate and both progression-free and overall survival. Gynecologic Oncology Group (GOG) 182-ICON5 is a five-arm international collaborative study designed to improve on the efficacy of standard platinum/taxane therapy by incorporating newer cytotoxic agents in sequential doublet and triplet combinations. Methods. The evolution of a standard regimen for treating advanced ovarian cancer is reviewed, and the reasons for selecting carboplatin and paclitaxel for the control arm of the study are presented. Among the newer agents available for the experimental treatment arms, three stood out-gemcitabine, polyethylene-glycol (PEG)-liposomal doxorubicin, and topotecan-based on evidence of their activity demonstrated in previous phase I and II trials and, with appropriate dosage modifications, manageable toxicity when used in combination with platinum. Results. GOG 182-ICON5 is now in its second year of accrual. Patient recruitment, which is anticipated to grow to between 3400 and 4000 patients by the time the study is closed, is meeting expectations, and no problems have been encountered, except for the initial slow pace of recruitment outside of the United States. Conclusions. Combination chemotherapy using newer cytotoxic agents with demonstrated activity in treating advanced-stage ovarian cancer and the ability to enhance platinum-based therapies appears to offer hope of prolonging life and reducing mortality from this disease. 0 2003 Elsevier Inc. All rights reserved. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Ohio State Univ, James Canc Hosp, Columbus, OH 43210 USA. RP Copeland, LJ (reprint author), Ohio State Univ, Coll Med & Publ Hlth, Dept Obstet & Gynecol, Solove Res Inst, 1654 Upharn Dr,505 Means Hall, Columbus, OH 43210 USA. NR 21 TC 36 Z9 37 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2003 VL 90 IS 2 SU S BP S1 EP S7 DI 10.1016/S0090-8258(03)00337-8 PN 2 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 717CP UT WOS:000185068300001 PM 12927999 ER PT J AU Fortney, J Sullivan, G Williams, K Jackson, C Morton, SC Koegel, P AF Fortney, J Sullivan, G Williams, K Jackson, C Morton, SC Koegel, P TI Measuring continuity of care for clients of public mental health systems SO HEALTH SERVICES RESEARCH LA English DT Article DE continuity of care; homeless; serious mental illness ID INTERNATIONAL DIAGNOSTIC INTERVIEW; CASE-MANAGEMENT; OUTCOMES; SCHIZOPHRENIA; DISORDERS; ILLNESS; ILL AB Objectives. The aims of this research were to generate a set of time-variant measures of continuity of outpatient care using administrative data, and to evaluate the validity of these measures for persons in the community with serious mental illness (SMI) who use public mental health services. Data Sources. Individuals with SMI were identified using multistage random sampling from shelters, streets, and public mental health clinics in Houston, Texas. Study Design. The study design was observational, cross-sectional, and retrospective. Based on a review of the literature, five distinct conceptual dimensions of continuity of care were defined: timeliness, intensity, comprehensiveness, stability, and coordination. Repeated measures of continuity were generated for each day of the year. Construct validity was assessed by comparing continuity for housed persons and homeless persons based on the assumption that homelessness is a risk factor for low continuity of outpatient care. Data Collection. Subjects were interviewed to collect sociodemographic and clinical information. Service use was retrospectively tracked through the administrative records of multiple public sector agencies. Principal Findings. AD five continuity measures demonstrated good construct validity by the fact that homelessness was significantly (p < 0.001) and substantially associated with lower continuity of care. Discussion. The five continuity-of care measures are relatively easy and inexpensive to generate using administrative data. The five continuity-of-care measures may be useful for identifying individuals at risk for poor outcomes and for evaluating the ability of public service systems to keep clients engaged in care over time. C1 Ctr Mental Healthcare Res, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72204 USA. VA HSR&D, Ctr Mental Hlth Serv & Outcomes Res, Cent Arkansas Vet Healthcare Syst, N Little Rock, AR USA. Univ Arkansas Med Sci, NIMH, Ctr Mental Healthcare Res, Dept Psychiat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Biometry, Little Rock, AR 72205 USA. RAND Corp, Hlth Program, Santa Monica, CA USA. RP Fortney, J (reprint author), Ctr Mental Healthcare Res, Cent Arkansas Vet Healthcare Syst, 5800 W 10th St,Suite 605, Little Rock, AR 72204 USA. FU NIAAA NIH HHS [R01 AA12328]; NIMH NIH HHS [P50 MH48197] NR 24 TC 20 Z9 20 U1 3 U2 5 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD AUG PY 2003 VL 38 IS 4 BP 1157 EP 1175 DI 10.1111/1475-6773.00168 PG 19 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 714ZL UT WOS:000184945500011 PM 12968822 ER PT J AU Kim, KY Lee, JW Ahn, BW Ryu, PD Nam, MJ AF Kim, KY Lee, JW Ahn, BW Ryu, PD Nam, MJ TI Loss of endogenous TGF-beta effect induces mouse hepatoma malignancy by correlation with cyclooxygenase-2 and VEGF SO HEPATOLOGY RESEARCH LA English DT Article DE transforming growth factor-beta (TGF-beta) cyclooxygenase (COX); vascular endothelial growth factor (VEGF); celecoxib; hepatoma ID GROWTH-FACTOR-BETA; INDUCED PROSTAGLANDIN SYNTHESIS; INTESTINAL EPITHELIAL-CELLS; COLON-CANCER CELLS; SYNTHASE-2 GENE; EXPRESSION; APOPTOSIS; RECEPTOR; INDUCTION; TUMORS AB The relation between transforming growth factor-beta (TGF-beta) and cyclooxygenase (COX) in hepatoma malignancy is not understood yet. To investigate regulation mechanism of endogenous TGF-beta on hepatoma, we established MH129F mouse hepatoma cell overexpressing the cytoplasmic domain of type II TGF-beta receptor (TRII). MH129F cell apoptosis was elevated almost 20% after 5 ng/ml TGF-beta1 treatment. However, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change of growth pattern after TGF-beta1 treatment because MH129F/TRIIs cells blocked the growth inhibitory effect of TGF-beta1. In MH129F/TRIIs cells, expression of cycooxygenase-2 (COX-2) and bcl-2 was remarkably elevated, and then enhancement of COX-2 mediated induction of prostaglandin E-2 (PGE(2)) production up to 7-fold. Especially, vascular endothelial growth factor (VEGF) expression was regulated by COX-2 in MH129F/TRIIs cells, which were inhibited endogenous TGF-beta response. Implantation of 5 x 10(6) MH129F/TRIIs cells into nude mice showed the significantly enhanced tumor formation, and intensity of COX-2 expression was slightly higher in MH129F/TRIls tumor section than control. Moreover, a strong antitumor response was observed in MH129F/TRIIs-bearing mice that were treated with a specific COX-2 inhibitor, celecoxib. Therefore, we suggest that COX-2 mediate the tumorigenicity of hepatoma cells blocking endogenous TGF-beta effect via VEGF regulation. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Natl Inst Hlth, Dept Biomed Sci, Div Cardiovasc Dis, Seoul 122701, South Korea. Korea Food & Drug Adm, Natl Inst Toxicol Res, Div Histopathol, Seoul 122704, South Korea. Seoul Natl Univ, Sch Agr Biotechnol, Suwon 441744, South Korea. Seoul Natl Univ, Coll Vet Med, Pharmacol Lab, Suwon 441744, South Korea. RP Kim, KY (reprint author), NHLBI, NIH, Bldg 10,8N228,10 Ctr Dr MSC 1762, Bethesda, MD 20892 USA. NR 41 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1386-6346 J9 HEPATOL RES JI Hepatol. Res. PD AUG PY 2003 VL 26 IS 4 BP 302 EP 310 DI 10.1016/S1386-6346(03)00155-4 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 725CF UT WOS:000185524900007 ER PT J AU Song, EY Kim, KA Kim, YD Lee, EY Lee, HS Kim, HJ Ahn, BM Choe, YK Kim, CH Chung, TW AF Song, EY Kim, KA Kim, YD Lee, EY Lee, HS Kim, HJ Ahn, BM Choe, YK Kim, CH Chung, TW TI Elevation of serum asialo-alpha(1) acid glycoprotein concentration in patients with hepatic cirrhosis and hepatocellular carcinoma as measured by antibody-lectin sandwich assay SO HEPATOLOGY RESEARCH LA English DT Article DE asialo-alpha 1 acid glycoprotein; asialoglycoproteins; antibody-lectin sandwich assay; hepatic disease serum marker ID ASIALOGLYCOPROTEIN RECEPTOR; ENDOCYTOSIS; HEPATOCYTES AB Serum asialoglycoproteins (desialylated glycoproteins) concentration was reported to be elevated in patients with hepatic disease as compared with that of normal subjects. In this study, we measured serum asialo-alpha(1), acid glycoprotein (AsAGP) level by a solid-phase sandwich assay in which monoclonal antibody (mAb) to alpha(1)-acid glycoprotein and galactose-binding lectin, ricinus communis (RCA), have been employed as capture protein and probe protein, respectively. The mAb-RCA sandwich assay was sensitive (0.02 mug/ml) and specific for AsAGP. We have determined AsAGP concentration of 869 serum specimens and analyzed the results using 1.38 and 2.24 mug/ml (AsAGP) as cut-off values, respectively. AsAGP level was 0.80 +/- 0.29 mug/ml (mean +/- S.D.) with 97 normal serum specimens and elevated primarily in patients with liver cirrhosis (LC) or hepatocellular carcinoma (HCC). Using 1.38 mug/ml as a cutoff, 4/97 normal subjects, 11/39 acute hepatitis and 26/159 non-hepatic disease exhibited a slight elevation, whereas, AsAGP level was significantly elevated in 182/230 LC and 63/72 HCC. Meanwhile, a cutoff of 2.24 mug/ml allowed significant differentiation of LC or HCC from chronic hepatitis. Serum AsAGP level appeared to increase progressively with increasing severity of liver disease in cirrhotic patients. Thus, serum AsAGP concentration, as measured by the new mAb-RCA sandwich assay, may be a useful differential marker as a diagnostic aid for LC or HCC. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Korea Res Inst Biosci & Biotechnol, Cell Biol Lab, Taejon 305600, South Korea. KOBIAS Inc, Res Lab, Taejon 305600, South Korea. Catholic Univ Korea, Taejon, South Korea. St Marys Hosp, Taejon 301723, South Korea. Coll Oriental Med, Dept Biochem & Mol Biol, Kyungju 780714, South Korea. RP Song, EY (reprint author), NICHD, LDN, NIH, Bd 49,Rm 5C08,MSC 4480, Bethesda, MD 20892 USA. NR 17 TC 14 Z9 16 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1386-6346 J9 HEPATOL RES JI Hepatol. Res. PD AUG PY 2003 VL 26 IS 4 BP 311 EP 317 DI 10.1016/S1386-6346(03)00156-6 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 725CF UT WOS:000185524900008 ER PT J AU Harold, D Peirce, T Moskvina, V Myers, A Jones, S Hollingworth, P Moore, P Lovestone, S Powell, J Foy, C Archer, N Walter, S Edmonson, A McIlroy, S Craig, D Passmore, PA Goate, A Hardy, J O'Donovan, M Williams, J Liddell, M Owen, MJ Jones, L AF Harold, D Peirce, T Moskvina, V Myers, A Jones, S Hollingworth, P Moore, P Lovestone, S Powell, J Foy, C Archer, N Walter, S Edmonson, A McIlroy, S Craig, D Passmore, PA Goate, A Hardy, J O'Donovan, M Williams, J Liddell, M Owen, MJ Jones, L TI Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease SO HUMAN GENETICS LA English DT Article ID NEUROTRANSMITTER-RELATED ENZYMES; CHOLINE-ACETYLTRANSFERASE GENE; SENILE DEMENTIA; LINKAGE DISEQUILIBRIUM; IDENTIFICATION; ABNORMALITIES; CHROMOSOME-10; SEVERITY; DEFICITS; NEURONS AB There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in, intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium. C1 Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. Univ Wales Coll Cardiff, Coll Med, Dept Psychol Med, Cardiff CF14 4XN, S Glam, Wales. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Inst Psychiat, London SE5 8AF, England. Queens Univ Belfast, Dept Geriatr Med, Belfast, Antrim, North Ireland. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. RP Jones, S (reprint author), Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. RI CRAIG, DAVID/C-6232-2009; Lovestone, Simon/E-8725-2010; Myers, Amanda/B-1796-2010; turton, miranda/F-4682-2011; Powell, John/G-4412-2011; Hardy, John/C-2451-2009; OI Myers, Amanda/0000-0002-3100-9396; Powell, John/0000-0001-6124-439X; O'Donovan, Michael/0000-0001-7073-2379; Harold, Denise/0000-0001-5195-0143; Escott-Price, Valentina/0000-0003-1784-5483 FU NIA NIH HHS [AG05681, AG06786, AG16208, AG16574, U24 AG021886] NR 31 TC 24 Z9 24 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2003 VL 113 IS 3 BP 258 EP 267 DI 10.1007/s00439-003-0960-2 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 712QD UT WOS:000184807600009 PM 12759818 ER PT J AU Tranebjaerg, L Teslovich, TM Jones, M Barmada, MM Fagerheim, T Dahl, A Escolar, DM Trent, JM Gillanders, EM Stephan, DA AF Tranebjaerg, L Teslovich, TM Jones, M Barmada, MM Fagerheim, T Dahl, A Escolar, DM Trent, JM Gillanders, EM Stephan, DA TI Genome-wide homozygosity mapping localizes a gene for autosomal recessive non-progressive infantile ataxia to 20q11-q13 SO HUMAN GENETICS LA English DT Article AB Autosomal recessive ataxias represent genetic and clinical heterogeneity. Unsteady gait is often accompanied by poor coordination of limbs, speech, and eye movements. To date, seven genes have been identified. In addition, five chromosomal loci have been localized in non-related families. Here, we report homozygosity mapping of a novel locus to a 19.5-cM region on chromosome 20q11-q13 in a large inbred Norwegian family with infantile non-progressive ataxia. C1 Bispebjerg Hosp, Dept Audiol, DK-2400 Copenhagen NV, Denmark. Univ Copenhagen, Wilhelm Johannsen Ctr Funct Genom, Copenhagen, Denmark. Univ Hosp, Dept Med Genet, Tromso, Norway. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. Univ Hosp Oslo, Dept Neurol, Oslo, Norway. RP Tranebjaerg, L (reprint author), Bispebjerg Hosp, Dept Audiol, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. OI Barmada, M Michael/0000-0002-3604-6460 FU NICHD NIH HHS [1P30HD40677] NR 3 TC 14 Z9 14 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2003 VL 113 IS 3 BP 293 EP 295 DI 10.1007/s00439-003-0967-8 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 712QD UT WOS:000184807600014 PM 12811539 ER PT J AU Rutter, JL Smith, AM Davila, MR Sigurdson, AJ Giusti, RM Pineda, MA Doody, MM Tucker, MA Greene, MH Zhang, JH Struewing, JP AF Rutter, JL Smith, AM Davila, MR Sigurdson, AJ Giusti, RM Pineda, MA Doody, MM Tucker, MA Greene, MH Zhang, JH Struewing, JP TI Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals SO HUMAN MUTATION LA English DT Article DE cancer; breast cancer; ovarian cancer; DHPLC; haplotype; linkage disequilibrium; ZNF350; ZBRK1; BRIP1; BACH1; BRCA1; BRCA2; SNP ID SUSCEPTIBILITY; PROTEIN AB Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high,risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Published 2003 Wiley-Liss, Inc. C1 NCI, LPG, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Struewing, JP (reprint author), NCI, LPG, Ctr Canc Res, NIH, 41 Lib Dr,Room D702, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; Rutter, Joni/0000-0002-6502-2361 NR 17 TC 36 Z9 39 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2003 VL 22 IS 2 BP 121 EP 128 DI 10.1002/humu.10238 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 707WL UT WOS:000184532800003 PM 12872252 ER PT J AU Wu, XH Rush, JS Karaoglu, D Krasnewich, D Lubinsky, MS Waechter, CJ Gilmore, R Freeze, HH AF Wu, XH Rush, JS Karaoglu, D Krasnewich, D Lubinsky, MS Waechter, CJ Gilmore, R Freeze, HH TI Deficiency of UDP-GlcNAc : dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij SO HUMAN MUTATION LA English DT Article DE CDG; developmental delay; DPAGT1; GPT1; glycosylation; hypotonia ID ENDOPLASMIC-RETICULUM STRESS; N-ACETYLGLUCOSAMINE; SACCHAROMYCES-CEREVISIAE; ALZHEIMERS-DISEASE; HAMSTER; PROTEIN; TUNICAMYCIN; EXPRESSION; APOPTOSIS; CLONING AB Defects in the assembly of dolichol-linked oligosaccharide or its transfer to proteins result in severe, multi. system human diseases called Type I congenital disorders of glycosylation. We have identified a novel CDG type, CDG-Ij, resulting from deficiency in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1. The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia. Metabolic labeling of cultured dermal fibroblasts from the patient with [2-(3)H]-mannose revealed lowered incorporation of radiolabel into full,length dolichol-linked oligosaccharides and glycoproteins. In vitro enzymatic analysis of microsomal fractions from the cultured cells indicated that oligosaccharyltransferase activity is normal, but the GPT activity is reduced to approximately 10% of normal levels while parents have heterozygous levels. The patient's paternal DPAGT1 allele contains a point mutation (660A > G) that replaces a highly conserved tyrosine with a cysteine (Y170C). The paternal allele cDNA produces a full-length protein with almost no activity when over-expressed in CHO cells. The maternal allele makes only about 12% normal mature mRNA, while the remainder shows a complex exon skipping pattern that shifts the reading frame encoding a truncated non-functional GPT protein. Thus, we conclude that the DPAGT1 gene defects are responsible for the CDG symptoms in this patient. (C) 2003 Wiley-Liss, Inc. C1 Burnham Inst, La Jolla, CA 92037 USA. Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA USA. NHGRI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Genet & Birth Defects Ctr, Milwaukee, WI USA. RP Freeze, HH (reprint author), Burnham Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM hudson@burnham.org OI Freeze, Hudson/0000-0001-6316-0501 FU NIDDK NIH HHS [R0DK-55615]; NIGMS NIH HHS [R01GM38545, R01GM-43768, R01GM36365] NR 29 TC 68 Z9 73 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2003 VL 22 IS 2 BP 144 EP 150 DI 10.1002/humu.10239 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 707WL UT WOS:000184532800006 PM 12872255 ER PT J AU Goldstein, DS Pechnik, S Holmes, C Eldadah, B Sharabi, Y AF Goldstein, DS Pechnik, S Holmes, C Eldadah, B Sharabi, Y TI Association between supine hypertension and orthostatic hypotension in autonomic failure SO HYPERTENSION LA English DT Article DE hypertension, essential; hypotension; Parkinson's disease; autonomic nervous system; sympathetic nervous system; norepinephrine ID CARDIAC SYMPATHETIC DENERVATION; MULTIPLE-SYSTEM ATROPHY; I-123 MIBG UPTAKE; PARKINSONS-DISEASE; DIAGNOSTIC-VALUE; PRESSOR; DIFFERENTIATION; ACCUMULATION; CATECHOLS; RESPONSES AB Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension ( OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine ( NE) levels were measured in pure autonomic failure (PAF), multiple- system atrophy (MSA) with or without OH, and Parkinson's disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest ( 109 +/- 3 mm Hg) than did those lacking OH ( 96 +/- 3 mm Hg, P = 0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74 +/- 0.10 ms/mm Hg) than did those lacking OH ( 3.13 +/- 0.72 ms/mm Hg, P = 0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 39 TC 94 Z9 101 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2003 VL 42 IS 2 BP 136 EP 142 DI 10.1161/01.HYP.0000081216.11623.C3 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 706VR UT WOS:000184476200004 PM 12835329 ER PT J AU Feng, HH Gu, H Silbersweig, D Stern, E Yang, YH AF Feng, HH Gu, H Silbersweig, D Stern, E Yang, YH TI Single-shot MR imaging using trapezoidal-gradient-based Lissajous trajectories SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE fast magnetic resonance imaging (MRI); image artifacts; image reconstruction; Lissajous trajectory ID ROSETTE TRAJECTORIES; GRIDDING ALGORITHM; FOURIER INVERSION; FUNCTIONAL MRI; RECONSTRUCTION; BRAIN AB A novel single-shot trapezoidal-gradient-based Lissajous trajectory is described and implemented on a 3-tesla magnetic resonance (MR) scanner. A feature of this trajectory is that its sampling points are located on a nonequidistant rectangular grid, which permits the usage of one-dimensional optimal algorithms to increase the robustness and speed of image reconstruction. Another advantage of the trajectory is that two images with different effective echo times can be obtained within a single excitation, which might be used for fast T-2* mapping, in functional MR imaging scanning of brain activity associated with mental processes. Potential artifacts in reconstructed images were investigated and methods for suppressing these artifacts were developed. Experiments on normal subjects at rest and during brain activation were performed to demonstrate the feasibility of the new sequence. C1 Cornell Univ, Weill Med Coll, Funct Neuroimaging Lab, Dept Psychiat, New York, NY 10021 USA. RP Yang, YH (reprint author), NIDA, NIH, Neuroimaging Res Branch, POB 5180, Baltimore, MD 21224 USA. RI Stern, Emily/E-6035-2011 NR 18 TC 5 Z9 5 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2003 VL 22 IS 8 BP 925 EP 932 DI 10.1109/TMI.2003.815902 PG 8 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 708KY UT WOS:000184567100001 PM 12906246 ER PT J AU Miga, MI Sinha, TK Cash, DM Galloway, RL Weil, RJ AF Miga, MI Sinha, TK Cash, DM Galloway, RL Weil, RJ TI Cortical surface registration for image-guided neurosurgery using laser-range scanning SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE cortical surface; image-guided surgery; iterative closest point; laser-range scanner; mutual information; registration ID BRAIN SHIFT; MUTUAL INFORMATION; OPTICAL SPECTROSCOPY; SURGERY; HEAD; NEURONAVIGATION; IMPLEMENTATION; VISUALIZATION; MAXIMIZATION; COMPENSATION AB In this paper, a method of acquiring intraoperative data using a laser range scanner (LRS) is presented within the context of model-updated image-guided surgery. Registering textured point clouds generated by the LRS to tomographic data is explored using established point-based and surface techniques as well as a novel method that incorporates geometry and intensity information via mutual information (SurfaceMI). Phantom registration studies were performed to examine accuracy and robustness for each framework. In addition, an in vivo registration is performed to demonstrate feasibility of the data acquisition system in the operating room. Results indicate that SurfaceMI performed better in many cases than point-based (PBR) and iterative closest point (ICP) methods for registration of textured point clouds. Mean target registration error (TRE) for simulated deep tissue targets in a phantom were 1.0 +/- 0.2, 2.0 +/- 0.3, and 1.2 +/- 0.3 mm for PBR, ICP, and SurfaceMI, respectively. With regard to in vivo registration, the mean TRE of vessel contour points for each framework was 1.9 +/- 1.0, 0.9 +/- 0.6, and 1.3 +/- 0.5 for PBR, ICP, and SurfaceMI, respectively. The methods discussed in this paper in conjunction with the quantitative data provide impetus for using LRS technology within the model-updated image-guided surgery framework. C1 Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. Vanderbilt Univ, Dept Neurosurg, Nashville, TN 37235 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Miga, MI (reprint author), Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. FU NINDS NIH HHS [R01 NS049251] NR 56 TC 100 Z9 104 U1 0 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2003 VL 22 IS 8 BP 973 EP 985 DI 10.1109/TMI.2003.815868 PG 13 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 708KY UT WOS:000184567100007 PM 12906252 ER PT J AU Boulay, JL O'Shea, JJ Paul, WE AF Boulay, JL O'Shea, JJ Paul, WE TI Molecular phylogeny within type I cytokines and their cognate receptors SO IMMUNITY LA English DT Review ID GENOME SEQUENCE; GROWTH-HORMONE; EVOLUTION; GENE; PATHWAY; PROTEIN; FAMILY AB Type I helical cytokines are ligands for receptors structurally related by a common sequence signature. Here we analyze the 27 ligands and 34 human type I cytokine receptor encoded by the human genome. We compare these to ligands and receptors found in mouse and insects. We describe their structural relatedness to one another and discuss the evolution of these gene families. C1 Univ Basel Hosp, Dept Res, CH-4031 Basel, Switzerland. NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Univ Basel Hosp, Dept Res, CH-4031 Basel, Switzerland. EM jean-louis.boulay@unibas.ch NR 19 TC 145 Z9 152 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG PY 2003 VL 19 IS 2 BP 159 EP 163 DI 10.1016/S1074-7613(03)00211-5 PG 5 WC Immunology SC Immunology GA 714TF UT WOS:000184929000003 PM 12932349 ER PT J AU Bergsagel, PL Kuehl, WM AF Bergsagel, PL Kuehl, WM TI Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma SO IMMUNOLOGICAL REVIEWS LA English DT Review ID UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; CHROMOSOMAL TRANSLOCATIONS; TUMOR PROGRESSION; GENETIC EVENTS; ABNORMALITIES; EXPRESSION; ONCOGENESIS; GENERATION; CORRELATE AB Multiple myeloma (MM) is a tumor of long-lived bone marrow plasma cells (PCs). Nearly 40% of MM tumors have immunoglobulin H (IgH) translocations involving four recurrent chromosomal loci (oncogenes): 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (MMSET and FGFR3), and 16q23 (c-maf). Other MM tumors have Ig translocations involving different loci, none of which is involved in more than 1% of tumors. At least 25% of MM tumors have no Ig translocation. Unlike normal PCs, MM tumors usually express one of the three cyclin D genes at a high level. Translocations involving 4p16 and 16q23 do not directly target a cyclin D gene, but they are associated with a high level of cyclin D2 expression. Although cyclin D1 is not expressed in normal hematopoietic cells, one-third of MM tumors ectopically express cyclin D1 in the absence of t(11;14). Despite a low proliferation index in MM, dysregulation of a cyclin D gene seems to be a unifying oncogenic event. Analysis of 34 MM cell lines indicates that tumors having an IgH translocation are significantly over-represented, whereas tumors that ectopically express cyclin D1 are not represented. We speculate that ectopic cyclin D1 expression without t(11;14) is dependent on tumor-specific interaction with bone marrow stromal cells. C1 Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NIH, Bethesda, MD 20892 USA. RP Bergsagel, PL (reprint author), Cornell Univ, Weill Med Coll, 1300 York Ave,Room C615, New York, NY 10021 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 NR 30 TC 95 Z9 97 U1 1 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2003 VL 194 IS 1 BP 96 EP 104 DI 10.1034/j.1600-065X.2003.00052.x PG 9 WC Immunology SC Immunology GA 697YF UT WOS:000183970300009 PM 12846810 ER PT J AU Potter, M AF Potter, M TI Neoplastic development in plasma cells SO IMMUNOLOGICAL REVIEWS LA English DT Review ID HUMAN MULTIPLE-MYELOMA; HUMAN BONE-MARROW; C-MYC ONCOGENE; INTERLEUKIN-6 TRANSGENIC MICE; IGM-FORMING CELLS; ZONE B-CELLS; BALB/C MICE; GROWTH-FACTOR; MURINE PLASMACYTOMAS; V-ABL AB An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane-induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Emu-v-abl), growth factors [interleukin-6 (IL-6)], and anti-apoptotic factors (Bcl-x(L) /Bcl-2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL-6) and cell-cell interactions. In mice, the activation and deregulation of c-myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice. Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far. C1 NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Potter, M (reprint author), NCI, Genet Lab, NIH, 37 convent Dr MSC4256,Bldg 37,Room 2B04, Bethesda, MD 20892 USA. NR 142 TC 85 Z9 86 U1 1 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2003 VL 194 IS 1 BP 177 EP 195 DI 10.1034/j.1600-065X.2003.00061.x PG 19 WC Immunology SC Immunology GA 697YF UT WOS:000183970300014 PM 12846815 ER PT J CA NICHD Early Child Care Res Net TI Early child care and mother-child interaction from 36 months through first grade SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE child care; mother-child interaction; NICHD study of early child care; mother-child relationship ID MATERNAL EMPLOYMENT; ATTACHMENT; BEHAVIOR; QUALITY; FAMILY; INFANTS; PREDICTORS; PATTERNS; LENGTH; NICHD AB Relations were examined between early non-maternal child care experience in the child's first 3 years and mother-child interaction when children were 3, 4.5, and in first grade. Longitudinal analyses investigated relations between cumulative child care experiences across the first 3 years and mother-child interaction from age 3 through first grade to test whether results pertaining to 4.5-year-olds and first graders deviated from those found across the first 36 months in this sample of 1,180 from the NICHD Study of Early Child Care. Previously found relations in the first 3 years were restricted to certain subsamples at these later ages: More non-maternal child-care experience across the first 3 years was associated with less maternal sensitivity and less positive engagement of mother for White children but greater maternal sensitivity and child positive engagement for non-White children through first grade. Positive associations of mother-child interaction with hours of child care were similar for both African-American and Hispanic children. Negative associations between hours of care and sensitivity diminished over time for all children. Higher quality early child care experience was related to greater maternal sensitivity through first grade primarily when children had experienced relatively few hours of care. Early experience with higher quality child care benefited children's positive engagement with mother through first grade when their mothers were depressed. Results were similar whether effects were examined for non-maternal care or for non-parental care in which father care was excluded from considerations of child care experience. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NICHD, Early Child Care Res Network, Rockville, MD 20852 USA. NR 61 TC 0 Z9 0 U1 5 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD AUG PY 2003 VL 26 IS 3 BP 345 EP 370 DI 10.1016/S0163-6383(03)00035-3 PG 26 WC Psychology, Developmental SC Psychology GA 713ZX UT WOS:000184888800005 ER PT J AU Baruch, DI Gamain, B Miller, LH AF Baruch, DI Gamain, B Miller, LH TI DNA immunization with the cysteine-rich interdomain region 1 of the Plasmodium falciparum variant antigen elicits limited cross-reactive antibody responses SO INFECTION AND IMMUNITY LA English DT Article ID CHONDROITIN SULFATE-A; ERYTHROCYTE SURFACE-ANTIGENS; NATURALLY ACQUIRED-IMMUNITY; RED-CELL SURFACE; INFECTED ERYTHROCYTES; PARASITE ADHESION; SEVERE MALARIA; PROTECTIVE IMMUNITY; CODON OPTIMIZATION; KNOWLESI MALARIA AB The variant surface antigens of Plasmodium falciparum are an important component of naturally acquired immunity and an important vaccine target. However, these proteins appear to elicit primarily variant-specific antibodies. We tested if naked DNA immunization can elicit more cross-reactive antibody responses and allow simultaneous immunization with several variant constructs. Mice immunized with plasmid DNA expressing variant cysteine-rich interdomain region 1 (CIDR1) domains of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) developed antibodies that were reactive to the corresponding PfEMP1s as measured by an enzyme-linked immunosorbent assay, flow cytometry, and agglutination of parasitized erythrocytes (PEs). We observed some cross-reactive immune responses; for example, sera from mice immunized with one domain agglutinated PEs of various lines and recognized heterologous domains expressed on the surface of Chinese hamster ovary (CHO) cells. We found no significant antigenic competition when animals were immunized with a mixture of plasmids or immunized sequentially with individual constructs. Moreover, mixed or sequential immunizations resulted in greater cross-reactive agglutination responses than immunization with a single domain. Recombinant protein (Sc y179) immunization after priming with DNA (prime-boost regimen) increased antibody titers to the homologous domain substantially but seemed to diminish the cross-reactive responses somewhat. The titer of agglutinating antibodies was previously shown to correlate with protection. Surprisingly, the agglutination titers of sera from DNA immunization were high, similar to those of pooled human hyperimmune sera. These sera also appeared to give limited low-titer variant transcending agglutination. Thus, DNA immunization appears to be a very useful tool for developing variant antigen vaccines. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Baruch, DI (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bldg 4,Room B1-37,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. NR 48 TC 18 Z9 20 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 AUG PY 2003 VL 71 IS 8 BP 4536 EP 4543 DI 10.1128/IAI.71.84536-4543.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 705JV UT WOS:000184392700037 PM 12874333 ER PT J AU Ariel, N Zvi, A Makarova, KS Chitlaru, T Elhanany, E Velan, B Cohen, S Friedlander, AM Shafferman, A AF Ariel, N Zvi, A Makarova, KS Chitlaru, T Elhanany, E Velan, B Cohen, S Friedlander, AM Shafferman, A TI Genome-based bioinformatic selection of chromosomal Bacillus anthracis putative vaccine candidates coupled with proteomic identification of surface-associated antigens SO INFECTION AND IMMUNITY LA English DT Review ID GRAM-POSITIVE BACTERIA; FIBRONECTIN-BINDING PROTEIN; GROUP-A STREPTOCOCCUS; STAPHYLOCOCCUS-AUREUS; S-LAYER; REVERSE VACCINOLOGY; VIRULENCE FACTORS; CELL-SURFACE; MOLECULAR CHARACTERIZATION; LISTERIA-MONOCYTOGENES AB Bacillus anthracis (Ames strain) chromosome-derived open reading frames (ORFs), predicted to code for surface exposed or virulence related proteins, were selected as B. anthracis-specific vaccine candidates by a multistep computational screen of the entire draft chromosome sequence (February 2001 version, 460 contigs, The Institute for Genomic Research, Rockville, Md.). The selection procedure combined preliminary annotation (sequence similarity searches and domain assignments), prediction of cellular localization, taxonomical and functional screen and additional filtering criteria (size, number of paralogs). The reductive strategy, combined with manual curation, resulted in selection of 240 candidate ORFs encoding proteins with putative known function, as well as 280 proteins of unknown function. Proteomic analysis of two-dimensional gels of a B. anthracis membrane fraction, verified the expression of some gene products. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analyses allowed identification of 38 spots cross-reacting with sera from B. anthracis immunized animals. These spots were found to represent eight in vivo immunogens, comprising of EA1, Sap, and 6 proteins whose expression and immunogenicity was not reported before. Five of these 8 immunogens were preselected by the bioinformatic analysis (EA1, Sap, 2 novel SLH proteins and peroxiredoxin/AhpC), as vaccine candidates. This study demonstrates that a combination of the bioinformatic and proteomic strategies may be useful in promoting the development of next generation anthrax vaccine. C1 Israel Inst Biol Res, Dept Biochem & Mol Genet, IL-74100 Ness Ziona, Israel. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Ariel, N (reprint author), Israel Inst Biol Res, Dept Biochem & Mol Genet, POB 19, IL-74100 Ness Ziona, Israel. NR 110 TC 78 Z9 87 U1 1 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 AUG PY 2003 VL 71 IS 8 BP 4563 EP 4579 DI 10.1128/IAI.71.8.4563-4579.2003 PG 17 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 705JV UT WOS:000184392700040 PM 12874336 ER PT J AU Somerville, GA Sayd-Salim, B Wickman, JM Raffel, SJ Kreiswirth, BN Musser, JM AF Somerville, GA Sayd-Salim, B Wickman, JM Raffel, SJ Kreiswirth, BN Musser, JM TI Correlation of acetate catabolism and growth yield in Staphylococcus aureus: Implications for host-pathogen interactions SO INFECTION AND IMMUNITY LA English DT Article ID AMINO-ACID-REQUIREMENTS; TOXIC-SHOCK-SYNDROME; GLOBAL REGULATOR; METABOLIC CYCLES; VIRULENCE GENES; ENTEROTOXIN-B; EVOLUTION; INFECTION; STRAINS; EXPRESSION AB Recently, we reported that the prototypical Staphylococcus aureus strain RN6390 (a derivative of NCTC 8325) had significantly reduced aconitase activity relative to a diverse group of S. aureus isolates, leading to the hypothesis that strain RN6390 has impaired tricarboxylic acid (TCA) cycle-mediated acetate catabolism. Analysis of the culture supernatant from RN6390 confirmed that acetate was incompletely catabolized, suggesting that the ability to catabolize acetate can be lost by S. aureus. To test this hypothesis, we examined the carbon catabolism of the S. aureus strains whose genome sequences are publicly available. All strains catabollized glucose and excreted acetate into the culture medium. However, strains NCTC 8325 and N315 failed to catabolize acetate during the postexponential growth phase, resulting in significantly lower growth yields relative to strains that catabolized acetate. Strains NCTC 8325 and RN6390 contained an 11-bp deletion in rsbU, the gene encoding a positive regulator of the alternative sigma factor sigma(B) encoded by sigB. An isogenic derivative strain of RN6390 containing the wild-type rsbU gene had significantly increased acetate catabolism, demonstrating that sigma(B) is required for acetate catabolism. Taken together, the data suggest that naturally occurring mutations can alter the ability of S. aureus to catabolize acetate, a surprising discovery, as TCA cycle function has been demonstrated to be involved in the virulence, survival, and persistence of several pathogenic organisms. Additionally, these mutations decrease the fitness of S. aureus by reducing the number of progeny placed into subsequent generations, suggesting that in certain situations a decreased growth yield is advantageous. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Publ Hlth Res Inst, Newark, NJ 07103 USA. RP Somerville, GA (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Somerville, Greg/B-1326-2013 OI Somerville, Greg/0000-0002-0991-8737 NR 57 TC 70 Z9 72 U1 0 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 AUG PY 2003 VL 71 IS 8 BP 4724 EP 4732 DI 10.1128/IAI.71.8.4724-4732.2003 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 705JV UT WOS:000184392700058 PM 12874354 ER PT J AU Piatigorsky, J AF Piatigorsky, J TI Gene sharing, lens crystallins and speculations on an eye/ear evolutionary relationship SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY JAN 04-08, 2003 CL TORONTO, CANADA SP Soc Integrat & Comparat Bio ID HEAT-SHOCK PROTEIN; PAX GENES; ALPHA-CRYSTALLIN; EYE LENS; CUBOMEDUSAN JELLYFISH; CONVERGENT EVOLUTION; OMEGA-CRYSTALLIN; EYELESS GENE; DROSOPHILA; EXPRESSION AB The crystallins comprise 80-90% of the water-soluble proteins of the transparent, cellular, refractive eye lens and are responsible for its optical properties. Comparative studies have established that the crystalline are surprisingly diverse and often differ among species in a taxon-specific fashion. In general, the crystallins are derived from or identical to metabolic enzymes or stress (small heat shock) proteins that are expressed to a lesser extent in other tissues where they have non-refractive roles. We call the phenomenon of having the small heat shock protein or enzyme and lens crystallin encoded in the identical gene "gene sharing"; examples include small heat shock protein/alphaB-crystallin, alpha-enolase/tau-crystallin and argininosuccinate lyase/delta2-crystallin. Lens crystallins have evolved by gene sharing in vertebrates (all) and invertebrates (cephalopods, scallops, jellyfish). Similar cis-elements and transcription factors (including Pax6 among others) appear to unify lens expression of crystallin genes in vertebrates and mollusks (especially scallops). Instead of Pax6, cnidarians have a PaxB gene encoding a Pax2 DNA-binding paired domain and octapeptide, and a Pax6 homeodomain; PaxB appears important for ocellus (eye) development and crystallin gene expression in the cubomedusan jellyfish, Tridpedalia cystophora. Finally, we speculate on the basis of our current studies on Tripedalia that eyes and statocysts (associated with mechanoreceptors in many cnidarians and thus possibly ears in vertebrates) are evolutionarily related. Numerous examples indicate that gene sharing is widely used, consistent with changes in gene regulation being an evolutionary driving force for innovation of protein function. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM joramp@nei.nih.gov NR 85 TC 19 Z9 20 U1 0 U2 2 PU SOC INTEGRATIVE COMPARATIVE BIOLOGY PI MCLEAN PA 1313 DOLLEY MADISON BLVD, NO 402, MCLEAN, VA 22101 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD AUG PY 2003 VL 43 IS 4 BP 492 EP 499 DI 10.1093/icb/43.4.492 PG 8 WC Zoology SC Zoology GA 776RB UT WOS:000189129400002 PM 21680457 ER PT J AU Shiono, H Wong, YL Matthews, I Liu, JL Zhang, W Sims, G Meager, A Beeson, D Vincent, A Willcox, N AF Shiono, H Wong, YL Matthews, I Liu, JL Zhang, W Sims, G Meager, A Beeson, D Vincent, A Willcox, N TI Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE anti-cytokine autoantibody; dendritic cell; human anti-IFN-alpha antibody; human anti-IL-12 antibody; paraneoplastic autoimmunity; tumor immunity ID NICOTINIC ACETYLCHOLINE-RECEPTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; THYMIC MYOID CELLS; T-CELLS; GERMINAL-CENTERS; THYROID-GLANDS; B-CELLS; LYMPHOCYTES; EXPRESSION; INTERFERON AB Myasthenia gravis (MG) is mediated by autoantibodies to the acetylcholine receptor (AChR), expressed in muscle and rare thymic myoid cells. Most early-onset cases show thymic lymph node-type infiltrates, including pre-activated plasma cells spontaneously producing anti-AChR antibodies. Since these are not evident in the associated thymomas found in another 10% of MG patients, AChR-specific B cells must be autosensitized elsewhere. Unexpectedly, at diagnosis, >70% of MG/thymoma patients also have high-titer neutralizing autoantibodies to IFN-alpha, and >50% to IL-12; moreover, titers increase strikingly if the thymomas recur, indicating a closer tumor relationship than for anti-AChR. To investigate this, we have measured autoantibody production by cells cultured from thymomas, any available thymic remnants and blood, with or without the B cell stimulant pokeweed mitogen (PWM). To check autoantibody specificity and clonal origins, we isolated Fabs from two combinatorial libraries from producer thymus/thymoma cells. Surprisingly, thymoma cells spontaneously produced antibodies to IFN-alpha and/or IL-12 in >40% of seropositive cases, showing typical plasma cell behavior, whereas they produced anti-AChR only after PWM stimulation. We isolated 15 combinatorial Fabs to IFN-alpha (versus only one to AChR). Their strong binding in radio-immunoprecipitation and Western blots implies high affinities. The four Fabs tested neutralized anti-viral actions of IFN-alpha. The diverse V genes clearly showed ongoing antigen-driven selection. These results imply pre-activation in situ by native IFN-alpha/IL-12 expressed within a 'dangerous' tumor microenvironment. With these molecules, it should be easier to identify provoking cell type(s) that may give novel additional clues to autoimmunization against T-cell epitopes from the more complex AChR. C1 Univ Oxford, Neurosci Grp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. NIAMSD, NIH, Bethesda, MD 20892 USA. Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. RP Willcox, N (reprint author), Univ Oxford, Neurosci Grp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. NR 49 TC 36 Z9 38 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 2003 VL 15 IS 8 BP 903 EP 913 DI 10.1093/intimm/dxg088 PG 11 WC Immunology SC Immunology GA 707WV UT WOS:000184533600002 PM 12882828 ER PT J AU Badamchian, M Fagarasan, MO Danner, RL Suffredini, AF Damavandy, H Goldstein, AL AF Badamchian, M Fagarasan, MO Danner, RL Suffredini, AF Damavandy, H Goldstein, AL TI Thymosin beta(4) reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article; Proceedings Paper CT Meeting on Combination Immunotherapy CY MAY 10-15, 2002 CL RHODES, GREECE SP Int Soc Immunopharmacol DE thymosin beta(4); septic shock; LPS; endotoxin ID ENDOTHELIAL-CELLS; IN-VIVO; BETA-4; SEPSIS; PEPTIDE; MECHANISMS; THYMOSINS; BETA(4); SERUM; RAT AB Thymosin beta(4) (Tbeta(4), a highly conserved peptide with immunomodulatory properties, is the major actin-sequestering peptide in mammalian cells. Recent studies have established that Tbeta(4) can accelerate wound healing in full thickness skin wounds and following burn injuries to the cornea. In the eye studies, the accelerated healing due to Tbeta(4) was accompanied by a significant reduction in polymorphonuclear leukocyte (PMN) infiltration and a several-fold decrease in interleukin-1beta (p less than or equal to 0.015) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), p less than or equal to 0.05). Given the recognized role of proinflammatory cytokines in septic shock and of extracellular F- and G-actin in the pathophysiology of multiple organ dysfunction, we have investigated the role of Tbeta(4) in sepsis. We report that an LD(50) dose of LPS (24 mg/kg) in rats resulted in a significant reduction of Tbeta(4) levels in the blood. Furthermore, administration of 100 mug of Tbeta(4) immediately following and at 2 and 4 It after an LD(50) dose of LPS (60 mg/kg) in mice significantly reduced mortality rates (p less than or equal to 0.024) and lowered blood levels of a number of inflammatory cytokines, eicosanoids. and other molecules that are highly elevated following endotoxin administration. In studies in human subjects given low doses of endotoxin (4 ng/kg LPS) and in patients with septic shock, we have also observed significant decreases in blood levels of Tbeta(4). The rapid disappearance of Tbeta(4) in the blood following LPS administration or during septic shock suggests that Tbeta(4) may be involved in early events leading to activation of the inflammatory cascade and ultimately the clinical sequelae of sepsis. The results of this study indicate that Tbeta(4) may have utility in the clinic in the treatment of septic shock and in syndromes associated with actin toxicities. (C) 2003 Elsevier Science B.V. All rights reserved. C1 George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Goldstein, AL (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, 2300 Eye St NW, Washington, DC 20037 USA. EM bcmalg@gwumc.edu NR 32 TC 61 Z9 72 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD AUG PY 2003 VL 3 IS 8 BP 1225 EP 1233 DI 10.1016/S1567-5769(03)00024-9 PG 9 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 709CL UT WOS:000184607100018 PM 12860178 ER PT J AU Poole, C Peters, U Il'yasova, D Arab, L AF Poole, C Peters, U Il'yasova, D Arab, L TI Commentary: This study failed? SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID AFFECT CARDIOVASCULAR-DISEASE; METAANALYSIS C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol CB 7435, Chapel Hill, NC 27599 USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol, Winston Salem, NC USA. RP Poole, C (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol CB 7435, Chapel Hill, NC 27599 USA. FU PHS HHS [P30 S10126] NR 8 TC 12 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2003 VL 32 IS 4 BP 534 EP 535 DI 10.1093/ije/dyg197 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 712ED UT WOS:000184783500014 PM 12913024 ER PT J AU Wilcox, AJ AF Wilcox, AJ TI Commentary: On the paradoxes of birthweight SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. OI Wilcox, Allen/0000-0002-3376-1311 NR 6 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2003 VL 32 IS 4 BP 632 EP 633 DI 10.1093/ije/dyg193 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 712ED UT WOS:000184783500031 PM 12913041 ER PT J AU Schonwalder, C Olden, K AF Schonwalder, C Olden, K TI Environment health moves into the 21(st) century SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE environment health; human health risk; toxicology; epidemiology; genetics; public health; toxicogenomics; molecular mechanisms AB Over the past half century, environmental health research has branched from a descriptive, observational process into one of hypothesis driven and mechanistically based science. Nevertheless, the meaning of observed effects of exposures in experimental systems to human public health remains elusive. Recent advances in genetics and "omics" hold great promise to further our abilities to assess potential human health effects and to manage exposures properly. But the comfort of 100% certainty will not be available in the foreseeable future, leaving us with the challenge of designing relevant experiments and test systems upon which to base "logical" policy in risk management. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Schonwalder, C (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 2 TC 2 Z9 2 U1 0 U2 1 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD AUG PY 2003 VL 206 IS 4-5 BP 263 EP 267 DI 10.1078/1438-4639-00222 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 716JD UT WOS:000185024300002 PM 12971681 ER PT J AU Hrynkow, SH Primack, A Bridbord, K AF Hrynkow, SH Primack, A Bridbord, K TI Paradigms and progress in building research capacity in international environment health SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE capacity building; environment health; research training; developing countries AB Populations in low- and middle-income nations bear significant risks for poor health due to air, land and water contamination; natural resource depletion; deterioration of ecosystems; contaminated food supplies and other conditions related to poverty, including poor housing, crowding and inadequate nutrition and health care. These risks, related to rapid industrialization, increasing urbanization, poor land use, natural changes in ecology and other conditions, will only increase in the coming decades if current trends persist. The implications on populations' health include increased spread or emergence of disease, particularly those that impact children disproportionately, and added stress on already overburdened or weakened health care systems. To address environmental health conditions in a relevant manner in resource-poor settings, the training of scientists and health professionals from these settings is key to setting priorities and identifying cost-effective interventions. Training of professionals in a range of environmental health disciplines is a prerequisite for the establishment of effective national and international policies. Working to strengthen local expertise and scientific capacity is one of the most effective and lasting ways to affect positive policy change in environmental health. This paper describes four paradigms that support research training and research programs to meet the increasing and changing needs in this field. Factors influencing the development of the programs and their evolution are discussed as well as trends for the future. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Hrynkow, SH (reprint author), NIH, Fogarty Int Ctr, Bldg 31,Room B2C02,31 Ctr Dr, Bethesda, MD 20892 USA. NR 5 TC 7 Z9 8 U1 1 U2 6 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD AUG PY 2003 VL 206 IS 4-5 BP 413 EP 422 DI 10.1078/1438-4639-00238 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 716JD UT WOS:000185024300018 PM 12971697 ER PT J AU Chhabra, RS Bucher, JR Wolfe, M Portier, C AF Chhabra, RS Bucher, JR Wolfe, M Portier, C TI Toxicity characterization of environmental chemicals by the US National Toxicology Program: an overview SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE subchronic toxicity; chronic toxicity; carcinogenicity; US National Toxicology Program; animal toxicology ID RISK-ASSESSMENT; B6C3F1 MICE; CARCINOGENICITY; RATS; EXPOSURE; NEOPLASMS; DESIGN AB The US National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. Chemicals substances or physical agents selected for toxicology and carcinogenesis evaluations by the NTP are usually studied in a series of subacute (14-day exposure), subchronic (90-day exposure) and chronic (2-year exposure) studies in rodents. The NTP has published more than 500 reports of the findings and conclusions from its toxicology and carcinogenesis studies. In more specialized studies, the NTP also evaluates adverse effects on the structure and function of the immune, reproductive, nervous, and respiratory systems. The program attempts to evaluate and appropriately incorporate new technologies to improve the way we study the toxicity of chemicals. For example, the program has extensively evaluated several transgenic mouse models for their potential use as short-term cancer screens and has been a full participant in an international effort to examine their usefulness in pharmaceutical registration. Toxicogenomics, an emerging scientific field that examines the expression of thousands of genes simultaneously in response to chemical exposure, holds promise for future application to better understand the underlying mechanisms of chemical toxicity. A number of public health issues being addressed by the NTP are not only of national importance but also have global impact, such as the potential for endocrine disruptors to influence development and carcinogenesis and the safety of herbal medicines and dietary supplements. The program participates in the preparation of national and international toxicity testing guidelines and the findings from NTP studies are widely used for risk assessments by international organizations and federal agencies. The NTP maintains databases that contain toxicity, and health and safety information on a large number of chemicals. These databases are available from the NTP web site (http://ntp-server.niehs.nih.gov) and are accessed over 100000 times a month from around the world. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Chhabra, RS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM chhabraR@niehs.nih.gov RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 28 TC 15 Z9 17 U1 0 U2 3 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD AUG PY 2003 VL 206 IS 4-5 BP 437 EP 445 DI 10.1078/1438-4639-00240 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 716JD UT WOS:000185024300020 PM 12971699 ER PT J AU Lavery, JV Upshur, REG Sharp, RR Hofman, KJ AF Lavery, JV Upshur, REG Sharp, RR Hofman, KJ TI Ethical issues in international environment health research SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE environmental health; global health; ethics; environmental justice ID DEVELOPING-COUNTRIES; GENETIC RESEARCH; PROTECTING COMMUNITIES; PARTICIPATORY RESEARCH; CLINICAL-RESEARCH; TRIALS; POPULATIONS; GUIDELINES; CHALLENGES; HELSINKI AB Environmental health problems are among the world's most significant health concerns. Although environmental risks are experienced disproportionately by people in developing countries, environmental health research (EHR) is conducted primarily in developed countries. Human subjects participate in five main types of EHR: (1) documentation and quantification of exposure to potentially hazardous substances; (2) elucidation of biological responses to these materials; (3) characterization and measurement of susceptibility to harmful effects of hazardous materials; (4) trials involving environmental interventions to reduce risk; and (5) documentation and measurement of various manifestations of disease putatively linked to environmental exposures. Although existing frameworks for the ethics of international clinical research are generally relevant to EHR, they currently lack the specificity necessary to confront three inherent problems in EHR, namely under-determination in EHR findings, the unavoidable nature of some environmental hazards, and environmental justice implications. We examine these issues as they relate to community partnership, risk assessment, and the assessment and management of economic and political interests in EHR. We believe that there are 3 general features of ethical EHR, it has health promoting value, the populations studied are not restricted in their ability to avoid environmental hazards by economic or political repression, and the justification for conducting EHR on populations with known exposure to environmental hazards gets stronger as the limits on populations to reduce the hazards or remove themselves from them becomes greater, as long as the first and second conditions are also met. C1 NIH, Fogarty Int Ctr, Div Adv Studies & Policy Anal, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Toronto, Sunnybrook & Womens Coll, Hlth Sci Ctr, Primary Care Res Unit, Toronto, ON, Canada. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. RP Lavery, JV (reprint author), NIH, Fogarty Int Ctr, Div Adv Studies & Policy Anal, Bldg 16,16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. RI Lavery, James/E-5254-2012 NR 63 TC 8 Z9 8 U1 0 U2 4 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD AUG PY 2003 VL 206 IS 4-5 BP 453 EP 463 DI 10.1078/1438-4639-00242 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 716JD UT WOS:000185024300022 PM 12971701 ER PT J AU Gelernter-Yaniv, L Feng, N Sebring, NG Hochberg, Z Yanovski, JA AF Gelernter-Yaniv, L Feng, N Sebring, NG Hochberg, Z Yanovski, JA TI Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE child; 11HSD1; glucocorticoids; cortisol; cortisone; polymorphism; linkage; adiposity; pediatric ID CORTISOL METABOLISM; HUMAN OBESITY; MASS INDEX; ADIPOSE-TISSUE; EXPRESSION; MODEL; TWINS; LOCI AB We investigated 11 beta hydroxysteriod dehydrogenase type 1 (11betaHSD-1) sequence variants in 103 healthy overweight (BMI 42 s.d.) and 160 nonoverweight (BMI-2 to +2 SD) children to examine the associations between body composition and 11betaHSD-1 polymorphisms. A total of 4.3% of children were homozygous and 30.0% heterozygous for an adenine insertion in intron 3 (ins4436A). By ANCOVA (adjusting for age, sex, race, and height), BMI-s.d. differed according to ins4436A genotype (P<0.005), with the greatest BMI-SD for ins4436A homozygotes (mean +/-s.d., 3.4+/-73.4, vs heterozygotes, 0.8+/-5.5, or wild-type, 1.8+/-7.5). Homozygotes also had greater waist circumference, waist-to-hip ratio, and insulin resistance indices than heterozygote or wild-type children (all P<0.05), but no significant differences in trunk fat by DXA, or in serum lipids. We conclude an intronic 11betaHSD-1 gene polymorphism is associated with greater body mass, altered body composition, and insulin resistance in children. 11betaHSD-1 may be one of the genes relevant for pediatric-onset obesity and its complications. C1 NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD USA. Meyer Childrens Hosp, Haifa, Israel. RP Yanovski, JA (reprint author), NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10N262,MSC 1962, Bethesda, MD 20892 USA. OI Yanovski, Jack/0000-0001-8542-1637 FU NICHD NIH HHS [HD-000641] NR 22 TC 42 Z9 42 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD AUG PY 2003 VL 27 IS 8 BP 983 EP 986 DI 10.1038/sj.ijo.0802327 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 702LA UT WOS:000184224300016 PM 12861241 ER PT J AU Payne, JL AF Payne, JL TI The role of estrogen in mood disorders in women SO INTERNATIONAL REVIEW OF PSYCHIATRY LA English DT Review ID PREMENSTRUAL DYSPHORIC DISORDER; RANDOMIZED CONTROLLED TRIAL; NATIONAL-COMORBIDITY-SURVEY; MONOAMINE-OXIDASE ACTIVITY; NEUROTROPHIC FACTOR GENE; FAMILY-BASED ASSOCIATION; TRKB MESSENGER-RNA; KINASE-C ACTIVITY; RAT-BRAIN; POSTPARTUM DEPRESSION AB Major depression is twice as common in women as men and depressive episodes appear to be more common in women with bipolar disorder. There is accumulating evidence that, in at least some women, reproductive-related hormonal changes may play a role in increasing the risk of depressive symptoms premenstrually, postpartum and in the perimenopausal period. In this review, the evidence for the role of hormonal fluctuations, specifically estrogen, in triggering depressive symptoms in a subgroup of women is summarized. In addition, the potential role of estrogen in triggering depressive symptoms via its effects on the serotonergic system, brain-derived neurotrophic factor and Protein Kinase C is reviewed. C1 NIMH, Mood & Anxiety Disorders Program, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Payne, JL (reprint author), 9000 Rockville Pike,Bldg 10,Room 3S243,MSC 1283, Bethesda, MD 20892 USA. NR 107 TC 66 Z9 70 U1 3 U2 11 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0954-0261 J9 INT REV PSYCHIATR JI Int. Rev. Psych. PD AUG PY 2003 VL 15 IS 3 BP 280 EP 290 DI 10.1080/0954026031000136893 PG 11 WC Psychiatry SC Psychiatry GA 712QN UT WOS:000184808500008 PM 15276966 ER PT J AU Nees, DW Fariss, RN Piatigorsky, J AF Nees, DW Fariss, RN Piatigorsky, J TI Serum albumin in mammalian cornea: Implications for clinical application SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALDEHYDE DEHYDROGENASE; SOLUBLE-PROTEINS; BOVINE CORNEA; TRANSKETOLASE; LENS; EYE; EXPRESSION; CRYSTALLIN; EPITHELIUM; DYNAMICS AB PURPOSE. To compare the abundance and spatial distribution of serum albumin in the mouse and bovine cornea. METHODS. Serum albumin from cornea was separated from transketolase by SDS-PAGE (+/-dithiothreitol [DTT]) and identified by peptide sequencing and immunoblot analyses. The fractional content of serum albumin was determined in water-soluble extracts of cornea by imaging analyses after SDS-PAGE. Serum albumin was localized in cornea by immunohistochemistry and by SDS-PAGE analyses of samples from separated epithelium and stroma. RESULTS. SDS-PAGE (-DTT) resolved mouse serum albumin and transketolase and indicated that serum albumin was 13% of the water-soluble protein in whole mouse corneas. By contrast, corneal epithelial fractions contained little (<1%) serum albumin. Immunohistochemistry indicated that mouse serum albumin was present throughout the stroma between Collagen lamellae. Immunohistochemical analyses of bovine cornea yielded similar results. In addition, immunohistochemistry for serum albumin revealed positive staining in a small number of basal epithelial cells next to Bowman's membrane, and greater staining in the anterior-peripheral stroma as well as immediately adjacent to Descemet's membrane. CONCLUSIONS. Mouse and bovine cornea have a similar content and spatial distribution of serum albumin. The appreciable serum albumin in the cornea documented here and elsewhere raise the possibility that it contributes to the physiological or optical functions of the cornea. Moreover, serum albumin's ability to bind drugs suggests that mice corneas could be exploited to study drug-serum albumin interactions in vivo and to test the usefulness of serum albumin as a drug carrier for corneal disorders. C1 NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. NEI, Lab Mech Ocular Dis, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NIH, 6 Ctr Dr,Room 201, Bethesda, MD 20892 USA. NR 35 TC 14 Z9 15 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2003 VL 44 IS 8 BP 3339 EP 3345 DI 10.1167/iovs.02-1161 PG 7 WC Ophthalmology SC Ophthalmology GA 705EV UT WOS:000184383500013 PM 12882779 ER PT J AU Bakalash, S Kessler, A Mizrahi, T Nussenblatt, R Schwartz, M AF Bakalash, S Kessler, A Mizrahi, T Nussenblatt, R Schwartz, M TI Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC UVEITIS; RETINAL GANGLION-CELLS; MYELIN BASIC-PROTEIN; OPTIC-NERVE; NOGO-A; PROTECTIVE AUTOIMMUNITY; T-CELLS; NEUROPROTECTIVE AUTOIMMUNITY; PHYSIOLOGICAL-RESPONSE AB PURPOSE. To investigate the antigenic specificity of the immune neuroprotective mechanism that can protect retinal ganglion cells (RGCs) against death caused by high intraocular pressure (lop). METHODS. A unilateral increase in IOP was induced in rats by argon laser photocoagulation of the episcleral veins and limbal plexus. Rats with high IOP were immunized with glatiramer acetate (Cop-1, a synthetic copolymer) or with myelin-derived or uveitogenic peptides. When the steroid drug methylprednisolone was used, it was administered intraperitoneally every other day for 12 days. RESULTS. Vaccination with myelin-derived peptides that reside in the axons failed to protect RGCs from death caused by high IOP. In contrast, IOP-induced RGC loss was reduced by vaccination with R16, a peptide derived from interphotoreceptor retinoid-binding protein, an immunodominant antigen residing in the eye. The benefit of protection against IOP-induced RGC loss outweighed the cost of the monophasic experimental autoimmune uveitis (EAU) that transiently developed in a susceptible rat strain. Treatment with methylprednisolone alleviated the disease symptoms, but caused further loss of RGCs. Cop-1 vaccination was effective in both EAU-resistant and EAU-susceptible strains. CONCLUSIONS. To benefit damaged neurons, immune neuroprotection should be directed against immunodominant antigens that reside in the site of damage. In a rat model of high IOP, RGCs can benefit from vaccination with peptides derived from proteins that are immunodominant in the eye but not from myelin-associated proteins. This suggests that the site of primary degeneration in IOP-induced RGC loss is in the eye. Cop-1 vaccination apparently circumvents the site-specificity barrier and provides protection without risk of inducing autoimmune disease. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. Ichilov Hosp, Dept Ophthalmol, IL-64239 Tel Aviv, Israel. NEI, Bethesda, MD 20892 USA. RP Schwartz, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NR 47 TC 54 Z9 66 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2003 VL 44 IS 8 BP 3374 EP 3381 DI 10.1167/iovs.03-0080 PG 8 WC Ophthalmology SC Ophthalmology GA 705EV UT WOS:000184383500018 PM 12882784 ER PT J AU Hooks, JJ Wang, Y Detrick, B AF Hooks, JJ Wang, Y Detrick, B TI The critical role of IFN-gamma in experimental coronavirus retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MOUSE HEPATITIS-VIRUS; INTERFERON-GAMMA; MEDIATED CONTROL; TRANSGENIC MICE; VIRAL-HEPATITIS; INFECTED MICE; RETINA; CLEARANCE; EYE AB PURPOSE. Experimental coronavirus retinopathy (ECOR) is an animal model of progressive retinal disease that is first manifest as an acute retinal inflammation followed by chronic, immune-associated retinal degeneration in genetically susceptible, BALB/c mice. In retinal degeneration-resistant CD-1 mice, only the acute infection is seen. In the present study, interferon (IFN)-gamma production during ECOR was studied and its role evaluated in the clearance of infectious virus from the retina. METHODS. BALB/c, CD-1, and IFN-gamma- deficient (IFN-gamma gko) mice were inoculated with the JHM strain of murine coronavirus by the intravitreal route. Mouse eyes were evaluated for infiltrating cells and major histocompatibility complex (MHC) expression by immunocytochemical staining. Isolated retinas were analyzed for IFN-gamma mRNA by RT-PCR, and sera were evaluated for IFN-gamma protein by ELISA assays. RESULTS. Virus infection in BALB/c mice was associated with an increase in the incidence and levels of systemic IFN-gamma. Moreover, IFN-gamma mRNA was detected within the retinas of infected animals during the acute phase of the disease but was not detected in normal or mock-injected animals. IFN-gamma mRNA was detected at the time of T-cell infiltration, and earlier studies have shown that this is temporally related to granzyme B gene expression and the clearance of infectious virus from the retina. Retinal IFN-gamma mRNA was also associated with the upregulation of MHC class I and II molecules within the retina. When this infection occurred in IFN-gamma gko mice, the virus was unchecked, and the infection led to death. CONCLUSIONS. These studies indicate that generation of IFN-gamma by cells infiltrating the retina is an essential part of an immune mechanism responsible for noncytolytic clearance of infectious virus from the retina. C1 NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Hooks, JJ (reprint author), NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bldg 10,Room 6N228, Bethesda, MD 20892 USA. NR 32 TC 15 Z9 16 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2003 VL 44 IS 8 BP 3402 EP 3408 DI 10.1167/iovs.02-1106 PG 7 WC Ophthalmology SC Ophthalmology GA 705EV UT WOS:000184383500022 PM 12882788 ER PT J AU Espinosa-Heidmann, DG Suner, IJ Hernandez, EP Monroy, D Csaky, KG Cousins, SW AF Espinosa-Heidmann, DG Suner, IJ Hernandez, EP Monroy, D Csaky, KG Cousins, SW TI Macrophage depletion diminishes lesion size and severity in experimental choroidal Neovascularization SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 05-10, 2002 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol ID INTRAVITREAL TRIAMCINOLONE ACETONIDE; SENILE MACULAR DEGENERATION; RETINAL-PIGMENT EPITHELIUM; BRUCHS MEMBRANE; DICHLOROMETHYLENE-DIPHOSPHONATE; LASER PHOTOCOAGULATION; DENDRITIC CELLS; UVEAL TRACT; AGE; EXPRESSION AB PURPOSE. Macrophage recruitment to the choroid has been proposed to contribute to the pathogenesis of choroidal neovascularization (CNV) in AMD. The study was conducted to determine whether treatment with clodronate liposomes (CL2MDP-lip), which cause depletion of blood monocytes and lymph node macrophages, diminishes the severity of neovascularization in a mouse model of laser-induced CNV. METHODS. Laser-induced CNV was performed in female 16-month-old C57BL/6 mice. Macrophages were depleted by use of CL2MDP-lip intraperitoneally and subcutaneously 72 and 24 hours before and every 2 to 3 days after laser injury. Control mice received injections of either PBS alone or PBS liposomes. Blood monocyte and choroidal macrophage depletion were documented by flow cytometry and choroidal flatmount preparation analysis, respectively. Two weeks after laser injury, mice were injected intravenously with fluoresceinated dextran. The right eyes were removed and prepared for flatmount analysis of CNV surface area (in relative disc areas or DA), vascularity (relative fluorescence), and cellularity (propidium. iodide stain). The mice were then perfused with 10% formaldehyde, and the left eyes were removed for histopathology. The means of the various parameters for four CNV lesions per eye were calculated. Fluorescein angiography was also performed. RESULTS. Flow cytometry of circulating monocytes and immunohistochemical analysis of choroidal macrophage density confirmed the effective depletion of blood monocytes and choroidal macrophages respectively in CL2MDP-lip-treated mice. Compared with the control, flatmount analysis of macrophage depleted mice demonstrated a significant reduction in size of the CNV area (2.8 +/- 0.5 DA vs. 1.4 +/- 0.1 DA; P < 0.043). The treated group also revealed less vascularity (1.6 +/- 0.1 units vs. 1.1 +/- 0.0 units; P < 0.0092) and cellularity of CNV lesions (3.3 +/- 0.6 DA vs. 1.7 +/- 0.1 DA, P < 0.04). Histopathology revealed that, in the macrophage-depleted group, CNV was smaller in diameter (1270 +/- 73 pixels vs. 770 +/- 82 pixels, P < 0.0006) and thickness (120 +/- 7 pixels vs. 96 +/- 7 pixels, P < 0.019). CONCLUSIONS. Macrophage depletion using CL2MDP-lip reduces size, cellularity, and vascularity of CNV. This observation supports the hypothesis that macrophages contribute to the severity of CNV lesions. C1 Univ Miami, Sch Med, Bascom Palmer Eye Inst, William L McKnight Vis Res Ctr,Dept Ophthalmol, Miami, FL 33136 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Cousins, SW (reprint author), Univ Miami, Sch Med, Bascom Palmer Eye Inst, William L McKnight Vis Res Ctr,Dept Ophthalmol, 1638 NW 10th Ave, Miami, FL 33136 USA. FU NEI NIH HHS [EY/AI 13318] NR 45 TC 206 Z9 223 U1 1 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2003 VL 44 IS 8 BP 3586 EP 3592 DI 10.1167/iovs.03-0038 PG 7 WC Ophthalmology SC Ophthalmology GA 705EV UT WOS:000184383500045 PM 12882811 ER PT J AU Raz, D Perlman, I Percicot, CL Lambrou, GX Ofri, R AF Raz, D Perlman, I Percicot, CL Lambrou, GX Ofri, R TI Functional damage to inner and outer retinal cells in experimental glaucoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPTIC-NERVE HEAD; PHOTOPIC NEGATIVE RESPONSE; MULTIFOCAL ERG; GANGLION-CELLS; RHESUS-MONKEY; ELECTRORETINOGRAM; MODEL; TOPOGRAPHY; COMPONENTS; LUMINANCE AB PURPOSE. To investigate the cellular sources underlying the functional damage observed by multifocal electroretinography (mfERG) responses of glaucomatous eyes of monkeys. METHODS. First- and second-order (K1 and K2, respectively) mfERG responses of three normal and three experimentally induced glaucomatous eyes of cynomolgus monkeys were measured at two different levels of luminance. Retinal contributors to the responses were isolated by intravitreal injections of pharmacological agents that suppress specific retinal cells. gamma-Aminobutyric acid (GABA) and glycine were administered to block inner retinal function, followed by 2-amino-4-phosphonobutyric acid (APB), to block ON-bipolar cells. RESULTS. An inner retinal component removed by GABA and glycine was found in both the normal and glaucomatous eyes. However, it was attenuated in the latter, correlating with changes observed in the baseline K1 responses. Delays in the latency of outer retinal components were found in the responses of the glaucomatous eyes. K2 responses were dominated by an inner retinal contribution and were diminished in the responses of glaucomatous eyes. The outer retina responded to increased luminance with a shorter implicit time. A distinct wave part of the inner retinal component responded to increased luminance with increased amplitudes. CONCLUSIONS. The integration of the retinal sources forming the mfERG response was compared between normal and glaucomatous monkey eves. Both inner and outer retinal functions were aberrant in the responses of the glaucomatous eyes, with the attenuation of the inner retinal function more conspicuous. Nevertheless, glaucomatous eyes retained certain inner retinal activity, despite the advanced stage of disease. K2 responses were more sensitive to glaucomatous changes than were K1 responses. C1 Hebrew Univ Jerusalem, Koret Sch Vet Med, IL-76100 Rehovot, Israel. Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. Novartis Ophthalm, Basel, Switzerland. Univ Strasbourg 1, Fac Med, Dept Ophthalmol, Strasbourg, France. RP Raz, D (reprint author), NEI, Bldg 50,Room 4340,50 S Dr,MSC 8021, Bethesda, MD 20892 USA. NR 42 TC 31 Z9 34 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2003 VL 44 IS 8 BP 3675 EP 3684 DI 10.1167/iovs.02-1236 PG 10 WC Ophthalmology SC Ophthalmology GA 705EV UT WOS:000184383500057 PM 12882823 ER PT J AU Tabet, SR Callahan, MM Mauck, CK Gai, F Coletti, AS Profy, AT Moench, TR Soto-Torres, LE Poindexter, AN Frezieres, RG Walsh, TL Kelly, CW Richardson, BA van Damme, L Celum, CL AF Tabet, SR Callahan, MM Mauck, CK Gai, F Coletti, AS Profy, AT Moench, TR Soto-Torres, LE Poindexter, AN Frezieres, RG Walsh, TL Kelly, CW Richardson, BA van Damme, L Celum, CL TI Safety and acceptability of penile application of 2 candidate topical microbicides: BufferGel and PRO 2000 Gel - 3 randomized trials in healthy low-risk men and HIV-positive men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; prevention; microbicide; male safety; acceptability; PRO 2000 Gel; BufferGel ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEXUALLY-TRANSMITTED DISEASES; TRANSMISSION; NONOXYNOL-9; INFECTION; WOMEN; PREVENTION; PRO-2000; TOLERABILITY; TYPE-1 AB Objectives: To assess safety and acceptability of penile application of BufferGel (ReProtect, Baltimore, MD) and PRO 2000 Gel (Indevus Pharmaceuticals, Lexington, MA)compared with placebo among low-risk sexually abstinent men and HIV-positive sexually abstinent men. Design: Seventy-two healthy low-risk men (36 uncircumcised) and 25 HIV-positive men (12 uncircumcised) were enrolled in 3 double-blind, single-center studies as follows: 36 low-risk men in a study of BufferGel and K-Y Jelly (McNeil-PPC, Skillman, NJ) placebo; 36 low-risk men in a study of PRO 2000 Gel and vehicle placebo; and 25 HIV-positive men in a crossover study of BufferGel, PRO 2000 Gel, and K-Y Jelly placebo. Methods: Participants applied product to the penis on 7 consecutive nights, kept study diaries, and were then interviewed and examined. Urine was tested for inflammation by leukocyte esterase. Results: No serious adverse events (AEs) or urethral inflammation was detected. During use of BufferGel, 3 low-risk men (13%) reported 6 AEs and 2 HIV-positive men (8%) reported 3 AEs. During use of PRO 2000 Gel, 4 low-risk men (17%) reported 6 AEs and 1 HIV-positive participant (4%) had 1 AE. AE rates during use of BufferGel and PRO 2000 Gel use were not significantly different from rates observed during placebo. One low-risk man (4%) would object to his partners using BufferGel and 3 (13%) to PRO 2000 Gel. Two HIV-positive men (8%) reported they would object to partners using either BufferGel or PRO 2000 Gel. Conclusions: Daily application of BufferGel and PRO 2000 Gel directly to the penis consecutively for 7 days was generally safe and well tolerated among healthy low-risk men and HIV-positive men. These microbicides have acceptable safety profiles to proceed with planned phase 3 vaginal microbicide trials. C1 Univ Washington, HIV Prevent Trials, Unit 901, Dept Med, Seattle, WA 98104 USA. Contracept Res & Dev Program, Arlington, VA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Family Hlth Int, Res Triangle Pk, NC 27709 USA. Indevus Pharmaceut Inc, Lexington, MA USA. ReProtect Inc, Baltimore, MD USA. NIAID, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Calif Family Hlth Council Inc, Los Angeles, CA USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Tabet, SR (reprint author), Univ Washington, HIV Prevent Trials, Unit 901, Dept Med, Boren Ave,Suite 1300, Seattle, WA 98104 USA. FU NIAID NIH HHS [U01-AI-47981, U01-AI-46749] NR 29 TC 38 Z9 38 U1 1 U2 1 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 AUG 1 PY 2003 VL 33 IS 4 BP 476 EP 483 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 703LA UT WOS:000184279800008 PM 12869836 ER PT J AU Schatz, M Dombrowski, MP Wise, R Thom, EA Landon, M Mabie, W Newman, RB Hauth, JC Lindheimer, M Caritis, SN Leveno, KJ Meis, P Miodovnik, M Wapner, RJ Paul, RH Varner, MW O'Sullivan, MJ Thurnau, GR Conway, D McNellis, D AF Schatz, M Dombrowski, MP Wise, R Thom, EA Landon, M Mabie, W Newman, RB Hauth, JC Lindheimer, M Caritis, SN Leveno, KJ Meis, P Miodovnik, M Wapner, RJ Paul, RH Varner, MW O'Sullivan, MJ Thurnau, GR Conway, D McNellis, D CA Nat I Child Hlth Dev Maternal Feta Nat Heart Lung Blood I TI Asthma morbidity during pregnancy can be predicted by severity classification SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE asthma; pregnancy; morbidity; severity AB Background: The 1993 National Asthma Education Program Working Group on Asthma and Pregnancy defined asthma severity as mild, moderate, or severe on the basis of symptoms and spirometry, but no studies have evaluated the relationship between this classification system and subsequent asthma morbidity during pregnancy. Objective: The objective of this study was to evaluate the relationship between asthma severity classification during pregnancy and gestational asthma exacerbations. Methods: Asthma severity was defined according to the 1993 classification, adjusted to include medication requirements, in a volunteer sample of 1739 pregnant asthmatic patients who were less than 26 weeks' gestation. Results: Initial asthma classification (mild, moderate, or severe) was significantly related to subsequent asthma morbidity during pregnancy (hospitalizations, unscheduled visits, corticosteroid requirements, and asthma symptoms during labor and delivery). Exacerbations during pregnancy occurred in 12.6% of patients initially classified as mild, 25.7% of patients classified as moderate, and 51.9% of patients classified as severe (P < .001). Asthma morbidity was similar, whether patients were classified as moderate or severe by symptoms and spirometry or by medication requirement. Thirty percent of initially mild patients were reclassified as moderate-severe during pregnancy, and 23% of the initially moderate-severe patients were reclassified as mild later in pregnancy; asthma morbidity in these patients changed accordingly. Conclusion: The National Asthma Education Program Working Group on Asthma and Pregnancy classification of asthma severity, adapted to include medication use, predicts subsequent asthma morbidity during pregnancy. C1 Kaiser Permanente Med Ctr, Dept Allergy, San Diego, CA 92111 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. Johns Hopkins Univ, Dept Pulm Med, Baltimore, MD 21218 USA. George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Univ Tennessee, Dept Obstet & Gynecol, Knoxville, TN 37996 USA. Med Coll S Carolina, Dept Obstet & Gynecol, Columbia, SC 29208 USA. Univ Alabama, Dept Obstet & Gynecol, Tuscaloosa, AL 35487 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. Univ Pittsburgh, Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA 15260 USA. Wake Forest Univ, Dept Obstet & Gynecol, Winston Salem, NC 27109 USA. Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH 45221 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84112 USA. Miami Univ, Dept Obstet & Gynecol, Oxford, OH 45056 USA. Univ Oklahoma, Dept Obstet & Gynecol, Norman, OK 73019 USA. Univ Texas, Dept Obstet & Gynecol, San Antonio, TX USA. NICHHD, Bethesda, MD 20892 USA. RP Schatz, M (reprint author), Kaiser Permanente Med Ctr, Dept Allergy, 7060 Clairemont Mesa Blvd, San Diego, CA 92111 USA. RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Wise, Robert/0000-0002-8353-2349; Varner, Michael/0000-0001-9455-3973 FU NICHD NIH HHS [HD27917, HD19897, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD34116, HD34122, HD34136, HD34208] NR 10 TC 112 Z9 117 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2003 VL 112 IS 2 BP 283 EP 288 DI 10.1067/mai.2003.1516 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 709WY UT WOS:000184650600011 PM 12897733 ER PT J AU Arbes, SJ Sever, M Archer, J Long, EH Gore, JC Schal, C Walter, M Nuebler, B Vaughn, B Mitchell, H Liu, E Collette, N Adler, P Sandel, M Zeldin, DC AF Arbes, SJ Sever, M Archer, J Long, EH Gore, JC Schal, C Walter, M Nuebler, B Vaughn, B Mitchell, H Liu, E Collette, N Adler, P Sandel, M Zeldin, DC TI Abatement of cockroach allergen (Bla g 1) in low-income, urban housing: A randomized controlled trial SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE cockroaches; cockroach allergen; Bla g 1; intervention ID INNER-CITY HOMES; ASTHMA; EXPOSURE; EXTERMINATION; CHILDREN AB Background: Clinically relevant reductions in exposure to cockroach allergen, an important risk factor for asthma in inner-city households, have proven difficult to achieve in intervention trials. Objective: This study investigated a method for the abatement of cockroach allergen in low-income, urban homes. The goal was to reduce mean Bla g 1 concentrations below the previously proposed thresholds for allergic sensitization and asthma morbidity. Methods: A prerandomized, nonmasked trial with 16 intervention and 15 control homes was conducted. Study inclusion was based on 50 to 500 cockroaches trapped in a 3-day period. The interventions consisted of occupant education, placement of insecticide bait, and professional cleaning. Vacuumed dust and multiple swab samples were collected at 0, 1, 2, 4, and 6 months in intervention homes and at 0 and 6 months in control homes. Room maps containing cockroach and allergen data were used to guide and monitor the interventions. Results: From 0 to 6 months among intervention homes, geometric mean Bla g 1 concentrations (U/g dust) decreased from 633 to 24 on kitchen floors (96% reduction), from 25 to 4.3 on living room floors/sofas (83% reduction), from 46 to 7.3 on bedroom floors (84% reduction), and from 6.1 to 1.0 in bedroom beds (84% reduction). These reductions, with the exception of that on the bedroom floor (P = .06), were statistically significant relative to changes in control homes. Conclusions: Substantial reductions in cockroach allergen levels can be achieved in inner-city homes. In this study, allergen levels were reduced below the sensitization threshold (2 U/g) in beds, arguably the most relevant site for exposure, and below the asthma morbidity threshold (8 U/g) on bedroom floors and living room floors/sofas. The level on kitchen floors, although reduced 96%, remained above the asthma morbidity threshold. Future studies will test the intervention's effectiveness in asthma prevention trials. C1 NIEHS, NIH, Div Intramural Res, Res Triangle Pk, NC 27709 USA. CODA Inc, Durham, NC USA. Univ N Carolina, Dept Entomol, Raleigh, NC 27515 USA. Rho Inc, Chapel Hill, NC USA. Boston Univ, Sch Med, Boston, MA USA. RP Zeldin, DC (reprint author), NIEHS, NIH, Div Intramural Res, 111 Alexander Dr,Bldg 101,D236, Res Triangle Pk, NC 27709 USA. RI Schal, Coby/A-8717-2010; OI Schal, Coby/0000-0001-7195-6358; Sever, Michelle/0000-0002-2435-1214; Sandel, Megan/0000-0001-6244-9418 NR 13 TC 65 Z9 65 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2003 VL 112 IS 2 BP 339 EP 345 DI 10.1067/mai.2003.1597 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 709WY UT WOS:000184650600018 PM 12897740 ER PT J AU Alexis, NE Eldridge, MW Peden, DB AF Alexis, NE Eldridge, MW Peden, DB TI Effect of inhaled endotoxin on airway and circulating inflammatory cell phagocytosis and CD11b expression in atopic asthmatic subjects SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE endotoxin; phagocytosis; CD11b; neutrophil response ID LIPOPOLYSACCHARIDE-BINDING PROTEIN; RECEPTOR-MEDIATED PHAGOCYTOSIS; RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; SOLUBLE CD14; ALLERGEN PROVOCATION; ALVEOLAR MACROPHAGES; NEUTROPHIL RESPONSE; LPS INHALATION; TNF-ALPHA AB Background: In a cohort of 8 normal and 10 allergic asthmatic volunteers, we previously reported that inhalation of 5 mug of endotoxin (LPS) induced airway inflammation that correlated with CD14 expression that was, in turn, correlated with eosinophil numbers in the airway. Macrophage and neutrophil functions have been reported to be modified by endotoxin in vitro and in vivo, and response to endotoxin is mediated largely by airway phagocytes and related to allergic inflammation. Objective: We sought to examine functional and cell-surface phenotype changes in phagocytes recovered from atopic asthmatic subjects after endotoxin challenge. Methods: Sputum and peripheral blood from 10 allergic asthmatic subjects was recovered after saline and LPS challenge. Assessment of phagocytosis and cell-surface phenotype (CD11b. CD14, and CD64) was performed on phagocytes obtained from sputum (n = 7) and blood samples (n = 10). Results: Phagocytosis of blood and sputum phagocytes was blunted after LPS challenge in a fashion that correlated with the increase in airway neutrophils after LPS challenge. Cell-surface expression of CD14 (membrane-bound CD14) was increased in sputum cells, whereas CD11b was decreased in sputum and circulating phagocytes. Baseline expression of CD11b in blood correlated with the magnitude of the neutrophil response after LPS inhalation, as well as (inversely) with baseline airway eosinophil levels. Conclusions: Inhalation of endotoxin at levels adequate to induce a neutrophil influx to the airways (but not systemic symptoms) and circulating cells and modifies CD11b expression in a way that implicates its involvement in pbagocyte responsiveness to inhaled LPS. C1 Univ N Carolina, Sch Med, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Gen Clin Res Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Peden, DB (reprint author), Univ N Carolina, Sch Med, Ctr Environm Med Asthma & Lung Biol, 104 Mason Farm Rd, Chapel Hill, NC 27599 USA. FU NHLBI NIH HHS [1R01HL62624-01]; NIEHS NIH HHS [N01-ES-35356] NR 38 TC 39 Z9 39 U1 1 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2003 VL 112 IS 2 BP 353 EP 361 DI 10.1067/mai.2003.1651 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 709WY UT WOS:000184650600020 PM 12897742 ER PT J AU Li, ZQ Mahesh, SP Kim, BJ Buggage, RR Nussenblatt, RB AF Li, ZQ Mahesh, SP Kim, BJ Buggage, RR Nussenblatt, RB TI Expression of glucocorticoid induced TNF receptor family related protein (GITR) on peripheral T cells from normal human donors and patients with non-infectious uveitis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE GITR; non-infectious uveitis; T helper cells; FACS; regulatory T cells ID EXPERIMENTAL AUTOIMMUNE UVEITIS; IMMUNOLOGICAL SELF-TOLERANCE; REGULATORY CELLS; LUNG-CANCER; MECHANISMS; DISEASE; IDENTIFICATION; UVEORETINITIS; INDUCTION; BLOCKADE AB The expression of the glucocorticoid induced TNF receptor family related gene (GITR) in subsets of T lymphocytes from human peripheral blood was studied. In normal human peripheral blood mononuclear cells, GITR expression on the resting CD4+ T cells was low but markedly increased after activation. The percentage of GITR+ T cells in the CD4+CD25+ T cell subpopulation (15.1%) was significantly higher than that in the CD4+CD25- T cell subpopulation (5.2%, P<0.01), suggesting a preferential co-expression of GITR with CD25. In a group of patients with non-infectious uveitis, a proposed T helper cell mediated autoimmune ocular disease, the GITR expression on the CD4+ T cells in both the active patients (34.5%) and the inactive patients (19.6%) was significantly higher as compared to that in the normal donors (10.7%; P<0.01 vs. active, P<0.05 vs. inactive). This increased GITR expression in T cells was only seen in the CD4 positive T helper cell subpopulation but not in the CD4 negative T cell subpopulation. GITR expression on the CD4+ T cells decreased when the patients became clinically quiescent. Therefore, GITR is an activation marker for the CD4+ T cells and preferentially co-expressed with CD25 on the CD4+ T cells in human peripheral blood. Its expression correlates with the clinical course of non-infectious uveitis. (C) 2003 Published by Elsevier Ltd. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20892 USA. RP Li, ZQ (reprint author), NEI, Immunol Lab, NIH, Bldg 10,10B22,10 Ctr Dr, Bethesda, MD 20892 USA. NR 31 TC 45 Z9 49 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD AUG PY 2003 VL 21 IS 1 BP 83 EP 92 DI 10.1016/S0896-8411(03)00085-4 PG 10 WC Immunology SC Immunology GA 707EF UT WOS:000184495900010 PM 12892739 ER PT J AU Csiszovszki, Z Buzas, Z Semsey, S Ponyi, T Papp, PP Orosz, L AF Csiszovszki, Z Buzas, Z Semsey, S Ponyi, T Papp, PP Orosz, L TI immX immunity region of Rhizobium phage 16-3: Two overlapping cistrons of repressor function SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GENETIC SWITCH; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; DISTINCT REGIONS; CLONING VECTOR; BINDING-SITES; PHYSICAL MAP; MELILOTI 41; C-CISTRON; TEMPERATE AB 16-3 is a temperate phage of the symbiotic nitrogen-fixing bacterium Rhizobium meliloti 41. Its prophage state and immunity against superinfection by homoimmune phages are governed by a complex set of controls: the immC and immX repressor systems and the avirT element are all located in well-separated, distinct regions which span 25 kb on the bacteriophage chromosome. The anatomy and function of the immC region are well documented; however, fewer analyses have addressed the immX and avirT regions. We focused in this paper on the immX region and dissected it into two major parts: X-U/L and X-V. The X-U/L part (0.6 kb) contained two overlapping cistrons, X-U and X-L coding for proteins pXU and pXL, respectively. Inactivation of either gene inactivated the repressor function of the immX region. Loss-of-function mutants of X-U and X-L complemented each other in trans in double lysogens. The X-V part (1 kb) contained a target for X-U/L repressor action. Mutations at three sites in X-V led to various degree of ImmX insensitivity in a hierarchic manner. Two sites (X-V1 and X-V3) exhibited the inverted-repeat structures characteristic of many repressor binding sites. However, X-V1 could also be folded into a transcription terminator. Of the two immunity regions of 16-3, immX seems to be unique both in its complex genetic anatomy and in its sequence. To date, no DNA or peptide sequence homologous to that of ImmX has been found in the data banks. In contrast, immC shares properties of a number of immunity systems commonly found in temperate phages. C1 Eotvos Lorand Univ, Dept Genet, Fac Sci, H-1117 Budapest, Hungary. Ctr Agr Biotechnol, Genet Inst, H-2100 Godollo, Hungary. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Eotvos Lorand Univ, Dept Genet, Fac Sci, Pazmany P 1-C, H-1117 Budapest, Hungary. EM orosz@falco.elte.hu RI Papp, Peter/A-6907-2013; Semsey, Szabolcs/L-6329-2013; OI Semsey, Szabolcs/0000-0002-4522-5495 NR 45 TC 7 Z9 7 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2003 VL 185 IS 15 BP 4382 EP 4392 DI 10.1128/JB.185.15.4382-4392.2003 PG 11 WC Microbiology SC Microbiology GA 702RT UT WOS:000184237800011 PM 12867446 ER PT J AU Kolker, E Purvine, S Galperin, MY Stolyar, S Goodlett, DR Nesvizhskii, AI Keller, A Xie, T Eng, JK Yi, E Hood, L Picone, AF Cherny, T Tjaden, BC Siegel, AF Reilly, TJ Makarova, KS Palsson, BO Smith, AL AF Kolker, E Purvine, S Galperin, MY Stolyar, S Goodlett, DR Nesvizhskii, AI Keller, A Xie, T Eng, JK Yi, E Hood, L Picone, AF Cherny, T Tjaden, BC Siegel, AF Reilly, TJ Makarova, KS Palsson, BO Smith, AL TI Initial proteome analysis of model microorganism Haemophilus influenzae strain Rd KW20 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; ESCHERICHIA-COLI; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; IDENTIFICATION TECHNOLOGY; VIBRIO-ALGINOLYTICUS; ACUTE EXACERBATIONS; STRUCTURAL GENES; DATABASE SEARCH; GLOBAL ANALYSIS AB The proteome of Haemophilus influenzae strain Rd KW20 was analyzed by liquid chromatography (LC) coupled with ion trap tandem mass spectrometry (MS/MS). This approach does not require a gel electrophoresis step and provides a rapidly developed snapshot of the proteome. In order to gain insight into the central metabolism of H. influenzae, cells were grown microaerobically and anaerobically in a rich medium and soluble and membrane proteins of strain Rd KW20 were proteolyzed with trypsin and directly examined by LC-MS/MS. Several different experimental and computational approaches were utilized to optimize the proteome coverage and to ensure statistically valid protein identification. Approximately 25% of all predicted proteins (open reading frames) of H. influenzae strain Rd KW20 were identified with high confidence, as their component peptides were unambiguously assigned to tandem mass spectra. Approximately 80% of the predicted ribosomal proteins were identified with high confidence, compared to the 33% of the predicted ribosomal proteins detected by previous two-dimensional gel electrophoresis studies. The results obtained in this study are generally consistent with those obtained from computational genome analysis, two-dimensional gel electrophoresis, and whole-genome transposon mutagenesis studies. At least 15 genes originally annotated as conserved hypothetical were found to encode expressed proteins. Two more proteins, previously annotated as predicted coding regions, were detected with high confidence; these proteins also have close homologs in related bacteria. The direct proteomics approach to studying protein expression in vivo reported here is a powerful method that is applicable to proteome analysis of any (micro) organism. C1 BIATECH, Bothell, WA 98011 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Inst Syst Biol, Seattle, WA 98103 USA. Univ Washington, Dept Comp Sci, Seattle, WA 98195 USA. Univ Washington, Dept Management Sci, Seattle, WA 98195 USA. Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. RP Kolker, E (reprint author), BIATECH, 19310 N Creek Pkwy,Suite 115, Bothell, WA 98011 USA. RI Nesvizhskii, Alexey/A-5410-2012; Eng, Jimmy/I-4202-2012; Kolker, Eugene/C-6711-2008; Galperin, Michael/B-5859-2013; Eng, Jimmy/C-6556-2017 OI Nesvizhskii, Alexey/0000-0002-2806-7819; Eng, Jimmy/0000-0001-6352-6737; Galperin, Michael/0000-0002-2265-5572; Eng, Jimmy/0000-0001-6352-6737 FU Intramural NIH HHS [Z99 LM999999]; NIAID NIH HHS [AI44002, R01 AI044002] NR 67 TC 53 Z9 55 U1 0 U2 3 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 AUG PY 2003 VL 185 IS 15 BP 4593 EP 4602 DI 10.1128/JB.185.15.4593-4602.2003 PG 10 WC Microbiology SC Microbiology GA 702RT UT WOS:000184237800035 PM 12867470 ER PT J AU Blehert, DS Palmer, RJ Xavier, JB Almeida, JS Kolenbrander, PE AF Blehert, DS Palmer, RJ Xavier, JB Almeida, JS Kolenbrander, PE TI Autoinducer 2 production by Streptococcus gordonii DL1 and the biofilm phenotype of a luxS mutant are influenced by nutritional conditions SO JOURNAL OF BACTERIOLOGY LA English DT Article ID QUORUM-SENSING SIGNAL; VIBRIO-HARVEYI; PORPHYROMONAS-GINGIVALIS; ESCHERICHIA-COLI; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; SALMONELLA-TYPHIMURIUM; ORAL BACTERIA; CO2 FIXATION; HUMAN-ENAMEL; EXPRESSION AB The luxS gene, present in many bacterial genera, encodes the autoinducer 2 (AI-2) synthase. AI-2 has been implicated in bacterial signaling, and this study investigated its role in biofilm formation by Streptococcus gordonii, an organism that colonizes human tooth enamel within the first few hours after professional cleaning. Northern blotting and primer extension analyses revealed that S. gordonii luxS is monocistronic. AI-2 production was dependent on nutritional conditions, and maximum AI-2 induction was detected when S. gordonii was grown in the presence of serum and carbonate. In planktonic cultures, AI-2 production rose sharply during the transition from exponential to stationary phase, and the AI-2 concentration peaked approximately 4 h into stationary phase. An S. gordonii luxS mutant that did not produce AI-2 was constructed by homologous recombination. Complementation of the mutant by insertion of an intact luxS gene into the chromosome in tandem with the disrupted gene restored AI-2 production to a level similar to that of the wild-type strain. In planktonic culture, no growth differences were observed between the mutant and wild-type strains when five different media were used. However, when grown for 4 h as biofilms in 25% human saliva under How, the luxS mutant formed tall microcolonies that differed from those formed by the wild-type and complemented mutant strains. Biofilms of the luxS mutant exhibited finger-like projections of cells that extended into the flow cell lumen. Thus, the inability to produce AI-2 is associated with altered microcolony architecture within S. gordonii biofilms formed in saliva during a time frame consistent with initial colonization of freshly cleaned enamel surfaces. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Nova Lisboa, P-1200 Lisbon, Portugal. Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. RP Kolenbrander, PE (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 310,30 Convent Dr MSC 4350, Bethesda, MD 20892 USA. NR 49 TC 83 Z9 92 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2003 VL 185 IS 16 BP 4851 EP 4860 DI 10.1128/JB.185.16.4851-4860.2003 PG 10 WC Microbiology SC Microbiology GA 710RG UT WOS:000184692800022 PM 12897005 ER PT J AU Heesch, KC Masse, LC Dunn, AL Frankowski, RF Mullen, PD AF Heesch, KC Masse, LC Dunn, AL Frankowski, RF Mullen, PD TI Does adherence to a lifestyle physical activity intervention predict changes in physical activity? SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE exercise; behavior change; health promotion; randomized clinical trials; adults ID HOME-BASED EXERCISE; MIDDLE-AGED MEN; RANDOMIZED-TRIAL; WEIGHT-LOSS; WOMEN; RELIABILITY; MAINTENANCE; PREVENTION; VALIDITY; PROGRAM AB This study examined whether adherence to a lifestyle physical activity intervention predicted weekly participation in at least 150 min of moderate to vigorous physical activity among 244 sedentary healthy adults. Structural equation modeling was used to assess the association between adherence and physical activity. Markers of adherence were attendance, homework completion, and self-monitoring for a group-based intervention and telephone call completion, homework completion, and self-monitoring for a telephone and mail-delivered intervention. For both interventions, adherence significantly predicted moderate to vigorous physical activity. Adherence to lifestyle physical activity interventions ought to be encouraged to increase the likelihood that participants will engage in an adequate amount of physical activity for health benefits to occur. C1 Univ Texas, Sch Publ Hlth, Houston, TX USA. NCI, Rockville, MD USA. Cooper Inst, Dallas, TX USA. RP Heesch, KC (reprint author), Univ Oklahoma, Dept Hlth & Sports Sci, 1401 Asp Ave, Norman, OK 73019 USA. RI Heesch, Kristi/B-7863-2009; Heesch, Kristiann/J-1288-2012 OI Heesch, Kristiann/0000-0003-1931-3683 FU NCI NIH HHS [R25 CA57712]; NHLBI NIH HHS [HL 58608] NR 44 TC 29 Z9 29 U1 0 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD AUG PY 2003 VL 26 IS 4 BP 333 EP 348 DI 10.1023/A:1024205011001 PG 16 WC Psychology, Clinical SC Psychology GA 691XH UT WOS:000183630900004 PM 12921007 ER PT J AU Doong, H Rizzo, K Fang, SY Kulpa, V Weissman, AM Kohn, EC AF Doong, H Rizzo, K Fang, SY Kulpa, V Weissman, AM Kohn, EC TI CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation - Accumulation of poly-ubiquitinated Hsp90 client proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEINS; GASTRIC-CANCER CELLS; BCL-2-BINDING PROTEIN; INDUCED APOPTOSIS; DEATH ACTIVITY; HT-29 CELLS; BAG-1; RECEPTOR; AKT; GELDANAMYCIN AB BAG family proteins are regulatory co-chaperones for heat shock protein (Hsp) 70. Hsp70 facilitates the removal of injured proteins by ubiquitin-mediated proteasomal degradation. This process can be driven by geldanamycin, an irreversible blocker of Hsp90. We hypothesize that CAIR-1/BAG-3 inhibits Hsp-mediated proteasomal degradation. Human breast cancer cells were engineered to overexpress either full-length CAIR-1 (FL), which binds Hsp70, or a BAG domain-deletion mutant (dBAG) that cannot bind Hsp70. FL overexpression prevented geldanamycin-mediated loss of total and phospho-Akt and other Hsp client proteins. dBAG provided no protection, indicating a requirement for Hsp70 binding. Ubiquitinated Akt accumulated in FL-expressing cells, mimicking the effect of lactacystin proteasomal inhibition, indicating that CAIR-1 inhibits proteasomal degradation distal to protein ubiquitination in a BAG domain-dependent manner. Protein protection in FL cells was generalizable to downstream Akt targets, GSK3beta, P70S6 kinase, CREB, and other Hsp client proteins, including Raf-1, cyclin-dependent kinase 4, and epidermal growth factor receptor. These findings suggest that Hsp70 is a chaperone driving a multiprotein degradation complex and that the inhibitory co-chaperone CAIR-1 functions distal to client ubiquitination. Furthermore, poly-ubiquitination is not sufficient for efficient proteasomal targeting of Hsp client proteins. C1 NCI, Mol Signaling Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Regulat Prot Funct Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Doong, H (reprint author), NCI, Mol Signaling Sect, Pathol Lab, NIH, 10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. RI Fang, Shengyun/H-3802-2011 NR 47 TC 105 Z9 106 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 AUG 1 PY 2003 VL 278 IS 31 BP 28490 EP 28500 DI 10.1074/jbc.M209682200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100019 PM 12750378 ER PT J AU Cui, XL Rouhani, FN Hawari, F Levine, SJ AF Cui, XL Rouhani, FN Hawari, F Levine, SJ TI An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOLUBLE IL-6 RECEPTOR; NECROSIS-FACTOR-ALPHA; SIGNAL TRANSDUCER GP130; METALLOPROTEINASE INHIBITOR; ANTIINFLAMMATORY CYTOKINE; MESSENGER-RNA; CELLS; PROTEIN; ASSOCIATION; KINASES AB Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding. Because hydroxamic acid-based metalloprotease inhibitors prevent shedding of both TNFR1 and the interleukin-6 receptor (IL-6Ralpha), we hypothesized that ARTS-1 might also regulate shedding of IL-6Ralpha, a member of the type I cytokine receptor superfamily that is structurally different from TNFR1. Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 directly binds to a 55-kDa IL-6Ralpha, a size consistent with soluble IL-6Ralpha generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6Ralpha shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6Ralpha shedding, and decreased membrane-associated IL-6Ralpha in cell lines overexpressing ARTS-1. The absence of basal IL-6Ralpha shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6Ralpha shedding. Furthermore, the mechanism of constitutive IL-6Ralpha shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6Ralpha) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6Ralpha and TNFR1 shedding. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. NR 45 TC 87 Z9 90 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 AUG 1 PY 2003 VL 278 IS 31 BP 28677 EP 28685 DI 10.1074/jbc.M300456200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100042 PM 12748171 ER PT J AU Duan, L Miura, Y Dimri, M Majumder, B Dodge, IL Reddi, AL Ghosh, A Fernandes, N Zhou, PC Mullane-Robinson, K Rao, N Donoghue, S Rogers, RA Bowtell, D Naramura, M Gu, H Band, V Band, H AF Duan, L Miura, Y Dimri, M Majumder, B Dodge, IL Reddi, AL Ghosh, A Fernandes, N Zhou, PC Mullane-Robinson, K Rao, N Donoghue, S Rogers, RA Bowtell, D Naramura, M Gu, H Band, V Band, H TI Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOWN-REGULATION; EGF RECEPTOR; TYROSINE KINASE; C-CBL; NEGATIVE REGULATION; PLASMA-MEMBRANE; RING FINGER; UBIQUITINATION; DEGRADATION; PROTEINS AB Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl(-/-) mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Peter MacCallum Canc Inst, Trescowthick Res Labs, Parkville, Vic 3050, Australia. NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. Tufts Univ New England Med Ctr, Div Radiat & Canc Biol, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Dept Radiat Oncol, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Dept Biochem, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Band, H (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Smith Bldg,Rm 538C,1 Jimmy Fund Way, Boston, MA 02115 USA. RI Bowtell, David/H-1007-2016; OI Bowtell, David/0000-0001-9089-7525; Naramura, Mayumi/0000-0003-3658-0767 FU NCI NIH HHS [CA 76118, CA 70195, CA 81076, CA 99163, CA87986, R01 CA105489]; NIAMS NIH HHS [T32ARO7530] NR 58 TC 138 Z9 143 U1 0 U2 12 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 AUG 1 PY 2003 VL 278 IS 31 BP 28950 EP 28960 DI 10.1074/jbc.M304474200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100075 PM 12754251 ER PT J AU Katz, BZ Romer, L Miyamoto, S Volberg, T Matsumoto, K Cukierman, E Geiger, B Yamada, KM AF Katz, BZ Romer, L Miyamoto, S Volberg, T Matsumoto, K Cukierman, E Geiger, B Yamada, KM TI Targeting membrane-localized focal adhesion kinase to focal adhesions - Roles of tyrosine phosphorylation and Src family kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-MATRIX ADHESIONS; EXTRACELLULAR-MATRIX; INTEGRIN FUNCTION; BINDING-SITE; IN-VIVO; FIBRONECTIN; FAK; CYTOSKELETAL; INHIBITION; MECHANISMS AB In the present study, we examined regulation of activated focal adhesion kinase localization in focal adhesions. By using focal adhesion kinase fused to an inert transmembrane anchor, we found that the focal contact targeting region within focal adhesion kinase was preserved in the membrane-targeted fusion protein. However, upon tyrosine phosphorylation, full-length focal adhesion kinase became excluded from focal adhesions. This negative regulation of localization could be abolished by mutating key amino acid residues of focal adhesion kinase shown previously to be involved in adhesion-mediated signal transduction. Hyper-phosphorylation of endogenous focal adhesion kinase induced by pervanadate resulted in a similar reduction of localization at focal adhesions. We also show here that Src family kinases are essential for the phosphorylation-dependent exclusion of focal adhesion kinase from focal adhesions. We propose here a molecular model for the tyrosine phosphorylation-dependent regulation of focal adhesion kinase organization involving Src kinases and an inhibitory phosphorylation of the C-terminal (Tyr-925) tyrosine residue. C1 Tel Aviv Med Ctr & Sch Med, Inst Hematol, IL-64239 Tel Aviv, Israel. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Anesthesiol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21224 USA. Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Katz, BZ (reprint author), Tel Aviv Med Ctr & Sch Med, Inst Hematol, 6 Weizman St, IL-64239 Tel Aviv, Israel. OI Yamada, Kenneth/0000-0003-1512-6805 FU FIC NIH HHS [F06TW02341]; NHLBI NIH HHS [HL03299] NR 37 TC 61 Z9 62 U1 0 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 1 PY 2003 VL 278 IS 31 BP 29115 EP 29120 DI 10.1074/jbcM212396200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100095 PM 12754219 ER PT J AU Naylor, MJ Ginsburg, E Iismaa, TP Vonderhaar, BK Wynick, D Ormandy, CJ AF Naylor, MJ Ginsburg, E Iismaa, TP Vonderhaar, BK Wynick, D Ormandy, CJ TI The neuropeptide galanin augments lobuloalveolar development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMARY-GLAND DEVELOPMENT; GROWTH-HORMONE; PROGESTERONE-RECEPTOR; MOLECULAR-CLONING; TRANSGENIC MICE; BREAST-CANCER; WISTAR RATS; PROLACTIN; GENE; MOUSE AB Mammary lobuloalveolar development during pregnancy is controlled by ovarian sex steroids and pituitary prolactin release. In organ culture these hormones are incapable of reproducing the density and size of lobuloalveoli seen in mice, suggesting the existence of other undiscovered factors. We showed previously that galanin knockout mice fail to lactate sufficiently for pup survival following their first pregnancy. Here we demonstrate that prolactin treatment of galanin knockout mice allows pup survival but does not completely rescue lobuloalveolar development or reduced milk protein expression. When galanin was used in combination with prolactin in mammary organ culture, larger and more numerous lobules were produced than with prolactin alone. Galanin alone produced sustained activation of STAT5a and the induction of milk protein expression but did not induce lobulogenesis. Examination of the transcriptional interaction between galanin and prolactin using oligonucleotide microarrays demonstrated synergistic and antagonistic modes of interaction between these hormones. These data establish a new role for galanin as a hormone augmenting mammary development during pregnancy in concert with prolactin. C1 St Vincents Hosp, Garvan Inst Med Res, Dev Grp, Canc Res Program, Sydney, NSW 2010, Australia. St Vincents Hosp, Garvan Inst Med Res, Neurobiol Program, Sydney, NSW 2010, Australia. NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Bristol, Univ Res Ctr Neuroendocrinol, Bristol BS2 8HW, Avon, England. RP Ormandy, CJ (reprint author), St Vincents Hosp, Garvan Inst Med Res, Dev Grp, Canc Res Program, Sydney, NSW 2010, Australia. RI Ormandy, Chris/G-4165-2014 NR 41 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 1 PY 2003 VL 278 IS 31 BP 29145 EP 29152 DI 10.1074/jbc.M303746200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100099 PM 12759342 ER PT J AU Zhang, JH Wang, SB Wesley, RA Danner, RL AF Zhang, JH Wang, SB Wesley, RA Danner, RL TI Adjacent sequence controls the response polarity of nitric oxide-sensitive Sp factor binding sites SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED-PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; VASCULAR ENDOTHELIAL-CELLS; NF-KAPPA-B; TRANSCRIPTION FACTOR SP1; GENE-EXPRESSION; CYCLIC-AMP; DNA-BINDING; HUMAN NEUTROPHILS; ALPHA PRODUCTION AB Nitric oxide (NO.) and cAMP-dependent protein kinase (PKA) inhibitors up-regulate tumor necrosis factor alpha (TNFalpha) by decreasing Sp1 binding to a proximal GC box element. Here, elements flanking GC boxes were tested for their role in determining whether Sp sites act as activators or repressors. Promoter studies in receptive human cell lines demonstrated that NO. down-regulated endothelial NO. synthase ( eNOS) but up-regulated TNFalpha. Like TNFalpha, Sp1 binding to the eNOS promoter was decreased by NO. and a PKA inhibitor, H89, and increased by a PKA activator, dibutyryl cAMP (Bt(2)cAMP). For either promoter, mutation of Sp sites abolished NO. responses. In contrast, mutation of an upstream AP1 site in the TNFalpha promoter ( not present in eNOS) maintained NO. responsiveness, but reversed the direction of NO. and cAMP effects. Using artificial constructs, NO. increased transcription when Sp and AP1 sites were both present (TNFalpha-like response), but decreased it when the adjacent AP1 site was disrupted (eNOS-like response). NO., H89, and Bt2cAMP were found to produce reciprocal protein binding changes at contiguous AP1 and Sp sites ( p < 0.0001 for an interaction). Chromatin immunoprecipitation assays demonstrated that Sp1 and to a lesser extent Sp3 bound to the GC box regions of eNOS and TNFα in intact cells. Thus, this NO&BULL;- and cAMP-responsive regulatory module has a Sp site sensor variably coupled to an adjacent element that determines response polarity. These results define a composite element that can utilize secondary inputs to convert off signals to on, thereby conferring complex functionalities to the same DNA binding motif. C1 NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 7D43, Bethesda, MD 20892 USA. NR 57 TC 17 Z9 18 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 AUG 1 PY 2003 VL 278 IS 31 BP 29192 EP 29200 DI 10.1074/jbc.M213043200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100104 PM 12759366 ER PT J AU Sakamoto, T Wang, F Schmitz, S Xu, YH Xu, Q Molloy, JE Veigel, C Sellers, JR AF Sakamoto, T Wang, F Schmitz, S Xu, YH Xu, Q Molloy, JE Veigel, C Sellers, JR TI Neck length and processivity of myosin V SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE MYOSIN; LEVER ARM; MOTOR; MOVEMENT; BINDING; ACTIN; MOLECULES; DOMAIN; HEAD; ROD AB Myosin V is an unconventional myosin that transports cargo such as vesicles, melanosomes, or mRNA on actin filaments. It is a two-headed myosin with an unusually long neck that has six IQ motifs complexed with calmodulin. In vitro studies have shown that myosin V moves processively on actin, taking multiple 36-nm steps that coincide with the helical repeat of actin. This allows the molecule to "walk" across the top of an actin filament, a feature necessary for moving large vesicles along an actin filament bound to the cytoskeleton. The extended neck length of the two heads is thought to be critical for taking 36-nm steps for processive movements. To test this hypothesis we have expressed myosin V heavy meromyosin-like fragments containing 6IQ motifs, as well as ones that shorten (2IQ, 4IQ) or lengthen (8IQ) the neck region or alter the spacing between 3rd and 4th IQ motifs. The step size was proportional to neck length for the 2IQ, 4IQ, 6IQ, and 8IQ molecules, but the molecule with the altered spacing took shorter than expected steps. Total internal reflection fluorescence microscopy was used to determine whether the heavy meromyosin IQ molecules were capable of processive movements on actin. At saturating ATP concentrations, all molecules except for the 2IQ mutant moved processively on actin. When the ATP concentration was lowered to 10 muM or less, the 2IQ mutant demonstrated some processive movements but with reduced run lengths compared with the other mutants. Its weak processivity was also confirmed by actin landing assays. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Electron Microscopy Core, NIH, Bethesda, MD 20892 USA. Natl Inst Med Res, Div Phys Biochem, London NW7 1AA, England. RP Sellers, JR (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Rm 8N202, Bethesda, MD 20892 USA. FU Medical Research Council [MC_U117570592] NR 30 TC 111 Z9 111 U1 4 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 1 PY 2003 VL 278 IS 31 BP 29201 EP 29207 DI 10.1074/jbc.M303662200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100105 PM 12740393 ER PT J AU Ulmer, TS Soelaiman, S Li, SP Klee, CB Tang, WJ Bax, A AF Ulmer, TS Soelaiman, S Li, SP Klee, CB Tang, WJ Bax, A TI Calcium dependence of the interaction between calmodulin and anthrax edema factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADENYLYL-CYCLASE; TARGET RECOGNITION; STRUCTURAL BASIS; CA2+ BINDING; ACTIVATION; TOXIN; NMR; PROTEINS; ASSIGNMENT; DIVERSITY AB Edema factor (EF), a toxin from Bacillus anthracis ( anthrax), possesses adenylyl cyclase activity and requires the ubiquitous Ca2+- sensor calmodulin (CaM) for activity. CaM can exist in three major structural states: an apo state with no Ca2+ bound, a two Ca2+ state with its C-terminal domain Ca2+- loaded, and a four Ca2+ state in which the lower Ca2+ affinity N-terminal domain is also ligated. Here, the interaction of EF with the three Ca2+ states of CaM has been examined by NMR spectroscopy and changes in the Ca2+ affinity of CaM in the presence of EF have been determined by flow dialysis. Backbone chemical shift perturbations of CaM show that EF interacts weakly with the N-terminal domain of apoCaM. The C-terminal CaM domain only engages in the interaction upon Ca2+ ligation, rendering the overall interaction much tighter. In the presence of EF, the C-terminal domain binds Ca2+ with higher affinity, but loses binding cooperativity, whereas the N-terminal domain exhibits strongly reduced Ca2+ affinity. As judged by chemical shift differences, the N-terminal CaM domain remains bound to EF upon subsequent Ca2+ ligation. This Ca2+ dependence of the EF-CaM interaction differs from that observed for most other CaM targets, which normally interact only with the Ca2+- bound CaM domains and become active following the transition to the four Ca2+ state. C1 Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Klee, CB (reprint author), Univ Chicago, Ben May Inst Canc Res, JFK T120,924 E 57th St, Chicago, IL 60637 USA. OI Tang, Wei-Jen/0000-0002-8267-8995 FU NIGMS NIH HHS [GM53459, GM62548] NR 29 TC 35 Z9 36 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 AUG 1 PY 2003 VL 278 IS 31 BP 29261 EP 29266 DI 10.1074/jbc.M302837200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100111 PM 12724328 ER PT J AU Martina, JA Moriyama, K Bonifacino, JS AF Martina, JA Moriyama, K Bonifacino, JS TI BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AP-3 ADAPTER COMPLEX; STORAGE POOL DEFICIENCY; PALE EAR EP; BETA-3A SUBUNIT; LIGHT-EAR; MOUSE; MUTATION; HOMOLOG; TRAFFICKING; BIOGENESIS AB The Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. HPS results from mutations in either one of six human genes named HPS1 to HPS6, most of which encode proteins of unknown function. Here we report that the human HPS1 and HPS4 proteins are part of a complex named BLOC-3 ( for biogenesis of lysosome-related organelles complex 3). Co-immunoprecipitation experiments demonstrated that epitope-tagged and endogenous HPS1 and HPS4 proteins assemble with each other in vivo. The HPS1 . HPS4 complex is predominantly cytosolic, with a small amount being peripherally associated with membranes. Size exclusion chromatography and sedimentation velocity analyses of the cytosolic fraction indicate that HPS1 and HPS4 form a moderately asymmetric protein complex with a molecular mass of similar to 175 kDa. HPS4-deficient fibroblasts from light ear mice display normal distribution and trafficking of the lysosomal membrane protein, Lamp-2, in contrast to fibroblasts from AP-3-deficient pearl mice (HPS2), which exhibit increased trafficking of this lysosomal protein via the plasma membrane. Similarly, light ear fibroblasts display an apparently normal accumulation of Zn2+ in intracellular vesicles, unlike pearl fibroblasts, which exhibit a decreased intracellular Zn2+ storage. Taken together, these observations demonstrate that the HPS1 and HPS4 proteins are components of a cytosolic complex that is involved in the biogenesis of lysosomal-related organelles by a mechanism distinct from that operated by AP-3 complex. C1 NICHD, Metab Branch, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHD, Metab Branch, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 45 TC 68 Z9 70 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 AUG 1 PY 2003 VL 278 IS 31 BP 29376 EP 29384 DI 10.1074/jbc.M301294200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705XC UT WOS:000184421100124 PM 12756248 ER PT J AU Brennan, PF Aronson, AR AF Brennan, PF Aronson, AR TI Towards linking patients and clinical information: detecting UMLS concepts in e-mail SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article ID WORLD-WIDE-WEB AB The purpose of this project is to explore the feasibility of detecting terms within the electronic messages of patients that could be used to effectively search electronic knowledge resources and bring health information resources into the hands of patients. Our team is exploring the application of the natural language processing (NLP) tools built within the Lister Hill Center at the National Library of Medicine (NLM) to the challenge of detecting relevant concepts from the Unified Medical Language System (UMLS) within the free text of lay people's electronic messages (e-mail). We obtained a sample of electronic messages sent by patients participating in a randomized field evaluation of an internet-based home care support service to the project nurse, and we subjected elements of these messages to a series of analyses using several vocabularies from the UMLS Metathesaurus and the selected NLP tools. The nursing vocabularies provide an excellent starting point for this exercise because their domain encompasses patient's responses to health challenges. In successive runs we augmented six nursing vocabularies (NANDA Nursing Diagnosis, Nursing Interventions Classification, Nursing Outcomes Classification, Home Health Classification, Omaha System, and the Patient Care Data Set) with selected sets of clinical terminologies (International Classification of Primary Care; International Classification of Primary Care- American English; Micromedex DRUGDEX; National Drug Data File; Thesaurus of Psychological Terms; WHO Adverse Drug Reaction Terminology) and then additionally with either Medical Subject Heading (MeSH) or SNOMED International terms. The best performance was obtained when the nursing vocabularies were complemented with selected clinical terminologies. These findings have implications not only for facilitating lay people's access to electronic knowledge resources,but may also be of assistance in developing new tools to aid in linking free text (e.g., clinical notes) to lexically complex knowledge resources such as those emerging from the Human Genome Project. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Wisconsin, Madison, WI 53706 USA. Natl Lib Med, Bethesda, MD 20894 USA. RP Brennan, PF (reprint author), Univ Wisconsin, 1513 Univ Ave, Madison, WI 53706 USA. FU NLM NIH HHS [LM 6247] NR 21 TC 24 Z9 24 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD AUG-OCT PY 2003 VL 36 IS 4-5 BP 334 EP 341 DI 10.1016/j.jbi.2003.09.017 PG 8 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 754TU UT WOS:000187348400013 PM 14643729 ER PT J AU Wu, ZG Delaglio, F Tjandra, N Zhurkin, VB Bax, A AF Wu, ZG Delaglio, F Tjandra, N Zhurkin, VB Bax, A TI Overall structure and sugar dynamics of a DNA dodecamer from homoand heteronuclear dipolar couplings and P-31 chemical shift anisotropy SO JOURNAL OF BIOMOLECULAR NMR LA English DT Review DE chemical shift anisotropy; Dickerson dodecamer; dipolar coupling; liquid crystal; NMR; sugar pucker ID LIQUID-CRYSTALLINE PHASE; MAGNETIC-RESONANCE STRUCTURES; HOMONUCLEAR PROTON COUPLINGS; CROSS-CORRELATED RELAXATION; SEQUENCE-SPECIFIC BINDING; RIGID-BODY MINIMIZATION; B-DNA; MINOR-GROOVE; MOLECULAR-DYNAMICS; NUCLEIC-ACIDS AB The solution structure of d(CGCGAATTCGCG)(2) has been determined on the basis of an exceptionally large set of residual dipolar couplings. In addition to the heteronuclear C-13-H-1 and N-15-H-1 and qualitative homonuclear H-1-H-1 dipolar couplings, previously measured in bicelle medium, more than 300 quantitative 1H-1H and 22 P-31-H-1 dipolar restraints were obtained in liquid crystalline Pf1 medium, and 22 P-31 chemical shift anisotropy restraints. High quality DNA structures can be obtained solely on the basis of these new restraints, and these structures are in close agreement with those calculated previously on the basis of C-13-H-1 and N-15-H-1 dipolar couplings. In the newly calculated structures, P-31-H-1 dipolar and (3)J(H3'P) couplings and P-31 CSA data restrain the phosphodiester backbone torsion angles. The final structure represents a quite regular B-form helix with a modest bending of similar to10degrees, which is essentially independent of whether or not electrostatic terms are used in the calculation. Combined, the number of homo-and heteronuclear dipolar couplings significantly exceeds the number of degrees of freedom in the system. Results indicate that the dipolar coupling data cannot be fit by a single structure, but are compatible with the presence of rapid equilibria between C2'-endo and C3'-endo deoxyribose puckers (sugar switching). The C2'-H2'/H2" dipolar couplings in B-form DNA are particularly sensitive to sugar pucker and yield the largest discrepancies when fit to a single structure. To resolve these discrepancies, we suggest a simplified dipolar coupling analysis that yields N/S equilibria for the ribose sugar puckers, which are in good agreement with previous analyses of NMR J(HH) couplings, with a population of the minor C3'-endo form higher for pyrimidines than for purines. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Wu, ZG (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 100 TC 109 Z9 111 U1 1 U2 16 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 2003 VL 26 IS 4 BP 297 EP 315 DI 10.1023/A:1024047103398 PG 19 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 686MA UT WOS:000183324500002 PM 12815257 ER PT J AU Ramakrishnan, B Qasba, PK AF Ramakrishnan, B Qasba, PK TI Comparison of the closed conformation of the beta 1,4-galactosyltransferase-1 (beta 4Gal-T1) in the presence and absence of alpha-lactalbumin (LA) SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article ID LACTOSE SYNTHETASE; CRYSTAL-STRUCTURE; N-ACETYLGLUCOSAMINE; CATALYTIC DOMAIN; GALACTOSYLTRANSFERASE; PROTEIN; BINDING; COMPLEX; MECHANISM; GLUCOSE AB beta1,4-Galactosyltransferase (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) in the presence of Mn2+ ion. However, in the presence of alpha-lactal-bumin (LA) it transfers Gal to glucose (Glc) instead to GlcNAc. Upon substrate binding, beta4Gal-T1 undergoes transition, from an open to a closed conformation. Although both the acceptor and donor substrates can induce the necessary conformational changes, the enzyme has been crystallized only in the closed conformation in the presence of its preferred donor, UDP-Gal. The closed conformation induced by the sugar acceptors or the less preferred donor substrates has been observed only when complexed with LA. The crystal structure of beta4Gal-T1 in the presence of UDP-Gal was previously determined at 2.8 Angstrom resolution. We report here the same structure at 2.3 Angstrom resolution, which provides a better description of this closed conformation. We have also further refined the structures of beta4Gal-T1.LA complexes containing the sugar acceptor and the less preferred sugar nucleotide donor substrates and compared the conformational. changes in the enzyme induced by substrates with and without LA. Based on the binding of UDP-sugar molecules, a rational hypothesis is proposed for the conformational changes induced by the donor substrate. C1 NCI, CCR, LECB, Struct Glycobiol Sect, Frederick, MD 21702 USA. NCI, CCR, LECB, SAIC Frederick Inc,Basic Res Program, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, CCR, LECB, Struct Glycobiol Sect, Bldg 469,Room 221, Frederick, MD 21702 USA. FU PHS HHS [N01-C0-12400] NR 27 TC 12 Z9 12 U1 0 U2 1 PU ADENINE PRESS INC PI GUILDERLAND PA PO BOX 355/340, GUILDERLAND, NY 12084 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD AUG PY 2003 VL 21 IS 1 BP 1 EP 8 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 712CF UT WOS:000184778200001 PM 12854954 ER PT J AU Chaplet, M De Leval, L Waltregny, D Detry, C Fornaciari, G Bevilacqua, G Fisher, LW Castronovo, V Bellahcene, A AF Chaplet, M De Leval, L Waltregny, D Detry, C Fornaciari, G Bevilacqua, G Fisher, LW Castronovo, V Bellahcene, A TI Dentin matrix protein 1 is expressed in human lung cancer SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE dentin matrix protein 1; bone metastasis; lung cancer ID BONE SIALOPROTEIN; BREAST-CANCER; OSTEOPONTIN EXPRESSION; METASTASES; PROSTATE; SEQUENCE AB We have previously shown that breast and prostate cancers express bone matrix proteins. DMPI expression was evaluated in 59 human lung cancer samples at the protein and mRNA levels. It was detectable in 80% of the cases, suggesting a potential role for DMP1 in tumor progression and bone metastasis. Introduction: Previously, we and others have shown that bone extracellular matrix proteins such as bone sialoprotein (BSP) and osteopontin (OPN) are expressed in various types of cancer that are characterized by a high affinity for bone including breast, prostate, and lung adenocarcinoma. Based on biochemical and genetic features, BSP, OPN, dentin matrix protein 1 (DMP1), and dentin sialophosphoprotein (DSPP) have been recently classified in a unique family named SIBLING (small integrin-binding ligand, N-linked glycoprotein). Therefore, we investigated whether DMPI could also be detected in osteotropic cancers. Materials and Methods: We first used a cancer array for evaluating the relative abundance of DMP1 transcript in a broad spectrum of human cancer tissues. This screening showed that DMP1 was strongly detectable in lung tumors compared with normal corresponding tissue. In a second step, we used an immunophosphatase technique and a specific polyclonal antibody directed against DMPI to examine the expression of DMP1 in 59 human non-small cell lung cancer samples, including 29 squamous carcinoma, 20 adenocarcinoma, and 10 bronchioloalveolar carcinoma. Student's t-test was used to determine the statistical significance of immunostaining scores between the lung cancer histological groups studied and between cancer and normal lung tissues. Results: Our results show that DMP1 is detectable in 90% of the adenocarcinoma and squamous carcinoma analyzed while 8 of 10 bronchioloalveolar specimens were negative. DMP1 immunostaining intensity and extent scores were significantly higher in adenocarcinoma (p = 0.0004) and squamous carcinoma (p < 0.0001) samples compared with adjacent normal lung tissue. In situ hybridization experiments confirmed that DMP1 mRNA is localized in lung cancer cells. Conclusion: In this study, we show that a third SIBLING protein is ectopically expressed in lung cancer. The role of DMPI in lung cancer is largely unknown. Further studies are required to determine the implication of this protein, next to its sisters SIBLING proteins, in tumor progression and bone metastasis development. C1 Univ Liege, Metastasis Res Lab, Liege, Belgium. Univ Liege, Dept Pathol, Ctr Expt Canc Res, Liege, Belgium. Univ Pisa, Dept Pathol, Pisa, Italy. NIDCR, Cranofacial & Skeletal Dis Branch, NIH, HHS, Bethesda, MD USA. RP Bellahcene, A (reprint author), CHU Sart Tilman, Tour Pathol B23, B-4000 Liege, Belgium. NR 21 TC 28 Z9 28 U1 1 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2003 VL 18 IS 8 BP 1506 EP 1512 DI 10.1359/jbmr.2003.18.8.1506 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 704CU UT WOS:000184320800014 PM 12929940 ER PT J AU Anderson, JL Krause-Steinrauf, H Goldman, S Clemson, BS Domanski, MJ Hager, WD Murray, DR Mann, DL Massie, BM McNamara, DM Oren, R Rogers, WJ AF Anderson, JL Krause-Steinrauf, H Goldman, S Clemson, BS Domanski, MJ Hager, WD Murray, DR Mann, DL Massie, BM McNamara, DM Oren, R Rogers, WJ CA Beta Blocker Evaluation Survival T TI Failure of benefit and early hazard of bucindolol for Class IV heart failure SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE beta-blocker; bucindolol; heart failure; survival ID IDIOPATHIC DILATED CARDIOMYOPATHY; ADRENERGIC-RECEPTOR BLOCKADE; INTRINSIC SYMPATHOMIMETIC ACTIVITY; CONGESTIVE CARDIOMYOPATHY; RANDOMIZED TRIAL; SURVIVAL TRIAL; BETA-BLOCKADE; DOUBLE-BLIND; MERIT-HF; METOPROLOL AB Objectives: The risks and benefits of beta-blockade with bucindolol were assessed in heart failure (HF) patients with Class IV symptoms within the Beta-blocker Evaluation of Survival Trial (BEST). Background: beta-blockade is accepted therapy for mild to moderate HF, but its safety and efficacy in advanced HF have not been established. Methods: BEST recruited 2708 HF patients; of these, 226 with Class IV symptoms (n = 114 randomized to bucindolol, n = 112 to placebo) formed the basis of this study. All-cause death, HF hospitalization, and drug discontinuations occurring early during therapy (less than or equal to6 months) and overall during follow-up were assessed. Compared with Class III, Class IV patients were older and had higher plasma norepinephrine levels, prevalence of coronary disease, S3 gallops, and lower ejection fractions, but characteristics of the 2 Class IV treatment groups were similar. Results: During a mean of 1.6 years, 49% Class IV patients died, and 54% were hospitalized for HE Bucindolol increased the combined endpoint of death or HE hospitalization within the first 6 months (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1-2.7) and did not result in benefit overall (HR = 1.2, 95% CI = 0.9-1.6). HF hospitalization alone within 6 months was increased by bucindolol (HR = 1.7), and an early adverse trend for death was seen (HR = 1.6) with no benefit overall (HR = 1.1). Bucindolol was discontinued more frequently than placebo for worsening HF (11% versus 4%) and hypotension (3% versus 0%). Conclusions: Class IV HF patients in BEST were at high risk. Bucindolol did not reduce death or HF hospitalization and was associated with early hazard. C1 Univ Utah, Latter Day St Hosp, Sch Med, Div Cardiol, Salt Lake City, UT 84143 USA. NHLBI, Bethesda, MD 20892 USA. Vet Adm Med Ctr, Tucson, AZ 85723 USA. Heart Care Midwest, Peoria, IL USA. Univ Connecticut, Farmington, CT USA. Vet Adm Med Ctr, San Antonio, TX USA. Baylor Coll Med, Houston, TX 77030 USA. Vet Adm Med Ctr, San Francisco, CA 94121 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Iowa, Iowa City, IA USA. Univ Alabama, Tuscaloosa, AL 35487 USA. RP Anderson, JL (reprint author), Univ Utah, Latter Day St Hosp, Sch Med, Div Cardiol, 8th Ave & C St, Salt Lake City, UT 84143 USA. OI Mann, Douglas /0000-0002-2516-0145 NR 29 TC 16 Z9 17 U1 1 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2003 VL 9 IS 4 BP 266 EP 277 DI 10.1054/jcaf.2003.42 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 715HP UT WOS:000184966000005 PM 13680547 ER PT J AU Takino, T Tamura, M Miyamori, H Araki, M Matsumoto, K Sato, H Yamada, KM AF Takino, T Tamura, M Miyamori, H Araki, M Matsumoto, K Sato, H Yamada, KM TI Tyrosine phosphorylation of the CrkII adaptor protein modulates cell migration SO JOURNAL OF CELL SCIENCE LA English DT Article DE CrkII; PTP1B; cell migration; tyrosine phosphorylation; phosphatase ID GROWTH-FACTOR RECEPTOR; TUMOR-SUPPRESSOR PTEN; FOCAL ADHESION KINASE; PHOSPHATASE 1B; INHIBITION; ACTIVATION; PATHWAY; JNK; BINDING; P130(CAS) AB CrkII belongs to a family of adaptor proteins that become tyrosine phosphorylated after various stimuli. We examined the role of CrkII tyrosine phosphorylation in fibronectin-induced cell migration. Overexpression of CrkII inhibited dephosphorylation of focal adhesion components such as p130 Crk-associated substrate (p130(cas)) and paxillin by protein tyrosine phosphatase 1B (PTP1B). Tyrosine-phosphorylated CrkII was dephosphorylated by PTP1B both in vitro and in vivo, showing for the first time that PTP1B directly dephosphorylates CAM A CrkII mutant in which tyrosine residue 221 was substituted by phenylalanine (CrkII-Y221F) could not be tyrosine phosphorylated, and it showed significantly increased binding to p130cas and paxillin. Enhanced binding of CrkII to p130(cas) has been reported to promote cell migration. Nonphosphorylated CrkII-Y221F promoted HT1080 cell migration on fibronectin, whereas wild-type CrkII did not at moderate expression levels. Moreover, co-expression of CrkII and PTP1B promoted HT1080 cell migration on fibronectin and retained tyrosine phosphorylation and binding of p130cas to CrkII, whereas paxillin tyrosine phosphorylation was reduced. These findings support the concepts that CrkII binding activity is regulated by tyrosine kinases and phosphatases, and that tyrosine phosphorylation of CrkII can downmodulate cell migration mediated by the focal adhesion kinase/p130(cas) pathway. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Kanazawa Univ, Dept Mol Oncol & Virol, Inst Canc Res, Kanazawa, Ishikawa 9200934, Japan. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RI TAKINO, Takahisa/D-8460-2015; SATO, Hiroshi/D-8454-2015; OI Yamada, Kenneth/0000-0003-1512-6805 NR 35 TC 43 Z9 45 U1 2 U2 9 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 AUG 1 PY 2003 VL 116 IS 15 BP 3145 EP 3155 DI 10.1242/jcs.00632 PG 11 WC Cell Biology SC Cell Biology GA 712TW UT WOS:000184814300012 PM 12799422 ER PT J AU Costin, GE Valencia, JC Vieira, WD Lamoreux, ML Hearing, VJ AF Costin, GE Valencia, JC Vieira, WD Lamoreux, ML Hearing, VJ TI Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4 SO JOURNAL OF CELL SCIENCE LA English DT Article DE OCA4; underwhite; trosinase; pigmentation; albinism ID HERMANSKY-PUDLAK-SYNDROME; MAMMALIAN TYROSINASE; MELANOMA-CELLS; ULTRASTRUCTURAL-LOCALIZATION; MELANOSOMAL PROTEINS; MOLECULAR-BASIS; GENE; PIGMENTATION; MUTANT; IDENTIFICATION AB Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 97 Z9 98 U1 0 U2 7 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 AUG 1 PY 2003 VL 116 IS 15 BP 3203 EP 3212 DI 10.1242/jcs.00598 PG 10 WC Cell Biology SC Cell Biology GA 712TW UT WOS:000184814300017 PM 12829739 ER PT J AU Foster, JA Bezin, L Groc, L Christopherson, PL Levine, RA AF Foster, JA Bezin, L Groc, L Christopherson, PL Levine, RA TI Kainic acid lesion-induced nigral neuronal death SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Article DE dopamine; kainic acid; Parkinson's disease; tyrosine hydroxylase ID PROGRAMMED CELL-DEATH; CENTRAL MONOAMINE NEURONS; GROWTH-FACTOR WITHDRAWAL; ACUTE NECROTIC INSULTS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; DOPAMINERGIC-NEURONS; OXIDATIVE STRESS; PC12 CELLS; TYROSINE-HYDROXYLASE AB Parkinson's disease (PD) is characterized by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta. We report a rat model that exhibits progressive death of nigral neurons following unilateral injection of kainic acid in the striatum. In situ end-labeling revealed significant numbers of dying nigral neurons ipsilateral to the lesion during the first 3 weeks following injection. An indication of the gradual nature of death was that similar small numbers of cells were detected at each time point. These early morphological markers of neuronal death led to a significant reduction (20%) at 5 months of tyrosine hydroxylase-positive neurons and total number of neurons in the ipsilateral substantia nigra compared with the contralateral control. To examine the role of nigrostriatal DA metabolism in the observed nigral neuronal death, we manipulated DA metabolism during the initial 2 weeks following kainic acid lesion. Neurons in the ventral tier of the substantia nigra pars compacta were protected from death by treatment with 2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydrolase, the initial enzyme in the synthesis of the tyrosine hydroxylase co-substrate, tetrahydrobiopterin (BH4). Neurons in both the dorsal and ventral tier of substantia nigra pars compacta were protected from death by treatment with DAHP and L-DOPA. These experiments suggest that intrastriatal kainic acid lesion is an in vivo model of trophic support withdrawal. This experimental procedure is useful for studying mechanisms underlying protracted death of nigral DA neurons and may provide valuable mechanistic information relevant to understanding the etiology of PD. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Henry Ford Hlth Syst, William T Gossett Neurol Labs, Detroit, MI 48202 USA. CNRS, UMR5542, Lab Mol Neuropharmacol, Lyon, France. Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI USA. Wayne State Univ, Dept Pharmaceut Sci, Detroit, MI USA. John D Dingle Vet Adm Med Ctr, Detroit, MI USA. RP Foster, JA (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Rm 2D-15,36 Convent Dr, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS39132] NR 65 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD AUG PY 2003 VL 26 IS 1 BP 65 EP 73 DI 10.1016/S0891-0618(03)00040-1 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 723DA UT WOS:000185416100005 PM 12954531 ER PT J AU Bunt, JC Salbe, AD Tschop, MH Delparigi, A Daychild, P Tataranni, PA AF Bunt, JC Salbe, AD Tschop, MH Delparigi, A Daychild, P Tataranni, PA TI Cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with anthropometric measures in Pima Indian children SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID STIMULATES INSULIN-SECRETION; GROWTH-HORMONE DEFICIENCY; ASSESSING RISK-FACTORS; PRADER-WILLI-SYNDROME; GH-RELEASING HORMONE; CIRCULATING GHRELIN; FOOD-INTAKE; ENERGY-BALANCE; HUMAN OBESITY; WEIGHT-GAIN AB Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat ( by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 +/- 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (beta = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. German Inst Human Nutr, Dept Hlth & Human Serv, D-14558 Bergholz Rehbrucke, Germany. RP Bunt, JC (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 541-A, Phoenix, AZ 85016 USA. EM jbunt@mail.nih.gov RI Tschoep, Matthias/I-5443-2014; OI Tschoep, Matthias/0000-0002-4744-371X NR 51 TC 29 Z9 31 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2003 VL 88 IS 8 BP 3756 EP 3761 DI 10.1210/jc.2003-030227 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 711HH UT WOS:000184733200047 PM 12915665 ER PT J AU Lonergan, M Aponso, D Marvin, KW Helliwell, RJA Sato, TA Mitchell, MD Chaiwaropongsa, T Romero, R Keelan, JA AF Lonergan, M Aponso, D Marvin, KW Helliwell, RJA Sato, TA Mitchell, MD Chaiwaropongsa, T Romero, R Keelan, JA TI Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, and the soluble receptor osteoprotegerin in human gestational membranes and amniotic fluid during pregnancy and labor at term and preterm SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN FETAL MEMBRANES; NF-KAPPA-B; BACTERIAL LIPOPOLYSACCHARIDE; MEDIATED APOPTOSIS; PREMATURE RUPTURE; CELL-DEATH; EXPRESSION; TISSUES; GLUCOCORTICOIDS; ACTIVATION AB We have studied TNF-related apoptosis-inducing ligand (TRAIL) and its membrane-bound (R1-R4) and soluble receptors [ osteoprotegerin (OPG)] in gestational membranes to assess their significance in preterm parturition and premature rupture of membranes ( PROM). TRAIL was detected by ELISA in extracts of term choriodecidual ( but not amnion) tissues and explant-conditioned media. Concentrations of OPG ( determined using ELISA) in gestational membranes were 20- to 50-fold greater than those of TRAIL. Median OPG concentrations in amniotic fluid (AF) at 15 - 17 wk gestation were similar to those at term before and during labor, whereas levels in pregnancies sampled preterm were significantly elevated. OPG levels in AF from women with preterm PROM were similar to those from women in preterm labor. In contrast, in pooled AF samples ( n = 23 - 33), TRAIL concentrations at term with and without labor were elevated compared with samples from preterm deliveries. TRAIL-R3 and - R4 decoy receptors were detected in term amnion and choriodecidual extracts by immunoblotting and were localized by immunohistochemistry to amnion epithelial cells and chorionic trophoblasts. TRAIL ( 100 ng/ml) had little or no effect on amnion or choriodecidual cell viability or apoptosis, although these tissues responded to TNF-alpha with increased prostaglandin E(2) production. Our findings suggest that OPG is abundant in gestational membranes and, in concert with TRAIL decoy receptors, may protect resident cells of the fetal membranes against the proapoptotic effects of TRAIL and other related ligands during pregnancy. C1 Univ Auckland, Fac Med & Hlth Sci, Liggins Inst, Auckland 1, New Zealand. Univ Auckland, Fac Med & Hlth Sci, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Keelan, JA (reprint author), Univ Auckland, Fac Med & Hlth Sci, Liggins Inst, 2-6 Pk Ave, Auckland 1, New Zealand. EM j.keelan@auckland.ac.nz RI Mitchell, Murray/A-8639-2010; Keelan, Jeffrey/G-2170-2011 OI Mitchell, Murray/0000-0002-6167-7176; Keelan, Jeffrey/0000-0002-5403-6266 NR 40 TC 32 Z9 39 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2003 VL 88 IS 8 BP 3835 EP 3844 DI 10.1210/jc.2002-021905 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 711HH UT WOS:000184733200059 PM 12915677 ER PT J AU Bourdeau, I Lacroix, A Schurch, W Caron, P Antakly, T Stratakis, CA AF Bourdeau, I Lacroix, A Schurch, W Caron, P Antakly, T Stratakis, CA TI Primary Pigmented nodular adrenocortical disease: Paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADRENAL CUSHINGS-SYNDROME; INHIBITORY POLYPEPTIDE RECEPTOR; MEMBRANE HORMONE-RECEPTORS; CARNEY COMPLEX; PRKAR1A GENE; REGULATORY SUBUNIT; CELLS; MUTATIONS; PROTEIN; CORTEX AB Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent adrenal Cushing's syndrome ( CS), which is often associated with Carney complex (CNC). We have recently described a paradoxical increase in cortisol excretion after dexamethasone administration in most patients with PPNAD. In the present study we investigated the hypothesis that this phenomenon is due to a primary abnormality of the tissues affected by PPNAD, rather than a defect of the patients' hypothalamic-pituitary-adrenal axis; as such it should be replicated in vitro by adrenal slices exposed directly to dexamethasone. We were able to study adrenal tissues from eight patients with CS caused by PPNAD; two patients were also studied in vivo according to a protocol first described in ACTH-independent macronodular adrenal hyperplasia (AIMAH) for the clinical detection of aberrant hormone receptor expression. Their DNA has been previously screened for inactivating mutations of the PRKAR1A gene, the most frequent molecular defect leading to PPNAD and/or CNC. We also investigated whether glucocorticoid receptor (GR) expression underlies paradoxical dexamethasone responses in PPNAD by immunohistochemistry and semiquantitative PCR, and we correlated GR expression with that of other markers for PPNAD (e.g. synaptophysin). Indeed, we demonstrated that dexamethasone induced cortisol secretion in vitro in five of these tumors; no such increase was seen in adenomatous or AIMAH tissues that were treated in the same manner. GR mRNA was expressed, and GR immunoreactivity was detected in PPNAD nodular cells. Staining for GR was not seen in surrounding cortical cells, and hence, it correlated with synaptophysin, which also stains PPNAD in a similar manner. In normal adrenal tissue, GR was detected mostly in medullary areas, whereas GR immunoreactivity was weak in adenomatous and AIMAH tissues. We conclude that 1) dexamethasone produces an increase in glucocorticoid synthesis by PPNAD adrenal slices in vitro, suggesting a direct effect on adrenocortical tissue, and 2) this phenomenon is accompanied by increased expression of the GR in PPNAD nodules. PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena. C1 NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Montreal, Ctr Hosp, Hotel Dieu, Div Endocrinol & Pathol, Montreal, PQ H2W 1T7, Canada. Univ Montreal, Dept Biochem, Montreal, PQ H2W 1T7, Canada. CHU Rangueil, Dept Endocrinol, F-31403 Toulouse, France. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Levesque, Isabelle/A-1899-2012 NR 36 TC 48 Z9 53 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2003 VL 88 IS 8 BP 3931 EP 3937 DI 10.1210/jc.2002-022001 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 711HH UT WOS:000184733200071 PM 12915689 ER PT J AU Heller, T Hoofnagle, JH AF Heller, T Hoofnagle, JH TI Denying the wolf access to sheep's clothing SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID HEPATITIS-DELTA-VIRUS; ANTIGEN; PRENYLATION; EXPRESSION; RNA AB Hepatitis delta virus (HDV) is a cause of acute and chronic liver disease for which no effective therapy is currently available. Previous research has demonstrated that prenylation of the large HDV antigen is essential for viral assembly. A new report (see the related article beginning on page 407) describes a novel small animal model for HDV replication and demonstrates that prenylation inhibitors are highly effective at clearing viremia and thus have potential relevance for the treatment of chronic delta hepatitis. C1 NIDDKD, Liver Dis Sect, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDKD, Liver Dis Sect, Liver Dis Res Branch, NIH, Bldg 31,Room 9A27, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2003 VL 112 IS 3 BP 319 EP 321 DI 10.1172/JCI200319417 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 708LQ UT WOS:000184569100004 PM 12897197 ER PT J AU Nong, ZX Gonzalez-Navarro, H Amar, M Freeman, L Knapper, C Neufeld, EB Paigen, BJ Hoyt, RF Fruchart-Najib, J Santamarina-Fojo, S AF Nong, ZX Gonzalez-Navarro, H Amar, M Freeman, L Knapper, C Neufeld, EB Paigen, BJ Hoyt, RF Fruchart-Najib, J Santamarina-Fojo, S TI Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; BONE-MARROW-TRANSPLANTATION; FOAM CELL-FORMATION; CORONARY-ARTERY DISEASE; IN-VIVO EVIDENCE; APOLIPOPROTEIN-E; SYNERGISTICALLY ENHANCE; PROMOTER POLYMORPHISM; HDL2 CHOLESTEROL; BUOYANT LDL AB Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO X HL-KO mice, as well as LCAT-Tg and LCAT-Tg X HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. Inst Pasteur, Dept Atherosclerose, F-59019 Lille, France. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Room 7N115, Bethesda, MD 20892 USA. NR 60 TC 40 Z9 41 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2003 VL 112 IS 3 BP 367 EP 378 DI 10.1172/JCI200316484 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 708LQ UT WOS:000184569100012 PM 12897204 ER PT J AU Seidman, MM Glazer, PM AF Seidman, MM Glazer, PM TI The potential for gene repair via triple helix formation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID DOUBLE-STRANDED DNA; FORMING-OLIGONUCLEOTIDES; MAMMALIAN-CELLS; BASE-PAIRS; TARGETED MUTAGENESIS; PHYSIOLOGICAL PH; 3RD STRAND; 2'-AMINOETHOXY-MODIFIED OLIGONUCLEOTIDES; HOMOLOGOUS RECOMBINATION; SELECTIVE RECOGNITION AB Triplex-forming oligonucleotides (TFOs) can bind to polypurine/polypyrimidine regions in DNA in a sequence-specific manner. The specificity of this binding raises the possibility of using triplex formation for directed genome modification, with the ultimate goal of repairing genetic defects in human cells. Several studies have demonstrated that treatment of mammalian cells with TFOs can provoke DNA repair and recombination, in a manner that can be exploited to introduce desired sequence changes. This review will summarize recent advances in this field while also highlighting major obstacles that remain to be overcome before the application of triplex technology to therapeutic gene repair can be achieved. C1 Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. Natl Inst Aging, NIH, Baltimore, MD USA. RP Glazer, PM (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, POB 208040, New Haven, CT 06520 USA. FU NCI NIH HHS [CA64186, R01 CA064186]; NIGMS NIH HHS [GM54731, R01 GM054731] NR 102 TC 115 Z9 118 U1 1 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2003 VL 112 IS 4 BP 487 EP 494 DI 10.1172/JCI200319552 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 713BB UT WOS:000184833900006 PM 12925687 ER PT J AU Adkins, HB Bianco, C Schiffer, SG Rayhorn, P Zafari, M Cheung, AE Orozco, O Olson, D De Luca, A Chen, LL Miatkowski, K Benjamin, C Normanno, N Williams, KP Jarpe, M LePage, D Salomon, D Sanicola, M AF Adkins, HB Bianco, C Schiffer, SG Rayhorn, P Zafari, M Cheung, AE Orozco, O Olson, D De Luca, A Chen, LL Miatkowski, K Benjamin, C Normanno, N Williams, KP Jarpe, M LePage, D Salomon, D Sanicola, M TI Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MAMMARY EPITHELIAL-CELLS; HUMAN BREAST CARCINOMAS; FACTOR-BETA; THERAPEUTIC TARGET; ACTIVIN RECEPTOR; TYROSINE KINASE; CANCER CELLS; EXPRESSION; PROTEINS; FRINGE AB Cripto, a cell surface-associated protein belonging to the EGF-CFC family of growth factor-like molecules, is overexpressed in many human solid tumors, including 70-80% of breast and colon tumors, yet how it promotes cell transformation is unclear. During embryogenesis, Cripto complexes with Alk4 via its unique cysteine-rich CFC domain to facilitate signaling by the TGF-beta ligand Nodal. We report, for the first time to our knowledge, that Cripto can directly bind to another TGF-beta ligand, Activin B, and that Cripto overexpression blocks Activin B growth inhibition of breast cancer cells. This result suggests a novel mechanism for antagonizing Activin signaling that could promote tumorigenesis by deregulating growth homeostasis. We show that an anti-CFC domain antibody, A8.G3.5, both disrupts Cripto-Nodal signaling and reverses Cripto blockade of Activin B induced growth suppression by blocking Cripto's association with either Alk4 or Activin B. In two xenograft models, testicular and colon cancer, A8.G3.5 inhibited tumor cell growth by up to 70%. Both Nodal and Activin B expression was found in the xenograft tumor, suggesting that either ligand could be promoting tumorigenesis. These data validate that functional blockade of Cripto inhibits tumor growth and highlight antibodies that block Cripto signaling mediated through its CFC domain as an important class of antibodies for further therapeutic development. C1 Biogen Inc, Cambridge, MA 02142 USA. Natl Canc Inst, Bethesda, MD USA. Ist Nazl Studio & Cura Tumori, Naples, Italy. RP Sanicola, M (reprint author), Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA. RI De Luca, Antonella/J-8737-2016; OI De Luca, Antonella/0000-0001-5762-447X; Normanno, Nicola/0000-0002-7158-2605 NR 49 TC 122 Z9 126 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2003 VL 112 IS 4 BP 575 EP 587 DI 10.1172/JCI200317788 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 713BB UT WOS:000184833900017 PM 12925698 ER PT J AU Norris, AW Chen, LH Fisher, SJ Szanto, I Ristow, M Jozsi, AC Hirshman, MF Rosen, ED Goodyear, LJ Gonzalez, FJ Spiegelman, BM Kahn, CR AF Norris, AW Chen, LH Fisher, SJ Szanto, I Ristow, M Jozsi, AC Hirshman, MF Rosen, ED Goodyear, LJ Gonzalez, FJ Spiegelman, BM Kahn, CR TI Muscle-specific PPAR gamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DEPENDENT DIABETES-MELLITUS; HUMAN SKELETAL-MUSCLE; GENE-EXPRESSION; RECEPTOR-ALPHA; ANTIDIABETIC THIAZOLIDINEDIONE; ADIPOCYTE DIFFERENTIATION; TROGLITAZONE ACTION; LIPID-METABOLISM; GLUCOSE; OBESITY AB Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. it remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/laxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle. C1 Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Beth Israel Med Ctr, Boston, MA USA. Natl Canc Inst, Mol Carcinogenesis Lab, NIH, Bethesda, MD USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. RI Ristow, Michael/O-9858-2014 OI Ristow, Michael/0000-0003-2109-2453 FU NIDDK NIH HHS [R37 DK031036, DK31036, DK45935, P30 DK036836, R01 DK031036, R01 DK045935, T32 DK063702, T32-DK63702-01] NR 65 TC 265 Z9 273 U1 1 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2003 VL 112 IS 4 BP 608 EP 618 DI 10.1172/JCI200317305 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 713BB UT WOS:000184833900020 PM 12925701 ER PT J AU Omura, GA Brady, MF Look, KY Averette, HE Delmore, JE Long, HJ Wadler, S Spiegel, G Arbuck, SG AF Omura, GA Brady, MF Look, KY Averette, HE Delmore, JE Long, HJ Wadler, S Spiegel, G Arbuck, SG TI Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: An intergroup study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; RANDOMIZED TRIAL; BREAST-CANCER; CHEMOTHERAPY; MULTICENTER; MOBILIZATION; CISPLATIN; INFUSION; LONG AB Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m(2), 175 mg/m(2), or 250 mg/m(2) over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m(2) were also randomly assigned to 5 or 10 mug/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135 -mg/m(2) arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m(2) (36%) was significantly higher than on 175 mg/m(2) (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m(2) and 250 mg/m(2), respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m(2) (p < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m(2) was 19% and 18% on the 5-μg/kg and 10-μg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m(2) without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m(2) plus filgrastim. Doubling the filgrastim dose from 5 to 10 μg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel. C1 Univ Alabama, Birmingham, AL USA. Roswell Pk Canc Inst, Gynecol Oncol Grp, Buffalo, NY 14263 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Univ Miami, Sch Med, Jackson Mem Med Ctr, Div Gynecol Oncol, Miami, FL USA. Univ Kansas, Sch Med, Wichita, KS 67214 USA. Mayo Clin & Mayo Fdn, Mayo Med Sch, Rochester, MN 55905 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Omura, GA (reprint author), Gynecol Oncol Grp, Adm Off, 1600 John F Kennedy Blvd,Suite 1020, Philadelphia, PA 19103 USA. FU NCI NIH HHS [CA 37517, CA27469] NR 17 TC 62 Z9 64 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2003 VL 21 IS 15 BP 2843 EP 2848 DI 10.1200/JCO.2003.10.082 PG 6 WC Oncology SC Oncology GA 706PJ UT WOS:000184461800006 PM 12807937 ER PT J AU Leonard, GD Hegde, U Butman, J Jaffe, ES Wilson, WH AF Leonard, GD Hegde, U Butman, J Jaffe, ES Wilson, WH TI Uncommon presentations of malignancies - Case 1. Extraocular muscle palsies in subcutaneous panniculitis-like T-cell lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article C1 NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. RP Leonard, GD (reprint author), NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 6 TC 2 Z9 2 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 AUG 1 PY 2003 VL 21 IS 15 BP 2993 EP 2995 DI 10.1200/JCO.2003.07.104 PG 3 WC Oncology SC Oncology GA 706PJ UT WOS:000184461800027 PM 12885820 ER PT J AU Kearns, GL Andersson, T James, LP Gaedigk, A Kraynak, RA Abdel-Rahman, SM Ramabadran, K van den Anker, JN AF Kearns, GL Andersson, T James, LP Gaedigk, A Kraynak, RA Abdel-Rahman, SM Ramabadran, K van den Anker, JN CA Pediat Pharmacology Res Unit Netwo TI Omeprazole disposition in children following single-dose administration SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT 102nd Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 06-10, 2001 CL ORLANDO, FLORIDA SP Amer Soc Clin Pharmacol & Therapeut DE omeprazole; pediatrics; gastroesophageal reflux; pharmacokinetics; CYP2C19 genotype ID PROTON PUMP INHIBITORS; CYP2C19 GENOTYPE; INTRAGASTRIC PH; INTRAVENOUS OMEPRAZOLE; S-MEPHENYTOIN; PHARMACOKINETICS; POLYMORPHISM; METABOLISM; PHARMACOGENETICS; PANTOPRAZOLE AB Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR-RFLP Data were available from 37 patients (19 female), 10 of whom were less than or equal to 5 years of age. No drug-associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n = 25), 1 (n = 11), and 0 (n = 1). Pharmacokinetic parameters (mean +/- SD, range) were as follows: t(max) (2.1 +/- 1.2,1-6 h), C-max (331.1 +/- 333.6,20.8-885.8 ng/mL), AUC(0-->infinity) (809.5 +/- 893.8, 236.9-1330.9 ng/mL.h), t(1/2) (0.98 +/- 0.22, 0.7-1.4h), and CL/F(1.8 +/- 1.4,0.3-5.8 L/h/kg). Comparison of mean AUC(0-->infinity) values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CLIF and apparent elimination rate constant (lambda(z))for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CLIF t(1/2), or lambda(z) was observed. The range of t(1/2) values for omeprazole was similar to those reported in adults (1-1.5h). Conclusions: (1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole. C1 Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp & Clin, Div Pediat Clin Pharmacol & Med Toxicol, Kansas City, MO USA. AstraZeneca LP, Wayne, PA USA. Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. Arkansas Childrens Hosp, Div Pediat Clin Pharmacol & Toxicol, Little Rock, AR 72202 USA. Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. Columbus Childrens Hosp, Div Pediat Clin Pharmacol & Toxicol, Columbus, OH USA. Natl Inst Hlth & Human Dev, Bethesda, MD USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. RP Kearns, GL (reprint author), Childrens Mercy Hosp & Clin, Div Pediat Pharmacol & Med Toxicol, 2401 Gillham Rd, Kansas City, MO 64108 USA. FU NICHD NIH HHS [1 U01 HD31313-08] NR 27 TC 26 Z9 30 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD AUG PY 2003 VL 43 IS 8 BP 840 EP 848 DI 10.1177/0091270003256122 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 703MA UT WOS:000184282100005 PM 12953341 ER PT J AU Baldessarini, RJ Hennen, J Wilson, M Calabrese, J Chengappa, R Keck, PE McElroy, SL Sachs, G Vieta, E Welge, JA Yatham, LN Zarate, CA Baker, RW Tohen, M AF Baldessarini, RJ Hennen, J Wilson, M Calabrese, J Chengappa, R Keck, PE McElroy, SL Sachs, G Vieta, E Welge, JA Yatham, LN Zarate, CA Baker, RW Tohen, M TI Olanzapine versus placebo in acute mania - Treatment responses in subgroups SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID BIPOLAR DISORDER; MAINTENANCE TREATMENT; PSYCHOTIC FEATURES; SCALE; EPISODES AB Two double-blind, placebo-controlled trials of olanzapine in acute mania showed significant overall antimanic efficacy, based on reductions in mania ratings. Their subject-level data were pooled to increase statistical power to test for differences in treatment responses among 10 subgroup pairs of interest using generalized estimating equations methods. Similar drug/placebo superiority and responsiveness to olanzapine was found in men versus women, psychotic versus nonpsychotic subjects, and those presenting in mania versus mixed states, and responses were independent of onset age, current age, or prior illness based on episodes, hospitalizations, recent rapid cycling, lifetime substance use, or previous antipsychotic treatment. Olanzapine and placebo responses paralleled closely (r(s) = 0.73). Patients were relatively more responsive to olanzapine who were younger at illness onset, lacked prior substance abuse, and had not previously received antipsychotic treatment (efficacy ratios 1.5-1.7, all P < 0.01). These well-powered comparisons of subgroups of interest indicate broad efficacy of olanzapine in the treatment of acute mania. C1 Harvard Univ, Sch Med, Dept Psychiat, Int Consortium Bipolar Diorder Res, Boston, MA USA. Harvard Univ, Sch Med, Neurosci Program, Int Consortium Bipolar Diorder Res, Boston, MA USA. Massachusetts Gen Hosp, McLean Div, Bipolar & Psychot Disorders Program, Belmont, MA USA. Butler Univ, Dept Pharm & Hlth Sci, Indianapolis, IN 46208 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst, Dept Psychiat, Pittsburgh, PA USA. Univ Cincinnati, Dept Psychiat, Cincinnati, OH USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. Univ Barcelona, Hosp Clin Barcelona, August Pi Sunyer Biomed Res Inst IDIBAPS, Barcelona, Spain. Univ British Columbia, Coll Med, Dept Psychiat, Vancouver, BC V5Z 1M9, Canada. NIMH, Bethesda, MD 20892 USA. Lilly Res Labs, Indianapolis, IN USA. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr, 115 Mill St, Belmont, MA 02478 USA. RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 NR 23 TC 47 Z9 50 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2003 VL 23 IS 4 BP 370 EP 376 DI 10.1097/01.jcp.0000085410.08426.9a PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 708ET UT WOS:000184554700009 PM 12920413 ER PT J AU Zaragoza, C Barrera, R Centeno, F Tapia, JA Mane, MC AF Zaragoza, C Barrera, R Centeno, F Tapia, JA Mane, MC TI Characterization of renal damage in canine leptospirosis by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting of the urinary proteins SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article DE bacterial infection; dog; leptospirosis; nephritis; urinary proteins ID DOGS; DISEASE; INFECTION AB Canine leptospirosis is a zoonotic disease that can cause interstitial nephritis. As a consequence of the renal damage, proteinuria may occur. To determine the urine protein pattern in the disease we performed sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) on the urine from 10 dogs with leptospirosis and 20 healthy dogs. Western blotting analysis of the urine samples with antibodies against canine IgG and IgA was also performed to identify these immunoglobulins in the urine. Urine electrophoresis showed three new bands in the dogs suffering from leptospirosis. Only two of the dogs with leptospirosis showed detectable concentrations of IgG and IgA in urine, while a third animal showed IgG alone. The study showed a 36.7% increase in the excretion of low molecular weight proteins in dogs with leptospirosis but almost no change in the high molecular weight protein pattern. These results, together with the low number of animal with detectable concentrations of IgG and IgA in the urine, support the view that canine leptospirosis is characterized by interstitial nephritis. (C) 2003 Elsevier Ltd. All rights reserved. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD USA. Univ Extremadura, Dept Med & Sanidad Anim, Caceres 10004, Spain. Univ Extremadura, Fac Vet, Dept Bioquim & Biol Mol & Genet, Caceres 10004, Spain. RP Zaragoza, C (reprint author), Fac Vet, Unidad Patol Med, Avda Univ S-N, Caceres 10071, Spain. RI Centeno, Francisco/F-7287-2016; Tapia, Jose/C-5181-2008 OI Tapia, Jose/0000-0002-3614-6867 NR 40 TC 18 Z9 19 U1 1 U2 9 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD AUG-OCT PY 2003 VL 129 IS 2-3 BP 169 EP 178 DI 10.1016/S0021-9975(03)00029-X PG 10 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 716UB UT WOS:000185046600010 PM 12921723 ER PT J AU Walis, A Bratosiewicz, J Sikorska, B Brown, P Gajdusek, DC Liberski, PP AF Walis, A Bratosiewicz, J Sikorska, B Brown, P Gajdusek, DC Liberski, PP TI Ultrastructural changes in the optic nerves of rodents with experimental Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS) or scrapie SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article DE CJD; GSS disease; hamster; man; mouse; optic nerve; prion disease; scrapie; sheep; TSE ID NECROSIS-FACTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; RETINAL DEGENERATION; PRION-PROTEIN; SPONGIFORM ENCEPHALOPATHIES; INTRAOCULAR INOCULATION; PANENCEPHALOPATHIC TYPE; HAMSTERS; MICE; AGENT AB This report describes the ultrastructural changes in the optic nerves of (1) hamsters infected with the Echigo-1 strain of Creutzfeldt-jakob disease (CJD), (2) hamsters infected with the 263K or 22GH strain of scrapie, and (3) mice infected with the Fujisaki strain of Gerstmann-Straussler-Scheinker disease (GSS). Vacuolation of myelinated fibres was present in the myelin sheaths, with splitting of myelin lamellae. These vacuoles contained typical secondary vacuoles and curled membrane fragments. Myelinated fibre vacuolation was also accompanied by an exuberant cellular reaction consisting of macrophages containing numerous mitochondria, abundant rough endoplasmic reticulum, and secondary lysosomes filled with digested myelin debris and other electron-dense material. Within macrophages, myelin fragments undergoing active digestion, lyre-like bodies and paracrystalline inclusions were frequently noted. Astrocytes and their processes were prominent; glial filaments and many mitochondria were readily detected. Proliferation of inner mesaxons was observed. Cross-sectional profiles of innumerable myelinated fibres contained membranous organelles continuous with the inner lamellae of the oligodendroglial cells. The proliferations of inner mesaxons formed whorls and loops, and intrusion of the membranous tongue of the inner mesaxon into the axoplasm was occasionally observed; dystrophic neurites were relatively numerous. In mice infected with the Fujisaki strain of GSS, fibres had undergone demyelination with stripping of the myelin lamellae, while others showed vesicular myelin degeneration. (C) 2003 Elsevier Ltd. All rights reserved. C1 Med Univ Lodz, Chair Oncol, Dept Mol Pathol, PL-92216 Lodz, Poland. Med Univ Lodz, Chair Oncol, Dept Neuropathol, PL-92216 Lodz, Poland. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD USA. Med Univ Silesia, Katowice, Poland. RP Liberski, PP (reprint author), Med Univ Lodz, Chair Oncol, Dept Mol Pathol & Neuropathol, Czechoslowacka St 8-10, PL-92216 Lodz, Poland. NR 56 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD AUG-OCT PY 2003 VL 129 IS 2-3 BP 213 EP 225 DI 10.1016/S0021-9975(03)00037-9 PG 13 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 716UB UT WOS:000185046600015 PM 12921728 ER PT J AU Arnold, LE Elliott, M Sachs, L Bird, H Kraemer, HC Wells, KC Abikoff, HB Comarda, A Conners, CK Elliott, GR Greenhill, LL Hechtman, L Hinshaw, SP Hoza, B Jensen, PS March, JS Newcorn, JH Pelham, WE Severe, JB Swanson, JM Vitiello, B Wigal, T AF Arnold, LE Elliott, M Sachs, L Bird, H Kraemer, HC Wells, KC Abikoff, HB Comarda, A Conners, CK Elliott, GR Greenhill, LL Hechtman, L Hinshaw, SP Hoza, B Jensen, PS March, JS Newcorn, JH Pelham, WE Severe, JB Swanson, JM Vitiello, B Wigal, T TI Effects of ethnicity on treatment attendance, stimulant response/dose, and 14-month outcome in ADHD SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; DOPAMINE TRANSPORTER GENE; MULTIMODAL TREATMENT; TREATMENT STRATEGIES; AFRICAN-AMERICAN; CHILDREN; MTA; COMORBIDITY; BEHAVIOR AB From the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder-a randomized clinical trial of 579 children ages 7-9 years receiving 14 months of medication management, behavioral treatment, combination, or community care-the authors matched each African American and Latino participant with randomly selected Caucasian participants of same sex, treatment group, and site. Although Caucasian children were significantly less symptomatic than African American and Latino children on some ratings, response to treatment did not differ significantly by ethnicity after controlling for public assistance. Ethnic minority families cooperated with and benefited significantly from combination (multimodal) treatment (d = 0.36, compared with medication). This incremental gain withstood statistical control for mother's education, sing-le-parent status, and public assistance. Treatment for lower socioeconomic status minority children, especially if comorbid, should combine medication and behavioral treatment. C1 Ohio State Univ, Columbus, OH 43210 USA. Stanford Univ, Stanford, CA 94305 USA. NYU, Sch Med, New York, NY USA. Duke Univ, Ctr Med, Durham, NC 27706 USA. Columbia Univ, New York, NY 10027 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. NIMH, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. McGill Univ, Montreal, PQ H3A 2T5, Canada. Purdue Univ, W Lafayette, IN 47907 USA. SUNY Coll Buffalo, Buffalo, NY 14222 USA. Univ Calif Irvine, Irvine, CA USA. RP Arnold, LE (reprint author), 479 S Galena Rd, Sunbury, OH 43074 USA. OI Jensen, Peter/0000-0003-2387-0650; Newcorn, Jeffrey /0000-0001-8993-9337 FU NIMH NIH HHS [MH50467, U01 MH50440, U01 MH50447, U01 MH50453, U01 MH50454, U01 MH50461, U01 MH50467, U01-MH50453, U01-MH50461] NR 44 TC 70 Z9 70 U1 4 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2003 VL 71 IS 4 BP 713 EP 727 DI 10.1037/0022-006X.71.4.713 PG 15 WC Psychology, Clinical SC Psychology GA 703QM UT WOS:000184292500010 PM 12924677 ER PT J AU Stein, MT Dickstein, DP Pine, DS AF Stein, MT Dickstein, DP Pine, DS TI Anxiety and labile hypertension in a 16-year-old male: The value of biopsychosocial medicine SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Editorial Material DE pheochromocytoma; adolescent anxiety; biopsychosocial ID PRACTICE PARAMETERS; DISORDERS; ADOLESCENTS; CHILDREN; RISK C1 Univ Calif San Diego, San Diego, CA 92103 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NIMH, Sect Dev Affect Neurosci, Bethesda, MD 20892 USA. RP Stein, MT (reprint author), Univ Calif San Diego, San Diego, CA 92103 USA. OI Dickstein, Daniel/0000-0003-1647-5329 NR 14 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD AUG PY 2003 VL 24 IS 4 BP 301 EP 305 PG 5 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 712CB UT WOS:000184777800015 PM 12915802 ER PT J AU Uwaifo, GL Koch, CA Hirshberg, B Chen, CC Hartzband, P Nieman, LK Pacak, K AF Uwaifo, GL Koch, CA Hirshberg, B Chen, CC Hartzband, P Nieman, LK Pacak, K TI Is there a therapeutic role for octreotide in patients with ectopic Cushing's syndrome? SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Article DE somatostatin analogs; ectopic ACTH syndrome; somatostatin receptors; radionuclide imaging; neuroenclocrine tumors ID SOMATOSTATIN RECEPTOR SUBTYPES; BRONCHIAL CARCINOID-TUMOR; CORTICOTROPIN-RELEASING HORMONE; ACTH-PRODUCING TUMORS; ANALOGS; LOCALIZATION; SCINTIGRAPHY; SECRETION; DIAGNOSIS; FAILURE AB Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS) has a high morbidity and mortality, because of the underlying tumor and the sequelae of severe hypercortisolemia. Therefore, rapid treatment of ectopic CS is mandatory. Scintigraphy shows that up to 80% of ectopic ACTH-producing tumors have somatostatin receptors. While this suggests that somatostatin analogs may reduce ACTH-production and treat patients with EAS, the therapeutic role of these agents is still evolving. Here we demonstrate the spectrum of responses to octreotide therapy in 3 patients with EAS. Diagnostic imaging with the In-111-pentetreoticle scan did not predict the therapeutic response to octreotide. Two patients with positive somato-statin receptor scintigraphy failed to respond to octreotide, while one with a negative scan reached eucortisolemia on a maintenance dose of 75 mug octreotide twice daily or octreotide LAR 30 mg per month. We conclude that octreotide is not a first line agent to control hypercortisolemia but may be a useful agent when other inhibitors of steroidogenesis fail or parenteral administration is required. Before therapy an octreotide challenge test may predict therapeutic response. Cortisol levels should be monitored regularly on somatostatin analog therapy, because of its unpredictable long-term pharmacodynamic profile. (C) 2003, Editrice Kurtis. C1 NIDDK, Autoimmun & Transplantat Branch, Bethesda, MD USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol, Boston, MA 02215 USA. RP Pacak, K (reprint author), NICHD, Dev Endocrinol Branch, Unit Clin Neuroendocrinol, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; Uwaifo, Gabriel/M-2361-2016; OI Koch, Christian/0000-0003-3127-5739; Uwaifo, Gabriel/0000-0002-6962-9304; Koch, Christian/0000-0003-0678-1242 NR 45 TC 18 Z9 19 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD AUG PY 2003 VL 26 IS 8 BP 710 EP 717 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 741ZE UT WOS:000186489600005 PM 14669823 ER PT J AU Yen, PM Cheng, SY AF Yen, PM Cheng, SY TI Germline and somatic thyroid hormone receptor mutations in man SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE thyroid hormone receptor; resistance to thyroid hormone; somatic mutation; thyrotropin ID DOMINANT-NEGATIVE ACTIVITY; SECRETING PITUITARY-TUMOR; RUBINSTEIN-TAYBI-SYNDROME; HEPATOCELLULAR-CARCINOMA; ESTROGEN-RECEPTOR; BETA GENE; IN-VIVO; RESPONSIVE PROMOTERS; RESISTANCE SYNDROME; NUCLEAR RECEPTORS AB Thyroid hormone plays important roles in metabolism, growth, and differentiation. Germline mutations in thyroid hormone receptor beta (TRbeta) have been identified in many individuals with resistance to thyroid hormone (RTH), a syndrome of hyposensitivity to T-3. However, it has become increasingly apparent that somatic mutations can also occur in individual tissues, and are associated with tumors and malignancies in man. Herein we review the occurrence and identification of germline and somatic TR mutations and characterization of their pathological effects on hormone resistance and tumorigenesis. (C) 2003, Editrice Kurtis. C1 NCI, Ctr Canc Res, Gene Regulat Sect, Mol Biol Lab,NIH, Bethesda, MD 20892 USA. RP Yen, PM (reprint author), NIDDK, Clin Endocrinol Branch, Mol Regulat & Neuroendocrinol Sect, NIH, Bethesda, MD 20892 USA. NR 59 TC 13 Z9 14 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD AUG PY 2003 VL 26 IS 8 BP 780 EP 787 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 741ZE UT WOS:000186489600019 PM 14669837 ER PT J AU Parascandola, M AF Parascandola, M TI Hazardous effects of tobacco industry funding SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, 6130 Execut Blvd,Suite 3109, Bethesda, MD 20892 USA. NR 8 TC 6 Z9 6 U1 1 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD AUG PY 2003 VL 57 IS 8 BP 548 EP 549 DI 10.1136/jech.57.8.548 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 705AL UT WOS:000184374000002 PM 12883047 ER PT J AU Anlauf, M Eissele, R Schafer, MKH Eiden, LE Arnold, R Pauser, U Kloppel, G Weihe, E AF Anlauf, M Eissele, R Schafer, MKH Eiden, LE Arnold, R Pauser, U Kloppel, G Weihe, E TI Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE vesicular monoamine transporter; EC cell; pancreatic islet; insulin; giucagon; somatostatin; pancreatic polypeptide; neuroendocrine tumor ID FUNCTIONING HUMAN INSULINOMAS; AMINO-ACID DECARBOXYLASE; GUINEA-PIG; IMMUNOHISTOCHEMICAL ANALYSIS; DIFFERENTIAL EXPRESSION; TYROSINE-HYDROXYLASE; CELLS; SECRETION; ISLETS; RAT AB The uptake of monoamines into the secretory granules of monoamine-storing neuroendocrine cells is mediated by vesicular monoamine transporter protein 1 or 2 (VMAT1 or VMAT2). This study analyzed the expression of VMAT1 and VMAT2 in endocrine cells of normal human and monkey pancreas. The expression of VMAT1 and VMAT2 was also examined in infants with hyperinsulinemic hypoglycemia and in adults with pancreatic endocrine tumors (PETs). Using immunohistochemistry (IHC) and in situ hybridization (ISH), we demonstrated the mutually exclusive expression of VMAT1 in endocrine cells of the duct system and of VMAT2 in many cells of the islets of Langerhans. By confocal laser scanning microscopy, VMAT1-positive cells were identified as enterochromaffin (EC) cells and VMAT2-positive cells as beta-cells. In PETs, VMAT1 was found exclusively in all serotonin-containing tumors. In contrast, VMAT2 expression was lost in many insulinomas, independent of their biological behavior. VMAT2 was expressed by some non-insulin-producing tumors. The mutually exclusive expression of VMAT1 in EC cells and of VMAT2 in beta-cells suggests that both cell types store monoamines. Monoamine storage mediated by VMAT1 in EC cells is apparently maintained in EC cell tumors. In contrast, many insulinomas appear to lose their ability to accumulate monoamines via VMAT2. C1 Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-350337 Marburg, Germany. Univ Marburg, Dept Gastroenterol & Endocrinol, D-350337 Marburg, Germany. NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. Univ Kiel, Dept Pathol, D-2300 Kiel, Germany. RP Weihe, E (reprint author), Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Robert Koch Str 6, D-350337 Marburg, Germany. OI Eiden, Lee/0000-0001-7524-944X NR 50 TC 67 Z9 67 U1 0 U2 5 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD AUG PY 2003 VL 51 IS 8 BP 1027 EP 1040 PG 14 WC Cell Biology SC Cell Biology GA 705HW UT WOS:000184390500006 PM 12871984 ER PT J AU Calarota, SA Otero, M Hermanstayne, K Lewis, M Rosati, M Felber, BK Pavlakis, GN Boyer, JD Weiner, DB AF Calarota, SA Otero, M Hermanstayne, K Lewis, M Rosati, M Felber, BK Pavlakis, GN Boyer, JD Weiner, DB TI Use of interleukin 15 to enhance interferon-gamma production by antigen-specific stimulated lymphocytes from rhesus macaques SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE IL-15; interferon-gamma; ELISPOT; rhesus macaques ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; IMMUNE-RESPONSES; ANTIRETROVIRAL THERAPY; CD8(+) LYMPHOCYTES; FLOW-CYTOMETRY; CELL RESPONSES; IL-15; PEPTIDE; EFFECTOR AB The enzyme-linked immune spot (ELISPOT) assay is receiving increased attention as a means for quantifying antigen-specific CD8 T-cell responses in rhesus macaques. Further improving the sensitivity of this assay could aid in the evaluation of vaccine candidates and/or immune therapeutic candidates. Interleukin (IL)-15 has been demonstrated to stimulate expansion of human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) and to regulate homeostatic proliferation of CD8+ memory cells. We evaluated the in vitro effect of IL-15 to increase the detection of interferon-gamma (IFN-gamma) production by antigen-specific stimulated lymphocytes from a group of rhesus macaques exposed to simian-human immunodeficiency virus (SHIV) and a second group infected with SIVmac251, before and after antiretroviral treatment (ART). Results from these studies demonstrate that the presence of IL-15 during stimulation in a peptide-based ELISPOT assay greatly enhanced IFN-gamma production in both SHIV and simian immunodeficiency virus (SIV)-infected macaques. IFN-gamma production was mainly mediated by CD8 lymphocytes. The optimal concentrations of IL-15 that give enhancement of IFN-gamma production to specific antigen, without a significant increase in the spontaneous IFN-gamma release, ranged from 0.5 to 2.5 ng/ml. The mean number of IFN-gamma spots was increased 3.1- to 3.6-fold in response to SIV gag or HIV env peptide pools, respectively, in peripheral blood mononuclear cells (PBMC) from SHIV-infected macaques. Similarly, in SIV-infected macaques, IL-15 increased the mean number of IFN-gamma spots 2.7-fold in response to both SIV gag and env peptide pools. In samples obtained after ART in the same macaques, the increase factor was 2.5 for SIV gag and 1.8 for the env peptide pools. Thus, the sensitivity of the ELISPOT assay can be enhanced by addition of IL-15. This modified assay will be useful for detection of low frequencies of IFN-gamma producing cells in rhesus macaques. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. So Res Inst, Frederick, MD 21791 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 21702 USA. RP Weiner, DB (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 422 Curie Blvd,505 Stellar Chance Bldg, Philadelphia, PA 19104 USA. RI Weiner, David/H-8579-2014; Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X FU NIAID NIH HHS [P01-AI-48241, P01-AI-05397] NR 31 TC 18 Z9 18 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2003 VL 279 IS 1-2 BP 55 EP 67 DI 10.1016/S0022-1759(03)00246-1 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 722ND UT WOS:000185381300005 PM 12969547 ER PT J AU Bettinotti, MP Hadzikadic, L Ruppe, E Dhillon, G Stroncek, DS Marincola, FM AF Bettinotti, MP Hadzikadic, L Ruppe, E Dhillon, G Stroncek, DS Marincola, FM TI New HLA-A, -B, and -C locus-specific primers for PCR amplification from cDNA: application in clinical immunology SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE human leukocyte antigen; complementary deoxyribonucleic acid; polymerase chain reaction ID MELANOMA; ALLELE AB The individual cellular immune response to intracellular antigens is modeled by the highly polymorphic major histocompatibility complex (HLA) class I molecules. The epitopes presented and the T cell repertoire that recognizes them depend on the HLA constitution of the individual. Therefore, to monitor and to modify an individual's HLA class I-driven cellular immune response, it is necessary to know the HLA class I alleles of the person and the possible epitopes of the target antigen presented by those alleles. In particular, this is necessary in order to design peptide-based vaccines and immune therapies for the treatment of diseases caused by viruses, intracellular parasites or cancer, and to monitor the immune response during those treatments. We describe a new set of HLA-A, -B, and -C locus-specific primers for the polymerase chain reaction (PCR) amplification of the whole coding sequence of these genes from complementary DNA (cDNA). We describe their use for typing and for the production of a library of recombinant HLA class I genes. We discuss two downstream applications of this gene collection: production of soluble HLA molecules and discovery of new epitopes. Crown Copyright (C) 2003 Published by Elsevier B.V. All rights reserved. C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Bettinotti, MP (reprint author), NIH, Ctr Clin, Dept Transfus Med, 10 Ctr Dr,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. NR 12 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2003 VL 279 IS 1-2 BP 143 EP 148 DI 10.1016/S0022-1759(03)00233-3 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 722ND UT WOS:000185381300013 PM 12969555 ER PT J AU Arlen, PM Gulley, JL Palena, C Marshall, J Schlom, J Tsang, KY AF Arlen, PM Gulley, JL Palena, C Marshall, J Schlom, J Tsang, KY TI A novel ELISPOT assay to enhance detection of antigen-specific T cells employing antigen-presenting cells expressing vector-driven human B7-1 SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE ELISPOT; immunoassay; T cells; costimulation; antigen-presenting cells; pox vectors ID RECOMBINANT VACCINIA VIRUS; COSTIMULATORY MOLECULES; CARCINOEMBRYONIC ANTIGEN; DENDRITIC CELLS; PROSTATE-CANCER; PHASE-I; IMMUNE-RESPONSES; EFFECTOR-CELLS; ACTIVATION; PEPTIDE AB The ELISPOT assay is used to detect T-cell responses in patients enrolled in vaccine clinical trials; it is a relatively sensitive assay that can be performed without in vitro stimulation (IVS) of PBMC. However, this assay may be limited in some cases because of a weak signal 1 (as is the case for tumor-associated antigens [TAA]), or by a limited number of PBMC available from patients. The objective of this study is to enhance the sensitivity of the ELISPOT by increasing the level of signal 2, in this case, B7-1 expression on antigen-presenting cells (APC), allowing for a more sensitive detection of antigen-specific T-cell precursors. C1RA2 cells were used as APC and were uninfected, or infected with either recombinant avipox (fowlpox)-B7-1 (rF-B7-1) or control fowlpox wild-type (FP-WT) vector. The expressions of B7-1, MHC Class II, as well as HLA-A2 on the infected cells were analyzed by flow cytometry. A nearly threefold increase in B7-1 mean fluorescence intensity (MFI) occurred in the rF-B7-1-infected C1RA2 cells with no changes in MHC Class II or HLA-A2 expression. Various PBMC/APC ratios were used to further analyze the use of rF-B7-1-infected C1RA2 cells as APC in the ELISPOT assay. Fewer APC were required to activate PBMC when C1RA2 infected with rF-B7-1 were used as APC. Furthermore, using a PBMC/APC ratio of 1:1, similar detection was achieved using fewer PBMC. In addition, we demonstrated that the reactivity can be blocked by adding anti-B7-1 antibody. We performed the assay using APC on five normal healthy donors. All five donors showed substantial increases in PF to the Flu matrix peptide (Flu peptide) using the rF-B7-1-infected C1RA2 cells. Finally, we evaluated five cancer patients who received a carcinoembryonic antigen (CEA) vaccine-based therapy. Increases in CEA peptide precursors were noted in all five patients using the B7-1-infected APC. In conclusion, we have demonstrated the ability to enhance the sensitivity of the ELISPOT assay through infection of C1RA2 with rF-B7-1. (C) Published by Elsevier Science B.V. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 31 TC 4 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2003 VL 279 IS 1-2 BP 183 EP 192 DI 10.1016/S0022-1759(03)00185-6 PG 10 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 722ND UT WOS:000185381300017 PM 12969559 ER PT J AU Berhanu, D Mortari, F De Rosa, SC Roederer, M AF Berhanu, D Mortari, F De Rosa, SC Roederer, M TI Optimized lymphocyte isolation methods for analysis of chemokine receptor expression SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE chemokine receptors; Ficoll; flow cytometry; human; memory and naive T cells; PBMC; T lymphocytes; whole blood; immunophenotyping; cell isolation ID T-CELLS; HIV-1 INFECTION; CC-CHEMOKINE; CORECEPTORS; DISEASES; SUBSETS; TROPISM; MEMORY; CXCR4 AB Manipulations typically used to isolate enriched lymphocyte populations from peripheral blood can impact on the measured levels of chemokine receptors. Optimum sensitivity and accurate discrimination of receptor-expressing cell subsets therefore requires cell isolation methods that minimally affect expression levels. We used flow cytometry to examine the effects of different protocols for processing and staining T lymphocytes on chemokine receptor expression. Our results confine that FACS analysis of some chemokine receptors is compromised after standard methods (such as Ficoll density separation). While the optimal method was typically to stain cells prior to lysing whole blood, this may not be practical in many experimental conditions. In general, we found that staining cells at 37C following Ficoll separation yielded excellent results. However, the precise method used will depend on which receptor is being measured. We used the optimal methods to compare the expression of chemokine receptors on naive and memory T-cell subsets using 8-color flow cytometry. Published by Elsevier B.V. C1 NIAID, ImmunoTechnol Sect, Immunol Lab, Vaccine Res Ctr,NIH, Bethesda, MD 20892 USA. R&D Syst Inc, Minneapolis, MN USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Immunol Lab, Vaccine Res Ctr,NIH, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 12 TC 33 Z9 34 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2003 VL 279 IS 1-2 BP 199 EP 207 DI 10.1016/S0022-1759(03)00186-8 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 722ND UT WOS:000185381300019 PM 12969561 ER PT J AU Bafica, A Scanga, CA Schito, ML Hieny, S Sher, A AF Bafica, A Scanga, CA Schito, ML Hieny, S Sher, A TI Cutting edge: In vivo induction of integrated HIV-1 expression by mycobacteria is critically dependent on toll-like receptor 2 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LONG TERMINAL REPEAT; TRANSGENIC MICE; IMMUNE ACTIVATION; TUBERCULOSIS; INFECTION; CELLS; REPLICATION; MACROPHAGES; RECOGNITION; RESISTANCE AB Mycobacterial infection has been implicated as a possible factor in AIDS progression in populations where HIV-1 and Mycobacterium tuberculosis are coendemic. In support of this concept, we have previously shown that HIV1-transgenic (Tg) mice infected with mycohacteria display enhanced viral gene and protein expression. In this study, we demonstrate that the induction of HIV-1 observed in this model is dependent on Toll-like receptor 2 (TLR2), a pattern recognition receptor known to be involved in mycobacteria-host interaction. Spleen cells from HIV-1-Tg mice deficient in TLR2 (Tg/TLR2(-/-)) were found to be completely defective in p24 production induced in response to live A tuberculosis or Mycobacterium avium as well as certain mycobacterial products. Importantly, following in vivo mycobacterial infection, Tg/TLR2(-/-) mice failed to display the enhanced HIV-1 gag/env mRNA and p24 protein synthesis exhibited by wild-type Tg animals. Together, these results argue that TLR2 plays a crucial role in the activation of HIV-1 expression by mycobacterial coinfections. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Chem Immunol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bafica, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6143,50 South Dr, Bethesda, MD 20892 USA. NR 28 TC 38 Z9 38 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 AUG 1 PY 2003 VL 171 IS 3 BP 1123 EP 1127 PG 5 WC Immunology SC Immunology GA 704FG UT WOS:000184327600001 PM 12874196 ER PT J AU Singh, UP Singh, S Taub, DD Lillard, JW AF Singh, UP Singh, S Taub, DD Lillard, JW TI Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10(-/-) mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CD4(+) T-CELLS; NECROSIS-FACTOR-ALPHA; CHEMOKINE RECEPTORS; CROHNS-DISEASE; INTERLEUKIN-10-DEFICIENT MICE; HUMAN NEUTROPHILS; INTERFERON-GAMMA; TRANSFER MODEL; MURINE MODELS AB A deficiency in understanding the steps responsible for colitis is the lack of comprehension for the role chemokines play in mucosal inflammation. IFN-gamma-inducible protein-10 (IP-10) and CXCR3 are highly expressed at sites of colitis. Our findings show that IP-10 significantly contributes to the development of Th1 and inflammatory responses. Specifically, IP-10 inhibition in IL-10(-/-) mice attenuates the associated increases in serum and/or local amyloid A, IL-2, IL-6, TNF-alpha, IFN-gamma, IL-1alpha, and IL-1beta with colitis as compared with IL-10(-/-) mice that develop colitis similar to human Crohn's disease. Correspondingly, the rate or intensity of inflammation in IL-10(-/-) mice treated with anti-IP-10 Abs showed improved scoring of inflammation, compared with control IL-10(-/-) mice. This study provides important and novel information regarding IP-10 as a target for the treatment of colitis. C1 Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. Morehouse Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30310 USA. NIA, Immunol Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Lillard, JW (reprint author), Morehouse Sch Med, Dept Microbiol Biochem & Immunol, 720 Westview Dr, Atlanta, GA 30310 USA. FU NCRR NIH HHS [RR03034]; NIDDK NIH HHS [DK58967] NR 47 TC 81 Z9 84 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2003 VL 171 IS 3 BP 1401 EP 1406 PG 6 WC Immunology SC Immunology GA 704FG UT WOS:000184327600036 PM 12874231 ER PT J AU Huang, LY Aliberti, J Leifer, CA Segal, DM Sher, A Golenbock, DT Golding, B AF Huang, LY Aliberti, J Leifer, CA Segal, DM Sher, A Golenbock, DT Golding, B TI Heat-killed Brucella abortus induces TNF and IL-12p40 by distinct MyD88-dependent pathways: TNF, unlike IL-12p40 secretion, is toll-like receptor 2 dependent SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INNATE IMMUNE-SYSTEM; CELL WALL COMPONENTS; CUTTING EDGE; SIGNAL-TRANSDUCTION; BACTERIAL-DNA; PATTERN-RECOGNITION; DENDRITIC CELLS; T-CELLS; LIPOPOLYSACCHARIDE; MICE AB Cattle and humans are susceptible to infection with the Gram-negative intracellular bacterium Brucella abortus. Heat-killed B. abortus (HKBA) is a strong Th1 adjuvant and carrier. Previously, we have demonstrated that dendritic cells produce IL-12 in response to HKBA stimulation. In the present study, we use knockout mice and in vitro reconstitution assays to examine the contribution of signaling by Toll-like receptors (TLRs) and their immediate downstream signaling initiator, myeloid differentiation protein MyD88, in the activation following stimulation by HKBA. Our results show that HKBA-mediated induction of IL-12p40 and TNF is dependent on the adapter molecule MyD88. To identify the TLR involved in HKBA recognition, we examined HKBA responses in TLR2- and TLR4-deficient animals. TNF responses to HKBA were TLR4 independent; however, the response in TLR2-deficient mice was significantly delayed and reduced, although not completely abolished. Studies using Chinese hamster ovary/CD14 reporter cell lines stably transfected with either human TLR2 or human TLR4 confirmed the results seen with knockout mice, namely TLR2, but not TLR4, can mediate cellular activation by HKBA. In addition, human embryonic kidney 293 cells, which do not respond to HKBA, were made responsive by transfecting TLR2, but not TLR4 or TLR9. Taken together, our data demonstrate that MyD88-dependent pathways are crucial for activation by HKBA and that TLR2 plays a role in TNF, but not IL-12p40 pathways activated by this microbial product. C1 US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Plasma Derivat, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. RP Golding, B (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Plasma Derivat, Bldg 29,Room 328,8800 Rockville Pike HFM-345, Bethesda, MD 20892 USA. RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 47 TC 50 Z9 52 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 AUG 1 PY 2003 VL 171 IS 3 BP 1441 EP 1446 PG 6 WC Immunology SC Immunology GA 704FG UT WOS:000184327600041 PM 12874236 ER PT J AU Odaka, C Mizuochi, T Yang, JX Ding, A AF Odaka, C Mizuochi, T Yang, JX Ding, A TI Murine macrophages produce secretory leukocyte protease inhibitor during clearance of apoptotic cells: Implications for resolution of the inflammatory response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD3/T-CELL RECEPTOR COMPLEX; BACTERIAL LIPOPOLYSACCHARIDE; MATRIX METALLOPROTEINASES; IMMATURE THYMOCYTES; DNA FRAGMENTATION; POTENT INHIBITOR; IN-VITRO; BETA; RECOGNITION; PHAGOCYTOSIS AB Macrophage-derived secretory leukocyte protease inhibitor (SLPI) can be induced locally as well as systemically in response to microbial products such as LPS and lipotechoic acid. It is not known whether phagocytosis of apoptotic cells, an essential function of macrophages, can regulate expression and secretion of SLPI. In this study, we report that exposure of peritoneal macrophages of BALB/c mice or murine macrophage cell lines RAW264.7 and J774.1 to apoptotic target cells induced an elevation in SLPI secretion. Secreted SLPI retained its antichymotrypsin activity. SLPI expression in thymuses from BALB/c mice that had been injected with anti-CD3 Ab to induce apoptosis of thymocytes was also elevated both at the mRNA and protein levels. Colchicine, a microtubular inhibitor, blocked the internalization of apoptotic cells by macrophages but not SLPI secretion, suggesting that surface recognition of apoptotic cells is sufficient for the induction of SLPI. Exposure of RAW264.7 cells to apoptotic CTLL-2 cells induced both SLPI and TNF-alpha, and addition of IFN-gamma inhibited SLPI but augmented TNF-alpha production. Transfection of either the secreted or a nonsecreted form of SLPI into RAW264.7 cells led to suppression of TNF-a production in response to apoptotic cells. Thus, macrophages secrete an increased amount of SLPI when encountering apoptotic cells, which may help to attenuate potential inflammation during clearance of these cells. C1 NIAID, Dept Safety Res Blood & Biol Prod, Shinjuku Ku, Tokyo 1628640, Japan. Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. RP Odaka, C (reprint author), NIAID, Dept Safety Res Blood & Biol Prod, Shinjuku Ku, 1-23-1 Toyama, Tokyo 1628640, Japan. RI Yang, Jingxuan/K-5047-2015 OI Yang, Jingxuan/0000-0003-3265-161X FU NIAID NIH HHS [AI30165]; NIGMS NIH HHS [GM61710] NR 52 TC 60 Z9 66 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 AUG 1 PY 2003 VL 171 IS 3 BP 1507 EP 1514 PG 8 WC Immunology SC Immunology GA 704FG UT WOS:000184327600049 PM 12874244 ER PT J AU Lippert, E Yowe, DL Gonzalo, JA Justice, JP Webster, JM Fedyk, ER Hodge, M Miller, C Gutierrez-Ramos, JC Borrego, F Keane-Myers, A Druey, KM AF Lippert, E Yowe, DL Gonzalo, JA Justice, JP Webster, JM Fedyk, ER Hodge, M Miller, C Gutierrez-Ramos, JC Borrego, F Keane-Myers, A Druey, KM TI Role of regulator of G protein signaling 16 in inflammation-induced T lymphocyte migration and activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL DIFFERENTIATION; IMMUNE-RESPONSES; IN-VIVO; AIRWAY HYPERRESPONSIVENESS; TRANSENDOTHELIAL MIGRATION; LUNG INFLAMMATION; ALLERGIC-ASTHMA; RGS PROTEINS; CHEMOKINES; EXPRESSION AB Chemokine-induced T lymphocyte recruitment to the lung is critical for allergic inflammation, but chemokine signaling pathways are incompletely understood. Regulator of G protein signaling (RGS)16, a GTPase accelerator (GTPase-activating protein) for Galpha subunits, attenuates signaling by chemokine receptors in T lymphocytes, suggesting a role in the regulation of lymphocyte trafficking. To explore the role of RGS16 in T lymphocyte-dependent immune responses in a whole-organism model, we generated transgenic (Tg) mice expressing.RGS16 in CD4+ and CD8+ cells. rgs16 Tg T lymphocytes migrated to CC chemokine ligand 21 or CC chemokine ligand 12 injection sites in the peritoneum, but not to CXC chemokine ligand 12. In a Th2-dependent model of allergic pulmonary inflammation, CD4(+) lymphocytes bearing CCR3, CCR5, and CXCR4 trafficked in reduced numbers to the lung after acute inhalation challenge with allergen (OVA). In contrast, spleens of sensitized and challenged Tg mice contained increased numbers of CD4(+)CCR3(+) cells producing more Th2-type cytokines (IL-4, IL-5, and IL-13), which were associated with increased airway hyperreactivity. Migration of Tg lymphocytes to the lung parenchyma after adoptive transfer was significantly reduced compared with wild-type lymphocytes. Naive lymphocytes displayed normal CCR3 and CXCR4 expression and cytokine responses, and compartmentation in secondary lymphoid organs was normal without allergen challenge. These results suggest that RGS16 may regulate T lymphocyte activation in response to inflammatory stimuli and migration induced by CXCR4, CCR3, and CCR5, but not CCR2 or CCR7. C1 NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. NIAID, Allerg Inflammat Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. Millennium Pharmaceut, Cambridge, MA 02139 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 59 TC 44 Z9 45 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 AUG 1 PY 2003 VL 171 IS 3 BP 1542 EP 1555 PG 14 WC Immunology SC Immunology GA 704FG UT WOS:000184327600053 PM 12874248 ER PT J AU Ma, X Reich, RA Wright, JA Tooker, HR Teeter, LD Musser, JM Graviss, EA AF Ma, X Reich, RA Wright, JA Tooker, HR Teeter, LD Musser, JM Graviss, EA TI Association between interleukin-8 gene alleles and human susceptibility to tuberculosis disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID NEUTROPHIL CHEMOTACTIC FACTOR; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; POLYMORPHONUCLEAR NEUTROPHILS; LINKAGE DISEQUILIBRIUM; ACTIVE TUBERCULOSIS; INFECTED MONOCYTES; RECEPTOR-A; KAPPA-B; EXPRESSION AB Interleukin (IL)-8 is involved in the pathogenesis of human tuberculosis (TB). However, the contribution of polymorphisms of the IL-8 gene and its receptor genes CXCR-1 and CXCR-2 to human TB susceptibility remains untested. In a case-control study, white subjects with TB disease were more likely to be homozygous for the IL-8 -251A allele, compared with control subjects (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.52-7.64). African Americans with TB also showed an increased odds of being homozygous for this allele (OR, 3.46; 95% CI, 1.48-8.08). To exclude population artifacts in the case-control study, a separate analysis that used a transmission-disequilibrium test with 76 informative families confirmed that the IL-8 -251A allele was preferentially transmitted to TB-infected children (P = .02). CXCR-1 and CXCR-2 did not demonstrate significant associations with TB susceptibility. These data suggest that IL-8 is important in the genetic control of human TB susceptibility. C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Graviss, EA (reprint author), Baylor Coll Med, Dept Pathol 209E, 1 Baylor Plaza, Houston, TX 77030 USA. FU NIAID NIH HHS [AI-41168]; PHS HHS [N01-A0-02738] NR 44 TC 48 Z9 50 U1 0 U2 4 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 AUG 1 PY 2003 VL 188 IS 3 BP 349 EP 355 DI 10.1086/376559 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 704BB UT WOS:000184316900002 PM 12870115 ER PT J AU Dybul, M Nies-Kraske, E Daucher, M Hertogs, K Hallahan, CW Csako, G Yoder, C Ehler, L Sklar, PA Belson, M Hidalgo, B Metcalf, JA Davey, RT Kress, DMR Powers, A Fauci, AS AF Dybul, M Nies-Kraske, E Daucher, M Hertogs, K Hallahan, CW Csako, G Yoder, C Ehler, L Sklar, PA Belson, M Hidalgo, B Metcalf, JA Davey, RT Kress, DMR Powers, A Fauci, AS TI Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: Effects on drug toxicity and on immunologic and virologic parameters SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHRONIC HIV-1 INFECTION; PROTEASE INHIBITORS; RISK-FACTORS; TREATMENT INTERRUPTIONS; HIV/AIDS TREATMENT; BODY-COMPOSITION; LIPODYSTROPHY; INDIVIDUALS; HYPERLIPIDEMIA; HEPATOTOXICITY AB We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4(+) or CD8(+) T cell counts or the percentage of cells that were CD4(+)CD25(+), CD8(+)CD25(+), or CD4(+)DR(+), patients who received SIT had a significantly higher percentage of CD8(+)CD38(+) and CD8(+)DR(+) cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cycle SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. Tibotec Virco, Mechelen, Belgium. RP Dybul, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 7A-03, Bethesda, MD 20892 USA. NR 41 TC 69 Z9 71 U1 0 U2 4 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 AUG 1 PY 2003 VL 188 IS 3 BP 388 EP 396 DI 10.1086/376535 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 704BB UT WOS:000184316900007 PM 12870120 ER PT J AU Hill, SA Lloyd, PA McDonald, S Wykoff, J Derse, D AF Hill, SA Lloyd, PA McDonald, S Wykoff, J Derse, D TI Susceptibility of human T cell leukemia virus type I to nucleoside reverse transcriptase inhibitors SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HTLV-I; ZIDOVUDINE; TRANSMISSION; LAMIVUDINE; MYELOPATHY; VITRO; INFECTION; RESISTANT; LYMPHOMA; EFFICACY AB A single-cycle infection assay with recombinant viral vectors was developed to study human T cell leukemia virus type I (HTLV-I) replication and its inhibition by antiviral agents. The susceptibility of HTLV-I to 6 nucleoside reverse-transcriptase inhibitors was examined. HTLV-I replication was inhibited by tenofovir, abacavir, lamivudine, zalcitabine, stavudine, and zidovudine. C1 Natl Canc Inst, Basic Res Lab, Canc Res Ctr, Frederick, MD 21702 USA. Natl Canc Inst, Sci Applicat Int Corp, Frederick, MD USA. RP Derse, D (reprint author), Natl Canc Inst, Basic Res Lab, Canc Res Ctr, Frederick, MD 21702 USA. NR 18 TC 27 Z9 28 U1 0 U2 3 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 AUG 1 PY 2003 VL 188 IS 3 BP 424 EP 427 DI 10.1086/376531 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 704BB UT WOS:000184316900011 PM 12870124 ER PT J AU Mitre, E Thompson, RW Carvalho, EM Nutman, TB Neva, FA AF Mitre, E Thompson, RW Carvalho, EM Nutman, TB Neva, FA TI Majority of interferon-gamma-producing CD4(+) cells in patients infected with human T cell lymphotrophic virus do not express tax protein SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID BLOOD MONONUCLEAR-CELLS; STRONGYLOIDES-STERCORALIS; CARRIERS; LEPROSY AB The present study was conducted to determine whether interferon (IFN)-gamma production by CD4(+) cells in patients infected with human T cell lymphotropic virus (HTLV) is associated with expression of Tax, an HTLV type 1 (HTLV-1) transactivator. The frequency of IFN-gamma production from CD4(+) cells was greater in HTLV-1-infected patients (n = 21) than in uninfected (n = 3) and Strongyloides stercoralis-infected patients (n = 4), and greater in patients with HTLV-1 with detectable Tax than in patients with HTLV-1 with undetectable Tax. In the patients with HTLV-1 with detectable Tax, the majority of CD4(+) cells making IFN-gamma did not express Tax. C1 NIAID, OPDS, LPD, NIH, Bethesda, MD 20892 USA. NIAID, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. Univ Fed Bahia, Serv Imunol, Hosp Univ Prof Edgard Santos, Bahia Blanca, Argentina. RP Neva, FA (reprint author), NIAID, OPDS, LPD, NIH, 4 Ctr Dr,Rm 4-126, Bethesda, MD 20892 USA. NR 15 TC 3 Z9 3 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 AUG 1 PY 2003 VL 188 IS 3 BP 428 EP 432 DI 10.1086/376529 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 704BB UT WOS:000184316900012 PM 12870125 ER PT J AU Manischewitz, J King, LR Bleckwenn, NA Shiloach, J Taffs, R Merchlinsky, M Eller, N Mikolajczyk, MG Clanton, DJ Monath, T Weltzin, RA Scott, DE Golding, H AF Manischewitz, J King, LR Bleckwenn, NA Shiloach, J Taffs, R Merchlinsky, M Eller, N Mikolajczyk, MG Clanton, DJ Monath, T Weltzin, RA Scott, DE Golding, H TI Development of a novel vaccinia-neutralization assay based on reporter-gene expression SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SMALLPOX VACCINATION; VIRUS; COMPLICATIONS; RESPONSES AB In anticipation of large-scale smallpox vaccination, clinical trials of new vaccine candidates with improved safety profiles, and new vaccinia immune globulin (VIG) products, there is an immediate need to develop new assays to measure vaccinia-specific immune responses. The classical assay to measure vaccinia neutralization, the plaque-reduction neutralization test (PRNT), is slow, labor intensive, and difficult to validate and transfer. Here we describe the development of a novel vaccinia-neutralization assay based on the expression of a reporter gene, beta-galactosidase (beta-Gal). Using a previously constructed vaccinia-beta-Gal recombinant virus, vSC56, we developed a neutralization assay that is rapid, sensitive, and reproducible. The readout is automated. We show that the neutralizing titers, ID50, for several VIG products measured by our assay were similar to those obtained by PRNTs. A new Food and Drug Administration VIG standard was established for distribution to other laboratories. The new assay will serve as an important tool both for preclinical and clinical trials of new smallpox vaccines and for evaluation of therapeutic agents to treat vaccine-associated adverse reactions. C1 US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Div Emerging Transfus Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Dynport Vaccine Co, Frederick, MD USA. Acambis, Cambridge, MA USA. NIDDKD, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Golding, H (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, HFM-454,Bldg 29A,Rm 1A21,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 17 TC 51 Z9 51 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 AUG 1 PY 2003 VL 188 IS 3 BP 440 EP 448 DI 10.1086/376557 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 704BB UT WOS:000184316900014 PM 12870127 ER PT J AU Willis, PG Katoch-Rouse, R Horti, AG AF Willis, PG Katoch-Rouse, R Horti, AG TI Regioselective F-18 radiolabeling of AM694, a CB1 cannabinoid receptor ligand SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE positron emission tomography; radiotracer; cannabinoid; F-18; regioselective fluorination; AM694 ID FLUORINATION; ANTAGONIST AB [F-18]AM694, [1-(5-[F-18]fluoropentyl)-1H-indol-3-yl]-(2-indophenyl)methanone, 1b, a potential radiotracer for imaging of cerebral cannabinoid receptor (CBI), has been synthesized by no-carrier-added regioselective radiofluorination of the corresponding tosylate. [F-18]AM694 was obtained in 20% radiochemical yield (non-decay-corrected) with a specific activity of 14 500 mCi/mumol, a radiochemical purity of > 99%, and a chemical purity of 95.5%. Copyright (C) 2003 John Wiley Sons, Ltd. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Horti, AG (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM ahorti@intra.nida.nih.gov NR 12 TC 12 Z9 13 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD AUG PY 2003 VL 46 IS 9 BP 799 EP 804 DI 10.1002/jlcr.720 PG 6 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 716UL UT WOS:000185047600003 ER PT J AU Ding, KY Gronenborn, AM AF Ding, KY Gronenborn, AM TI Sensitivity-enhanced 2D IPAP, TROSY-anti-TROSY, and E.COSY experiments: alternatives for measuring dipolar N-15-H-1(N) couplings SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE residual dipolar couplings; IPAP; TROSY-anti-TROSY; E.COSY; sensitivity enhancement ID QUANTITATIVE J-CORRELATION; ACCURATE MEASUREMENT; NMR-SPECTROSCOPY; PROTEINS; PHASE; IMPROVEMENT; RELAXATION; HSQC AB Sensitivity-enhanced versions of the IPAP, TROSY-anti-TROSY, and E.COSY experiments for measuring one-bond N-15-H-1(N) couplings are presented. Together with the previously developed sensitivity-enhanced E.COSY-type HSQC experiment they comprise a suite of sensitivity-enhanced experiments that allows one to chose the optimal spectrum for accurate measurement of one-bond N-15-H-1(N) residual dipolar couplings in proteins. Since one-bond N-15-H-1(N) residual dipolar couplings play uniquely important roles in structural NMR, these additional methods provide further tools for improving structure determination of proteins and other biological macromolecules. Published by Elsevier Science (USA). C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 130, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 22 TC 37 Z9 38 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD AUG PY 2003 VL 163 IS 2 BP 208 EP 214 DI 10.1016/S1090-7807(03)00081-8 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 714YB UT WOS:000184941200002 PM 12914836 ER PT J AU Bomprezzi, R Kovanen, PE Martin, R AF Bomprezzi, R Kovanen, PE Martin, R TI New approaches to investigating heterogeneity in complex traits SO JOURNAL OF MEDICAL GENETICS LA English DT Review ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; MULTIPLE-SCLEROSIS PATIENTS; MONOZYGOTIC TWINS DISCORDANT; GENE-EXPRESSION PATTERNS; GENOME SCREEN; LINKAGE DISEQUILIBRIUM; LYMPHOCYTE APOPTOSIS; PARKINSONS-DISEASE; PERIPHERAL-BLOOD; INNATE IMMUNITY AB Great advances in the field of genetics have been made in the last few years. However, resolving the complexity that underlies the susceptibility to many polygenic human diseases remains a major challenge to researchers. The fast increase in availability of genetic data and the better understanding of the clinical and pathological heterogeneity of many autoimmune diseases such as multiple sclerosis, but also Parkinson's disease, Alzheimer's disease, and many more, have changed our views on their pathogenesis and diagnosis, and begins to influence clinical management. At the same time, more powerful methods that allow the analysis of large numbers of genes and proteins simultaneously open opportunities to examine their complex interactions. Using multiple sclerosis as a prototype, we review here how new methodologies such as gene expression profiling can be exploited to gain insight into complex trait diseases. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Bomprezzi, R (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Room 5150, Bethesda, MD 20892 USA. NR 95 TC 23 Z9 26 U1 0 U2 5 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD AUG PY 2003 VL 40 IS 8 BP 553 EP 559 DI 10.1136/jmg.40.8.553 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 711VH UT WOS:000184761400001 PM 12920061 ER PT J AU Berg, J Porteous, M Reinhardt, D Gallione, C Holloway, S Umasunthar, T Lux, A McKinnon, W Marchuk, D Guttmacher, A AF Berg, J Porteous, M Reinhardt, D Gallione, C Holloway, S Umasunthar, T Lux, A McKinnon, W Marchuk, D Guttmacher, A TI Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PULMONARY ARTERIOVENOUS-MALFORMATIONS; HUMAN ENDOTHELIAL-CELLS; GROWTH-FACTOR BETA-1; SMOOTH-MUSCLE CELLS; KINASE-1 GENE; I RECEPTOR; ACTIVIN; PROTEIN; TYPE-2; EXPRESSION AB Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectasis, epistaxis, gastrointestinal haemorrhage, and arteriovenous malformations in the lung and brain. Causative mutations for HHT have been identified in two genes, endoglin and ALK1, which encode proteins involved in serine-threonine kinase signalling in the endothelial cell. Methods: A number of people affected with HHT had completed a postal questionnaire as part of an international study to delineate the HHT phenotype. We identified questionnaires completed by subjects in whom we had identified a mutation in endoglin or ALK1. Further questionnaires were sent to families with known mutations. Data were only included from questionnaires returned by people known to carry disease causing mutations. Results: Questionnaires were completed by 83 subjects with known mutations. Of these, 49 had endoglin mutations (HHT1) and 34 had ALK1 mutations (HHT2). Subjects with HHT1 reported an earlier onset of epistaxis (p=0.01) and telangiectasis (p=0.0001) than those with HHT2. Pulmonary arteriovenous malformations were only reported in the endoglin mutation group in our study (p<0.001). Conclusions: Our questionnaire based study provides evidence that the HHT phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). This has significant implications for diagnosis, screening, and treatment in the two different forms of HHT, as well as for understanding the pathogenesis of the disease. C1 Univ London Kings Coll, Dept Med & Mol Genet, GKT Sch Med, London SE1 9RT, England. Univ Dundee, Ninewells Hosp & Med Sch, Dept Mol & Cellular Pathol, Dundee DD1 9SY, Scotland. Western Gen Hosp, SE Scotland Reg Genet Serv, Mol Med Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. Duke Univ, Med Ctr, Dept Genet, Durham, NC 27710 USA. Univ Mannheim, Univ Clin, Heidelberg, Germany. Univ Appl Sci, D-69163 Mannheim, Germany. Univ Vermont, Vermont Reg Genet Ctr, Coll Med, Burlington, VT 05401 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Berg, J (reprint author), Univ London Kings Coll, Dept Med & Mol Genet, GKT Sch Med, 8th Floor,Guys Tower, London SE1 9RT, England. FU NHLBI NIH HHS [HL49171] NR 41 TC 83 Z9 93 U1 0 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD AUG PY 2003 VL 40 IS 8 BP 585 EP 590 DI 10.1136/jmg.40.8.585 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 711VH UT WOS:000184761400005 PM 12920067 ER PT J AU Veazey, RS Lifson, JD Schmitz, JE Kuroda, MJ Piatak, M Pandrea, I Purcell, J Bohm, R Blanchard, J Williams, KC Lackner, AA AF Veazey, RS Lifson, JD Schmitz, JE Kuroda, MJ Piatak, M Pandrea, I Purcell, J Bohm, R Blanchard, J Williams, KC Lackner, AA TI Dynamics of Simian immunodeficiency virus-specific cytotoxic T-cell responses in tissues SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 20th Annual Symposium on Nonhuman Primate Models for AIDS CY SEP 08-11, 2002 CL MONTEREY, CALIFORNIA SP Calif Natl Primate Res Ctr DE cytotoxic T cell; human immunodeficiency virus; intestine; mucosal immunity; Simian immunodeficiency virus ID INFECTED RHESUS-MONKEYS; PERIPHERAL-BLOOD; SIV INFECTION; HIV-INFECTION; LYMPHOCYTES; MACAQUES; DEPLETION; CTL; EMERGENCE; TYPE-1 AB Although the dynamics of human immunodeficiency virus and Simian immunodeficiency virus (SIV)-specific cytotoxic T cells (CTLs) have been well documented in the blood, little is known regarding CTL development in other tissues. In this study, seven Mamu-A*01+ macaques were inoculated with SIVmac. Two macaques were killed at 21 days of infection, and SIV gag p11C tetramer responses were measured in the blood, axillary and mesenteric lymph nodes, spleen, bone marrow, and thymus. Three with clinical signs of disease were killed and similarly examined. Four macaques were followed throughout disease progression, and intestinal biopsies and blood were examined at regular time points after inoculation. In animals followed prospectively, peak early tetramer responses were detected in the blood (3.9-19% of CD3+ CD8+ T cells) between day 14-21 post-inoculation (p.i.). After day 49, tetramer responses in the blood diminished and remained relatively stable through day 200, ranging from 0.7-6.5% of CD3+ CD8+ T cells. In contrast, tetramer-positive T cells increased in the intestine in later stages of infection (100-200 days p.i.) in all four infected animals (peak values from 5.3 to 28.8%). Percentages of tetramer-positive cells were consistently higher in the intestine than in the blood in all four animals after day 100. In animals with acquired immunodeficiency syndrome, percentages of CTL in tissues were variable, but were consistently higher in the intestine and spleen compared with blood. These data suggest that while high CTL responses develop at a similar rate, and magnitude in both peripheral and mucosal lymphoid tissues in primary SIV infection, mucosal CTL responses may predominate later in the course of the disease. C1 Tulane Univ, Ctr Hlth Sci, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Retroviral Pathogenesis Lab, Frederick, MD 21701 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Veazey, RS (reprint author), Tulane Univ, Ctr Hlth Sci, Tulane Natl Primate Res Ctr, 18703 3 Rivers Rd, Covington, LA 70433 USA. FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [RR00164, P51 RR000164]; NIAID NIH HHS [R01 AI049080, AI49080, AI48349]; NICHD NIH HHS [HD36310]; NIDDK NIH HHS [R01 DK050550, DK50550] NR 21 TC 25 Z9 26 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2003 VL 32 IS 4-5 BP 194 EP 200 DI 10.1034/j.1600-0684.2003.00025.x PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 715QJ UT WOS:000184983500004 PM 14498979 ER PT J AU Lifson, JD Piatak, M Cline, AN Rossio, JL Purcell, J Pandrea, I Bischofberger, N Blanchard, J Veazey, RS AF Lifson, JD Piatak, M Cline, AN Rossio, JL Purcell, J Pandrea, I Bischofberger, N Blanchard, J Veazey, RS TI Transient early post-inoculation anti-retroviral treatment facilitates controlled infection with sparing of CD4(+) T cells in gut-associated lymphoid tissues in SIVmac239-infected rhesus macaques, but not resistance to rechallenge SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 20th Annual Symposium on Nonhuman Primate Models for AIDS CY SEP 08-11, 2002 CL MONTEREY, CALIFORNIA SP Calif Natl Primate Res Ctr DE CD8 depletion; HIV; intestine; PMPA; SIV; T cell; tenofovir ID SIMIAN IMMUNODEFICIENCY VIRUS; CD8(+) LYMPHOCYTES; IMMUNE-RESPONSES; SIV INFECTION; PREVENTION; PROTECTION; MUCOSAL; PMPA; LOAD AB Like human immunodeficiency virus infection of humans, infection of rhesus macaques with pathogenic simian immunodeficiency virus (SIV) strains typically results in persistent progressive infection, leading to clinically significant immunosuppression. In previous studies, we administered short term anti-retroviral treatment, shortly after intravenous inoculation with SIVsmE660, in an effort to allow immunologic sensitization under conditions not characterized by overwhelming cytopathic infection compromising the developing immune response. We showed that such treatment allowed control of off treatment viremia and was associated with resistance to rechallenge. Control of off treatment viremia was associated, at least in part, with CD8(+) lymphocytes, based on in vivo CD8 depletion studies. In the present study, six rhesus macaques were infected intravenously with 100 MID(50) of SIVmac239; four then received 30 days of treatment with tenofovir 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA); 20-30 mg/kg, subcutaneously) starting 24 hours post-inoculation. Tenofovir-treated animals showed low (<500 copy Eq/ml) or undetectable (<100 copy Eq/ml) plasma SIV RNA levels during treatment, with undetectable plasma viremia following discontinuation of treatment. Plasma SIV RNA remained <100 copy Eq/ml, even after depletion of CD8(+) lymphocytes, 6 weeks after discontinuation of tenofovir treatment. In contrast to untreated infected control animals that showed substantial depletion of CD4(+) T cells from gut-associated lymphoid tissues (GALT), tenofovir-treated animals showed sparing of GALT CD4(+) T cells both during the treatment period and in the off treatment follow-up period. However, in contrast to earlier results with animals infected with SIVsmE660, in the present study, the animals did not develop readily measurable cellular anti-SIV immune responses, and did not resist homologous rechallenge with SIVmac239, administered 44 weeks after the initial infection. Differences in the animals and virus strains employed may in part account for the differences in results observed. Comparative analysis of virologic and immunologic parameters in this model system may provide important insights for understanding the basis of effective immunologic control of SIN infection. C1 NCI, SAIC Frederick Inc, Retroviral Pathogenesis Lab, AIDS Vaccine Program, Ft Detrick, MD 21702 USA. Tulane Univ, Ctr Hlth Sci, Tulane Natl Primate Res Ctr, Covington, LA USA. Gilead Sci Inc, Foster City, CA 94404 USA. RP Lifson, JD (reprint author), NCI, SAIC Frederick Inc, Retroviral Pathogenesis Lab, AIDS Vaccine Program, Bldg 535,5th Floor, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [R24 RR016001, RR00164]; NIAID NIH HHS [AI49080]; NICHD NIH HHS [HD36310] NR 21 TC 34 Z9 34 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2003 VL 32 IS 4-5 BP 201 EP 210 DI 10.1034/j.1600-0684.2003.00026.x PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 715QJ UT WOS:000184983500005 PM 14498980 ER PT J AU Busch, M Lu, D Fritts, L Lifson, JD Miller, CJ AF Busch, M Lu, D Fritts, L Lifson, JD Miller, CJ TI Comparison of virology and immunology in SHIV 89.6 proviral DNA and virus-inoculated rhesus macaques SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 20th Annual Symposium on Nonhuman Primate Models for AIDS CY SEP 08-11, 2002 CL MONTEREY, CALIFORNIA SP Calif Natl Primate Res Ctr DE plasmid; simian immunodeficiency virus; vaccine ID SIMIAN IMMUNODEFICIENCY VIRUS; PATHOGENIC SIVMAC239; VAGINAL CHALLENGE; SIV; INFECTION; LIVE; IMMUNIZATION; PROTECTION; GENERATION; LYMPHOCYTE AB Inoculation of cats, goats and monkeys with plasmids encoding full-length proviral genomes results in persistent lentiviral infections. This system could be used as a method for administration of an attenuated human immunodeficiency virus (HIV) vaccine. Here, we compare the virology and immunology in rhesus macaques inoculated with either simian/human immunodeficiency virus 89.6 (SHIV 89.6) virus or a plasmid containing the SHIV 89.6 proviral genome. There was a delay in appearance of systemic infection in DNA-inoculated animals compared with virus-inoculated animals, but otherwise the pattern of infection was similar. The serum immunoglobulin G anti-simian immunodeficiency virus (SIV) binding antibody response in DNA-inoculated animals was also delayed compared with virus-inoculated animals, but ultimately there was no difference between live virus and DNA-inoculation in the ability to induce the anti-SIV immune responses that were measured. Thus, the data support the concept that plasmid DNA encoding an attenuated virus could be used instead live virus for vaccination. C1 Univ Calif Davis, CNPRC, Davis, CA 95616 USA. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Retroviral Pathogenesis Lab,AIDS Vaccine Program, Frederick, MD USA. RP Miller, CJ (reprint author), Univ Calif Davis, CNPRC, 1 Shields Ave Davis, Davis, CA 95616 USA. FU NCRR NIH HHS [RR00169, RR14555]; NIAID NIH HHS [AI44480] NR 23 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2003 VL 32 IS 4-5 BP 240 EP 246 DI 10.1034/j.1600-0684.2003.00029.x PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 715QJ UT WOS:000184983500009 PM 14498984 ER PT J AU Kuznetsova, NV McBride, DJ Leikin, S AF Kuznetsova, NV McBride, DJ Leikin, S TI Changes in thermal stability and microunfolding pattern of collagen helix resulting from the loss of alpha 2(I) chain in osteogenesis imperfecta murine SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE collagen; osteogenesis imperfecta; microunfolding; thermal stability ID EHLERS-DANLOS SYNDROME; I COLLAGEN; MOUSE MODEL; HOMOTRIMER; MUTATION; VARIANT; PATIENT; FIBRILS; GENE AB Homozygous mutations resulting in formation of alpha1(I)(3) homotrimers instead of normal type I collagen cause mild to severe osteogenesis imperfecta (OI) in humans and mice. Limited studies of changes in thermal stability of type I homotrimers were reported previously, but the results were not fully consistent. We revisited this question in more detail using purified tendon collagen from wild-type (alpha1(I)(2)alpha2(I) heterotrimers) and oim (alpha1(I)(3)) mice as well as artificial alpha1(I)(3) homotrimers obtained by refolding of rat-tail-tendon collagen. We found that at the same heating rate oim homotrimers completely denature at similar to2.5 deg.C higher temperature than wild-type heterotrimers, as determined by differential scanning calorimetry. At the same, constant temperature, homotrimers denature similar to100 times slower than heterotrimers, as determined by circular dichroism. Detailed analysis of proteolytic cleavage at different temperatures revealed that microunfolding of oim homotrimers and wild-type heterotrimers occurs at similar rate but within a number of different sites. In particular, the weakest spot on the oim triple helix is located similar to100 amino acid residues from the C-terminal end within the cyanogen bromide peptide CB6. The same microunfolding site is also present in wild-type collagen, but the weakest spot of the latter is located close to the N-terminal end of CB8. Amino acid analysis and differential gel electrophoresis showed virtually no posttranslational overmodification of oim mouse tendon collagen. Moreover, thermal stability and microunfolding of artificial rat-tail-tendon homotrimers were similar to oim homotrimers. Thus, the observed changes are associated with difference in the amino acid composition of alpha1(I) and alpha2(I) chains rather than posttranslational overmodification. (C) 2003 Elsevier Ltd. All rights reserved. C1 NICHHD, NIH, DHHS, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Leikin, S (reprint author), NICHHD, NIH, DHHS, Bldg 9,Rm 1E-125, Bethesda, MD 20892 USA. RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU NIAMS NIH HHS [AR43739] NR 22 TC 35 Z9 36 U1 0 U2 2 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 AUG 1 PY 2003 VL 331 IS 1 BP 191 EP 200 DI 10.1016/S0022-2836(03)00715-0 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 704QL UT WOS:000184351300015 PM 12875845 ER PT J AU Weber, F Asher, A Bucholz, R Berger, M Prados, M Chang, S Bruce, J Hall, W Rainov, NG Westphal, M Warnick, RE Rand, RW Floeth, F Rommel, F Pan, H Hingorani, VN Puri, RK AF Weber, F Asher, A Bucholz, R Berger, M Prados, M Chang, S Bruce, J Hall, W Rainov, NG Westphal, M Warnick, RE Rand, RW Floeth, F Rommel, F Pan, H Hingorani, VN Puri, RK TI Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE astrocytoma; glioblastoma multiforme; immunotoxin; intratumoral therapy; malignant glioma ID PERMUTED INTERLEUKIN 4-TOXIN; BRAIN-TUMORS; IL-4 RECEPTORS; EGF RECEPTOR; THERAPY; TOXIN; EXPRESSION; PROTEIN; CELLS; REGRESSION AB Purpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores greater than or equal to 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 mug/ml x 40 ml, 9 mug/ml x 40 ml, 15 mug/ml x 40 ml, or 9 mug/ml x 100 ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 mug/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma. C1 Neurocrine Biosci Inc, San Diego, CA 92121 USA. Univ Dusseldorf, Dept Neurol Surg, D-4000 Dusseldorf, Germany. Carolina Neurosurg & Spine Associates, Charlotte, NC USA. St Louis Univ, Sch Med, St Louis, MO USA. Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. Columbia Univ, New York, NY USA. Univ Minnesota, Minneapolis, MN USA. Univ Halle Wittenberg, Neurochirurg Klin, Halle Saale, Germany. Univ Hamburg, Krankenhaus Eppendorf, Neurochirurg Klin, D-2000 Hamburg, Germany. Univ Cincinnati, Cincinnati, OH USA. John Wayne Canc Inst, Santa Monica, CA USA. NIH, Lab Mol Tumor Biol,Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, US FDA, Bethesda, MD 20892 USA. RP Pan, H (reprint author), Neurocrine Biosci Inc, 10555 Sci Ctr Dr, San Diego, CA 92121 USA. NR 25 TC 111 Z9 114 U1 1 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG-SEP PY 2003 VL 64 IS 1 BP 125 EP 137 DI 10.1007/BF02700027 PG 13 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 706TL UT WOS:000184471100014 PM 12952293 ER PT J AU Bungay, PM Newton-Vinson, P Isele, W Garris, PA Justice, JB AF Bungay, PM Newton-Vinson, P Isele, W Garris, PA Justice, JB TI Microdialysis of dopamine interpreted with quantitative model incorporating probe implantation trauma SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dopamine; implantation trauma; in vivo microdialysis; in vivo voltammetry; striatum ID BLOOD-BRAIN-BARRIER; IN-VIVO MICRODIALYSIS; MICE LACKING; INTRACEREBRAL MICRODIALYSIS; EXTRACELLULAR DOPAMINE; INVIVO MICRODIALYSIS; REGIONAL DIFFERENCES; NUCLEUS-ACCUMBENS; RAT HIPPOCAMPUS; UPTAKE KINETICS AB Although microdialysis is widely used to sample endogenous and exogenous substances in vivo , interpretation of the results obtained by this technique remains controversial. The goal of the present study was to examine recent criticism of microdialysis in the specific case of dopamine (DA) measurements in the brain extracellular microenvironment. The apparent steady-state basal extracellular concentration and extraction fraction of DA were determined in anesthetized rat striatum by the concentration difference (no-net-flux) microdialysis technique. A rate constant for extracellular clearance of DA calculated from the extraction fraction was smaller than the previously determined estimate by fast-scan cyclic voltammetry for cellular uptake of DA. Because the relatively small size of the voltammetric microsensor produces little tissue damage, the discrepancy between the uptake rate constants may be a consequence of trauma from microdialysis probe implantation. The trauma layer has previously been identified by histology and proposed to distort measurements of extracellular DA levels by the no-net-flux method. To address this issue, an existing quantitative mathematical model for microdialysis was modified to incorporate a traumatized tissue layer interposed between the probe and surrounding normal tissue. The tissue layers are hypothesized to differ in their rates of neurotransmitter release and uptake. A post-implantation traumatized layer with reduced uptake and no release can reconcile the discrepancy between DA uptake measured by microdialysis and voltammetry. The model predicts that this trauma layer would cause the DA extraction fraction obtained from microdialysis in vivo calibration techniques, such as no-net-flux, to differ from the DA relative recovery and lead to an underestimation of the DA extracellular concentration in the surrounding normal tissue. C1 NIH, DBEPS, Div Bioengn & Phys Sci, DHHS, Bethesda, MD 20892 USA. Emory Univ, Dept Chem, Atlanta, GA 30322 USA. Illinois State Univ, Dept Biol Sci, Normal, IL 61761 USA. RP Bungay, PM (reprint author), NIH, DBEPS, Div Bioengn & Phys Sci, DHHS, Bldg 13,3N17 MSC 5766, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 OD010276-10] NR 55 TC 102 Z9 103 U1 1 U2 12 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2003 VL 86 IS 4 BP 932 EP 946 DI 10.1046/j.1471-4159.2003.01904.x PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 706JW UT WOS:000184451400015 PM 12887691 ER PT J AU Liu, D Slevin, JR Lu, CB Chan, SL Hansson, M Elmer, E Mattson, MP AF Liu, D Slevin, JR Lu, CB Chan, SL Hansson, M Elmer, E Mattson, MP TI Involvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis; cytochrome c; glutamate; hippocampus; hypoxia; pre-conditioning ID MANGANESE SUPEROXIDE-DISMUTASE; FOCAL CEREBRAL-ISCHEMIA; PROTECT HIPPOCAMPAL-NEURONS; CYTOCHROME-C RELEASE; INJURY IN-VIVO; ATP CHANNELS; POTASSIUM CHANNEL; OXIDATIVE STRESS; BRAIN INJURY; PEROXYNITRITE PRODUCTION AB We measured and manipulated intracellular potassium (K+ ) fluxes in cultured hippocampal neurons in an effort to understand the involvement of K+ in neuronal death under conditions of ischemia and exposure to apoptotic stimuli. Measurements of the intracellular K+ concentration using the fluorescent probe 1,3-benzenedicarboxylic acid, 4,4'-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis [(acetyloxy) methyl] ester (PBFI) revealed that exposure of neurons to cyanide (chemical hypoxia), glutamate (excitotoxic insult) or staurosporine (apoptotic stimulus) results in efflux of K+ and cell death. Treatment of neurons with 5-hydroxydecanoate (5HD), an inhibitor of mitochondrial K+ channels, reduced K+ fluxes in neurons exposed to each insult and increased the resistance of the cells to death. K+ efflux was attenuated, levels of oxyradicals were decreased, mitochondrial membrane potential was stabilized and release of cytochrome c from mitochondria was attenuated in neurons treated with 5HD. K+ was rapidly released into the cytosol from mitochondria when neurons were exposed to the K+ channel opener, diazoxide, or to the mitochondrial uncoupler, carbonyl cyanide 4(trifluoromethoxy)phenylhydrazone (FCCP), demonstrating that the intramitochondrial K+ concentration is greater than the cytosolic K+ concentration. The release of K+ from mitochondria was followed by efflux through plasma membrane K+ channels. In vivo studies showed that 5HD reduces ischemic brain damage without affecting cerebral blood flow in a mouse model of focal ischemic stroke. These findings suggest that intracellular K+ fluxes play a key role in modulating neuronal oxyradical production and cell survival under ischemic conditions, and that agents that modify K+ fluxes may have therapeutic benefit in stroke and related neurodegenerative conditions. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Expt Brain Res Lab, Wallenberg Neurosci Ctr, Lund, Sweden. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Hansson, Magnus/G-4486-2014; Elmer, Eskil/F-9341-2014 OI Hansson, Magnus/0000-0002-0201-0638; Elmer, Eskil/0000-0001-7901-1826 NR 76 TC 61 Z9 65 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2003 VL 86 IS 4 BP 966 EP 979 DI 10.1046/j.1471-4159.2003.01913.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 706JW UT WOS:000184451400018 PM 12887694 ER PT J AU Raju, R Vasconcelos, O Granger, R Dalakas, MC AF Raju, R Vasconcelos, O Granger, R Dalakas, MC TI Expression of IFN-gamma-inducible chemokines in inclusion body myositis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Mig; IP-10; CXCR3; myotube; inclusion body myositis; chemokines ID CELL-ADHESION MOLECULES; INFLAMMATORY MYOPATHIES; MUSCLE-FIBERS; T-CELLS; MATRIX METALLOPROTEINASES; DIFFERENTIAL EXPRESSION; CYTOKINE EXPRESSION; DUCHENNE DYSTROPHY; IN-VITRO; DERMATOMYOSITIS AB Because IFN-gamma-inducible chemokines, Mig (CXCL9), IP-10 (CXCL10), I-TAC (CXCL11) and their receptor, CXCR3, are critical molecules in T cell trafficking and generation of effector T cells, we examined their expression in the muscle biopsies of patients with sporadic inclusion body myositis (s-IBM) and disease controls. The functional role of these molecules was also studied by examining the effect and time kinetics of IFN-gamma in inducing Mig and IP-10 expression in human myotubes in vitro. We found significantly high levels of Mig and IP-10 mRNA expression in s-IBM muscles compared to controls. IFN-gamma upregulated the mRNA expression of Mig and IP-10 by human myotubes in a dose-dependent manner. By double-label immunohistochemistry, Mig was expressed on a subset of CD8(+) cells and the areas of the muscle fiber in contact or contiguous to the T cells; CXCR3 was expressed only on a subset of the autoinvasive CD8(+) T cells but not the myofibers. IP-10 and I-TAC were not detected by immunocytochemistry. The findings indicate that in s-IBM, IFN-gamma is involved in the upregulation and in situ production of proinflammatory chemokines, which, in turn, participate in the recruitment of activated T cells and contribute to the self-sustaining nature of endomysial inflammation. Crown Copyright (C) 2003 Published by Elsevier B.V. All rights reserved. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10 Room 4N248,10 Ctr Dr, Bethesda, MD 20892 USA. RI Raju, Raghavan/E-9219-2011 NR 36 TC 44 Z9 45 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2003 VL 141 IS 1-2 BP 125 EP 131 DI 10.1016/S0165-5758(03)00218-2 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 724LN UT WOS:000185489200016 PM 12965263 ER PT J AU Read, JCA Cumming, BG AF Read, JCA Cumming, BG TI Measuring V1 receptive fields despite eye movements in awake monkeys SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PRIMARY VISUAL-CORTEX; LATENCY DISPARITY VERGENCE; STRIATE CORTEX; HORIZONTAL DISPARITY; MACAQUE V1; FIXATION DISPARITY; VIEWING DISTANCE; ALERT MONKEYS; SIMPLE CELLS; NEURONS AB One difficulty with measuring receptive fields in the awake monkey is that even well-trained animals make small eye movements during fixation. These complicate the measurement of receptive fields by blurring out the region where a response is observed, causing underestimates of the ability of individual neurons to signal changes in stimulus position. In simple cells, this blurring may severely disrupt estimates of receptive field structure. An accurate measurement of eye movements would allow correction of this blurring. Scleral search coils have been used to provide such measurements, although little is known about their accuracy. We have devised a range of approaches to address this issue: implanting two coils into a single eye, exploiting the small size of V1 receptive fields and developing maximum-likelihood fitting techniques to extract receptive field parameters in the presence of eye movements. All our investigations lead to the same conclusion: our scleral search coils (which were not sutured to the globe) are subject to an error of approximately the same magnitude as the small eye movements which occur during fixation: SD similar to 0.1degrees. This error is large enough to explain the SD of measured vergence in the absence of any real changes in vergence state. This, and a variety of other arguments, indicate that the real variation in vergence is much smaller than coil measurements suggest. These results suggest that monkeys, like humans, maintain very stable vergence. The error has a slower time course than fixational eye movements so that search coils report the difference in eye position between two consecutive trials more accurately than the eye position itself on either trial. Receptive field estimates are unlikely to be improved by assuming the coil record is veridical and correcting for eye position accordingly. However, receptive field parameters can reliably be determined by a fitting technique that allows for eye movements. It is possible that suturing coils to the globe reduces the artifacts, but no method has been available to demonstrate this. These receptive field measurements provide a general means by which the reliability of eye-position measurements can be assessed. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Read, JCA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. RI Read, Jenny/A-7493-2013 OI Read, Jenny/0000-0002-9029-5185 FU NEI NIH HHS [Z01 EY000404-04] NR 31 TC 20 Z9 20 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2003 VL 90 IS 2 BP 946 EP 960 DI 10.1152/jn.01068.2002 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 708KE UT WOS:000184565300043 PM 12711706 ER PT J AU Bofill-Mas, S Clemente-Casares, P Major, EO Curfman, B Girones, R AF Bofill-Mas, S Clemente-Casares, P Major, EO Curfman, B Girones, R TI Analysis of the excreted JC virus strains and their potential oral transmission SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE archetype; environment; gastrointestinal route; infectivity; JC virus; SVG cells ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PERIPHERAL-BLOOD LEUKOCYTES; RENAL-TRANSPLANT PATIENTS; HUMAN POLYOMAVIRUSES; DNA SEQUENCE; BK VIRUS; GASTROINTESTINAL-TRACT; REGULATORY REGIONS; BRAIN-TUMORS; BONE-MARROW AB JC virus (JCV) particles have been detected in urban sewage of divergent geographical areas. In this study, the authors evaluate the genetic characteristics and the infective capabilities of JCV strains in relation to the potential oral transmission of JCV in the population. JCV strains excreted in urine and detected in sewage have been described as presenting archetypal structure of the regulatory region of the viral genome. The regulatory region of JCV viral particles detected in two urban sewage samples have been cloned and characterized. From a total of 40 clones tested, 39 presented archetypal-like regulatory regions, whereas 1 of the clones analyzed presented a tandem repeated structure. Archetypal strains present in the urine of a pregnant woman were able to infect SVG cells, producing infectious virions, as demonstrated by confirmative cell culture, electron microscopy, and in situ DNA hybridization. This is the first description of archetypal JCV productive infection of SVG cells. SVG cells were also successfully infected with Mad-4 JCV viral particles subjected to pH 3 for 1 h at 37degreesC and to 10 mug/ml of trypsin in the same conditions. A decrease in the viral progeny production was observed when Mad-4 was subjected to acidic pH. Mad-4 did not produce any detectable infection in the enteric cell line CaCo-2. The oral route could represent a significant route of transmission of JCV infections because JCV virions have demonstrated relative resistance in the environment and to some of the conditions present in the gastrointestinal tract. The archetypal strains commonly detected in the environment may be implicated in the transmission of JCV among the population. Sporadic infection with strains presenting tandem repeated structures may have implications in pathogenicity. C1 Univ Barcelona, Fac Biol, Dept Microbiol, Sch Biol, E-08028 Barcelona, Catalonia, Spain. NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Girones, R (reprint author), Univ Barcelona, Fac Biol, Dept Microbiol, Sch Biol, Avinguda Diagonal 645, E-08028 Barcelona, Catalonia, Spain. RI Girones, Rosina/B-2975-2009 OI Girones, Rosina/0000-0002-1097-6395 NR 60 TC 14 Z9 15 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2003 VL 9 IS 4 BP 498 EP 507 DI 10.1080/13550280390218887 PG 10 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 708LA UT WOS:000184567400008 PM 12907394 ER PT J AU Al-Saleh, MF Zheng, G AF Al-Saleh, MF Zheng, G TI Controlled sampling using ranked set sampling SO JOURNAL OF NONPARAMETRIC STATISTICS LA English DT Article DE controlled sampling; distribution of concomitants; mean; multistage ranked set; preferable sample; steady state sample ID EFFICIENCY AB Based on ranked set sampling procedure, a technique to obtain a controlled preferable sample is introduced. Using this technique it is possible to obtain an approximate preferable sample from a population of interest. In particular, the technique can be used to obtain sample points that tend to be from a specific portion of a distribution such as the lower or upper quartiles. The performance of the technique is investigated under perfect and imperfect ranking. Some other related topics are also discussed. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Yarmouk Univ, Dept Stat, Irbid, Jordan. RP Al-Saleh, MF (reprint author), NHLBI, Off Biostat Res, Rockledge 2,Room 8223,6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 20 TC 7 Z9 7 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1048-5252 J9 J NONPARAMETR STAT JI J. Nonparametr. Stat. PD AUG-OCT PY 2003 VL 15 IS 4-5 BP 505 EP 516 DI 10.1080/10485250310001604640 PG 12 WC Statistics & Probability SC Mathematics GA 746QD UT WOS:000186756300009 ER PT J AU Mariani, G Filocamo, M Giona, F Villa, G Amendola, A Erba, P Buffoni, F Copello, F Pierini, A Minichilli, F Gatti, R Brady, RO AF Mariani, G Filocamo, M Giona, F Villa, G Amendola, A Erba, P Buffoni, F Copello, F Pierini, A Minichilli, F Gatti, R Brady, RO TI Severity of bone marrow involvement in patients with Gaucher's disease evaluated by scintigraphy with Tc-99m-sestamibi SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE Gaucher's disease; bone marrow involvement; Tc-99m-sestamibi; scintigraphic score; disease severity ID ENZYME REPLACEMENT THERAPY; MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; TC-99M SESTAMIBI; SKELETAL INVOLVEMENT; MULTIPLE-MYELOMA; PLASMA; TECHNETIUM-99M-SESTAMIBI; DEFICIENCY; TYPE-1; ADULTS AB Gaucher's disease is a lysosomal storage disorder due to a genetically transmitted deficiency of the enzyme glucocerebrosidase. In the most common form of the disease (type 1), accumulation of glucosylceramide in the reticuloendothelial cells of liver, spleen, and bone marrow leads to visceromegaly, anemia, thrombocytopenia, and osteopenia. Skeletal manifestations secondary to infiltration of the bone marrow by Gaucher's cells are detectable by radiography only in advanced stages. Imaging of bone marrow involvement can be performed indirectly by magnetic resonance techniques or by bone marrow scintigraphy with radiocolloids. However, both procedures lack specificity because the normal bone marrow, rather than the pathologic process, is imaged. The aim of this study was to assess the reliability of Tc-99m-sestamibi scintigraphy for direct evaluation of bone marrow involvement. Methods: Seventy-two patients with type 1 and 2 patients with type 3 Gaucher's disease (35 males, 39 females) were enrolled in the study. The mean age +/- SD was 31.9 +/- 16.5 y (range, 3-76 y), and the average duration of the disease manifestations when performing scintigraphy was 12.95 y (median, 10.5 y; range, 0-44 y). Forty-three of 74 patients had never received enzyme replacement therapy (ERT), whereas 31 patients were already being treated with ERT. Tc-99m-Sestamibi was injected intravenously (6-8 MBq/kg of body weight) and imaging was recorded at the lower limbs 30 min after injection, at the plateau of tracer accumulation in the involved bone marrow. The scans were evaluated visually, assigning a semiquantitative score based on the extension and intensity of uptake in the bone marrow of the lower limbs (0 = no uptake; 8 = maximum uptake). The scintigraphic score was entered into complex statistical analysis, which included a series of clinical and blood chemistry parameters defining overall severity of the disease. Results: Tc-99m-Sestamibi scintigraphy showed that 71 of 74 patients had some degree of bone marrow involvement. The scintigraphic score was highly correlated with an overall clinical severity score index (SSI) and with various parameters contributing to the SSI, either positively or negatively. The highest correlation of the scintigraphic score was found with an overall biochemical marker of disease severity (serum chitotriosidase). ERT-naive patients showed high correlation of the scintigraphic score with the clinical SSI, with a radiographically based score, and with serum chitotriosidase. In the ERT-treated patients, the scintigraphic score was correlated with the clinical SSI, with hepatomegaly, and with hemoglobin. Conclusion: Tc-99m-Sestamibi uptake reliably identifies bone marrow infiltration by Gaucher's cells. The scintigraphic score is helpful for defining the severity of bone marrow involvement and for comparing patients. Tc-99m-Sestamibi scintigraphy, which provides topographic information about the sites involved by the disease, is highly correlated with other parameters of disease severity and appears to correlate with response to ERT. C1 Univ Pisa, Sch Med, Reg Ctr Nucl Med, I-56126 Pisa, Italy. Italian Natl Res Council, Inst Clin Physiol, Pisa, Italy. G Gaslini Childrens Hosp, Lab Prepostnatal Diag Metab Dis, Genoa, Italy. Univ Roma La Sapienza, Dept Cell Biotechnol & Hematol, Rome, Italy. Univ Genoa, Sch Med, Nucl Med Serv, Dept Internal Med & Med Specialties, Genoa, Italy. San Martino Hosp, Occupat Med, Genoa, Italy. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Mariani, G (reprint author), Univ Pisa, Sch Med, Reg Ctr Nucl Med, Via Roma 67, I-56126 Pisa, Italy. FU Telethon [GTF01009] NR 43 TC 18 Z9 18 U1 0 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2003 VL 44 IS 8 BP 1253 EP 1262 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 709XB UT WOS:000184650900014 PM 12902415 ER PT J AU Kurdziel, KA Kiesewetter, DO Carson, RE Eckelman, WC Herscovitch, P AF Kurdziel, KA Kiesewetter, DO Carson, RE Eckelman, WC Herscovitch, P TI Biodistribution, radiation dose estimates, and in vivo Pgp modulation studies of F-18-paclitaxel in nonhuman primates SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET; multidrug resistance; modulation; dosimetry; paclitaxel ID BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN EXPRESSION; MULTIDRUG-RESISTANCE; GRAPHICAL ANALYSIS; DRUG-INTERACTIONS; NORMAL-TISSUES; CANCER-CELLS; PACLITAXEL; INHIBITORS; REVERSAL AB Multidrug resistance (MDR) associated with increased expression and function of the P-glycoprotein (Pgp) efflux pump often causes chemotherapeutic failure in cancer. To provide insight into both the dynamics of the pump and the effects of MDR, we radiolabeled paclitaxel, a substrate for the Pgp pump, with F-18 to study MDR in vivo with PET. We obtained biodistribution arid radiation dose estimates for F-18-paclitaxel (FPAC) in monkeys and studied the effects of a Pgp blocker (XR9576, tariquidar) on FPAC kinetics. Methods: Paired baseline and Pgp modulation (2 mg/kg XR9576) 4-h whole-body dynamic PET scans were obtained in 3 rhesus monkeys after injection of FPAC. Measured residence times were extrapolated to humans and radiation dose estimates were obtained using MIRDOSE3.1. The post-modulator area under the time-activity curves (AUCs) and Logan plot slopes, a measure of tracer distribution volume (equilibrium tissue-to-plasma ratio) that is inversely proportional to tracer efflux, were compared with baseline values to determine changes in FPAC distribution. Results: Cumulative activities of the organs sampled accounted for 80% of the injected dose. The critical organ is gallbladder wall (0.19 mGy/MBq [0.69 rad/mCi]), followed by liver (0.14 mGy/MBq [0.52 rad/mCi]); the effective dose is 0.022 mSv/MBq (0.083 rem/mCi). XR9576 preinfusion changed the Logan plot slope for liver by +104% (P = 0.02), lung by +87% (P = 0.11), and kidney by -14% (P = 0.08). Changes in the mean AUC (normalized to the plasma AUC) were +54% (P = 0.08), +97% (P = 0.04), and -12% (P = 0.02), respectively, for liver, lung, and kidney. No significant difference was found in the metabolite-corrected plasma AUC (normalized to the injected dose) between the baseline and XR9576 modulator studies (P = 0.69). Conclusion: Under Radioactive Drug Research Committee guidelines, 266 MBq (7.2 mCi) FPAC can be administered to humans up to 3 times a year. The increase in FPAC accumulation in liver and lung after XR9576 is consistent with Pgp inhibition and demonstrates the potential of FPAC to evaluate MDR. C1 NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kurdziel, KA (reprint author), Virginia Commonwealth Univ, Dept Radiol, Med Coll Virginia Campus,POB 980001, Richmond, VA 23298 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 41 TC 60 Z9 60 U1 0 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2003 VL 44 IS 8 BP 1330 EP 1339 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 709XB UT WOS:000184650900024 PM 12902425 ER PT J AU Coble, JB Brown, LM Hayes, RB Huang, WY Winn, DM Gridley, G Bravo-Otero, E Fraumeni, JF AF Coble, JB Brown, LM Hayes, RB Huang, WY Winn, DM Gridley, G Bravo-Otero, E Fraumeni, JF TI Sugarcane farming, occupational solvent exposures, and the risk of oral cancer in Puerto Rico SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID LUNG-CANCER; CAVITY; LARYNGEAL; MESOTHELIOMA; OROPHARYNX; PHARYNGEAL; COMMUNITY; INDUSTRY; WORKERS; SWEDEN AB The work history information from a population-based case-control study conducted in Puerto Rico was analyzed using a Job exposure matrix to investigate the relationship between occupational exposures and cancers of the oral cavity or pharynx. After adjustment for age, alcohol, smoking, and residence in a logistic model, the risk for cancer of the oral cavity, but not the pharynx, was significantly elevated among farm workers in the sugarcane industry (OR = 4.4, 95 % CI = 1.4-13.6). An exposure-response trend was seen for cumulative exposure to solvents, with an OR = 3.2 (95 % CI = 0.8 -12.6) in the highest exposure category. The overall contribution to the risk of cancer of the oral cavity or pharynx. Puerto Rico appears to be small, however, the elevated risks were seen among sugarcane farmers and subjects with high cumulative exposure to solvents. C1 NCI, DCEG, NIH, DHHS, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, DHHS, Bethesda, MD 20892 USA. Univ Puerto Rico, San Juan, PR 00936 USA. RP Coble, JB (reprint author), NCI, DCEG, NIH, DHHS, 6120 Execut Blvd,Room 8110,MSC 7240, Bethesda, MD 20892 USA. OI Hayes, Richard/0000-0002-0918-661X NR 32 TC 8 Z9 9 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2003 VL 45 IS 8 BP 869 EP 874 DI 10.1097/01.jom.0000083034.56116.0f PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 712BX UT WOS:000184777400012 PM 12915788 ER PT J AU O'Connell, BC Zheng, CY Jacobson-Kram, D Baum, BJ AF O'Connell, BC Zheng, CY Jacobson-Kram, D Baum, BJ TI Distribution and toxicity resulting from adenoviral vector administration to a single salivary gland in adult rats SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE adenovirus; gene transfer; safety; salivary, submandibular ID MEDIATED GENE-TRANSFER; IN-VIVO; RECOMBINANT ADENOVIRUS; A-I; EXPRESSION; REPLICATION; PROMOTERS; RESPONSES; SECRETION; DELIVERY AB Background: We examined the distribution and toxicity associated with a single salivary gland administration of a recombinant adenoviral vector, AdCMVH3, encoding human histatin 3. Methods: Adult rats received different doses of AdCMVH3 (0, 10(6) , 3 x 10(7) , and 10(9) pfu; 50 mul) via the right submandibular gland and were followed for 15 days. Food consumption, weight gain, clinical appearance, and serum chemistry were monitored, and a necropsy was performed. Vector distribution was examined by polymerase chain reaction, and selected saliva samples were tested for replication-competent adenovirus (RCA). Results: All animals survived to sacrifice (days 2, 8, and 15), and appeared normal clinically. There were no differences in food consumption, weight gain, and serum chemistry. The only consistent necropsy findings were lymphoid infiltrates and necrosis in the target submandibular glands of high-dosage animals. AdCMVH3 detection was virus dose dependent, decreased with time, and at low dose preferentially observed in the targeted gland. No RCA was detected. Conclusions: Salivary gland administration of 10(9) pfu AdCMVH3 elicits an initial focal pathologic response and wide tissue distribution. There is no associated systemic toxicity up to 15 days, and lower doses are primarily found in glands. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. Univ Dublin Trinity Coll, Sch Dent Sci, Dublin 2, Ireland. Bioreliance Inc, Rockville, MD USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1 N113,MSC-1190, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 22 TC 18 Z9 20 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD AUG PY 2003 VL 32 IS 7 BP 414 EP 421 DI 10.1034/j.1600-0714.2003.t01-1-00004.x PG 8 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 697WU UT WOS:000183966900006 PM 12846788 ER PT J AU Salzer, W Steinberg, SM Liewehr, DJ Freifeld, A Balis, FM Widemann, BC AF Salzer, W Steinberg, SM Liewehr, DJ Freifeld, A Balis, FM Widemann, BC TI Evaluation and treatment of fever in the non-neutropenic child with cancer SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE cancer; children; fever; non-neutropenia; treatment ID EARLY HOSPITAL DISCHARGE; PEDIATRIC ONCOLOGY PATIENTS; LOW-RISK; OUTPATIENT MANAGEMENT; FEBRILE NEUTROPENIA; PHYSICIAN RESPONSE; ORAL CIPROFLOXACIN; PROSPECTIVE TRIAL; ANTIBIOTICS; BACTEREMIA AB Purpose: To document the current approach to the evaluation and treatment of febrile non-neutropenic children with cancer by surveying American Society of Pediatric Hematology/Oncology (ASPHO) members. Methods: Five hundred ninety-five ASPHO members were sent questionnaires polling their current practices in the evaluation and treatment of clinically stable, febrile (oral temperature of 38degreesC x 2, or greater than or equal to38.3degreesC, non-neutropenic (absolute neutrophil count > 500/muL) pediatric cancer patients who have no identifiable bacterial infection. Patients were assigned to one of four groups based on the presence or absence of a central venous catheter (CVC) and no source (NS) or presumed viral source (VS) for fever. Results: Three hundred sixteen ASPHO members (53%) responded and 300 questionnaires were evaluable. If a CVC was present, respondents universally drew blood cultures (99% NS, 96% VS) from the CVC, but only one third drew peripheral blood cultures (33% NS, 29% VS). If a CVC was not present, the majority of respondents (80% NS, 61% VS) drew peripheral cultures. ASPHO members started empiric antibiotics more frequently in patients with a CVC (69% NS, 55% VS) than in patients without a CVC (33% NS, 23% VS). Most did not admit these patients to the hospital (40% CVC and NS, 33% CVC and VS, 22% no CVC and NS, 19% no CVC and VS). ASPHO members with more years of experience were more likely to obtain peripheral blood cultures if a CVC was present and to admit a patient without a CVC. Conclusions: Nearly all respondents obtained a blood culture from the CVC in the initial assessment of the febrile, non-neutropenic patient with a CVC, but other evaluation and management practices varied considerably. C1 NCI, Pharmacol & Therapeut Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Keesler Med Ctr, Biloxi, MS USA. Univ Nebraska, Med Ctr, Omaha, NE USA. RP Salzer, W (reprint author), Keesler Med Ctr, 81st MDG-SGOC,301 Fisher St,Room 1A132, Keesler AFB, MS 39534 USA. NR 29 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG PY 2003 VL 25 IS 8 BP 606 EP 612 DI 10.1097/00043426-200308000-00004 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 708EC UT WOS:000184553300004 PM 12902912 ER PT J AU Manzitti, C Mereu, P Haupt, R Di Blasi, A Bellani, FF Dallorso, S AF Manzitti, C Mereu, P Haupt, R Di Blasi, A Bellani, FF Dallorso, S TI Parotid carcinoma after autologous bone marrow transplantation for relapsed nephroblastoma SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE hematopoietic stem cell transplantation; nephroblastoma; secondary cancer ID 2ND MALIGNANT NEOPLASMS; NATIONAL WILMS-TUMOR; CHILDREN AB Abdominal irradiation, especially if associated with doxorubicin administration, increases the risk of a secondary malignant neoplasm (SMN) after treatment of nephroblastoma. Secondary malignant salivary tumors are rare and usually occur in patients with previous cranial irradiation. The authors describe the case of a parotid mucoepidermoid carcinoma arising 13 years after diagnosis of nephroblastoma. This patient showed no characteristics reported in the literature as statistically significant for the development of an SMN. The authors believe that long-term, regular clinical examination is necessary even in patients at low risk of developing an SMN. C1 G Gaslini Childrens Hosp, BMT Unit, Dept Pediat Hematol Oncol, Sci Directorate, I-16148 Genoa, Italy. Natl Canc Inst, Div Surg Oncol, Genoa, Italy. G Rummo Hosp, Div Anatom Pathol, Benevento, Italy. NCI, Pediat Oncol Unit, Milan, Italy. RP Dallorso, S (reprint author), G Gaslini Childrens Hosp, BMT Unit, Dept Pediat Hematol Oncol, Sci Directorate, Largo G Gaslini 5, I-16148 Genoa, Italy. RI Haupt, Riccardo/C-2237-2012 NR 10 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG PY 2003 VL 25 IS 8 BP 672 EP 673 DI 10.1097/00043426-200308000-00020 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 708EC UT WOS:000184553300020 PM 12902928 ER PT J AU Clericuzio, CL Chen, E McNeil, DE O'Connor, T Zackai, EH Medne, L Tomlinson, G DeBaun, M AF Clericuzio, CL Chen, E McNeil, DE O'Connor, T Zackai, EH Medne, L Tomlinson, G DeBaun, M TI Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia SO JOURNAL OF PEDIATRICS LA English DT Article ID HEMIHYPERTROPHY; CANCER AB An elevated risk of hepatoblastoma for children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia is well established. We describe five children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia for whom serial serum alpha-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma. C1 Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. Univ Texas SW, Dept Pediat, Dallas, TX 75235 USA. Boone Cty Hosp, Dept Pediat, Columbia, MO USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. RP Clericuzio, CL (reprint author), Univ New Mexico, Dept Pediat, ACC-3, Albuquerque, NM 87131 USA. NR 10 TC 44 Z9 45 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2003 VL 143 IS 2 BP 270 EP 272 DI 10.1067/S0022-3476(03)00306-8 PG 3 WC Pediatrics SC Pediatrics GA 717YL UT WOS:000185118300027 PM 12970646 ER PT J AU Goker-Alpan, O Schiffmann, R Park, JK Stubblefield, BK Tayebi, N Sidransky, E AF Goker-Alpan, O Schiffmann, R Park, JK Stubblefield, BK Tayebi, N Sidransky, E TI Phenotypic continuum in neuronopathic Gaucher disease: An intermediate phenotype between type 2 and type 3 SO JOURNAL OF PEDIATRICS LA English DT Article ID HUMAN GLUCOCEREBROSIDASE GENE; ACID BETA-GLUCOSIDASE; MUTATION; PSEUDOGENE; TRAITS AB Neuronopathic Gaucher disease, classically divided into two types, can have a continuum of phenotypes, often defying categorization. Nine children had an intermediate phenotype characterized by a delayed age of onset but rapidly progressive neurological disease. including refractory seizures and oculomotor abnormalities. There was genotypic heterogeneity among these patients. C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NIMH, Sect Mol Neurogenet, NIH, 49 Convent Dr,MSC4405,49-BIEE16, Bethesda, MD 20892 USA. EM sidranse@irp.nimh.nih.gov NR 18 TC 47 Z9 49 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2003 VL 143 IS 2 BP 273 EP 276 DI 10.1067/S0022-3476(03)00302-0 PG 4 WC Pediatrics SC Pediatrics GA 717YL UT WOS:000185118300028 PM 12970647 ER PT J AU Wu, Z Prahl, A Powell, R Ericksen, B Lubkowski, J Lu, W AF Wu, Z Prahl, A Powell, R Ericksen, B Lubkowski, J Lu, W TI From pro defensins to defensins: synthesis and characterization of human neutrophil pro alpha-defensin-1 and its mature domain SO JOURNAL OF PEPTIDE RESEARCH LA English DT Article DE antimicrobial peptide/protein; defensin; disulfide mapping; fluorescence spectroscopy; native chemical ligation; pro defensin; solid-phase pepticle synthesis ID ANTIMICROBIAL PEPTIDES; BETA-DEFENSINS; CHEMICAL LIGATION; MASS-SPECTROMETRY; CYANOGEN-BROMIDE; PROTEINS; PURIFICATION; HNP-1; ANTIBIOTICS; SEQUENCE AB Human neutrophil alpha-defensins (HNPs) are small, cationic, Cys-rich antimicrobial proteins that play important roles in innate immunity against infectious microbes such as bacteria, fungi and enveloped viruses. Synthesized as inactive precursors in vivo (pre-proHNPs), HNPs are activated through proteolytic removal of the inhibitory pro-peptide required for subcellular sorting and correct folding. We seek to understand the molecular basis for the recognition between the 45-residue propeptide and the C-terminal functional domain. Here we described, total chemical synthesis of the 75-residue human neutrophil pro alpha-defensin-1 (proHNP1) via native chemical ligation. After oxidative folding, proHNP1 is cleaved by cyanogen bromide at the Met(45)-Ala(46) peptide bond to release the mature form. The native disulfide connectivity in HNP1, i.e. Cys(1)-Cys(6), Cys(2)-Cys(4) and Cys(3)-Cys(5), is verified by mass mapping of peptide fragments generated by proteolytic digestion and Edman degradation. Fluorescence spectroscopy studies and antimicrobial activity assays further support that synthetic proHNP1 and HNP1 are correctly folded. While largely unstructured in aqueous solution, the pro-peptide binds to HNP1 intermolecularly with an apparent K-d value of 6.2 mum at pH 7.4, confirming the mode of intramolecular inactivation of human alpha-defensin precursors. C1 Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. NCI, Macromol Assembly Struct & Cell Signaling Sect, Frederick, MD 21702 USA. RP Lu, W (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. RI Lu, Wuyuan/B-2268-2010; Ericksen, Bryan/F-9047-2012; Prahl, Adam/H-7654-2014 NR 41 TC 32 Z9 33 U1 0 U2 8 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1397-002X J9 J PEPT RES JI J. Pept. Res. PD AUG PY 2003 VL 62 IS 2 BP 53 EP 62 DI 10.1034/j.1399-3011.2003.00068.x PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 698CG UT WOS:000183979600001 PM 12823617 ER PT J AU Moykkynen, T Korpi, ER Lovinger, DM AF Moykkynen, T Korpi, ER Lovinger, DM TI Ethanol inhibits alpha-amino-3-hydyroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function in central nervous system neurons by stabilizing desensitization SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID EXCITATORY SYNAPTIC TRANSMISSION; MOUSE HIPPOCAMPAL-NEURONS; GLUTAMATE RECEPTORS; KAINATE RECEPTORS; RAPID DESENSITIZATION; XENOPUS OOCYTES; TIME-COURSE; RAT; RELEASE; CELLS AB Ethanol actions on alpha-amino-3-hydyroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors were studied using voltage-clamp recordings from mouse cortical and hippocampal neurons. During whole-cell recordings ethanol (EtOH) inhibited AMPA receptor-mediated currents in a dose-dependent manner at concentrations from 10 to 500 mM. The steady-state component of AMPA-activated current was more sensitive to EtOH than the peak component. To examine the effect of EtOH on a well resolved peak current component, patches were excised from cultured cortical neurons, to which AMPA and EtOH were applied using a piezoelectric solution application system. Under this condition, the peak current was not inhibited significantly by EtOH. To further study possible mechanisms of EtOH inhibition, kainate and AMPA were used to evoke currents in the absence and presence of cyclothiazide. Ethanol inhibition was stronger when receptors were activated by low than high kainate concentrations. Cyclothiazide reduced inhibition by EtOH regardless of the agonist used to activate the receptor. Finally, EtOH inhibition was reduced in a point mutated (L497Y) GluRAi receptor that lacks desensitization. These findings suggest that EtOH inhibits AMPA receptors by stabilizing the desensitized state. Our results can explain some of the variation observed in EtOH inhibition in previous studies, and support the idea that physiologically relevant concentrations of EtOH can have a strong effect on AMPA receptor function. C1 NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. Univ Turku, Dept Pharmacol & Clin Pharmacol, Turku, Finland. Univ Helsinki, Inst Biomed, Helsinki, Finland. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, 12420 Parklawn Dr, Rockville, MD 20852 USA. FU NIAAA NIH HHS [AA08986] NR 39 TC 41 Z9 43 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2003 VL 306 IS 2 BP 546 EP 555 DI 10.1124/jpet.103.050666 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 703AP UT WOS:000184258100018 PM 12734392 ER PT J AU Hayashi, T Su, TP AF Hayashi, T Su, TP TI sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: Roles in endoplasmic reticulum lipid compartmentalization and export SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RAT-BRAIN; PROTEIN-KINASE; CHOLESTEROL; COCAINE; CELLS; GENE; EXPRESSION; ISOMERASE; CAVEOLIN; LIGANDS AB The brain sigma-1 receptors can bind neurosteroids and psychotropic drugs, including neuroleptics and cocaine and are implicated in schizophrenia, depression, and drug dependence. In this study, we found that sigma-1 receptors specifically target lipid storage sites ( lipid droplets) on the endoplasmic reticulum by forming a distinct class of lipid microdomains. Both endogenously expressing sigma-1 receptors and transfected C-terminally enhanced yellow fluorescent protein (EYFP)-tagged sigma-1 receptors (Sig-1R-EYFP) target unique "ring-like" structures associated with endoplasmic reticulum reticular networks in NG108-15 cells. The ring-like structures contain neutral lipids and are enlarged by the oleate treatment, indicating that they are endoplasmic reticulum-associated lipid droplets (ER-LDs). sigma-1 receptors colocalize with caveolin-2, a cholesterol-binding protein in lipid rafts on the ER-LDs, but not with adipocyte differentiation-related protein (ADRP), a cytosolic lipid droplet (c-LD)-specific protein. When the double-arginine ER retention signal on the N terminus of sigma-1 receptors is truncated, sigma-1 receptors no longer exist on ER-LDs, but predominantly target c-LDs, which contain ADRP. sigma-1 receptors on ER-LDs form detergent-resistant raft-like lipid microdomains, the buoyancy of which is different from that of plasma membrane lipid rafts. (+)-Pentazocine causes sigma-1 receptors to disappear from the microdomains. N-Terminally EYFP-tagged sigma-1 receptors (EYFP-Sig-1R) failed to target ER-LDs. EYFP-Sig-1R-transfected cells showed an unrestricted distribution of neutral lipids all over the endoplasmic reticulum network, decreases in c-LDs and cholesterol in plasma membranes, and the bulbous aggregation of endoplasmic reticulum. Thus, sigma-1 receptors are unique endoplasmic reticulum proteins that regulate the compartmentalization of lipids on the endoplasmic reticulum and their export from the endoplasmic reticulum to plasma membrane and c-LDs. C1 NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,US Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 40 TC 129 Z9 131 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2003 VL 306 IS 2 BP 718 EP 725 DI 10.1124/jpet.103.051284 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 703AP UT WOS:000184258100039 PM 12730355 ER PT J AU Hayashi, T Su, TP AF Hayashi, T Su, TP TI Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-KINASE; LIPID DROPLETS; RAT-BRAIN; CHOLESTEROL; LOCALIZATION; INHIBITORS; ISOMERASE; LIGANDS; CLONING AB The sigma-1 receptors bind diverse kinds of psychoactive compounds, including cocaine, and translocate upon stimulation by these compounds. However, the exact intracellular localization and dynamics of sigma-1 receptors have been unclear. We recently found that sigma-1 receptors specifically localize on cholesterol-enriched loci on the endoplasmic reticulum ( ER) membrane that function as neutral lipid storage sites (i.e., ER lipid droplets or ER-LDs) from which neutral lipids bud out to form cytosolic lipid droplets. By combining immunocytochemistry and real-time monitoring of enhanced yellow fluorescent protein (EYFP)tagged sigma-1 receptors (Sig-1R-EYFP) in living cells, we characterized the sigma-1 receptor translocation in this study. (+)-Pentazocine, a selective sigma-1 receptor agonist, causes a significant decrease of sigma-1 receptors in ER-LDs and a diffused distribution of sigma-1 receptors over the entire endoplasmic reticulum reticular network in NG108-15 cells. In the presence of sigma-1 receptor agonists, Sig-1R-EYFP move out from ER-LDs and slide along the endoplasmic reticulum network toward nuclear envelope and the tip of neurites. Fluorescence recovery after photobleaching analysis demonstrates that Sig-1R-EYFP on endoplasmic reticulum reticular network are highly mobile compared with those in ER-LDs. A sucrose gradient fractionation study shows that (+)-pentazocine shifts sigma-1 receptors from ER-LD membranes to higher density membranes. These results indicate that sigma-1 receptors localize on ER-LDs and upon stimulation translocate on continuous endoplasmic reticulum reticular network toward peripheries of cells. Because sigma-1 receptors specifically target ER lipid storage sites and compartmentalize neutral lipids therein, these results suggest that sigma-1 receptors' dynamic translocation might affect lipid transport and distribution in neuronal cells. C1 NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,US Dept HHS, TRIAD Bldg,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 40 TC 102 Z9 105 U1 2 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2003 VL 306 IS 2 BP 726 EP 733 DI 10.1124/jpet.103.051292 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 703AP UT WOS:000184258100040 PM 12730356 ER PT J AU McGowan, JA AF McGowan, JA TI Perspectives on the future of bone and joint diseases SO JOURNAL OF RHEUMATOLOGY LA English DT Article; Proceedings Paper CT International Conference for the Bone and Joint Decade CY APR 17-19, 2002 CL TOKYO, JAPAN DE musculoskeletal diseases; arthritis; osteoporosis; osteoarthritis initiative; Bone and joint decade AB The diseases of bones, joints, and muscles are common, chronic, and very costly to society. While the impact of these diseases falls across the age spectrum, the worldwide growth in the. percentage of elderly in the population makes attention to musculoskeletal disorders and conditions particularly critical. An effective prevention strategy, driven by an understanding of the fundamental biology of bone and connective tissue, can only result from an upshift in the efforts of many sectors-public and private, academic, scientific, and patient-based-with new opportunities for partnerships and collaborative efforts flourishing. The Decade of the Bone and Joint can serve as a catalyst in this effort. The National Institutes of Health (NIH) are pleased to join with other national and international organizations to promote new activities and initiatives during the next decade. The NIH Osteoarthritis Initiative is highlighted as an example of a public-private partnership to develop resources and information on the natural history of the disease process that can drive new clinical intervention studies in osteoarthritis. Hopefully, this initiative and others will pave the way for important, scientifically driven prevention strategies during the next decade. C1 NIAMSD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP McGowan, JA (reprint author), NIAMSD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 1 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2003 VL 30 SU 67 BP 62 EP 64 PG 3 WC Rheumatology SC Rheumatology GA 712FZ UT WOS:000184788300022 ER PT J AU Cain, VS Johannes, CB Avis, NE Mohr, B Schocken, M Skurnick, J Ory, M AF Cain, VS Johannes, CB Avis, NE Mohr, B Schocken, M Skurnick, J Ory, M TI Sexual functioning and practices in a multi-ethnic study of midlife women: Baseline results from SWAN SO JOURNAL OF SEX RESEARCH LA English DT Article ID MIDDLE-AGED WOMEN; MENOPAUSE; COMMUNITY; BEHAVIOR; SYMPTOMS; HORMONES; DYSFUNCTION; ETHNICITY; LIFE AB This study examined the sexual practices and function of midlife women by ethnicity (African American, Caucasian, Chinese, Hispanic, Japanese) and menopausal status. Sexual behavior was compared in 3,262 women in the baseline cohort of SWAN. Participants were 42 to 52 years old, premenopausal or early perimenopausal, and not hysterectomized or using hormones. Analysis used multivariate proportional odds regression. In our sample, 79% had engaged in sex with a partner in the last 6 months, and a third considered sex to be very important. Common reasons for no sex (n = 676) were lack of partner (67%), lack of interest (33%), and fatigue (16%). Compared with Caucasians, Japanese and Chinese women were less likely, and African Americans more likely, to report sex as very important (p < 0.005). Significant ethnic differences were found for frequency of all practices. Perimenopause status was associated only with higher frequencies of masturbation and pain during intercourse. C1 NIH, Off Behav Social Sci Res, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Texas A&M Univ, College Stn, TX 77843 USA. RP Cain, VS (reprint author), NIH, Off Behav Social Sci Res, 1 Ctr Dr,Room 256, Bethesda, MD 20892 USA. FU NIA NIH HHS [U01 AG12546, U01 AG12495, U01 AG12505, U01 AG12531, U01 AG12535, U01 AG12539, U01 AG12553, U01 AG12554]; NINR NIH HHS [U01 NR04061] NR 43 TC 141 Z9 142 U1 3 U2 8 PU SOC SCIENTIFIC STUDY SEX INC PI MT VERNON PA PO BOX 208, MT VERNON, IA 52314 USA SN 0022-4499 J9 J SEX RES JI J. Sex Res. PD AUG PY 2003 VL 40 IS 3 BP 266 EP 276 PG 11 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 722LR UT WOS:000185376700007 PM 14533021 ER PT J AU Zhang, PJ Borgnia, MJ Mooney, P Shi, D Pan, M O'Herron, P Mao, A Brogan, D Milne, JLS Subramaniam, S AF Zhang, PJ Borgnia, MJ Mooney, P Shi, D Pan, M O'Herron, P Mao, A Brogan, D Milne, JLS Subramaniam, S TI Automated image acquisition and processing using a new generation of 4K x 4K CCD cameras for cryo electron microscopic studies of macromolecular assemblies SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE cryo electron microscopy; CCD camera; image processing ID LOW-RESOLUTION MAPS; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; ATOMIC-RESOLUTION; VITREOUS ICE; PERFORMANCE; COMPLEX; SYSTEM; TOMOGRAPHY; DETECTORS AB We have previously reported the development of AutoEM, a software package for semi-automated acquisition of data from a transmission electron microscope. In continuing efforts to improve the speed of structure determination of macromolecular assemblies by electron microscopy, we report here on the performance of a new generation of 4K CCD cameras for use in cryo electron microscopic applications. We demonstrate that at 120 kV, and at a nominal magnification of 67 000 x, power spectra and signal-to-noise ratios for the new 4K CCD camera are comparable to values obtained for film images scanned using a Zeiss scanner to resolutions as high as similar to1/6.5 Angstrom(-1). The specimen area imaged for each exposure on the 4K CCD is about one-third of the area that can be recorded with a similar exposure on film. The CCD camera also serves the purpose of recording images at low magnification from the center of the hole to measure the thickness of vitrified ice in the hole. The performance of the camera is satisfactory under the low-dose conditions used in cryo electron microscopy, as demonstrated here by the determination of a three-dimensional map at 15 Angstrom for the catalytic core of the 1.8 MDa Bacillus stearothermophilus icosahedral pyruvate dehydrogenase complex, and its comparison with the previously reported atomic model for this complex obtained by X-ray crystallography. Published by Elsevier Inc. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Labs, NIH, Bethesda, MD 20892 USA. GATAN Inc, Pleasanton, CA USA. RP Subramaniam, S (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 32 TC 38 Z9 40 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2003 VL 143 IS 2 BP 135 EP 144 DI 10.1016/S1047-8477(03)00124-2 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 725AY UT WOS:000185521500005 PM 12972350 ER PT J AU Bhathena, SJ Ali, AA Haudenschild, C Latham, P Ranich, T Mohamed, AI Hansen, CT Velasquez, MT AF Bhathena, SJ Ali, AA Haudenschild, C Latham, P Ranich, T Mohamed, AI Hansen, CT Velasquez, MT TI Protective effects of flax meal against hypercholesterolemia and hypertriglyceridemia in rats - Response SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Letter ID DIETARY PHYTOESTROGENS; LIPIDS; FAT C1 USDA ARS, Beltsville Agr Res Ctr, Beltsville, MD 20705 USA. Ain Shams Univ, Dept Food Sci, Cairo, Egypt. Amer Red Cross, Jerome H Holland Lab, Rockville, MD USA. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. Virginia State Univ, Petersburg, VA USA. Natl Inst Hlth, Bethesda, MD USA. RP Bhathena, SJ (reprint author), USDA ARS, Beltsville Agr Res Ctr, Beltsville, MD 20705 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL NUTRITION PI NEW YORK PA C/O HOSP. JOINT DIS. 301 E. 17TH ST., NEW YORK, NY 10003 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD AUG PY 2003 VL 22 IS 4 BP 327 EP 329 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 707RR UT WOS:000184524100012 ER PT J AU Michaud, DS Troiano, RP Subar, AF Runswick, S Bingham, S Kipnis, V Schatzkin, A AF Michaud, DS Troiano, RP Subar, AF Runswick, S Bingham, S Kipnis, V Schatzkin, A TI Comparison of estimated renal net acid excretion from dietary intake and body size with urine pH SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRES; N-GLUCURONIDATION; BENZIDINE; VALUES AB Objective The aim of this study was to examine whether estimated net acid excretion (NAE) from two dietary assessment instruments can predict urine pH in healthy volunteers. Design The Observing Protein and Energy Nutrition (OPEN) study, which was designed to assess dietary measurement error, included men and women aged 40 to 69 years. Participants were asked to complete two food frequency questionnaires (FFQs) and two 24-hour recalls at approximately three-month intervals, and to return two 24-hour urine samples during the same period. NAE was estimated using a previously described equation. The estimates obtained from the different dietary assessment measures were correlated with actual urine pH. Subjects/setting Four hundred eighty-four subjects were enrolled in the OPEN study. All participants were included in this study on urine pH, given that they had all completed at least one dietary assessment and one urine sample. The study took place in Montgomery County, MD, between September 1999 and March 2000. Results Correlation coefficients between NAE estimates using the FFQ data and the average of two urine pH measures were -0.34 and -0.39 for women and men, respectively. Removing within-person variance in the urine pH levels resulted in a deattenuated overall correlation of -0.50 for the FFQ. Correlations between the 24-hour recall estimates of NAE were -0.41 and -0.32 for women and men, respectively. For. the 24-hour recalls, the deattenuated overall correlation was -0.50. Application/conclusions Our findings suggest that FFQs provide adequate dietary data to estimate renal NAE and could be used as a surrogate for urinary pH levels in large epidemiologic studies. C1 NCI, Appl Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. MRC, Dunn Human Nutr Unit, Cambridge, England. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Michaud, DS (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-320 MSC 7232, Bethesda, MD 20892 USA. RI Michaud, Dominique/I-5231-2014; OI Troiano, Richard/0000-0002-6807-989X NR 19 TC 22 Z9 23 U1 1 U2 4 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 2003 VL 103 IS 8 BP 1001 EP 1007 DI 10.1053/jada.2003.50189 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 706PD UT WOS:000184461300011 PM 12891148 ER PT J AU Geroldi, C Ferrucci, L Bandinelli, S Cavazzini, C Zanetti, O Guralnik, JM Frisoni, GB AF Geroldi, C Ferrucci, L Bandinelli, S Cavazzini, C Zanetti, O Guralnik, JM Frisoni, GB TI Mild cognitive deterioration with subcortical features: Prevalence, clinical characteristics, and association with cardiovascular risk factors in community-dwelling older persons (The InCHIANTI study) SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cognitive impairment; parkinsonism; subcortical features; vascular risk factor ID IMPAIRMENT; MORTALITY; AGE; PEOPLE; GAIT; POPULATION; DEMENTIA; WALKING; DISEASE; HEALTH AB OBJECTIVES: To identify subjects with minimal or mild nonamnestic cognitive impairment with parkinsonian stance and gait and investigate vascular correlates of this condition. DESIGN: First wave of an epidemiological longitudinal study (InCHIANTI) on factors predicting loss of mobility in older persons. SETTING: The Chianti geographic area (Tuscany, Italy). PARTICIPANTS: Five hundred fifty-six subjects aged 70 to 90 with Mini-Mental State Examination (MMSE) scores greater than 23 of 30, of the 1,260 persons aged 65 and older randomly selected from the population registry of Greve in Chianti and Bagno a Ripoli, two small towns near Florence. METHODS: Low cognitive performance (LCP) was defined as an age- and education-adjusted MMSE below the 50th percentile for the InCHIANTI population. Subcortical features were plastic rigidity on neurological examination (parkinsonism), gait disturbance (small-step gait or parkinsonian gait), and dysexecutive features. Two hundred forty-three participants had high cognitive performance, 166 had LCP without subcortical features, and 75 had LCP with subcortical features. Vascular risk factors were hypertension, atrial fibrillation or pathological findings on electrocardiogram (ECG), low serum high-density lipoprotein (HDL) or high low-density lipoprotein cholesterol, diabetes mellitus, obesity, and heavy smoking. RESULTS: Three main vascular risk factors were significantly more prevalent in LCP with subcortical features: hypertension (P = .02), atrial fibrillation or ECG changes (P = .04), and low HDL cholesterol (P = .001). LCP with subcortical features was significantly associated with cerebrovascular risk factors (P = .001). CONCLUSION: Gait disturbance and nonamnestic cognitive symptoms might be the consequence of subcortical vascular damage. C1 IRCCS San Giovanni di Dio, FBF, Lab Epidemiol & Neuroimaging, I-25125 Brescia, Italy. IRCCS San Giovanni di Dio, Alzheimers Unit, I-25125 Brescia, Italy. NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. RP Frisoni, GB (reprint author), IRCCS San Giovanni di Dio, FBF, Lab Epidemiol & Neuroimaging, Via Pilastroni 4, I-25125 Brescia, Italy. RI Geroldi, Cristina/K-1524-2016; Frisoni, Giovanni B/K-1360-2016; Zanetti, Orazio/K-9967-2016 OI Geroldi, Cristina/0000-0001-7861-1678; Frisoni, Giovanni B/0000-0002-6419-1753; Zanetti, Orazio/0000-0002-5408-0048 NR 30 TC 40 Z9 47 U1 5 U2 7 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2003 VL 51 IS 8 BP 1064 EP 1071 DI 10.1046/j.1532-5415.2003.51353.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 706RT UT WOS:000184468400002 PM 12890067 ER PT J AU Reuben, DB Judd-Hamilton, L Harris, TB Seeman, TE AF Reuben, DB Judd-Hamilton, L Harris, TB Seeman, TE TI The associations between physical activity and inflammatory markers in high-functioning older persons: MacArthur studies of successful aging SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE inflammation; physical activity; cytokines ID CARDIOVASCULAR RISK-FACTORS; CORONARY HEART-DISEASE; C-REACTIVE PROTEIN; DISABILITY; MORTALITY; HEALTH; ADULTS; INTERLEUKIN-6; QUESTIONNAIRE; CYTOKINES AB OBJECTIVES: To determine the relationships between recreational activity, house/yard work activity, work activity, and total physical activity and high levels of two peripheral blood markers of inflammation: interleukin-6 (IL-6) and C-reactive protein (CRP). DESIGN: Cross-sectional study. SETTING: Three communities (Durham, NC; New Haven, CT; and East Boston, MA). PARTICIPANTS: Eight hundred seventy persons aged 70 to 79 who were in the top third of community-dwelling older persons with respect to physical and cognitive functioning. MEASUREMENTS: Blood levels of IL-6 and CRP and self-reported recreational activity, house/yard work activity, work activity, and total physical activity. RESULTS: The adjusted odds ratios (AORs) for individuals with high levels of recreational activity to have values in the top tertiles of IL-6 and CRP were 0.65 (95% confidence interval (CI) = 0.48-0.87) and 0.70 (95% CI = 0.51-0.95), respectively. The AORs for those with a high level of house/yard work activity to have values in the top tertile of IL-6 and CRP were 0.90 (95% CI = 0.67-1.20) and 0.70 (95% CI = 0.50-0.96), respectively. High levels of house/yard work and recreational activity were independently associated with lower risk of high CRP. CONCLUSION: The association between high levels of recreational activity and lower levels of the inflammatory markers IL-6 and CRP suggests a mechanism for its protective effect and supports interventions that increase physical activity in older persons. Such potential benefits of increased physical activity on inflammatory markers will need to be confirmed in clinical trials. C1 Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. NIA, Bethesda, MD 20892 USA. RP Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM dreuben@mednet.ucla.edu NR 28 TC 117 Z9 124 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2003 VL 51 IS 8 BP 1125 EP 1130 DI 10.1046/j.1532-5415.2003.51380.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 706RT UT WOS:000184468400012 PM 12890077 ER PT J AU Butler, RN AF Butler, RN TI Selected as the best paper in JAGS in the 1970s - Mission of the national institute on aging SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT 33rd Annual Meeting of the American-Geriatrics-Society CY APR 21-23, 1976 CL HOUSTON, TEXAS SP American Geriatrics Soc AB The National Institute on Aging (NIA), the newest of the 11 National Institutes of Health, is dedicated to improving the quality of life of the old in America through biomedical, social, and behavioral research. Aging is viewed as more than just decline and deterioration; it is also a process of continued development and accumulated knowledge. The NIA will encourage innovative research but will not support the delivery of health services, as that is the domain of the other agencies. In areas of overlap, such as diseases common to the old, the NIA will collaborate with other Institutes. A good target area for collaboration is senile dementia. Other areas of interest to the NIA are: encouraging the incorporation of geriatric medicine as a subspecialty, developing retirement test patterns, and investigating drug-drug and drug-age interactions, personality and social processes, and immunocompetence. C1 NIA, Bethesda, MD 20892 USA. RP Butler, RN (reprint author), Care Of Shure JE, Bldg 31,Room 4B-32,9000 Rockville Pike, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2003 VL 51 IS 8 BP 1169 EP 1173 DI 10.1046/j.1532-5415.2003.t01-1-51371.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 706RT UT WOS:000184468400019 PM 12890084 ER PT J AU Guo, Q Qian, SY Mason, RP AF Guo, Q Qian, SY Mason, RP TI Separation and identification of DMPO adducts of oxygen-centered radicals formed from organic hydroperoxides by HPLC-ESR, ESI-MS and MS/MS SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID LINOLEIC-ACID HYDROPEROXIDE; TERT-BUTYL HYDROPEROXIDE; MASS-SPECTROMETRY; SOYBEAN LIPOXYGENASE; CYTOCHROME-C; PEROXYL RADICALS; SPIN-RESONANCE; ALKOXYL; DECOMPOSITION; DISEASE AB Many electron spin resonance (ESR) spectra of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) radical adducts from the reaction of organic hydroperoxides with heme proteins or Fe2+ were assigned to the adducts of DMPO with peroxyl, alkoxyl, and alkyl radicals. In particular, the controversial assignment of DMPO/peroxyl radical adducts was based on the close similarity of their ESR spectra to that of the DMPO/superoxide radical adduct in conjunction with their insensitivity to superoxide dismutase, which distinguishes the peroxyl adducts from the DMPO/superoxide adduct. Although recent reports assigned the spectra suggested to be DMPO/peroxyl radical adducts to the DMPO/methoxyl adduct based on independent synthesis of the adduct and/or O-17-labeling, O-17-labeling is extremely expensive, and both of these assignments were still based on hyperfine coupling constants, which have not been confirmed by independent techniques. In this study, we have used online high performance liquid chromatography (HPLC or LC)/ESR, electrospray ionization-mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) to separate and directly characterize DMPO oxygen-centered radical adducts formed from the reaction of Fe2+ with t-butyl or cumene hydroperoxide. In each reaction system, two DMPO oxygen-centered radical adducts were separated and detected by online LC/ESR. The first DMPO radical adduct from both systems showed identical chromatographic retention times (t(R) = 9.6 min) and hyperfine coupling constants (a(N) = 14.51 G, a(beta)(H) = 10.71 G, and a(gamma)(H) = 1.32 G). The ESI-MS and MS/MS spectra demonstrated that this radical was the DMPO/methoxyl radical adduct, not the peroxyl radical adduct as was thought at one time, although its ESR spectrum is nearly identical to that of the DMPO/superoxide radical adduct. Similarly, based on their MS/MS spectra, we verified that the second adducts (a(N) = 14.86 G and a(beta)(H) = 16.06 G in the reaction system containing t-butyl hydroperoxide and a(N) = 14.60 G and a(beta)(H) = 15.61 G in the reaction mixture containing cumene hydroperoxide), previously assigned as DMPO adducts of t-butyloxyl and cumyloxyl radical, were indeed from trapping t-butyloxyl and cumyloxyl radicals, respectively. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Guo, Q (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 54 Z9 56 U1 4 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 2003 VL 14 IS 8 BP 862 EP 871 DI 10.1016/S1044-0305(03)00336-2 PG 10 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 708MD UT WOS:000184570500006 PM 12892910 ER PT J AU Shigehara, T Zaragoza, C Kitiyakara, C Takahashi, H Lu, HY Moeller, M Holzman, LB Kopp, JB AF Shigehara, T Zaragoza, C Kitiyakara, C Takahashi, H Lu, HY Moeller, M Holzman, LB Kopp, JB TI Inducible podocyte-specific gene expression in transgenic mice SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID SEGMENTAL GLOMERULOSCLEROSIS; CONDITIONAL EXPRESSION; BIOLOGY; LUNG AB The podocyte plays a key role in glomerular function and glomerular disease. To facilitate studies of podocyte function, we have developed a transgenic mouse model with inducible expression in the podocyte. The tetracycline-inducible transgenic system facilitates gene expression with restricted cellular distribution and tight temporal control. Recently, Bujard and colleagues have developed a functionally improved reverse tetracycline-controlled transcriptional activator (rtTA) with substantially lower background in the off state (the absence of tetracycline) and greater inducibility in the on state (the presence of tetracycline). We used the human podocin (NPHS2) gene promoter to control expression of the rtTA cassette and bred these mice with a reporter mouse line that contains the cytomegalovirus minimal promoter and tetO promoter elements together with LacZ, encoding beta-galactosidase. Dual transgenic mice, bearing both podocin-rtTA and tetO-LacZ transgenes, had no detectable expression in kidney or other organs in the absence of tetracycline. Administration of tetracycline in the drinking water was associated with podocyte expression of beta-galactosidase, in a fashion that was time dependent (maximal at 1 wk) and dose-dependent (maximal at 2 mg/ml). Podocyte expression was confirmed in two ways: histochemical staining for beta-galactosidase and double-immunostaining using the podocyte marker WT-1 and beta-galactosidase. This transgenic system should aid future investigations of podocyte function. C1 NIDDK, Kidney Dis Sect, Metab Dis Branch, NIH,Dept Hlth & Human Sci, Bethesda, MD USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. RP Kopp, JB (reprint author), 10 Ctr Dr,MSC 1268, Bethesda, MD 20892 USA. RI Moeller, Marcus/L-1836-2015; OI Kopp, Jeffrey/0000-0001-9052-186X NR 19 TC 60 Z9 61 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2003 VL 14 IS 8 BP 1998 EP 2003 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 704QZ UT WOS:000184352600005 PM 12874453 ER PT J AU Unruh, M Yan, GF Radeva, M Hays, RD Benz, R Athienites, NV Kusek, J Levey, AS Meyer, KB AF Unruh, M Yan, GF Radeva, M Hays, RD Benz, R Athienites, NV Kusek, J Levey, AS Meyer, KB CA Hemo Study Grp TI Bias in assessment of health-related quality of life in a hemodialysis population: A comparison of self-administered and interviewer-administered surveys in the HEMO study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; DIALYSIS PATIENTS; COMORBIDITY ASSESSMENT; FUNCTIONAL HEALTH; HOSPITALIZATION; MORTALITY; INDEX AB Examined is the relationship of patient-reported health-related quality of life (HRQOL) to the mode of survey administration in the Hemodialysis Study. In addition to self-administered surveys to assess HRQOL, interviewer-administered surveys were made available to include patients with poor vision, decreased manual dexterity, or strong preference. For examining the predictors of participation by self-administration of the survey, multiple logistic regression was performed. For examining the relationship of HRQOL results to mode of survey administration, adjusted differences between the selfadministered and interviewer-administered groups were obtained from multiple linear regression models accounting for sociodemographic and case-mix factors. A total of 978 of the first 1000 subjects in the Hemodialysis Study completed the survey by interview (n = 427) or by self-administration (n = 55 1). The interviewer-administered group was older, was more likely black, had longer duration of ESRD, had a higher prevalence of diabetes, and had more severe comorbidity (all P < 0.01). After adjustment for these differences, patients in the interviewer-administered group had higher scores on scales that measured Role-Physical, Role-Emotional, and Effects of Kidney Disease (all P < 0.001). Dialysis studies that restrict HRQOL measurement to patients who are able to complete surveys without assistance will not accurately represent the health of the overall hemodialysis population. Clinical studies and clinical practices using HRQOL as an outcome should include interviewer administration or risk a selection bias against subjects with older age, minority status, and higher level of comorbidity. Future investigation should include research of survey modalities with a low response burden such as telephone interview, computer-assisted interview, and proxy administration. C1 Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15231 USA. Cleveland Clin Data Coordinating Ctr, Cleveland, OH USA. Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA USA. Lankenau Hosp, Wynnewood, PA USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. NIDDKD, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. RP Unruh, M (reprint author), Univ Pittsburgh, Med Ctr, A909 Scaife Hall, Pittsburgh, PA 15231 USA. RI Hays, Ronald/D-5629-2013 FU NIA NIH HHS [AG-02-004]; NIDDK NIH HHS [U01DK 46126, NIH/T32-DK07777, U01DK 46109, U01DK 46114, U01DK 46143, U01DK 49240, U01DK 49241, U01DK 49242, U01DK 49243, U01DK 49244, U01DK 49249, U01DK 49252, U01DK 49254, U01DK 49259, U01DK 49261, U01DK 49264, U01DK 49271]; NIMHD NIH HHS [P20-MD00148] NR 36 TC 29 Z9 29 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2003 VL 14 IS 8 BP 2132 EP 2141 DI 10.1097/01.ASN.0000076076.88336.B1 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 704QZ UT WOS:000184352600020 PM 12874468 ER PT J AU Dagher, PC Herget-Rosenthal, S Ruehm, SG Jo, SK Star, RA Agarwal, R Molitoris, BA AF Dagher, PC Herget-Rosenthal, S Ruehm, SG Jo, SK Star, RA Agarwal, R Molitoris, BA TI Newly developed techniques to study and diagnose acute renal failure SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION RATE; ACUTE TUBULAR-NECROSIS; MAGNETIC-RESONANCE ANGIOGRAPHY; LASER-SCANNING MICROSCOPY; INTRARENAL OXYGENATION; CONTRAST AGENT; BOLD MRI; TIME; APOPTOSIS; KIDNEY AB Progress in treating human acute renal failure (ARF) is dependent on developing techniques that allow for the rapid diagnosis, quantification of injury, further understanding of the pathophysiology, and the effects of therapy. Therefore, four techniques that will facilitate this progress are described and illustrated by four different investigative teams. Techniques to measure rapid changes in GFR are available for rapid diagnosis and quantification of ARF in humans. State-of-the-art magnetic resonance imaging (MRI) presently allows for enhanced resolution of regional renal blood flow and functional evaluations in patients. Furthermore, new probes and techniques for MRI that allow for identification and quantitation of inflammation, applicable to human ARF, are being developed and tested in animal models. Finally, two-photon microscopy will allow for four-dimensional cellular and subcellular studies in animal models of ARF providing rapid insights into pathophysiology and the therapeutic effects of a variety of promising agents. Further development and utilization of these techniques, especially in concert with genetic, proteomic, and molecular approaches, will allow for needed insights into the pathophysiology and therapy in human ARF. C1 Indiana Univ, Sch Med, Div Nephrol, Indianapolis, IN 46202 USA. Univ Essen Gesamthsch, Dept Nephrol, Essen, Germany. Univ Essen Gesamthsch, Dept Diagnost Radiol, Essen, Germany. NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD USA. Roudebush VA Med Ctr, Indianapolis, IN USA. RP Molitoris, BA (reprint author), Indiana Univ, Sch Med, Div Nephrol, 1120 S Dr,Fesler Hall 115, Indianapolis, IN 46202 USA. RI Agarwal, Rajiv/A-8725-2008 NR 48 TC 32 Z9 36 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2003 VL 14 IS 8 BP 2188 EP 2198 DI 10.1097/01.ASN.0000079790.91292.4A PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 704QZ UT WOS:000184352600027 PM 12874475 ER PT J AU Rhee, SG Chang, TS Bae, YS Lee, SR Kang, SW AF Rhee, SG Chang, TS Bae, YS Lee, SR Kang, SW TI Cellular regulation by hydrogen peroxide SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 4th Hyonam Kidney Laboratory International Diabetes Symposium CY JAN 18-19, 2003 CL SOON CHUN HYANG UNIV, SEOUL, SOUTH KOREA HO SOON CHUN HYANG UNIV ID PROTEIN-TYROSINE PHOSPHATASES; THIOL-SPECIFIC ANTIOXIDANT; EPIDERMAL-GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; MAMMALIAN PEROXIREDOXIN; THIOREDOXIN PEROXIDASE; SIGNAL-TRANSDUCTION; SMOOTH-MUSCLE; IN-VIVO; GENERATION AB Substantial evidence suggests that the transient production of H2O2 is an important signaling event triggered by the activation of various cell surface receptors. Understanding the intracellular messenger function of H2O2 calls for studies of how receptor occupation elicits the production of H2O2, what kinds of molecules are targeted by the produced H2O2, and how H2O2 is eliminated after the completion of its mission. Recent studies suggest that growth factor-induced H2O2 production requires the activation of PtdIns 3-kinase. The essential role of PtdIns 3-kinase is likely to provide PI(3,4,5)P-3 that recruits and activates a guanine nucleotide exchange factor of Rac, which is required for the activation of NADPH oxidase. The targets of H2O2 action include proteins that contain a reactive Cys residue. Thus, H2O2 produced in response to growth factor causes inactivation of protein tyrosine phosphatases in various cells by oxidizing specifically the catalytic Cys. These results, together with other observations, indicate that the activation of a receptor tyrosine kinase per se by binding of the corresponding growth factor might not be sufficient to increase the steady-state level of protein tyrosine phosphorylation in cells. Rather, the concurrent inhibition of protein tyrosine phosphatases by H2O2 might also be required. Peroxiredoxins, members of a newly discovered family of peroxidases, efficiently reduced the intracellular level of H2O2 produced in the cells stimulated with various cell surface ligands. Furthermore, the activity of peroxiredoxin enzymes seems to be regulated via protein phosphorylation as in the case of many other intracellular messenger metabolizing enzymes. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Ctr Cell Signaling Res, Seoul, South Korea. Ewha Womans Univ, Div Mol Life Sci, Seoul, South Korea. RP Rhee, SG (reprint author), Bldg 50,Room 3523,S Dr,MSC 8015, Bethesda, MD 20892 USA. NR 28 TC 211 Z9 219 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2003 VL 14 SU 3 BP S211 EP S215 DI 10.1097/01.ASN.0000077404.45564.7E PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 706AT UT WOS:000184430000002 PM 12874433 ER PT J AU Crainich, P Jenny, NS Tang, Z Arnold, AM Kuller, LH Manolio, T Sharrett, AR Tracy, RP AF Crainich, P Jenny, NS Tang, Z Arnold, AM Kuller, LH Manolio, T Sharrett, AR Tracy, RP TI Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE cardiovascular disease; elderly; fibrinolysis; genetic polymorphism; plasminogen activator inhibitor-1 ID MYOCARDIAL-INFARCTION; GENE POLYMORPHISMS; THROMBOTIC DISEASE; INSULIN-RESISTANCE; RISK-FACTORS; PAI-1 GENE; HEALTH; PLASMA; ARTERIAL; OBESITY AB Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi(2) P = 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes, The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly. C1 Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth Epidemiol, Baltimore, MD USA. Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. RP Tracy, RP (reprint author), Univ Vermont, Coll Med, Dept Pathol, Lab Clin Biochem Res,Colchester Res Facil, 208 S Pk Dr,Suite 2, Colchester, VT 05446 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85082, N01-HC-85084, N01-HC-85086, N01-HC-85080, N01-HC-85085, N01-HC-85083, N01-HC-85081, N01-HC-35129, N01-HC-15103] NR 39 TC 28 Z9 28 U1 0 U2 0 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD AUG PY 2003 VL 1 IS 8 BP 1799 EP 1804 DI 10.1046/j.1538-7836.2003.00255.x PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 709RL UT WOS:000184638100023 PM 12911596 ER PT J AU Linehan, WM AF Linehan, WM TI Editorial: molecular targeting of the VHL gene pathway in clear cell kidney cancer SO JOURNAL OF UROLOGY LA English DT Editorial Material ID PAPILLARY RENAL CARCINOMAS; TUMOR-SUPPRESSOR GENE; MET PROTOONCOGENE; MUTATIONS; GERMLINE C1 NCI, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Bethesda, MD 20892 USA. NR 13 TC 17 Z9 22 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2003 VL 170 IS 2 BP 593 EP 594 DI 10.1097/01.ju.0000077210.05543.ae PN 1 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 700WL UT WOS:000184134100074 PM 12853837 ER PT J AU Miller, DL Balter, S Cole, PE Lu, HT Berenstein, A Albert, R Schueler, BA Georgia, JD Noonan, PT Russell, EJ Malisch, TW Vogelzang, RL Geisinger, M Cardella, JF St George, J Miller, GL Anderson, J AF Miller, DL Balter, S Cole, PE Lu, HT Berenstein, A Albert, R Schueler, BA Georgia, JD Noonan, PT Russell, EJ Malisch, TW Vogelzang, RL Geisinger, M Cardella, JF St George, J Miller, GL Anderson, J TI Radiation doses in interventional radiology procedures: The RAD-IR study - Part II: Skin dose SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID AREA PRODUCT; ABLATION PROCEDURES; PATIENT DOSIMETRY; EXPOSURE; FLUOROSCOPY; INJURIES; NEURORADIOLOGY; FILTRATION; RISK AB PURPOSE: To determine peak skin dose (PSD), a measure of the likelihood of radiation-induced skin effects, for a variety of common interventional radiology and interventional neuroradiology procedures, and to identify procedures associated with a PSD greater than 2 Gy. MATERIALS AND METHODS: An observational study was conducted at seven academic medical centers in the United States. Sites prospectively contributed demographic and radiation dose data for subjects undergoing 21 specific procedures in a fluoroscopic suite equipped with built-in dosimetry capability. Comprehensive physics evaluations and periodic consistency checks were performed on each unit to verify the stability and consistency of the dosimeter. Seven of 12 fluoroscopic suites in the study were equipped with skin dose mapping software. RESULTS: Over a 3-year period, skin dose data were recorded for 800 instances of 21 interventional radiology procedures. Wide variation in PSD was observed for different instances of the same procedure. Some instances of each procedure we studied resulted in a PSD greater than 2 Gy, except for nephrostomy, pulmonary angiography, and inferior vena cava filter placement. Some instances of transjugular intrahepatic portosystemic shunt (TIPS) creation, renal/visceral angioplasty, and angiographic diagnosis and therapy of gastrointestinal hemorrhage produced PSDs greater than 3 Gy. Some instances of hepatic chemoembolization, other tumor embolization, and neuroembolization procedures in the head and spine produced PSDs greater than 5 Gy. In a subset of 709 instances of higher-dose procedures, there was good overall correlation between PSD and cumulative dose (r = 0.86; P < .000001) and between PSD and dose-area-product (r = 0.85, P < .000001), but there was wide variation in these relationships for individual instances. CONCLUSIONS: There are substantial variations in PSD among instances of the same procedure and among different procedure types. Most of the procedures observed may produce a PSD sufficient to cause deterministic effects in skin. It is suggested that dose data be recorded routinely for TIPS creation, angioplasty in the abdomen or pelvis, all embolization procedures, and especially for head and spine embolization procedures. Measurement or estimation of PSD is the best method for determining the likelihood of radiation-induced skin effects. Skin dose mapping is preferable to a single-point measurement of PSD. C1 Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Radiol & Nucl Med, Bethesda, MD 20814 USA. NCI, Ctr Canc Res, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. Lenox Hill Hosp, Dept Med, New York, NY 10021 USA. Beth Israel Med Ctr, Ctr Endovasc Surg, Hyman Newman Inst Neurol & Neurosurg, New York, NY 10003 USA. SUNY Upstate Med Univ, Dept Radiol, Syracuse, NY USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. Mayo Clin, Dept Radiol, Rochester, MN USA. Cleveland Clin Fdn, Dept Radiol, Cleveland, OH 44195 USA. NW Mem Hosp, Feinberg Sch Med, Dept Radiol, Chicago, IL 60611 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. RP Miller, DL (reprint author), Natl Naval Med Res Inst, Dept Radiol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM dm72v@nih.gov NR 44 TC 143 Z9 153 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2003 VL 14 IS 8 BP 977 EP 990 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 708MY UT WOS:000184572800005 PM 12902555 ER PT J AU Graham, DRM Chertova, E Hilburn, JM Arthur, LO Hildreth, JEK AF Graham, DRM Chertova, E Hilburn, JM Arthur, LO Hildreth, JEK TI Cholesterol depletion of human immunodeficiency virus type 1 and simian immunodeficiency virus with beta-cyclodextrin inactivates and permeabilizes the virions: Evidence for virion-associated lipid rafts SO JOURNAL OF VIROLOGY LA English DT Article ID LEUCINE-ZIPPER DOMAIN; MEMBRANE CHOLESTEROL; CELLULAR-PROTEINS; GAG PROTEIN; HOST-CELLS; PLASMA-MEMBRANE; HIV-1 GP41; ACTIN; SIV; CYTOSKELETON AB Recent evidence suggests that human immunodeficiency virus type 1 (HIV-1) particles assemble and bud selectively through areas in the plasma membrane of cells that are highly enriched with glycosyllphosphatidy-linositol-anchored proteins and cholesterol, called lipid rafts. Since cholesterol is required to maintain lipid raft structure and function, we proposed that virion-associated cholesterol removal with the compound 2-hydroxy-propyl-beta-cyelodextrin (beta-CD) might be disruptive to HIV-1 and simian immunodeficiency virus (SIV). We examined the effect of beta-CD on the structure and infectivity of cell-free virions. We found that beta-CD inactivated HIV-1 and SIV in a dose-dependent manner and permeabilized the viral membranes, resulting in the loss of mature Gag proteins (capsid, matrix, nucleocapsid, p1, and p6) without loss of the envelope glycoproteins. SIV also lost reverse transcriptase (RT), integrase (IN), and viral RNA. IN appeared to be only slightly diminished in HIV-1, and viral RNA, RT, matrix, and nucleocapsid proteins were retained in HIV-1 but to a much lesser degree. Host proteins located internally in the virus (actin, moesin, and ezrin) and membrane-associated host proteins (major histocompatibillity complex classes I and II) remained associated with the treated virions. Electron microscopy revealed that under conditions that permeabilized the viruses, holes were present in the viral membranes and the viral core structure was perturbed. These data provide evidence that an intact viral membrane is required to maintain mature virion core integrity. Since the viruses were not fixed before beta-CD treatment and intact virion particles were recovered, the data suggest that virions may possess a protein scaffold that can maintain overall structure despite disruptions in membrane integrity. C1 Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Leukocyte Immunochem Lab, Baltimore, MD 21205 USA. NCI Frederick, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Hildreth, JEK (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Leukocyte Immunochem Lab, 725 N Wolfe St,320A Physiol Bldg, Baltimore, MD 21205 USA. FU NCI NIH HHS [N01CO12400]; NIAID NIH HHS [AI46291, AI31806, R01 AI031806]; NICHD NIH HHS [HD39613]; PHS HHS [N01C0-12400] NR 62 TC 129 Z9 131 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 15 BP 8237 EP 8248 DI 10.1128/JVI.77.15.8237-8248.2003 PG 12 WC Virology SC Virology GA 702FP UT WOS:000184214300007 PM 12857892 ER PT J AU Grivel, JC Santoro, F Chen, S Faga, G Malnati, MS Ito, Y Margolis, L Lusso, P AF Grivel, JC Santoro, F Chen, S Faga, G Malnati, MS Ito, Y Margolis, L Lusso, P TI Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN HERPESVIRUS-6 INFECTION; MULTIPLE-SCLEROSIS; CXCR4-TROPIC HIV-1; DOWN-REGULATION; TROPISM; CELLS; HHV-6; CD4; HISTOCULTURES AB Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4(+) T lymphocytes expressing a nonnaive phenotype, while CD8(+) T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4(+) and CD8(+) T cells, whereas in HFUV-6B-infected tissue CD4(+) T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodullation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines. C1 San Raffaele Sci Inst, DIBIT, Unit Human Virol, Dept Biol & Technol Res, I-20132 Milan, Italy. Univ Cagliari, Dept Med Sci, I-09123 Cagliari, Italy. NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. NIH, NASA, Ctr 3 Dimens Tissue Culture, Bethesda, MD 20892 USA. RP Margolis, L (reprint author), San Raffaele Sci Inst, DIBIT, Unit Human Virol, Dept Biol & Technol Res, Via Olgettina 58, I-20132 Milan, Italy. NR 30 TC 59 Z9 61 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 15 BP 8280 EP 8289 DI 10.1128/JVI.77.15.8280-8289.2003 PG 10 WC Virology SC Virology GA 702FP UT WOS:000184214300012 PM 12857897 ER PT J AU Zhao, J Pinczewski, J Gomez-Roman, VR Venzon, D Kalyanaraman, VS Markham, PD Aldrich, K Moake, M Montefiori, DC Lou, YM Pavlakis, GN Robert-Guroff, M AF Zhao, J Pinczewski, J Gomez-Roman, VR Venzon, D Kalyanaraman, VS Markham, PD Aldrich, K Moake, M Montefiori, DC Lou, YM Pavlakis, GN Robert-Guroff, M TI Improved protection of rhesus macaques against intrarectal simian immunodeficiency virus SIVmac251 challenge by a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODY-RESPONSE; CELLULAR IMMUNE-RESPONSES; HOST-RANGE MUTANT; VIRAL LOAD; DISEASE PROGRESSION; VACCINE PROTECTION; DENDRITIC CELLS; PATHOGENIC SIV; GAG-POL; ADENOVIRUS AB In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virus(mac251). Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIVmac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A*01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8(+) T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Adv Biosci Lab Inc, Kensington, MD 20895 USA. Duke Univ, Med Ctr, Ctr AIDS Res, Durham, NC 27710 USA. NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. RP Robert-Guroff, M (reprint author), NCI, Basic Res Lab, NIH, 41 Lib Dr,Bldg 41,Rm D804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 FU NIAID NIH HHS [N01-AI15430, N01AI15430] NR 55 TC 43 Z9 44 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 15 BP 8354 EP 8365 DI 10.1128/JVI.77.15.8354-8354-8365.2003 PG 12 WC Virology SC Virology GA 702FP UT WOS:000184214300020 PM 12857905 ER PT J AU McGrath, CF Buckman, JS Gagliardi, TD Bosche, WJ Coren, LV Gorelick, RJ AF McGrath, CF Buckman, JS Gagliardi, TD Bosche, WJ Coren, LV Gorelick, RJ TI Human cellular nucleic acid-binding protein Zn2+ fingers support replication of human immunodeficiency virus type 1 when they are substituted in the nucleocapsid protein SO JOURNAL OF VIROLOGY LA English DT Article ID STEROL REGULATORY ELEMENT; MURINE LEUKEMIA-VIRUS; LIPOPROTEIN RECEPTOR PROMOTER; ZINC-FINGER; 3D QSAR; IN-VITRO; DEVELOPMENTAL EXPRESSION; RNA RECOGNITION; GENOMIC RNA; VIRAL-RNA AB A family of cellular nucleic acid binding proteins (CNBPs) contains seven Zn2+ fingers that have many of the structural characteristics found in retroviral nucleocapsid (NC) Zn2+ fingers. The sequence of the NH2-terminal NC Zn2+ finger of the pNL4-3 clone of human immunodeficiency virus type 1 (HIV-1) was replaced individually with sequences from each of the seven fingers from human CNBP. Six of the mutants were normal with respect to protein composition and processing, full-length genomic RNA content, and infectivity. One of the mutants, containing the fifth CNBP Zn2+ finger (CNBP-5) packaged reduced levels of genomic RNA and was defective in infectivity. There appear to be defects in reverse transcription in the CNBP-5 infections. Models of Zn2+ fingers were constructed by using computational methods based on available structural data, and atom-atom interactions were determined by the hydropathic orthogonal dynamic analysis of the protein method. Defects in the CNBP-5 mutant could possibly be explained, in part, by restrictions of a set of required atom-atom interactions in the CNBP-5 Zn2+ finger compared to mutant and wild-type Zn2+ fingers in NC that support replication. The present study shows that six of seven of the Zn2+ fingers from the CNBP protein can be used as substitutes for the Zn2+ finger in the NH2-terminal position of HIV-1 NC. This has obvious implications in antiviral therapeutics and DNA vaccines employing NC Zn2+ finger mutants. C1 NCI, Aids Vaccine Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Target Struct Based Drug Discovery Grp, Frederick, MD USA. RP Gorelick, RJ (reprint author), NCI, Aids Vaccine Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO12400]; PHS HHS [N01-C0-12400] NR 56 TC 19 Z9 20 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 15 BP 8524 EP 8531 DI 10.1128/JVI.77.15.8524-8531.2003 PG 8 WC Virology SC Virology GA 702FP UT WOS:000184214300036 PM 12857921 ER PT J AU Julias, JG McWilliams, MJ Sarafianos, SG Alvord, WG Arnold, E Hughes, SH AF Julias, JG McWilliams, MJ Sarafianos, SG Alvord, WG Arnold, E Hughes, SH TI Mutation of amino acids in the connection domain of human immunodeficiency virus type 1 reverse transcriptase that contact the template-primer affects RNase H activity SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; RIBONUCLEASE-H; DNA-SYNTHESIS; REPLICATION; SPECIFICITY; INTEGRATION; SEQUENCE; CLEAVAGE; REMOVAL; DEFECTS AB The crystal structure of human immunodeficiency virus type I (HIV-1) reverse transcriptase in a complex with an RNA-DNA template-primer identified amino acids in the connection domain that make specific contacts with the nucleic acid. We analyzed the effects of mutations in these amino acids by using a one-round HIV-1 vector. Mutations in amino acids in the connection domain generally had small effects on virus titers. To determine whether the mutations affected the level of RNase H activity or the specificity of RNase H cleavage, we used the two-long-terminal-repeat circle junction as a surrogate for the ends of linear viral DNA; specific RNase H cleavages determine the ends of the viral DNA. Several of the mutations in the connection domain affected the frequency of the generation of viral DNAs with aberrant ends. The mutation H361A had the largest effect on the titer and on the generation of DNAs with aberrant ends. H361 contacts the phosphate backbone of the nucleic acid in the same location as amino acid Y501 in the RNase H primer grip. Mutations at Y501 have been shown to decrease the virus titer and affect the specificity of RNase H cleavage. H361A affected the frequency of the generation of linear viral DNAs with aberrant ends, but in general the connection domain mutations had subtle effects on the efficiency of RNase H cleavage. The results of this study suggest that, in addition to its primary role in linking the polymerase and RNase H domains, the connection subdomain has a modest role in binding and positioning the nucleic acid. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Data Management Serv, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. EM Hughes@ncifcrf.gov OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [AI 27690, AI 09578, F32 AI009578, R37 AI027690]; NIGMS NIH HHS [GM55609] NR 29 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 15 BP 8548 EP 8554 DI 10.1128/JVI.77.15.8548-8554.2003 PG 7 WC Virology SC Virology GA 702FP UT WOS:000184214300039 PM 12857924 ER PT J AU Patterson, LJ Malkevitch, N Pinczewski, J Venzon, D Lou, YM Peng, B Munch, C Leonard, M Richardson, E Aldrich, K Kalyanaraman, VS Pavlakis, GN Robert-Guroff, M AF Patterson, LJ Malkevitch, N Pinczewski, J Venzon, D Lou, YM Peng, B Munch, C Leonard, M Richardson, E Aldrich, K Kalyanaraman, VS Pavlakis, GN Robert-Guroff, M TI Potent, persistent induction and modulation of cellular immune responses in rhesus macaques primed with ad5hr-simian immunodeficiency virus (SIV) env/rev, gag, and/or nef vaccines and boosted with SIV gp120 SO JOURNAL OF VIROLOGY LA English DT Article ID REGIMEN INDUCES BROAD; HOST-RANGE MUTANT; NEUTRALIZING ANTIBODIES; VAGINAL CHALLENGE; MONOCLONAL-ANTIBODIES; DISEASE PROGRESSION; CD8(+) LYMPHOCYTES; VIRAL REPLICATION; ADENOVIRUS TYPE-7; T-LYMPHOCYTES AB Immunity elicited by multicomponent vaccines delivered by replication-competent Ad5hr-simian immunodeficiency virus (SIV) recombinants was systematically investigated. Rhesus macaques were immunized mucosally at weeks 0 and 12 with Ad5hr-SIVsmH4 env/rev, with or without Ad5hr-SIV(mac239)gag or Ad5hr-SIVmac239 nef, or with all three recombinants. The total Ad5hr dosage was comparably adjusted among all animals with empty Ad5hr-DeltaE3 vector. The macaques were boosted with SIV gp120 in monophosphoryl A-stable emulsion adjuvant at 24 and 36 weeks. Controls received Ad5hr-DeltaE3 vector or adjuvant only. By ELISPOT analysis, all four SIV gene products elicited potent cellular immune responses that persisted 42 weeks post-initial immunization. Unexpectedly, modulation of this cellular immune response was observed among macaques receiving one, two, or three Ad5hr-SIV recombinants. Env responses were significantly enhanced throughout the immunization period in macaques immunized with Ad5hr-SIV env/rev plus Ad5hr-SIV gag and tended to be higher in macaques that also received Ad5hr-SIV nef. Macaques primed with all three recombinants displayed significant down-modulation in numbers of gamma interferon (IFN-gamma)-secreting cells specific for SIV Nef, and the Env- and Gag-specific responses were also diminished. Modulation of antibody responses was not observed. Down-modulation was seen only during the period of Ad5hr-recombinant priming, not during subunit boosting, although SIV-specific IFN-gamma-secreting cells persisted. The effect was not attributable to Ad5hr replication differences among immunization groups. Vaccine delivery via replication-competent live vectors, which can persistently infect new cells and continuously present low-level antigen, may be advantageous in overcoming competition among complex immunogens for immune recognition. Effects of current multicomponent vaccines on individual immune responses should be evaluated with regard to future vaccine design. C1 NCI, NIH, Basic Res Labs, Bethesda, MD 20892 USA. NCI, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Adv Biosci Labs Inc, Kensington, MD 20895 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Basic Res Labs, 41 Lib Dr,MSC5055,Bldg 41,Room D804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 66 TC 48 Z9 48 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 16 BP 8607 EP 8620 DI 10.1128/JVI.77.16.8607-8620.2003 PG 14 WC Virology SC Virology GA 706PU UT WOS:000184462800001 PM 12885879 ER PT J AU Barouch, DH McKay, PF Sumida, SM Santra, S Jackson, SS Gorgone, DA Lifton, MA Chakrabarti, BK Xu, L Nabel, GJ Letvin, NL AF Barouch, DH McKay, PF Sumida, SM Santra, S Jackson, SS Gorgone, DA Lifton, MA Chakrabarti, BK Xu, L Nabel, GJ Letvin, NL TI Plasmid chemokines and colony-stimulating factors enhance the immunogenicity of DNA priming-viral vector boosting human immunodeficiency virus type 1 vaccines SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-CELLS; GM-CSF; INFECTION; LYMPHOCYTES; INDUCTION; RESPONSES; IMMUNITY; ANTIGEN; VIREMIA; AIDS AB Heterologous "prime-boost" regimens that involve priming with plasmid DNA vaccines and boosting with recombinant viral vectors have been shown to elicit potent virus-specific cytotoxic T-lymphocyte responses. Increasing evidence, however, suggests that the utility of recombinant viral vectors in human populations will be significantly limited by preexisting antivector immunity. Here we demonstrate that the coadministration of plasmid chemokines and colony-stimulating factors with plasmid DNA vaccines markedly increases the immunogenicity of DNA prime-recombinant adenovirus serotype 5 (rAd5) boost and DNA prime-recombinant vaccinia virus (rVac) boost vaccine regimens in BALB/c mice. In mice with preexisting anti-Ad5 immunity, priming with the DNA vaccine alone followed by rAd5 boosting elicited only marginal immune responses. In contrast, cytokine-augmented DNA vaccine priming followed by rAd5 vector boosting was able to generate potent immune responses in mice with preexisting anti-Ad5 immunity. These data demonstrate that plasmid cytokines can markedly improve the immunogenicity of DNA prime-viral vector boost vaccine strategies and can partially compensate for antivector immunity. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Barouch, DH (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Res E Rm 113,330 Brookline Ave, Boston, MA 02215 USA. FU NCI NIH HHS [R01 CA050139, CA-50139]; NIAID NIH HHS [K08 AI-51223, K08 AI051223, P30 AI-28691, P30 AI028691, R01 AI020729, R37 AI020729, AI-20729] NR 24 TC 96 Z9 98 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 16 BP 8729 EP 8735 DI 10.1128/JVI.77.16.8729-8735.2003 PG 7 WC Virology SC Virology GA 706PU UT WOS:000184462800014 PM 12885892 ER PT J AU Veazey, RS Lifson, JD Pandrea, I Purcell, J Piatak, M Lackner, AA AF Veazey, RS Lifson, JD Pandrea, I Purcell, J Piatak, M Lackner, AA TI Simian immunodeficiency virus infection in neonatal macaques SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL ACTIVATION; PERINATAL HIV-1 INFECTION; POLYMERASE CHAIN-REACTION; RHESUS MACAQUES; TYPE-1 INFECTION; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; LYMPHOCYTE SUBSETS; VIRAL REPLICATION; SIV INFECTION AB Children with human immunodeficiency virus infection often have higher viral loads and progress to AIDS more rapidly than adults. Since the intestinal tract is a major site of early viral replication and CD4(+) T-cell depletion in adults, we examined the effects of simian immunodeficiency virus (SIV) on both peripheral and intestinal lymphocytes from 13 neonatal macaques infected with SlVmac239. Normal neonates had more CD4(+) T cells and fewer CD8(+) T cells in all tissues than adults. Surprisingly, neonates had substantial percentages of CD4(+) T cells with an activated, memory phenotype (effector CD4(+) T cells) in the lamina propria of the intestine compared to peripheral lymphoid tissues, even when examined on the day of birth. Moreover, profound and selective depletion of jejunum lamina propria CD4(+) T cells occurred in neonatal macaques within 21 days of infection, which was preceded by large numbers of SIV-infected cells in this compartment. Furthermore, neonates with less CD4(+) T-cell depletion in tissues tended to have higher viral loads. The persistence of intestinal lamina propria CD4(+) T cells in some neonates with high viral loads suggests that increased turnover and/or resistance to CD4(+) T-cell loss may contribute to the higher viral loads and increased severity of disease in neonatal hosts. C1 Tulane Univ, Hlth Sci Ctr, Div Comparat Pathol, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Frederick, MD 21702 USA. RP Veazey, RS (reprint author), Tulane Univ, Hlth Sci Ctr, Div Comparat Pathol, Tulane Natl Primate Res Ctr, 18703 3 Rivers Rd, Covington, LA 70433 USA. FU NCI NIH HHS [N01 CO012400]; NICHD NIH HHS [HD36310]; NIDDK NIH HHS [R01 DK050550, DK50550]; NINDS NIH HHS [R01 NS030769, NS30769] NR 46 TC 26 Z9 27 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 16 BP 8783 EP 8792 DI 10.1128/JVI.77.16.8783-8792.2003 PG 10 WC Virology SC Virology GA 706PU UT WOS:000184462800020 PM 12885897 ER PT J AU Husain, M Moss, B AF Husain, M Moss, B TI Intracellular trafficking of a palmitoylated membrane-associated protein component of enveloped vaccinia virus SO JOURNAL OF VIROLOGY LA English DT Article ID TRANS-GOLGI NETWORK; COATED VESICLE FORMATION; PLASMA-MEMBRANE; EXTRACELLULAR VIRUS; F13L PROTEIN; ENDOPLASMIC-RETICULUM; LATE ENDOSOMES; CELL-SURFACE; MEDIATED ENDOCYTOSIS; CATALYTIC MOTIF AB The F13L protein of vaccinia virus, an essential and abundant palmitoylated peripheral membrane component of intra- and extracellular enveloped virions, associates with Golgi, endosomal, and plasma membranes in the presence or absence of other viral proteins. In the present study, the trafficking of a fully functional F13L-green fluorescent protein (GFP) chimera in transfected and productively infected cells was analyzed using specific markers and inhibitors. We found that Sar1(H79G), a trans-dominant-negative protein inhibitor of cargo transport from the endoplasmic reticulum, had no apparent effect on the intracellular distribution of F13L-GFP, suggesting that the initial membrane localization occurs at a downstream compartment of the secretory pathway. Recycling of F13L-GFP from the plasma membrane was demonstrated by partial colocalization with FM4-64, a fluorescent membrane marker of endocytosis. Punctate F13L-GFP fluorescence overlapped with clathrin and Texas red-conjugated transferrin, suggesting that endocytosis occurred via clathrin-coated pits. The inhibitory effects of chlorpromazine and trans-dominant-negative forms of dynamin and Eps15 protein on the recycling of F13L-GFP provided further evidence for clathrin-mediated endocytosis. In addition, the F13L protein was specifically coimmunoprecipitated with alpha-adaptin, a component of the AP-2 complex that interacts with Eps15. Nocodazole and wortmannin perturbed the intracellular trafficking of F13L-GFP, consistent with its entry into late and early endosomes through the secretory and endocytic pathways, respectively. The recycling pathway described here provides a mechanism for the reutilization of the F13L protein following its deposition in the plasma membrane during the exocytosis of enveloped virions. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 70 TC 28 Z9 29 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2003 VL 77 IS 16 BP 9008 EP 9019 DI 10.1128/JVI.77.16.9008-9019.2003 PG 12 WC Virology SC Virology GA 706PU UT WOS:000184462800040 PM 12885917 ER PT J AU Newman, AB Haggerty, CL Kritchevsky, SB Nevitt, MC Simonsick, EM AF Newman, AB Haggerty, CL Kritchevsky, SB Nevitt, MC Simonsick, EM CA Hlth ABC Collaborative Res Grp TI Walking performance and cardiovascular response: Associations with age and morbidity - The health, aging and body composition study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID HEART-RATE RECOVERY; OLDER-ADULTS; AEROBIC EXERCISE; MUSCLE MASS; MORTALITY; FITNESS; HYPERTENSION; DYSFUNCTION; STRENGTH; PROGRAM AB Background. The long-distance corridor walk is a timed 400-meter walk test used to assess walking endurance in well-functioning men and women aged 70-79 in the Health, Aging and Body Composition Study. Methods. We examined walking time along with heart rate and blood pressure response in relationship to prevalent chronic conditions, weight, physical activity, and markers of subclinical disease. Of 3075 participants, 2324 (76%) completed the test with heart rate and blood pressure responses in the range expected for a moderate level of exertion. Results. Slower walking time was influenced by both clinical and subclinical disease, and also was strongly related to both low and high body weight and low self-reported physical activity. Heart rate and blood pressure responses were higher with several clinical and subclinical diseases, but heart rate response and recovery were more strongly related to walking time than to disease. Higher body mass index and lower physical activity were associated with greater heart rate response and recovery. Conclusions. The independent contribution of both clinical and subclinical disease to walking time supports the use of walking tests as a summary measure of disease in older adults. The independent association of walking time with physical activity suggests that it is sensitive to levels of fitness as well. Together these findings show that walking performance is a valid indicator of physiologic reserve in older adults. C1 Univ Pittsburgh, Healthy Aging Res Program, Div Geriatr Med, Dept Med, Pittsburgh, PA 15213 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38163 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Newman, AB (reprint author), Univ Pittsburgh, Healthy Aging Res Program, Div Geriatr Med, Dept Med, Bellefiedl Proffess Bldg,130 N Bellefield Ave,Roo, Pittsburgh, PA 15213 USA. RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Haggerty, Catherine/0000-0002-9849-7865 FU NIA NIH HHS [ANO1-AG-6-2103, ANO1-AG-6-2101, ANO1-AG-6-2106] NR 26 TC 93 Z9 95 U1 2 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2003 VL 58 IS 8 BP 715 EP 720 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 713BA UT WOS:000184833800006 PM 12902529 ER PT J AU Lan, TY Deeg, DJH Guralnik, JM Melzer, D AF Lan, TY Deeg, DJH Guralnik, JM Melzer, D TI Responsiveness of the index of mobility limitation: Comparison with gait speed alone in the longitudinal aging study Amsterdam SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID HEALTH-STATUS MEASURES; EXPIRATORY FLOW-RATE; PHYSICAL PERFORMANCE; OLDER ADULTS; ELDERLY POPULATION; WOMENS HEALTH; DISABILITY; RELIABILITY; INTERVENTION; INSTRUMENTS AB Background. Interpreting self-reported disability differences between diverse older populations is complicated by differences in attitudes and environment. We have previously reported on the index of mobility-related limitation tests (MOBLI), and shown that it predicts mortality over 4 years. In this article, we examine whether the index is responsive to changes in self-reported mobility disability. Methods. Data on gait speed, time to complete 5 chair stands, and peak expiratory flow rate, with self-reported difficulty walking for 5 minutes, were available from the baseline and two 3-year follow-ups in the Longitudinal Aging Study Amsterdam. Analysis used data on changes in the index (or walking speed alone) and corresponding change over 3 years in self-reported difficulty or inability with a medium-distance walk. Results. During all follow-ups, groups reporting deterioration in functioning had relatively larger changes in gait speed and MOBLI score than did the "no deterioration" groups. In comparative analyses of responsiveness, the MOBLI score had a larger responsiveness index, higher odds ratios, and larger receiving operating characteristic area than gait speed alone. Conclusions. The MOBLI index of mobility-related physical limitation tests is responsive to changes in self-reported mobility disability over two 3-year periods, and performs better than gait speed alone. This property is strongly supportive of its validity for epidemiological comparison of older populations across countries or over longer periods of time. C1 Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 2SR, England. Vrije Univ Amsterdam, Dept Psychiat, NL-1081 HV Amsterdam, Netherlands. Vrije Univ Amsterdam, Inst Res Extramural Med, NL-1081 HV Amsterdam, Netherlands. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Melzer, D (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Forvie Site,Robinson Way, Cambridge CB2 2SR, England. RI Lan, Tzuo-Yun /E-3844-2010; OI Melzer, David/0000-0002-0170-3838 NR 34 TC 22 Z9 23 U1 0 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2003 VL 58 IS 8 BP 721 EP 727 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 713BA UT WOS:000184833800007 PM 12902530 ER PT J AU Bean, JF Leveille, SG Kiely, DK Bandinelli, S Guralnik, JM Ferrucci, L AF Bean, JF Leveille, SG Kiely, DK Bandinelli, S Guralnik, JM Ferrucci, L TI A comparison of leg power and leg strength within the InCHIANTI study: Which influences mobility more? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; FUNCTIONAL PERFORMANCE; SUBSEQUENT DISABILITY; MUSCULAR STRENGTH; SKELETAL-MUSCLE; WOMENS HEALTH; OLDER ADULTS; AGE; MEN AB Background. In a clinical study evaluating the functioning of mobility-limited elders, muscle power accounted for more of the variation in function than strength did. There was also evidence that the power-function relationship may be described as curvilinear. However, these findings have never been confirmed in a representative population. Methods. An analysis was conducted using data from the InCHIANTI study, a population-based cohort of 1032 adults living in Italy. To assess the relationships between impairments in power and strength and mobility performance, we created separate multivariate linear and log-transformed regression models as well as separate logistic regression models. Results. Subjects were age greater than or equal to65 years, predominately female (54%), with a mean age of 74.2 years, and most had mild-moderate mobility limitations (Short Physical Performance Battery score 10.5 +/- 2.1). Though leg extension power and isometric hip extension strength were closely associated, in several separate multivariate linear regression models, leg power consistently explained more of the variance than strength did in several measures of physical performance. Differences were even larger when observed in curvilinear models of power and strength. Using separate multivariate logistic regression models to examine the odds ratios for mobility limitations in persons with low muscle power versus high muscle power, and in persons with low muscle strength versus high muscle strength, we found that both factors influenced risk for mobility limitations, but low power was associated with a 2-3-fold greater likelihood than low strength. Conclusion. These findings identified muscle power to be a more influential proximal determinant of physical performance than impairments in strength and emphasized muscle power as an important determinant of mobility skills in older adults. C1 Hebrew Rehabil Ctr Aged, Geriatr PM&R, Boston, MA 02131 USA. Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Boston, MA 02115 USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Bethesda, MD 20892 USA. RP Bean, JF (reprint author), Hebrew Rehabil Ctr Aged, Geriatr PM&R, 1200 Ctr St, Boston, MA 02131 USA. RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 FU NIA NIH HHS [K12-AG00294] NR 30 TC 201 Z9 203 U1 0 U2 7 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2003 VL 58 IS 8 BP 728 EP 733 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 713BA UT WOS:000184833800008 PM 12902531 ER PT J AU Kirshenbaum, AS Akin, C Wu, YL Rottem, M Goff, JP Beaven, MA Rao, VK Metcalfe, DD AF Kirshenbaum, AS Akin, C Wu, YL Rottem, M Goff, JP Beaven, MA Rao, VK Metcalfe, DD TI Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of Fc epsilon RI or Fc gamma RI SO LEUKEMIA RESEARCH LA English DT Article DE mast cells; SCF; Fc epsilon RI; Fc epsilon RI receptors ID PHENOTYPIC CHARACTERIZATION; UP-REGULATION; BONE-MARROW; C-KIT; MASTOCYTOSIS; EXPRESSION AB Two novel stein cell factor (SCF) dependent human mast cell lines, designated LAD I and 2, were established from bone marrow aspirates from a patient with mast cell sarcoma/leukemia. LAD1 and 2 cells have the ultrastructural features of human mast cells, and express FcepsilonRI, CD4, 9, 13, 14, 22, 31, 32, 45, 64, 71, 103, 117, 132, CXCR4 (CD 184), CCR5 (CD 195); and intracytoplasmic histamine, tryptase and chymase. LAD I and 2 do not exhibit activating mutations at codon 816 of c-kit. Both LAD I and 2 release beta-hexosaminidase following FcepsilonRI or FcgammaRI aggregation. The availability of these cell lines offers an unparalleled circumstance to examine the biology of human mast cells. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kirshenbaum, AS (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Akin, Cem/0000-0001-6301-4520 NR 14 TC 266 Z9 270 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2003 VL 27 IS 8 BP 677 EP 682 DI 10.1016/S0145-2126(02)00343-0 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 692JZ UT WOS:000183659100002 PM 12801524 ER PT J AU Mulshine, JL Hirsch, FR AF Mulshine, JL Hirsch, FR TI Lung cancer chemoprevention: moving from concept to a reality SO LUNG CANCER LA English DT Article; Proceedings Paper CT 1st IASLC/ASCO International Conference on Molecular Targeted Therapies in Lung Cancer CY JAN 15-19, 2003 CL MARBELLA, SPAIN SP IASLC, ASCO DE chemoprevention; lung cancer; computerized tomography; aerosolized drug delivery; intraepithelial neoplasia ID GROWTH-FACTOR RECEPTOR; SQUAMOUS-CELL CARCINOMA; ARACHIDONIC-ACID METABOLITES; PROSTAGLANDIN-E SYNTHASE; TRANS-RETINOIC ACID; 2ND PRIMARY TUMORS; BREAST-CANCER; BRONCHIAL EPITHELIUM; COLON-CANCER; 13-CIS-RETINOIC ACID AB Vast numbers of individuals who have stopped smoking have already been exposed to critical amounts of tobacco combustion products and are at significant risk of developing lung cancer. If these individuals are diagnosed with regional or distant metastatic disease this condition is not typically curable with existing systemic therapy. The need for more effective tools to detect and intervene with early lung cancer detection is a pressing public health priority. A major challenge in this regard is the development of safe and effective lung cancer chemoprevention. The factors influencing the development of this new clinical tool. are reviewed in the context of existing trends for lung cancer care. Existing pharmaceutical efforts have involved evaluation of existing treatments for advanced cancer or other disorders in early lung cancer. The paper describes approaches to tailor chemoprevention development specifically to the biological, pharmacological and anatomical realities of this most Lethal cancer. (C) 2003 Elsevier Science Ireland Ltd and American Society of Clinical Oncology. Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Intervent Sect, Cell & Canc Biol Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect, Cell & Canc Biol Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. NR 133 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD AUG PY 2003 VL 41 SU 1 BP S163 EP S174 DI 10.1016/S0169-5002(03)00160-0 PG 12 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 712FY UT WOS:000184788100021 PM 12867075 ER PT J AU Kalish, H Arbab, AS Miller, BR Lewis, BK Zywicke, HA Bulte, JWM Bryant, LH Frank, JA AF Kalish, H Arbab, AS Miller, BR Lewis, BK Zywicke, HA Bulte, JWM Bryant, LH Frank, JA TI Combination of transfection agents and magnetic resonance contrast agents for cellular imaging: Relationship between relaxivities, electrostatic forces, and chemical composition SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; contrast agent; zeta potential; relaxivities; transfection agents ID EMBRYONIC STEM-CELLS; IN-VITRO; POLYAMIDOAMINE DENDRIMERS; PAMAM DENDRIMER; MAMMALIAN-CELLS; DNA DELIVERY; PH; GADOLINIUM; DIFFERENTIATION; EXPRESSION AB The purpose of this study was to investigate the changes in electrostatic and magnetic resonance (MR) properties observed when MR contrast agents (CAs) (Feridex(R), MION-46L, or G5-dendrimer-DOTA-Gd) are combined with transfection agents (TAs) under various conditions for use as a CA-TA complex basis for cellular labeling and MRI. CAs were incubate with various classes of TAs for 0-48 hr in solutions of varying concentrations and pH values. NMR relaxation rates (1/T-1, 1/T-2), MRI and zeta potential (ZP) of CA-TA solutions were measured. TAs decreased the 1/T-1 and 1/T-2 of G5-DOTA-Gd, Feridex(R), and MION-46L by 0-95%. Altering the pH of G5-DOTA-Gd-TA decreased the T-1-weighted signal intensity (SI) on MRI from 0 to 78%. Measured ZP values for G5-DOTA-Gd, Feridex(R) and MION-46L were -51, -41, and -2.0 mV, respectively. The TA LV had a negative ZP, while the other TAs had ZPs ranging from +20 to +65 mV. The alteration of the ZP and NMR relaxivities of the MR CAs, Feridex(R), MION-46L, and G5-DOTA-Gd by TAs has been demonstrated. These results enhance our understanding of the relationship between electrostatic and MR properties. Published 2003 Wiley-Liss, Inc. C1 NIH, Expt Neuroimaging Sect, Lab Diagnot Radiol Res, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NIH, Mol Imaging Lab, Bethesda, MD 20892 USA. RP Kalish, H (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnot Radiol Res, Bldg 10,Room B1N258,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008; Miller, Bradley/G-7426-2014 OI Bulte, Jeff/0000-0003-1202-1610; NR 37 TC 99 Z9 107 U1 3 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2003 VL 50 IS 2 BP 275 EP 282 DI 10.1002/mrm.10556 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 707UY UT WOS:000184529300007 PM 12876703 ER PT J AU Guttman, MA Kellman, P Dick, AJ Lederman, RJ McVeigh, ER AF Guttman, MA Kellman, P Dick, AJ Lederman, RJ McVeigh, ER TI Real-time accelerated interactive MRI with adaptive TSENSE and UNFOLD SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE real time; interventional; magnetic resonance imaging; cardiac; adaptive imaging; parallel MRI; SENSE; TSENSE; UNFOLD ID ACQUISITION; CATHETERS AB Reduced field-of-view (FOV) acceleration using time-adaptive sensitivity encoding (TSENSE) or unaliasing by Fourier encoding the overlaps using the temporal dimension (UNFOLD) can improve the depiction of motion in real-time MRI. However, increased computational resources are required to maintain a high frame rate and low latency in image reconstruction and display. A high-performance software system has been implemented to perform TSENSE and UNFOLD reconstructions for real-time MRI with interactive, on-line display. Images were displayed in the scanner room to investigate image-guided procedures. Examples are shown for normal volunteers and cardiac interventional experiments in animals using a steady-state free precession (SSFP) sequence. In order to maintain adequate image quality for interventional procedures, the imaging rate was limited to seven frames per second after an acceleration factor of 2 with a voxel size of 1.8 x 3.5 x 8 mm. Initial experiences suggest that TSENSE and UNFOLD can each improve the compromise between spatial and temporal resolution in real-time imaging, and can function well in interactive imaging. UNFOLD places no additional constraints on receiver coils, and is therefore more flexible than SENSE methods; however, the temporal image filtering can blur motion and reduce the effective acceleration. Methods are proposed to overcome the challenges presented by the use of TSENSE in interactive imaging. TSENSE may be temporarily disabled after changing the imaging plane to avoid transient artifacts as the sensitivity coefficients adapt. For imaging with a combination of surface and interventional coils, a hybrid reconstruction approach is proposed whereby UNFOLD is used for the interventional coils, and TSENSE with or without UNFOLD is used for the surface coils. Published 2003 Wiley-Liss, Inc. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Guttman, MA (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL005062-05, Z01 HL004608-08] NR 22 TC 55 Z9 56 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2003 VL 50 IS 2 BP 315 EP 321 DI 10.1002/mrm.10504 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 707UY UT WOS:000184529300012 PM 12876708 ER PT J AU Winter, PM Caruthers, SD Yu, X Song, SK Chen, JJ Miller, B Bulte, JWM Robertson, JD Gaffney, PJ Wickline, SA Lanza, GM AF Winter, PM Caruthers, SD Yu, X Song, SK Chen, JJ Miller, B Bulte, JWM Robertson, JD Gaffney, PJ Wickline, SA Lanza, GM TI Improved molecular imaging contrast agent for detection of human thrombus SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE contrast agent; nanoparticle; molecular imaging; vulnerable plaque; fibrin ID MYOCARDIAL-INFARCTION; PLAQUE RUPTURE; ENHANCEMENT AB Molecular imaging of microthrombus within fissures of unstable atherosclerotic plaques requires sensitive detection with a thrombus-specific agent. Effective molecular imaging has been previously demonstrated with fibrin-targeted Gd-DTPA-bis-oleate (BOA) nanoparticles. In this study, the relaxivity of an improved fibrin-targeted paramagnetic formulation, Gd-DTPA-phosphatidylethanolamine (PE), was compared with Gd-DTPA-BOA at 0.05-4.7 T. Ion- and particle-based r(1) relaxivities (1.5 T) for Gd-DTPA-PE (33.7 (s*mM)(-1) and 2.48 x 10(6) (s*mM)(-1), respectively) were about twofold higher than for Gd-DTPA-BOA, perhaps due to faster water exchange with surface gadolinium. Gd-DTPA-PE nanoparticles bound to thrombus surfaces via anti-fibrin antibodies (1H10) induced 72% +/- 5% higher change in R, values at 1.5 T (DeltaR(1) = 0.77 +/- 0.02 1/s) relative to Gd-DTPA-BOA (DeltaR(1) = 0.45 +/- 0.02 1/s). These studies demonstrate marked improvement in a fibrin-specific molecular imaging agent that might allow sensitive, early detection of vascular microthrombi, the antecedent to stroke and heart attack. (C) 2003 Wiley-Liss, Inc. C1 Washington Univ, Barnes Jewish Hosp, Sch Med, Dept Med,Cardiovasc Div,Cardiovasc MR Labs, St Louis, MO USA. Washington Univ, Dept Biomed Engn, St Louis, MO USA. Philips Med Syst, Best, Netherlands. Washington Univ, Sch Med, Dept Chem, St Louis, MO USA. Natl Inst Hlth, Lab Diagnost Radiol Res, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. Univ Missouri, Res Reactor, Analyt Chem Grp, Columbia, MO 65211 USA. St Thomas Hosp, Dept Surg, London SE1 7EH, England. RP Winter, PM (reprint author), Washington Univ, Sch Med, Dept Cardiol, Campus Box 8086,660 S Euclid Ave, St Louis, MO 63110 USA. RI Bulte, Jeff/A-3240-2008; Chen, Junjie/E-8095-2010; Miller, Bradley/G-7426-2014; OI Bulte, Jeff/0000-0003-1202-1610; Winter, Patrick/0000-0001-5975-5465 FU NCI NIH HHS [CO07121, R24 CA83060]; NHLBI NIH HHS [HL59865] NR 20 TC 131 Z9 135 U1 1 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2003 VL 50 IS 2 BP 411 EP 416 DI 10.1002/mrm.10532 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 707UY UT WOS:000184529300023 PM 12876719 ER PT J AU Childs, JD Piva, SR Erhard, RE Hicks, G AF Childs, JD Piva, SR Erhard, RE Hicks, G TI Side-to-side weight-bearing asymmetry in subjects with low back pain SO MANUAL THERAPY LA English DT Article ID SACROILIAC JOINT; THERAPY; MANIPULATION; DRAWINGS; TIME AB The purpose of this project was to determine if subjects with low back pain (LBP) exhibit greater side-to-side weight-bearing (WB) asymmetry compared to healthy control subjects without LBP. This study utilized an observational double cohort design and consisted of 35 subjects with LBP and 31 healthy control subjects. Side-to-side WB asymmetry was calculated as the average of the absolute value of the difference between the right and left lower extremity from three trials. The percentage of the average side-to-side WB asymmetry relative to the total body weight was calculated to normalize expected differences in magnitude of asymmetry based on a subject's total body weight. An 11-point numeric pain rating scale was used to represent the subject's current level of pain. Patients with LBP demonstrated significantly greater normalized side-to-side WB asymmetry than healthy control subjects (8.8% vs. 3.6%, respectively, P<0.001). In patients with LBP, higher magnitudes of side-to-side WB asymmetry were significantly associated with increased pain (r = 0.39, P = 0.021). In conclusion patients with LBP exhibited increased side-to-side WB asymmetry compared to healthy control subjects without LBP. This asymmetry was associated with increased levels of pain. This finding is relevant for planning future studies that will attempt to provide evidence for the construct validity of manipulation by determining if side-to-side WB asymmetry normalizes after a manipulation intervention and if this improvement is associated with improvements in pain and function. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 MMKPP, Phys Therapy Serv, Wilford Hall Med Ctr, Lackland AFB, TX 78236 USA. Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Phys Therapy, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Med, Hlth Syst Spine Special Ctr, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Phys Therapy, Pittsburgh, PA 15260 USA. Natl Inst Aging, Gerontol Res Ctr, Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Childs, JD (reprint author), MMKPP, Phys Therapy Serv, Wilford Hall Med Ctr, 2200 Bergquist Dr,Suite 1, Lackland AFB, TX 78236 USA. NR 26 TC 15 Z9 15 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1356-689X J9 MANUAL THER JI Man. Ther. PD AUG PY 2003 VL 8 IS 3 BP 166 EP 169 DI 10.1016/S1356-689X(03)00014-6 PG 4 WC Rehabilitation SC Rehabilitation GA 714NC UT WOS:000184919500005 PM 12909437 ER PT J AU Thomas, RJ Liu, K Jacobs, DR Bild, DE Kiefe, CI Hulley, SB AF Thomas, RJ Liu, K Jacobs, DR Bild, DE Kiefe, CI Hulley, SB TI Positional change in blood pressure and 8-year risk of hypertension: The CARDIA study SO MAYO CLINIC PROCEEDINGS LA English DT Article ID LEFT-VENTRICULAR MASS; ORTHOSTATIC HYPERTENSION; INCIDENT HYPERTENSION; POSTURAL CHANGES; HEART-RATE; REACTIVITY; PREDICTORS; YOUNG; STRESS; ASSOCIATION AB Objective: To assess the relationship between positional blood pressure change and 8-year incidence of hypertension in a biracial cohort of young adults. Subjects and Methods: Participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with complete data from year 2 (1987-1988), year 5 (1990-1991), year 7 (1992-1993), and year 10 (1995-1996) examinations were included (N=2781). Participants were classified into 3 groups based on their year 2 systolic blood pressure response to standing: drop, a decrease in systolic blood pressure of more than 5 mm Hg; same, a change of between -5 and +5 mm Hg; and rise, more than 5-mm Hg increase. Results: The number of participants in each group was as follows: drop, 741; same, 1590; and rise, 450. The 8-year incidence of hypertension was 8.4% in the drop group, 6.8% in the same group, and 12.4% in the rise group (P<.001). Adjusted odds ratios for developing hypertension during the follow-up period in the rise group vs the same group were as follows: in black men, 2.85 (95% confidence interval [CI], 1.43-5.69), in black women, 2.47 (95% CI, 1.19-5.11), in white men, 2.17 (95% CI, 1.00-4.73), and in white women, 4.74 (95% CI, 1.11-20.30). Conclusions: A greater than 5-mm Hg increase in blood pressure on standing identified a group of young adults at increased risk of developing hypertension within 8 years. These findings support a physiologic link between sympathetic nervous system reactivity and risk of hypertension in young adults. C1 Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN 55905 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Oslo, Inst Nutr Res, Oslo, Norway. NHLBI, Bethesda, MD 20892 USA. Univ Alabama, Div Prevent Med, Birmingham, AL USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Thomas, RJ (reprint author), Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, 200 1st St SW, Rochester, MN 55905 USA. OI Thomas, Randal/0000-0003-1448-7182 FU NHLBI NIH HHS [N01HC-48048, N01HC-48049, N01HC-95095, N01HC-48047, N01HC-48050] NR 33 TC 28 Z9 38 U1 0 U2 4 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD AUG PY 2003 VL 78 IS 8 BP 951 EP 958 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 708CQ UT WOS:000184549900004 PM 12911043 ER PT J AU Wei, Q Lipardi, C Paterson, BM AF Wei, Q Lipardi, C Paterson, BM TI Analysis of the 3 '-hydroxyl group in Drosophila siRNA function SO METHODS LA English DT Article ID DEPENDENT RNA-POLYMERASE; DOUBLE-STRANDED-RNA; MESSENGER-RNA; C-ELEGANS; GENE; INTERFERENCE; NEUROSPORA; HELICASE; ARABIDOPSIS; REQUIRES AB Members of the RNA-dependent RNA polymerase (RdRP) gene family have been shown to be essential for dsRNA-mediated gene silencing based on venetic screens in a variety of organisms, including Caenorhabditis elegans, Arabidopsis, Neilrospora, and Dictyostelium. A hallmark of this process is the formation of small 21- to 25-bp dsRNAs, termed siRNAs for small interfering RNAs, which are derived from the dsRNA that initiates gene silencing. We have developed methods to demonstrate that these siRNAs produced in Drosophila embryo extract can be uniformly incorporated into dsRNA in a template-specific manner that is subsequently degraded by RNase III-related enzyme activity to create a second generation of siRNAs. SiRNA function in dsRNA synthesis and mRNA degradation depends upon the integrity of the 3'-hydroxyl of the siRNA, consistent with the interpretation that siRNAs serve as primers for RdRP activity in the formation of dsRNA. This process of siRNA incorporation into dsRNA followed by degradation and the formation of new siRNAs has been termed "degradative PCR" and the proposed mechanism is consistent with the genetic and biochemical data derived from studies in C elegans, Arabidopsis, Drosophila, and Dictyostelium. The methods used to study the function of both natural and synthetic siRNAs in RNA interference in Drosophila embryo extracts are detailed. The importance of the 3'-hydroxyl group for siRNA function and its incorporation into dsRNA is emphasized and the results support a model that places RNA-dependent RNA polymerase as a key mediator in the RNA interference mechanism in Drosophila. Published by Elsevier Science (USA). C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 28 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD AUG PY 2003 VL 30 IS 4 BP 337 EP 347 DI 10.1016/S1046-2023(03)00053-7 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700MX UT WOS:000184116700008 PM 12828948 ER PT J AU Su, XZ Mu, JB Joy, DA AF Su, XZ Mu, JB Joy, DA TI The "Malaria's Eve" hypothesis and the debate concerning the origin of the human malaria parasite Plasmodium falciparum SO MICROBES AND INFECTION LA English DT Review DE Malaria; evolution; TMRCA; genome diversity; single nucleotide polymorphism ID ANCIENT ORIGIN; POPULATION; RECOMBINATION; RESISTANCE; DIVERSITY; GENES; POLYMORPHISMS; MUTATIONS; EVOLUTION; SURFACE AB The debate over whether the human malaria parasite Plasmodium falciparum underwent a recent severe population bottleneck ("Malaria's Eve" hypothesis) has attracted great attention recently. Understanding the genetic diversity and evolutionary history of the parasite has practical implications for developing disease control measures. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,Room 4-126,MSC 0425, Bethesda, MD 20892 USA. OI Su, Xinzhuan/0000-0003-3246-3248 NR 33 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD AUG PY 2003 VL 5 IS 10 BP 891 EP 896 DI 10.1016/S1286-4579(03)00173-4 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 717JP UT WOS:000185085600009 PM 12919857 ER PT J AU Sand, O Gingras, M Beck, N Hall, C Trun, N AF Sand, O Gingras, M Beck, N Hall, C Trun, N TI Phenotypic characterization of overexpression or deletion of the Escherichia coli crcA, cspE and crcB genes SO MICROBIOLOGY-SGM LA English DT Article ID H-NS; TOPOISOMERASE-IV; MULTICOPY SUPPRESSORS; BACTERIOPHAGE-LAMBDA; DNA-REPLICATION; SHOCK PROTEIN; IN-VITRO; FAMILY; RNA; TRANSCRIPTION AB The authors have previously shown that overexpression of the Escherichia coli K-12 crcA, cspE and crcB genes protects the chromosome from decondensation by camphor. In this study they examine the phenotypic consequences of deleting or overexpressing crcA, cspE and crcB. Overexpressing crcA, cspE and crcB increases supercoiling levels of plasmids in wild-type cells and in temperature-sensitive (Ts) gyrase mutants, suppresses the sensitivity of gyrase and topoisomerase IV (topo IV) Ts mutants to nalidixic acid, makes gyrase and topo IV Ts mutants more resistant to camphor and corrects the nucleoid morphology defects in topo IV Ts mutants. Overexpression of crcA, cspE and crcB results in a slight (2.2-fold) activation of the rcsA gene. Deleting crcA, cspE and crcB is not lethal to cells but results in an increase in sensitivity to camphor. Deletion of crcA, cspE and crcB exacerbates the nucleoid morphology defects of the topo IV Ts mutants. When the individual crcA, cspE or crcB genes were tested for their effects on camphor resistance and regulation of rcsA, cspE alone conferred 10-fold camphor resistance and 1.7-fold activation of rcsA. These activities were augmented when crcB was overexpressed with cspE (100-fold camphor resistance and 2.1-fold induction of rcsA). C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA. RP NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM trun@duq.edu FU NIGMS NIH HHS [GM065121] NR 43 TC 19 Z9 21 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD AUG PY 2003 VL 149 BP 2107 EP 2117 DI 10.1099/mic.0.26363-0 PN 8 PG 11 WC Microbiology SC Microbiology GA 713FK UT WOS:000184846300017 PM 12904550 ER PT J AU Goping, G Pollard, HB Srivastava, M Leapman, R AF Goping, G Pollard, HB Srivastava, M Leapman, R TI Mapping protein expression in mouse pancreatic islets by immunolabeling and electron energy loss spectrum-imaging SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE microscopy; elemental mapping; electron energy-loss spectroscopy; spectrum-imaging; endocrine cells; insulin; IP3 receptor; Anx7 knockout mice ID SECRETORY GRANULES; INSULIN; CELLS; MICROSCOPE; LIGHT; GENE AB A combination of immuno-electron microscopy and electron energy-loss spectrum-imaging was used to map the distributions of endocrine polypeptide hormones and proteins in mouse pancreatic islet of Langerhans. Tissue was analyzed from control animals and from mice that were heterozygous for the Anx7 gene, which defines a Ca2+/GTP-dependent membrane fusion and ion channel protein. The heterozygous Anx7 (+/-) mouse displays defects in IP3 receptor mediated Ca2+ signaling and insulin secretion. Therefore, information was obtained about the distributions of the hormones insulin and glucagon, as well as the proteins ANX7 and the IP3 receptor. Insulin secretion appears to be defective in the mutants. It was found from immunolabeling experiments that expression of the IP3 receptor is reduced in mutant islets compared to control islets. Subcellular distributions of sulfur and nitrogen obtained by electron energy-loss spectrum-imaging showed that the insulin concentrations of beta granules were essentially the same in control and mutant islets. By contrast, immunogold labeling of mutant islets shows more insulin immunoreactivity in the beta granules. It follows that insulin may be packaged differently in mutant islets, making antigenic determinants more available to the labeling antibody. The increased rate of insulin secretion in the hyperplastic mutant islets can be explained by compensatory increases in islet size, rather than by an increased insulin concentration in the beta cells. The results indicate that reduced ANX7 expression leads to defects in the IP3 receptor expression in the endocrine cells of the mutant mouse. Increased size of the islet or of adrenal medulla may be a compensatory mechanism for secretion defect by individual endocrine cells. Defects in IP3 receptor expression, and documented consequences of a Ca2+ signaling defect, lead to other changes in organelles such as the mitochondrial number in islet beta-cells. The effects and consequences of reduced ANX7 expression on mitochondria are evident in ultrastructural observations. Published 2003 Wiley-Liss, Inc.(dagger) C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Inst Mol Med, Bethesda, MD 20814 USA. ORS, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Srivastava, M (reprint author), USU, Sch Med, Dept Anat & Cell Biol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 19 TC 12 Z9 12 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD AUG 1 PY 2003 VL 61 IS 5 BP 448 EP 456 DI 10.1002/jemt.10294 PG 9 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 700QC UT WOS:000184121800007 PM 12845571 ER PT J AU Bulger, M Schubeler, D Bender, MA Hamilton, J Farrell, CM Hardison, RC Groudine, M AF Bulger, M Schubeler, D Bender, MA Hamilton, J Farrell, CM Hardison, RC Groudine, M TI A complex chromatin landscape revealed by patterns of nuclease sensitivity and histone modification within the mouse beta-globin locus SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CONTROL REGION FUNCTIONS; DNASE-I SENSITIVITY; GENE-EXPRESSION; ERYTHROID-CELLS; HYPERSENSITIVE SITE-5; ACETYLATION PATTERN; ENHANCER BLOCKING; TRANSGENIC MICE; RECEPTOR GENES; ACTIVE GENES AB In order to create an extended map of chromatin features within a mammalian multigene locus, we have determined the extent of nuclease sensitivity and the pattern of histone modifications associated with the mouse beta-globin genes in adult erythroid tissue. We show that the nuclease-sensitive domain encompasses the beta-globin genes along with several flanking olfactory receptor genes that are inactive in erythroid cells. We describe enhancer-blocking or boundary elements on either side of the locus that are bound in vivo by the transcription factor CTCF, but we found that they do not coincide with transitions in nuclease sensitivity flanking the locus or with patterns of histone modifications within it. In addition, histone hyperacetylation and dimethylation of histone H3 K4 are not uniform features of the nuclease-sensitive mouse beta-globin domain but rather define distinct subdomains within it. Our results reveal a complex chromatin landscape for the active beta-globin locus and illustrate the complexity of broad structural changes that accompany gene activation. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. RP Groudine, M (reprint author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, POB 19024, Seattle, WA 19024 USA. RI Hardison, Ross/G-1142-2010 OI Hardison, Ross/0000-0003-4084-7516 FU NHGRI NIH HHS [HG 02238, R01 HG002238]; NHLBI NIH HHS [HL 57620]; NIDDK NIH HHS [DK 27635, DK 44746, R37 DK044746] NR 59 TC 127 Z9 130 U1 3 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2003 VL 23 IS 15 BP 5234 EP 5244 DI 10.1128/MCB.23.15.5234-5244.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 703MP UT WOS:000184283700012 PM 12861010 ER PT J AU Forgues, M Difilippantonio, MJ Linke, SP Ried, T Nagashima, K Feden, J Valerie, K Fukasawa, K Wang, XW AF Forgues, M Difilippantonio, MJ Linke, SP Ried, T Nagashima, K Feden, J Valerie, K Fukasawa, K Wang, XW TI Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SMALL GTPASE RAN; CENTROSOME AMPLIFICATION; HEPATOCELLULAR-CARCINOMA; GENOMIC INSTABILITY; CELL-DIVISION; HBX PROTEIN; BOUND RAN; GENE; HEPATOCARCINOGENESIS; CYCLE AB Hepatitis B virus (HBV) includes an X gene (HBx gene) that plays a critical role in liver carcinogenesis. Because centrosome abnormalities are associated with genomic instability in most human cancer cells, we examined the effect of HBx on centrosomes. We found that HBx induced supernumerary centrosomes and multipolar spindles. This effect was independent of mutations in the p21 gene. Furthermore, the ability of HBV to induce supernumerary centrosomes was dependent on the presence of physiological HBx expression. We recently showed that HBx induces cytoplasmic sequestration of Crm1, a nuclear export receptor that binds to Ran GTPase, thereby inducing nuclear localization of NF-kappaB. Consistently, supernumerary centrosomes were observed in cells treated with a Crm1-specific inhibitor but not with an HBx mutant that lacked the ability to sequester Crm1 in the cytoplasm. Moreover, a fraction of Crm1 was found to be localized at the centrosomes. Immunocytochemical and ultrastructural examination of these supernumerary centrosomes revealed that inactivation of Crm1 was associated with abnormal centrioles. The presence of more than two centrosomes led to an increased frequency of defective mitoses and chromosome transmission errors. Based on this evidence, we suggest that Crm1 is actively involved in maintaining centrosome integrity and that HBx disrupts this process by inactivating Crm1 and thus contributes to HBV-mediated carcinogenesis. C1 NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, SAIC, Frederick, MD 21702 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. Univ Cincinnati, Coll Med, Dept Cell Biol, Cincinnati, OH 45267 USA. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, 37 Convent Dr,MSC 4255,Bldg 37,Room 2C25, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [CA 90522, R01 CA090522] NR 40 TC 95 Z9 103 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2003 VL 23 IS 15 BP 5282 EP 5292 DI 10.1128/MCB.23.15.5282-5292.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 703MP UT WOS:000184283700016 PM 12861014 ER PT J AU He, H von der Haar, T Singh, CR Ii, M Li, B Hinnebusch, AG McCarthy, JEG Asano, K AF He, H von der Haar, T Singh, CR Ii, M Li, B Hinnebusch, AG McCarthy, JEG Asano, K TI The yeast eukaryotic initiation factor 4G (eIF4G) HEAT domain interacts with eIF1 and eIF5 and is involved in stringent AUG selection SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MESSENGER-RNA 5'-CAP; FACTOR 4E EIF4E; TRANSLATION INITIATION; SACCHAROMYCES-CEREVISIAE; IN-VIVO; MULTIFACTOR COMPLEX; PROTEIN-SYNTHESIS; BINDING-PROTEIN; MEDIATE BINDING; START CODON AB Eukaryotic initiation factor 4G (eIF4G) promotes mRNA recruitment to the ribosome by binding to the mRNA cap- and poly(A) tail-binding proteins eIF4E and Pap1p. eIF4G also binds eIF4A at a distinct HEAT domain composed of five stacks of antiparallel alpha-helices. The role of eIF4G in the later steps of initiation, such as scanning and AUG recognition, has not been defined. Here we show that the entire HEAT domain and flanking residues of Saccharomyces cerevisiae eIF4G2 are required for the optimal interaction with the AUG recognition factors eIF5 and eIF1. eIF1 binds simultaneously to eIF4G and eIF3c in vitro, as shown previously for the C-terminal domain of eIF5. In vivo, cooverexpression of eIF1 or eIF5 reverses the genetic suppression of an eIF4G HEAT domain Ts- mutation by eIF4A overexpression. In addition, excess eIF1 inhibits growth of a second eIF4G mutant defective in eIF4E binding, which was also reversed by cooverexpression of eIF4A. Interestingly, excess eIF1 carrying the sui1-1 mutation, known to relax the accuracy of start site selection, did not inhibit the growth of the eIF4G mutant, and sui1-1 reduced the interaction between eIF4G and eIF1 in vitro. Moreover, a HEAT domain mutation altering eIF4G moderately enhances translation from a non-AUG codon. These results strongly suggest that the binding of the eIF4G HEAT domain to eIF1 and eIF5 is important for maintaining the integrity of the scanning ribosomal preinitiation complex. C1 Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. Kansas State Univ, Dept Biochem, Manhattan, KS 66506 USA. UMIST, Dept Biomol Sci, Manchester M60 1QD, Lancs, England. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Asano, K (reprint author), Kansas State Univ, Div Biol, Ackert Hall, Manhattan, KS 66506 USA. RI von der Haar, Tobias/A-5413-2008 OI von der Haar, Tobias/0000-0002-6031-9254 FU NCRR NIH HHS [P20 RR015563, 1P20 RR 15563]; NIGMS NIH HHS [R01 GM064781, GM 64781] NR 41 TC 55 Z9 56 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2003 VL 23 IS 15 BP 5431 EP 5445 DI 10.1128/MCB.23.15.5431-5445.2003 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 703MP UT WOS:000184283700030 PM 12861028 ER PT J AU Lin, Y Ryan, J Lewis, J Wani, MA Lingrel, JB Liu, ZG AF Lin, Y Ryan, J Lewis, J Wani, MA Lingrel, JB Liu, ZG TI TRAF2 exerts its antiapoptotic effect by regulating the expression of Kruppel-like factor LKLF SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; NECROSIS-FACTOR RECEPTOR; GROWTH-FACTOR-I; INDUCED CELL-DEATH; DOMAIN KINASE RIP; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; INDUCED APOPTOSIS; TERMINAL KINASE; IKK ACTIVATION AB Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) is one of the key factors that mediate TNF signaling. The deletion of TRAF2 renders cells more sensitive to TNF-induced apoptosis. Although TRAF2 is known to be required for TNF-induced JNK and NF-kappaB activation, the underlying mechanism of the increased sensitivity of TRAF2 null cells (TRAF2(-/-)) to TNF-induced apoptosis is not fully understood. To study the underlying mechanism, we examined the difference in gene expression between TRAF2(-/-) and wild-type fibroblast cells by using microarray technology. We found that one of the genes whose expression was dramatically decreased in TRAF2(-/-) cells was the lung Kruppel-like factor (LKLF). Our results indicate that the expression of LKLF requires TRAF2 but is independent of TNF signaling. Although it appears that TRAF2 regulates the expression of the LKLF gene at the transcription level, TRAF2 does not function as a transcription factor itself. Our results suggest that TRAF2 regulates LKLF expression through the mitogen-activated protein kinase p38 pathway. More importantly, ectopic expression of LKLF in TRAF2(-/-) cells protected cells against TNF-induced apoptosis. These results reveal a novel aspect of TRAF2 function: by regulating the expression of genes, such as LKLF, TRAF2 controls cell sensitivity to apoptosis. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 6N105,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2003 VL 23 IS 16 BP 5849 EP 5856 DI 10.1128/MCB.23.16.5849-5856.2003 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 707TZ UT WOS:000184527100031 PM 12897154 ER PT J AU Kinyamu, HK Archer, TK AF Kinyamu, HK Archer, TK TI Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in Mdm2 protein expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HUMAN-BREAST-CANCER; STEROID-HORMONE RECEPTORS; RING-FINGER DOMAIN; GENE-EXPRESSION; MDM2-MEDIATED DEGRADATION; MEDIATED DEGRADATION; CHROMATIN-STRUCTURE; ANDROGEN RECEPTOR; NUCLEAR EXCLUSION; 26S PROTEASOME AB Glucocorticoids and estrogens regulate a number of vital physiological processes. We developed a model breast cancer cell line, MCF-7 M, to examine potential mechanisms by which the ligand-bound estrogen receptor (ER) regulates glucocorticoid receptor (GR)-mediated transcription. MCF-7 cells, which endogenously express ERalpha, were stably transfected with mouse mammary tumor virus promoter-luciferase (MMTV-LUC) reporter and GR expression constructs. Our results demonstrate that treatment with estrogen agonists (17beta-estradiol [E2], diethylstilbestrol, genistein), but not antagonists (tamoxifen or raloxifene), for 48 h inhibits GR-mediated MMTV-LUC transcription and chromatin remodeling. Furthermore, estrogen agonists inhibit glucocorticoid induction of p21 mRNA and protein levels, suggesting that the repressive effect applies to other GR-regulated genes and proteins in MCF-7 cells. Importantly, GR transcriptional activity is compromised because treatment with estrogen agonists down regulates GR protein levels. The protein synthesis inhibitor cycloheximide and the proteasome inhibitor MG132 block E2-mediated decrease in GR protein levels, suggesting that estrogen agonists down regulate the GR via the proteasomal degradation pathway. In support of this, we demonstrate that E2-mediated GR degradation is coupled to an increase in p53 and its key regulator protein Mdm2 (murine double minute 2), an E3 ubiquitin ligase shown to target the GR for degradation. Using the chromatin immunoprecipitation assay, we demonstrate an E2-dependent recruitment of ERalpha to the Mdm2 promoter, suggesting a role of ER in the regulation of Mdm2 protein expression and hence the enhanced GR degradation in the presence of estrogen agonists. Our study shows that cross talk between the GR and ER involves multiple signaling pathways, indicative of the mechanistic diversity within steroid receptor-regulated transcription. C1 NIEHS, Reprod & Dev Toxicol Lab, Chromatin & Gene Express Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Chromatin & Gene Express Sect, NIH, 111 Alexander Dr,POB 12233,MD E4-06, Res Triangle Pk, NC 27709 USA. NR 79 TC 104 Z9 111 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2003 VL 23 IS 16 BP 5867 EP 5881 DI 10.1128/MCB.23.16.5867-5881.2003 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 707TZ UT WOS:000184527100033 PM 12897156 ER PT J AU Venkatesan, S Rose, JJ Lodge, R Murphy, PM Foley, JF AF Venkatesan, S Rose, JJ Lodge, R Murphy, PM Foley, JF TI Distinct mechanisms of agonist-induced endocytosis for human chemokine receptors CCR5 and CXCR4 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-SURFACE EXPRESSION; C-TERMINAL TAIL; LIPID RAFTS; MEMBRANE DOMAINS; ENDOPLASMIC-RETICULUM; MEDIATED ENDOCYTOSIS; SIGNAL-TRANSDUCTION; HIV-1 CORECEPTOR; GOLGI-COMPLEX AB Desensitization of the chemokine receptors, a large class of G protein-coupled receptors, is mediated in part by agonist-driven receptor endocytosis. However, the exact pathways have not been fully defined. Here we demonstrate that the rate of ligand-induced endocytosis. of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease. C1 NIAID, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Invest, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Venkatesan, S (reprint author), NIAID, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 76 TC 84 Z9 86 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2003 VL 14 IS 8 BP 3305 EP 3324 DI 10.1091/mbc.E02-11-0714 PG 20 WC Cell Biology SC Cell Biology GA 713UY UT WOS:000184877400020 PM 12925765 ER PT J AU Crowell, JA Steele, VE Sigman, CC Fay, JR AF Crowell, JA Steele, VE Sigman, CC Fay, JR TI Is inducible nitric oxide synthase a target for chemoprevention? SO MOLECULAR CANCER THERAPEUTICS LA English DT Review ID HUMAN COLORECTAL-CANCER; HUMAN BREAST-CANCER; TRANSITIONAL-CELL CARCINOMA; MURINE MELANOMA-CELLS; ABERRANT CRYPT FOCI; INCREASED EXPRESSION; INOS EXPRESSION; COLON CARCINOGENESIS; SELECTIVE-INHIBITION; MOLECULAR-BIOLOGY AB The molecular messenger nitric oxide (NO) is synthesized endogenously from L-arginine by three isoforms of the enzyme NO synthase. The isoform most consistently associated with neoplasia is the inducible form, inducible nitric oxide synthase (iNOS). However, the role played by the NO/iNOS system in tumor development is complex, and both promoting and inhibitory effects on neoplasia have been reported. This review attempts to clarify the role of iNOS in carcinogenesis, with particular emphasis on the early stages of tumor development, offers possible explanations for the confused picture presented in the literature regarding the association of the NO/iNOS pathway with neoplasia, and identifies selective iNOS inhibitors that may have chemopreventive potential. C1 NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. CCS Associates, Mountain View, CA 94043 USA. RP Crowell, JA (reprint author), NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Execut Plaza N,Room 2117,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 95 TC 103 Z9 108 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2003 VL 2 IS 8 BP 815 EP 823 PG 9 WC Oncology SC Oncology GA 714MK UT WOS:000184917900014 PM 12939472 ER PT J AU Eder, IE Haag, P Basik, M Mousses, S Bektic, J Bartsch, G Klocker, H AF Eder, IE Haag, P Basik, M Mousses, S Bektic, J Bartsch, G Klocker, H TI Gene expression changes following androgen receptor elimination in LNCaP prostate cancer cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE androgen receptor; gene array; antisense treatment; bicalutamide; prostate cancer ID BINDING-PROTEIN; REGULATED EXPRESSION; SIGNAL-TRANSDUCTION; CLUSTER-ANALYSIS; GROWTH-FACTOR; LINE LNCAP; ACTIVATION; CARCINOMA; MECHANISM; INDUCTION AB We have shown recently that inhibition of androgen receptor (AR) expression with an antisense AR oligonucleotide (ODN) inhibits LNCaP prostate tumor cells in vitro as well as in vivo. In this study, we investigated gene expression changes that occur after AR signaling blockade, either through AR elimination by antisense treatment or through complete androgen receptor inhibition by androgen deprivation combined with the antiandrogen bicalutamide, in order to search for genes that are directly or indirectly regulated through the AR. Gene expression changes were investigated with cDNA NIH 10K gene microarrays in response to treatment over 48 h. Expression of selected genes was further analyzed by real-time reverse transcriptase (RT)-polymerase chain reaction (PCR), Western blotting, and radioimmunoassay. A comparison of antisense-treated and androgen-deprived cells revealed several concordances such as significant downregulation of prostate-specific genes, cell-cycle regulatory genes, genes of the cholesterol biosynthesis pathway, and several cytoskeletal genes. However, there were also several genes that were differentially regulated. Among the genes that were exclusively changed by treatment with the antisense AR ODN were the insulin-like growth factor binding protein 2 (IGFBP2) and the phosphatidylinositol-4-phosphate 5-kinase type I alpha (PIP5KIA). On the other hand, complete androgen receptor blockade induced changes in the expression of the prostate over-expressed gene 1 and the S100 calcium binding protein P. In summary, we identified a cohort of interesting genes whose expression was highly affected by elimination of the AR in LNCaP prostate cancer cells. Further investigations are warranted to clarify their role in the AR signaling pathway and their susceptibility as a target for the treatment of prostate cancer. (C) 2003 Wiley-Liss, Inc. C1 Univ Innsbruck, Dept Urol, A-6020 Innsbruck, Austria. NIH, Dept Natl Human Genome Res Inst, Bethesda, MD USA. RP Klocker, H (reprint author), Univ Innsbruck, Dept Urol, Anichstr 35, A-6020 Innsbruck, Austria. NR 58 TC 23 Z9 23 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 2003 VL 37 IS 4 BP 181 EP 191 DI 10.1002/mc.10136 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 709LR UT WOS:000184627100002 PM 12891627 ER PT J AU Guo, M Aston, C Burchett, SA Dyke, C Fields, S Rajarao, SJR Uetz, P Wang, YQ Young, K Dohlman, HG AF Guo, M Aston, C Burchett, SA Dyke, C Fields, S Rajarao, SJR Uetz, P Wang, YQ Young, K Dohlman, HG TI The yeast G protein alpha subunit Gpa1 transmits a signal through an RNA binding effector protein Scp160 SO MOLECULAR CELL LA English DT Article ID GUANINE-NUCLEOTIDE EXCHANGE; SACCHAROMYCES-CEREVISIAE; P115 RHOGEF; G-BETA; PHEROMONE; DOMAIN; G-ALPHA(13); STIMULATION; ASSOCIATION; INHIBITION AB In yeast Saccharomyces cerevisiae the G protein betagamma subunits (Ste4/Ste18) have long been known to transmit the signal required for mating. Here we demonstrate that GTPase-deficient mutants of Galpha (Gpa1) directly activate the mating response pathway. We also show that signaling by activated Gpa1 requires direct coupling to an RNA binding protein Scp160. These findings suggest an additional role for Gpa1 and reveal Scp160 as a component of the mating response pathway in yeast. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Yale Univ, Interdepartmental Neurosci Program, New Haven, CT 06520 USA. Wyeth Ayerst Res, Neurosci Res, Princeton, NJ 08543 USA. NIH, Lab Neural Connect, Bethesda, MD 20892 USA. Univ Washington, Dept Genome Sci & Med, Seattle, WA 98195 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Dohlman, HG (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RI Uetz, Peter/A-7119-2012 OI Uetz, Peter/0000-0001-6194-4927 FU NCRR NIH HHS [P41 RR11823]; NIGMS NIH HHS [GM065533, GM59167, P01 GM065533, R01 GM059167] NR 35 TC 44 Z9 46 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG PY 2003 VL 12 IS 2 BP 517 EP 524 DI 10.1016/S1097-2765(03)00307-1 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 716VJ UT WOS:000185050000024 PM 14536090 ER PT J AU Mittelstadt, PR Ashwell, JD AF Mittelstadt, PR Ashwell, JD TI Disruption of glucocorticoid receptor exon 2 yields a ligand-responsive C-terminal fragment that regulates gene expression SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID T-CELL ACTIVATION; PROTEIN-PROTEIN-INTERACTION; MAMMARY-GLAND DEVELOPMENT; NF-KAPPA-B; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; TRANSACTIVATION DOMAIN; FUNCTIONAL ANTAGONISM; MOLECULAR MECHANISMS; TARGETED DISRUPTION AB Mice in which exon 2 of the glucocorticoid receptor (GR) has been disrupted [GR exon 2 knockout (GR2KO)] have been used as a model to study the requirement for this receptor in a number of biological systems. A recent report showed that these mice actually express a truncated ligand-binding GR fragment, prompting us to ask whether this mutation truly results in a glucocorticoid-insensitive phenotype. Based on cDNA microarray analysis of fetal thymocytes, we found that glucocorticoids were able to enhance or repress activation-induced gene expression in GR2KO and wild-type thymocytes to a similar degree. Moreover, although changes in gene expression induced by glucocorticoids alone were blunted, the expression of a substantial number of genes in GR2KO thymocytes was modulated by stimulation with glucocorticoids. Among these genes, as confirmed by quantitative real-time PCR, was the classic glucocorticoid-responsive gene glutamine synthetase as well as genes implicated in T cell development and function such as IL-7 receptor a-chain and glucocorticoid-induced leucine zipper (GIL2). Thus, the truncated C-terminal GR2KO product, which lacks the major transactivation domain, retains, to a large extent, the ability to regulate gene expression both positively and negatively in a ligand-responsive manner when expressed in vivo. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 10,Room 1B-40, Bethesda, MD 20892 USA. NR 65 TC 40 Z9 40 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2003 VL 17 IS 8 BP 1534 EP 1542 DI 10.1210/me.2002-0429 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 705ZV UT WOS:000184427900007 PM 12750452 ER PT J AU Maffucci, T Razzini, G Ingrosso, A Chen, H Iacobelli, S Sciacchitano, S Quon, MJ Falasca, M AF Maffucci, T Razzini, G Ingrosso, A Chen, H Iacobelli, S Sciacchitano, S Quon, MJ Falasca, M TI Role of pleckstrin homology domain in regulating membrane targeting and metabolic function of insulin receptor substrate 3 SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID RNA PROCESSING FACTORS; NUCLEAR SPECKLES; ADIPOSE-CELLS; LOCALIZATION; SPECIFICITY; EXPRESSION; MECHANISM; 3-KINASE; BINDING; CLONING AB The insulin receptor phosphorylates insulin receptor substrate (IRS) proteins on multiple tyrosine residues that act as docking sites to recruit a number of downstream signaling molecules. Here we show that IRS3 is localized both at the plasma membrane and in the nucleus. Interestingly, the nuclear localization of the protein is restricted to specific regions involved in mRNA processing and known as speckles. By using different truncated versions of the protein, we demonstrate that the pleckstrin homology (PH) domain is involved in IRS3 localization at the level of both plasma membrane and nucleus. To our knowledge this is the first report of a PH domain responsible for a nuclear targeting of the host protein. By site-directed mutagenesis, we identify residues within the PH domain critical for proper localization of IRS3. Mutations within the PH domain preventing IRS3 intracellular localization result in an inhibition of IRS3-induced glucose uptake. We conclude that the PH domain is required for IRS3 intracellular localization and, furthermore, that it has a key role in metabolic functions of IRS3. In particular, our data suggest that IRS3 intracellular localization at the plasma membrane and in the nucleus is the result of two different cooperative mechanisms both involving the PH domain. C1 UCL, Sackler Inst Muscular Skeletal Res, Dept Med, London WC1E 6JJ, England. NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20893 USA. Univ G DAnnunzio, Dept Oncol & Neurosci, Sect Med Oncol, I-66100 Chieti, Italy. Univ Roma La Sapienza, Fac Med 2, Ctr Ric Osped S Pietro Fatebenefratelli, Assoc Fatebenefratelli Ric, I-00189 Rome, Italy. RP Falasca, M (reprint author), UCL, Sackler Inst Muscular Skeletal Res, Dept Med, Rayne Bldg,5 Univ St, London WC1E 6JJ, England. EM m.falasca@ucl.ac.uk RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 19 TC 12 Z9 13 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2003 VL 17 IS 8 BP 1568 EP 1579 DI 10.1210/me.2001-0211 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 705ZV UT WOS:000184427900010 PM 12738760 ER PT J AU Suzuki, H Cheng, SY AF Suzuki, H Cheng, SY TI Compensatory role of thyroid hormone receptor (TR)alpha 1 in resistance to thyroid hormone: Study in mice with a targeted mutation in the TR beta gene and deficient in TR alpha 1 SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID DOMINANT-NEGATIVE ACTIVITY; GENERALIZED RESISTANCE; GROWTH; BONE; THYROTROPIN; EXPRESSION; PHENOTYPE; ISOFORMS; ALPHA-1 AB Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TRbeta) gene. Almost all PITH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TRalpha1 isoform in maintaining the normal functions of thyroid hormone (T-3) in these patients. To understand the role of TRalpha1 in the manifestation of PITH, we compared the phenotypes of mice with a targeted dominantly negative mutant TRbeta (TRbetaPV) with or without TRalpha1. TRbetaPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TRalpha1 in TRbetaPV mice, and severe impairment of postnatal growth was manifested in TRbetaPV mice deficient in TRalpha1. Furthermore, abnormal expression patterns of T-3-target genes in TRbetaPV mice were altered by the lack of TRalpha1. These results demonstrate that the lack of TRalpha1 exacerbates the manifestation of RTH in TRbetaPV mice. Therefore, TRalpha1 could play a compensatory role in mediating the functions of T-3 in heterozygous patients with PITH. This compensatory role may be especially crucial for postnatal growth. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. NR 23 TC 11 Z9 11 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2003 VL 17 IS 8 BP 1647 EP 1655 DI 10.1210/me.2003-0114 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 705ZV UT WOS:000184427900016 PM 12750454 ER PT J AU Knodler, LA Vallance, BA Hensel, M Jackel, D Finlay, BB Steele-Mortimer, O AF Knodler, LA Vallance, BA Hensel, M Jackel, D Finlay, BB Steele-Mortimer, O TI Salmonella type III effectors PipB and PipB2 are targeted to detergent-resistant microdomains on internal host cell membranes SO MOLECULAR MICROBIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; LATE ENDOCYTIC COMPARTMENTS; PHAGOCYTE NADPH OXIDASE; PATHOGENICITY ISLAND 2; SECRETION SYSTEM; LIPID RAFTS; EPITHELIAL-CELLS; GENE-EXPRESSION; PLASMA-MEMBRANE; ESCHERICHIA-COLI AB The intracellular pathogen, Salmonella enterica, translocates type III effectors across its vacuolar membrane into host cells. Herein we describe a new Salmonella effector, PipB2, which has sequence similarity to another type III effector, PipB. In phagocytic cells, PipB2 localizes to the Salmonella-containing vacuole (SCV) and tubular extensions from the SCV, Salmonella-induced filaments (Sifs). We used the specific targeting of PipB2 in macrophages to characterize Sifs in phagocytic cells for the first time. In epithelial cells, PipB2 has a unique localization pattern, localizing to SCVs and Sifs and additionally to vesicles at the periphery of infected cells. We further show that the N-terminal 225-amino-acid residues of PipB2 are sufficient for type III translocation and association with SCVs and Sifs, but not peripheral vesicles. Subcellular fractionation demonstrated that both PipB and PipB2 associate with host cell membranes and resist extraction by high salt, high pH and to a significant extent, non-ionic detergent. Furthermore, PipB and PipB2 are enriched in detergent-resistant microdomains (DRMs), also known as lipid rafts, present on membranes of SCVs and Sifs. The enrichment of Salmonella effectors in DRMs on these intracellular membranes probably permits specific interactions with host cell molecules that are concentrated in these signalling platforms. C1 Univ British Columbia, Biotechnol Lab, Vancouver, BC V6T 1W5, Canada. NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. FAU Erlangen Nurnberg, Inst Klin Mikrobiol Immunol & Hyg, Erlangen, Germany. RP Knodler, LA (reprint author), Univ British Columbia, Biotechnol Lab, Vancouver, BC V6T 1W5, Canada. OI Vallance, Bruce/0000-0003-1345-6747 NR 94 TC 98 Z9 102 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2003 VL 49 IS 3 BP 685 EP 704 DI 10.1046/j.1365-2958.2003.03598.x PG 20 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 710HE UT WOS:000184674100009 PM 12864852 ER PT J AU Mu, JB Ferdig, MT Feng, XR Joy, DA Duan, JH Furuya, T Subramanian, G Aravind, L Cooper, RA Wootton, JC Xiong, M Su, XZ AF Mu, JB Ferdig, MT Feng, XR Joy, DA Duan, JH Furuya, T Subramanian, G Aravind, L Cooper, RA Wootton, JC Xiong, M Su, XZ TI Multiple transporters associated with malaria parasite responses to chloroquine and quinine SO MOLECULAR MICROBIOLOGY LA English DT Article ID RESISTANT PLASMODIUM-FALCIPARUM; TRANSMEMBRANE PROTEIN PFCRT; LINKAGE DISEQUILIBRIUM; DRUG-RESISTANCE; GENE; MUTATIONS; PFMDR1; ANTIMALARIALS; MEFLOQUINE; LOCI AB Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CO), quinine (ON) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CO resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CO and ON. Such molecules may contribute to increasing incidences of ON treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CO and ON responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CO and ON and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or ON in P. faliparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites. C1 NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. Human Genome Sci, Rockville, MD USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. Univ Texas, Ctr Human Genet, Houston, TX USA. RP Su, XZ (reprint author), NIH, Lab Malaria & Vector Res, Bldg 10, Bethesda, MD 20892 USA. RI feng, xiaorong/G-4811-2010; Furuya, Tetsuya/J-5916-2013; Ferdig, Michael/C-6627-2016; Furuya, Tetsuya/H-2412-2013; OI feng, xiaorong/0000-0001-8410-3020; Furuya, Tetsuya/0000-0003-3979-7072; Su, Xinzhuan/0000-0003-3246-3248 NR 43 TC 186 Z9 188 U1 0 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2003 VL 49 IS 4 BP 977 EP 989 DI 10.1046/j.1365-2958.2003.03627.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 714WJ UT WOS:000184936200010 PM 12890022 ER PT J AU Chen, YP Ferguson, SS Negishi, M Goldstein, JA AF Chen, YP Ferguson, SS Negishi, M Goldstein, JA TI Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter SO MOLECULAR PHARMACOLOGY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; PREGNANE-X RECEPTOR; CYP3A4 GENE-EXPRESSION; HUMAN HEPATOCYTES; TRANSCRIPTIONAL REGULATION; XENOBIOTIC INDUCTION; ENHANCER MODULE; HEPATIC GENES; CAR; DEXAMETHASONE AB CYP2C19 is an important human drug-metabolizing enzyme that metabolizes a number of clinically used drugs including the antiulcer drug omeprazole, the anxiolytic drug diazepam, the beta-blocker propranolol, the antimalarial drug proguanil, certain antidepressants and barbiturates, and the prototype substrate S-mephenytoin. Previous studies show that compounds such as rifampicin and dexamethasone induce CYP2C19 both in vivo in humans and in vitro in human hepatocytes. This study examines the transcriptional regulation of CYP2C19. Analysis of the CYP2C19 promoter revealed a single constitutive androstane receptor (CAR) binding site (CAR-RE; -1891/-1876 bp) and a glucocorticoid-responsive element (GRE; -1750/-1736 bp). Gel-shift assays showed that CAR-RE binds CAR and pregnane X receptor (PXR). Cotransfection with hCAR, mCAR, or hPXR in HepG2 cells up-regulated transcription of CYP2C19 promoter constructs, whereas mutation of the -1891-bp CAR-RE abolished up-regulation. Expression with hCAR also up-regulated endogenous CYP2C19 mRNA content in HepG2 cells. Androstenol repressed the mCAR-mediated constitutive activation of the CYP2C19 promoter in HepG2 cells, whereas the potent mCAR ligand 1,4-bis[2-3,5-dichloropyridyloxyl)] benzene derepressed this response. Rifampicin produced a modest increase in promoter activity in cells cotransfected with hPXR. Dexamethasone activated the -2.7-kb CYP2C19 promoter constructs in HepG2 cells only in the presence of cotransfected glucocorticoid receptor (GR), whereas the GR antagonist mifepristone inhibits this response. Mutation of the GRE abolishes dexamethasone activation. This is the first study to identify nuclear receptor binding sites (CAR/PXR and GR) in the CYP2C19 promoter and to suggest that these receptors may up-regulate CYP2C19 constitutively and possibly its response to drugs. C1 NIEHS, Human Metab Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Goldstein, JA (reprint author), NIEHS, Human Metab Sect, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. RI Goldstein, Joyce/A-6681-2012 NR 25 TC 100 Z9 105 U1 0 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 316 EP 324 DI 10.1124/mol.64.2.316 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900015 PM 12869636 ER PT J AU Wang, Y Toth, A Tran, R Szabo, T Welter, JD Blumberg, PM Lee, J Kang, SU Lim, JO Lee, J AF Wang, Y Toth, A Tran, R Szabo, T Welter, JD Blumberg, PM Lee, J Kang, SU Lim, JO Lee, J TI High-affinity partial agonists of the vanilloid receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID ROOT GANGLION NEURONS; CAPSAICIN; VR1; RESINIFERATOXIN; CAPSAZEPINE; ANTAGONIST; ANALGESICS; ANANDAMIDE; POTENT; MECHANISMS AB The vanilloid receptor VR1 is a polymodal nociceptor sensitive to capsaicin, protons, and heat. Because VR1 represents an attractive therapeutic target for conditions ranging from long-term pain to bladder hyperreflexia, we and other groups have sought to develop novel ligands with enhanced potencies and novel pharmacological properties. Here, we characterize two compounds, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-[4-(methylsulfonylamino) benzyl] thiourea (JYL827) and N-(4-tert-butylbenzyl)N'-[3-methoxy-4-(methylsulfonylamino) benzyl] thiourea (JYL1511), that function as partial agonists for rat VR1 heterologously expressed in Chinese hamster ovary cells. Both compounds showed substantially enhanced potency, inhibiting [H-3] resiniferatoxin binding with K-i values of 29.3 +/- 7.6 and 50.4 +/- 16.5 nM, respectively, compared with 1810 +/- 270 nM for capsaicin. The compounds showed different extents of partial agonism, 6.8 +/- 0.7% and 17.4 +/- 0.6%, respectively, and the expected corresponding degrees of partial antagonism (93.9 +/- 0.9 and 84.1 +/- 3.2%, respectively). Their IC50 values for antagonism of Ca-45(2+) uptake in response to capsaicin were 67.3 +/- 24.9 nM and 3.4 +/- 0.5 nM, respectively. Protons, temperature, and protein kinase C all function as coactivators/modulators of rVR1. All enhanced the extent of partial agonism of JYL827 and JYL1511. Thus, at pH 5.5, for example, the extents of partial agonism increased to 54.9 +/- 2.5% and to 90.7 +/- 1.7%, respectively, relative to the response elicited by 300 nM capsaicin. The extents of partial antagonism decreased correspondingly. Compounds such as JYL827 and JYL1511 now permit exploration of the potential utility of partial agonists of rVR1 in animal models. Our results emphasize, moreover, the strong dependence of such partial agonists on other modulators of rVR1 and predict that their biological behavior will depend strongly on biological context. C1 NCI, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul, South Korea. RP Blumberg, PM (reprint author), NCI, Bldg 37,Room 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Toth, Attila/F-4859-2010; OI Toth, Attila/0000-0001-6503-3653; Lee, Jiyoun/0000-0003-3819-5889 NR 32 TC 32 Z9 32 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 325 EP 333 DI 10.1124/mol.64.2.325 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900016 PM 12869637 ER PT J AU Wang, WF Sonders, MS Ukairo, OT Scott, H Kloetzel, MK Surratt, CK AF Wang, WF Sonders, MS Ukairo, OT Scott, H Kloetzel, MK Surratt, CK TI Dissociation of high-affinity cocaine analog binding and dopamine uptake inhibition at the dopamine transporter SO MOLECULAR PHARMACOLOGY LA English DT Article ID SEROTONIN TRANSPORTER; RAT-BRAIN; TRANSMEMBRANE DOMAIN; MOLECULAR-CLONING; EXPRESSION; HYPERTONICITY; SUBSTRATE; RECEPTOR; RESIDUE; CDNA AB Cocaine initiates its euphoric effects by binding to the dopamine transporter (DAT), blocking uptake of synaptic dopamine. It has been hypothesized that the DAT transmembrane aspartic acid residue D79 forms an ionic interaction with charged nitrogen atoms in both dopamine and cocaine. We examined the consequences of novel and previously studied mutations of the D79 residue on DAT uptake of [H-3] dopamine, DAT binding of the cocaine analog [H-3] WIN 35,428, and drug inhibition of each process, all under identical conditions. The rat D79E DAT mutation decreased dopamine uptake V-max by 7-fold and decreased dopamine turnover by 4-fold. Wild-type DAT displayed near-perfect agreement in the uptake and binding inhibition potencies for substrates, but cocaine and other nonsubstrate inhibitor drugs were similar to3-fold less potent in uptake than in binding assays. Apparent affinities for substrates were unaffected by the D79E mutation unless the catechol moiety was modified. Strikingly, potencies for nonsubstrate inhibitors in uptake and binding assays matched for D79E DAT, because of a 3-fold lowering of binding affinities relative to WT DAT. The present findings reveal a complex role for D79 in determining substrate specificity and high-affinity binding of DAT inhibitors. We propose that at least two discrete inhibitor-binding DAT conformations or populations exist and that the DAT conformation/ population responsible for inhibitor high-affinity binding is less responsible for dopamine uptake. The findings may be extensible to other psychostimulants and antidepressants that display discrepancies between binding affinity and monoamine uptake inhibition potency and may be relevant to development of a long-sought "cocaine antagonist". C1 Duquesne Univ, Div Pharmaceut Sci, Dept Pharmacol & Toxicol, Pittsburgh, PA 15282 USA. Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR USA. Natl Inst Drug Abuse, Medicat Discovery Res Branch, Baltimore, MD USA. RP Surratt, CK (reprint author), Duquesne Univ, Div Pharmaceut Sci, Dept Pharmacol & Toxicol, 453 Mellon Hall,600 Forbes Ave, Pittsburgh, PA 15282 USA. NR 34 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 430 EP 439 DI 10.1124/mol.64.2.430 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900027 PM 12869648 ER PT J AU Kilic, F Murphy, DL Rudnick, G AF Kilic, F Murphy, DL Rudnick, G TI A human serotonin transporter mutation causes constitutive activation of transport activity SO MOLECULAR PHARMACOLOGY LA English DT Article ID TRANSMEMBRANE DOMAIN-I; NITRIC-OXIDE; SCANNING MUTAGENESIS; EXPRESSION; RECEPTORS; PHOSPHORYLATION; RECOGNITION; PERMEATION; SUBSTRATE; PROTEINS AB A rarely occurring variant of human serotonin transporter (hSERT) was tested for its functional consequences in HeLa and COS-7 cells. The variant, in which Ile-425 is converted to Val, was significantly different from wild type with respect to its catalytic properties. In both cell types, rates of serotonin (5-HT) transport were higher for the I425V variant. Both an increase in V-max and a decrease in K-M caused this increase in rate. The increase in V-max was not accounted for by increases in transporter expression or in the distribution of transporter between the cell surface and intracellular pools. The decrease in K-M was accompanied by a decrease in the K-D for binding of the cocaine analog 2beta-carbomethoxy-3beta- (4-[I-125] iodophenyl) tropane. In both HeLa and COS-7 cells, the nitric oxide donor S-nitroso-N-acetylpenicillamine increased the activity of wild-type hSERT to that of the variant but did not change the activity of the I425V variant. This stimulation was prevented by the presence of oxyhemoglobin, which quenches nitric oxide, and by an inhibitor of guanylyl cyclase. C1 Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Rudnick, G (reprint author), Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. NR 33 TC 97 Z9 101 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 440 EP 446 DI 10.1124/mol.64.2.440 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900028 PM 12869649 ER PT J AU Wyde, ME Bartolucci, E Ueda, A Zhang, H Yan, BF Negishi, M You, L AF Wyde, ME Bartolucci, E Ueda, A Zhang, H Yan, BF Negishi, M You, L TI The environmental pollutant 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene induces rat hepatic cytochrome P4502B and 3A expression through the constitutive androstane receptor and pregnane X receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID NUCLEAR RECEPTORS; HUMAN HEPATOCYTES; REPRODUCTIVE DYSFUNCTION; XENOBIOTIC RESPONSE; PRENATAL EXPOSURE; DRUG-INTERACTIONS; SPRAGUE-DAWLEY; CYP2B GENE; IN-UTERO; INDUCTION AB 1,1-Dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE), a persistent environmental contaminant, is a metabolite of the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT). DDE is similar to phenobarbital (PB) in that both compounds are inducers of rat hepatic cytochrome P450 2B and 3A (CYP 2B and 3A). The induction of CYP 2B and 3A by PB is known to be regulated through the nuclear receptors constitutive androstane receptor ( CAR) and pregnane X receptor (PXR), respectively. In the current study, the induction of hepatic CYP 3A1 and 2B1 by DDE was correlated with CAR and PXR activity. Induction of 3A1 and 2B1 was observed in the livers of adult and developing male Sprague-Dawley rats following exposure to DDE. Increased hepatic expression of 3A1, but not 2B1, in developing rats exposed during gestation and lactation persisted into adulthood. In receptor transactivation assays, both CAR and PXR transcriptional activities were significantly enhanced by DDE. Nuclear accumulation of CAR, but not PXR, was observed in the liver tissue following DDE and PB treatment. These data support the idea that induction of hepatic 3A1 and 2B1 by DDE is mediated through the activation of CAR and PXR. This study suggests that regulation by environmental compounds of hepatic enzymes via CAR and PXR may have impact on the metabolism of endogenous and exogenous substrates. C1 CIIT, Ctr Hlth Res, Div Biol Sci, Res Triangle Pk, NC 27709 USA. Univ Rhode Isl, Dept Biomed Sci, Kingston, RI 02881 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP You, L (reprint author), CIIT, Ctr Hlth Res, Div Biol Sci, 6 Davis Dr, Res Triangle Pk, NC 27709 USA. FU NIGMS NIH HHS [R01-GM61988] NR 37 TC 74 Z9 79 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 474 EP 481 DI 10.1124/mol.64.2.474 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900032 PM 12869653 ER PT J AU Przybyla-Zawislak, BD Srivastava, PK Vazquez-Matias, J Mohrenweiser, HW Maxwell, JE Hammock, BD Bradbury, JA Enayetallah, AE Zeldin, DC Grant, DF AF Przybyla-Zawislak, BD Srivastava, PK Vazquez-Matias, J Mohrenweiser, HW Maxwell, JE Hammock, BD Bradbury, JA Enayetallah, AE Zeldin, DC Grant, DF TI Polymorphisms in human soluble epoxide hydrolase SO MOLECULAR PHARMACOLOGY LA English DT Article ID BLOOD-PRESSURE REGULATION; ARACHIDONIC-ACID; CATALYTIC MECHANISM; MOUSE-LIVER; GENE EPHX2; IDENTIFICATION; RAT; HYPERTENSION; PURIFICATION; DETERMINANTS AB Human soluble epoxide hydrolase (hsEH) metabolizes a variety of epoxides to the corresponding vicinal diols. Arachidonic and linoleic acid epoxides are thought to be endogenous substrates for hsEH. Enzyme activity in humans shows high interindividual variation ( e. g., 500-fold in liver) suggesting the existence of regulatory and/or structural gene polymorphisms. We resequenced each of the 19 exons of the hsEH gene (EPHX2) from 72 persons representing black, Asian, and white populations. A variety of polymorphisms was found, six of which result in amino acid substitutions. Amino acid variants were localized on the crystal structure of the mouse sEH, resulting in the prediction that at least two of these (Arg287Gln and Arg103Cys) might significantly affect enzyme function. The six variants of the hsEH cDNA corresponding to each single polymorphism and one corresponding to a double polymorphism were then constructed by site-directed mutagenesis and expressed in insect cells. As predicted, Arg287Gln and the double mutant Arg287Gln/Arg103Cys showed decreased enzyme activity using trans-stilbene oxide, trans-diphenylpropene oxide, and 14,15-epoxyeicosatrienoic acid as substrates. Lys55Arg and Cys154Tyr mutants had elevated activity for all three substrates. Detailed kinetic studies revealed that the double mutant Arg287Gln/Arg103Cys showed significant differences in K-m and V-max. In addition, stability studies showed that the double mutant was less stable than wild-type protein when incubated at 37 degreesC. These results suggest that at least six hsEH variants exist in the human population and that at least four of these may influence hsEH-mediated metabolism of exogenous and endogenous epoxide substrates in vivo. C1 Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. Univ Calif Davis, Ctr Canc Res, Davis, CA 95616 USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. FU NIEHS NIH HHS [R37-ES02710, P42-ES04699, P30-ES05707]; NIGMS NIH HHS [GM56708] NR 36 TC 89 Z9 94 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2003 VL 64 IS 2 BP 482 EP 490 DI 10.1124/mol.64.2.482 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 702JN UT WOS:000184220900033 PM 12869654 ER PT J AU Bres, V Kiernan, RE Linares, LK Chable-Bessia, C Plechakova, O Treand, C Emiliani, S Peloponese, JM Jeang, KT Coux, O Scheffner, M Benkirane, M AF Bres, V Kiernan, RE Linares, LK Chable-Bessia, C Plechakova, O Treand, C Emiliani, S Peloponese, JM Jeang, KT Coux, O Scheffner, M Benkirane, M TI A non-proteolytic role for ubiquitin in Tat-mediated transactivation of the HIV-1 promoter SO NATURE CELL BIOLOGY LA English DT Article ID REGULATORY PARTICLE; CYCLIN T1; PROTEASOME; DEGRADATION; MDM2; TRANSCRIPTION; PROTEIN; PATHWAY; P53; IDENTIFICATION AB The human immunodeficiency virus type 1 (HIV-1) encodes a potent transactivator, Tat, which functions through binding to a short leader RNA, called transactivation responsive element (TAR). Recent studies suggest that Tat activates the HIV-1 long terminal repeat (LTR), mainly by adapting co-activator complexes, such as p300, PCAF and the positive transcription elongation factor P-TEFb, to the promoter. Here, we show that the proto-oncoprotein Hdm2 interacts with Tat and mediates its ubiquitination in vitro and in vivo. In addition, Hdm2 is a positive regulator of Tat-mediated transactivation, indicating that the transcriptional properties of Tat are stimulated by ubiquitination. Fusion of ubiquitin to Tat bypasses the requirement of Hdm2 for efficient transactivation, supporting the notion that ubiquitin has a non-proteolytic function in Tat-mediated transactivation. C1 Inst Human Genet, Mol Virol Lab, CNRS, UPR 1142, Montpellier, France. Univ Cologne, Zentrum Biochem, D-50931 Cologne, Germany. Ctr Rech Biochim Macromol, UPR 1086, Montpellier, France. Inst Cochin Genet Mol, Dept Malad Infect, F-75014 Paris, France. NIAID, Mol Virol Lab, NIH, Bethesda, MD 20892 USA. RP Benkirane, M (reprint author), Inst Human Genet, Mol Virol Lab, CNRS, UPR 1142, Montpellier, France. RI Coux, Olivier/B-3406-2010; Jeang, Kuan-Teh/A-2424-2008; Scheffner, Martin/K-2940-2012 OI Coux, Olivier/0000-0001-8455-3849; Scheffner, Martin/0000-0003-2229-0128 NR 32 TC 118 Z9 122 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2003 VL 5 IS 8 BP 754 EP 761 DI 10.1038/ncb1023 PG 8 WC Cell Biology SC Cell Biology GA 710NX UT WOS:000184687300018 PM 12883554 ER PT J AU Canelles, M Park, ML Schwartz, OM Fowlkes, BJ AF Canelles, M Park, ML Schwartz, OM Fowlkes, BJ TI The influence of the thymic environment on the CD4-versus-CD8 T lineage decision SO NATURE IMMUNOLOGY LA English DT Article ID RECEPTOR TRANSGENIC MICE; ACTIVATED PROTEIN-KINASE; CELL-RECEPTOR; POSITIVE SELECTION; CD8 LINEAGE; IMMATURE THYMOCYTES; ANTIGEN RECEPTOR; CYTOPLASMIC DOMAIN; NEGATIVE SELECTION; COMMITMENT AB T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II-restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II-specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Fowlkes, BJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111, Bethesda, MD 20892 USA. NR 53 TC 31 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2003 VL 4 IS 8 BP 756 EP 764 DI 10.1038/ni953 PG 9 WC Immunology SC Immunology GA 706FA UT WOS:000184441500012 PM 12858172 ER PT J AU Jin, RS Banke, TG Mayer, ML Traynelis, SF Gouaux, E AF Jin, RS Banke, TG Mayer, ML Traynelis, SF Gouaux, E TI Structural basis for partial agonist action at ionotropic glutamate receptors SO NATURE NEUROSCIENCE LA English DT Article ID POTASSIUM CHANNELS I; LIGAND-BINDING CORE; AMPA RECEPTORS; HIPPOCAMPAL-NEURONS; CRYSTAL-STRUCTURES; ION-CHANNEL; ACTIVATION; GLUR2; DESENSITIZATION; KAINATE AB An unresolved problem in understanding neurotransmitter receptor function concerns the mechanism(s) by which full and partial agonists elicit different amplitude responses at equal receptor occupancy. The widely held view of 'partial agonism' posits that resting and active states of the receptor are in equilibrium, and partial agonists simply do not shift the equilibrium toward the active state as efficaciously as full agonists. Here we report findings from crystallographic and electrophysiological studies of the mechanism of activation of an AMPA-subtype glutamate receptor ion channel. In these experiments, we used 5-substituted willardiines, a series of partial agonists that differ by only a single atom. Our results show that the GluR2 ligand-binding core can adopt a range of ligand-dependent conformational states, which in turn control the open probability of discrete subconductance states of the intact ion channel. Our findings thus provide a structure-based model of partial agonism. C1 Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. Natl Inst Child Hlth & Dev, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gouaux, E (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, 650 W 168 St, New York, NY 10032 USA. RI Mayer, Mark/H-5500-2013; Jin, Rongsheng/M-7797-2013; OI Jin, Rongsheng/0000-0003-0348-7363; Banke, Tue/0000-0001-8417-4400 NR 43 TC 275 Z9 282 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2003 VL 6 IS 8 BP 803 EP 810 DI 10.1038/nn1091 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 705UP UT WOS:000184413700008 PM 12872125 ER PT J AU Yevenes, GE Peoples, RW Tapia, JC Parodi, J Soto, X Olate, J Aguayo, LG AF Yevenes, GE Peoples, RW Tapia, JC Parodi, J Soto, X Olate, J Aguayo, LG TI Modulation of glycine-activated ion channel function by G-protein beta gamma subunits SO NATURE NEUROSCIENCE LA English DT Article ID VOLTAGE-DEPENDENT MODULATION; RAT SYMPATHETIC NEURONS; MOUSE SPINAL NEURONS; DORSAL HORN NEURONS; CALCIUM-CHANNELS; CA2+ CHANNELS; GABA(B) RECEPTOR; K+ CHANNELS; INHIBITION; EXPRESSION AB Glycine receptors (GlyRs), together with GABA(A) and nicotinic acetylcholine (ACh) receptors, form part of the ligand-activated ion channel superfamily and regulate the excitability of the mammalian brain stem and spinal cord. Here we report that the ability of the neurotransmitter glycine to gate recombinant and native ionotropic GlyRs is modulated by the G protein betagamma dimer (Gbetagamma). We found that the amplitude of the glycine-activated Cl(-) current was enhanced after application of purified Gbetagamma or after activation of a G protein-coupled receptor. Overexpression of three distinct G protein alpha subunits (Galpha), as well as the Gbetagamma scavenger peptide ct-GRK2, significantly blunted the effect of G protein activation. Single-channel recordings from isolated membrane patches showed that Gbetagamma increased the GlyR open probability (nP(o)). Our results indicate that this interaction of Gbetagamma with GlyRs regulates both motor and sensory functions in the central nervous system. C1 Univ Concepcion, Dept Physiol, Neurophysiol Lab, Concepcion, Chile. NIAAA, Unit Cellular Neuropharmacol, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Concepcion, Dept Mol Biol, Mol Genet Lab, Concepcion, Chile. RP Aguayo, LG (reprint author), Univ Concepcion, Dept Physiol, Neurophysiol Lab, Box 160-C, Concepcion, Chile. EM laguayo@udec.cl NR 46 TC 60 Z9 64 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2003 VL 6 IS 8 BP 819 EP 824 DI 10.1038/nn1095 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 705UP UT WOS:000184413700010 PM 12858180 ER PT J AU Miller, GJ Mattera, R Bonifacino, JS Hurley, JH AF Miller, GJ Mattera, R Bonifacino, JS Hurley, JH TI Recognition of accessory protein motifs by the gamma-adaptin ear domain of GGA3 SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID APPENDAGE DOMAIN; TRANS-GOLGI; VHS DOMAINS; BINDING; CLATHRIN; FAMILY; COMPLEX; TRAFFICKING; RECRUITMENT; ENDOCYTOSIS AB Adaptor proteins load transmembrane protein cargo into transport vesicles and serve as nexuses for the formation of large multiprotein complexes on the nascent vesicles. The gamma-adaptin ear (GAE) domains of the AP-1 adaptor protein complex and the GGA adaptor proteins recruit accessory proteins to these multiprotein complexes by binding to a hydrophobic motif. We determined the structure of the GAE domain of human GGA3 in complex with a peptide based on the DFGPLV sequence of the accessory protein Rabaptin-5 and refined it at a resolution of 2.2 Angstrom. The leucine and valine residues of the peptide are partly buried in two contiguous shallow, hydrophobic depressions. The anchoring phenylalanine is buried in a deep pocket formed by the aliphatic portions of two conserved arginine residues, along with an alanine and a proline, illustrating the unusual function of a cluster of basic residues in binding a hydrophobic motif. C1 NIDDKD, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. NR 32 TC 47 Z9 47 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD AUG PY 2003 VL 10 IS 8 BP 599 EP 606 DI 10.1038/nsb953 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 705UA UT WOS:000184412400008 PM 12858162 ER PT J AU Kimmel, PL AF Kimmel, PL TI HIV-associated nephropathy: virologic issues related to renal sclerosis SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article; Proceedings Paper CT Symposium on Minimal Change Disease, Focal Segmental Glomerular Sclerosis and Proteinuria CY JUL 13-14, 2000 CL MANCHESTER, ENGLAND DE FSGS; HIV; nephropathy; renal sclerosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; CHEMOKINE RECEPTOR CCR5; COLLAPSING GLOMERULOPATHY; NEPHROTIC SYNDROME; EPITHELIAL-CELLS; KIDNEY-DISEASES; FOLLOW-UP; INFECTION; PATHOGENESIS AB Human immunodeficiency virus (HIV) associated nephropathy (HIVAN) is the most common disease delineated in biopsy series of patients with HIV infection and renal disease. Although the renal histologic lesions in patients with HIV infection present a spectrum of findings, several groups have emphasized characteristic clinical and pathologic features of HIVAN. Consensus has since been reached that HIVAN has a distinctive pathology, consistent with focal segmental glomerulosclerosis, but involving all subunits of the kidney. Several studies have linked the pathogenesis of focal glomerulosclerosis to abnormalities of the glomerular epithelial cell. Recent advances in molecular histologic studies and treatment link the pathogenesis of HIVAN to factors associated with the viral lifecycle. Cytopathic effects of HIV gene products, apoptosis mediated by HIV infection, the elaboration of chemokines and cytokines as a result of viral or host protein synthesis in patients with genetic susceptibility to nephropathy, and the subversion of the host metabolic and synthetic machinery by the virus might be sufficient to create a rapidly progressive disease. If HIV infects and has cytopathic effects on glomerular epithelial cells, and dysfunction of these cells is intimately related to the pathogenesis and progression of renal disease, a reasonable pathogenic mechanism for the development of HIVAN may be inferred. The similarities of HIVAN and the collapsing variant of focal segmental glomerulosclerosis pose the intriguing possibility that the latter is a viral illness as well. The disease is marked by glomerular sclerosis with varying degrees of collapse, tubular epithelial cell degeneration, simplification, microcystic dilatation, interstitial fibrosis and immune cell infiltration. At the level of electron microscopy, tubular reticular inclusions in renal endothelial cells are typical, but not pathognomonic feature of HIVAN. C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. NR 54 TC 10 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD AUG PY 2003 VL 18 SU 6 BP 59 EP 63 DI 10.1093/ndt/gfg1062 PG 5 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 722AZ UT WOS:000185353300012 ER PT J AU Shapiro, DA Renock, S Arrington, E Chiodo, LA Liu, LX Sibley, DR Roth, BL Mailman, R AF Shapiro, DA Renock, S Arrington, E Chiodo, LA Liu, LX Sibley, DR Roth, BL Mailman, R TI Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE atypical antipsychotic; schizophrenia; aripiprazole; partial agonist; receptor pharmacology ID SEROTONIN RECEPTOR SUBTYPES; DOPAMINE D2 RECEPTORS; HIGH-AFFINITY; FUNCTIONAL SELECTIVITY; OLANZAPINE THERAPY; MOLECULAR-CLONING; 5-HT2A RECEPTORS; LIGAND-BINDING; WEIGHT-GAIN; AGONIST AB Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D-2-dopamine receptors and relatively high affinities for 5-HT2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D-2-dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT2B-, hD(2L)-, and hD(3)-dopamine receptors, but also has significant affinity (5-30 nM) for several other 5-HT receptors (5-HT1A, 5-HT2A, 5-HT7), as well as alpha(1A)-adrenergic and hH(1)-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT1D, 5-HT2C, alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H-3-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT2B receptors and displays partial agonist actions at 5-HT2A, 5-HT2C, D-3, and D-4 receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D-2-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D-2-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D-2-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has 'functionally selective' actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of 'functionally selective' activation of D-2 (and possibly D-3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors-particularly 5-HT receptor subtypes (5-HT1A, 5-HT2A). C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Univ N Carolina, Sch Med, Dept Pharmacol & Psychiat, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Neurobiol Curriculum, Chapel Hill, NC USA. Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol, Lubbock, TX 79430 USA. NINDS, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH USA. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, W438,10900 Euclid Ave, Cleveland, OH 44106 USA. RI Roth, Bryan/F-3928-2010; OI Mailman, Richard/0000-0003-1353-2738 FU NIMH NIH HHS [N02 MH 80005, K02 MH 01366, MH 40537, MH 53356] NR 67 TC 535 Z9 566 U1 13 U2 44 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2003 VL 28 IS 8 BP 1400 EP 1411 DI 10.1038/sj.npp.1300203 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 704DD UT WOS:000184321700002 PM 12784105 ER PT J AU Hall, FS Drgonova, J Goeb, M Uhl, GR AF Hall, FS Drgonova, J Goeb, M Uhl, GR TI Reduced Behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE transgenic mice; gene knockout; dopamine; serotonin; brain-derived neurotrophic factor; conditioned place preference ID NIGROSTRIATAL DOPAMINERGIC FUNCTION; RAT-BRAIN; MUTANT MICE; NEURONAL DIFFERENTIATION; DEVELOPMENTAL REGULATION; LOCOMOTOR-ACTIVITY; SUBSTANTIA-NIGRA; PLACE PREFERENCE; NERVOUS-SYSTEM; CELL-DEATH AB Brain-derived neurotrophic factor (BDNF) affects the development of brain neurotransmitter systems, including dopamine and serotonin systems that are important for cocaine's rewarding and locomotor stimulatory properties. Human genomic markers within or near the BDNF locus have been linked to or associated with substance abuse. Post-mortem human brain specimens reveal individual differences in the levels of BDNF mRNA and in mRNA splicing patterns. To assess the effects of lifelong alterations in the levels of BDNF expression on a measure of psychostimulant reward, we have compared locomotor stimulant and rewarding effects of cocaine in heterozygous BDNF knockout mice with effects in their wild-type littermates. Heterozygous BDNF knockout mice displayed less locomotion during habituation and less locomotion after cocaine injections. Cocaine-conditioned place preferences were reduced in the BDNF heterozygotes. These mice displayed no significant difference from saline control values at a dose of 10 mg/kg s.c. cocaine, although they exhibited cocaine-induced preference at a 20 mg/kg dose. These data confirm important roles for BDNF in psychostimulant actions, presumably via neurotrophic effects on dopamine and serotonin systems. Furthermore, these data support suggestions that differences in human BDNF expression may underlie associations between markers near the human BDNF gene locus and drug addiction. C1 NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Hall, FS (reprint author), NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Drgonova, Jana/B-2903-2008; Hall, Frank/C-3036-2013; OI Hall, Frank/0000-0002-0822-4063; Drgonova, Jana/0000-0002-4623-8466 NR 40 TC 120 Z9 122 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2003 VL 28 IS 8 BP 1485 EP 1490 DI 10.1038/sj.npp.1300192 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 704DD UT WOS:000184321700011 PM 12784114 ER PT J AU Weickert, TW Goldberg, TE Marenco, S Bigelow, LB Egan, MF Weinberger, DR AF Weickert, TW Goldberg, TE Marenco, S Bigelow, LB Egan, MF Weinberger, DR TI Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: Critical examination of confounds SO NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 09-14, 2000 CL SAN JUAN, PUERTO RICO SP Amer Coll Neuropsychopharmacol DE schizophrenia; placebo; cognition; antipsychotic agents; learning; dopamine ID NEUROPSYCHOLOGICAL TEST-PERFORMANCE; PATIENTS RECEIVING CLOZAPINE; WORKING-MEMORY; RISPERIDONE; DRUGS; DIMENSIONS; OLANZAPINE; IMPROVEMENT; MEDICATIONS; HALOPERIDOL AB Although previous studies report cognitive improvement following atypical antipsychotic administration in schizophrenia (SC), few placebo-controlled within-subject studies with examination of confounds (symptom reduction, cooperation, learning, and outliers) have been reported. The present study examines the effects of atypicals and confounds upon cognition in SC. The hypothesis tested was that relative to placebo, atypicals as a general class of medication would elicit cognitive improvement in SC. In all, 19 patients with SC (15 males) completed the double-blind, counterbalanced, randomized within-subject study of the effects of atypical antipsychotics (risperidone, clozapine, olanzapine, or quetiapine) vs placebo administration upon cognitive performance in the domains of executive function, attention, memory, language, visual perception, and general intellect. Significant cognitive improvement during atypical antipsychotic administration relative to placebo withdrawal occurred in most cognitive domains with robust improvements in intelligence (p = 0.001), memory (p = 0.0009), and fluency (p<0.002) even after outliers and unmotivated performances were excluded. These findings suggest that relative to placebo withdrawal, atypicals improve cognitive performance in SC. However, this finding may not be specific to atypicals, since analogous studies of typicals have not been performed. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weickert, TW (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4N 202,MSC 1379, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 58 TC 61 Z9 61 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2003 VL 28 IS 8 BP 1491 EP 1500 DI 10.1038/sj.npp.1300216 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 704DD UT WOS:000184321700012 PM 12799617 ER PT J AU Matsumoto, M Weickert, CS Beltaifa, S Kolachana, B Chen, JS Hyde, TM Herman, MM Weinberger, DR Kleinman, JE AF Matsumoto, M Weickert, CS Beltaifa, S Kolachana, B Chen, JS Hyde, TM Herman, MM Weinberger, DR Kleinman, JE TI Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cortical layer; DLPFC; dopamine; functional Val/Met polymorphism; human brain; in situ hybridization histochemistry; pyramidal neuron ID WORKING-MEMORY DEFICITS; MONKEY CEREBRAL-CORTEX; HIGH-ACTIVITY ALLELE; DOPAMINE TRANSPORTER; PYRAMIDAL NEURONS; CATECHOLAMINERGIC INNERVATION; FUNCTIONAL POLYMORPHISM; STRIATAL DOPAMINE; NUCLEUS-ACCUMBENS; SOMAL SIZE AB Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val(108/158) Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N = 14) and of normal controls (N = 15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F = 2.68, df = 4,108, P<0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (P<0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val(108/158) Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Matsumoto, M (reprint author), Yamanouchi Pharmaceut Co Ltd, Genom Res, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan. RI Shannon Weickert, Cynthia/G-3171-2011; Matsumoto, Mitsuyuki/G-3207-2012 OI Matsumoto, Mitsuyuki/0000-0002-1172-2354 NR 65 TC 95 Z9 96 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2003 VL 28 IS 8 BP 1521 EP 1530 DI 10.1038/sj.npp.1300218 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 704DD UT WOS:000184321700016 PM 12799619 ER PT J AU Raedler, TJ Knable, MB Jones, DW Urbina, RA Egan, MF Weinberger, DR AF Raedler, TJ Knable, MB Jones, DW Urbina, RA Egan, MF Weinberger, DR TI Central muscarinic acetylcholine receptor availability in patients treated with clozapine SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE muscarinic receptor; clozapine; IQNB; SPECT; schizophrenia; antipsychotic ID POSITRON-EMISSION-TOMOGRAPHY; HAMSTER OVARY CELLS; SCHIZOPHRENIC-PATIENTS; CHOLINERGIC RECEPTORS; ANTIPSYCHOTIC-DRUGS; CAUDATE-PUTAMEN; OCCUPANCY; BINDING; PET; RISPERIDONE AB Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D-2 receptor blockade as well as high serotonin 5HT(2) receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275 +/- 88 mg/day), these differences were highly significant (p<0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine. C1 NIMH, Clin Brain Disorders Branch, NIH, Intramural Res Program, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Intramural Res Program, 10 Ctr Dr,4S-235 MSC 1379, Bethesda, MD 20892 USA. NR 43 TC 31 Z9 32 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2003 VL 28 IS 8 BP 1531 EP 1537 DI 10.1038/sj.npp.1300210 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 704DD UT WOS:000184321700017 PM 12799613 ER PT J AU Lu, L Shepard, JD Hall, FS Shaham, Y AF Lu, L Shepard, JD Hall, FS Shaham, Y TI Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE amphetamine; cocaine; conditioned place preference; drug discrimination; drug self-administration; heroin; maternal deprivation; morphine; reward; relapse; social isolation; stress ID CONDITIONED PLACE PREFERENCE; CORTICOTROPIN-RELEASING-FACTOR; CHRONIC MILD STRESS; COCAINE-SEEKING BEHAVIOR; SOCIAL-DEFEAT STRESS; DOPAMINE-RECEPTOR ANTAGONISTS; INTRA-PERIFORNICAL SULPIRIDE; BRAIN-STIMULATION REWARD; CHRONIC FOOD RESTRICTION; DOSE-RESPONSE FUNCTIONS AB Studies in humans suggest that exposure to life stressors is correlated with compulsive drug abuse and relapse to drugs during periods of abstinence. The behavioral and neurobiological mechanisms involved in the effect of stress on drug abuse, however, are not known. Here, we review data from studies using preclinical models in rats on the effect of environmental stressors on opiate and psychostimulant reinforcement, as measured by the intravenous drug self-administration and conditioned place preference procedures, on relapse to these drugs, as measured by the reinstatement procedure, and on the subjective effects of these drugs, as measured by the drug discrimination procedure. The results of the studies reviewed here suggest that while stressors are important modulators of the behavioral effects of opiate and pychostimulant drugs, the effect of stress on behavior in these animal models is stressor-specific, and to some degree, procedure- and drug-class-specific. The review of studies on the neurobiological mechanisms underlying stress-drug interactions in these animal models indicate that central noradrenaline and extrahypothalamic corticotropin-releasing factor mediate the effect of one form of stress (intermittent footshock) on reinstatement of opiate and psychostimulant seeking after prolonged drug-free periods. At present, however, little is known about the neuronal events that mediate the effect of environmental stressors on opiate and psychostimulant reinforcement or discrimination. The broader implications of the data reviewed here for future research and for the treatment of opiate and psychostimulant addiction are briefly discussed. Published by Elsevier Ltd. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 282 TC 187 Z9 195 U1 4 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD AUG PY 2003 VL 27 IS 5 BP 457 EP 491 DI 10.1016/S0149-7634(03)00073-3 PG 35 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 728AU UT WOS:000185693700004 PM 14505687 ER PT J AU Winickoff, JP Pbert, L Klein, JD Lando, HA Carroll, BC Mermelstein, R Moolchan, ET Prokhorov, AV Ossip-Klein, D AF Winickoff, JP Pbert, L Klein, JD Lando, HA Carroll, BC Mermelstein, R Moolchan, ET Prokhorov, AV Ossip-Klein, D TI Youth tobacco control research and activities in the United States: The current national landscape SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID ADOLESCENT SMOKING; CIGARETTES AB This paper highlights the increasing level of collaboration, resource sharing, and consensus building in youth tobacco control taking place in the United States. Better knowledge of the current research, activities, and collaborations in this area will help in the planning of activities and the rational allocation of funds for tobacco control programs, research, advocacy, and counter-advertising initiatives. We defined three general classifications for organizations that had national youth tobacco control activities: Government centers and institutes, nongovernment organizations, and bridging organizations. We asked national experts in our own organization and at all other included organizations to suggest additional groups for inclusion. After gathering available public information on each organization from Web sites and printed materials, we then solicited additional information by personal communication with individuals in leadership positions for youth tobacco control within each group. We developed a uniform framework to present a clear picture of each group in the areas of institutional conception, general goals, youth tobacco control research, and youth tobacco control activities. We identified 16 organizations that met the selection criteria. This paper contains an overview of each institution and its youth tobacco control research and activities. The tables provide a helpful reference guide presenting the institutional conception, goals, funding for research, activities, and Web sites for the institutions and organizations discussed here. Many groups have current youth tobacco control priorities in the United States. This synthesis of current research, funding sources, programmatic activities, and collaborations in the United States will be a valuable resource for clinicians, tobacco control advocates, researchers, and program planners. C1 Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Policy, Div Gen Pediat, MGH, Boston, MA 02114 USA. Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA 01605 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Illinois, Hlth Res & Policy Ctr, Dept Psychol & Publ Hlth, Chicago, IL 60680 USA. NIDA, Teen Tobacco Addict Treatment Res Ctr, NIH, Baltimore, MD USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp, Ctr Child & Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. NR 17 TC 3 Z9 3 U1 1 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2003 VL 5 IS 4 BP 435 EP 454 DI 10.1080/1462220031000118612 PG 20 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 718LM UT WOS:000185147700001 PM 12959780 ER PT J AU Chappell, LL Ma, D Milenic, DE Garmestani, K Venditto, V Beitzel, MP Brechbiel, MW AF Chappell, LL Ma, D Milenic, DE Garmestani, K Venditto, V Beitzel, MP Brechbiel, MW TI Synthesis and evaluation of novel bifunctional chelating agents based on 1,4,7,10-tetraazacyclododecane-N,N ',N '',N '''-tetraacetic acid for radiolabeling proteins SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE DOTA; bifunctional chelating agent; lutetium-177; monoclonal antibody; biodistribution; stability ID RADIOIMMUNOTHERAPY; ANTIBODY; STABILITY; COMPLEXES; DOTA; STEREOISOMERS; RADIONUCLIDES; DERIVATIVES; CARCINOMA; LIGANDS AB Detailed synthesis of the bifunctional chelating agents 2-methyl-6-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (1BM-DOTA) and 2-(p-isothiocyanatobenzyl)-5, 6-cyclohexano-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetate (CHX-DOTA) are reported. These chelating agents were compared to 2-(p-isothiocyanatobenzyl)-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (C-DOTA) and 1, 4, 7, 10-Tetraaza-N-(1-carboxy-3-(4-nitrophenyl)propyl)-N', N", N'''-tris(acetic acid) cyclododecane (PA-DOTA) as their Lu-177 radiolabeled conjugates with Herceptin(TM). In vitro stability of the immunoconjugates radiolabeled with Lu-177 was assessed by serum stability studies. The in vivo stability of the radiolabeled immunoconjugates and their targeting characteristics were determined by biodistribution studies in LS-174T xenograft tumor-bearing mice. Relative radiolabeling rates and efficiencies were determined for all four immunoconjugates. Insertion of the 1B4M moiety into the DOTA backbone increases radiometal chelation rate and provides complex stability comparable to C-DOTA and PA-DOTA while the CHX-DOTA appears to not form as stable a Lu-177 complex while exhibiting a substantial increase in formation rate. The 1BM-DOTAmay have potential for radioimmunotherapy applications. Published by Elsevier Inc. All rights reserved. C1 NCI, Radioimmune & Inorgan Chem Sect, ROB, CCR,NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, ROB, CCR,NIH, Bethesda, MD 20892 USA. NR 33 TC 51 Z9 51 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2003 VL 30 IS 6 BP 581 EP 595 DI 10.1016/S0969-8051(03)00033-7 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 711CZ UT WOS:000184723200003 PM 12900284 ER PT J AU Sato, N Park, CW Kim, HS Han, ES Wong, KJ Paik, RS Park, LS Yao, ZS Carrasquillo, JA Paik, CH AF Sato, N Park, CW Kim, HS Han, ES Wong, KJ Paik, RS Park, LS Yao, ZS Carrasquillo, JA Paik, CH TI Synthesis of dendrimer-based biotin radiopharmaceuticals to enhance whole-body clearance SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE biotinylated; iodinated dendrimer; succinylation; lysine co-injection; reduced renal and hepatic uptake ID DISULFIDE-STABILIZED FV; MONOCLONAL-ANTIBODY FRAGMENTS; BLOCKS RENAL UPTAKE; STARBURST DENDRIMERS; PHARMACOKINETICS; BIODISTRIBUTION; REDUCTION; INJECTION AB To synthesize a biotin radiopharmaceutical that clears rapidly, dendrimer was used as a carrier and conjugated with succinimidyl 3-[I-125]iodobenzoate and tetrafluorophenyl norbiotinamidosuccinate. Then, succinic anhydride was used to reduce its pI. In mice, the non-succinylated product showed high liver (67% ID/g) and kidney (44% ID/g) uptakes and whole-body retention (94% ID) at 20 min that persisted for 12 hr. The corresponding organ uptakes (22% and 11% ID/g) and the whole-body retention (47% ID) were drastically reduced by succinylation (p < 0.0001). Lysine co-injection further lowered renal uptake. Published by Elsevier Inc. All rights reserved. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 35 TC 9 Z9 11 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2003 VL 30 IS 6 BP 617 EP 625 DI 10.1016/S0969-8051(03)00052-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 711CZ UT WOS:000184723200006 PM 12900287 ER PT J AU Pelletier, B Beaudoin, J Philpott, CC Labbe, S AF Pelletier, B Beaudoin, J Philpott, CC Labbe, S TI Fep1 represses expression of the fission yeast Schizosaccharomyces pombe siderophore-iron transport system SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; SACCHAROMYCES-CEREVISIAE; ASPERGILLUS-NIDULANS; TRANSCRIPTION FACTOR; NEUROSPORA-CRASSA; CANDIDA-ALBICANS; USTILAGO-MAYDIS; GATA FACTOR; FERRICHROME TRANSPORTER; TRIACETYLFUSARININE-C AB When iron repletes, Schizosaccharomyces pombe cells repress transcription of genes encoding components involved in the reductive iron transport system. Fep1 mediates this transcriptional control by interacting specifically with GATA-type cis-acting elements. To further investigate the role that Fep1 plays in iron homeostasis, we searched for additional Fep1-regulated genes. We found that str1(+) is subject to negative transcriptional regulation, which is exerted through binding of Fep1 to a single GATA element in the str1(+) promoter. Introduction of str1(+) into a Saccharomyces cerevisiae fet3Delta arn1-4Delta strain led to assimilation of iron from ferrichrome, revealing that Str1 functions as a siderophore-iron transporter in S.pombe. We also identified two additional target genes of Fep1, named str2(+) and str3(+). We demonstrate that the str1(+), str2(+) and str3(+) genes share a common promoter element, 5'-(A/T)GATAA-3'. We found that the N-terminal 241 residue segment of Fep1 expressed in Escherichia coli specifically interacts with the 5'-(A/T)GATAA-3' element present in each of these promoters. Consistent with this, constitutive high level str1(+), str2(+) and str3(+) gene expression was observed in a fep1Delta mutant strain. Taken together, these results demonstrate that Fep1 occupies a central role in coordinating transcriptional regulation of genes encoding components of the reductive and non-reductive iron transport systems in fission yeast. C1 Univ Sherbrooke, Dept Biochim, Sherbrooke, PQ J1H 5N4, Canada. NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Labbe, S (reprint author), Univ Sherbrooke, Dept Biochim, Sherbrooke, PQ J1H 5N4, Canada. NR 47 TC 48 Z9 54 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 AUG 1 PY 2003 VL 31 IS 15 BP 4332 EP 4344 DI 10.1093/nar/gkg647 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707WM UT WOS:000184532900016 PM 12888492 ER PT J AU Kozmin, SG Pavlov, YI Kunkel, TA Sage, E AF Kozmin, SG Pavlov, YI Kunkel, TA Sage, E TI Roles of Saccharomyces cerevisiae DNA polymerases Pol eta and Pol zeta in response to irradiation by simulated sunlight SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CYCLOBUTANE PYRIMIDINE DIMERS; THYMINE-THYMINE DIMER; SINGLE-STRAND BREAKS; ESCHERICHIA-COLI; ULTRAVIOLET-LIGHT; UV-RADIATION; HUMAN-CELLS; IN-VIVO; YEAST; MUTAGENESIS AB Sunlight causes lesions in DNA that if unrepaired and inaccurately replicated by DNA polymerases yield mutations that result in skin cancer in humans. Two enzymes involved in translesion synthesis (TLS) of UV-induced photolesions are DNA polymerase eta (Poleta) and polymerase zeta (Polzeta), encoded by the RAD30A and REV3 genes, respectively. Previous studies have investigated the TLS roles of these polymerases in human and yeast cells irradiated with monochromatic, short wavelength UVC radiation (254 nm). However, less is known about cellular responses to solar radiation, which is of higher and mixed wavelengths (310-1100 nm) and produces a different spectrum of DNA lesions, including Dewar photoproducts and oxidative lesions. Here we report on the comparative cytotoxic and mutagenic effects of simulated sunlight (SSL) and UVC radiation on yeast wild-type, rad30Delta, rev3Delta and rev3Delta rad30Delta strains. The results with SSL support several previous interpretations on the roles of these two polymerases in TLS of photodimers and (6-4) photoproducts derived from studies with UVC. They further suggest that Poleta participates in the non-mutagenic bypass of SSL-dependent cytosine-containing Dewar photoproducts and 8-oxoguanine, while Polzeta is mainly responsible for the mutagenic bypass of all types of Dewar photoproducts. They also suggest that in the absence of Polzeta, Poleta contributes to UVC- and SSL-induced mutagenesis, possibly by the bypass of photodimers containing deaminated cytosine. C1 Ctr Univ, Inst Curie, CNRS, IC UMR 2027, F-91405 Orsay, France. St Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. NIEHS, Labs Mol Genet, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Sage, E (reprint author), Ctr Univ, Inst Curie, CNRS, IC UMR 2027, Bat 110, F-91405 Orsay, France. EM evelyne.sage@curie.u-psud.fr RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 NR 53 TC 42 Z9 44 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 AUG 1 PY 2003 VL 31 IS 15 BP 4541 EP 4552 DI 10.1093/nar/gkg489 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707WM UT WOS:000184532900039 PM 12888515 ER PT J AU Kaczmarczyk, SJ Green, JE AF Kaczmarczyk, SJ Green, JE TI Induction of cre recombinase activity using modified androgen receptor ligand binding domains: a sensitive assay for ligand-receptor interactions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SITE-SPECIFIC RECOMBINATION; INDUCIBLE GENE-EXPRESSION; EMBRYONIC STEM-CELLS; CANCER CELLS; TRANSGENIC MICE; MOUSE GENOME; LNCAP CELLS; SYSTEM; ACTIVATION; ANTIANDROGENS AB Novel systems of inducible gene expression are presented in which CRE-M, an altered form of cre recombinase (cre), is fused to and activated by ligand binding to two forms of the androgen receptor (AR) ligand binding domain (LBD). Selective activation or inactivation of gene transcription is induced upon the addition of appropriate ligand. The coupling of this cre-LBD system with our previously reported highly sensitive assay to measure cre activity in vitro using a dual fluorescent gene switch reporter provides a novel, high-throughput assay system for identifying compounds that bind to and activate various forms of the LBD of androgen receptor. This method can similarly be applied to screen compounds for their activating properties on other steroid hormone LBDs. Three different forms of the AR-LBD were fused to CRE-M, including the wild-type AR-LBD (wt), a non-ligand binding truncated form, LBD (T), and a mutated form (Thr-->Ala substitution) identified in the LNCaP prostate cancer cell line, LBD (LNCaP). We demonstrate a 10-fold induction of cre activity by the addition of androgen agonists to the CRE-M-AR-LBD(wt) fusion protein, but not in the presence of the anti-androgen, flutamide. However, cre activity can be induced by flutamide with the CRE-M-AR-LBD(LNCaP) fusion protein. Similar activation properties were obtained when these fusion proteins were expressed using adenoviral vectors. When combined with our previously reported cre-lox gene switch system, the CRE-M-AR-LBD system can be utilized in gene therapy systems in which a therapeutic product may be initially expressed, replaced by a second product, or turned-off following exposure to ligand. This provides an important, additional level of regulation to gene therapy sytems. C1 NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Green, JE (reprint author), NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NR 35 TC 3 Z9 3 U1 1 U2 1 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 AUG 1 PY 2003 VL 31 IS 15 AR e86 DI 10.1093/nar/gng087 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707WM UT WOS:000184532900010 PM 12888538 ER PT J AU Yang, YP Sharan, SK AF Yang, YP Sharan, SK TI A simple two-step, 'hit and fix' method to generate subtle mutations in BACs using short denatured PCR fragments SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BACTERIAL ARTIFICIAL CHROMOSOMES; ESCHERICHIA-COLI; HOMOLOGOUS RECOMBINATION; SYSTEM; MICE AB The bacteriophage lambda recombination system has proven to be a valuable tool for engineering bacterial artificial chromosomes (BAC). Due to its high efficiency, subtle alterations in the BACs can be generated using oligonucleotides as targeting vectors. Since no selection marker is used, recombinant clones are identified utilizing a selective PCR screening method. However, occasionally the selective PCR screening is not feasible. We describe here a two-step 'hit and fix' method that can be reliably used for generating any subtle alteration in BACs using short denatured PCR fragments as targeting vectors. In the first step of this method, 6-20 nucleotides are changed around the base where the mutation has to be generated. In the second step, these altered nucleotides are reverted to the original sequence and simultaneously a subtle alteration is introduced. Since in each step several nucleotides are changed, PCR primers specific for such alterations can be designed. This two-step method provides a simple and efficient tool for generating subtle alterations in BACs that can be very valuable for functional analysis of 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,Bldg 560 Room 32-31C,POB B, Frederick, MD 21702 USA. NR 16 TC 38 Z9 39 U1 0 U2 1 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 AUG 1 PY 2003 VL 31 IS 15 AR e80 DI 10.1093/nar/gng080 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 707WM UT WOS:000184532900004 PM 12888532 ER PT J AU Riemann, B Law, MP Kopka, K Wagner, S Luthra, S Pike, VW Neumann, J Kirchhefer, U Schmitz, W Schober, O Schafers, M AF Riemann, B Law, MP Kopka, K Wagner, S Luthra, S Pike, VW Neumann, J Kirchhefer, U Schmitz, W Schober, O Schafers, M TI High non-specific binding of the beta(1)-selective radioligand 2-I-125-ICI-H SO NUKLEARMEDIZIN-NUCLEAR MEDICINE LA English DT Article DE SPECT; PET; beta(1)-adrenoceptor radioligands; cardiac imaging ID POSITRON-EMISSION-TOMOGRAPHY; CARDIAC SYMPATHETIC INNERVATION; BETA-ADRENOCEPTOR ANTAGONISTS; HUMAN HEART; ASYMMETRIC-SYNTHESIS; IN-VIVO; DERIVATIVES; BETA-2-ADRENOCEPTORS; BETA-1-ADRENOCEPTORS; (S)-CGP12388 AB Aim: As results of cardiac biopsies suggest, myocardial beta(1)-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac beta(2)- adrenoceptors vary. With suitable radiopharmoceuticols single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess beta-adrenoceptors non-invasively. Among the novel racemic analogues of the established beta(1)-selective odrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to beta(1)-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative subtype selective beta(1)-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac beta-adrenoceptors in mice and rots. In addition, the radiosynthesis of 2-I-125-ICI-H from the silylated precursor 2-SiMe3-ICI-H was established. The specific activity was 80 GBq/pmol, the radiochemical yield ranged from 70 to 80%. Results: The unlabelled compound 2-I-ICI-H showed high beta(1)-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac beta-adrenoceptors. The radiolabelled counterpart 2-I-125-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac beta(1)-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-I-125-ICI-H is no suitable radiotrocer for imaging in vivo. C1 Univ Munster, Dept Nucl Med, D-4400 Munster, Germany. Univ Munster, Inst Pharmacol & Toxicol, D-4400 Munster, Germany. Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London, England. Imaging Res Solut Ltd, London, England. Hammersmith Hosp, London, England. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Riemann, B (reprint author), Univ Munster, Dept Nucl Med, D-4400 Munster, Germany. RI Schober, Otmar/A-8670-2008 NR 39 TC 8 Z9 8 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0029-5566 J9 NUKLEARMED-NUCL MED JI Nuklearmedizin PD AUG PY 2003 VL 42 IS 4 BP 173 EP 180 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 717BD UT WOS:000185065000007 PM 12937696 ER PT J AU Alguacil, J Pollan, M Gustavsson, P AF Alguacil, J Pollan, M Gustavsson, P TI Occupations with increased risk of pancreatic cancer in the Swedish population SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID REDUCTION PLANT WORKERS; 24 US STATES; DIAGNOSTIC CERTAINTY; DEATH CERTIFICATES; MORTALITY; SWEDEN; EXPOSURES; COHORT; HAIRDRESSERS; METAANALYSIS AB Aims: To identify occupations with increased risk of pancreatic cancer in the Swedish population gainfully employed in 1970 over the period 1971-89. Methods: The base population was made up of Swedish men (1 779 646) and Swedish women (1 10 1 669) gainfully employed at the time of the 1970 census and were still alive and over age 24 on 1 January 1971. Information was drawn from two data sets: the Swedish cancer environment register and a background population register. After 19 years of follow up, 4420 men and 2143 women were diagnosed with histologically confirmed incident pancreatic adenocarcinoma. Log linear Poisson models were fitted, allowing for geographical area and town size. Risk estimators were also calculated for workers reporting the same occupation in 1960 and 1970. Results: Among women, a statistically significant risk excess of pancreatic cancer was observed for educational methods advisors", "librarian, archivist, curator", "motor vehicle driver", "typographer, lithographer", "purser, steward, stewardess", "other housekeeping and related workers", and the groups of occupations of "electrical, electronic, and related" and "glass, pottery, and tile workers". Men showed a higher incidence of pancreatic cancer among "technical assistants", "travelling agents", "other metal processing workers", "baker and pastry cook", "docker and freight handler", and "waiters". Conclusions: This study does not indicate that occupational factors play an important role in the aetiology of pancreatic cancer in Sweden. Few occupations were at increased risk of pancreatic cancer in both men and women, and the associations observed are in accordance with some previous studies from Western countries. C1 Carlos III Inst Hlth, Natl Ctr Epidemiol, Canc Epidemiol Unit, Madrid 28029, Spain. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Stockholm Ctr Publ Hlth, Dept Environm & Occupat Hlth, Stockholm, Sweden. RP Pollan, M (reprint author), Carlos III Inst Hlth, Natl Ctr Epidemiol, Canc Epidemiol Unit, Sinesio Delgado 6, Madrid 28029, Spain. RI Pollan, Marina/M-3259-2014; OI Pollan, Marina/0000-0002-4328-1565 NR 60 TC 15 Z9 17 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2003 VL 60 IS 8 BP 570 EP 576 DI 10.1136/oem.60.8.570 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 705AF UT WOS:000184373500006 PM 12883017 ER PT J AU Hoppin, JA Umbach, DM London, SJ Alavanja, MCR Sandler, DP AF Hoppin, JA Umbach, DM London, SJ Alavanja, MCR Sandler, DP TI Animal production and wheeze in the Agricultural Health Study: interactions with atopy, asthma, and smoking SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CHRONIC RESPIRATORY SYMPTOMS; NEW-ZEALAND FARMERS; LUNG-FUNCTION; DAIRY FARMERS; OCCUPATIONAL ASTHMA; FARMING POPULATION; CHRONIC-BRONCHITIS; PIG FARMERS; PESTICIDE APPLICATORS; CONFINEMENT WORKERS AB Background: Exposure to animals, their feeds, and by-products contribute to respiratory symptoms among farmers. Aims: To investigate the role of animal exposures and wheeze, and to assess whether their impact differs among susceptible subgroups, including atopics, asthmatics, and smokers. Methods: Using the Agricultural Health Study, a cohort of pesticide applicators in Iowa and North Carolina enrolled in 1994-97, wheeze associated with animal production was evaluated and interactions among susceptible subgroups assessed. Logistic regression models were used to examine risk factors for wheeze in the past year among 20 468 farmers. Results: Individuals raising animals requiring direct contact had the highest odds ratios (OR) for wheeze (ORdairy = 1.26; OReggs = 1.70). A significant dose response was observed for both the number of poultry ani the number of livestock on the farm. Farmers who performed veterinary procedures on a daily basis had an OR of 1.51. The odds of wheeze associated with poultry production was greater among atopic than non-atopic individuals. Milking cows daily increased the odds of wheeze in all individuals, with the largest association observed among atopic asthmatic individuals. The impact of dairy, poultry, and egg production varied among smoking groups. Past smokers had the highest odds ratios, followed by never smokers, and then current smokers. The OReggs was 2.88 among past smokers but only 1.46 for never smokers. The OReggs for current smokers of 0.80 might reflect self selection of exposure among smokers. Conclusions: Results are consistent with animal production and respiratory symptoms, and suggest that subgroups may respond differently to exposure. C1 NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NCI, Occupat Epidemiol Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20892 USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. NR 60 TC 25 Z9 25 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2003 VL 60 IS 8 AR e3 DI 10.1136/oem.60.8.e3 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 705AF UT WOS:000184373500020 PM 12883030 ER PT J AU Gold, A Nam, TG Jayaraj, K Sangaiah, R Klapper, DG Ball, LM French, JE Nylander-French, LA AF Gold, A Nam, TG Jayaraj, K Sangaiah, R Klapper, DG Ball, LM French, JE Nylander-French, LA TI Synthesis of S-aryl-D,L-cysteines and incorporation into keratin sequences SO ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL LA English DT Article C1 Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Gold, A (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. NR 8 TC 3 Z9 3 U1 0 U2 0 PU ORGANIC PREP PROCEDURES INC PI NEWTON HIGHLANDS PA PO BOX 9, NEWTON HIGHLANDS, MA 02161 USA SN 0030-4948 J9 ORG PREP PROCED INT JI Org. Prep. Proced. Int. PD AUG PY 2003 VL 35 IS 4 BP 375 EP 382 PG 8 WC Chemistry, Organic SC Chemistry GA 703NU UT WOS:000184287100003 ER PT J AU Eliav, E Teich, S Nitzan, D El Raziq, DA Nahlieli, O Tal, M Gracely, RH Benoliel, R AF Eliav, E Teich, S Nitzan, D El Raziq, DA Nahlieli, O Tal, M Gracely, RH Benoliel, R TI Facial arthralgia and myalgia: can they be differentiated by trigeminal sensory assessment? SO PAIN LA English DT Article DE temporomandibular disorders (TMD); neuritis; orofacial pain; temporomandibular joint ID JOINT INTERNAL DERANGEMENTS; TUMOR-NECROSIS-FACTOR; TEMPOROMANDIBULAR-JOINT; SYNOVIAL-FLUID; NEUROPATHIC PAIN; MUSCLE PAIN; DISORDERS; NERVE; INTERLEUKIN-1-BETA; INFLAMMATION AB Heat and electrical detection thresholds were assessed in 72 patients suffering from painful temporomandibular disorder. Employing widely accepted criteria, 44 patients were classified as suffering from temporomandibular joint (TMJ) arthralgia (i.e. pain originating from the TMJ) and 28 from myalgia (i.e. pain originating from the muscles of mastication). Electrical stimulation was employed to assess thresholds in large myelinated nerve fibers (Abeta) and heat application to assess thresholds ill unmyelinated nerve fibers (C). The sensory tests were performed bilaterally in three trigeminal nerve sites: the auriculotemporal nerve territory (AUT), buccal nerve territory (BUC) and the mental nerve territory (MNT). In addition, 22 healthy asymptomatic controls were examined. A Subset of tell arthralgia patients underwent arthrocentesis and electrical detection thresholds were additionally assessed Following the procedure. Electrical detection threshold ratios were calculated by dividing the affected side by the control side, thus reduced ratios indicate hypersensitivity of the affected side. In control patients, ratios obtained at all sites did not vary significantly from the expected Value of 'one' (mean with 95% confidence intervals AUT, 1:0.95- 1.06 BUC, 1.01:0.93- 1.11; MNT, 0.97:0.88- 1.05, all areas one sample analysis P > 0.05). In arthralgia patients mean ratios (+/- SEM) obtained for the AUT territory (0.63 +/- 0.03) were significantly lower compared to ratios for the MNT (1.02 +/- 0.03) and BUC (0.96 +/- 0.04) territories (repeated measures analysis of variance (RANOVA), P < 0.0001) and compared to the AUT ratios in myalgia (1.27 +/- 0.09) and control subjects (1 +/- 0.06, ANOVA, P < 0.0001) In the myalgia group the electrical detection threshold ratios in the AUT territory were significantly elevated compared to the AUT ratios in control subjects (Dunnett test, P < 0.05), but only approached statistical significance compared to the MNT (1.07 +/- 0.04) and BUC (1.11 +/- 0.06) territories (RANOVA, F-2.27 = 3.12, P = 0.052). There were no significant differences between and within the groups for electrical detection threshold ratios in the BUC and MNT nerve territories, and for the heat detection thresholds in all tested sites, Following arthrocentesis, mean electrical detection threshold ratios in the AUT territory were significantly elevated from 0.64 +/- 0.06 to 0.99 +/- 0.04 indicating resolution of the hypersensitivity (paired t-test, P = 0.001). In conclusion. large myelinated fiber hypersensitivity is found in the skin overlying TMJs with clinical pain and pathology but is not found in controls. In patients with muscle-related facial pain there was significant elevation of the electrical detection threshold ill the AUT region. (C) 2003 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Dept Oral Diag Oral Med & Radiol, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Dept Maxillofacial Surg, IL-91120 Jerusalem, Israel. Barzilai Govt Hosp, Dept Maxillofacial Surg, Ashqelon, Israel. Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Dept Anat & Cell Biol, Jerusalem, Israel. NICDR, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD USA. RP Eliav, E (reprint author), Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Dept Oral Diag Oral Med & Radiol, POB 12272, IL-91120 Jerusalem, Israel. NR 46 TC 32 Z9 33 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 2003 VL 104 IS 3 BP 481 EP 490 DI 10.1016/S0304-3959(03)00077-0 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 717QV UT WOS:000185101600007 PM 12927620 ER PT J AU Hernandez, D Hanson, M Singleton, A Gwinn-Hardy, K Freeman, J Ravina, B Doheny, D Gallardo, M Weiser, R Hardy, J Singleton, A AF Hernandez, D Hanson, M Singleton, A Gwinn-Hardy, K Freeman, J Ravina, B Doheny, D Gallardo, M Weiser, R Hardy, J Singleton, A TI Mutation at the SCA17 locus is not a common cause of parkinsonism SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE SCA17; ataxia; parkinsonism; triplet repeat; TATA-binding protein ID CAG TRINUCLEOTIDE REPEAT; TATA-BINDING PROTEIN; SPINOCEREBELLAR ATAXIA TYPE-2; MACHADO-JOSEPH-DISEASE; EXPANSION; GENE; POLYGLUTAMINE; DIAGNOSIS; ACCURACY; CRITERIA AB Spinocerebellar ataxia (SCA) 17 is a dominant, progressive, neurodegenerative disorder. The disease is caused by a triplet repeat expansion mutation within TATA-binding protein (TBP). Ataxia, dementia, parkinsonism and dystonia are common features. We have previously shown in several pedigrees that SCA-2 and SCA-3 can cause both parkinsonism and typical Parkinson's disease in the absence of prominent ataxia; a finding which has been confirmed by others. Given these previous findings and the description of parkinsonism as a common feature of SCA-17 we examined this locus in a series of probands from families with 2 or more members affected with parkinsonism (n = 51) and a group of sporadic parkinsonism patients (n = 59). We did not find any repeat sizes in the pathogenic range. The repeats we observed ranged from 29 to 41 (mean 36.8; median 37). We conclude that SCA-17 repeat expansion mutations are not a common cause of familial parkinsonism. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. CUNY, Mt Sinai Med Ctr, Dept Neurol, New York, NY 10029 USA. Hosp Univ Caracas, Caracas 1060, Venezuela. RP Singleton, A (reprint author), NIA, Mol Genet Sect, NIH, Bldg 10 Room 6C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 19 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD AUG PY 2003 VL 9 IS 6 BP 317 EP 320 DI 10.1016/S1353-8020(03)00027-0 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 701LL UT WOS:000184169000001 PM 12853230 ER PT J AU Passwell, JH Ashkenazi, S Harlev, E Miron, D Ramon, R Farzam, N Lerner-Geva, L Levi, Y Chu, CY Shiloach, J Robbins, JB Schneerson, R AF Passwell, JH Ashkenazi, S Harlev, E Miron, D Ramon, R Farzam, N Lerner-Geva, L Levi, Y Chu, CY Shiloach, J Robbins, JB Schneerson, R CA Israel Shigella Study Grp TI Safety and immunogenicity of Shigella sonnei-CRM9 and Shigella flexneri type 2a-rEPA(succ) conjugate vaccines in one- to four-year-old children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE Shigellosis; immunization; conjugate vaccines ID O-SPECIFIC POLYSACCHARIDE; DYSENTERIAE TYPE-1; LIPOPOLYSACCHARIDE ANTIBODIES; PUBLIC-HEALTH; INFECTIONS; EFFICACY; ISRAEL; 2A; EPIDEMIOLOGY; HYPOTHESIS AB Background and objective. Shigella conjugate vaccines have been shown to be safe, immunogenic and efficacious in adult volunteers. We have now investigated the safety and immunogenicity of investigational Shigella sonnei and Shigella flexneri 2a conjugate vaccines in 1- to 4-year-old children, the age group at greatest risk for shigellosis. Methods. The O-specific polysaccharides of S. sonnei and S. flexneri 2a, the two most common shigellae from patients in Israel, were bound to medically useful carrier proteins to form conjugates. Eighty healthy 1- to 4-year-olds were ran domized to receive two 0.5-ml im injections 6 weeks apart of either S. sonnei-CRM9 or S. flexneri 2a-rEPA(succ). Blood was taken before, 6 weeks after the first injection, 4 weeks after the second injections and 2 years after immunization for assay of IgG anti-lipopolysaccharide, diphtheria toxin and Pseudomonas aeruginosa exotoxin A antibodies by enzyme-linked immunosorbent assay. Results. During an 8-day surveillance period after each immunization, low fever (37.8-39.0degreesC) lasting only 24 to 48 h occurred in 2 of 40 recipients after the first injection and 4 of 40 recipients after the second injection of S. flexneri 2a-rEPA(succ) and in 2 of 38 of S. sonnei-CRM9 after the second injection; no fever was detected after the first injection. Liver function tests were normal in all vaccinees. S. sonnei-CRM9 elicited a >4-fold rise in IgG anti-LPS in 92.1% and S. flexneri 2a-rEPA(succ) in 85% (P < 0.0001) after the second injection; both conjugates elicited type-specific booster responses. At 2 years the geometric mean concentrations of both IgG anti-lipopolysaccharides were significantly higher than preimmunization levels. A >4-fold rise of IgG anti-diphtheria (65.8%) and IgG anti-ETA (77.5%) was observed. Conclusion. These experimental Shigella conjugate vaccines were safe and immunogenic in 1-to 4-year-old children. C1 Chaim Sheba Med Ctr, Safra Childrens Hosp, Samuel Jared Kushnick Immunol Lab, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, FMRC, Schneider Childrens Med Ctr, IL-69978 Tel Aviv, Israel. Haemek Med Ctr, Pediat Infect Dis Unit, Afula, Israel. NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Passwell, JH (reprint author), Chaim Sheba Med Ctr, Safra Childrens Hosp, Samuel Jared Kushnick Immunol Lab, IL-52621 Tel Hashomer, Israel. FU NICHD NIH HHS [N01 HD 53226] NR 31 TC 50 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2003 VL 22 IS 8 BP 701 EP 706 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 714JX UT WOS:000184911300005 PM 12913770 ER PT J AU Brenner, RA Bull, MJ Agran, P Dowd, MD Garcia, V Gardner, HG Smith, GA Tenenbein, M Weiss, JC Wright, J AF Brenner, RA Bull, MJ Agran, P Dowd, MD Garcia, V Gardner, HG Smith, GA Tenenbein, M Weiss, JC Wright, J CA Comm Injury Violence Poison Preven TI Prevention of drowning in infants, children, and adolescents SO PEDIATRICS LA English DT Article ID LOS-ANGELES-COUNTY; SUBMERSION INJURY; SWIMMING POOLS; NEAR-DROWNINGS; UNITED-STATES; CHILDHOOD; POPULATION; RESUSCITATION; ACCIDENTS; EPILEPSY AB Drowning is a leading cause of injury-related death in children. In 2000, more than 1400 US children younger than 20 years drowned. Most (91%) of these deaths were unintentional and were not related to boating. For each drowning death, it is estimated that at least 1 to 4 children suffer a serious nonfatal submersion event, many of which leave children with permanent disabilities. Environmental strategies, such as installation of 4-sided fences around swimming pools, and behavioral strategies, such as increased supervision of children while around water, are needed to prevent these tragedies. C1 NICHHD, US Dept HHS, Bethesda, MD 20892 USA. RP Brenner, RA (reprint author), NICHHD, US Dept HHS, Bethesda, MD 20892 USA. NR 63 TC 55 Z9 57 U1 1 U2 17 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2003 VL 112 IS 2 BP 440 EP 445 DI 10.1542/peds.112.2.440 PG 6 WC Pediatrics SC Pediatrics GA 707YX UT WOS:000184538500048 PM 12897306 ER PT J AU Maloney, EM Wiktor, SZ Palmer, P Cranston, B Pate, EJ Cohn, S Kim, N Miley, W Thomas, TL Blattner, WA Hanchard, B AF Maloney, EM Wiktor, SZ Palmer, P Cranston, B Pate, EJ Cohn, S Kim, N Miley, W Thomas, TL Blattner, WA Hanchard, B TI A cohort study of health effects of human T-cell lymphotropic virus type I infection in Jamaican children SO PEDIATRICS LA English DT Article; Proceedings Paper CT 9th International Conference on Human Retrovirology CY APR, 1999 CL KAGOSHIMA, JAPAN DE HTLV-I; pediatric; morbidity ID TROPICAL SPASTIC PARAPARESIS; HTLV-I; BLOOD-DONORS; DERMATITIS; MYELOPATHY; PREVALENCE; LYMPHOMA; CARRIERS; ANTIBODIES; DISEASES AB Objective. Human T-cell lymphotropic virus type I (HTLV-I) infection in childhood is believed to play an important role in risk for adult T-cell leukemia/lymphoma. Although HTLV-I is known to be associated with infective dermatitis in childhood, other HTLV-I-associated morbidity in children has not been well studied. We sought to determine the HTLV-I-associated health effects in Jamaican children. Methods. We compared incidence rates of several health outcomes in 28 HTLV-I-infected and 280 uninfected children clinically followed from age 6 weeks to a maximum of 10 years. Cox proportional hazards regression analysis was used to analyze these prospectively collected data, adjusting for confounding effects of other variables as necessary. Results. HTLV-I-infected children had significantly higher incidence rates of seborrheic dermatitis ( rate ratio [RR]=4.8, 95% confidence interval [CI]=1.9 - 12.5), eczema (RR=3.1, CI=1.2-7.9) and persistent hyperreflexia (RR=3.7, CI=1.6-8.2). Additionally, HTLV-I infected children had increased rates of severe anemia (RR=2.5, CI=0.8-7.9) and abnormal lymphocytes (RR=2.4, CI=0.8-7.6) that were of borderline statistical significance. Conclusions. Our study suggests that HTLV-I-associated skin diseases of childhood may include seborrheic dermatitis and eczema. Additionally, these data suggest that persistent hyperreflexia of the lower limbs may be an early sign of HTLV-I-associated neurologic involvement in children. Expansion and continued clinical observation of this cohort would be valuable. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ W Indies, Dept Pathol, Kingston 7, Jamaica. Res Triangle Inst, Rockville, MD USA. Sci Applicat Int Inc, Frederick, MD USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Maloney, EM (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-8006,MSC 7248, Rockville, MD 20852 USA. EM em34w@nih.gov NR 33 TC 12 Z9 12 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2003 VL 112 IS 2 BP E136 EP E142 DI 10.1542/peds.112.2.e136 PG 7 WC Pediatrics SC Pediatrics GA 707YX UT WOS:000184538500008 PM 12897319 ER PT J AU Silber, TJ Pao, M AF Silber, TJ Pao, M TI Somatization disorders in children and adolescents SO PEDIATRICS IN REVIEW LA English DT Article C1 George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. Childrens Natl Med Ctr, Adolescent Med Fellowship Program, Washington, DC 20010 USA. NIMH, Off Clin Director, NIH, Bethesda, MD USA. RP Silber, TJ (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. NR 9 TC 15 Z9 15 U1 2 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0191-9601 J9 PEDIATR REV JI Pediatr. Rev. PD AUG PY 2003 VL 24 IS 8 BP 255 EP 261 DI 10.1542/pir.24-8-255 PG 7 WC Pediatrics SC Pediatrics GA 746DE UT WOS:000186730600001 PM 12897265 ER PT J AU Bauer, B Miller, DS Fricker, G AF Bauer, B Miller, DS Fricker, G TI Compound profiling for p-glycoprotein at the blood-brain barrier using a microplate screening system SO PHARMACEUTICAL RESEARCH LA English DT Article DE blood-brain barrier; calcein-AM; compound profiling; microplate screening system; p-glycoprotein ID MICROVESSEL ENDOTHELIAL-CELLS; MULTIDRUG-RESISTANCE PROTEIN; DRUG TRANSPORT; IN-VITRO; CALCEIN; PENETRATION; EXPRESSION; BINDING; CYCLOSPORINE; INHIBITORS AB Purpose. The purpose of this study was to establish a fluorescent dye (calcein - acetoxymethylester; calcein- AM)-based assay to rapidly screen compounds for interactions with p-glycoprotein (p-gp) at the blood - brain barrier and to determine whether such an assay can be useful for kinetic analysis. Methods. Porcine brain capillary endothelial cells (PBCECs) were isolated and cultured in 96-well plates. Cells were incubated with calcein- AM in the absence and presence of substrates and inhibitors of ABC transporters and the extent of intracellularly appearing fluorescence was monitored with a fluorescence plate reader in a time- and a concentration-dependent manner. Results. PBCECs showed stable expression of p-gp and as a result calcein- AM was extruded by the cells. In the presence of p-gp substrates and inhibitors a significant increase of intracellular fluorescence was observed ( decreased calcein- AM efflux), the increase being well correlated with the p-gp affinity of the compounds used. Inhibitors of Mrp1 and Mrp2 did not influence fluorescence intensity. Time-dependent readouts and Michaelis-Menten kinetic analysis separated inhibitors into those showing competitive, mixed and noncompetitive inhibition of p-glycoprotein-mediated transport. Conclusion. The calcein- AM-assay based on PBCECs can be used as a rapid microplate screening system for interactions of drugs with p-glycoprotein at the blood-brain barrier and represents therefore a useful tool in the profiling of drugs. In addition, convenient kinetic assays can provide information about the mode of interaction. C1 Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. NIEHS, NIH, Res Triangle Pk, NC USA. RP Fricker, G (reprint author), Univ Heidelberg, Inst Pharm & Mol Biotechnol, INF 366, D-69120 Heidelberg, Germany. NR 35 TC 34 Z9 36 U1 2 U2 5 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD AUG PY 2003 VL 20 IS 8 BP 1170 EP 1176 DI 10.1023/A:1025040712857 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 708XW UT WOS:000184596500010 PM 12948014 ER PT J AU Lee, SJ Usmani, KA Chanas, B Ghanayem, B Xi, T Hodgson, E Mohrenweiser, HW Goldstein, JA AF Lee, SJ Usmani, KA Chanas, B Ghanayem, B Xi, T Hodgson, E Mohrenweiser, HW Goldstein, JA TI Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups SO PHARMACOGENETICS LA English DT Article DE CYP3A5; CYP3A5 polymorphisms; human; drug metabolism; SNP; cDNA expression system ID OXIDATIVE DRUG-METABOLISM; HUMAN-LIVER; ESCHERICHIA-COLI; EXPRESSION; IDENTIFICATION; PURIFICATION; VARIANTS; SEQUENCE; CANCER; FORM AB Objectives Genetic polymorphisms of cytochromes P450 (CYPs) are a principal reason for inter-individual variations in the metabolism of therapeutic drugs and environmental chemicals in humans. The present study identifies 34 single nucleotide polymorphisms (SNPs) of CYP3A5 including 27 previously unidentified SNPs by direct sequencing of the exons, intron-exon junctions and 5'-upstream region of CYP3A5 from 92 racially diverse individuals (24 Caucasians, 24 Africans, 24 Asians, and 20 individuals of unknown racial origin). Results Four new CYP3A5 SNPs produced coding changes: R28C, L82R, A337T, and F446S. CYP3A5 R28C occurred in African populations (allelic frequency of 4%). CYP3A5 A337T occurred in Asians (2% allelic frequency), CYP3A5 L82R (occurred in the racially unidentified group) and CYP3A5 F446S (identified in Caucasians with a 2% allelic frequency) were on an allele containing the splice change g.6986A>G known as CYP3A5*3. The newly identified allelic proteins were constructed by site-directed mutagenesis, expressed in Escherichia coli and purified. CYP3A5 L82R was expressed only as denatured CYP420, suggesting it may be unstable. CYP3A5*1 exhibited the highest maximal clearance for testosterone followed by CYP3A5 A337T>CYP3A5 R28C CYP3A5 F446S. CYP3A5*1 exhibited a higher V-max for nifedipine oxidation than CYP3A5 A337T>CYP3A5 R28Cmuch greater thanCYP3A5 F446S. CYP3A5 A337T and CYP3A5 R28C exhibited a 42-64% lower V-max for nifedipine oxidation than CYP3A5*1. CYP3A5 F446S exhibited a >95% decrease in the intrinsic clearance for both 6beta-hydroxytestosterone and nifedipine oxidation. Conclusion This study identifies four new potentially defective coding alleles. CYP3A5 F446S is predicted to be more catalytically defective than the splice change alone. (C) 2003 Lippincott Williams Wilkins. C1 NIEHS, Human Metab Sect, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Metab Exposure Markers Grp, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. Lawrence Livermore Natl Lab, Livermore, CA USA. RP Goldstein, JA (reprint author), NIEHS, Human Metab Sect, NIH, POB 12233,A3-02, Res Triangle Pk, NC 27709 USA. RI Goldstein, Joyce/A-6681-2012 FU NIEHS NIH HHS [ES-8054-05] NR 47 TC 103 Z9 111 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD AUG PY 2003 VL 13 IS 8 BP 461 EP 472 DI 10.1097/01.fpc.0000054117.14659.ac PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 714JY UT WOS:000184911500004 PM 12893984 ER PT J AU Insel, TR AF Insel, TR TI Is social attachment an addictive disorder? SO PHYSIOLOGY & BEHAVIOR LA English DT Article; Proceedings Paper CT 11th Annual Meeting of the International-Behavioral-Neuroscience-Society (IBNS) CY JUN 23, 2002 CL CAPRI, ITALY SP Int Behav Neurosci Soc DE dopamine; reward; attachment; affiliation; oxytocin ID MEDIAL PREOPTIC AREA; PARTNER-PREFERENCE FORMATION; VOLES MICROTUS-OCHROGASTER; RECEPTOR GENE-EXPRESSION; PAIR-BOND FORMATION; MALE PRAIRIE VOLES; NUCLEUS-ACCUMBENS; MATERNAL-BEHAVIOR; SEXUAL-BEHAVIOR; FEMALE RATS AB There is a considerable literature on the neurobiology of reward, based largely on studies of addiction or substance abuse. This review considers the possibility that the neural circuits that mediate reward evolved for ethologically relevant cues, such as social attachment. Specifically, mesocorticolimbic dopamine appears important for maternal behavior in rats and pair bonding in monogamous voles. It is not yet clear that dopamine in this pathway mediates the hedonic properties of social bond formation or whether dopamine's role is more relevant to developing associative networks or assigning salience to social stimuli. The neuropeptides oxytocin (OT) and vasopressin (AVP) appear to be critical for linking social signals to the mesocorticolimbic circuit. Published by Elsevier Inc. C1 Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30322 USA. RP Insel, TR (reprint author), NIMH, Room 8230,6001 Execut Blvd, Bethesda, MD 20892 USA. RI chen, xuanlan/H-4158-2011 NR 57 TC 186 Z9 188 U1 2 U2 29 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD AUG PY 2003 VL 79 IS 3 BP 351 EP 357 DI 10.1016/S0031-9384(03)00148-3 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 720YY UT WOS:000185291300003 PM 12954430 ER PT J AU Newman, JD AF Newman, JD TI Vocal communication and the triune brain SO PHYSIOLOGY & BEHAVIOR LA English DT Article; Proceedings Paper CT 11th Annual Meeting of the International-Behavioral-Neuroscience-Society (IBNS) CY JUN 23, 2002 CL CAPRI, ITALY SP Int Behav Neurosci Soc DE triune brain model; vocal communication; brain organization ID PERIAQUEDUCTAL GRAY; AFFILIATIVE BEHAVIOR; AGELAIUS-PHOENICEUS; SQUIRREL-MONKEYS; LARYNGEAL EMG; VOCALIZATION; LESIONS; STIMULATION; EVOLUTION; RELEVANT AB This paper tests the 'fit' between Paul MacLean's triune brain scheme of brain organization and existing knowledge about the pathways mediating vocal communication in mammals. One component of MacLean's limbic system ('paleomammalian brain'), the 'thalamocingulate circuit,' is found to have an important role in expression of vocalizations, particularly the 'isolation call' (such as are given by mammalian infants when distressed or separated from their caregivers). Recent evidence suggests that this circuit may also have a role in perception of infant cries in humans. Outside of this circuit, the triune brain model has little to offer in the way of insights into how the brain is organized to mediate vocal communication. There is little evidence that the striatal complex ('R-complex' or 'protoreptilian formation') is involved in any major way in vocal communication, although it appears to be involved in some visual displays in both reptiles and nonhuman primates. Interestingly, components of the reptilian brain may be involved in human speech production, and avian homologues involved in birdsong. The neocortex ('neomammalian formation') has well-known importance in speech production and perception, but little evidence exists for a role in vocal production in nonhuman mammals. However, cortical mechanisms do play a role in perception of vocalizations, at least in nonhuman primates. It is concluded that a set of neural structures termed the 'communication brain' mediate vocal communication in mammals, and that this model does not fit well into the triune brain scheme of brain organization. Published by Elsevier Inc. C1 NICHD, Dept Hlth & Human Serv, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. RP Newman, JD (reprint author), NIH, Anim Ctr, Elmer Sch Rd,Room 205,Bldg 112,Box 529, Poolesville, MD 20837 USA. NR 61 TC 8 Z9 8 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD AUG PY 2003 VL 79 IS 3 BP 495 EP 502 DI 10.1016/S0031-9384(03)00155-0 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 720YY UT WOS:000185291300017 PM 12954444 ER PT J AU Pesaresi, P Gardner, NA Masiero, S Dietzmann, A Eichacker, L Wickner, R Salamini, F Leister, D AF Pesaresi, P Gardner, NA Masiero, S Dietzmann, A Eichacker, L Wickner, R Salamini, F Leister, D TI Cytoplasmic N-terminal protein acetylation is required for efficient photosynthesis in Arabidopsis SO PLANT CELL LA English DT Article ID DOUBLE-STRANDED-RNA; SACCHAROMYCES-CEREVISIAE; EUKARYOTIC PROTEINS; GENE-EXPRESSION; PLANT-GROWTH; YEAST; CHLOROPLAST; ACETYLTRANSFERASE; IDENTIFICATION; THALIANA AB The Arabidopsis atmak3-1 mutant was identified on the basis of a decreased effective quantum yield of photosystem II. In atmak3-1, the synthesis of the plastome-encoded photosystem II core proteins D1 and CP47 is affected, resulting in a decrease in the abundance of thylakoid multiprotein complexes. DNA array-based mRNA analysis indicated that extraplastid functions also are altered. The mutation responsible was localized to AtMAK3, which encodes a homolog of the yeast protein Mak3p. In yeast, Mak3p, together with Mak10p and Mak31p, forms the N-terminal acetyltransferase complex C (NatC). The cytoplasmic AtMAK3 protein can functionally replace Mak3p, Mak10p, and Mak31p in acetylating N termini of endogenous proteins and the L-A virus Gag protein. This result, together with the finding that knockout of the Arabidopsis MAK10 homolog does not result in obvious physiological effects, indicates that AtMAK3 function does not require NatC complex formation, as it does in yeast. We suggest that N-acetylation of certain chloroplast precursor protein(s) is necessary for the efficient accumulation of the mature protein(s) in chloroplasts. C1 Max Planck Inst Zuchtungsforsch, Abt Pflanzenzuchtung & Ertragsphysiol, D-50829 Cologne, Germany. NIDDKD, Lab Biochem & Genet, Bethesda, MD 20892 USA. Max Planck Inst Zuchtungsforsch, Abt Mol Pflanzengenet, D-50829 Cologne, Germany. Univ Munich, Inst Bot, D-80638 Munich, Germany. RP Max Planck Inst Zuchtungsforsch, Abt Pflanzenzuchtung & Ertragsphysiol, D-50829 Cologne, Germany. EM leister@mpiz-koeln.mpg.de RI Leister, Dario/D-5587-2009; Masiero, Simona/J-2898-2013; OI Leister, Dario/0000-0003-1897-8421; Pesaresi, Paolo/0000-0002-3236-7005 NR 66 TC 61 Z9 62 U1 1 U2 12 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 EI 1532-298X J9 PLANT CELL JI Plant Cell PD AUG PY 2003 VL 15 IS 8 BP 1817 EP 1832 DI 10.1105/tpc.012377 PG 16 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 713PL UT WOS:000184867100012 PM 12897255 ER PT J AU Kerner, JF Yedidia, M Padgett, D Muth, B Washington, KS Tefft, M Yabroff, KR Makariou, E Freeman, H Mandelblatt, JS AF Kerner, JF Yedidia, M Padgett, D Muth, B Washington, KS Tefft, M Yabroff, KR Makariou, E Freeman, H Mandelblatt, JS TI Realizing the promise of breast cancer screening: clinical follow-up after abnormal screening among Black women SO PREVENTIVE MEDICINE LA English DT Article DE mammography; mass screening; adherence; social class; follow-up studies ID INCREASE MAMMOGRAPHY USE; INCOME MINORITY WOMEN; PAPANICOLAOU SMEARS; PAP SMEARS; EDUCATIONAL BROCHURES; US WOMEN; ADHERENCE; INTERVENTIONS; TRENDS; RATES AB Background. Delayed or incomplete follow-up after abnormal screening results may compromise the effectiveness of breast cancer screening programs, particularly in medically underserved and minority populations. This study examined the role of socioeconomic status, breast cancer risk factors, health care system barriers, and patient cognitive-attitudinal factors in the timing of diagnostic resolution after abnormal breast cancer screening exams among Black women receiving breast cancer screening at three New York city clinics. Methods. We identified 184 Black women as having an abnormal mammogram or clinical breast exam requiring immediate follow-up and they were interviewed and their medical records examined. Bivariate and multivariate logistic regression analyses were used to assess the association between patient and health care system factors and diagnostic resolution within 3 months of the abnormal finding. Results. Within 3 months, 39% of women were without diagnostic resolution and 28% within 6 months. Neither socioeconomic status nor system barriers were associated with timely diagnostic resolution. Timely resolution was associated with mammogram severity, patients asking questions (OR, 2.73; 95% Cl, 1.25-5.96), or receiving next step information (OR, 2.6; 95% Cl, 1.08-6.21) at the initial mammogram. Women with prior breast abnormalities were less likely to complete timely diagnostic resolution (OR, 0.42; 95% Cl, 0.20-0.85), as were women with higher levels of cancer anxiety (OR, 0.50; 95% CI, 0.27-0.92). Conclusions. Interventions that address a woman's prior experience with abnormal findings and improve patient/provider communication may improve timely and appropriate follow-up. (C) 2003 American Health Foundation and Elsevier Science (USA). All rights reserved. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NYU, Robert F Wagner Grad Sch Publ Serv, New York, NY 10003 USA. NYU, Ehrenkranz Sch Social Work, New York, NY USA. Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Columbia Univ, Sch Med, New York, NY USA. Columbia Univ, No Gen Hosp, New York, NY USA. Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Dept Oncol & Med, Washington, DC USA. RP Kerner, JF (reprint author), NCI, NIH, 6130 Execut Blvd,EPN 6144, Rockville, MD 20852 USA. OI Kerner, Jon/0000-0002-8792-3830; Yabroff, K. Robin/0000-0003-0644-5572 FU AHRQ HHS [R01 HS 08395]; NCI NIH HHS [R01 CA 65881, R01 CA72908] NR 48 TC 56 Z9 56 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 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2003 VL 37 IS 2 BP 92 EP 101 DI 10.1016/S0091-7435(03)00087-2 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 703UJ UT WOS:000184299200003 PM 12855208 ER PT J AU Carey, MA Germolec, DR Langenbach, R Zeldin, DC AF Carey, MA Germolec, DR Langenbach, R Zeldin, DC TI Cyclooxygenase enzymes in allergic inflammation and asthma SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID SMOOTH-MUSCLE CELLS; ASPIRIN-SENSITIVE ASTHMA; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SYNTHASE-DEFICIENT MICE; PROSTAGLANDIN E-2; INHALED PGE(2); INDUCED BRONCHOCONSTRICTION; AIRWAY HYPERRESPONSIVENESS; PROSTANOID RECEPTORS; ARACHIDONIC-ACID AB The cyclooxygenase enzyme system produces eicosanoids which mediate many important physiological and pathological functions. Experimental and clinical data suggest a role for this enzyme system in the pathogenesis of allergic inflammation and asthma. This article focuses on the function of this pathway in the lung, reviews evidence implicating the involvement of this pathway in asthma and allergic airway inflammation, and discusses implications for the treatment of asthmatics with cyclooxygenase inhibitors. Published by Elsevier Science Ltd. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 Alexander Dr Mail Drop D2-02, Res Triangle Pk, NC 27709 USA. NR 77 TC 44 Z9 45 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD AUG-SEP PY 2003 VL 69 IS 2-3 BP 157 EP 162 DI 10.1016/S0952-3278(03)00076-0 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 712WT UT WOS:000184822600009 PM 12895598 ER PT J AU Ma, B Nussinov, R AF Ma, B Nussinov, R TI Molecular dynamics simulations of the unfolding of beta(2)-microglobulin and its variants SO PROTEIN ENGINEERING LA English DT Article DE amyloid; beta(2-)microglobulin; beta(2-)microglobulin variant; beta-strand alpha-helix transition; molecular dynamics simulation; protein folding; protein unfolding ID AMYLOID FIBRIL FORMATION; BETA-SHEET; DISULFIDE BOND; IN-VITRO; PROTEIN; BETA-2-MICROGLOBULIN; FIBRILLOGENESIS; PEPTIDES; STATE; CONVERSION AB In this study, we examined the unfolding processes of native beta(2)-microglobulin and two related variants, one with an N-terminal hexapeptide deletion DeltaN6 and another with Lys57-Asp58 cleavage, by high-temperature molecular dynamics simulations. Three simulation models were used, molecular dynamics (MD) simulations with explicit water solvation, MD simulations with the CHARMM EEF1 force field and Langevin dynamics with the CHARMM EEF1 force field. Our simulations reproduce many of the experimentally observed structural changes. The most striking agreement is in the beta-strands to alpha-helix transition. In our simulations, strands beta(3), beta(4) and beta(5) consistently change to alpha-helix, whereas beta(8) changes to an alpha-helix only briefly. Through comparisons of the conformational behavior of the native, the DeltaN6 and the Lys-cut beta(2)-m, using the three simulation methods, we identified the consensus conformational changes that differentiate between the native beta(2)-m and its two variants. We found that the main effect of the removal of the N-terminal hexapeptide is to increase the separation between strands beta(2) and beta(6) and to facilitate the beta to alpha transition. On the other hand, the lysine cleavage only increases the flexibility of strand beta(5) and does not affect the interactions between strands beta(2) and beta(6). These conformational changes may relate to polymerization tendencies of these variants. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol,FCRDC, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol,FCRDC, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU PHS HHS [N01-C0-12400] NR 46 TC 23 Z9 25 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD AUG PY 2003 VL 16 IS 8 BP 561 EP 575 DI 10.1093/protein/gzg079 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 721FW UT WOS:000185307200003 PM 12968074 ER PT J AU Ouellette, T Destrau, S Ouellette, T Zhu, JW Roach, JM Coffman, JD Hecht, T Lynch, JE Giardina, SL AF Ouellette, T Destrau, S Ouellette, T Zhu, JW Roach, JM Coffman, JD Hecht, T Lynch, JE Giardina, SL TI Production and purification of refolded recombinant human IL-7 from inclusion bodies SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE interleukin-7; purification; refolding; chromatography ID CYTOTOXIC T-LYMPHOCYTES; B-LINEAGE CELLS; GROWTH-FACTOR; HUMAN INTERLEUKIN-7; KILLER-CELLS; GAMMA-CHAIN; RECEPTOR; GENERATION; ACTIVATION; EXPRESSION AB A recombinant form of human rhIL-7 was overexpressed in Escherichia coli HMS174 (DE3) pLysS under the control of a T7 promoter. The resulting insoluble inclusion bodies were separated from cellular debris by cross-flow filtration and solubilized by homogenization with 6 M guanidine HCl. Attempts at refolding rhIL-7 from solubilized inclusion bodies without prior purification of monomeric, denatured rhIL-7 were not successful. Denatured, monomeric rhIL-7 was therefore initially purified by size-exclusion chromatography using Prep-Grade Pharmacia Superdex 200. Correctly folded rhIL-7 monomer was generated by statically refolding the denatured protein at a final protein concentration of 80-100 mug/mL in 100 mM Tris, 2 mM EDTA, 500 MM L-arginine, pH 9.0, buffer with 0.55 g/L oxidized glutathione at 2-8degreesC for at least 48h. The refolded rhIL-7 was subsequently purified by low-pressure liquid chromatography, using a combination of hydrophobic interaction, cation-exchange, and size-exclusion chromatography. The purified final product was >95% pure by SDS-PAGE stained with Coomassie brilliant blue, high-pressure size-exclusion chromatography (SEC-HPLC), and reverse-phase HPLC. The endotoxin level was <0.05 EU/mg. The final purified product was biologically active in a validated IL-7 dependent pre-B-cell bioassay. In anticipation of human clinical trials, this material is currently being evaluated for safety and efficacy in non-human primate toxicology studies. (C) 2003 Elsevier Science (USA). All rights reserved. C1 SAIC Frederick Inc, NCI, Biopharmaceut Dev Program, Ft Detrick, MD 21702 USA. Cytheris, F-92170 Vanves, France. NCI, Biol Resources Branch, Frederick, MD 21702 USA. RP Giardina, SL (reprint author), SAIC Frederick Inc, NCI, Biopharmaceut Dev Program, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 27 TC 16 Z9 16 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD AUG PY 2003 VL 30 IS 2 BP 156 EP 166 DI 10.1016/S1046-5928(03)00134-7 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 707JA UT WOS:000184506500002 PM 12880763 ER PT J AU Boeggeman, EE Ramakrishnan, B Qasba, PK AF Boeggeman, EE Ramakrishnan, B Qasba, PK TI The N-terminal stem region of bovine and human beta 1,4-galactosyltransferase I increases the in vitro folding efficiency of their catalytic domain from inclusion bodies SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE beta 1,4-galactosyltransferase; N-terminus; folding; stem region; Escherichia coli ID MALTOSE-BINDING PROTEIN; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; BETA-1-4 GALACTOSYLTRANSFERASE; EXPRESSION; PURIFICATION; CDNA; SOLUBILITY; COMPLEX; ACETYLGLUCOSAMINE AB Many recombinant proteins overexpressed in Escherichia coli are generally misfolded, which then aggregate and accumulate as inclusion bodies. The catalytic domain (CD) of bovine and human beta1,4-galactosyltransferase (beta4Gal-T), expressed in E. coli, it also accumulates as inclusion bodies. We studied the effect of the fusion of the stem region (SR), as an N-terminal extension of the catalytic domain, on the in vitro folding efficiencies of the inclusion bodies. The stem region fused to the catalytic domain (SRCD) increases the folding efficiency of recombinant protein with native fold compared to the protein that contains only the CD. During in vitro folding, also promotes considerably the solubility of the misfolded proteins, which do not bind to UDP-agarose columns and exhibit no galactosyltransferase activity. In contrast, the misfolded proteins that consist of only the CD are insoluble and precipitate out of solution. It is concluded that a protein domain that is produced in a soluble form does not guarantee the presence of the protein molecules in a properly folded and active form. The stem domain has a positive effect on the in vitro folding efficiency of the catalytic domain of both human and bovine beta4Gal-T1, suggesting that the stem region acts as a chaperone during protein folding. Furthermore, investigation of the folding conditions of the sulphonated inclusion bodies resulted in identifying a condition in which the presence of PEG-4000 and L-arginine, compared to their absence, increased the yields of native CD and SRCD 7- and 3-fold, respectively. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Struct Glycobiol Sect, Lab Expt & Computat Biol, Ctr Canc Res, Frederick, MD 21702 USA. NCI, BRP, SAIC Frederick Inc, Lab Expt & Computat Biol,Ctr Canc Res, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, Lab Expt & Computat Biol, Ctr Canc Res, POB B,Bldg 469,Rm 221, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 41 TC 26 Z9 27 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD AUG PY 2003 VL 30 IS 2 BP 219 EP 229 DI 10.1016/S1046-5928(03)00093-7 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 707JA UT WOS:000184506500010 PM 12880771 ER PT J AU Liu, YY Woo, JH Neville, DM AF Liu, YY Woo, JH Neville, DM TI Targeted introduction of a diphtheria toxin resistant mutation into the chromosomal EF-2 locus of Pichia pastoris and expression of immunotoxin in the EF-2 mutants SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID ELONGATION FACTOR-II; SINGLE-CHAIN IMMUNOTOXIN; SACCHAROMYCES-CEREVISIAE; AMINO-ACID; YEAST; GENE; PROTEINS; TRANSLOCATION; DIPHTHAMIDE; CLONING AB In an attempt to increase the production of a diphtheria toxin (DT) based immunotoxin by Pichia pastoris, we have created DT-resistant mutants that contain a substitution of arginine for glycine at position 701 in elongation factor 2 (EF-2). To achieve this, we first cloned and characterized the EF-2 gene (PEF1), and then made a construct pBLURA-Delta5'mutEF-2 that efficiently introduces specific mutations into the chromosomal EF-2 gene in P. pastoris by in vivo homologous recombination. pBLURA-Delta5'mutEF-2 contains a selection marker URA3 and a 5' truncated form of the P. pastoris PEP that had been modified in vitro to carry the nucleotide mutations for the Gly(701) to Arg transition. Unlike the non-mutated strains, the EF-2 mutants are resistant to high-level intracellular expression of DT A chain that can catalyze the ADP-ribosylation. When used to express the secreted bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(G4S), the EF-2 mutant strains showed increased viability compared to the non-mutated strains. However, they did not show an advantage over the non-mutated expressing strain in the production of the immunotoxin. Western blotting analysis revealed that although the EF-2 mutants did not increase the accumulation of intact A-dmDT390-bisFv(G4S) in the culture medium, they generated larger amounts of degraded products found in both the medium and cell pellets compared to the non-mutant expressing clone. In addition, double copy expression resulted in greater amounts of intact immunotoxin being retained within cellular compartments as well as degraded products. Based on these findings, we suggest that the secretory capacity may be rate limiting for divalent immunotoxin production in P. pastoris. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIMH, Sect Biophys Chem, Mol Biol Lab, Bethesda, MD USA. RP Liu, YY (reprint author), NIMH, Sect Biophys Chem, Mol Biol Lab, Bldg 36 Rm 1 B08,36 Convent Dr, Bethesda, MD USA. NR 28 TC 16 Z9 19 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD AUG PY 2003 VL 30 IS 2 BP 262 EP 274 DI 10.1016/S1046-5928(03)00129-3 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 707JA UT WOS:000184506500015 PM 12880776 ER PT J AU Medjahed, D Luke, BT Tontesh, TS Smythers, GW Munroe, DJ Lemkin, PF AF Medjahed, D Luke, BT Tontesh, TS Smythers, GW Munroe, DJ Lemkin, PF TI Tissue Molecular Anatomy Project (TMAP): An expression database for comparative cancer proteomics SO PROTEOMICS LA English DT Article; Proceedings Paper CT 2nd Annual Congress of the Swiss-Proteomics-Society CY DEC 03-05, 2002 CL LAUSANNE, SWITZERLAND SP Swiss Proteom Soc DE expressed sequence tags; protein expression map; Tissue Molecular Anatomy Project; two-dimensional gel electrophoresis; VIRTUAL2D ID MICROARRAYS AB By mining publicly accessible databases, we have developed a collection of tissue-specific predictive protein expression maps as a function of cancer histological state. Data analysis is applied to the differential expression of gene products in pooled libraries from the normal to the altered state(s). We wish to report the initial results of our survey across different tissues and explore the extent to which this comparative approach may help uncover panels of potential biomarkers of tumorigenesis which would warrant further examination in the laboratory. C1 NCI, Lab Mol Technol, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. NCI, Lab Computat & Expt Biol, CCR, Frederick, MD 21702 USA. Sci Applicat Int, Frederick, MD USA. RP Medjahed, D (reprint author), NCI, Lab Mol Technol, POB B, Frederick, MD 21702 USA. NR 6 TC 5 Z9 5 U1 1 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2003 VL 3 IS 8 BP 1445 EP 1453 DI 10.1002/pmic.200300488 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716LZ UT WOS:000185031500009 PM 12923770 ER PT J AU Bremner, JD Vythilingam, M Vermetten, E Adil, J Khan, S Nazeer, A Afzal, N McGlashan, T Elzinga, B Anderson, GM Heninger, G Southwick, SM Charney, DS AF Bremner, JD Vythilingam, M Vermetten, E Adil, J Khan, S Nazeer, A Afzal, N McGlashan, T Elzinga, B Anderson, GM Heninger, G Southwick, SM Charney, DS TI Cortisol response to a cognitive stress challenge in posttraumatic stress disorder (PTSD) related to childhood abuse SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE PTSD; childhood abuse; stress; cortisol; hippocampus ID CORTICOTROPIN-RELEASING-FACTOR; VIETNAM COMBAT VETERANS; PITUITARY-ADRENOCORTICAL AXIS; PLASMA-CORTISOL; HIPPOCAMPAL VOLUME; URINARY CORTISOL; SEXUAL ABUSE; MATERNAL-DEPRIVATION; MESSENGER-RNA; RAT-BRAIN AB Preclinical studies show that animals with a history of chronic stress exposure have increased hypothalamic-pituitary-adrenal (HPA) axis reactivity following reexposure to stress. Patients with posttraumatic stress disorder (PTSD) have been found to have normal or decreased function of the HPA axis, however no studies have looked at the HPA response to stress in PTSD. The purpose of this study was to assess cortisol responsivity to a stressful cognitive challenge in patients with PTSD related to childhood abuse. Salivary cortisol levels, as well as heart rate and blood pressure, were measured before and after a stressful cognitive challenge in patients with abuse-related PTSD (N = 23) and healthy comparison subjects (N = 18). PTSD patients had 61% higher group mean cortisol levels in the time period leading up to the cognitive challenge, and 46% higher cortisol levels during the time period of the cognitive challenge, compared to controls. Both PTSD patients and controls had a similar 66-68% increase in cortisol levels from their own baseline with the cognitive challenge. Following the cognitive challenge, cortisol levels fell in both groups and were similar in PTSD and control groups. PTSD patients appeared to have an increased cortisol response in anticipation of a cognitive challenge relative to controls. Although cortisol has been found to be low at baseline, there does not appear to be an impairment in cortisol response to stressors in PTSD. Published by Elsevier Science Ltd. C1 Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomography, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomography, Dept Radiol, Atlanta, GA 30322 USA. Atlanta VAMC, Decatur, GA 30033 USA. NIMH, Program Mood & Anxiety Disorders, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. RP Bremner, JD (reprint author), Emory Univ, Emory Univ Hosp, Sch Med, PET Ctr Nucl Med, Room E154,1364 Clifton Rd, Atlanta, GA 30322 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404 FU NIMH NIH HHS [1R01MH56120-02, R01MH56120-01 A1] NR 94 TC 121 Z9 122 U1 5 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD AUG PY 2003 VL 28 IS 6 BP 733 EP 750 DI 10.1016/S0306-4530(02)00067-7 PG 18 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 695TY UT WOS:000183847500002 PM 12812861 ER PT J AU Grillon, C Cordova, J Levine, LR Morgan, CA AF Grillon, C Cordova, J Levine, LR Morgan, CA TI Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans SO PSYCHOPHARMACOLOGY LA English DT Article DE glutamate; LY354740; fear; anxiolytic; fear-potentiated startle; darkness ID LIGHT-ENHANCED STARTLE; BASE-LINE STARTLE; ACOUSTIC STARTLE; CONDITIONED FEAR; PANIC DISORDER; REFLEX; ANXIETY; AMYGDALA; DIAZEPAM; BENZODIAZEPINES AB Rationale. LY354740, a structural analogue of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models. Objective. This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodology. Methods. Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examined startle potentiation to shock anticipation and to darkness. Results. Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and negative affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740. Conclusions. These results suggest that LY354740 has an anxiolytic profile in humans without being sedative. C1 NIMH, NIH, DHHS, Mood & Anxiety Disorder Program, Bethesda, MD 20892 USA. Vet Adm Med Ctr, West Haven, CT 06516 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Grillon, C (reprint author), NIMH, NIH, DHHS, Mood & Anxiety Disorder Program, 15k North Dr,Msc 2670, Bethesda, MD 20892 USA. NR 46 TC 138 Z9 140 U1 4 U2 10 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2003 VL 168 IS 4 BP 446 EP 454 DI 10.1007/s00213-003-1444-8 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 711TA UT WOS:000184756100009 PM 12709777 ER PT J AU Goldberg, SN Charboneau, JW Dodd, GD Dupuy, DE Gervais, DA Gillams, AR Kane, RA Lee, FT Livraghi, T McGahan, JP Rhim, H Silverman, SG Solbiati, L Vogl, TJ Wood, BJ AF Goldberg, SN Charboneau, JW Dodd, GD Dupuy, DE Gervais, DA Gillams, AR Kane, RA Lee, FT Livraghi, T McGahan, JP Rhim, H Silverman, SG Solbiati, L Vogl, TJ Wood, BJ CA Int Working Grp Image-Guided Tumor TI Image-guided tumor ablation: Proposal for standardization of terms and reporting criteria SO RADIOLOGY LA English DT Article DE radiofrequency (RF) ablation; radiology and radiologists; review ID PERCUTANEOUS RADIOFREQUENCY ABLATION; SMALL HEPATOCELLULAR-CARCINOMA; LASER-INDUCED THERMOTHERAPY; QUALITY IMPROVEMENT GUIDELINES; MICROWAVE COAGULATION THERAPY; RENAL-CELL CARCINOMA; THERMAL ABLATION; HEPATIC-TUMORS; LIVER METASTASES; TISSUE ABLATION AB The field of image-guided tumor ablation requires standardization of terms and reporting criteria to facilitate effective communication of ideas and appropriate comparison between treatments with different technologies, such as chemical ablation (ethanol or acetic acid) and thermal therapies, such as radiofrequency, laser, microwave, ultrasound, and cryoablation. On the basis of this premise, a working committee was established with the goal of producing a proposal on such standardization. The intent of the Working Group is to provide a framework that will facilitate the clearest communication between investigators and will provide the greatest flexibility in comparisons between the many new, exciting, and emerging technologies. The members of the Working Group now propose a vehicle for reporting the various aspects of image-guided ablation therapy, including classifications of therapies and procedures, appropriate descriptors of image guidance, and terms to define imaging and pathologic findings. Methods for standardizing the reporting of follow-up findings and complications and other important aspects that require attention when reporting clinical results are addressed. It is the group's hope and intention that adherence to the recommendations of this proposal will facilitate achievement of the group's main objective: improved precision and communication in this field that lead to more accurate comparison of technologies and results and ultimately to improved patient outcomes. (C) RSNA, 2003. C1 Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Univ Texas, Rhode Isl Hosp, Hlth Sci Ctr, Providence, RI USA. Massachusetts Gen Hosp, Boston, MA USA. Middlesex Hosp, London, England. Univ Wisconsin, Madison, WI USA. Osped Civile, Virnercate, Italy. Univ Calif Davis, Ctr Med, Sacramento, CA 95817 USA. Hanyang Univ Hosp, Seoul 133791, South Korea. Brigham & Womens Hosp, Boston, MA 02115 USA. Osped Gen, Busto Arsizio, Italy. Univ Klinikum, Frankfurt, Germany. Imaging Sci Program, NIH, Bethesda, MD USA. RP Goldberg, SN (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. OI Dupuy, Damian/0000-0003-0524-5982; Solbiati, Luigi/0000-0002-3109-1449 NR 89 TC 259 Z9 291 U1 3 U2 11 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2003 VL 228 IS 2 BP 335 EP 345 DI 10.1148/radiol.2282021787 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 705DU UT WOS:000184381100009 PM 12893895 ER PT J AU Frank, JA Miller, BR Arbab, AS Zywicke, HA Jordan, EK Lewis, BK Bryant, LH Bulte, JWM AF Frank, JA Miller, BR Arbab, AS Zywicke, HA Jordan, EK Lewis, BK Bryant, LH Bulte, JWM TI Clinically applicable labeling of mammalian and stem cells by combining; Superparamagnetic iron oxides and transfection agents SO RADIOLOGY LA English DT Article DE cell labeling; experimental study; iron; magnetic resonance (MR), experimental studies; stem cells ID NONVIRAL GENE DELIVERY; IN-VIVO TRACKING; CONTRAST AGENTS; T-CELLS; NANOPARTICLES; DENDRIMERS; MIGRATION; SYSTEM; LIVER; RAT AB PURPOSE: To label mammalian and stem cells by combining commercially available transfection agents (TAs) with superparamagnetic iron oxide (SPIO) magnetic resonance (MR) imaging contrast agents. MATERIALS AND METHODS Three TAs were incubated with ferumoxides and MION-46L in cell culture medium at various concentrations. Human mesenchymal i stem cells, mouse lymphocytes, rat oligodendrocyte progenitor CG-4 cells, and human cervical carcinoma cells were incubated 2-48 hours with 25 mug of iron per milliliter of combined TAs and SPIO. Cellular labeling was evaluated with T2 relaxometry, MR imaging of labeled cell suspensions, and Prussian blue staining for iron assessment. Proliferation and viability of mesenchymal stem cells and human cervical carcinoma cells labeled with a combination of TAs and ferumoxides were evaluated. RESULTS: When ferumoxides-TA or MION-46L-TA was used, intracytoplasmic particles stained with Prussian blue stain were detected for all cell lines with a labeling efficiency of nearly 100%. Limited or no uptake was observed for cells incubated i with ferumoxides or MION-46L alone. For TA-SPIO-labeled cells, MR images and relaxometry findings showed a. 50%-90% decrease in signal intensity and a more than 40-fold increase in T2s, Cell viability varied from 103.7% +/- 9 to 123.0% +/- 9 compared with control cell viability at 9 days, and cell proliferation was not affected by endosomal incorporation of SPIO nanoparticles. Iron concentrations varied with, ferumoxides-TA combinations and cells with a maximum of 30.1 pg +/- 3.7 of iron per cell for labeled mesenchymal stem cells. CONCLUSION: Magnetic labeling of mammalian cells with use of ferumoxides and TAs is possible and may enable cellular MR imaging and tracking in experimental and clinical settings. (C) RSNA, 2003. C1 NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, Bldg 10,Rm B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008; Miller, Bradley/G-7426-2014 OI Bulte, Jeff/0000-0003-1202-1610; NR 30 TC 487 Z9 556 U1 4 U2 56 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2003 VL 228 IS 2 BP 480 EP 487 DI 10.1148/radiol.2281020638 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 705DU UT WOS:000184381100028 PM 12819345 ER PT J AU Mazerbourg, S Bondy, CA Zhou, J Monget, P AF Mazerbourg, S Bondy, CA Zhou, J Monget, P TI The Insulin-like Growth Factor system: a key determinant role in the growth and selection of ovarian follicles? A comparative species study SO REPRODUCTION IN DOMESTIC ANIMALS LA English DT Article; Proceedings Paper CT 7th Annual Conference of the European-Society-for-Domestic-Animal-Reproduction (ESDAR) CY SEP 04-06, 2003 CL UNIV COLL DUBLIN, DUBLIN, IRELAND SP European Soc Domestic Animal Reproduct HO UNIV COLL DUBLIN ID PLASMA-PROTEIN-A; FACTOR-BINDING PROTEIN-4; I IGF-I; MESSENGER-RIBONUCLEIC-ACID; OVINE GRANULOSA-CELLS; PORCINE PREOVULATORY FOLLICLES; MAJOR BASIC-PROTEIN; FOLLICULAR-FLUID; PROTEOLYTIC ACTIVITY; GENE-EXPRESSION AB The aim of the present paper is to make a comparative study of the expression of the elements of the insulin-like growth factor (IGF) system in different mammalian species and thus illuminate their potential role in the process of ovarian folliculogenesis in mammals. In most mammalian species, IGFs and IGFBPs (in particular IGFBP-2 and IGFBP-4) are considered, respectively, as stimulators and inhibitors of follicular growth and maturation. In mammalian species, IGFs might play a key role in sensitizing ovarian granulosa cells to FSH action during terminal follicular growth. Concentrations of IGFBP-2 and IGFBP-4 in follicular fluid strongly decrease and increase during follicular growth and atresia, respectively, leading to an increase and a decrease in IGF bioavailability, respectively. The decrease in these IGFBPs is because of a decrease in mRNA expression (IGFBP-2) and an increase in proteolytic degradation by PAPP-A in follicular fluid (IGFBP-2, IGFBP-4 and IGFBP-5), and likely participates in the selection of dominant follicles. In contrast, levels and/or sites of expression of IGF-I, IGF-II, IGFBP-4, IGFBP-5 and type II receptor in follicular cells strongly differ between mammalian species, suggesting that these phenomena might play species-specific or secondary roles in ovarian folliculogenesis. C1 Univ Tours, CNRS, INRA, UMR 6078, F-37380 Nouzilly, France. Stanford Univ, Med Ctr, Dept Gynecol & Obstet, Stanford, CA 94305 USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. RP Monget, P (reprint author), Univ Tours, CNRS, INRA, UMR 6078, F-37380 Nouzilly, France. NR 90 TC 77 Z9 82 U1 0 U2 7 PU BLACKWELL VERLAG GMBH PI BERLIN PA KURFURSTENDAMM 57, D-10707 BERLIN, GERMANY SN 0936-6768 J9 REPROD DOMEST ANIM JI Reprod. Domest. Anim. PD AUG PY 2003 VL 38 IS 4 BP 247 EP 258 DI 10.1046/j.1439-0531.2003.00440.x PG 12 WC Agriculture, Dairy & Animal Science; Reproductive Biology; Veterinary Sciences SC Agriculture; Reproductive Biology; Veterinary Sciences GA 706RM UT WOS:000184467700003 PM 12887564 ER PT J AU Rao, M Carlson, BA Novoselov, SV Weeks, DP Gladyshev, VN Hatfield, DL AF Rao, M Carlson, BA Novoselov, SV Weeks, DP Gladyshev, VN Hatfield, DL TI Chlamydomonas reinhardtii selenocysteine tRNA ([Ser]Sec) SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE phylogenetic tree; RT-PCR; selenium; selenocysteyl-tRNA; tRNA sequences ID SERINE TRANSFER-RNA; LEISHMANIA-TARENTOLAE; GENETIC-CODE; TRNA(SEC); TRANSCRIPTION; PROMOTER; POINT; MUTATIONS; SEQUENCES; LIBRARIES AB Eukaryotic selenocysteine (Sec) protein insertion machinery was thought to be restricted to animals, but the occurrence of both Sec-containing proteins and the See insertion system was recently found in Chlamydomonas reinhardtii, a member of the plant kingdom. Herein, we used RT-PCR to determine the sequence of C. reinhardtii See tRNA([Ser]Sec), the first non-animal eukaryotic See tRNA([Ser]Sec) sequence. Like its animal counterpart, it is 90 nucleotides in length, is aminoacylated with serine by seryl-tRNA synthetase, and decodes specifically UGA. Evolutionary analyses of known See tRNAs identify the C. reinhardtii form as the most diverged eukaryotic Sec tRNA([Ser]Sec) and reveal a common origin for this tRNA in bacteria, archaea, and eukaryotes. C1 NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bldg 37,Room 2D09,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU NIGMS NIH HHS [GM061603, R01 GM061603] NR 31 TC 22 Z9 22 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD AUG PY 2003 VL 9 IS 8 BP 923 EP 930 DI 10.1261/rna.5510503 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705DZ UT WOS:000184381600003 PM 12869703 ER PT J AU Grigor'ev, IV Makhnovskii, YA Berezhkovskii, AM Zitserman, VY AF Grigor'ev, IV Makhnovskii, YA Berezhkovskii, AM Zitserman, VY TI The kinetics of heminal recombination in a cavity SO RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY LA English DT Article ID DIFFUSION-INFLUENCED REACTIONS; DYNAMIC DISORDER AB A theory of heminal recombination in a cavity containing a reaction center and an orifice that stochastically opens and closes is suggested. A particle broken away from the reaction center diffuses in the cavity until it either escapes through the orifice into the volume or recombines. The model qualitatively describes the special features of several biologically important processes, in particular, the recombination of ligands in myoglobin. It is shown that, at small reaction center and orifice sizes, diffusion process calculations reduce to solving simple kinetic equations, which allow the probability of recombination and the kinetics of the process to be found in the form of explicit functions of model parameters. C1 Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Russian Acad Sci, Inst High Temp Sci Assoc, Moscow 127412, Russia. RP Grigor'ev, IV (reprint author), Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Leninskii Pr 29, Moscow 117912, Russia. RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X NR 19 TC 3 Z9 3 U1 0 U2 0 PU INTERPERIODICA PI BIRMINGHAM PA PO BOX 1831, BIRMINGHAM, AL 35201-1831 USA SN 0036-0244 J9 RUSS J PHYS CHEM+ JI Russ. J. Phys. Chem. PD AUG PY 2003 VL 77 IS 8 BP 1277 EP 1281 PG 5 WC Chemistry, Physical SC Chemistry GA 710VC UT WOS:000184702700011 ER PT J AU Stayner, L Steenland, K Dosemeci, M Hertz-Picciotto, I AF Stayner, L Steenland, K Dosemeci, M Hertz-Picciotto, I TI Attenuation of exposure-response curves in occupational cohort studies at high exposure levels SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Editorial Material DE epidemiology; flat dose-response ID QUANTITATIVE RISK ASSESSMENT; COPPER SMELTER WORKERS; LUNG-CANCER; ARSENIC EXPOSURE; RESPIRATORY CANCER; NONDIFFERENTIAL MISCLASSIFICATION; MEASUREMENT ERRORS; VINYL-CHLORIDE; HEART-DISEASE; MORTALITY AB Numerous occupational cohort mortality studies have observed exposure-response curves to have an increasing slope at low exposure levels that attenuates or even turns negative at high exposure levels. Examples discussed in this paper include dioxin, silica, 1,3-butadiene, cadmium, beryllium, radon daughters, diesel fumes, nickel, arsenic, and hexavalent chromium. Possible explanations for this phenomenon include (i) bias introduced by the healthy worker survivor effect, (ii) a depletion of the number of susceptible people in the population at high exposure levels, (iii) a natural limit on the relative risk for diseases with a high background rate, (iv) mismeasurement or misclassification of exposures, (v) the influence of other risk factors that vary by the level of the main exposure, and (vi) the saturation of key enzyme systems or other processes involved in the development of disease. C1 NIOSH, Educ & Informat Div, Risk Evaluat Branch, Cincinnati, OH 45226 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. Univ Calif Davis, Dept Epidemiol & Prevent, Davis, CA USA. RP Stayner, L (reprint author), NIOSH, Educ & Informat Div, Risk Evaluat Branch, 4676 Colombia Pkwy,C 15, Cincinnati, OH 45226 USA. NR 50 TC 86 Z9 87 U1 1 U2 10 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD AUG PY 2003 VL 29 IS 4 BP 317 EP 324 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 711XH UT WOS:000184766000010 PM 12934726 ER PT J AU Perantoni, AO AF Perantoni, AO TI Renal development: perspectives on a Wnt-dependent process SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE epithelial conversion; inductive signaling; metanephric mesenchyme; nephric duct; ureteric bud ID FIBROBLAST GROWTH-FACTORS; DEVELOPING KIDNEY; URETERAL BUD; BRANCHING MORPHOGENESIS; METANEPHRIC MESENCHYME; EPITHELIAL TRANSFORMATION; INTERMEDIATE MESODERM; NEUROTROPHIC FACTOR; CELL-LINE; EXPRESSION AB Specification of embryonic progenitors to generate the branched collecting duct system and tubular epithelia of the nephron in the metanephros is mediated by families of soluble factors that cooperate to regulate morphogenesis. These include multiple members of the FGF, TGF-beta, and Wnt families; however, the complexity of interactions through cell-cell and extracellular matrix-mediated contacts, the redundancy of factors involved, and multiplicity of cooperative signaling mechanisms limit our understanding of events responsible for this development. With available in vitro and targeted mutagenesis models, we are now beginning to comprehend how the secreted inductive proteins and associated transcription factors direct competent cells to produce a functional filtering tubular epithelium and its tightly integrated vascular network. Published by Elsevier Science Ltd. C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Perantoni, AO (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NR 60 TC 34 Z9 38 U1 1 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD AUG PY 2003 VL 14 IS 4 BP 201 EP 208 DI 10.1016/S1084-9521(03)00022-3 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 714TY UT WOS:000184930600002 PM 14627118 ER PT J AU Doroshow, JH Synold, TW Gandara, D Mani, S Remick, SC Mulkerin, D Hamilton, A Sharma, S Ramanathan, RK Lenz, HJ Graham, M Longmate, J Takimoto, CH Ivy, P AF Doroshow, JH Synold, TW Gandara, D Mani, S Remick, SC Mulkerin, D Hamilton, A Sharma, S Ramanathan, RK Lenz, HJ Graham, M Longmate, J Takimoto, CH Ivy, P TI Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: A preliminary report of the national cancer institute organ dysfunction working group SO SEMINARS IN ONCOLOGY LA English DT Review ID CARCINOMA CELL-LINES; HUMAN COLON; CISPLATIN; PHARMACOKINETICS; 5-FLUOROURACIL; COMBINATION; RESISTANCE C1 City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Case Western Reserve Univ, Ctr Comprehens Canc, Cleveland, OH 44106 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. NYU, Kaplan Canc Ctr, New York, NY 10016 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Ctr Comprehens Canc, Pittsburgh, PA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. Sanofi Synthelabo Inc, Dept Clin Pharmacokinet & Drug Met, Malvern, PA USA. Univ Texas, Hlth Sci Ctr, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD USA. RP Doroshow, JH (reprint author), City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, 1500 E Duarte Rd, Duarte, CA 91010 USA. OI Longmate, Jeffrey/0000-0002-0869-7928 FU NCI NIH HHS [CA 62502, CA 69853, CA 69855, CA 76642, CA 13330, CA 62491, CA 69856, CA33572, CA62505, U01 CA062491]; NCRR NIH HHS [RR00056] NR 16 TC 34 Z9 38 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2003 VL 30 IS 4 SU 15 BP 14 EP 19 DI 10.1053/S0093-7754(03)00400-7 PG 6 WC Oncology SC Oncology GA 731RL UT WOS:000185900200003 PM 14523790 ER PT J AU Takimoto, CH Remick, SC Sharma, S Mani, S Ramanathan, RK Doroshow, JH Hamilton, A Mulkerin, D Graham, M Lockwood, GF Ivy, P Egorin, M Greenslade, D Goetz, A Grem, JL AF Takimoto, CH Remick, SC Sharma, S Mani, S Ramanathan, RK Doroshow, JH Hamilton, A Mulkerin, D Graham, M Lockwood, GF Ivy, P Egorin, M Greenslade, D Goetz, A Grem, JL TI Administration of oxaliplatin to patients with renal dysfunction: A preliminary report of the National Cancer Institute Organ Dysfunction Working Group SO SEMINARS IN ONCOLOGY LA English DT Review ID CELL-LINES; OVARIAN-CANCER; SINGLE-AGENT; PHASE-II; CISPLATIN; PHARMACOKINETICS; CYTOTOXICITY; CARBOPLATIN; RESISTANCE; NSCLC C1 Univ Texas, Hlth Sci Ctr, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. NCI, Med Branch Navy, Natl Naval Med Ctr, Bethesda, MD USA. Univ Hosp Cleveland, Ctr Comprehens Canc, Cleveland, OH 44106 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Albert Einstein Coll Med, Montefiore Hosp, Bronx, NY 10467 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. City Hosp, Duarte, CA USA. NYU, New York, NY USA. Univ Wisconsin, Madison, WI USA. Sanofi Synthelabo Inc, Dept Clin Met & Pharmacokinet, Malvern, PA USA. RP Takimoto, CH (reprint author), Univ Texas, Hlth Sci Ctr, Inst Drug Dev, Canc Therapy & Res Ctr, 7979 Wurzbach Rd,Room Z415, San Antonio, TX 78229 USA. FU NCI NIH HHS [U01CA069856, U01 CA062491, U01CA062491, U01CA062502, U01CA062505, U01CA069853, U01CA069855, U01CA076642] NR 22 TC 21 Z9 22 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2003 VL 30 IS 4 SU 15 BP 20 EP 25 DI 10.1053/S0093-7754(03)00401-9 PG 6 WC Oncology SC Oncology GA 731RL UT WOS:000185900200004 PM 14523791 ER PT J AU Frankel, AE Neville, DM Bugge, TA Kreitman, RJ Leppla, SH AF Frankel, AE Neville, DM Bugge, TA Kreitman, RJ Leppla, SH TI Immunotoxin therapy of hematologic malignancies SO SEMINARS IN ONCOLOGY LA English DT Review ID RICIN-A-CHAIN; PHASE-I TRIAL; B-CELL LYMPHOMA; COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; RIBOSOME-INACTIVATING PROTEINS; NONSPECIFIC ANIMAL TOXICITY; VASCULAR LEAK SYNDROME; NON-HODGKINS-LYMPHOMA C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. NIMH, Bethesda, MD 20892 USA. Nat Inst Inst Dent & Craniofacial Res, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. RP Frankel, AE (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd,Hanes 406, Winston Salem, NC 27157 USA. NR 126 TC 42 Z9 44 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2003 VL 30 IS 4 BP 545 EP 557 DI 10.1016/S0093-7754(03)00241-0 PG 13 WC Oncology SC Oncology GA 712UD UT WOS:000184815300014 PM 12939723 ER PT J AU Ehrenkranz, RA Wright, LL AF Ehrenkranz, RA Wright, LL TI NICHD Neonatal Research Network: Contributions and future challenges SO SEMINARS IN PERINATOLOGY LA English DT Review ID BIRTH-WEIGHT INFANTS; INHALED NITRIC-OXIDE; MATERNAL LIFE-STYLE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; HYPOXIC RESPIRATORY-FAILURE; PARENTERAL GLUTAMINE SUPPLEMENTATION; PREVENT BRONCHOPULMONARY DYSPLASIA; PERSISTENT PULMONARY-HYPERTENSION; VITAMIN-A SUPPLEMENTATION; EARLY-ONSET SEPSIS C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NICHHD, Ctr Res Mothers & Children, Rockville, MD USA. RP Ehrenkranz, RA (reprint author), Yale Univ, Sch Med, Dept Pediat, 333 Cedar St,POB 208064, New Haven, CT 06520 USA. NR 87 TC 11 Z9 11 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD AUG PY 2003 VL 27 IS 4 BP 264 EP 280 DI 10.1016/S0146-0005(03)00041-7 PG 17 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 718LE UT WOS:000185146900002 PM 14510317 ER PT J AU Vohr, BR O'Shea, M Wright, LL AF Vohr, BR O'Shea, M Wright, LL TI Longitudinal multicenter follow-up of high-risk infants: Why, who, when, and what to assess SO SEMINARS IN PERINATOLOGY LA English DT Review ID BIRTH-WEIGHT INFANTS; INHALED NITRIC-OXIDE; HYPOXIC RESPIRATORY-FAILURE; PRETERM INFANTS; CEREBRAL-PALSY; CHILD-HEALTH; TERM INFANTS; INDOMETHACIN PROPHYLAXIS; NATIONAL-INSTITUTE; PREMATURE-INFANTS C1 Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02905 USA. Wake Forest Univ, Dept Pediat, Winston Salem, NC USA. NICHHD, Ctr Res Mothers & Children, Rockville, MD USA. RP Vohr, BR (reprint author), Women & Infants Hosp Rhode Isl, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. NR 48 TC 27 Z9 34 U1 1 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD AUG PY 2003 VL 27 IS 4 BP 333 EP 342 DI 10.1016/S0146-0005(03)00045-4 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 718LE UT WOS:000185146900009 PM 14510324 ER PT J AU Foley, DJ Masaki, K White, L Larkin, EK Monjan, A Redline, S AF Foley, DJ Masaki, K White, L Larkin, EK Monjan, A Redline, S TI Sleep-disordered breathing and cognitive impairment in elderly Japanese-American men SO SLEEP LA English DT Article DE sleep-disordered breathing; cognition; aging; epidemiology; Japanese-American ID HEART HEALTH; CARDIOVASCULAR-DISEASE; DAYTIME SLEEPINESS; ALZHEIMERS-DISEASE; APNEA; DEMENTIA; PREVALENCE; POPULATION; MORTALITY; SYMPTOMS AB Study Objective: To assess the association between sleep-disordered breathing and cognitive functioning in an elderly cohort of Japanese-American men Design: Cross-sectional study Setting: The Honolulu-Asia Aging Study of Sleep Apnea, Oahu, Hawaii Participants: 718 men between 79 and 97 years of age examined in 1999 and 2000 Measurements: Apnea-hypopnea index from in-home overnight polysomnography, performance on the Cognitive Abilities Screening Instrument, body mass index, neck circumference, Epworth Sleepiness Scale, snoring, Center for Epidemiologic Studies Depression 11-item depression scale, physical disability, and history of heart disease, stroke, hypertension, diabetes, and dementia. Results: Less than 30% of the men had no sleep-disordered breathing (apnea-hypopnea index <5) and nearly one-fifth (19%) had severe sleep-disordered breathing (apnea-hypopnea index greater than or equal to 30). Severe sleep-disordered breathing was associated with higher body mass index, habitual snoring, and daytime drowsiness. No association was found between sleep-disordered breathing and cognitive functioning, including measures of memory function, concentration, and attention. Conclusions: Sleep-disordered breathing was associated with more drowsiness but not with poor performance on standardized cognitive tests used to screen for Alzheimer disease and other dementias in older persons. Because a healthy-participant effect may have contributed to this finding, more extensive cognitive testing may be necessary to reveal more subtle deficits from sleep-disordered breathing. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Hawaii, Dept Geriatr Med, Honolulu, HI 96817 USA. Pacific Hlth Res Inst, Honolulu, HI 96813 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. NIA, Neurosci & Neuropsychol Aging Program, Bethesda, MD 20892 USA. RP Foley, DJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [N01-AG-4-2149] NR 32 TC 48 Z9 48 U1 6 U2 9 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD AUG 1 PY 2003 VL 26 IS 5 BP 596 EP 599 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 708BN UT WOS:000184546800014 PM 12938814 ER PT J AU Kung, HC Pearson, JL Liu, XH AF Kung, HC Pearson, JL Liu, XH TI Risk factors for male and female suicide decedents ages 15-64 in the United States - Results from the 1993 National Mortality Followback Survey SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE gender; substance use; depression; firearm accessibility; mental health service utilization; suicide ID ADOLESCENT SUICIDE; COMPLETED SUICIDE; COMMIT SUICIDE; PSYCHOLOGICAL AUTOPSY; LIFE; BEHAVIORS; WOMEN; COMORBIDITY; RESPONDENTS; PREVENTION AB Background Few controlled studies have examined possible gender differences in risk factors for suicide. This paper examined the associations of certain risk factors with suicide among males and females aged 15-64, and the variation in the associations by gender. Methods A case-control study was constructed from the 1993 National Mortality Followback Survey in the United States. Information concerning age, race, education, living arrangement, marijuana use, excessive alcohol consumption, access to a firearm, depressive symptoms, and mental health service utilization was collected via death certificate and proxy respondent. Decedents between the ages of 15 and 64 who died by suicide were compared with those who died of natural causes. Logistic regression analysis was used to examine the associations between risk factors and suicide in males and females. Results In comparison to those who died of natural causes, we found that marijuana use, excessive alcohol consumption, and access to a firearm increased the odds of suicide for both genders. For male decedents, the presence of depressive symptoms was more frequently reported for the suicide decedents in the 45-64 age group, and the proportion of mental health service use was higher among suicide decedents who did not complete high school. For female decedents, depressive symptoms were related to suicide in all age groups, and the use of mental health services was more frequent in the suicides of the 15-29 and 45-64 age groups. Conclusions The risk factors of marijuana use, excessive alcohol use, and firearm accessibility in the last year of life increased the odds of suicide in both genders. When compared to natural deaths, depressive symptomatology was common in female suicide decedents, whereas it was only associated with older age among male suicide decedents. The interactions of mental health service use with demographic factors suggested possible gender differences in suicide risk associated with severity of mental disorders, as well as the likelihood of treatment seeking. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NIMH, NIH, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, New York, NY USA. RP Kung, HC (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 7318, Hyattsville, MD 20782 USA. NR 50 TC 68 Z9 69 U1 2 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD AUG PY 2003 VL 38 IS 8 BP 419 EP 426 DI 10.1007/s00127-003-0656-x PG 8 WC Psychiatry SC Psychiatry GA 703QE UT WOS:000184291800002 PM 12910337 ER PT J AU Wassif, CA Yu, JH Cui, JS Porter, FD Javitt, NB AF Wassif, CA Yu, JH Cui, JS Porter, FD Javitt, NB TI 27-hydroxylation of 7-and 8-dehydrocholesterol in Smith-Lemli-Opitz syndrome: a novel metabolic pathway SO STEROIDS LA English DT Article DE oxysterols; cholesterol synthesis; nuclear receptors; mutations ID A REDUCTASE-ACTIVITY; BILE-ACID SYNTHESIS; LIVER-X RECEPTORS; RAT-LIVER; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE; OXYGENATED DERIVATIVES; STEROL SYNTHESIS; CHOLESTEROL; 25-HYDROXYCHOLESTEROL; 26-HYDROXYCHOLESTEROL AB Smith-Lemli-Opitz syndrome (SLOS) is attributable to mutations in the gene coding for 7-dehydrocholesterol reductase. Low to absent enzyme activity accounts for the accumulation of both 7-dehydrocholesterol and 8-dehydrocholesterol in plasma and other tissues. Since oxysterols can participate in the regulation of cholesterol homeostasis, we examined the possibility that they are formed from these dehydrocholesterol intermediates. In patients with SLOS, we found serum levels of 27-hydroxy-7-dehydrocholesterol ranging from 0.1 to 0.25 muM and evidence for circulating levels of 27-hydroxy-8-dehydrocholesterol (0.04--0.51 muM). Picomolar quantities of 27-hydroxy-7-dehydrocholesterol were identified in normal individuals. Biologic activities of 27-hydroxy-7-dehydrocholesterol were found to include inhibition of sterol synthesis and the activation of nuclear receptor LXRalpha but not that of LXRbeta. These activities occurred at concentrations found in plasma and presumably at those existing in tissues. Thus, patients with SLOS have increased levels of metabolites derived from intermediates in cholesterol synthesis that are biologically active and may contribute to the regulation of cholesterol synthesis in vivo. (C) 2003 Elsevier Inc. All rights reserved. C1 NYU, Sch Med, Dept Pediat & Med, New York, NY 10016 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Merck Res Labs, Dept Atherosclerosis Endocrinol & Metab Res, Rahway, NJ 07065 USA. RP Javitt, NB (reprint author), NYU, Sch Med, Dept Pediat & Med, 550 1St Ave, New York, NY 10016 USA. OI Wassif, Christopher/0000-0002-2524-1420 FU NHLBI NIH HHS [HL 63304] NR 26 TC 36 Z9 36 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD AUG PY 2003 VL 68 IS 6 BP 497 EP 502 DI 10.1016/S0039-128X(03)00090-4 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 713FH UT WOS:000184846100002 PM 12906934 ER PT J AU Leker, RR Gai, N Mechoulam, R Ovadia, H AF Leker, RR Gai, N Mechoulam, R Ovadia, H TI Drug-induced hypothermia reduces ischemic damage - Effects of the cannabinoid HU-210 SO STROKE LA English DT Article DE cannabinoids; cerebral ischemia; hypothermia; neuroprotection; rats ID FOCAL CEREBRAL-ISCHEMIA; MILD HYPOTHERMIA; RAT-BRAIN; NITRIC-OXIDE; RECEPTOR; MODEL; APOPTOSIS; GLUTAMATE; ARTERY; INJURY AB Background and Purpose-Cannabinoids confer neuroprotection in several experimental paradigms, but the responsible mechanisms remain unknown. Therefore, we sought to examine whether the synthetic CB1 agonist HU-210 is capable of reducing ischemic damage and to determine the mechanisms responsible for such protection. Methods-Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO). After dose-response and therapeutic time window-finding experiments, the rats were injected with HU-210 (45 mug/kg IV) or vehicle 1 hour after PMCAO. Physiological parameters and cerebral blood flow in the peri-infarct zone were monitored. The animals were examined with a motor disability scale, and the infarct volumes were measured 72 hours later. We also examined the effects of the selective CB1 antagonist SR-141716 and of controlled warming on the neuroprotection conferred by HU-210. Results-HU-210 reduced blood pressure and heart rate but did not alter the cerebral blood flow in the infarct border zone. Motor disability and infarct volumes were significantly reduced (by up to 77%; P<0.05) in animals treated with HU-210. A single injection of HU-210 significantly lowered the body temperature compared with vehicle as measured both at 1 hour (32.3+/-1.3&DEG;C versus 35+/-1.6&DEG;C; P=0.0024) and at 24 hours (31.5+/-2.5&DEG;C versus 37.25+/-0.3&DEG;C; P=0.0031) after PMCAO. The protective effects of HU-210 were partially reversed by pretreatment with SR-141716 but were completely abolished by warming of the animals to the levels observed in controls. Conclusions-HU-210 confers robust protection against ischemic damage. This protection is mediated at least in part by binding to CB1 receptors and is also associated with the indirect protective effects of hypothermia. C1 Hadassah Univ Hosp, Agnes Ginges Ctr Human Neurogenet, Dept Neurol, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Sch Med, Fac Med, Dept Med Chem & Nat Prod, IL-91010 Jerusalem, Israel. RP Leker, RR (reprint author), NINDS, NIH, Mol Biol Lab, Bldg 36,Room 3C12,36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. NR 40 TC 80 Z9 84 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2003 VL 34 IS 8 BP 2000 EP 2006 DI 10.1161/01.STR.0000079817.68944.1E PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 706YF UT WOS:000184482100040 PM 12829867 ER PT J AU Singletary, SE Allred, C Ashley, P Bassett, LW Berry, D Bland, KI Borgen, PI Clark, GM Edge, SB Hayes, DF Hughes, LL Hutter, RVP Morrow, M Page, DL Recht, A Theriault, RL Thor, A Weaver, DL Wieand, HS Greene, FL AF Singletary, SE Allred, C Ashley, P Bassett, LW Berry, D Bland, KI Borgen, PI Clark, GM Edge, SB Hayes, DF Hughes, LL Hutter, RVP Morrow, M Page, DL Recht, A Theriault, RL Thor, A Weaver, DL Wieand, HS Greene, FL TI Staging system for breast cancer: revisions for the 6th edition of the AJCC Cancer Staging Manual SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID AXILLARY LYMPH-NODES; PATHOLOGICAL PROGNOSTIC FACTORS; TERM FOLLOW-UP; NEOADJUVANT CHEMOTHERAPY; HISTOLOGICAL GRADE; ADJUVANT THERAPY; SURVIVAL; MICROMETASTASES; METASTASES; CARCINOMA AB The purpose of this article is to present the revised American joint Committee on Cancer staging system for breast carcinoma. The changes and additions, as recommended by the Breast Task Force, are based on clinical evidence or are consistent with widespread clinical consensus about the management of breast cancer. Major changes fall into two categories: (1) changes related to the detection and description of microscopic metastatic lesions; and (2) changes related to the location and number of lymph node metastases. C1 Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Scott & White Mem Hosp & Clin, Certified Tumor Registry, Temple, TX 76508 USA. Univ Calif Los Angeles, Breast Imaging Sect, Dept Radiol Sci, Los Angeles, CA 90095 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Alabama, Dept Surg, Birmingham, AL 35233 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. OSI Farmaceut Inc, Biostat & Data Management, Boulder, CO 80301 USA. Roswell Pk Canc Inst, Div Surg Oncol, Buffalo, NY 14263 USA. Univ Michigan, Breast Oncol Program, Ann Arbor, MI 48109 USA. St Barnabas Hosp, Dept Pathol, Livingston, NJ 07039 USA. NW Mem Hosp, Dept Surg, Chicago, IL 60611 USA. Vanderbilt Univ, Med Ctr, Dept Anat Pathol, Nashville, TN 37232 USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Pathol BMSB 451, Oklahoma City, OK 73104 USA. Fletcher Allen Hlth Care, Dept Pathol Smith 247, Burlington, VT 05401 USA. Univ Pittsburgh, Biostat Grad Sch Publ Hlth, Canc Inst Biostat Facil, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15213 USA. Carolinas Med Ctr, Dept Gen Surg, Charlotte, NC 28232 USA. RP Singletary, SE (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, 1515 Holcombe Blvd,Box 106, Houston, TX 77030 USA. NR 50 TC 193 Z9 202 U1 1 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2003 VL 83 IS 4 BP 803 EP + DI 10.1016/S0039-6109(03)00034-3 PG 18 WC Surgery SC Surgery GA 700AK UT WOS:000184090300006 PM 12875597 ER PT J AU Norton, JA Jensen, RT AF Norton, JA Jensen, RT TI Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1) SO SURGICAL ONCOLOGY-OXFORD LA English DT Article ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; PROXIMAL GASTRIC-VAGOTOMY; ISLET-CELL TUMORS; DUODENAL GASTRINOMAS; NEUROENDOCRINE TUMORS; LONG-TERM; NATURAL-HISTORY; CLINICAL COURSE; LOCALIZATION; RESECTION AB The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence. Published by Elsevier Ltd. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. NR 64 TC 41 Z9 41 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0960-7404 J9 SURG ONCOL JI Surg. Oncol.-Oxf. PD AUG PY 2003 VL 12 IS 2 BP 145 EP 151 DI 10.1016/S0960-7404(03)00035-5 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 720KW UT WOS:000185260800008 PM 12946485 ER PT J AU Szabo, R Wu, QY Dickson, RB Netzel-Arnett, S Antalis, TM Bugge, TH AF Szabo, R Wu, QY Dickson, RB Netzel-Arnett, S Antalis, TM Bugge, TH TI Type II transmembrane serine proteases SO THROMBOSIS AND HAEMOSTASIS LA English DT Review DE serine proteases; cell surface proteolysis; transmembrane ID AUTOSOMAL RECESSIVE DEAFNESS; BREAST-CANCER CELLS; PROATRIAL NATRIURETIC PEPTIDE; SURFACE PROTEOLYTIC-ENZYMES; MATRIX-DEGRADING PROTEASE; EPITHELIAL SODIUM-CHANNEL; HEPATOCYTE GROWTH-FACTOR; TRYPSIN-LIKE PROTEASE; PROSTATE-CANCER; GENE-EXPRESSION AB The recent availability of human and mouse genome sequences and expressed sequence tag databases facilitated the identification of a large new family of membrane anchored serine proteases, the type II transmembrane serine proteases or TTSPs. Analyses of human inherited disorders and gene targeting studies in mice have revealed that several members of this new protease family have critical functions in development and health. Preliminary studies also suggest that aberrant expression of type II transmembrane serine proteases may be linked to disease progression. The knowledge gathered thus far of the genetics, physiology, and pathology of this interesting new serine protease family will be reviewed here in brief. C1 Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Berlex Biosci, Richmond, CA USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Amer Red Cross, Jerome H Holland Lab Biomed Sci, Vasc Biol Dept, Rockville, MD USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. NR 81 TC 72 Z9 77 U1 0 U2 5 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2003 VL 90 IS 2 BP 185 EP 193 DI 10.1160/TH03-02-0071 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 712AV UT WOS:000184774000004 PM 12888865 ER PT J AU Cannon, RE AF Cannon, RE TI The Tg.AC mouse model passes test by failing to respond SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material AB This issue highlights two companion articles, "Selection of Drugs to Test the Specificity of the Tg.AC Assay by Screening for Induction of the gadd153 Promoter in Vitro" by Karol L. Thompson and Frank D. Sistare (pp. 260-270) and "Evaluation of the Tg.AC Assay: Specificity Testing with Three Noncarcinogenic Pharmaceuticals that Induce Selected Stress Gene Promoters in Vitro and the Inhibitory Effects of Solvent Components" by Karol L. Thompson, Barry A. Rosenzweig, James L. Weaver, Jun Zhang, Karl K. Lin, and Frank D. Sistare (pp. 271-278). These articles outline a unique paradigm for selecting and assaying chemicals for carcinogenic activity using the short-term in vivo Tg.AC mouse model. This Tg.AC mouse model was the primary focus of the work; however, the strategy employed could be exploited for the other alternative mouse models. C1 NIEHS, Canc Biol Grp, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. RP Cannon, RE (reprint author), NIEHS, Canc Biol Grp, Natl Ctr Toxicogenom, POB 12233, Res Triangle Pk, NC 27709 USA. NR 5 TC 1 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2003 VL 74 IS 2 BP 233 EP 234 DI 10.1093/toxsci/kfg170 PG 2 WC Toxicology SC Toxicology GA 705LU UT WOS:000184397200003 PM 12892072 ER PT J AU Ress, NB Chou, BJ Renne, RA Dill, JA Miller, RA Roycroft, JH Hailey, JR Haseman, JK Bucher, JR AF Ress, NB Chou, BJ Renne, RA Dill, JA Miller, RA Roycroft, JH Hailey, JR Haseman, JK Bucher, JR TI Carcinogenicity of inhaled vanadium pentoxide in F344/N rats and B6C3F(1) mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE carcinoma; adenoma; soluble particles; lung; vanadium pentoxide; vanadium; reactive-oil-fly-ash (ROFA); inflammation; fibrosis; boilermaker's bronchitis ID FREE-RADICAL REACTIONS; ZERO DOSE CONTROL; NF-KAPPA-B; 2'-DEOXYGUANOSINE HYDROXYLATION; DIET NTP-2000; INDUCTION; TOXICOLOGY; ACTIVATION; CELLS; MACROPHAGES AB Vanadium pentoxide (V2O5) is a slightly soluble compound found in airborne particle emissions from metallurgical works and oil and coal burning. Because the carcinogenic potential of V2O5 was not known, F344/N rats and B6C3F(1) mice (N = 50/sex/ species) were exposed to V2O5 at concentrations of 0, 0.5 (rats only), 1, 2, or 4 (mice only) mg/m(3), by whole-body inhalation for 2 years. The survival and body weights of rats were minimally affected by exposure to V2O5. The survival and body weights of male mice exposed to 4 mg/m(3) and body weights of all exposed groups of female mice were lower than the controls. Alveolar/ bronchiolar (A/B) neoplasms occurred in male rats exposed to 0.5 and 2 mg/m(3) at incidences exceeding the National Toxicology Program (NTP) historical control ranges. A marginal increase in A/B neoplasms was also observed in female rats exposed to 0.5 mg/m(3). Increases in chronic inflammation, interstitial fibrosis, and alveolar and bronchiolar hyperplasia/metaplasia and squamous metaplasia were observed in exposed male and female rats. A/B neoplasms were significantly increased in all groups of exposed mice. As with rats, increases in chronic inflammation, interstitial fibrosis, and alveolar and bronchiolar epithelial hyperplasia were observed in mice exposed to V2O5. Thus, V2O5 exposure was a pulmonary carcinogen in male rats and male and female mice. The marginal tumor response in the lungs of female rats could not be attributed conclusively to exposure to V2O5. These responses were noted at and slightly above the OSHA permissible occupational exposure limit of 0.5 mg/m(3) (dust) (National Institute for Occupational Safety and Health, NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Washington, DC, 1997, p. 328). C1 NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. Battelle Toxicol NW, Richland, WA 99352 USA. RP Bucher, JR (reprint author), NIEHS, Natl Toxicol Program, 79 Alexander Dr,Mail Drop EC-34, Res Triangle Pk, NC 27709 USA. NR 46 TC 46 Z9 49 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2003 VL 74 IS 2 BP 287 EP 296 DI 10.1093/toxsci/kfg136 PG 10 WC Toxicology SC Toxicology GA 705LU UT WOS:000184397200010 PM 12773761 ER PT J AU Bowman, CJ Barlow, NJ Turner, KJ Wallace, DG Foster, PMD AF Bowman, CJ Barlow, NJ Turner, KJ Wallace, DG Foster, PMD TI Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat SO TOXICOLOGICAL SCIENCES LA English DT Article DE finasteride; 5a-reductase; development; dihydrotestosterone; in utero exposure; antiandrogen ID ALTERS SEXUAL-DIFFERENTIATION; 5-ALPHA-REDUCTASE INHIBITOR; ENZYME 5-ALPHA-REDUCTASE; DI(N-BUTYL) PHTHALATE; ANOGENITAL DISTANCE; CRL-CD(SD)BR RAT; NIPPLE RETENTION; LATE-GESTATION; DIHYDROTESTOSTERONE; FLUTAMIDE AB Finasteride is a specific inhibitor of type II 5alpha-reductase, the enzyme that converts testosterone (T) to the more potent androgen receptor agonist dihydrotestosterone (DHT). In utero exposure to androgen receptor antagonists and T biosynthesis inhibitors have induced permanent effects on androgen-sensitive end points such as anogenital distance (AGD), nipple retention, and malformations of the male rat reproductive tract. The objectives of this study were to (1) characterize the dose response of finasteride-mediated alterations in androgen-dependent developmental end points, (2) determine whether prenatal exposure to finasteride permanently decreases AGD or results in nipple retention, and (3) evaluate whether AGD or nipple retention is predictive of adverse alterations in the male reproductive tract. Pregnant Crl:CD(SD)BR rats (n = 5-6/group) were gavaged with either vehicle or finasteride at 0.01, 0.1, 1.0, 10, or 100 mg/kg/day on gestation days 12 to 21. All male offspring were monitored individually until necropsy on postnatal day (PND) 90. The present study design has been used previously for other antiandrogens and is sensitive to perturbations of the male rat reproductive tract. Decreases in AGD on PND 1 and increases in areolae-nipple retention on PND 13 were significantly different from controls in all finasteride-exposed male rats. Finasteride-induced changes in AGD and nipple retention were permanent in male rats exposed to finasteride at and above 0.1 mg/kg/day. On PND 90, dorsolateral and ventral prostate lobes were absent in 21 to 24% of rats exposed to 100 mg/kg/day finasteride and weighed significantly less at and above 10 mg/kg/day. In the highest dose group, 73% of animals had ectopic testes, much higher than previously reported. The most sensitive malformation other than decreased AGD and nipple retention was the dose-dependent increase in hypospadias. The lowest observed adverse effect level (LOAEL) for finasteride-induced permanent effects in this study was 0.1 mg/kg/day based on permanent changes in AGD and nipple retention. Finasteride-induced changes in AGD and retention of nipples were highly predictive of hypospadias, ectopic testes, and prostate malformations even though some animals with retained nipples or decreased AGD may not have had other reproductive tract malformations. In summary, prenatal exposure to finasteride specifically inhibited DHT-mediated development with little to no change in T-mediated development. C1 CIIT, Ctr Hlth Res, Res Triangle Pk, NC 27709 USA. RP Foster, PMD (reprint author), NIEHS, POB 12233,MD E1-06, Res Triangle Pk, NC 27709 USA. NR 33 TC 59 Z9 63 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2003 VL 74 IS 2 BP 393 EP 406 DI 10.1093/toxsci/kfg128 PG 14 WC Toxicology SC Toxicology GA 705LU UT WOS:000184397200021 PM 12773767 ER PT J AU Li, CX Liu, J Saavedra, JE Keefer, LK Waalkes, MP AF Li, CX Liu, J Saavedra, JE Keefer, LK Waalkes, MP TI The nitric oxide donor, V-PYRRONO, protects against acetaminophen-induced nephrotoxicity in mice SO TOXICOLOGY LA English DT Article DE acetaminophen; renal pathology; nitric oxide; mice ID ACUTE-RENAL-FAILURE; CYCLOSPORINE NEPHROTOXICITY; COVALENT BINDING; L-ARGININE; IN-VIVO; LIVER; HEPATOTOXICITY; TOXICITY; MOUSE; RATS AB The nitric oxide (NO) donor, O-2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P450 enzymes to release NO in the liver and possibly other tissues. V-PYRRO/NO has been shown to be hepatoprotective, but little is known about its effect in the kidney, another organ rich in P450s. Thus, mice were given V-PYRRO/NO (0.4-5.4 mg/ml, 8 mul/h) before and/or after a nephrotoxic dose of acetaminophen (APAP; 600 mg/kg, i.p.) to examine its nephroprotective effects. V-PYRRO/NO administration significantly reduced APAP-induced nephrotoxicity in a dose- and time-dependent manner, as evidenced by mitigation of increased blood urea nitrogen levels and by amelioration of renal pathology, specifically interstitial congestion, proximal tubular cell degeneration and necrosis. The best protection was observed at the highest dose (5.4 mg/ml) and with V-PYRRO/NO pretreatment (4-16 h). Implanting V-PYRRO/NO pumps simultaneously with APAP also attenuated APAP nephrotoxicity. The protection is probably not due to a decreased APAP toxication metabolism, as similar depletion of renal glutathione levels was observed regardless of V-PYRRO/NO treatment. APAP-induced renal lipid peroxidation was reduced by V-PYRRO/NO, as determined by the concentrations of hydroxynonenals and malondialdehyde. In summary, this study demonstrates that the NO donor V-PYRRO/NO is effective in blocking APAP-induced nephrotoxicity in mice. The protection is probably due to multiple mechanisms involving attenuation of APAP-induced congestion and lipid peroxidation in the kidney. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27706 USA. SAIC Frederick, Frederick, MD USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27706 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-12400] NR 24 TC 30 Z9 30 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 AUG 1 PY 2003 VL 189 IS 3 BP 173 EP 180 DI 10.1016/S0300-483X(03)00129-X PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 701JL UT WOS:000184164400002 PM 12832150 ER PT J AU Parada, LA Roix, JJ Misteli, T AF Parada, LA Roix, JJ Misteli, T TI An uncertainty principle in chromosome positioning SO TRENDS IN CELL BIOLOGY LA English DT Article ID NUCLEAR ARCHITECTURE; GENE-EXPRESSION; MAMMALIAN-CELLS; INTERPHASE; DYNAMICS; DNA; ARRANGEMENTS; CONSERVATION; TERRITORIES; DROSOPHILA AB Chromosomes are non-randomly positioned in the mammalian interphase nucleus. It is not known how patterns of chromosome positions are established or to what degree spatial arrangements of chromosomes change during the cell cycle, especially during mitosis, Two reports have applied in vivo microscopy to track chromosomes in space and time. The results highlight the inherently imperfect and probabilistic nature of chromosome positioning in the cell nucleus. C1 NCI, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, Bethesda, MD 20892 USA. NR 21 TC 45 Z9 45 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 2003 VL 13 IS 8 BP 393 EP 396 DI 10.1016/S0962-8924(03)00149-1 PG 4 WC Cell Biology SC Cell Biology GA 711FV UT WOS:000184729700001 PM 12888289 ER PT J AU Hu, JX Spiegel, AM AF Hu, JX Spiegel, AM TI Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID CALCIUM-SENSING RECEPTOR; HUMAN CA2+ RECEPTOR; AUTOSOMAL-DOMINANT HYPOCALCEMIA; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; METABOTROPIC GLUTAMATE-RECEPTOR; CELL-SURFACE EXPRESSION; PROTEIN-COUPLED RECEPTOR; SIGNAL-TRANSDUCTION; INTERMOLECULAR INTERACTIONS; 7-TRANSMEMBRANE DOMAIN AB The extracellular Ca2+ sensing receptor is a member of the G-protein-coupled receptor family 3 in which agonists bind to a dimeric Venus-flytrap domain in the extracellular portion of the receptor. How agonist binding to this domain leads to activation of the seven-transmembrane domain is a major unresolved question. Information derived from the three-dimensional structure of the Venus-flytrap domain of the related metabotropic glutamate type 1 receptor, and from naturally occurring mutations of the Ca2+ -sensing receptor identified in subjects with familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia offers new insights into the mechanism of receptor activation, and into the mechanism of action of allosteric modulators of the receptor. C1 Natl Inst Deafness & Other Commun Disorders, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. RP Hu, JX (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. NR 43 TC 82 Z9 86 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD AUG PY 2003 VL 14 IS 6 BP 282 EP 288 DI 10.1016/S1043-2760(03)00104-8 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 711FM UT WOS:000184729000007 PM 12890593 ER PT J AU Racanelli, V Rehermann, B AF Racanelli, V Rehermann, B TI Hepatitis C virus infection: when silence is deception SO TRENDS IN IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; HYPERVARIABLE REGION 1; CORE PROTEIN; ENVELOPE PROTEIN; LOW-DENSITY; RECOVERED CHIMPANZEES; PROTECTIVE IMMUNITY; EXOGENOUS ANTIGEN; PERIPHERAL-BLOOD; DENDRITIC CELLS AB Hepatitis C virus (HCV) uses complex and unique mechanisms to prevent, evade or subvert innate and adaptive immune responses and to establish persistent infection and chronic hepatitis. Recently developed experimental systems have significantly facilitated the analysis of HCV replication, virus-host interaction and pathogenesis of chronic hepatitis and have provided new insights into the mechanisms of HCV clearance and persistence. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Room 9B16, Bethesda, MD 20892 USA. OI RACANELLI, Vito/0000-0002-8639-1940 NR 75 TC 82 Z9 82 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2003 VL 24 IS 8 BP 456 EP 464 DI 10.1016/S1471-4906(03)00178-9 PG 9 WC Immunology SC Immunology GA 714TM UT WOS:000184929600013 PM 12909460 ER PT J AU Shea, TB Jung, CL Pant, HC AF Shea, TB Jung, CL Pant, HC TI Does neurofilament phosphorylation regulate axonal transport? SO TRENDS IN NEUROSCIENCES LA English DT Article ID SUBUNITS; DISRUPTION; PROTEINS; VELOCITY AB Phosphorylation of neurofilaments has long been considered to regulate their axonal transport rate and, in doing so, to provide stability to mature axons. Interpretation of data recently obtained following C-terminal deletion experiments has prompted a challenge to this hypothesis. We present evidence that these deletion studies remain consistent with, rather than refute, a role for C-terminal phosphorylation in regulation of neurofilament axonal transport. C1 Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Sci Biol, Lowell, MA 01854 USA. Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Biochem, Lowell, MA 01854 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Shea, TB (reprint author), Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Sci Biol, 1 Univ Ave, Lowell, MA 01854 USA. NR 20 TC 48 Z9 49 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2003 VL 26 IS 8 BP 397 EP 400 DI 10.1016/S0166-2236(03)00199-1 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 713WF UT WOS:000184880400003 PM 12900166 ER PT J AU Liu, Y Rao, M AF Liu, Y Rao, M TI Oligodendrocytes, GRPs and MNOPs SO TRENDS IN NEUROSCIENCES LA English DT Letter ID SPINAL-CORD; RESTRICTED PRECURSORS; TRANSCRIPTION FACTORS; SUBVENTRICULAR ZONE; LINEAGE; CELL; DIFFERENTIATION; OLIG2; IDENTIFICATION; EXPRESSION C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. RP Rao, M (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 21 TC 14 Z9 14 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2003 VL 26 IS 8 BP 410 EP 412 DI 10.1016/S0166-2236(03)00201-7 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 713WF UT WOS:000184880400008 PM 12900171 ER PT J AU Plenz, D AF Plenz, D TI When inhibition goes incognito: feedback interaction between spiny projection neurons in striatal function SO TRENDS IN NEUROSCIENCES LA English DT Review ID NEURAL-NETWORK MODEL; RAT BASAL GANGLIA; GABAERGIC INTERNEURONS; HORSERADISH-PEROXIDASE; STRIATONIGRAL NEURONS; REINFORCEMENT SIGNAL; SYNAPTIC CONNECTIONS; EXCITATORY ACTIONS; SLICE PREPARATIONS; DOPAMINE-RECEPTOR AB Theories about basal ganglia function have always been driven by our knowledge about the spiny projection neurons of the striatum. At the core of these theories lies the question of how, precisely, spiny projection neurons process cortical inputs. Most recently, studies demonstrating the role of spiny projection neurons in local synaptic GABA transmission have provided several new avenues for exploring striatal dynamics. They have also suggested new experimental directives for examining the specific ways in which spiny projection neurons both compete and cooperate through their local axon collaterals during cortical input processing. C1 NIMH, Lab Syst Neurosci, Unit Neural Network Physiol, NIH, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Lab Syst Neurosci, Unit Neural Network Physiol, NIH, Bethesda, MD 20892 USA. NR 80 TC 143 Z9 145 U1 1 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2003 VL 26 IS 8 BP 436 EP 443 DI 10.1016/S0166-2236(03)00196-6 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 713WF UT WOS:000184880400012 PM 12900175 ER PT J AU Gao, HM Liu, B Zhang, WQ Hong, JS AF Gao, HM Liu, B Zhang, WQ Hong, JS TI Novel anti-inflammatory therapy for Parkinson's disease SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; PROTECTS DOPAMINERGIC-NEURONS; SINGLE INTRANIGRAL INJECTION; MICROGLIAL ACTIVATION; NEUROTROPHIC FACTOR; SUBSTANTIA-NIGRA; NITRIC-OXIDE; MOUSE MODEL; TNF-ALPHA; INFLAMMATORY REACTION AB Parkinson's disease (PD) is a movement disorder that is characterized by progressive degeneration of the nigrostriatal dopamine system. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Recently, increasing evidence from human and animal studies has suggested that neuroinflammation is an important contributor to the neuronal loss in PD. Moreover, the pro-inflammatory agent lipopolysaccharide itself can directly initiate degeneration of dopamine-containing neurons or combine with other environmental factor(s), such as the pesticide rotenone, to exacerbate such neurodegeneration. These effects provide strong support for the involvement of inflammation in the pathogenesis of PD. Furthermore, growing experimental evidence demonstrates that inhibition of the inflammatory response can, in part, prevent degeneration of nigrostriatal dopamine-containing neurons in several animal models of PD, suggesting that inhibition of inflammation might become a promising therapeutic intervention for PD. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 66 TC 211 Z9 220 U1 3 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2003 VL 24 IS 8 BP 395 EP 401 DI 10.1016/S0165-6147(03)00176-7 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 714TP UT WOS:000184929800004 PM 12915048 ER PT J AU Wess, J AF Wess, J TI Novel insights into muscarinic acetylcholine receptor function using gene targeting technology SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; CEREBRAL BLOOD-FLOW; KNOCK-OUT MICE; SMOOTH-MUSCLE; RAT-BRAIN; SEIZURE ACTIVITY; URINARY-BLADDER; MESSENGER-RNA; MUTANT MICE; M1 RECEPTOR AB Muscarinic acetylcholine receptors (mAChRs) modulate the activity of an extraordinarily large number of physiological functions. Individual members of the mAChR family (M-1-M-5) are expressed in a complex, overlapping fashion in most tissues and cell types. However, the identification of the precise physiological roles of individual mAChR subtypes remains a challenging task because, with the exception of a few snake toxins, mAChR ligands that can activate or inhibit specific mAChR subtypes with a high degree of selectivity are not yet available. Knowledge of the specific roles of mAChR subtypes is of considerable interest for the development of novel, clinically useful mAChR ligands. In this article, recent studies of mutant mouse strains developed, using gene targeting techniques, to be deficient in one of the three G(q)-coupled mAChR subtypes (M-1, M-3 and M-5) are discussed. These investigations have led to many important new insights into the physiological roles of these receptor subtypes. C1 NIDDKD, Mol Signalling Sect, Bioorgan Chem Lab, DHHS, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Mol Signalling Sect, Bioorgan Chem Lab, DHHS, Bethesda, MD 20892 USA. NR 67 TC 64 Z9 68 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2003 VL 24 IS 8 BP 414 EP 420 DI 10.1016/S0165-6147(03)00195-0 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 714TP UT WOS:000184929800007 PM 12915051 ER PT J AU Pavlovich, CP Schmidt, LS Phillips, JL AF Pavlovich, CP Schmidt, LS Phillips, JL TI The genetic basis of renal cell carcinoma SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Review ID COMPARATIVE GENOMIC HYBRIDIZATION; TUMOR-SUPPRESSOR GENE; VONHIPPEL-LINDAU DISEASE; HOGG-DUBE-SYNDROME; COLLECTING DUCT CARCINOMA; IN-SITU HYBRIDIZATION; TUBEROUS SCLEROSIS COMPLEX; INCREASED COPY NUMBER; CLEAR-CELL; MET PROTOONCOGENE AB The recognition of hereditary forms of renal cancer and the development of high-throughput genetic analysis have led to the identification of genes responsible for familial renal epithelial tumors of differing histologies and cytogenetic features. Some of these genes (VHL) are known to have an important role in sporadic renal neoplasia. This article describes the various epithelial renal tumors most commonly encountered by the urologist, the molecular and cytogenetic distinctions between them, and the hereditary syndromes that predispose to these tumors. Consideration of these syndromes is important for proper treatment when one encounters patients with multiple renal tumors, tumors at an early age of onset, or patients with a positive family history of renal cell carcinoma. C1 A345 Johns Hopkins Bayview Med Ctr, James Buchanan Brady Urol Inst, Baltimore, MD 21224 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Canc Res Ctr, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Pavlovich, CP (reprint author), A345 Johns Hopkins Bayview Med Ctr, James Buchanan Brady Urol Inst, 4940 Eastern Ave, Baltimore, MD 21224 USA. FU NCI NIH HHS [N01-CO-12400] NR 133 TC 24 Z9 28 U1 2 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD AUG PY 2003 VL 30 IS 3 BP 437 EP + DI 10.1016/S0094-0143(03)00023-5 PG 19 WC Urology & Nephrology SC Urology & Nephrology GA 716AK UT WOS:000185006500003 PM 12953747 ER PT J AU Drachenberg, D Childs, RW AF Drachenberg, D Childs, RW TI Allogeneic stem cell transplantation as immunotherapy for renal cell carcinoma: from immune enhancement to immune replacement SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID BONE-MARROW TRANSPLANTATION; BREAST-CANCER; T-CELLS; MYELOABLATIVE THERAPY; CHEMOTHERAPY; ENGRAFTMENT; INTERLEUKIN-2; REGRESSION; LEUKEMIA; MALIGNANCIES AB Spontaneous regressions of metastatic RCC strongly suggest a proclivity of this tumor to be regulated by the immune system and have led investigators to test allogeneic based immunotherapy in this type of malignancy. Graft-versus-tumor effects are generated against immunosensitive RCC following the transplantation of allogeneic donor T lymphocytes. This article reviews the development and outcome of pilot immunotherapy trials based on the use of an allogeneic immune system to treat metastatic RCC and describes some of the early in vitro data implicating donor T cells as mediators of disease regression. C1 NHLBI, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 13 Z9 15 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD AUG PY 2003 VL 30 IS 3 BP 611 EP + DI 10.1016/S0094-0143(03)00025-9 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 716AK UT WOS:000185006500015 PM 12953759 ER PT J AU Lee, CSD Komenaka, IK Hurst-Wicker, KS Deraffele, G Mitcham, J Kaufman, HL AF Lee, CSD Komenaka, IK Hurst-Wicker, KS Deraffele, G Mitcham, J Kaufman, HL TI Management of metastatic malignant melanoma of the bladder SO UROLOGY LA English DT Article ID INTERLEUKIN-2; LYMPHOCYTES AB Recombinant interleukin-2 (IL-2) has demonstrated antitumor activity and durable clinical responses in patients with metastatic melanoma. Careful screening and selection of appropriate patients has improved the safety profile of IL-2 administration. Gross hematuria would ordinarily preclude the safe delivery of IL-2. We report a case of metastatic melanoma to the bladder presenting with hematuria. A complete resection was performed and subsequently allowed the administration of high-dose, bolus IL-2. The combination of resection and IL-2 therapy resulted in a partial response maintained for more than 18 months. Symptomatic bladder melanoma should be aggressively treated to allow for systemic immunotherapy, which can provide durable responses. C1 Columbia Univ Coll Phys & Surg, Columbia Presbyterian Med Ctr, Sect Surg Oncol, New York, NY 10032 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA. RP Kaufman, HL (reprint author), Columbia Univ Coll Phys & Surg, Columbia Presbyterian Med Ctr, Sect Surg Oncol, Milstein Hosp Bldg,7SK-12,177 Ft Washington Ave, New York, NY 10032 USA. NR 13 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 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2003 VL 62 IS 2 DI 10.1016/S0090-4295(03)00354-6 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 708FU UT WOS:000184557200047 ER PT J AU Voronin, YA Pathak, VK AF Voronin, YA Pathak, VK TI Frequent dual initiation of reverse transcription in murine leukemia virus-based vectors containing two primer-binding sites SO VIROLOGY LA English DT Article DE MLV; SNV; PBS; initiation; tRNA; reverse transcription ID ROUS-SARCOMA-VIRUS; DEPENDENT DNA POLYMERASE; 5' NONTRANSLATED REGION; SPLEEN NECROSIS VIRUS; LONG TERMINAL REPEAT; NUCLEOTIDE-SEQUENCE; RETROVIRAL RECOMBINATION; TRANSPOSABLE ELEMENTS; AVIAN RETROVIRUSES; INTERNAL ENTRY AB Retroviruses package two copies of viral RNA into each virion. Although each RNA contains a primer-binding site for initiation of DNA synthesis, it is unknown whether reverse transcription is initiated on both RNAs. To determine whether a single virion is capable of initiating reverse transcription more than once, we constructed a murine leukemia virus-based vector containing a second primer-binding site (PBS) derived from spleen necrosis virus and inserted the green fluorescent protein gene (GFP) between the two PBSs. Initiation of reverse transcription at either PBS results in a provirus that expresses GFP. However, initiation at both PBSs can result in the deletion of GFP, which can be detected by flow cytometry and Southern blotting analysis. Approximately 22-29% of the proviruses formed deleted the GFP in a single replication cycle, indicating the minimum proportion of virions that initiated reverse transcription on both PBSs. These results show that a significant proportion of MLV-based vectors containing two PBSs have the capacity to initiate reverse transcription more than once. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. W Virginia Univ, Dept Biochem, Morgantown, WV 25606 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Bldg 535,Room 334, Frederick, MD 21702 USA. NR 51 TC 6 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 1 PY 2003 VL 312 IS 2 BP 281 EP 294 DI 10.1016/S0042-6822(03)00300-3 PG 14 WC Virology SC Virology GA 715AH UT WOS:000184948000004 PM 12919734 ER PT J AU Mahanty, S Gupta, M Paragas, J Bray, M Ahmed, R Rollin, PE AF Mahanty, S Gupta, M Paragas, J Bray, M Ahmed, R Rollin, PE TI Protection from lethal infection is determined by innate immune responses in a mouse model of Ebola virus infection SO VIROLOGY LA English DT Article DE Ebola virus; filovirus; cytokines; viral kinetics; innate immunity; protective immunity; pathogenesis; interferons ID CYTOTOXIC T-LYMPHOCYTES; HEMORRHAGIC-FEVER; ENDOTHELIAL-CELLS; FILOVIRUS INFECTIONS; VIRAL-INFECTIONS; PASSIVE TRANSFER; ZAIRE-VIRUS; IFN-ALPHA; IN-VITRO; MICE AB A mouse-adapted strain of Ebola Zaire virus produces a fatal infection when BALB/cj mice are infected intraperitoneally (ip) but subcutaneous (sc) infection with the same virus fails to produce illness and confers long-term protection from lethal ip rechallenge. To identify immune correlates of protection in this model, we compared viral replication and cytokine/chemokine responses to Ebola virus in mice infected ip (10 PFU/mouse), or sc (100 PFU/mouse) and sc "immune" mice rechallenged ip (106 PFU/mouse) at several time points postinfection (pi). Ebola viral antigens were detected in the serum, liver, spleen, and kidneys of ip-infected mice by day 2 pi, increasing up to day 6. Sc-infected mice and immune mice rechallenged ip had no detectable viral antigens until day 6 pi, when low levels of viral antigens were detected in the livers of sc-infected mice only. TNF-alpha and MCP-1 were detected earlier and at significantly higher levels in the serum and tissues of ip-infected mice than in sc-infected or immune mice challenged ip. In contrast, high levels of IFN-alpha and IFN-gamma were found in tissues within 2 days after challenge in sc-infected and immune mice but not in ip-infected mice. Mice became resistant to ip challenge within 48 h of sc infection, coinciding with the rise in tissue IFN-alpha levels. In this model of Ebola virus infection, the nonlethal sc route of infection is associated with an attenuated inflammatory response and early production of antiviral cytokines, particularly IFN-alpha, as compared with lethal ip infection. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, Special Pathogens Branch, Atlanta, GA 30333 USA. Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. USA, Med Res Inst Infect Dis, Dept Viral Therapeut, Frederick, MD 21702 USA. NIAID, Biodef Clin Res Branch, Off Director, NIH, Bethesda, MD 20892 USA. RP Mahanty, S (reprint author), NIAID, Malaria Vaccine Dev Unit, NIH, Twinbrook 1,5640 Fishers Lane, Rockville, MD 20852 USA. EM smahanty@niaid.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 NR 47 TC 48 Z9 52 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 1 PY 2003 VL 312 IS 2 BP 415 EP 424 DI 10.1016/S0042-6822(03)00233-2 PG 10 WC Virology SC Virology GA 715AH UT WOS:000184948000016 PM 12919746 ER PT J AU Tan, ML Fischer, JT Chandra, A Brooks, BR Ichiye, T AF Tan, ML Fischer, JT Chandra, A Brooks, BR Ichiye, T TI A temperature of maximum density in soft sticky dipole water SO CHEMICAL PHYSICS LETTERS LA English DT Article ID RADIAL-DISTRIBUTION FUNCTIONS; STATIC DIELECTRIC-CONSTANT; FLUCTUATING CHARGE MODEL; LIQUID WATER; POTENTIAL FUNCTIONS; MOLECULAR-DYNAMICS; SELF-DIFFUSION; SIMULATION; DEPENDENCE; PRESSURE AB A temperature of maximum density near 260 K at 1 atm has been found for the soft sticky dipole (SSD) water model in molecular dynamics simulations. The parameters of SSD have been optimized to reproduce the density of water as well as other structural, thermodynamic, dielectric, and dynamic properties at room temperature and 1 atm. Remarkably, this simple model is able to reproduce the anomalous temperature dependence of the density using parameters optimized at room temperature. Furthermore, these results indicate that the tetrahedral nature of water is important in determining this anomalous behavior. (C) 2003 Elsevier B.V. All rights reserved. C1 Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ichiye, T (reprint author), Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NR 35 TC 21 Z9 21 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD JUL 31 PY 2003 VL 376 IS 5-6 BP 646 EP 652 DI 10.1016/S0009-2614(03)01044-3 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 708KL UT WOS:000184565900015 ER PT J AU Yoshinari, K Kobayashi, K Moore, R Kawamoto, T Negishi, M AF Yoshinari, K Kobayashi, K Moore, R Kawamoto, T Negishi, M TI Identification of the nuclear receptor CAR : HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital SO FEBS LETTERS LA English DT Article DE nuclear receptor CAR; phenobarbital; nuclear translocationl; heat shock protein; protein phosphatase ID HEAT-SHOCK-PROTEIN; REQUIRES INTACT CYTOSKELETON; GLUCOCORTICOID-RECEPTOR; CYP2B GENE; CAR; GELDANAMYCIN; INDUCTION; TRANSLOCATION; IMMUNOPHILIN; INVOLVEMENT AB The nuclear receptor CAR, a phenobarbital (PB)-responsive transcription factor, translocates into the nucleus of hepatocytes after PB induction. In non-induced mice, CAR forms a physical complex with heat shock protein 90 (HSP90) in the cytoplasm. In response to PB induction, protein phosphatase 2A is recruited to the CAR:HSP90 complex. This recruitment may lead CAR to translocate into the nucleus, consistent with the inhibitions of nuclear CAR accumulation in PB-induced mouse primary hepatocytes by okadaic acid as well as by gel-danamycin. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RI Kawamoto, Takeshi/D-7938-2015 OI Kawamoto, Takeshi/0000-0003-3337-1775 NR 25 TC 106 Z9 111 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 31 PY 2003 VL 548 IS 1-3 BP 17 EP 20 DI 10.1016/S0014-5793(03)00720-8 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 707XW UT WOS:000184536100004 PM 12885400 ER PT J AU de Dios, AC Tycko, R Ursos, LMB Roepe, PD AF de Dios, AC Tycko, R Ursos, LMB Roepe, PD TI NMR studies of chloroquine-ferriprotoporphyrin IX complex SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; UROPORPHYRIN-I; CHLORIDE; BINDING AB By examining natural-abundance C-13 and N-15 solid-state nuclear magnetic resonance (NMR) spectra of acid-precipitated chloroquine-ferriprotoporphyrin IX (CQ-FPlX) aggregates, the first direct evidence is provided for CQ-FPIX complexes in the solid state, formed in a physiologic aqueous solution that mimics the environment inside the digestive vacuole of the malaria parasite. The C-13 spectra demonstrate a loss of signal from aromatic sites, whereas N-15 experiments indicate the disappearance of the signal from the N atom of the quinoline ring. These signal losses are due to the paramagnetic Fe(III) center of FPIX. In addition, contact shifts are also observed for both C-13 and N-15 spectra, suggesting the formation of a covalent complex between CQ and FPIX in the solid state. C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. Georgetown Univ, Dept Biochem & Mol Biol, Washington, DC 20057 USA. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP de Dios, AC (reprint author), Georgetown Univ, Dept Chem, 37th & O St, Washington, DC 20057 USA. RI de Dios, Angel/H-4034-2011 NR 14 TC 59 Z9 59 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JUL 31 PY 2003 VL 107 IS 30 BP 5821 EP 5825 DI 10.1021/jp0342982 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 704TC UT WOS:000184355300021 ER PT J AU Oddo, S Caccamo, A Shepherd, JD Murphy, MP Golde, TE Kayed, R Metherate, R Mattson, MP Akbari, Y LaFerla, FM AF Oddo, S Caccamo, A Shepherd, JD Murphy, MP Golde, TE Kayed, R Metherate, R Mattson, MP Akbari, Y LaFerla, FM TI Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular A beta and synaptic dysfunction SO NEURON LA English DT Article ID AMYLOID PRECURSOR PROTEIN; LONG-TERM POTENTIATION; INCLUSION-BODY MYOSITIS; NEUROFIBRILLARY TANGLES; P301L TAU; MOUSE MODELS; CELL-DEATH; MICE; PRESENILIN-1; ACCUMULATION AB The neuropathological correlates of Alzheimer's disease (AD) include annyloid-beta (AD) plaques and neurofibrillary tangles. To study the interaction between AD and tau and their effect on synaptic function, we derived a triple-transgenic model (3 x Tg-AD) harboring PSM146V, APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3 x Tg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal AD with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed. C1 Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Mayo Clin Jacksonville, Dept Neurosci & Pharmacol, Jacksonville, FL 32224 USA. NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP LaFerla, FM (reprint author), Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA. RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [AG17968] NR 48 TC 1836 Z9 1897 U1 36 U2 219 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 31 PY 2003 VL 39 IS 3 BP 409 EP 421 DI 10.1016/S0896-6273(03)00434-3 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 709LC UT WOS:000184625800006 PM 12895417 ER PT J AU Xu, DS Hopf, C Reddy, R Cho, RW Guo, LP Lanahan, A Petralia, RS Wenthold, RJ O'Brien, RJ Worley, P AF Xu, DS Hopf, C Reddy, R Cho, RW Guo, LP Lanahan, A Petralia, RS Wenthold, RJ O'Brien, RJ Worley, P TI Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity SO NEURON LA English DT Article ID CULTURED SPINAL NEURONS; BINDING PROTEIN 49; HIPPOCAMPAL-NEURONS; EXCITATORY SYNAPSES; AMPA RECEPTORS; GLUTAMATE; PENTRAXIN; MATURATION; GENES; MECHANISMS AB Narp is a neuronal immediate early gene that plays a role in excitatory synaptogenesis. Here, we report that native Narp in brain is part of a pentraxin complex that includes NP1. These proteins are covalently linked by disulfide bonds into highly organized complexes, and their relative ratio in the complex is dynamically dependent upon the neuron's activity history and developmental stage. Complex formation is dependent on their distinct N-terminal coiled-coil domains, while their closely homologous C-terminal pentraxin domains mediate association with AMPA-type glutamate receptors. Narp is substantially more effective in assays of cell surface cluster formation, coclustering of AMPA receptors, and excitatory synaptogenesis, yet their combined expression results in supraadditive effects. These studies support a model in which Narp can regulate the latent synaptogenic activity of NP1 by forming mixed pentraxin assemblies. This mechanism appears to contribute to both activity-independent and activity-dependent excitatory synaptogenesis. C1 Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Worley, P (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. FU NIMH NIH HHS [KO2 MH01153]; NINDS NIH HHS [R01-NS37694, R01-NSNS39156]; PHS HHS [R01-K02 53608] NR 37 TC 115 Z9 117 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 31 PY 2003 VL 39 IS 3 BP 513 EP 528 DI 10.1016/S0896-6273(03)00463-X PG 16 WC Neurosciences SC Neurosciences & Neurology GA 709LC UT WOS:000184625800013 PM 12895424 ER PT J AU Jaskiw, GE Lipska, BK Weinberger, DR AF Jaskiw, GE Lipska, BK Weinberger, DR TI The anxiogenic beta-carboline FG-7142 inhibits locomotor exploration similarly in postweanling and adult rats SO NEUROSCIENCE LETTERS LA English DT Article DE stress; development; gamma-aminobutyric acid ID BENZODIAZEPINE RECEPTOR LIGANDS; PREFRONTAL CORTEX; GABAERGIC TRANSMISSION; SOCIAL-INTERACTION; STRESS; BRAIN; BEHAVIOR; ANXIETY; HIPPOCAMPUS; ANTAGONISTS AB The beta-carboline FG-7142 exerts many stress-like effects in the adult rat, including the inhibition of locomotor exploration. However, comparable effects in immature animals have not been reported. Stress-like effects of FG-7142 are mediated via its inverse agonist actions on gamma-aminobutyric acid (GABA) receptors. GABA systems change considerably with development and GABA agonists such as diazepam have opposite behavioral actions in immature and adult rats. Accordingly, we compared FG-7142 effects on locomotor exploration in postweanling and adult rats. Postweanling male rats (24 days) and adult rats (90 days) received a single injection of vehicle or FG-7142 (15 mg/kg i.p.) and 15 min later were placed in photocell monitors for I h. Although postweanling animals traveled a smaller distance overall than adults. FG-7142 inhibited locomotor exploration to a similar degree in both groups. We conclude that FG-7142 exerts stress-like effects in postweanling rats and may be considered for use as a model of childhood stress. (C) 2003 Published by Elsevier Science Ireland Ltd. C1 Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Jaskiw, GE (reprint author), VAMC Cleveland, GMHB, 1000 Brecksville Rd, Brecksville, OH 44141 USA. NR 30 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 31 PY 2003 VL 346 IS 1-2 BP 5 EP 8 DI 10.1016/S0304-3940(03)00384-7 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 701WP UT WOS:000184192200002 PM 12850534 ER PT J AU Porciuncula, LO Rocha, JBT Cimarosti, H Vinade, L Ghisleni, G Salbego, CG Souza, DO AF Porciuncula, LO Rocha, JBT Cimarosti, H Vinade, L Ghisleni, G Salbego, CG Souza, DO TI Neuroprotective effect of ebselen on rat hippocampal slices submitted to oxygen-glucose deprivation: correlation with immunocontent of inducible nitric oxide synthase SO NEUROSCIENCE LETTERS LA English DT Article DE ebselen; brain ischemia; nitric oxide; cellular death; oxygen-glucose deprivation ID GLUTAMATE; GLUTATHIONE; EXPRESSION; INHIBITION; ISCHEMIA; COMPOUND; NEURONS AB Ebselen is a seleno organic compound with antioxidant and anti-inflammatory properties, which is under clinical trials for the treatment of ischemic stroke. In this study, we attempted to correlate the protective effects of ebselen and the inducible nitric oxide synthase (iNOS) immunocontent in hippocampal slices submitted to oxygen-glucose deprivation (OGD), since the exacerbated production of nitric oxide by iNOS plays a role in the mechanisms of cellular death in ischemic insults. Ebselen (10 muM) protected slices from the deleterious effects of OGD (as assessed by MTT assay) only when present during all the recovery period (180 min). Moreover, ebselen added 5 and 15 min after the beginning of recovery only partially protected the slices from cellular death, while when added 30 min after the beginning of recovery no protection was observed. OGD increased the immunocontent of iNOS, and this increase was abolished also only when ebselen was present during all the recovery period. Our results indicate that the neuroprotective effect of ebselen could be related to this decrease in the iNOS immunocontent. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, BR-90035003 Porto Alegre, RS, Brazil. Univ Fed Santa Maria, CCNE, Dept Quim, BR-97105900 Santa Maria, RS, Brazil. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Porciuncula, LO (reprint author), Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, Rua Ramiro Barcelos 2600, BR-90035003 Porto Alegre, RS, Brazil. RI Ghisleni, Gabriele/D-5032-2013; Souza, Diogo/J-8894-2014; Salbego, Christianne/C-5247-2013; OI Souza, Diogo/0000-0002-4322-0404; Rocha, Joao Batista Teixeira da/0000-0003-3829-0595 NR 20 TC 42 Z9 42 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 31 PY 2003 VL 346 IS 1-2 BP 101 EP 104 DI 10.1016/S0304-3940(03)00580-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 701WP UT WOS:000184192200026 PM 12850558 ER PT J AU Marini, JC AF Marini, JC TI Do bisphosphonates make children's bones better or brittle? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NICHHD, Heritable Disorders Branch, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHHD, Heritable Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 76 Z9 80 U1 0 U2 4 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 JUL 31 PY 2003 VL 349 IS 5 BP 423 EP 426 DI 10.1056/NEJMp038103 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 706FV UT WOS:000184443700003 PM 12890840 ER PT J AU Yang, JC Haworth, L Sherry, RM Hwu, P Schwartzentruber, DJ Topalian, SL Steinberg, SM Chen, HX Rosenberg, SA AF Yang, JC Haworth, L Sherry, RM Hwu, P Schwartzentruber, DJ Topalian, SL Steinberg, SM Chen, HX Rosenberg, SA TI A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUMOR-SUPPRESSOR GENE; HYPOXIA-INDUCIBLE FACTORS; EMBRYONIC LETHALITY; ANGIOGENESIS; CARCINOMA; EXPRESSION; INHIBITION; PRODUCT; PROTEIN; THERAPY AB BACKGROUND: Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. METHODS: A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. RESULTS: Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose-antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose-antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose-antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons). CONCLUSIONS: Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, NIH, Rm 2B-37,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-32] NR 19 TC 1870 Z9 1949 U1 10 U2 73 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 JUL 31 PY 2003 VL 349 IS 5 BP 427 EP 434 DI 10.1056/NEJMoa021491 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 706FV UT WOS:000184443700004 PM 12890841 ER PT J AU Flegal, KM Williamson, DF Graubard, BI AF Flegal, KM Williamson, DF Graubard, BI TI Obesity and cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. NCI, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 3 TC 5 Z9 5 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 JUL 31 PY 2003 VL 349 IS 5 BP 502 EP 502 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 706FV UT WOS:000184443700018 PM 12892101 ER PT J AU Mulholland, NM Soeth, E Smith, CL AF Mulholland, NM Soeth, E Smith, CL TI Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation SO ONCOGENE LA English DT Article DE histone deacetylase; transcription; chromatin; mouse mammary tumor virus ID TUMOR VIRUS PROMOTER; LONG TERMINAL REPEAT; GLUCOCORTICOID-RECEPTOR; DEACETYLASE INHIBITORS; GENE-EXPRESSION; IN-VIVO; SACCHAROMYCES-CEREVISIAE; SODIUM-BUTYRATE; N-COR; ACTIVATION AB Increased histone acetylation has been associated with activated gene transcription and decreased acetylation with repression. However, there is a growing number of genes known, which are downregulated by histone deacetylase (HDAC) inhibitors through unknown mechanisms. This study examines the mechanism by which the mouse mammary tumor virus (MMTV) promoter is repressed by the HDAC inhibitor, trichostatin A (TSA). We find that this repression is transcriptional in nature and that it occurs in the presence and absence of glucocorticoids. TSA decreases MMTV transcription at a rapid rate, reaching maximum in 30-60 min. In contrast with previous reports, the repression does not correlate with an inhibition of glucocorticoid-induced nuclease hypersensitivity or NF1-binding at the MMTV promoter. Surprisingly, TSA does not induce sizable increases in histone acetylation at the MMTV promoter nor does it inhibit histone deacetylation, which accompanies deactivation of the glucocorticoid-activated MMTV promoter. Repression of MMTV transcription by TSA does not depend on the chromatin organization of the promoter because a transiently transfected MMTV promoter construct with a disorganized nucleoprotein structure was also repressed by TSA treatment. Mutational analysis of the MMTV promoter indicates that repression by TSA is mediated through the TATA box region. These results suggest a novel mechanism that involves acetylation of nonhistone proteins necessary for basal transcription. C1 NCI, Signal Transduct Grp, Lab Receptor Biol & Gene Express, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Genet, Washington, DC 20052 USA. RP Smith, CL (reprint author), NCI, Signal Transduct Grp, Lab Receptor Biol & Gene Express, Ctr Canc Res,NIH, Bldg 41,Room B608,41 Library Dr,MSC 5055, Bethesda, MD 20892 USA. NR 61 TC 43 Z9 43 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 31 PY 2003 VL 22 IS 31 BP 4807 EP 4818 DI 10.1038/sj.onc.1206722 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 704MZ UT WOS:000184344600004 PM 12894222 ER PT J AU Biesecker, LG AF Biesecker, LG TI Response to "chromosome bands and ends (revisited)" SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter C1 NHGRI, NIH, Lab Genet Res, Human Dev Unit, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Lab Genet Res, Human Dev Unit, 49 Convent Dr,Rm 4A80, Bethesda, MD 20892 USA. NR 1 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 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 30 PY 2003 VL 120A IS 3 BP 445 EP 445 DI 10.1002/ajmg.a.20155 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 698AE UT WOS:000183974800028 PM 12838574 ER PT J AU Hall, D Minton, AP AF Hall, D Minton, AP TI Macromolecular crowding: qualitative and semiquantitative successes, quantitative challenges SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Review DE macromolecular solution; excluded volume; thermodynamic nonideality ID BOVINE SERUM-ALBUMIN; THERMODYNAMIC ACTIVITY; VOLUME EXCLUSION; ALPHA-SYNUCLEIN; SURFACE-AREA; PROTEIN; CONSEQUENCES; SOLUBILITY; MOLECULES; CYTOPLASM AB The concept of excluded volume and the theory of effects of excluded volume on the equilibria and rates of macromolecular reactions in fluid media containing high total concentrations of macromolecules ('crowded' media) are summarized. Reports of experimental studies of crowding effects published during the last year are tabulated. Limitations of current excluded volume theory are discussed, and a determination is made of conditions under which this theory may and may not be validly applied. Recently suggested novel approaches to quantitative analysis of crowding phenomena, which may help to overcome some of the limitations of current theory, are summarized. Published by Elsevier B.V. C1 NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, Natl Inst Hlth,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, Natl Inst Hlth,US Dept Hlth & Human Serv, Bldg 8,Room 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov RI Hall, Damien/D-9927-2012; OI Hall, Damien/0000-0003-1538-7618; Minton, Allen/0000-0001-8459-1247 NR 40 TC 293 Z9 301 U1 1 U2 56 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD JUL 30 PY 2003 VL 1649 IS 2 BP 127 EP 139 DI 10.1016/S1570-9639(03)00167-5 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 706YZ UT WOS:000184483800003 PM 12878031 ER PT J AU Curco, D Zanuy, D Aleman, C AF Curco, D Zanuy, D Aleman, C TI EVEBAT: A fast strategy for the examination of the empty space in polymer matrices SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE EVEBAT; polymer matrices; free volume; unoccupied volume ID MOLECULAR-DYNAMICS SIMULATION; FREE-VOLUME; PENETRANT DIFFUSION; AMORPHOUS POLYMERS; GAS SOLUBILITIES; FREE-ENERGY; POLYSTYRENE; TRANSPORT; SPECTROSCOPY; POLYETHYLENE AB A very efficient strategy to evaluate the "free volume" and the "unoccupied volume" in polymer matrices is proposed. The method, which has been denoted EVEBAT (Empty Volume Evaluation Based on Atom-Types), emerges from the concept of atom type, which is the basis of a force field. Accordingly, the numerical treatment is minimized by analyzing the atom types used to describe the polymer matrix, which are always a few, rather than all the explicit, atoms involved in it. The performance of the new method has been pointed out by a detailed comparison with the classical insertion algorithms. (C) 2003 Wiley Periodicals, Inc. C1 Univ Politecn Catalunya, Dept Engn Quim, ETS Engn Ind Barcelon, E-08028 Barcelona, Spain. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Curco, D (reprint author), Univ Politecn Catalunya, Dept Engn Quim, ETS Engn Ind Barcelon, Diagonal 647, E-08028 Barcelona, Spain. RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 NR 31 TC 6 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JUL 30 PY 2003 VL 24 IS 10 BP 1208 EP 1214 DI 10.1002/jcc.10254 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 695CF UT WOS:000183813000006 PM 12820128 ER PT J AU Ivanic, J Ruedenberg, K AF Ivanic, J Ruedenberg, K TI A MCSCF method for ground and excited states based on full optimizations of successive Jacobi rotations SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE electronic structure theory; variation principle orbital optimization; Jacobi-rotation based minimization; multi-configuration self-consistent field method (MCSCF) ID GENERALIZED BRILLOUIN THEOREM; MULTICONFIGURATION WAVEFUNCTIONS; ORBITAL OPTIMIZATION; WAVE-FUNCTIONS; MATRIX; SCF; CL AB A new multiconfigurational self-consistent field (MCSCF) method based on successive optimizations of Jacobi rotation angles is presented. For given one- and two-particle density matrices and an initial set of corresponding integrals, a technique is developed for the determination of a Jacobi angle for the mixing of two orbitals, such that the exact energy, written as a function of the angle, is fully minimized. Determination of the energy-minimizing orbitals for given density matrices is accomplished by successive optimization and updating of Jacobi angles and integrals. The total MCSCF energy is minimized by alternating between CI and orbital optimization steps. Efficiency is realized by optimizing CI and orbital vectors quasi-simultaneously by not fully optimizing each in each improvement step. On the basis of the Jacobi-rotation based approach, a novel MCSCF procedure is formulated for excited states, which avoids certain shortcomings of traditional excited-state MCSCF methods. Applications to specific systems show the practicability of the developed methods. (C) 2003 Wiley Periodicals, Inc. C1 Iowa State Univ Sci & Technol, Dept Chem, Ames, IA 50011 USA. US DOE, Ames Lab, Ames, IA 50011 USA. RP Ivanic, J (reprint author), NCI, Canc Res & Dev Ctr, POB B, Frederick, MD 21792 USA. NR 38 TC 12 Z9 12 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JUL 30 PY 2003 VL 24 IS 10 BP 1250 EP 1262 DI 10.1002/jcc.10291 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 695CF UT WOS:000183813000011 PM 12820133 ER PT J AU Hariri, AR Goldberg, TE Mattay, VS Kolachana, BS Callicott, JH Egan, MF Weinberger, DR AF Hariri, AR Goldberg, TE Mattay, VS Kolachana, BS Callicott, JH Egan, MF Weinberger, DR TI Brain-derived neurotrophic factor val(66)met polymorphism affects human memory-related hippocampal activity and predicts memory performance SO JOURNAL OF NEUROSCIENCE LA English DT Article DE BDNF; hippocampus; human memory; gene; polymorphism; BOLD fMRI ID MEDIAL TEMPORAL-LOBE; ALZHEIMERS-DISEASE; RISK; RETRIEVAL; AMYGDALA; BDNF; MRI AB BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val (66)met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val (66)met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val (66)met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA. RI Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 24 TC 627 Z9 641 U1 2 U2 34 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 JUL 30 PY 2003 VL 23 IS 17 BP 6690 EP 6694 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 706RW UT WOS:000184469200003 PM 12890761 ER PT J AU Tao, YX Rumbaugh, G Wang, GD Petralia, RS Zhao, CS Kauer, FW Tao, F Zhuo, M Wenthold, RJ Raja, SN Huganir, RL Bredt, DS Johns, RA AF Tao, YX Rumbaugh, G Wang, GD Petralia, RS Zhao, CS Kauer, FW Tao, F Zhuo, M Wenthold, RJ Raja, SN Huganir, RL Bredt, DS Johns, RA TI Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein SO JOURNAL OF NEUROSCIENCE LA English DT Article DE PSD-93; NMDA receptors; surface expression; persistent pain; spinal cord; forebrain ID TUMOR-SUPPRESSOR PROTEIN; PARALLEL FIBER SYNAPSES; MOUSE CORTICAL-NEURONS; EXCITATORY SYNAPSES; AMPA RECEPTORS; SPINAL-CORD; SYNAPTIC TRANSMISSION; UP-REGULATION; THERMAL HYPERALGESIA; GLUTAMATE RECEPTORS AB Modification of synaptic NMDA receptor( NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain. C1 Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Neurosci, Baltimore, MD 21205 USA. Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. RP Tao, YX (reprint author), Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, 355 Ross,720 Rutland Ave, Baltimore, MD 21205 USA. RI Zhuo, Min/A-2072-2008; Tao, Feng/Q-7827-2016; OI Zhuo, Min/0000-0001-9062-3241; Tao, Feng/0000-0002-0623-6298; Yang, Shuman/0000-0002-9638-0890 FU NIGMS NIH HHS [R01 GM 49111]; NINDS NIH HHS [NS 44219, NS360017]; PHS HHS [38680, 10833] NR 66 TC 82 Z9 90 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 30 PY 2003 VL 23 IS 17 BP 6703 EP 6712 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 706RW UT WOS:000184469200005 PM 12890763 ER PT J AU Li, SH Yu, ZX Li, CL Nguyen, HP Zhou, YX Deng, CX Li, XJ AF Li, SH Yu, ZX Li, CL Nguyen, HP Zhou, YX Deng, CX Li, XJ TI Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington's disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE hypothalamus; degeneration; EGFR; Huntington; polyglutamine; huntingtin ID GROWTH-FACTOR RECEPTOR; LATERAL TUBERAL NUCLEUS; MUTANT HUNTINGTIN; INTRANUCLEAR INCLUSIONS; GENE-EXPRESSION; EGF RECEPTOR; MICE LACKING; BODY-WEIGHT; MOUSE MODEL; PC12 CELLS AB Huntington's disease (HD) is caused by a polyglutamine expansion in the disease protein huntingtin. The polyglutamine expansion causes huntingtin to interact abnormally with a number of proteins. However, it is unclear whether, and how, huntingtin-associated proteins are involved in the neurodegeneration in HD. Here, we show that huntingtin-associated protein-1 (HAP1), which is involved in intracellular trafficking of epidermal growth factor receptor ( EGFR), is highly expressed in the hypothalamus. Mice lacking HAP1 die after birth because of depressed feeding activity. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and electron microscopic examination revealed the degeneration in hypothalamic regions that control feeding behavior. Hypothalamic degeneration was also observed in HD transgenic mice that have a significant loss of body weight. Inhibition of HAP1 expression decreases EGFR signaling and cell viability, whereas overexpression of HAP1 enhances this signaling activity and inhibits mutant huntingtin-mediated cytotoxicity. These results suggest that the effect of mutant huntingtin on HAP1 and EGFR signaling may contribute to the hypothalamic neurodegeneration and loss of body weight in HD. C1 Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Li, XJ (reprint author), Emory Univ, Sch Med, Dept Human Genet, 615 Michael St, Atlanta, GA 30322 USA. RI Nguyen, Huu Phuc/F-5390-2015; deng, chuxia/N-6713-2016 OI Nguyen, Huu Phuc/0000-0001-6139-788X; FU NIA NIH HHS [AG19206]; NINDS NIH HHS [NS36232] NR 50 TC 84 Z9 89 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 30 PY 2003 VL 23 IS 17 BP 6956 EP 6964 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 706RW UT WOS:000184469200032 PM 12890790 ER PT J AU Ulmer, TS Ramirez, BE Delaglio, F Bax, A AF Ulmer, TS Ramirez, BE Delaglio, F Bax, A TI Evaluation of backbone proton positions and dynamics in a small protein by liquid crystal NMR spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; HIGH-RESOLUTION NMR; MODEL-FREE APPROACH; BIOLOGICAL MACROMOLECULES; MOLECULAR ALIGNMENT; POLYPEPTIDE BACKBONE; POLYACRYLAMIDE GELS; CHEMICAL-SHIFTS; PEPTIDE ANALOGS; MAGNETIC-FIELD AB NMR measurements of a large set of protein backbone one-bond dipolar couplings have been carried out to refine the structure of the third IgG-binding domain of Protein G (GB3), previously solved by X-ray crystallography at a resolution of 1.1 Angstrom. Besides the commonly used bicelle, poly(ethylene glycol), and filamentous phage liquid crystalline media, dipolar couplings were also measured when the protein was aligned inside either positively or negatively charged stretched acrylamide gels. Refinement of the GB3 crystal structure against the C-13(alpha)-C-13' and C-13'-N-15 dipolar couplings improves the agreement between experimental and predicted N-15-H-1(N) as well as C-13(alpha)-H-1(alpha) dipolar couplings. Evaluation of the peptide bond N-H orientations shows a weak anticorrelation between the deviation of the peptide bond torsion angle omega from 180degrees and the angle between the N-H vector and the C'-N-C-alpha, plane. The slope of this correlation is -1, indicating that, on average, pyramidalization of the peptide N contributes to small deviations from peptide bond planarity ( = 179.3 +/- 3.1degrees) to the same degree as true twisting around the C'-N bond. Although hydrogens are commonly built onto crystal structures assuming the N-H vector orientation falls on the line bisecting the C'-N-C-alpha, angle, a better approximation adjusts the C-alpha-C'-N-H torsion angle to -2degrees. The N-15-H-1(N) dipolar data do not contradict the commonly accepted motional model where angular fluctuations of the N-H bond orthogonal to the peptide plane are larger than in-plane motions, but the amplitude of angular fluctuations orthogonal the C-i-1(alpha)-N-i-C-i(alpha) plane exceeds that of in-plane motions by at most 10-15degrees. Dipolar coupling analysis indicates that for most of the GB3 backbone, the amide order parameters, S, are highly homogeneous and vary by less than +/-7%. Evaluation of the H-alpha proton positions indicates that the average C-alpha-H-alpha vector orientation deviates by less than 1degrees from the direction that makes ideal tetrahedral angles with the C-alpha-C-beta and C-alpha-N vectors. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 66 TC 210 Z9 210 U1 1 U2 24 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 JUL 30 PY 2003 VL 125 IS 30 BP 9179 EP 9191 DI 10.1021/ja0350684 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 704WT UT WOS:000184364500051 PM 15369375 ER PT J AU Cabib, E Schmidt, M AF Cabib, E Schmidt, M TI Chitin synthase III activity, but not the chitin ring, is required for remedial septa formation in budding yeast SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE chitin; septation; chitin synthases; Saccharomyces cerevisiae ID CELL-WALL; SACCHAROMYCES-CEREVISIAE; MORPHOGENESIS; ARCHITECTURE; INTEGRITY; LINKAGE AB Chitin is a minor but essential component of the Saccharomyces cerevisiae cell wall. In wild-type, chitin synthase II is required for the formation of primary septa and chitin synthase III (CSIII) is not essential. However, in chs2 mutants CSIII becomes essential for the formation of aberrant septa. We examined which of two CSIII functions, the formation of a chitin ring at bud emergence or of chitin in the remedial septa, was required for viability. By using cell cycle synchronization in combination with nikkomycin Z, a specific inhibitor of CSIII, we inhibited chitin synthesis in a chs2 mutant, during formation of either the ring or the remedial septa. The results show that only synthesis of the chitin during aberrant septa formation is essential for viability. Thus, the unique function of the chitin ring seems to be maintenance of the integrity of the mother-bud neck, as we recently found, and the importance of chitin in septum closure, both in normal and abnormal situations, is underlined. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIDDKD, Lab Biochem & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Univ Salamanca, CSIC, Dept Genet & Microbiol, Inst Microbiol Bioquim, Campus Miguel De Unamuno,Edif Departamental, E-37007 Salamanca, Spain. EM enricoc@usal.es NR 17 TC 26 Z9 26 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD JUL 29 PY 2003 VL 224 IS 2 BP 299 EP 305 DI 10.1016/S0378-1097(03)00477-4 PG 7 WC Microbiology SC Microbiology GA 708LW UT WOS:000184569700020 PM 12892896 ER PT J AU Baker, CJ Rench, MA McInnes, P AF Baker, CJ Rench, MA McInnes, P TI Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine SO VACCINE LA English DT Article; Proceedings Paper CT International Symposium on Protection of Newborns through Maternal Immunization CY DEC 08-11, 2002 CL VEYRIER DU LAC, FRANCE SP Fdn Merieux, WHO DE group B streptococcal (GBS) infections; immunization; conjugate vaccine; pregnancy ID IMMUNOGENICITY; ANTIBODY; DISEASE AB Aim: To determine the safety and inummogenicity of group B streptococcal (GBS) type III CPS-TT conjugate vaccine in pregnant women. Methods: Prospective, randomized (2: 1, vaccine:placebo), double-blind, placebo-controlled trial in women at 30-32 weeks' gestation and their infants. Immune responses were measured with IgG-specific ELISA assays; killing of III GBS by 1 - and 2-month infant sera was assessed by opsonophagocytosis. Results: Immunization was well-tolerated; maternal and infant outcomes were similar in vaccine and placebo groups. III-TT conjugate elicited good levels of IgG to III CPS that were functionally active against type III GBS through age 2 months. Conclusion: Maternal immunization with GBS CPS-TT conjugates could prevent maternal, neonatal and young infant GBS disease. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol Virol, Houston, TX 77030 USA. Baylor Coll Med, Dept Microbiol, Houston, TX 77030 USA. Natl Inst Allergy & Immunol, NIH, Bethesda, MD USA. RP Baker, CJ (reprint author), Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. FU NIAID NIH HHS [N01 AI-65316] NR 13 TC 76 Z9 79 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 JUL 28 PY 2003 VL 21 IS 24 BP 3468 EP 3472 DI 10.1016/S0264-410X(03)00353-0 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 705NZ UT WOS:000184402300026 PM 12850362 ER PT J AU Ioannidis, JPA Contopoulos-Ioannidis, DG Rosenberg, PS Goedert, JJ De Rossi, A Espanol, T Frenkel, L Mayaux, MJ Newell, ML Pahwa, SG Rousseau, C Scarlatti, G Sei, S Sen, L O'Brien, TR AF Ioannidis, JPA Contopoulos-Ioannidis, DG Rosenberg, PS Goedert, JJ De Rossi, A Espanol, T Frenkel, L Mayaux, MJ Newell, ML Pahwa, SG Rousseau, C Scarlatti, G Sei, S Sen, L O'Brien, TR CA HIV Host Genetics Int Meta Anal TI Effects of CCR5-Delta 32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis SO AIDS LA English DT Article DE CCR5-Delta 32; CCR2-64I; death; disease progression; HIV-1; perinatal transmission ID INDIVIDUAL-PATIENT DATA; PEDIATRIC HIV-1 INFECTION; CHEMOKINE GENE VARIANT; CORECEPTOR USAGE; VIRAL PHENOTYPE; CCR5; TRANSMISSION; POLYMORPHISMS; RISK; PATHOGENESIS AB Objective: Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-Delta32 and CCR2-641 in an international meta-analysis. Methods: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. Results: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-Delta32 and CCR2-641 showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (0) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-Delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P = 0.01 for the time-dependent model). For CCR2-641, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P < 0.01 for the time-dependent model). CCR5-Delta32 and CCR2-641 offered no clear protection after clinical AIDS had developed. Conclusion: The CCR5-Delta32 and CCR2-641 alelles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life. (C) 2003 Lippincott Williams Wilkins. C1 Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. Univ Ioannina, Dept Pediat, Sch Med, GR-45110 Ioannina, Greece. Fdn Res & Technol Hellas, Inst Biomed Res, Ioannina, Greece. Tufts Univ, New England Med Ctr, Dept Med, Boston, MA 02111 USA. George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. Univ Padua, AIDS Reference Ctr, Oncol Sect, Dept Oncol & Surg Sci, I-35100 Padua, Italy. Hosp Gen Valle Hebron, Immunol Unit, Barcelona, Spain. Univ Washington, Sch Med, Childrens Hosp & Reg Med Ctr, Div Pediat Infect Dis,Dept Pediat, Seattle, WA 98195 USA. INSERM, Paris, France. UCL, Inst Child Hlth, Ctr Paediat Epidemiol, London WC1E 6BT, England. NYU, Sch Med, N Shore Univ Hosp, Div Immunol,Dept Pediat, Manhasset, NY USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. DIBIT San Raffaele Sci Inst, Viral Evolut & Transmiss Unit, Milan, Italy. NCI, HIV Clin Interface Lab, NIH, Frederick, MD 21701 USA. Hosp Pediat JP Garrahan, Lab Biol Celular & Retrovirus, Buenos Aires, DF, Argentina. RP Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. EM jioannid@cc.uoi.gr RI Ioannidis, John/G-9836-2011; De Rossi, Anita/L-3128-2015 OI De Rossi, Anita/0000-0001-6435-7509 NR 39 TC 37 Z9 40 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 25 PY 2003 VL 17 IS 11 BP 1631 EP 1638 DI 10.1097/01.aids.0000060411.18106.0f PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 710BW UT WOS:000184661800007 PM 12853745 ER PT J AU Cejtin, HE Lisa, JB Springer, C Watts, DH Levine, A Greenblatt, R Anastos, K Minkoff, HL Massad, LS Schmidt, JB AF Cejtin, HE Lisa, JB Springer, C Watts, DH Levine, A Greenblatt, R Anastos, K Minkoff, HL Massad, LS Schmidt, JB TI Effect of hormonal contraceptive use on plasma HIV-1-RNA levels among HIV-infected women SO AIDS LA English DT Article ID PREGNANCY; TRANSMISSION; PROGESTERONE; PROGRESSION AB We compared the HIV-1-RNA and CD4 lymphocyte counts from users and non-users of hormonal contraception cross-sectionally upon entry into the Women's Interagency HIV Study, and again longitudinally. There did not appear to be an association between hormonal contraception use and HIV-1-RNA levels in our study. There was a small increase in CD4 cell counts among hormonal users of doubtful clinical significance. C1 Cook Cty Hosp, Dept Obstet & Gynecol, Chicago, IL 60612 USA. Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. Univ So Calif, Div Hematol, Los Angeles, CA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Lincoln Med & Mental Hlth Ctr, Bronx, NY 10451 USA. Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. RP Cejtin, HE (reprint author), Cook Cty Hosp, Dept Obstet & Gynecol, Chicago, IL 60612 USA. FU NICHD NIH HHS [U01-HD-32632]; PHS HHS [U01-A1-35004, U01-A1-42590, U01-A1-34994, U01-A1-34933, U01-A1-31834] NR 16 TC 23 Z9 24 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 25 PY 2003 VL 17 IS 11 BP 1702 EP 1704 DI 10.1097/01.aids.0000076297.76477.fe PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 710BW UT WOS:000184661800019 PM 12853757 ER PT J AU Nagiec, MM Young, CL Zaworski, PG Kobayashi, SD AF Nagiec, MM Young, CL Zaworski, PG Kobayashi, SD TI Yeast sphingolipid bypass mutants as indicators of antifungal agents selectively targeting sphingolipid synthesis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE sphingolipid synthesis; antifungals; myriocin; aureobasidin A; IPC synthase ID INOSITOL PHOSPHORYLCERAMIDE SYNTHASE; SACCHAROMYCES-CEREVISIAE; AUREOBASIDIN-A; STRAINS; ACYLTRANSFERASE; AUSTRALIFUNGIN; KHAFREFUNGIN; INHIBITORS; RUSTMICIN; LAC1P AB Standard methods for evaluating the target specificity of antimicrobial agents often involve the use of microorganisms with altered expression of selected targets and thus either more resistant or more susceptible to target specific inhibitors. In this study we present an alternative approach that utilizes physiological bypass mutants. The Saccharomyces cerevisiae sphingolipid bypass mutant strain AGD is able to grow without making sphingolipids and importantly, tolerates loss-of-function mutations in the otherwise essential genes for both serine palmitoyltransferase (SPT) and inositol phosphorylceramide (IPC) synthase. We found that strain AGD was > 1000-fold more resistant than the wild-type strain to selective inhibitors of SPT and IPC synthase. In contrast, strain AGD. which due to abnormal composition of the plasma membrane is sensitive to a variety of environmental stresses, was more susceptible than the wild-type to amphotericin 13, voriconazole, and to cycloheximide. We show that in a simple growth assay the AGD strain is an appropriate and useful indicator for inhibitors of IPC synthase, a selective antifungal target. (C) 2003 Elsevier Inc. All rights reserved. C1 Pharmacia & Upjohn Inc, Kalamazoo, MI 49001 USA. RP Nagiec, MM (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Kalamazoo, MI 49001 USA. NR 19 TC 9 Z9 9 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 25 PY 2003 VL 307 IS 2 BP 369 EP 374 DI 10.1016/S0006-291X(03)01164-1 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 702TP UT WOS:000184240300025 PM 12859966 ER PT J AU Choe, H Li, WH Wright, PL Vasilieva, N Venturi, M Huang, CC Grundner, C Dorfman, T Zwick, MB Wang, LP Rosenberg, ES Kwong, PD Burton, DR Robinson, JE Sodroski, JG Farzan, M AF Choe, H Li, WH Wright, PL Vasilieva, N Venturi, M Huang, CC Grundner, C Dorfman, T Zwick, MB Wang, LP Rosenberg, ES Kwong, PD Burton, DR Robinson, JE Sodroski, JG Farzan, M TI Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120 SO CELL LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; AMINO-TERMINAL DOMAIN; ENVELOPE GLYCOPROTEIN; CHEMOKINE RECEPTORS; CORECEPTOR USAGE; DISTINCT CCR5; N-TERMINUS; ENTRY; NEUTRALIZATION AB Sulfated tyrosines at the amino terminus of the principal HIV-1 coreceptor CCR5 play a critical role in its ability to bind the HIV-1 envelope glycoprotein gp120 and mediate HIV-1 infection. Here, we show that a number of human antibodies directed against gp120 are tyrosine sulfated at their antigen binding sites. Like that of CCR5, antibody association with gp120 is dependent on sulfate moieties, enhanced by CD4, and inhibited by sulfated CCR5-derived peptides. Most of these antibodies preferentially associate with gp120 molecules of CCR5-utilizing (R5) isolates and neutralize primary R5 isolates more efficiently than laboratory-adapted isolates. These studies identify a distinct subset of CD4-induced HIV-1 neutralizing antibodies that closely emulate CCR5 and demonstrate that tyrosine sulfation can contribute to the potency and diversity of the human humoral response. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Microbiol & Mol Genet,Div AIDS, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol,Div AIDS, Boston, MA 02115 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70012 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Farzan, M (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Microbiol & Mol Genet,Div AIDS, Boston, MA 02115 USA. OI Li, Wenhui/0000-0003-1305-7404 FU NIAID NIH HHS [R01 AI043891] NR 55 TC 126 Z9 129 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 25 PY 2003 VL 114 IS 2 BP 161 EP 170 DI 10.1016/S0092-8674(03)00508-7 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 705CN UT WOS:000184378700006 PM 12887918 ER PT J AU Seo, DW Li, HM Guedez, L Wingfield, PT Diaz, T Salloum, R Wei, BY Stetler-Stevenson, WG AF Seo, DW Li, HM Guedez, L Wingfield, PT Diaz, T Salloum, R Wei, BY Stetler-Stevenson, WG TI TIMP-2 mediated inhibition of angiogenesis: An MMP-independent mechanism SO CELL LA English DT Article ID ENDOTHELIAL-CELL PROLIFERATION; PROTEIN-TYROSINE-PHOSPHATASE; TISSUE INHIBITOR; METALLOPROTEINASE INHIBITORS; TUMOR-GROWTH; ACTIVATION; CANCER; GENE; ALPHA-3-BETA-1; INVASION AB Tissue inhibitors of metalloproteinases (TIMPs) suppress matrix metalloproteinase (MMP) activity critical for extracellular matrix turnover associated with both physiologic and pathologic tissue remodeling. We demonstrate here that TIMP-2 abrogates angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects require alpha3beta1 integrin-mediated binding of TIMP-2 to endothelial cells. Further,TIMP-2 induces a decrease in total protein tyrosine phosphatase (PTP) activity associated with beta1 integrin subunits as well as dissociation of the phosphatase SHP-1 from beta1. TIMP-2 treatment also results in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. Our findings establish an unexpected, MMP-independent mechanism for TIMP-2 inhibition of endothelial cell proliferation in vitro and reveal an important component of the antiangiogenic effect of TIMP2 in vivo. C1 NCI, Canc Res Ctr, Vasc Biol Fac, Extracellular Matrix Pathol Sect, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Pathol Lab, Extracellular Matrix Pathol Sect, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Canc Res Ctr, Vasc Biol Fac, Extracellular Matrix Pathol Sect, Bethesda, MD 20892 USA. RI Guedez, Liliana/H-4951-2012; Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Seo, Dong-Wan/0000-0003-4971-834X NR 39 TC 313 Z9 328 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 25 PY 2003 VL 114 IS 2 BP 171 EP 180 DI 10.1016/S0092-8674(03)00551-8 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 705CN UT WOS:000184378700007 PM 12887919 ER PT J AU Xu, JS Wang, F Van Keymeulen, A Herzmark, P Straight, A Kelly, K Takuwa, Y Sugimoto, N Mitchison, T Bourne, HR AF Xu, JS Wang, F Van Keymeulen, A Herzmark, P Straight, A Kelly, K Takuwa, Y Sugimoto, N Mitchison, T Bourne, HR TI Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils SO CELL LA English DT Article ID BIOLOGICAL PATTERN FORMATION; BINDING PROTEIN-RHO; CELL POLARITY; LYSOPHOSPHATIDIC ACID; FOCAL ADHESIONS; CULTURED-CELLS; DISTINCT ROLES; LEADING-EDGE; P115 RHOGEF; CHEMOTAXIS AB Like neutrophilic leukocytes, differentiated HL-60 cells respond to chemoattractant by adopting a polarized morphology, with F-actin in a protruding pseudopod at the leading edge and contractile actin-myosin complexes at the back and sides. Experiments with pharmacological inhibitors, toxins, and mutant proteins show that this polarity depends on divergent, opposing "frontness" and "backness" signals generated by different receptor-activated trimeric G proteins. Frontness depends upon Gi-mediated production of X-phosphoinositol lipids (PI3Ps), the activated form of Rac, a small GTPase, and F-actin. G12 and G13 trigger backness signals, including activation of a second GTPase (Rho), a Rho-dependent kinase, and myosin If. Functional incompatibility causes the two resulting actin assemblies to aggregate into separate domains, making the leading edge more sensitive to attractant than the back. The latter effect explains both the neutrophil's ability to polarize in uniform concentrations of chemoattractant and its response to reversal of an attractant gradient by performing a U-turn. C1 Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Free Univ Brussels, Inst Rech Interdisciplinaire Biol Humaine & Mol, B-1070 Brussels, Belgium. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. NCI, Ctr Canc Res, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Kanazawa Univ, Dept Physiol, Kanazawa, Ishikawa 9208640, Japan. RP Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM bourne@cmp.ucsf.edu RI Wang, Fei/A-7968-2013; Sugimoto, Naotoshi/C-4739-2015; OI Sugimoto, Naotoshi/0000-0003-1995-5002; Straight, Aaron/0000-0001-5885-7881 FU NHLBI NIH HHS [HL07713]; NIGMS NIH HHS [GM 27810] NR 67 TC 469 Z9 476 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 25 PY 2003 VL 114 IS 2 BP 201 EP 214 DI 10.1016/S0092-8674(03)00555-5 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 705CN UT WOS:000184378700010 PM 12887922 ER PT J AU Wang, F Kovacs, M Hu, AH Limouze, J Harvey, EV Sellers, JR AF Wang, F Kovacs, M Hu, AH Limouze, J Harvey, EV Sellers, JR TI Kinetic mechanism of non-muscle myosin IIB - Functional adaptations for tension generation and maintenance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE MYOSIN; ACTOMYOSIN SUBFRAGMENT-1; SKELETAL-MUSCLE; MOTOR DOMAIN; FLUORESCENT-PROBE; SINGLE TRYPTOPHAN; HEAVY-CHAINS; I ATPASE; ACTIN; ADP AB Besides driving contraction of various types of muscle tissue, conventional (class II) myosins serve essential cellular functions and are ubiquitously expressed in eukaryotic cells. Three different isoforms in the human myosin complement have been identified as non-muscle class II myosins. Here we report the kinetic characterization of a human non-muscle myosin IIB subfragment-1 construct produced in the baculovirus expression system. Transient kinetic data show that most steps of the actomyosin ATPase cycle are slowed down compared with other class II myosins. The ADP affinity of subfragment-1 is unusually high even in the presence of actin filaments, and the rate of ADP release is close to the steady-state ATPase rate. Thus, non-muscle myosin IIB subfragment-1 spends a significantly higher proportion of its kinetic cycle strongly attached to actin than do the muscle myosins. This feature is even more pronounced at slightly elevated ADP levels, and it may be important in carrying out the cellular functions of this isoform working in small filamentous assemblies. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Rm 8N202, Bethesda, MD 20892 USA. RI Kovacs, Mihaly/A-6841-2011 NR 42 TC 137 Z9 139 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 JUL 25 PY 2003 VL 278 IS 30 BP 27439 EP 27448 DI 10.1074/jbc.M302510200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702UL UT WOS:000184242700015 PM 12704189 ER PT J AU Sheng, Y Tsai-Morris, CH Dufau, ML AF Sheng, Y Tsai-Morris, CH Dufau, ML TI Cell-specific and hormone-regulated expression of gonadotropinregulated testicular RNA helicase gene (GRTH/Ddx25) resulting from alternative utilization of translation initiation codons in the rat testis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MALE GERM-CELLS; MESSENGER-RNA; LEYDIG-CELLS; PROTEIN; SPERMATOGENESIS; BINDING; FAMILY; VASA AB Gonadotropin-regulated testicular RNA helicase (GRTH) is a novel DEAD-box protein with ATPase and RNA helicase activities. GRTH gene transcription is stimulated by human chorionic gonadotropin (hCG) via cyclic AMP-induced androgen formation in testicular Leydig cells. In this study, immunocytochemical and Western analyses identified GRTH as a developmentally regulated protein in Leydig cells and in germ cells (pachytene spermatocytes and round spermatids) of the rat testis. Three ATGs with the potential for generation of multiple protein species were identified. Germ cells primarily utilized the 1st ATG codon (+1) and contained major proteins of 61/56 kDa, whereas Leydig cells utilized preferentially the 2nd ATG codon (+343) with expression of 48/43 kDa species. A 3rd ATG was weakly utilized and yielded a 33-kDa protein only in germ cells. The increase in GRTH 43-kDa protein in Leydig cells caused by hCG treatment was prevented by the androgen receptor antagonist, flutamide. In round spermatids, hCG caused a significant decrease of 61 kDa species and an induction 48/43 kDa species, whereas no changes were observed in pachytene spermatocytes. Reversal of this hormone-induced switch of expression by flutamide indicated a role of androgen in utilization of the 2nd ATG. These studies have demonstrated a cell-specific and hormone-dependent alternative usage of ATG codons in the testis. They have also revealed that the androgen-dependent transcription of GRTH expression in Leydig cells is accompanied by a marked increase of 43-kDa species. The findings indicate that expression of GRTH proteins is regulated by gonadotropin/androgen at the translational level. C1 NICHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. NR 22 TC 28 Z9 29 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 JUL 25 PY 2003 VL 278 IS 30 BP 27796 EP 27803 DI 10.1074/jbc.M302411200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702UL UT WOS:000184242700060 PM 12734186 ER PT J AU Vos, MD Ellis, CA Elam, C Ulku, AS Taylor, BJ Clark, GJ AF Vos, MD Ellis, CA Elam, C Ulku, AS Taylor, BJ Clark, GJ TI RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL TRANSFORMATION; APOPTOSIS; GENE; ACCUMULATION; PATHWAYS; PROTEIN; MOUSE; LUNG AB Ras proteins regulate a wide range of biological processes by interacting with a broad assortment of effector proteins. Although activated forms of Ras are frequently associated with oncogenesis, they may also provoke growth-antagonistic effects. These include senescence, cell cycle arrest, differentiation, and apoptosis. The mechanisms that underlie these growth-inhibitory activities are relatively poorly understood. Recently, two related novel Ras effectors, NORE1 and RASSF1, have been identified as mediators of apoptosis and cell cycle arrest. Both of these proteins exhibit many of the properties normally associated with tumor suppressors. We now identify a novel third member of this family, designated RASSF2. RASSF2 binds directly to K-Ras in a GTP-dependent manner via the Ras effector domain. However, RASSF2 only weakly interacts with H-Ras. Moreover, RASSF2 promotes apoptosis and cell cycle arrest and is frequently down-regulated in lung tumor cell lines. Thus, we identify RASSF2 as a new member of the RASSF1 family of Ras effectors/tumor suppressors that exhibits a specificity for interacting with K-Ras. C1 NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Clark, GJ (reprint author), NCI, Dept Cell & Canc Biol, NIH, 9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 30 TC 114 Z9 122 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 JUL 25 PY 2003 VL 278 IS 30 BP 28045 EP 28051 DI 10.1074/jbc.M300554200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702UL UT WOS:000184242700090 PM 12732644 ER PT J AU Voloshin, ON Vanevski, F Khil, PP Camerini-Otero, RD AF Voloshin, ON Vanevski, F Khil, PP Camerini-Otero, RD TI Characterization of the DNA damage-inducible helicase DinG from Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; SINGLE-STRANDED-DNA; RNA HELICASE; SACCHAROMYCES-CEREVISIAE; XERODERMA-PIGMENTOSUM; HOMOLOGOUS RECOMBINATION; DEPENDENT ATPASE; COUPLING FACTOR; LEXA REPRESSOR; GENE ENCODES AB The dinG promoter was first isolated in a genetic screen scoring for damage-inducible loci in Escherichia coli (Lewis, L. K., Jenkins, M. E., and Mount, D. W. (1992) J. Bacteriol. 174, 3377-3385). Sequence analysis suggests that the dinG gene encodes a putative helicase related to a group of eukaryotic helicases that includes mammalian XPD (Koonin, E. V. (1993) Nucleic Acids Res. 21, 1497), an enzyme involved in transcription-coupled nucleotide excision repair and basal transcription. We have characterized the dinG gene product from E. coli using genetic and biochemical approaches. Deletion of dinG has no severe phenotype, indicating that it is nonessential for cell viability. Both dinG deletion and overexpression of the DinG protein from a multicopy plasmid result in a slight reduction of UV resistance. DinG, purified as a fusion protein from E. coli cells, behaves as a monomer in solution, as judged from gel filtration experiments. DinG is an ATP-hydrolyzing enzyme; single-stranded (ss) DNA stimulates the ATPase activity 15-fold. Kinetic data yield a Hill coefficient of 1, consistent with one ATP-hydrolyzing site per DinG molecule. DinG possesses a DNA helicase activity; it translocates along ssDNA in a 5' --> 3' direction, as revealed in experiments with substrates containing non-natural 5'-5' and 3'-3' linkages. The ATP-dependent DNA helicase activity of DinG requires divalent cations (Mg2+, Ca2+, and Mn2+) but is not observed in the presence of Zn2+. The DinG helicase does not discriminate between ribonucleotide and deoxyribonucleotide triphosphates, and it unwinds duplex DNA with similar efficiency in the presence of ATP or dATP. We discuss the possible involvement of the DinG helicase in DNA replication and repair processes. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), Bldg 5,Rm 205A,5 Mem Dr,MSC 0538, Bethesda, MD 20892 USA. OI Khil, Pavel/0000-0002-4903-8777 NR 52 TC 44 Z9 46 U1 2 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 JUL 25 PY 2003 VL 278 IS 30 BP 28284 EP 28293 DI 10.1074/jbc.M301188200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702UL UT WOS:000184242700119 PM 12748189 ER PT J AU Wilson, DM AF Wilson, DM TI Properties of and substrate determinants for the exonuclease activity of human apurinic endonuclease Ape1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ape1; abasic (AP) endonuclease; proofreading exonuclease; mismatch DNA; polymerase beta ID BASE EXCISION-REPAIR; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; TYROSYL-DNA PHOSPHODIESTERASE; HUMAN ABASIC ENDONUCLEASE; WERNER-SYNDROME PROTEIN; TOPOISOMERASE-I; MAJOR HUMAN; COVALENT COMPLEXES; IONIZING-RADIATION; SITE RECOGNITION AB Ape1 is the major human abasic endonuclease, initiating repair of this common DNA lesion by incising the phosphodiester backbone 5' to the damage site. This enzyme also functions in specific contexts to excise 3'-blocking termini, e.g. phosphate and phosphoglycolate residues, from DNA. Recently, the comparatively "minor" 3' to 5' exonuclease activity of Ape1 was found to contribute to the excision of certain 3'-mismatched nucleotides. In this study, I characterize more thoroughly the 3'-nuclease properties of Ape1 and define the effects of specific DNA determinants on this function. Data within shows that Ape1 is a non- or poorly processive exonuclease, which degrades one nucleotide gap, 3'-recessed, and nicked DNAs, but exhibits no detectable activity on blunt end or single-stranded DNA. A 5'-phosphate, compared to a 5'-hydroxyl group, reduced Ape1 degradation activity roughly tenfold, suggesting that the biological impact of certain DNA single strand breaks may be influenced by the terminal chemistry. In the context of a base excision repair-like DNA intermediate, a 5'-abasic residue exerted an about tenfold attenuation on the 3' to 5' exonuclease efficiency of Ape1. A 3'-phosphate group had little impact on Ape1 exonuclease activity, and oligonucleoticles harboring these blocking termini were activated by Ape1 for DNA polymerase beta extension. Ape1 was also found to remove 3'-tyrosyl residues from 3'-recessed and nicked DNAs, suggesting a potential role in processing covalent topoisomerase I-DNA intermediates formed during chromosome relaxation. While exhibiting preferential excision of thymine in a T:G mismatch context, Ape1 was unable to degrade a triple 3'-thymine mispair. However, Ape1 was able to excise double nucleotide mispairs, apparently through a novel 3'-flap-type endonuclease activity, again activating these substrates for polymerase beta extension. Published by Elsevier Ltd. C1 NIA, Lab Mol Gerontol, GRC,IRP, NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, GRC,IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 67 TC 56 Z9 60 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 25 PY 2003 VL 330 IS 5 BP 1027 EP 1037 DI 10.1016/S0022-2836(03)00712-5 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 703UG UT WOS:000184299000011 PM 12860125 ER PT J AU Zheng, SQL Mychaleckyj, JC Hawkins, GA Isaacs, SD Wiley, KE Turner, A Chang, BL von Kap-Herr, C Carpten, JD Pettenati, M Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB Xu, JF AF Zheng, SQL Mychaleckyj, JC Hawkins, GA Isaacs, SD Wiley, KE Turner, A Chang, BL von Kap-Herr, C Carpten, JD Pettenati, M Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB Xu, JF TI Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE prostate cancer; mutation screen; hereditary; association; DLC1; SNPs ID CHROMOSOME; LOCUS; EXPRESSION; TUMORS AB A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p 122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5' UTR, all 14 exons, exon-intron junctions, and 3' UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21287 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Isaacs, WB (reprint author), Johns Hopkins Med Inst, Dept Urol, Marburg 115,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCI NIH HHS [CA58236] NR 21 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUL 25 PY 2003 VL 528 IS 1-2 BP 45 EP 53 DI 10.1016/S0027-5107(03)00081-2 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 707XL UT WOS:000184535200005 PM 12873722 ER PT J AU Grass, S Jacoby, AS Iismaa, TP Crawley, JN Xu, XJ Wiesenfeld-Hallin, Z AF Grass, S Jacoby, AS Iismaa, TP Crawley, JN Xu, XJ Wiesenfeld-Hallin, Z TI Flexor reflex excitability in mice lacking galanin receptor galanin-R1 SO NEUROSCIENCE LETTERS LA English DT Article DE central sensitization; nociception; pain; knockout; wind-up; intrathecal; spinal cord ID SPINAL-CORD; INTRATHECAL GALANIN; ALZHEIMERS-DISEASE; SENSORY NEURONS; RAT; IMMUNOREACTIVITY; STIMULATION; INCREASE; PATHWAYS; GALR1 AB This study was conducted to examine the excitability of the nociceptive flexor reflex and its sensitization by repetitive stimulation of C-fibers in anesthetized mice that lack the galanin-R1 receptor. Repetitive stimulation of C-fibers induced a gradual increase in reflex magnitude during the stimulation (wind-up), and a subsequent increase in spinal reflex excitability (central sensitization). This occurred in GAL-R1 - /-, GAL-R1 + /-, and +/+ wild-type controls, with no significant differences observed between genotypes. Intrathecal administration of galanin markedly blocked the sensitization following the repetitive stimulation in all three groups. No differences between wild-type or galanin-R1 receptor knockout mice were seen. These results confirm previous studies in rats, showing that intrathecal galanin reduces the central sensitization following wind-up. The present data indicate that this effect is probably mediated by receptors other than GAL-R1. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 Huddinge Univ Hosp, Karolinska Inst, Div Clin Neurophysiol, Dept Lab Med, S-14186 Stockholm, Sweden. Garvan Inst Med Res, Neurobiol Program, Sydney, NSW, Australia. NIMH, Sect Behav Genom, Bethesda, MD 20815 USA. RP Grass, S (reprint author), Huddinge Univ Hosp, Dept Clin Neurophysiol, S-14186 Stockholm, Sweden. NR 19 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 24 PY 2003 VL 345 IS 3 BP 153 EP 156 DI 10.1016/S0304-3940(03)00516-0 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 695XT UT WOS:000183856200003 PM 12842279 ER PT J AU Schechter, AN Gladwin, MT AF Schechter, AN Gladwin, MT TI Hemoglobin and nitric oxide - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID S-NITROSOHEMOGLOBIN; HEME C1 NIH, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIH, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 24 PY 2003 VL 349 IS 4 BP 404 EP 405 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 703ZH UT WOS:000184312800030 ER PT J AU Malozowski, S AF Malozowski, S TI Use of growth hormone in elderly individuals SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID AMERICAN-DIABETES-ASSOCIATION; POPULATION; CRITERIA C1 NIDDKD, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. RP Malozowski, S (reprint author), NIDDKD, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 23 PY 2003 VL 290 IS 4 BP 462 EP 462 DI 10.1001/jama.290.4.462-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 703JB UT WOS:000184275300015 PM 12876088 ER PT J AU Travis, LB Hill, DA Dores, GM Gospodarowicz, M van Leeuwen, FE Holowaty, E Glimelius, B Andersson, M Wiklund, T Lynch, CF Van't Veer, MB Glimelius, I Storm, H Pukkala, E Stovall, M Curtis, R Boice, JD Gilbert, E AF Travis, LB Hill, DA Dores, GM Gospodarowicz, M van Leeuwen, FE Holowaty, E Glimelius, B Andersson, M Wiklund, T Lynch, CF Van't Veer, MB Glimelius, I Storm, H Pukkala, E Stovall, M Curtis, R Boice, JD Gilbert, E TI Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HORMONE REPLACEMENT THERAPY; 2ND MALIGNANT NEOPLASMS; MANTLE IRRADIATION; RADIATION-THERAPY; OVARIAN-FUNCTION; RISK; SURVIVORS; MORTALITY; ESTROGEN; COHORT AB Context Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk. Objective To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD. Design, Setting, and Subjects Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998. Main Outcome Measures Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents. Results Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 9-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P=.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P=.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. Conclusions Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Netherlands Canc Inst, Amsterdam, Netherlands. Canc Care Ontario, Toronto, ON, Canada. Uppsala Univ, Uppsala, Sweden. Danish Canc Soc, Copenhagen, Denmark. Univ Helsinki, Cent Hosp, Helsinki, Finland. Univ Iowa, Iowa City, IA USA. Dr Daniel den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Stat, NIH, Dept Hlth & Human Serv,EPS 7086,MSC 7238, Bethesda, MD 20892 USA. OI Glimelius, Ingrid/0000-0001-6158-3041 FU NCI NIH HHS [CP-33013-18, N01-CP-61119, N01-CP-61120, N01-CP-61121, N01-CP-61122, N01-CP-91024, N02-CP-81005] NR 61 TC 325 Z9 329 U1 1 U2 6 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 JUL 23 PY 2003 VL 290 IS 4 BP 465 EP 475 DI 10.1001/jama.290.4.465 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 703JB UT WOS:000184275300018 PM 12876089 ER PT J AU Virtamo, J Pietinen, P Huttunen, JK Malila, N Virtanen, MJ Albanes, D Taylor, PR Albert, P AF Virtamo, J Pietinen, P Huttunen, JK Malila, N Virtanen, MJ Albanes, D Taylor, PR Albert, P CA ATBC Study Grp TI Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation - A postintervention follow-up SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CONTROLLED TRIAL FINLAND; LUNG-CANCER; CARDIOVASCULAR-DISEASE; CIGARETTE-SMOKE; PROSTATE-CANCER; VITAMIN-A; PREVENTION; MICRONUTRIENTS; FERRETS; RISK AB Context In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, alpha-tocopherol supplementation decreased prostate cancer incidence, whereas beta-carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants. Objective To analyze postintervention effects of alpha-tocopherol and beta-carotene on cancer incidence and total and cause-specific mortality. Design, Setting, and Participants Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25563 men. In the ATBC Study, 29133 male smokers aged 50 to 69 years received a-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were, confirmed through medical record review. Main Outcome Measures Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality. Results Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of beta-carotene compared with nonrecipients. For prostate cancer incidence (n=672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving alpha-tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for beta-carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for beta-carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases. Conclusions The beneficial and adverse effects of supplemental alpha-tocopherol and beta-carotene disappeared during postintervention follow-up. The preventive effects of alpha-tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid beta-carotene supplementation. C1 Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, FIN-00300 Helsinki, Finland. NCI, Bethesda, MD 20892 USA. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. Univ Turku, Cent Hosp, SF-20500 Turku, Finland. Jorvi Hosp, SF-02740 Espoo, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. RP Virtamo, J (reprint author), Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Mannerheimintie 166, FIN-00300 Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 FU CCR NIH HHS [N01-RC-45035]; NCI NIH HHS [N01-CN-45165] NR 28 TC 250 Z9 259 U1 2 U2 12 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 JUL 23 PY 2003 VL 290 IS 4 BP 476 EP 485 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 703JB UT WOS:000184275300019 PM 12876090 ER PT J AU Pare, M Hanes, DP AF Pare, M Hanes, DP TI Controlled movement processing: Superior colliculus activity associated with countermanded saccades SO JOURNAL OF NEUROSCIENCE LA English DT Article DE superior colliculus; saccade; fixation; motor control; countermanding; monkey ID FRONTAL EYE-FIELD; NIGRA PARS RETICULATA; REVERSIBLE INACTIVATION; FUNCTIONAL-PROPERTIES; FIXATION ACTIVITY; NEURONAL-ACTIVITY; REACTION-TIME; NO-RETURN; MONKEY; INHIBITION AB We investigated whether the monkey superior colliculus (SC), an important midbrain structure for the regulation of saccadic eye movements, contains neurons with activity patterns sufficient to control both the cancellation and the production of saccades. We used a countermanding task to manipulate the probability that, after the presentation of a stop signal, the monkeys canceled a saccade that was planned in response to an eccentric visual stimulus. By modeling each animal's behavioral responses, with a race between GO and STOP processes leading up to either saccade initiation or cancellation, we estimated that saccade cancellation took on average 110 msec. Neurons recorded in the superior colliculus intermediate layers during this task exhibited the discharge properties expected from neurons closely involved in behavioral control. Both saccade- and fixation-related discharged differently when saccades were countermanded instead of executed, and the time at which they changed their activity preceded the behavioral estimate of saccade cancellation obtained from the same trials by 10 and 13 msec, respectively. Furthermore, these intervals exceed the minimal amount of time needed for SC activity to influence eye movements. The additional observation that saccade- related neurons discharged significantly less when saccades were countermanded instead of executed suggests that saccades are triggered when these neurons reach a critical activation level. Altogether, these findings provide solid evidence that the superior colliculus contains the necessary neural signals to be directly involved in the decision process that regulates whether a saccade is to be produced. C1 Queens Univ, Dept Physiol, Kingston, ON K7L 3N6, Canada. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Pare, M (reprint author), Queens Univ, Dept Physiol, Botterell Hall,Room 438, Kingston, ON K7L 3N6, Canada. NR 56 TC 158 Z9 160 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 23 PY 2003 VL 23 IS 16 BP 6480 EP 6489 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 704DX UT WOS:000184323900011 PM 12878689 ER PT J AU Chou, JJ Case, DA Bax, A AF Chou, JJ Case, DA Bax, A TI Insights into the mobility of methyl-bearing side chains in proteins from (3)J(CC) and (3)J(CN) couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ISOTOPICALLY ENRICHED PROTEINS; CALMODULIN-PEPTIDE COMPLEX; DENSITY-FUNCTIONAL THEORY; LIQUID-CRYSTALLINE PHASE; DIPOLAR COUPLINGS; NMR RELAXATION; BIOLOGICAL MACROMOLECULES; STAPHYLOCOCCAL NUCLEASE; MOLECULAR-DYNAMICS; CORRELATION-ENERGY AB Side-chain dynamics in proteins can be characterized by the NMR measurement of C-13 and 2 H relaxation rates. Evaluation of the corresponding spectral densities limits the slowest motions that can be studied quantitatively to the time scale on which the overall molecular tumbling takes place. A different measure for the degree of side-chain order about the C-alpha-C-beta bond (chi(1) angle) can be derived from (3)J(C'-Cgamma) and (3)J(N-Cgamma) couplings. These couplings can be measured at high accuracy, in particular for Thr, lle, and Val residues. In conjunction with the known backbone structures of ubiquitin and the third IgG-binding domain of protein G, and an extensive set of C-13-H-1 side-chain dipolar coupling measurements in oriented media, these (3)J couplings were used to parametrize empirical Karplus relationships for (3)J(C'-Cgamma) and (3)J(N-Cgamma). These Karplus curves agree well with results from DFT calculations, including an unusual phase shift, which causes the maximum (3)J(CC) and (3)J(CN) couplings to occur for dihedral angles slightly smaller than 180, particularly noticeable in Thr residues. The new Karplus curves permit determination of rotamer populations for the X, torsion angles. Similar rotamer populations can be derived from side-chain dipolar couplings. Conversion of these rotamer populations into generalized order parameters, S-J(2) and S-D(2), provides a view of side-chain dynamics that is complementary to that obtained from C-13 and H-2 relaxation. On average, results agree well with literature values for H-2-relaxation-derived S-rel(2) values in ubiquitin and HIV protease, but also identify a fraction of residues for which S-J,D(2) < S-rel(2). This indicates that some of the rotameric averaging occurs on a time scale too slow to be observable in traditional relaxation measurements. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Chou, James/N-9840-2013 FU NIGMS NIH HHS [GM45811] NR 47 TC 101 Z9 104 U1 1 U2 17 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 JUL 23 PY 2003 VL 125 IS 29 BP 8959 EP 8966 DI 10.1021/ja029972s PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 702UN UT WOS:000184243000052 PM 12862493 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 BIOCHEMISTRY 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. 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 51 BP 8605 EP 8605 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000076 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 BIOCHEMISTRY 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, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NCI, Lab Drug Discovery Res, NIH, CCR, Bethesda, MD 20892 USA. RI Barchi Jr., Joseph/N-3784-2014 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 63 BP 8607 EP 8607 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000088 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 BIOCHEMISTRY 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, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. Natl Child Hlth & Human Dev, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 72 BP 8610 EP 8610 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000097 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 BIOCHEMISTRY 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 Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. Vanderbilt Univ, Dept Chem, Ctr Mol Toxicol, Nashville, TN 37235 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 76 BP 8611 EP 8611 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000101 ER PT J AU Wolfe, MD AF Wolfe, MD TI Mechanistic insights revealed through characterization of a novel chromophore in selenophosphate synthetase from Escherichia coli . SO BIOCHEMISTRY 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 NHLBI, Biochem 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 103 BP 8617 EP 8617 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000128 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 BIOCHEMISTRY 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 Natl Inst Child Hlth & Human Dev, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 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 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 22 PY 2003 VL 42 IS 28 MA 249 BP 8651 EP 8651 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 702XA UT WOS:000184249000274 ER PT J AU Roberts, AB Wakefield, LM AF Roberts, AB Wakefield, LM TI The two faces of transforming growth factor beta in carcinogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID BREAST-CANCER CELLS; TGF-BETA; SIGNALING PATHWAYS; MAMMARY-TUMOR; COLON-CANCER; METASTASIS; TUMORIGENESIS; GROWTH-FACTOR-BETA-1; EXPRESSION; RECEPTORS C1 NCI, Lab Cell Regulat & Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. NR 34 TC 457 Z9 490 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2003 VL 100 IS 15 BP 8621 EP 8623 DI 10.1073/pnas.1633291100 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000005 PM 12861075 ER PT J AU Frolov, VA Lizunov, VA Dunina-Barkovskaya, AY Samsonov, AV Zimmerberg, J AF Frolov, VA Lizunov, VA Dunina-Barkovskaya, AY Samsonov, AV Zimmerberg, J TI Shape bistability of a membrane neck: A toggle switch to control vesicle content release SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HIGH-CALCIUM CONCENTRATIONS; EXOCYTOTIC FUSION PORE; LIPID-BILAYER VESICLES; CHROMAFFIN CELLS; SMALL GRANULES; FISSION PORE; ENDOCYTOSIS; NETWORKS; DYNAMICS; CONDUCTANCE AB Shape dynamics and permeability of a membrane neck connecting a vesicle and plasma membrane are considered. The neck is modeled by a lipid membrane tubule extended between two parallel axisymmetric rings. Within a range of lengths, defined by system geometry and mechanical properties of the membrane, the tubule has two stable shapes: catenoidal microtubule and cylindrical nanotubule. The permeabilities of these two shapes, measured as ionic conductivity of the tubule interior, differ by up to four orders of magnitude. Near the critical length the transitions between the shapes occur within less than a millisecond. Theoretical estimates show that the shape switching is controlled by a single parameter, the tubule length. Thus the tubule connection can operate as a conductivity microswitch, toggling the release of vesicle content in such cellular processes as "kiss-and-run" exocytosis. In support of this notion, bistable behavior of membrane connections between vesicles and the cell plasma membrane in macrophages is demonstrated. C1 Russian Acad Sci, AN Frumkin Electrochem Inst, Moscow 117071, Russia. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119899, Russia. RP Frolov, VA (reprint author), Russian Acad Sci, AN Frumkin Electrochem Inst, Moscow 117071, Russia. EM frolovv@cc1.nichd.nih.gov; joshz@helix.nih.gov RI Lizunov, Vladimir/B-5468-2009; OI Frolov, Vadim/0000-0002-0653-5669 NR 52 TC 26 Z9 26 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2003 VL 100 IS 15 BP 8698 EP 8703 DI 10.1073/pnas.1432962100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000021 PM 12857952 ER PT J AU Bourgeois, D Vallone, B Schotte, F Arcovito, A Miele, AE Sciara, G Wulff, M Anfinrud, P Brunori, M AF Bourgeois, D Vallone, B Schotte, F Arcovito, A Miele, AE Sciara, G Wulff, M Anfinrud, P Brunori, M TI Complex landscape of protein structural dynamics unveiled by nanosecond Laue crystallography SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE myoglobin; protein dynamics; conformational states; functional intermediates; protein crystallography ID LIGAND-BINDING; CRYSTAL-STRUCTURE; CONFORMATIONAL RELAXATION; CARBONMONOXY-MYOGLOBIN; CAVITIES; MIGRATION; INTERMEDIATE; MOTIONS AB Although conformational changes are essential for the function of proteins, little is known about their structural dynamics at atomic level resolution. Myoglobin (Mb) is the paradigm to investigate conformational dynamics because it is a simple globular heme protein displaying a photosensitivity of the iron-ligand bond. Upon laser photodissociation of carboxymyoglobin Mb a nonequilibrium population of protein structures is generated that relaxes over a broad time range extending from picoseconds to milliseconds. This process is associated with migration of the ligand to cavities in the matrix and with a reduction in the geminate rebinding rate by several orders of magnitude. Here we report nanosecond time-resolved Laue diffraction data to 1.55-Angstrom resolution on a Mb mutant, which depicts the sequence of structural events associated with this extended relaxation. Motions of the distal E-helix, including the mutated residue Gin-64(E7), and of the CID-turn are found to lag significantly (100-300 ns) behind local rearrangements around the heme such as heme tilting, iron motion out of the heme plane, and swinging of the mutated residue Tyr-29(113110), all of which occur promptly (less than or equal to3 ns). Over the same delayed time range, CO is observed to migrate from a cavity distal to the heme known to bind xenon (called Xe4 to another such cavity proximal to the heme (Xe1). We propose that the extended relaxation of the globin moiety reflects reequilibration among conformational substates known to play an essential role in controlling protein function. C1 Univ Grenoble 1, Commiss Energie Atom, Inst Biol Struct,Unite Mixte Rech 9015, Lab Cristallog & Cristalloggenese Prot, F-38027 Grenoble 1, France. European Synchrotron Radiat Facil, F-38043 Grenoble, France. Univ Roma La Sapienza, Dipartimento Sci Biochim, I-00185 Rome, Italy. Univ Roma La Sapienza, Ist Pasteur, Fondaz Cenci Bolognetti, I-00185 Rome, Italy. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Bourgeois, D (reprint author), Univ Grenoble 1, Commiss Energie Atom, Inst Biol Struct,Unite Mixte Rech 9015, Lab Cristallog & Cristalloggenese Prot, 41 Rue Jules Horowitz, F-38027 Grenoble 1, France. RI Miele, Adriana Erica/F-4083-2011; Vallone, Beatrice/F-4174-2012; Arcovito, Alessandro/I-5552-2012; OI Miele, Adriana Erica/0000-0002-4637-2606; Arcovito, Alessandro/0000-0002-8384-4844; Brunori, Maurizio/0000-0002-7795-1635 NR 34 TC 154 Z9 158 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2003 VL 100 IS 15 BP 8704 EP 8709 DI 10.1073/pnas.1430900100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000022 PM 12847289 ER PT J AU Dey, A Chitsaz, F Abbasi, A Misteli, T Ozato, K AF Dey, A Chitsaz, F Abbasi, A Misteli, T Ozato, K TI The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HISTONE H4 ACETYLATION; LIVING CELLS; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; RAPID EXCHANGE; DROSOPHILA; MOBILITY; RECEPTOR; CODE; GENE AB Previous in vitro studies showed that the bromodomain binds to acetyllysines on histone tails, leading to the proposal that the domain is involved in deciphering the histone code. However, there is little in vivo evidence supporting the binding of bromodomains to acetylated chromatin in the native environment. Brd4 is a member of the BET family that carries two bromodomains. It associates with mitotic chromosomes, a feature characteristic of the family. Here, we studied the interaction of Brd4 with chromatin in living cells by photobleaching. Brd4 was mobile and interacted with chromatin with a rapid "on and off" mode of binding. This interaction required both bromodomains. Indicating a preferential interaction with acetylated chromatin, Brd4 became less mobile upon increased chromatin acetylation caused by a histone deacetylase inhibitor. Providing biochemical support, salt solubility of Brd4 was markedly reduced upon increased histone acetylation. This change also required both bromodomains. In peptide binding assays, Brd4 avidly bound to di- and tetraacetylated histone H4 and diacetylated H3, but weakly or not at all to mono- and unacetylated H3 and H4. By contrast, it did not bind to unacetylated H4 or H3. Further, Brd4 colocalized with acetylated H4 and H3 in noncentromeric regions of mitotic chromosomes. This colocalization also required both bromodomains. These observations indicate that Brd4 specifically recognizes acetylated histone codes, and this recognition is passed onto the chromatin of newly divided cells. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NR 48 TC 287 Z9 293 U1 2 U2 30 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 JUL 22 PY 2003 VL 100 IS 15 BP 8758 EP 8763 DI 10.1073/pnas.1433065100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000032 PM 12840145 ER PT J AU Pao, W Klimstra, DS Fisher, GH Varmus, HE AF Pao, W Klimstra, DS Fisher, GH Varmus, HE TI Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSGENIC MICE; GENE-EXPRESSION; CANCER; SYSTEM; ONCOGENES; OVEREXPRESSION; TRANSFORMATION; MUTATIONS; INDUCTION; VIRUSES AB A key issue in cancer biology is whether genetic lesions involved in tumor initiation or progression are required for tumor maintenance. This question can be addressed with mouse models that conditionally express oncogenic transgenes, i.e., under the control of tetracycline (tet)-dependent transcriptional regulators. We have developed a system for studying tumor maintenance by using avian retroviral [i.e., replication-competent avian leukosis virus long terminal repeat with splice acceptor (RCAS)] vectors to deliver the reverse tet transcriptional transactivator (rtTA) gene to somatic mammalian cells. rtTA can regulate any transgene in which the protein coding sequence is preceded by a tet-operator (tet-o); RCAS viruses infect only cells engineered to express ectopically the avian retroviral receptor, TVA. One vector, RCAS-rtTA-IRES-GFP, also encodes GFP to identify infected cells. infection of cells from beta-actin TVA transgenic mice with this vector permits efficient regulation of tet-responsive transgenes. Sarcomas arise when p53-deficient murine embryonic fibroblasts carrying beta-actin TVA and tet-o-Kras4b(G12D) transgenes are infected with RCAS-rtTA-IRES-GFP and introduced into nude mice treated with the tet analog, doxycycline (dox); when dox is withdrawn, K-ras4b(G12D) levels fall, cells undergo apoptosis, and tumors regress. Regression can be prevented by means of a genetic complementation assay in which tumors are superinfected before dox withdrawal with other RCAS viruses, such as those carrying an active allele of K-ras. Many TVA and tet-regulated transgenic mice have been generated; thus, this method for somatic cell-specific and temporally controlled gene expression may have broad applications for the study of oncogenesis and tumor maintenance, as well as other cell functions and development. C1 Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pao, W (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave,Box 62, New York, NY 10021 USA. FU NCI NIH HHS [K12-CA09712] NR 24 TC 41 Z9 43 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2003 VL 100 IS 15 BP 8764 EP 8769 DI 10.1073/pnas.1133333100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000033 PM 12857957 ER PT J AU Wu, ZB Hoover, DM Yang, D Boulegue, C Santamaria, F Oppenheim, JJ Lubkowski, J Lu, WY AF Wu, ZB Hoover, DM Yang, D Boulegue, C Santamaria, F Oppenheim, JJ Lubkowski, J Lu, WY TI Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN NEUTROPHIL DEFENSINS; ACID SIDE-CHAINS; BETA-DEFENSINS; MEMBRANOLYTIC SELECTIVITY; PEPTIDE ANTIBIOTICS; SERINE PROTEINASES; CATIONIC PEPTIDES; CYSTIC-FIBROSIS; PANETH CELLS; HOST-DEFENSE AB Human defensins form a family of small, cationic, and Cys-rich antimicrobial proteins that play important roles in innate immunity against invading microbes. They also function as effective immune modulators in adaptive immunity by selectively chemoattracting T lymphocytes and immature dendritic cells. On the basis of sequence homology and the connectivity of six conserved Cys residues, human clefensins are classified into alpha and beta families. Structures of several beta-defensins have recently been characterized, confirming the disulfide connectivity conserved within the family, i.e., Cys(1)-Cys(5), Cys(2)-Cys(4), and Cys(3)-Cys(6). We found that human beta-defensin 3 (hBD3), a recently described member of the growing beta family, did not fold preferentially into a native conformation in vitro under various oxidative conditions. Using the orthogonal protection of Cys(1)-Cys(5) and of Cys(1)-Cys(6), we chemically synthesized six topological analogs of hBD3 with predefined disulfide connectivities, including the (presumably) native beta pairing. Unexpectedly, all differently folded hBD3 species exhibited similar antimicrobial activity against Escherichia coli, whereas a wide range of chemotactic activities was observed with these analogs for monocytes and cells transfected by the chemokine receptor CCR6. Furthermore, whereas substitution of all Cys residues by alpha-aminobutyric acid completely abolished the chemotactic activity of hBD3, the bactericidal activity remained unaffected in the absence of any disulfide bridge. Our findings demonstrate that disulfide bonding in hBD3, although required for binding and activation of receptors for chemotaxis, is fully dispensable for its antimicrobial function, thus shedding light on the mechanisms of action for human beta-defensins and the design of novel peptide antibiotics. C1 Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. NCI, Macromol Assembly Struct & Cell Signaling Sect, Immunoregulat Lab, Frederick, MD 21702 USA. RP Lu, WY (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. RI Boulegue, Cyril/A-4092-2009; Lu, Wuyuan/B-2268-2010 NR 56 TC 269 Z9 282 U1 1 U2 30 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 JUL 22 PY 2003 VL 100 IS 15 BP 8880 EP 8885 DI 10.1073/pnas.1533186100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000053 PM 12840147 ER PT J AU Schneerson, R Kubler-Kielb, J Liu, TY Dai, ZD Leppla, SH Yergey, A Backlund, P Shiloach, J Majadly, F Robbins, JB AF Schneerson, R Kubler-Kielb, J Liu, TY Dai, ZD Leppla, SH Yergey, A Backlund, P Shiloach, J Majadly, F Robbins, JB TI Poly(gamma-D-glutamic acid) protein conjugates induce IgG antibodies in mice to the capsule of Bacillus anthracis: A potential addition to the anthrax vaccine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INFLUENZAE TYPE-B; SHIGELLA-DYSENTERIAE TYPE-1; PROTECTIVE ANTIGEN; IMMUNOGENICITY; POLYSACCHARIDE; TOXIN; RECOVERY; PEPTIDES; PLASMID; HUMANS AB Both the protective antigen (PA) and the poly(gamma-D-glutamic acid) capsule (gammaDPGA) are essential for the virulence of Bacillus anthracis. A critical level of vaccine-induced IgG anti-PA confers immunity to anthrax, but there is no information about the protective action of IgG anti-gammaDPGA. Because the number of spores presented by bioterrorists might be greater than encountered in nature, we sought to induce capsular antibodies to expand the immunity conferred by available anthrax vaccines. The nonimmunogenic -yDPGA or corresponding synthetic peptides were bound to BSA, recombinant B. anthracis PA (rPA), or recombinant Pseudomonas aeruginosa exotoxin A (rEPA). To identify the optimal construct, conjugates of B. anthracis gammaDPGA, Bacillus pumilus gammaDLPGA, and peptides of varying lengths (5-, 10-, or 20-mers), of the D or L configuration with active groups at the Nor C termini, were bound at 5-32 mol per protein. The conjugates were characterized by physico-chemical and immunological assays, including GLC-MS and matrix-assisted laser desorption ionization time-of-flight spectrometry, and immunogenicity in 5- to 6-week-old mice. IgG anti-gammaDPGA and antiprotein were measured by ELISA. The highest levels of IgG anti-,gammaDPGA were elicited by decamers of gammaDPGA at 10-20 mol per protein bound to the N- or C-terminal end. High IgG anti-gammaDPGA levels were elicited by two injections of 2.5 mug of gammaDPGA per mouse, whereas three injections were needed to achieve high levels of protein antibodies. rPA was the most effective carrier. Anti-gammaDPGA induced opsonophagocytic killing of B. anthracis tox-, cap+. gammaDPGA conjugates may enhance the protection conferred by PA alone. gammaDPGA-rPA conjugates induced both anti-PA and anti-gammaDPGA. C1 NICHHD, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP NICHHD, NIH, Bethesda, MD 20892 USA. EM schneerr@mail.nih.gov NR 42 TC 104 Z9 109 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2003 VL 100 IS 15 BP 8945 EP 8950 DI 10.1073/pnas.1633512100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000064 PM 12857944 ER PT J AU Zhao, YG Marin, O Hermesz, E Powell, A Flames, N Palkovits, M Rubenstein, JLR Westphal, H AF Zhao, YG Marin, O Hermesz, E Powell, A Flames, N Palkovits, M Rubenstein, JLR Westphal, H TI The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SPATIALLY RESTRICTED EXPRESSION; COMBINED FLUORESCENT TRACER; BASAL FOREBRAIN; STRIATAL INTERNEURONS; ALZHEIMERS-DISEASE; MOTOR-NEURON; RAT STRIATUM; TELENCEPHALON; PROJECTIONS; SYSTEMS AB Forebrain cholinergic neurons play important roles as striatal local circuit neurons and basal telencephalic projection neurons. The genetic mechanisms that control development of these neurons suggest that most of them are derived from the basal telencephalon where Lhx8, a LIM-homeobox gene, is expressed. Here we report that mice with a null mutation of Lhx8 are deficient in the development of forebrain cholinergic neurons. Lhx8 mutants lack the nucleus basalis, a major source of the cholinergic input to the cerebral cortex. In addition, the number of cholinergic neurons is reduced in several other areas of the subcortical forebrain in Lhx8 mutants, including the caudate-putamen, medial septal nucleus, nucleus of the diagonal band, and magnocellular preoptic nucleus. Although cholinergic neurons are not formed, initial steps in their specification appear to be preserved, as indicated by a presence of cells expressing a truncated Lhx8 mRNA and mRNA of the homeobox gene Gbx1. These results provide genetic evidence supporting an important role for Lhx8 in development of cholinergic neurons in the forebrain. C1 NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. Univ Calif San Francisco, Langley Porter Psychiat Inst, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94143 USA. Univ Szeged, Dept Biochem, H-6701 Szeged, Hungary. Semmelweis Univ, Neuromorphol Lab, H-1094 Budapest, Hungary. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. EM hw@helix.nih.gov RI Marin, Oscar/F-3856-2012; Palkovits, Miklos/F-2707-2013; OI Marin, Oscar/0000-0001-6264-7027; flames, nuria/0000-0003-0961-0609; Palkovits, Miklos/0000-0003-0578-0387 FU NIDA NIH HHS [R01 DA012462, R01DA12462]; NIMH NIH HHS [K02MH01046-01] NR 42 TC 128 Z9 135 U1 2 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 JUL 22 PY 2003 VL 100 IS 15 BP 9005 EP 9010 DI 10.1073/pnas.1537759100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZC UT WOS:000184371000074 PM 12855770 ER PT J AU von Stebut, E Ehrchen, JM Belkaid, Y Kostka, SL Molle, K Knop, J Sunderkotter, C Udey, MC AF von Stebut, E Ehrchen, JM Belkaid, Y Kostka, SL Molle, K Knop, J Sunderkotter, C Udey, MC TI Interleukin 1 alpha promotes Th-1 differentiation and inhibits disease progression in Leishmania major - Susceptible BALB/c mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE dendritic cell; IL-1; Leishmania major; infection; T helper cell type l/T helper cell type 2 immune response ID DENDRITIC CELLS; T-CELLS; IFN-GAMMA; CUTANEOUS LEISHMANIASIS; INTRACELLULAR PATHOGENS; RESISTANT MICE; C57BL/6 MICE; TNF-ALPHA; INFECTION; IMMUNITY AB Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12-dependent Th-1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1alpha in response to lipopolysaccharide/interferon gamma or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1alpha mRNA accumulation in lymph nodes of L. major-infected BALB/c mice was similar to3-fold lower than that in C57BL/6 mice. Local injections of IL-1alpha during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major-infected BALB/c mice, IL-1alpha administration resulted in increased Th-1- and strikingly decreased Th-2-cytokine production. IL-1alpha and IL-12 treatments were similarly effective, and IL-1alpha efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1alpha acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th-1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains. C1 Univ Mainz, Dept Dermatol, D-55131 Mainz, Germany. Univ Munster, Inst Expt Dermatol, D-48149 Munster, Germany. Univ Cincinnati, Childrens Hosp Res Fdn, Dept Mol Immunol, Cincinnati, OH 45229 USA. NCI, Canc Res Ctr, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP von Stebut, E (reprint author), Univ Mainz, Dept Dermatol, Langenbeckstr 1, D-55131 Mainz, Germany. NR 48 TC 92 Z9 93 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 21 PY 2003 VL 198 IS 2 BP 191 EP 199 DI 10.1084/jem.20030159 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 704YA UT WOS:000184368200002 PM 12860932 ER PT J AU Shah, JA Darrah, PA Ambrozak, DR Turon, TN Mendez, S Kirman, J Wu, CY Glaichenhaus, N Seder, RA AF Shah, JA Darrah, PA Ambrozak, DR Turon, TN Mendez, S Kirman, J Wu, CY Glaichenhaus, N Seder, RA TI Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE plasmacytoid dendritic cell; Toll-like receptor; Leishmania major; vaccine; Th1 cells ID T-HELPER-CELL; INTERFERON-PRODUCING CELLS; TOLL-LIKE RECEPTORS; IN-VIVO; BACTERIAL-DNA; LYMPH-NODES; ANTIGEN; MOUSE; CD8-ALPHA(+); INTERLEUKIN-12 AB Vaccination with leishmanial Ag and CpG oligodeoxynucleotides (ODN) confers sustained cellular immunity and protection to infectious challenge up to 6 mo after immunization. To define the cellular mechanism by which CpG ODN mediate their adjuvant effects in vivo, the functional capacity of distinct dendritic cell (DC) subsets was assessed in the lymph nodes (LNs) of BALB/c mice, 36 h after immunization with the leishmanial antigen (LACK) and CpG ODN. After this immunization, there was a striking decrease in the frequency of the CD11c(+)B220(+) plasmacytoid DCs with a proportionate increase in CD11c(+)CD8(-)B220(-) cells. CD11c(+)CD8(+)B220(-) cells were the most potent producers of interleukin (IL)-12 p70 and interferon (IFN)-gamma, while plasmacytoid DCs were the only subset capable of secreting IFN-alpha. In terms of antigen presenting capacity, plasmacytoid DCs were far less efficient compared with the other DC subsets. To certify that DCs were responsible for effective vaccination, we isolated CD11c(+) and CD11c(-) cells 36 h after immunization and used such cells to elicit protective immunity after adoptive transfer in naive, Leishmania major susceptible BALB/c mice. CD11c(+) cells but not 10-fold higher numbers of CD11c(-) cells from such immunized mice mediated protection. Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c(+) DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant. C1 NIAID, VRC, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, Intracellular Parasite Biol Sect, NIH, Bethesda, MD 20892 USA. CNRS, Inst Pharmacol Mol & Cellulaire, UMR 6097, F-06560 Valbonne, France. RP Seder, RA (reprint author), NIAID, VRC, Human Immunol Sect, NIH, 40 Convent Dr,Room 40-3512, Bethesda, MD 20892 USA. NR 54 TC 61 Z9 64 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 21 PY 2003 VL 198 IS 2 BP 281 EP 291 DI 10.1084/jem.20030645 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 704YA UT WOS:000184368200010 PM 12874261 ER PT J AU Karlsson, MCI Guinamard, R Bolland, S Sankala, M Steinman, RM Ravetch, JV AF Karlsson, MCI Guinamard, R Bolland, S Sankala, M Steinman, RM Ravetch, JV TI Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE SHIP; Btk; MARCO; migration; Staphylococcus aureus ID SCAVENGER RECEPTOR MARCO; BRUTONS TYROSINE KINASE; BLOOD-BORNE ANTIGENS; C-TYPE LECTIN; IN-VIVO; MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; IMMUNE-RESPONSE; TEC FAMILY; SPLEEN AB The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing mositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage-B cell interactions. C1 Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA. Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. Univ Mediterranee, INSERM, CNRS, Ctr Immunol Marseille Luminy, F-13288 Marseille, France. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden. RP Ravetch, JV (reprint author), Rockefeller Univ, Lab Mol Genet & Immunol, 1230 York Ave,Box 98, New York, NY 10021 USA. RI Steinman, Ralph/F-7729-2012 NR 43 TC 159 Z9 161 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 21 PY 2003 VL 198 IS 2 BP 333 EP 340 DI 10.1081/jem.20030684 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 704YA UT WOS:000184368200015 PM 12874264 ER PT J AU Grant, BF Dawson, DA Stinson, FS Chou, PS Kay, W Pickering, R AF Grant, BF Dawson, DA Stinson, FS Chou, PS Kay, W Pickering, R TI The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV): reliability of alcohol consumption, tobacco use, family history of depression and psychiatric diagnostic modules in a general population sample SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE reliability; diagnostic interview; psychiatric disorders; alcohol and drug use disorders; tobacco use and dependence; family history of depression ID DRUG MODULES; VALIDITY; CIDI; COMORBIDITY AB Background: the purpose of this study was to assess the test-retest reliability of newly introduced or revised modules of the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV), including alcohol consumption, tobacco use, family history of depression, and selected DSM-IV axis I and II psychiatric disorders. Methods: kappa and intraclass correlation coefficients were calculated for the AUDADIS-IV modules using a test-retest design among a total of 2657 respondents, in subsets of approximately 400, randomly drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Results: reliabilities for alcohol consumption, tobacco use and family history of major depression measures were good to excellent, while reliabilities for selected DSM-IV axis I and II disorders were fair to good. The reliabilities of dimensional symptom scales of DSM-IV axis I and axis II disorders exceeded those of their dichotomous diagnostic counterparts and were generally in the good to excellent range. Conclusions: the high reliability of alcohol consumption, tobacco use, family history of depression and psychiatric disorder modules found in this study suggests that the AUDADIS-IV can be a useful tool in various research settings, particularly in studies of the general population, the target population for which it was designed. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, Div Biometry & Epidemiol, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Div Biometry & Epidemiol, Suite 514,6000 Execut Blvd,MSC 7003, Bethesda, MD 20892 USA. NR 32 TC 775 Z9 777 U1 1 U2 22 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 JUL 20 PY 2003 VL 71 IS 1 BP 7 EP 16 DI 10.1016/S0376-8716(03)00070-X PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 699KU UT WOS:000184056700002 PM 12821201 ER PT J AU Conway, KP Kane, RJ Ball, SA Poling, JC Rounsaville, BJ AF Conway, KP Kane, RJ Ball, SA Poling, JC Rounsaville, BJ TI Personality, substance of choice, and polysubstance involvement among substance dependent patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE drug abuse; personality; polysubstance abuse ID ALCOHOL-USE DISORDERS; SENSATION SEEKING; PSYCHIATRIC-DISORDERS; ADDICTIVE PERSONALITY; DRUG-ABUSE; BEHAVIORAL DISINHIBITION; ANXIETY DISORDERS; COPING STYLES; COMORBIDITY; COCAINE AB The authors compared the association of several personality traits, drug of choice, and polysubstance involvement in 325 individuals (44% male) receiving treatment for substance dependence on heroin, cocaine, and/or alcohol. Measures included the Structured Clinical Interview for DSM-III-R, the MacAndrew Alcoholism Scale (MAC), the socialization scale of the California Psychological Inventory (CPI-Soc), the novelty seeking dimension of the Temperament and Character Inventory (TCI-NS), and the conscientiousness domain of the NEO Five-Factor Inventory (NEO-C). Analyses adjusted for demographic covariates, affective and antisocial personality disorder, and substance dependence severity. Although scant evidence supported the hypothesis that these personality traits were associated with substance choice, CPI-Soc and MAC were associated linearly with the extent of polysubstance involvement. Also, patients who were dependent on two or more substances displayed higher levels of TCI-NS, CPI-Soc, and MAC. Findings implicate an association between behavioral disinhibition and a continuum of addiction defined primarily in terms of polysubstance involvement. Published by Elsevier Science Ireland Ltd. C1 Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. American Univ, Dept Justice Law & Soc, Washington, DC 20016 USA. Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. RP Conway, KP (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd Suite 5153 MSC 9589, Bethesda, MD 20892 USA. OI Conway, Kevin/0000-0002-7638-339X; Poling, James/0000-0002-0133-3136 FU NIDA NIH HHS [K05 DA00089, P50 DA09241] NR 79 TC 86 Z9 86 U1 1 U2 20 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 JUL 20 PY 2003 VL 71 IS 1 BP 65 EP 75 DI 10.1016/S0376-8716(03)00068-1 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 699KU UT WOS:000184056700008 PM 12821207 ER PT J AU Wilson, LC Baek, SJ Call, A Eling, TE AF Wilson, LC Baek, SJ Call, A Eling, TE TI Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE genistein; colon cancer; anti-tumorigenesis; NAG-1; NSAIDs; cyclooxygenase ID BETA SUPERFAMILY MEMBER; GROWTH-FACTOR-BETA; COLON-CANCER; DNA-DAMAGE; ISOFLAVONE GENISTEIN; SIGNALING PATHWAY; DEPENDENT MANNER; SOY ISOFLAVONES; DOWN-REGULATION; UP-REGULATION AB Genistein is an isoflavenoid found in soy that has antitumorigenic activities. Treatment of colorectal carcinoma HCT-116 cells with 50 muM genistein results in a 50% reduction in cell proliferation and a 6-fold increase in apoptosis. Genistein induces nonsteroidal anti-inflammatory drug-activated gene I (NAG-I), a protein with antiturnorigenic activities, in a time- and concentration-dependent manner in HCT-116 cells. In addition, p53 and p21 are induced in HCT-116 cells. The induction of p53 (3 hr) precedes the induction of NAG-1 (12 hr), suggesting that genistein-induced NAG-I expression is mediated by p53. In contrast, NAG-I is not induced by genistein in the p53-negative colorectal carcinoma cell line HCT-15. Luciferase reporter constructs of the NAG-I promoter containing 2 p53 sites showed that the p53 sites within the NAG-1 promoter are critical to genistein-induced NAG4 expression in p53-positive U20S cells. The expression of p53 was critical for NAG4 promoter activity since no promoter activity was observed with genistein treatment in HCT-15 cells. However, genistein-induced promoter activity was restored in HCT-15 cells by transfection with wild-type p53. Together our data suggest a relationship between genistein, p53 and NAG4 forming a novel pathway responsible for the antiturnorigenic activity of genistein. (C) 2003 Wiley-Liss, Inc. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. OI Baek, Seung/0000-0001-7866-7778 NR 38 TC 90 Z9 93 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 20 PY 2003 VL 105 IS 6 BP 747 EP 753 DI 10.1002/ijc.11173 PG 7 WC Oncology SC Oncology GA 689WD UT WOS:000183515200002 PM 12767058 ER PT J AU Radaelli, A Nacsa, J Tsai, WP Edghill-Smith, Y Zanotto, C Elli, V Venzon, D Tryniszewska, E Markham, P Mazzara, GP Panicali, D Morghen, CD Franchini, G AF Radaelli, A Nacsa, J Tsai, WP Edghill-Smith, Y Zanotto, C Elli, V Venzon, D Tryniszewska, E Markham, P Mazzara, GP Panicali, D Morghen, CD Franchini, G TI Prior DNA immunization enhances immune response to dominant and subdominant viral epitopes induced by a fowlpox-based SIVmac vaccine in long-term slow-progressor macaques infected with SIVmac251 SO VIROLOGY LA English DT Article DE vaccination; AIDS; immunodeficiency diseases ID T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; STRUCTURED TREATMENT INTERRUPTIONS; PROTECTIVE EFFICACY; TYPE-1 INFECTION; DENDRITIC CELLS; RHESUS-MONKEYS; HIV-1 INFECTION; VIREMIA CONTROL AB A therapeutic vaccine for individuals infected with HIV-1 and treated with antiretroviral therapy (ART) should be able to replenish virus-specific CD4+ T-cells and broaden the virus-specific CD8+ T-cell response in order to maintain CD8+ T-cell function and minimize viral immune escape after ART cessation. Because a combination of DNA and recombinant poxvirus vaccine modalities induces high levels of virus-specific CD4+ T-cell response and broadens the cytolytic activity in naive macaques, we investigated whether the same results could be obtained in SIVmac251-infected macaques. The macaques studied here were long-term nonprogressors that naturally contained viremia but were nevertheless treated with a combination of antiviral drugs to assess more carefully the effect of vaccination in the context of ART. The combination of a DNA expressing the gag and pol genes (DNA-SIV-gp) of SIVmac239 followed by a recombinant fowlpox expressing the same SIVmac genes (FP-SIV-gp) was significantly more immunogenic than two immunizations of FP-SIV-gp in SIVmac25I-infected macaques treated with ART. The DNA/FP combination significantly expanded and broadened Gag-specific T-cell responses measured by tetramer staining, ELISPOT, and intracellular cytokine staining and measurement of ex vivo cytolytic function. Importantly, the combination of these vaccine modalities also induced a sizeable expansion in most macaques of Gag-specific CD8-(CD4+) T-cells able to produce TNF-alpha. Hopefully, this modality of vaccine combination may be useful in the clinical management of HIV-1-infected individuals. (C) 2003 Elsevier-Science (USA). All rights reserved. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. Univ Milan, Dept Pharmacol Sci, I-20129 Milan, Italy. CNR, Inst Neurosci, Cellular & Mol Pharmacol Sect, I-20129 Milan, Italy. Univ Milan, Dept Pharmacol, Mol Virol Lab, I-20129 Milan, Italy. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Med Acad Bialystok, Dept Pediat 3, PL-15274 Bialystok, Poland. Adv BioSci Labs Inc, Kensington, MD 20895 USA. Therion Biol Corp, Cambridge, MA 02142 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, 41-D804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008; OI Radaelli, Antonia/0000-0002-5683-6216 NR 59 TC 16 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL 20 PY 2003 VL 312 IS 1 BP 181 EP 195 DI 10.1016/S0042-6822(03)00184-3 PG 15 WC Virology SC Virology GA 708EF UT WOS:000184553600017 PM 12890631 ER PT J AU Hanley, KA Manlucu, LR Gilmore, LE Blaney, JE Hanson, CT Murphy, BR Whitehead, SS AF Hanley, KA Manlucu, LR Gilmore, LE Blaney, JE Hanson, CT Murphy, BR Whitehead, SS TI A trade-off in replication in mosquito versus mammalian systems conferred by a point mutation in the NS4B protein of dengue virus type 4 SO VIROLOGY LA English DT Article DE flavivirus; dengue virus; vaccine; NS4B; mutation; Aedes aegypti; Vero; HuH-7; C6/36; Toxorhynchites splendens ID HUMAN LIVER-CELLS; SINDBIS VIRUS; HOST-RANGE; VACCINE CANDIDATE; AEDES-ALBOPICTUS; NONCODING REGION; ATTENUATION; IMMUNOGENICITY; MUTAGENESIS; MUTANTS AB An acceptable live-attenuated dengue virus vaccine candidate should have low potential for transmission by mosquitoes. We have identified and characterized a mutation in dengue virus type 4 (DEN4) that decreases the ability of the virus to infect mosquitoes. A panel of 1248 mutagenized virus clones generated previously by chemical mutagenesis was screened for decreased replication in mosquito C6/36 cells but efficient replication in simian Vero cells. One virus met these criteria and contained a single coding mutation: a C-to-U mutation at nucleotide 7129 resulting in a Pro-to-Leu change in amino acid 101 of the nonstructural 4B gene (NS4B P101L). This mutation results in decreased replication in C6/36 cells relative to wild-type DEN4, decreased infectivity for mosquitoes, enhanced replication in Vero and human HuH-7 cells, and enhanced replication in SCID mice implanted with HuH-7 cells (SCID-HuH-7 mice). A recombinant DEN4 virus (rDEN4) beating this mutation exhibited the same set of phenotypes. Addition of the NS413 P101L mutation to rDEN4 bearing a 30 nucleotide deletion (Delta30) decreased the ability of the double-mutant virus to infect mosquitoes but increased its ability to replicate in SCID-HuH-7 mice. Although the NS4B P101L mutation decreases infectivity of DEN4 for mosquitoes, its ability to enhance replication in SCID-HuH-7 mice suggests that it might not be advantageous to include this specific mutation in an rDEN4 vaccine. The opposing effects of the NS413 P10IL mutation in mosquito and vertebrate systems suggest that the NS4B protein is involved in maintaining the balance between efficient replication in the mosquito vector and the human host. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Entomol, Silver Spring, MD 20955 USA. RP Hanley, KA (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6515,50 South Dr, Bethesda, MD 20892 USA. NR 38 TC 61 Z9 62 U1 2 U2 9 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 JUL 20 PY 2003 VL 312 IS 1 BP 222 EP 232 DI 10.1016/S0042-6822(03)00197-1 PG 11 WC Virology SC Virology GA 708EF UT WOS:000184553600021 PM 12890635 ER PT J AU Yang, XH Thiele, CJ AF Yang, XH Thiele, CJ TI Targeting the tumor necrosis factor-related apoptosis-inducing ligand path in neuroblastoma SO CANCER LETTERS LA English DT Article; Proceedings Paper CT Conference on Advances in Neuroblastoma Research CY JUN 17-19, 2002 CL PARIS, FRANCE DE neuroblastoma; tumor necrosis factor-related apoptosis-inducing ligand; caspase 8; promoter; methylation; demethylation; interferon-gamma; death receptor; TR1; TR2; MYCN; TrkA; TrkB; multiple lesions; stoichiometrical model; amplification; FAS; N-myc; cytotoxic ID DRUG-INDUCED APOPTOSIS; CASPASE-8 EXPRESSION; CELLS; ACTIVATION; FADD; SENSITIZES; RECEPTOR-5; RESISTANCE; MEMBER; FAMILY AB The identification of the tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) a few years ago generated considerable enthusiasm for it as a potential cancer therapeutic agent. This is because TRAIL shows potent apoptosis inducing activity in a wide spectrum of transformed cell lines but not in cell lines derived from normal tissue origin. As the details in the signal transduction pathway of TRAIL-induced apoptosis are clarified, various defects of TRAIL pathway have been identified in TRAIL resistant cancer cells. Neuroblastoma. is the most common extracranial solid tumor in children and those with a poor prognosis require more sensitive therapies. Unlike other cancer cells, most neuroblastoma cell lines are resistant to TRAIL induced apoptosis and the resistance correlates with caspase 8 deficiency, which is attributed to the methylation of the gene. Interferon (IFN)-gamma induces caspase 8 expression in most neuroblastoma cell lines regardless of the methylation status but fails to sensitize most NB to TRAIL. Further analysis indicates a TRAIL receptor deficiency contributes to TRAIL resistance in NB. Multiple lesions suggest that this path may play an important role in tumorigenesis and/ or evasion from therapies. Furthermore it indicates that the clinical application of TRAIL in NB will require a multi-modality approach. Important questions remain unanswered: How does IFN-gamma induce caspase 8 and why is the induction heterogeneous? How to stimulate the caspase 8 induction in cells that fail to respond to IFN-gamma? How to target other TRAIL pathway lesions with the clinically feasible approaches? (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Canc Res Ctr, Pediat Oncol Branch, Cell & Mol Biol Sect,NIH, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Canc Res Ctr, Pediat Oncol Branch, Cell & Mol Biol Sect,NIH, 10 Ctr Dr,MSC-1928, Bethesda, MD 20892 USA. NR 22 TC 19 Z9 27 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 18 PY 2003 VL 197 IS 1-2 BP 137 EP 143 DI 10.1016/S0304-3835(03)00093-4 PG 7 WC Oncology SC Oncology GA 710LE UT WOS:000184681000022 PM 12880973 ER PT J AU Bourgeois, C Okazaki, I Cavanaugh, E Nightingale, M Moss, J AF Bourgeois, C Okazaki, I Cavanaugh, E Nightingale, M Moss, J TI Identification of regulatory domains in ADP-ribosyltransferase-1 that determine transferase and NAD glycohydrolase activities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NICOTINAMIDE ADENINE-DINUCLEOTIDE; SKELETAL-MUSCLE CELLS; ADP-RIBOSYLTRANSFERASE; CRYSTAL-STRUCTURE; MOLECULAR CHARACTERIZATION; DIPHTHERIA-TOXIN; CHOLERA-TOXIN; MOTIF; CONSERVATION; RECOGNITION AB Mono-ADP-ribosyltransferases (ART1-7) transfer ADP- ribose from NAD(+) to proteins (transferase activity) or water (NAD glycohydrolase activity). The mature proteins contain two domains, an alpha-helical amino terminus and a beta-sheet- rich carboxyl terminus. A basic region in the carboxyl termini is encoded in a separate exon in ART1 and ART5. Structural motifs are conserved among ART molecules. Successive amino- or carboxyl-terminal truncations of ART1, an arginine-specific transferase, identified regions that regulated transferase and NAD glycohydrolase activities. In mouse ART1, amino acids 24-38 (ART-specific extension) were needed to inhibit both activities; amino acids 39-45 (common ART coil) were required for both. Successive truncations of the alpha-helical region reduced transferase and NAD glycohydrolase activities; however, truncation to residue 106 enhanced both. Removal of the carboxyl-terminal basic domain decreased transferase, but enhanced NAD glycohydrolase, activity. Thus, amino- and carboxyl-terminal regions of ART1 are required for transferase activity. The enhanced glycohydrolase activity of the shorter mutants indicates that sequences, which are not part of the NAD binding, core catalytic site, exert structural constraints, modulating substrate specificity and catalytic activity. These functional domains, defined by discrete exons or structural motifs, are found in ART1 and other ARTs, consistent with conservation of structure and function across the ART family. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 6D05, Bethesda, MD 20892 USA. EM bourgeoc@nhlbi.nih.gov NR 28 TC 8 Z9 9 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2003 VL 278 IS 29 BP 26351 EP 26355 DI 10.1074/jbc.M303193200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700010 PM 12721285 ER PT J AU Lener, D Kvaratskhelia, M Le Grice, SFJ AF Lener, D Kvaratskhelia, M Le Grice, SFJ TI Nonpolar thymine isosteres in the Ty3 polypurine tract DNA template modulate processing and provide a model for its recognition by Ty3 reverse transcriptase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEQUENCE FEATURES IMPORTANT; RIBONUCLEASE-H DOMAIN; MURINE LEUKEMIA-VIRUS; GROOVE BINDING TRACK; RNASE-H; IMMEDIATELY UPSTREAM; PRIMER-UTILIZATION; CRYSTAL-STRUCTURE; SARCOMA VIRUS AB Despite diverging in sequence and size, the polypurine tract (PPT) primers of retroviruses and long terminal repeat-containing retrotransposons are accurately processed from (+) U3 RNA and DNA by their cognate reverse transcriptases (RTs). In this paper, we demonstrate that misalignment of the Ty3 retrotransposon RT on the human immunodeficiency virus-1 PPT induces imprecise removal of adjacent (+)-RNA and failure to release (+)-DNA from the primer. Based on these observations, we explored the structural basis of Ty3 PPT recognition by chemically synthesizing RNA/DNA hybrids whose (+)- DNA template was substituted with the non-hydrogen-bonding thymine isostere 2,4-difluoro-5-methylbenzene ( F). We observed a consistent spatial correlation between the site of T 3 F substitution and enhanced ribonuclease H ( RNase H) activity similar to12-13 bp downstream. In the most pronounced case, dual T 3 F substitution at PPT positions -1/-2 redirects RNase H cleavage almost exclusively to the novel site. The structural features of this unusual base suggest that its insertion into the Ty3 PPT (-)- DNA template weakens the duplex, inducing a destabilization that is recognized by a structural element of Ty3 RT similar to12-13 bp from its RNase H catalytic center. A likely candidate for this interaction is the thumb subdomain, whose minor groove binding tract most likely contacts the duplex. The spatial relationship derived from T-->F substitution also infers that Ty3 PPT processing requires recognition of sequences in its immediate 5' vicinity, thereby locating the RNase H catalytic center over the PPT-U3 junction, a notion strengthened by additional mutagenesis studies of this paper. C1 NCI, Resistance MechLab, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, Resistance MechLab, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. NR 35 TC 19 Z9 19 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 JUL 18 PY 2003 VL 278 IS 29 BP 26526 EP 26532 DI 10.1074/jbc.M302374200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700032 PM 12730227 ER PT J AU Shen, YH Godlewski, J Zhu, J Sathyanarayana, P Leaner, V Birrer, MJ Rana, A Tzivion, G AF Shen, YH Godlewski, J Zhu, J Sathyanarayana, P Leaner, V Birrer, MJ Rana, A Tzivion, G TI Cross-talk between JNK/SAPK and ERK/MAPK pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MIXED-LINEAGE KINASE; ACTIVATED PROTEIN-KINASE; C-JUN; MESANGIAL CELLS; DNA-SYNTHESIS; TNF-ALPHA; IDENTIFICATION; EXPRESSION; SCAFFOLD; BINDING AB Mixed lineage kinases (MLKs) are a family of serine/threonine kinases that function in the SAPK signaling cascade. MLKs activate JNK/SAPK in vivo by directly phosphorylating and activating the JNK kinase SEK-1 (MKK4 and -7). Importantly, the MLK member MLK3/SPRK has been shown recently to be a direct target of ceramide and tumor necrosis factor-alpha (TNF-alpha) and to mediate the TNF-alpha and ceramide-induced JNK activation in Jurkat cells. Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. Surprisingly, this induction of MEK phosphorylation does not result in ERK activation in vivo. Rather, in cells expressing active MLK3, ERK becomes resistant to activation by growth factors and mitogens. This restriction in ERK activation requires MLK3 kinase activity, is independent of Raf activation, and is reversed by JNK pathway inhibition either at the level of SEK-1, JNK, or Jun. These results demonstrate that sustained JNK activation uncouples ERK activation from MEK in a manner requiring Jun-mediated gene transcription. This in turn points to the existence of a negative cross-talk relationship between the stress-activated JNK pathway and the mitogen-activated ERK pathway. Thus, our findings imply that some of the biological functions of JNK activators, such as TNF-alpha and ceramide, may be attributed to their ability to block cell responses to growth and survival factors acting through the ERK/MAPK pathway. C1 Texas A&M Univ Syst, Hlth Sci Ctr, Coll Med, Div Mol Cardiol,Cardiovasc Res Inst, Temple, TX 76504 USA. NCI, Cell & Canc Biol Dept, NIH, Rockville, MD 20850 USA. RP Tzivion, G (reprint author), Texas A&M Univ, Cardiovasc Res Inst, HSC, 1901 S 1st St,Bldg 162, Temple, TX 76504 USA. RI Tzivion, Guri/D-8954-2011 FU NIGMS NIH HHS [R01 GM 558385, R01 GM 067134] NR 33 TC 137 Z9 139 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 JUL 18 PY 2003 VL 278 IS 29 BP 26715 EP 26721 DI 10.1074/jbc.M303264200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700054 PM 12738796 ER PT J AU Wang, WG Yang, XL de Silanes, IL Carling, D Gorospe, M AF Wang, WG Yang, XL de Silanes, IL Carling, D Gorospe, M TI Increased AMP : ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AU-RICH ELEMENT; RNA-BINDING PROTEIN; MESSENGER-RNA; SIGNALING PATHWAYS; OXIDATIVE STRESS; ELAV PROTEIN; IN-VIVO; TRANSCRIPTION; DEGRADATION; EXPRESSION AB Cytoplasmic export of the RNA-binding protein HuR, a process that critically regulates its function, was recently shown to be inhibited by the AMP-activated protein kinase ( AMPK). In the present investigation, treatment of human fibroblasts with AMPK activators such as 5-amino-imidazole-4-carboxamide riboside, antimycin A, and sodium azide inhibited cell growth and lowered the expression of proliferative genes. As anticipated, AMPK activation also decreased both the cytoplasmic HuR levels and the association of HuR with target radiolabeled transcripts encoding such proliferative genes. HuR function was previously shown to be implicated in the maintenance of a "young cell" phenotype in models of replicative cellular senescence. We therefore postulated that AMPK activation in human fibroblasts might contribute to the implementation of the senescence phenotype through mechanisms that included a reduction in HuR cytoplasmic presence. Indeed, AMP: ATP ratios were 2 -3-fold higher in senescent fibroblasts compared with young fibroblasts. Accordingly, in vitro senescence was accompanied by a marked elevation in AMPK activity. Evidence that increased AMPK activity directly contributed to the implementation of the senescent phenotype was obtained through two experimental approaches. First, use of AMPK activators triggered senescence characteristics in fibroblasts, such as the acquisition of senescence-associated beta-galactosidase (beta-gal) activity and increased p16(INK4a) expression. Second, infection of cells with an adenoviral vector that expresses active AMPK increased senescence-associated beta-gal activity, whereas infection with an adenovirus that expresses dominant-negative AMPK decreased senescence-associated beta-gal activity. Together, our results indicate that AMPK activation can cause premature fibroblast senescence through mechanisms that likely involve reduced HuR function. C1 NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. Imperial Coll Sch Med, MRC, Ctr Clin Sci, London W12 0NN, England. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Carling, David/F-1943-2014; Lopez de Silanes, Isabel/K-4962-2015 OI Carling, David/0000-0002-2316-1830; Lopez de Silanes, Isabel/0000-0001-6762-9792 NR 44 TC 114 Z9 120 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 JUL 18 PY 2003 VL 278 IS 29 BP 27016 EP 27023 DI 10.1074/jbc.M300318200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700093 PM 12730239 ER PT J AU He, HJ Kole, S Kwon, YK Crow, MT Bernier, M AF He, HJ Kole, S Kwon, YK Crow, MT Bernier, M TI Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-SENSING RECEPTOR; ACTIN CYTOSKELETON; LIPID RAFTS; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; MEMBRANE DOMAINS; TARGETS FILAMIN; TERMINAL TAIL; CROSS-LINKING; GROWTH-FACTOR AB The biological actions of insulin are associated with a rapid reorganization of the actin cytoskeleton within cells in culture. Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. The colocalization of endogenous FLNa with IR was detected at the surface of HepG2 cells. Ectopic expression of a C-terminal fragment of FLNa ( FLNaCT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. Expression of FLNaCT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway. C1 NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. NIA, Vasc Studies Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP NIA, Diabet Sect, Clin Invest Lab, NIH, 5600 Nathan Shock Dr,Box 23, Baltimore, MD 21224 USA. EM Bernierm@vax.grc.nia.nih.gov OI Bernier, Michel/0000-0002-5948-368X NR 47 TC 45 Z9 48 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2003 VL 278 IS 29 BP 27096 EP 27104 DI 10.1074/jbc.M301003200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700103 PM 12734206 ER PT J AU Brazer, SCW Singh, BB Liu, XB Swaim, W Ambudkar, IS AF Brazer, SCW Singh, BB Liu, XB Swaim, W Ambudkar, IS TI Caveolin-1 contributes to assembly of store-operated Ca2+ influx channels by regulating plasma membrane localization of TRPC1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIPID RAFTS; SIGNAL-TRANSDUCTION; CATION CHANNELS; CALCIUM-ENTRY; C-TERMINUS; RECEPTOR; CELLS; PROTEINS; COMPLEX; DOMAINS AB TRPC1, a component of store-operated Ca2+ entry (SOCE) channels, is assembled in a complex with caveolin-1 (Cav1) and key Ca2+ signaling proteins. This study examines the role of Cav1 in the function of TRPC1. TRPC1 and Cav1 were colocalized in the plasma membrane region of human submandibular gland and Madin-Darby canine kidney cells. Full-length Cav1 bound to both the N and C termini of TRPC1. Amino acids 271 - 349, which includes a Cav1 binding motif ( amino acids 322 - 349), was identified as the Cav1 binding domain in the TRPC1 N terminus. Deletion of amino acids 271 - 349 or 322 - 349 prevented plasma membrane localization of TRPC1. Importantly, TRPC1Delta271-349 induced a dominant suppression of SOCE and was associated with wild-type TRPC1. Although the role of the C-terminal Cav1 binding domain is not known, its deletion did not affect localization of TRPC1 (Singh, B. B., Liu, X., and Ambudkar, I. S. ( 2000) J. Biol. Chem. 275, 36483 36486). Further, expression of a truncated Cav1 ( Cav1Delta51-169), but not full-length Cav1, similarly disrupted plasma membrane localization of endogenously and exogenously expressed TRPC1 in human submandibular gland and Madin-Darby canine kidney cells. Cav1Delta51-169 also suppressed thapsigargin- and carbachol-stimulated Ca2+ influx and increased the detergent solubility of TRPC1, although plasma membrane lipid raft domains were not disrupted. These data demonstrate that plasma membrane localization of TRPC1 depends on an interaction between its N terminus and Cav1. Thus, our data suggest that Cav1 has an important role in the assembly of SOCE channel(s). C1 NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. NIDCR, Cellular Imaging Core, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, Dept Hlth & Human Serv,NIH, Bldg 10,Rm 1N-113, Bethesda, MD 20892 USA. OI Singh, Brij/0000-0003-0535-5997 FU NIDCR NIH HHS [R01 DE017102-03, R01 DE017102, R01 DE017102-01A1, R01 DE017102-02, R01 DE017102-04, R01 DE017102-05, R01 DE017102-06A1, R01 DE017102-07] NR 43 TC 141 Z9 148 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 JUL 18 PY 2003 VL 278 IS 29 BP 27208 EP 27215 DI 10.1074/jbc.M301118200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 701ER UT WOS:000184155700116 PM 12732636 ER PT J AU Mayasundari, A Rice, WG Diminnie, JB Baker, DC AF Mayasundari, A Rice, WG Diminnie, JB Baker, DC TI Synthesis, resolution, and determination of the absolute configuration of the enantiomers of cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide, an HIV-1NCp7 inhibitor SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 NUCLEOCAPSID PROTEIN; ANTI-HIV AGENTS; ZINC FINGERS; IN-VITRO; PYRIDINIOALKANOYL THIOESTERS; REVERSE-TRANSCRIPTASE; INFECTIVITY; THERAPY; TARGET AB The anti-HIV activity of (+/-)-cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide [(+/-)-(cis-1,1-dioxo-[1,2]-dithiane-4,5-diol, NSC-624151] and its attack on the zinc finger domain of the HIV-1 nucleocapsid p7 (NCp7) protein has been established [Rice, W. G.; Baker. D. C.: Schaeffer, C. A.; Graham, L.; Bu, M.; Terpening, S.; Clanton, D.; Schultz, R.; Bader, J. P.; Buckheit, R. W.; Field, L.; Singh, P. K. Turpin, J. A. Antimicrob. Agents Chemother. 1497, 41, 419]. In order to determine which enantiomer of NSC-624151 is the more active component, the compound was resolved via its bis-'Mosher ester', which was prepared via its reaction with two equiv of (-)-(R)-alpha-methoxy-alpha-(trifluoromethyl) phenylacetyl chloride. The diastereoisomeric esters were separated. and each ester was hydrolyzed to yield enantiomers with [alpha](D)(21) + 151degrees (c 0.5, MeOH) and [alpha](D)(21) -146degrees (c 0.5, MeOH). Single-crystal X-ray analysis of the (-)-bis-'Mosher ester' showed that the (-)-enantiomer is the (4S, 5R)-compound. The (-)-enantiomer (NSC 693195) was ca. twice as active (EC50 8.8 +/- 0.2 muM) as its (+)-counterpart (NSC 693194) (EC50 16.2 +/- 2.4 muM) in the XTT assay against HIV-1. All three compounds were found to be approximately equally effective in promoting Zn ejection from the NCp7 zinc finger. As the more anti-HIV active enantiomer is only slightly more active than the racemic form, it appears to offer no advantages over the racemic form. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Tennessee, Dept Chem, Knoxville, TN 37996 USA. SAIC Frederick, NCI, FCRDC, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. RP Baker, DC (reprint author), Univ Tennessee, Dept Chem, Knoxville, TN 37996 USA. FU NCI NIH HHS [N01-CM-47038] NR 49 TC 11 Z9 11 U1 0 U2 5 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 JUL 17 PY 2003 VL 11 IS 14 BP 3215 EP 3219 DI 10.1016/S0968-0896(03)00269-4 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 695FM UT WOS:000183820500019 PM 12818684 ER PT J AU Chyan, YJ Rawson, TY Wilson, SH AF Chyan, YJ Rawson, TY Wilson, SH TI Cloning and characterization of a novel member of the human ATF/CREB family: ATF2 deletion, a potential regulator of the human DNA polymerase beta promoter SO GENE LA English DT Article DE DNA repair; transcriptional regulation; cAMP response element; mRNA splicing; DNA polymerase beta; base excision repair ID HAMSTER OVARY CELLS; RESPONSE ELEMENT; LEUCINE ZIPPER; MESSENGER-RNA; TRANSCRIPTIONAL ACTIVATION; CYCLIC-AMP; BINDING; PHOSPHORYLATION; GENE; CREB AB The solitary cAMP response element (CRE)(1) in the human DNA polymerase beta (beta-pol) core promoter plays a key role in both basal expression and the DNA-alkylating agent response of the promoter. To further understand the role of the CRE in the regulation of this promoter. we searched for novel CRE-binding proteins by using a (32)p-labeled beta-pol CRE oligodeoxynucleotide and a human cDNA expression library constructed in phage X. A total of fourteen phage clones were isolated, corresponding to various members of the CRE-binding protein family. One of these clones, termed ATF2 deletion (ATF2d), encodes a novel ATF2 isoform and was chosen for further characterization in this study. Relative to ATF2 mRNA, this clone contains an internal 97-nt deletion and a unique 3' region. The 97-nt deletion causes a frame shift, resulting in a ATF2-like polypeptide of similar to60 kDa. ATF2d retains the bZIP domain of ATF2, lacks the N-terminal zinc-finger region, and includes novel characteristics in its N- and C-terminal regions. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. RP Wilson, SH (reprint author), NIEHS, Lab Struct Biol, NIH, POB 12233,111 T W Alexander Dr,Bldg 101,Room B246, Res Triangle Pk, NC 27709 USA. NR 29 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUL 17 PY 2003 VL 312 BP 117 EP 124 DI 10.1016/S0378-1119(03)00607-3 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 715JG UT WOS:000184967900012 PM 12909347 ER PT J AU Okada, Y Tsuda, Y Fujita, Y Yokoi, T Sasaki, Y Ambo, A Konishi, R Nagata, M Salvadori, S Jinsmaa, Y Bryant, SD Lazarus, LH AF Okada, Y Tsuda, Y Fujita, Y Yokoi, T Sasaki, Y Ambo, A Konishi, R Nagata, M Salvadori, S Jinsmaa, Y Bryant, SD Lazarus, LH TI Unique high-affinity synthetic mu-opioid receptor agonists with central- and systemic-mediated analgesia SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DMT-TIC PHARMACOPHORE; MESSAGE-ADDRESS CONCEPT; ENDOGENOUS AGONIST; DELTA-ANTAGONISTS; BINDING ACTIVITY; OPIATE RECEPTOR; PEPTIDE FAMILY; POTENT; ANALOGS; SELECTIVITY AB Unique opioid mimetic substances containing identical N-terminal aromatic residues separated by an unbranched alkyl chain containing two to eight methylene groups were developed. Regardless of the length of interposing alkyl chain, the bis-Tyr and bis-Phe compounds were inactive; however, replacement by a single Dint (2',6'-dimethyl-L-tyrosine) residue enhanced activity by orders of magnitude. Moreover, the bis-Dmt compounds were another 10-fold more potent with an optimum intra-aromatic ring distance of about four to six methylene units. 1,4-Bis(Dmt-NH)butane (7) had high mu-opioid receptor affinity (K-i = 0.041 nM) and functional mu-opioid agonist bioactivity (IC50 = 5.3 nM) with in vivo central (intracerebroventricular) and systemic (subcutaneous) analgesia in mice (1.5- to 2.5-fold greater than and 10-12% relative to morphine, respectively); these activities were reversed by naloxone to the same degree. It appears that the bis-Dmt compounds indiscriminately act as both message and address domains. C1 Kobe Gakuin Univ, Dept Med Chem, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, High Technol Res Ctr, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. Teikoku Seiyaku Co Ltd, Oochi 7692695, Japan. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. RP Okada, Y (reprint author), Kobe Gakuin Univ, Dept Med Chem, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. EM okada@pharm.kobegakuin.ac.jp; lazarusC@niehs.nih.gov NR 41 TC 35 Z9 36 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 17 PY 2003 VL 46 IS 15 BP 3201 EP 3209 DI 10.1021/jm020459z PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 699YM UT WOS:000184084800006 PM 12852751 ER PT J AU Fox, BM Xiao, XS Antony, S Kohlhagen, G Pommier, Y Staker, BL Stewart, L Cushman, M AF Fox, BM Xiao, XS Antony, S Kohlhagen, G Pommier, Y Staker, BL Stewart, L Cushman, M TI Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-Camptothecin hybrids SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RING; DERIVATIVES; MECHANISM AB The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1. poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential. The first strategy involved the synthesis of indenoiso-quinoline-camptothecin hybrid molecules to take advantage of a proposed structural analogy between the indenoisoquinolines and camptothecin. The desired hybrids were synthesized by reaction of halogenated phthalides with a dihydropyrroloquinoline. The second strategy involved the attachment of various alkenyl substituents to the C-11 position of the indenoisoquinolines, which were assumed to project into the DNA minor groove. The required C-11-substituted indenoisoquinolines were synthesized by McMurry reactions of 11-ketoindenoisoquinolines with aldehydes, and the geometries of the resulting alkenes were established by nuclear Overhauser effect difference NMR spectroscopy. All of the new indenoisoquinolines were examined for cytotoxicity in human cancer cell cultures as well as for activity vs top1. Although the indenoiso-quinoline-camptothecin hybrid molecules proved to be less cytotoxic and displayed less activity against top1, an analogue incorporating a 3'-aminoalkenyl substituent at the C-11 position of the indenoisoquinoline system was significantly more potent than the prototype indenoisoquinoline in both assays. These results indicate that C-11 aminoalkyl substituents that are assumed to project into the minor groove enhance the cytotoxicity and top1 inhibitory activity of the parent indenoisoquinoline system. C1 Purdue Univ, Sch Pharm & Pharm Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. DeCODE Genet Inc, Biostruct Grp, Bainbridge Isl, WA 98110 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharm Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu FU NCI NIH HHS [R44 CA79439-02, U01 CA89566, R43 CA79439-01, R43-CA82964-01, N01-CO-56000]; OHS HRSA HHS [ST32CA09634] NR 22 TC 73 Z9 74 U1 1 U2 9 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 JUL 17 PY 2003 VL 46 IS 15 BP 3275 EP 3282 DI 10.1021/jm0300476 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 699YM UT WOS:000184084800012 PM 12852757 ER PT J AU Choi, YS George, C Comin, MJ Barchi, JJ Kim, HS Jacobson, KA Balzarini, J Mitsuya, H Boyer, PL Hughes, SH Marquez, VE AF Choi, YS George, C Comin, MJ Barchi, JJ Kim, HS Jacobson, KA Balzarini, J Mitsuya, H Boyer, PL Hughes, SH Marquez, VE TI A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; NUCLEOSIDES; NORTHERN AB The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N-3-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T. C1 NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Katholieke Univ Leuven, Rega Inst, B-3000 Louvain, Belgium. NCI, Expt Retrovirol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, HIV Durg Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), NCI, Ctr Canc Res, Med Chem Lab, 376 Boyles St,Bldg 376,Rm 104, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov RI Jacobson, Kenneth/A-1530-2009; Barchi Jr., Joseph/N-3784-2014; Choi, Yongseok/F-8375-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; Choi, Yongseok/0000-0002-3622-3439 NR 18 TC 49 Z9 50 U1 1 U2 8 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 JUL 17 PY 2003 VL 46 IS 15 BP 3292 EP 3299 DI 10.1021/jm030116g PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 699YM UT WOS:000184084800014 PM 12852759 ER PT J AU Agrawal, A Lingappa, J Leppla, SH Agrawal, S Jabbar, A Quinn, C Pulendran, B AF Agrawal, A Lingappa, J Leppla, SH Agrawal, S Jabbar, A Quinn, C Pulendran, B TI Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin SO NATURE LA English DT Article AB Anthrax poses a clear and present danger as an agent of biological terrorism(1-3). Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death(4-8). Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells-which are pivotal to the establishment of immunity against pathogens- and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response. C1 Emory Vaccine Res Ctr, Atlanta, GA 30329 USA. CDCP, Meningitis & Special Pathogens Branch, Div Bacterial & Mycot Dis, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. NIAID, Microbial Pathogenesis Sect, Bethesda, MD 20892 USA. RP Pulendran, B (reprint author), Emory Vaccine Res Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. NR 30 TC 213 Z9 224 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 17 PY 2003 VL 424 IS 6946 BP 329 EP 334 DI 10.1038/nature01794 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 701RZ UT WOS:000184183900046 PM 12867985 ER PT J AU Jiang, GY Giannone, G Critchley, DR Fukumoto, E Sheetz, MP AF Jiang, GY Giannone, G Critchley, DR Fukumoto, E Sheetz, MP TI Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin SO NATURE LA English DT Article AB Mechanical forces on matrix-integrin-cytoskeleton linkages are crucial for cell viability, morphology and organ function(1). The production of force depends on the molecular connections from extracellular-matrix-integrin complexes to the cytoskeleton(2,3). The minimal matrix complex causing integrin-cytoskeleton connections is a trimer of fibronectin's integrin-binding domain FNIII7-10 (ref. 4). Here we report a specific, molecular slip bond that was broken repeatedly by a force of 2 pN at the cellular loading rate of 60 nm s(-1); this occurred with single trimer beads but not with monomer. Talin1, which binds to both integrins and actin filaments in vitro, is required for the 2-pN slip bond and rapid cytoskeleton binding. Further, inhibition of fibronectin binding to alpha(v)beta(3) and deletion of beta(3) markedly decreases the 2-pN force peak. We suggest that talin1 initially forms a molecular slip bond between closely packed fibronectin-integrin complexes and the actin cytoskeleton, which can apply a low level of force to fibronectin until many bonds form or a signal is received to activate a force response. C1 Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. NIH, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Sheetz, MP (reprint author), Columbia Univ, Dept Biol Sci, 1212 Amsterdam Ave, New York, NY 10027 USA. NR 30 TC 269 Z9 273 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 17 PY 2003 VL 424 IS 6946 BP 334 EP 337 DI 10.1038/nature01805 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 701RZ UT WOS:000184183900047 PM 12867986 ER PT J AU Thompson, IM Goodman, PJ Tangen, CM Lucia, MS Miller, GJ Ford, LG Lieber, MM Cespedes, RD Atkins, JN Lippman, SM Carlin, SM Ryan, A Szczepanek, CM Crowley, JJ Coltman, CA AF Thompson, IM Goodman, PJ Tangen, CM Lucia, MS Miller, GJ Ford, LG Lieber, MM Cespedes, RD Atkins, JN Lippman, SM Carlin, SM Ryan, A Szczepanek, CM Crowley, JJ Coltman, CA TI The influence of finasteride on the development of prostate cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANDROGEN RECEPTOR GENE; RADICAL PROSTATECTOMY; PREVENTION TRIAL; THERAPY; RISK; HYPERPLASIA; FEATURES; ANTIGEN; VOLUME; BIOPSY AB Background: Androgens are involved in the development of prostate cancer. Finasteride, an inhibitor of 5alpha-reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate, and may reduce the risk of prostate cancer. Methods: In the Prostate Cancer Prevention Trial, we randomly assigned 18,882 men 55 years of age or older with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng per milliliter or lower to treatment with finasteride (5 mg per day) or placebo for seven years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the digital rectal examination was abnormal. It was anticipated that 60 percent of participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. The primary end point was the prevalence of prostate cancer during the seven years of the study. Results: Prostate cancer was detected in 803 of the 4368 men in the finasteride group who had data for the final analysis (18.4 percent) and 1147 of the 4692 men in the placebo group who had such data (24.4 percent), for a 24.8 percent reduction in prevalence over the seven-year period (95 percent confidence interval, 18.6 to 30.6 percent; P<0.001). Tumors of Gleason grade 7, 8, 9, or 10 were more common in the finasteride group (280 of 757 tumors [37.0 percent], or 6.4 percent of the 4368 men included in the final analysis) than in the placebo group (237 of 1068 tumors [22.2 percent], P<0.001 for the comparison between groups; or 5.1 percent of the 4692 men included in the final analysis, P=0.005 for the comparison between groups). Sexual side effects were more common in finasteride-treated men, whereas urinary symptoms were more common in men receiving placebo. Conclusions: Finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer. C1 SW Oncol Grp, Operat Off, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. NCI, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN USA. Wilford Hall USAF Med Ctr, San Antonio, TX 78236 USA. SE Med Oncol Ctr, Goldsboro, NC USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Grand Rapids Community Clin Oncol Program, Grand Rapids, MI USA. SW Oncol Grp, Ctr Stat, San Antonio, TX 78245 USA. Univ Colorado, Denver, CO 80202 USA. RP Thompson, IM (reprint author), SW Oncol Grp, Operat Off, 14980 Omicron Dr, San Antonio, TX 78245 USA. FU NCI NIH HHS [CA37429, CA35178, CA45808] NR 30 TC 1496 Z9 1546 U1 4 U2 49 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 17 PY 2003 VL 349 IS 3 BP 215 EP 224 DI 10.1056/NEJMoa030660 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 701KA UT WOS:000184165700005 PM 12824459 ER PT J AU Renou, JP Bierie, B Miyoshi, K Cui, YZ Djiane, J Reichenstein, M Shani, M Hennighausen, L AF Renou, JP Bierie, B Miyoshi, K Cui, YZ Djiane, J Reichenstein, M Shani, M Hennighausen, L TI Identification of genes differentially expressed in mouse mammary epithelium transformed by an activated beta-catenin SO ONCOGENE LA English DT Article DE mammary gland; beta-catenin; transdifferentiation; metaplasia; microarrays Mammochip ID LYSOSOMAL CYSTEINE PROTEASES; CRE RECOMBINASE; DEPENDENT EXPRESSION; GLAND INVOLUTION; BREAST-CANCER; HAMSTER CELLS; CATHEPSIN-L; PROTEIN; SPECIFICITY; ADIPOCYTES AB beta-Catenin is an executor of Wnt signaling and it can control cell fate and specification. Deletion of exon 3 from the endogenous beta-catenin gene in differentiating mammary alveolar epithelium of the mouse results in the generation of an activated protein that lacks amino acids 5-80. This is accompanied by a loss of mammary epithelial differentiation and a transdifferentiation process to squamous metaplasias. To further understand the molecular process of transdifferentiation, the expression of genes in mammary tissue was profiled in the absence and presence of activated of beta-catenin. Microarrays were generated that carry about 8500 cDNA clones with approximately 6000 obtained from mammary tissue. Mutant tissues, which had undergone either partial (TD1) or complete (TD2) squamous transdifferentiation, were compared with wild-type mammary tissue. Four groups of genes were identified. Group I contained genes whose expression was induced in both mutant tissues. Groups 2 and 3 contained genes that were active preferentially in TD2 and TD1, respectively. Group 4 contained genes suppressed in both samples. Using this approach, known and unknown genes activated in the transdifferentiation process were identified. A new 20 kDa protein (PANE1) induced upon transdifferentiation was nuclear in nonconfluent cells and cytoplasmic in confluent or dividing cells. Lastly, stabilization of beta-catenin resulted in the retention of differentiated epithelium upon involution and altered activities of several proteases in transdifferentiated mammary epithelium. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. INRA, Jouy En Josas, France. Univ Tokushima, Dept Biochem, Sch Dent, Tokushima 770, Japan. Agr Res Org, Volcani Ctr, IL-50250 Bet Dagan, Israel. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101, Bethesda, MD 20892 USA. NR 33 TC 24 Z9 27 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 17 PY 2003 VL 22 IS 29 BP 4594 EP 4610 DI 10.1038/sj.onc.1206596 PG 17 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 699JX UT WOS:000184054700016 PM 12881717 ER PT J AU Gao, HM Liu, B Hong, JS AF Gao, HM Liu, B Hong, JS TI Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE pesticides; microglia; superoxide; NADPH oxidase; Parkinson's disease; inflammation ID ENVIRONMENTAL RISK-FACTORS; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; NEURODEGENERATIVE DISEASES; PESTICIDE EXPOSURE; FREE-RADICALS; NITRIC-OXIDE; ACTIVATION; BRAIN; CELLS AB Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase - null ( gp91(phox-/-)) or wild-type (gp91(phox+/+)) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced rotenone neurotoxicity. In neuron-glia cultures, dopaminergic neurons from gp91(phox-/-) mice were more resistant to rotenone neurotoxicity than those from gp91(phox+/+) mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91(phox+/+) mice but not from gp91(phox-/-) mice to neuron-enriched cultures markedly increased rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91(phox-/-) mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 48 TC 196 Z9 202 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 16 PY 2003 VL 23 IS 15 BP 6181 EP 6187 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 702BQ UT WOS:000184205100004 PM 12867501 ER PT J AU Soda, T Nakashima, R Watanabe, D Nakajima, K Pastan, I Nakanishi, S AF Soda, T Nakashima, R Watanabe, D Nakajima, K Pastan, I Nakanishi, S TI Segregation and coactivation of developing neocortical layer 1 neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Cajal-Retzius cell; transgenic mouse; green fluorescent protein; neocortex; layer 1; synaptic transmission; neural circuit; reelin ID CAJAL-RETZIUS CELLS; MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; CEREBRAL-CORTEX; NEONATAL HIPPOCAMPUS; EXCITATORY ACTIONS; CORTICAL-NEURONS; FEATURE ARTICLE; NMDA RECEPTORS; LOW MG2+ AB Layer 1 in the developing cerebral cortex is populated by two basic neuronal cell types, Cajal-Retzius (CR) cells and non-CR cells. We generated transgenic mice in which green fluorescent protein (GFP) was driven by the promoter of metabotropic glutamate receptor subtype 2 and expressed specifically in CR cells during cortical development. On the basis of the precise identification of CR cells with GFP fluorescence, we pursued developmental changes and synaptic mechanisms of both CR and non-CR cells during the postnatal period. Immunostaining in combination with GFP fluorescence imaging showed that GFP and reelin, a protein involved in corticogenesis, completely overlap in CR cells at postnatal day 0. At the subsequent postnatal stage, reelin-positive neurons are segregated and categorized into GFP-positive/GABA-negative CR cells and GFP-negative/GABA-positive non-CR cells. Individual and simultaneous whole-cell recordings of CR and non-CR cells in developing cerebral slices revealed that spontaneous and electrically evoked postsynaptic currents ( sPSCs and ePSCs) measured in CR and non-CR cells are differentially mediated by GABA(A) receptors versus GABA(A), AMPA, and NMDA receptors, respectively. Furthermore, CR and non-CR cells show synchronized repetitive barrages of sPSCs that reflect a network-driven activity in the developing cerebral cortex. These findings imply that the layer 1 neurons dynamically change and play a distinct and integral role in the postnatal developing neocortex. C1 Kyoto Univ, Fac Med, Dept Biol Sci, Sakyo Ku, Kyoto 6068501, Japan. Kyoto Univ, Grad Sch Biostudies, Dept Mol & Syst Biol, Kyoto 6068501, Japan. Keio Univ, Sch Med, Dept Anat, Tokyo 1608582, Japan. Jikei Univ, Sch Med, Inst DNA Med, Dept Mol Neurobiol, Tokyo 1058461, Japan. NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nakanishi, S (reprint author), Kyoto Univ, Fac Med, Dept Biol Sci, Sakyo Ku, Kyoto 6068501, Japan. RI Nakajima, Kazunori/L-3396-2013 OI Nakajima, Kazunori/0000-0003-1864-9425 NR 47 TC 59 Z9 61 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 16 PY 2003 VL 23 IS 15 BP 6272 EP 6279 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 702BQ UT WOS:000184205100015 PM 12867512 ER PT J AU Strickler, HD Palefsky, JM Shah, KV Anastos, K Klein, RS Minkoff, H Duerr, A Massad, LS Celentano, DD Hall, C Fazzari, M Cu-Uvin, S Bacon, M Schuman, P Levine, AM Durante, AJ Gange, S Melnick, S Burk, RD AF Strickler, HD Palefsky, JM Shah, KV Anastos, K Klein, RS Minkoff, H Duerr, A Massad, LS Celentano, DD Hall, C Fazzari, M Cu-Uvin, S Bacon, M Schuman, P Levine, AM Durante, AJ Gange, S Melnick, S Burk, RD TI Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CERVICAL CYTOLOGIC ABNORMALITIES; INFECTION; RISK; PREVALENCE; HIV; DNA; PERSISTENCE; DYSPLASIA AB Background: Human papillomavirus (HPV) type 16 is etiologically associated with approximately half of all cervical cancers. It is important, therefore, to determine the characteristics that distinguish HPV16 from other HPV types. A preliminary result based on cross-sectional baseline data in the Women's Interagency Human Immunodeficiency Virus (HIV) Study (WIHS) suggested that the prevalence of HPV16 might have a weaker association with immune status in HIV-seropositive women than that of other HPV types. To address this issue, we examined HPV test results from repeated study visits in the WIHS and from an independent study, the HIV Epidemiology Research Study (HERS). Methods: HIV-seropositive women in the WIHS (n = 2058) and in the HERS (n = 871) were assessed semiannually. HPV DNA was detected in cervicovaginal lavage specimens by using polymerase chain reaction assays. Prevalence ratios were used to compare the prevalence of each HPV type in women with the lowest CD4+ T-cell counts (<200 T cells/mm(3)) with that of women with the highest CD4+ T-cell counts (greater than or equal to500 T cells/mm(3)). A summary prevalence ratio for each HPV type (i.e., across visits and studies) was estimated using generalized estimating equations. The association of CD4+ T-cell stratum with type-specific HPV incidence was measured using multivariable Cox regression models. All statistical tests were two-sided. Results: The prevalence ratio for HPV16 was low compared with that of other HPV types at every study visit in both cohorts. The generalized estimating equation summary prevalence ratio for HPV16 (1.25, 95% confidence interval [CI] = 0.97 to 1.62) was the smallest measured, and it was statistically significantly lower than that of all other HPV types combined (P = .01). The association of CD4+ T-cell stratum with HPV16 incidence was also among the smallest measured (hazard ratio = 1.69, 95% CI = 1.01 to 2.81). Conclusions: The prevalent and incident detection of HPV16 is more weakly associated with immune status in HIV-seropositive women than that of other HPV types, suggesting that HPV16 may be better at avoiding the effects of immune surveillance, which could contribute to HPV16's strong association with cervical cancer. C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Johns Hopkins Univ, Baltimore, MD USA. Lincoln Med Ctr, Lincoln, NE USA. Maimonides Hosp, Brooklyn, NY 11219 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. So Illinois Univ, Sch Med, Springfield, IL USA. Brown Univ, Providence, RI 02912 USA. Georgetown Univ, Ctr Med, Washington, DC USA. Wayne State Univ, Detroit, MI USA. Univ So Calif, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. RP Strickler, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, 1300 Morris Pk Ave,Belfer 1308, Bronx, NY 10461 USA. OI Durante, Amanda/0000-0002-6721-7285; Gange, Stephen/0000-0001-7842-512X FU NCI NIH HHS [CA85178-01]; NCRR NIH HHS [5 M01-RR-00079]; NIAID NIH HHS [U01 AI35004-07] NR 29 TC 122 Z9 127 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 16 PY 2003 VL 95 IS 14 BP 1062 EP 1071 PG 10 WC Oncology SC Oncology GA 703QB UT WOS:000184291500012 PM 12865452 ER PT J AU Rutter, JL Wacholder, S Chetrit, A Lubin, F Menczer, J Ebbers, S Tucker, MA Struewing, JP Hartge, P AF Rutter, JL Wacholder, S Chetrit, A Lubin, F Menczer, J Ebbers, S Tucker, MA Struewing, JP Hartge, P TI Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: An Israeli population-based case-control study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TUBAL-LIGATION; PROPHYLACTIC OOPHORECTOMY; BREAST-CANCER; ORAL-CONTRACEPTIVES; JEWISH WOMEN; CARRIERS; STERILIZATION; HYSTERECTOMY; EPIDEMIOLOGY; CARCINOMA AB Background: In the general population, the risk of developing ovarian cancer is reduced in women who have undergone tubal ligation, hysterectomy, or oophorectomy, although peritoneal cancer can arise after bilateral oophorectomy. In studies from genetic screening clinics, women with mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2 have been found to have a low risk of peritoneal carcinoma in the first years after bilateral oophorectomy. We assessed the level and persistence of reduction of ovarian (including peritoneal) cancer risk after gynecologic surgeries for women who carry BRCA1/2 mutations but were not selected from high-risk clinics. Methods: We identified 1124 Israeli women with incident ovarian cancer or primary peritoneal cancer and tested 847 of them for the three Ashkenazi founder mutations. We compared gynecologic surgery history among all case patients, BRCA1 (n = 187) and BRCA2 (n = 64) carrier case patients, and the non-carrier case patients (n = 598) with that in control subjects drawn from a population registry (n = 2396). We estimated ovarian cancer risk (odds ratios [ORs] with 95% confidence intervals [CIs]) after gynecologic surgery in mutation carriers and non-carriers with logistic regression models. Results: Eight women with primary peritoneal cancer and 128 control subjects reported a previous bilateral oophorectomy (OR = 0.12, 95% CI = 0.06 to 0.24). Other gynecologic surgeries were associated with a 30%-50% reduced risk of ovarian cancer, depending on the type of surgery, with surgery to remove some ovarian tissue associated with the most risk reduction (OR = 0.34, 95% CI = 0.16 to 0.74). Reduced risks were seen in BRCA1/2 carriers and non-carriers. Age at surgery and years since surgery did not affect risk reductions. Conclusion: Both BRCA1/2 mutation carriers and non-carriers have reduced risk of ovarian or peritoneal cancer after gynecologic surgery. The magnitude of the reduction depends upon the type and extent of surgery. C1 NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Edith Wolfson Med Ctr, Holon, Israel. RP Hartge, P (reprint author), NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, NIH, Execut Pl S,Rm 8090,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; Rutter, Joni/0000-0002-6502-2361 FU NCI NIH HHS [N02-CP-81005, N02-CP-91026, N02-CP-60534, R01 CA61126-01-03] NR 36 TC 58 Z9 58 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 JUL 16 PY 2003 VL 95 IS 14 BP 1072 EP 1078 PG 7 WC Oncology SC Oncology GA 703QB UT WOS:000184291500013 PM 12865453 ER PT J AU Hsing, A Chua, S AF Hsing, A Chua, S TI Re: Insulin resistance and prostate cancer risk - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID BODY-SIZE C1 NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA. RP Hsing, A (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, EPS-7058,MSC-7234,6120 Executive Blvd, Rockville, MD 20852 USA. NR 6 TC 0 Z9 0 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 JUL 16 PY 2003 VL 95 IS 14 BP 1087 EP 1087 PG 1 WC Oncology SC Oncology GA 703QB UT WOS:000184291500016 ER PT J AU Merchant, MS Thiele, CJ AF Merchant, MS Thiele, CJ TI Re: Potential use of imatinib in Ewing's sarcoma: Evidence for in vitro and in vivo activity - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID C-KIT; CELLS C1 NCI, NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Merchant, MS (reprint author), NCI, NIH, Pediat Oncol Branch, 10 Ctr Dr,MSC 1298,Bldg 10-13N240, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 16 PY 2003 VL 95 IS 14 BP 1088 EP 1089 PG 2 WC Oncology SC Oncology GA 703QB UT WOS:000184291500018 ER PT J AU McDermott, MM Green, D Greenland, P Liu, K Criqui, MH Chan, CL Guralnik, JM Pearce, WH Ridker, PM Taylor, L Rifai, N Schneider, JR AF McDermott, MM Green, D Greenland, P Liu, K Criqui, MH Chan, CL Guralnik, JM Pearce, WH Ridker, PM Taylor, L Rifai, N Schneider, JR TI Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; C-REACTIVE PROTEIN; ATHEROSCLEROSIS; CHOLESTEROL; SERUM; ASSOCIATION; CORONARY AB Associations between hemostatic and inflammatory markers relative to the ankle brachial index (ABI), an indicator of the presence and severity of peripheral arterial disease (PAD), are not fully understood. We studied relations among selected hemostatic factors, inflammatory markers, and the ankle brachial index (ABI) in patients with and without peripheral arterial disease (PAD). Participants were 370 men and women with ABI <0.90 and 231 patients with ABI 0.90 to 1.50 identified from noninvasive vascular laboratories and general medicine practice. Blood factors were D-dimer, prothrombin 1.2, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), and inflammatory markers (high-sensitivity C-reactive protein [CRP], fibrinogen, and serum amyloid A [SAA]). Among patients without a history of cardiac or cerebrovascular disease, the ABI was significantly inversely associated with log D-dimer (p <0.001), log prothrombin 1.2 (p = 0.001), log CRP (p < 0.001), and log fibrinogen (p = 0.005) in unadjusted analyses. In multivariable regression analyses adjusting for all blood factors as well as potential confounders, D-dimer was associated independently with ABI in participants with a history of cardiac or cerebrovascular disease (p = 0.003) and in participants without a history of cardiac or cerebrovascular disease (p = 0.017). In these analyses, CRP was associated independently with ABI among participants with a history of cardiac or cerebrovascular disease (P = 0.026). CRP was not associated independently with ABI in participants without a history of cardiac or cerebrovascular disease. We conclude that D-dimer levels may be more sensitive than other blood markers for measuring the extent of atherosclerosis in lower extremity arteries. (C) 2003 by Excerpta Medica, Inc. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Rehabil Inst Chicago, Chicago, IL 60611 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Northwestern Univ, Evanston Hosp, Evanston, IL 60201 USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. FU NCRR NIH HHS [RR 00048]; NHLBI NIH HHS [R01 HL 58099, R01 HL 64739] NR 18 TC 87 Z9 92 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2003 VL 92 IS 2 BP 194 EP 199 DI 10.1016/S0002-9149(03)00537-X PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 701HW UT WOS:000184163000014 PM 12860223 ER PT J AU Alper, OM Wong, LJC Hostetter, G Cook, J Tenenholz, B Hsu, E Woo, MS AF Alper, OM Wong, LJC Hostetter, G Cook, J Tenenholz, B Hsu, E Woo, MS TI 1154insTC is not a rare CFTR mutation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID CYSTIC-FIBROSIS MUTATIONS; GENE C1 Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Washington, DC 20057 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Geisinger Hlth Syst, Danville, PA USA. Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA. RP Wong, LJC (reprint author), Georgetown Univ, Med Ctr, Inst Mol & Human Genet, POB 571477,3800 Reservoir Rd,NW M4000, Washington, DC 20057 USA. NR 10 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 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 15 PY 2003 VL 120A IS 2 BP 294 EP 295 DI 10.1002/ajmg.a.20038 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 695DT UT WOS:000183816400026 PM 12833419 ER PT J AU White, CC Viernes, H Krejsa, CM Botta, D Kavanagh, TJ AF White, CC Viernes, H Krejsa, CM Botta, D Kavanagh, TJ TI Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE glutamate-cysteine ligase; glutathione; microtiter plate; fluorescence ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; AMINO-ACID-SEQUENCE; PERFORMANCE LIQUID-CHROMATOGRAPHY; RAT-KIDNEY; GLUTATHIONE SYNTHETASE; CATALYTIC SUBUNIT; REGULATORY SUBUNIT; MOLECULAR-CLONING; MESSENGER-RNA; LIGHT SUBUNIT AB Glutamate-cysteine ligase (GCL; also known as gamma-glutamyleysteine synthetase) is the rate-limiting enzyme in glutathione (GSH) synthesis. Traditional assays for the activity of this enzyme are based either on coupled reactions with other enzymes or on high-performance liquid chromatography (HPLC) assessment of gamma-glutamylcysteine (gamma-GC) product formation. We took advantage of the reaction of naphthalene dicarboxaldehyde (NDA) with GSH or gamma-GC to form cyclized products that are highly fluorescent. Hepa-1 cells which were designed to overexpress mouse GCL and mouse liver homogenates were used to evaluate and compare the utility of the NDA method with an assay based on monobromobimane derivatization and HPLC analysis with fluorescence detection. Excellent agreement was found between GCL activities measured by HPLC and NDA-microtiter plate analyses. This assay should be useful for high-throughput GCL activity analyses. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Washington, NIEHS, Ctr Ecogenet & Environm Hlth, Dept Environm Hlth, Seattle, WA 98195 USA. RP Kavanagh, TJ (reprint author), Univ Washington, NIEHS, Ctr Ecogenet & Environm Hlth, Dept Environm Hlth, Seattle, WA 98195 USA. FU NCI NIH HHS [1P01 CA 74184]; NIA NIH HHS [1P01 AG 01751]; NIEHS NIH HHS [1P42 ES 04696, 1T32 ES 07032, P30 ES 07033] NR 25 TC 134 Z9 134 U1 4 U2 13 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 JUL 15 PY 2003 VL 318 IS 2 BP 175 EP 180 DI 10.1016/S0003-2697(03)00143-X PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 694QG UT WOS:000183785000001 PM 12814619 ER PT J AU Yoon, TJ Lei, TC Yamaguchi, Y Batzer, J Wolber, R Hearing, VJ AF Yoon, TJ Lei, TC Yamaguchi, Y Batzer, J Wolber, R Hearing, VJ TI Reconstituted 3-dimensional human skin of various ethnic origins as an in vitro model for studies of pigmentation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE reconstituted 3-dimensional human epidermis; co-culture; melanocyte; keratinocyte; pigmentation ID NORMAL HUMAN MELANOCYTES; EPIDERMAL RECONSTRUCTS; ULTRAVIOLET-RADIATION; KERATINOCYTES CONTROL; TYROSINASE ACTIVITY; EQUIVALENT MODEL; DIFFERENTIATION; MELANOGENESIS; COCULTURE; MELANOMA AB Reconstituted 3-dimensional human skin equivalents containing melanocytes and keratinocytes on an artificial dermal substitute are gaining popularity for studies of skin metabolism because they exhibit morphological and growth characteristics similar to human epidermis. In this study, we show that such a pigmented epidermis model can be used to assess the regulation of pigmentation by known melanogenic compounds. In monolayers or in melanocyte-keratinocyte co-cultures, melanocyte-keratinocyte interactions are missing or are spatially limited. The commercial skin equivalents used in this study were derived from epidermal cells obtained from donors of three different ethnic origins (African- American, Asian, and Caucasian), and they reflect those distinct skin phenotypes. We used these pigmented human epidermis models to test compounds for potential effects on pigmentation in a more physiologically relevant context, which allows further characterization and validation of interesting melanogenic factors. We used known melanogenic stimulators (alpha-melanocyte-stimulating hormone and 3,4-dihydroxyphenylalanine) and inhibitors (hydroquinone, arbutin, kojic acid, and niacinamide) and examined their effects on the production of melanin and its distribution in upper layers of the skin. Our studies indicate that commercial skin equivalents provide a convenient and cost-effective alternative to animal testing for evaluating the regulation of mammalian pigmentation by melanogenic factors and for elucidating their mechanisms of action. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Beiersdorf AG, R&D Cosmed, Skin Res, D-20245 Hamburg, Germany. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RI Yamaguchi, Yuji/B-9312-2008 NR 42 TC 31 Z9 33 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUL 15 PY 2003 VL 318 IS 2 BP 260 EP 269 DI 10.1016/S0003-2697(03)00172-6 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 694QG UT WOS:000183785000012 PM 12814630 ER PT J AU LaCroix, AZ Cauley, JA Pettinger, M Hsia, J Bauer, DC McGowan, J Chen, Z Lewis, CE McNeeley, SG Passaro, MD Jackson, RD AF LaCroix, AZ Cauley, JA Pettinger, M Hsia, J Bauer, DC McGowan, J Chen, Z Lewis, CE McNeeley, SG Passaro, MD Jackson, RD TI Statin use, clinical fracture, and bone density in postmenopausal women: Results from the women's health initiative observational study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID COA REDUCTASE INHIBITORS; CORONARY-HEART-DISEASE; CHOLESTEROL LEVELS; MINERAL DENSITY; RISK; TRIAL; PRAVASTATIN; SIMVASTATIN; PREVENTION; LOVASTATIN AB Background: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to stimulate bone formation in laboratory studies, both in vitro and in vivo. While early epidemiologic studies showed lower risk for hip fracture among statin users than nonusers, subsequent studies have produced mixed results. Objective: To examine the association of statin use with incidence of hip, lower arm or wrist, and other clinical fractures and with baseline levels of bone density. Design: Prospective study. Setting: women's Health Initiative Observational Study conducted in 40 clinical centers in the United States. Participants: 93 716 postmenopausal women ages 50 to 79 years. Measurements: Rates of hip, lower arm or wrist, and other clinical fractures were compared among 7846 statin users and 85 870 nonusers over a median follow-up of 3.9 years. In 6442 women enrolled at three clinical centers, baseline levels of total hip, posterior-anterior spine, and total-body bone density measured by using dual-energy x-ray absorptiometry were compared according to statin use. Results: Age-adjusted rates of hip, lower arm or wrist, and other clinical fractures were similar between statin users and nonusers regardless of duration of statin use. The multivadate-adjusted hazard ratios for current statin use were 1.22 (95% CI, 0.83 to 1.81) for hip fracture, 1.04 (CI, 0.85 to 1.27) for lower arm or wrist fracture, and 1.11 (CI, 1.00 to 1.22) for other clinical fracture. Bone density levels did not statistically differ between statin users and nonusers at any skeletal site after adjustment for age, ethnicity, body mass index, and other factors. Conclusion: Statin use did not improve fracture risk or bone density in the Women's Health Initiative Observational Study. The cumulative evidence does not warrant use of statins to prevent or treat osteoporosis. C1 Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98109 USA. Univ Pittsburgh, Pittsburgh, PA USA. George Washington Univ, Washington, DC USA. Medlant Res Inst, Washington, DC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Natl Inst Arthrit & Musculoskeletal Dis, NIH, Bethesda, MD USA. Univ Arizona, Tucson, AZ USA. Univ Alabama, Birmingham, AL USA. Wayne State Univ, Detroit, MI USA. Ohio State Univ, Columbus, OH 43210 USA. RP LaCroix, AZ (reprint author), Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, 1100 Fairview Ave N,MP-1002,POB 19024, Seattle, WA 98109 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 22 TC 98 Z9 107 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2003 VL 139 IS 2 BP 97 EP 104 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 701HX UT WOS:000184163100003 PM 12859159 ER PT J AU Golinelli, MP Hughes, SH AF Golinelli, MP Hughes, SH TI Secondary structure in the nucleic acid affects the rate of HIV-1 nucleocapsid-mediated strand annealing SO BIOCHEMISTRY LA English DT Article ID STRONG-STOP DNA; HAMMERHEAD RIBOZYME CATALYSIS; PRIMER BINDING-SITE; HETEROPOLYMERIC RNA TEMPLATES; REVERSE-TRANSCRIPTASE; MINUS-STRAND; IN-VITRO; CHAPERONE ACTIVITY; VIRAL-DNA; WILD-TYPE AB We studied the effects of human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein on the kinetics of annealing of nucleic acids using model substrates derived from the 3' end of the HIV-1 minus-strand strong-stop DNA (-sssDNA). We used HIV-1 reverse transcriptase (RT) to monitor the annealing reaction. Using several different DNA primers and acceptor oligonucleotides, we found that the rate of annealing increased with the size of the complementary region of the primer and the acceptor strands and decreased when secondary structures could be formed in either the primer or the acceptor strands. The secondary structure had a larger effect on the rate of annealing if the secondary structure extends to the 3' end of the nucleic acid(s). NC protein reduced the rate of annealing between strands with short homologies. NC had no major effect on the rate of annealing when there were at least 13 bases of complementarity between the primer and the acceptor strands and neither strand could form a stable secondary structure. NC increased the rate of annealing when the primer and/or the acceptor strand could form a secondary structure in the region of complementarity. When two strands were in competition as acceptors in an annealing reaction, the specificity of the annealing was determined by the length of the complementarity between the primer and the acceptor strands, the presence or the absence of secondary structures in the primer and/or the acceptor strand, and the presence or the absence of NC in the reaction. This suggests that NC facilitates strand transfer where the nucleic acids have considerable secondary structure (for example, the first strand transfers for viruses whose genomes have considerable secondary structure at their 3' ends). However, NC also appears to increase the fidelity of recombination by reducing strand transfers between segments that have limited complementarity. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. RI Golinelli, Marie-Pierre/K-4287-2013 OI Golinelli, Marie-Pierre/0000-0002-6738-8631 NR 77 TC 18 Z9 18 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 15 PY 2003 VL 42 IS 27 BP 8153 EP 8162 DI 10.1021/bi027039 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700ET UT WOS:000184100200006 PM 12846564 ER PT J AU Bodine, DM AF Bodine, DM TI Another advance for globin gene therapy SO BLOOD LA English DT Editorial Material C1 NHGRI, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2003 VL 102 IS 2 BP 416 EP 416 PG 1 WC Hematology SC Hematology GA 699XY UT WOS:000184083500003 ER PT J AU Chaussabel, D Semnani, RT McDowell, MA Sacks, D Sher, A Nutman, TB AF Chaussabel, D Semnani, RT McDowell, MA Sacks, D Sher, A Nutman, TB TI Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites SO BLOOD LA English DT Article ID NF-KAPPA-B; TOXOPLASMA-GONDII TACHYZOITES; LEISHMANIA-DONOVANI INFECTION; LYMPHATIC FILARIASIS; MYCOBACTERIUM-TUBERCULOSIS; IL-12P70 PRODUCTION; IMMUNE-RESPONSES; INTERFERON-ALPHA; IN-VITRO; ACTIVATION AB Monocyte-derived dendritic cells (DCs) and macrophages (Mphis) generated in vitro from the same individual blood donors were exposed to 5 different pathogens, and gene expression profiles were assessed by microarray analysis. Responses to Mycobacterium tuberculosis and to phylogenetically distinct protozoan (Leishmania major, Leishmania donovani, Toxoplasma gondii) and helminth (Brugia malayi) parasites were examined, each of which produces chronic infections in humans yet vary considerably in the nature of the immune responses they trigger. In the absence of microbial stimulation, DCs and Mphis constitutively expressed approximately 4000 genes, 96% of which were shared between the 2 cell types. In contrast, the genes altered transcriptionally in DCs and Mphis following pathogen exposure were largely cell specific. Profiling of the gene expression data led to the identification of sets of tightly coregulated genes across all experimental conditions tested. A newly devised literature-based clustering algorithm enabled the identification of functionally and transcriptionally homogenous groups of genes. A comparison of the responses induced by the individual pathogens by means of this strategy revealed major differences in the function-ally related gene profiles associated with each infectious agent. Although the intracellular pathogens induced responses clearly distinct from the extracellular B malayi, they each displayed a unique pattern of gene expression that would not necessarily be predicted on the basis of their phylogenetic relationship. The association of characteristic functional clusters with each infectious agent is consistent with the concept that antigen-presenting cells have prewired signaling patterns for use in the response to different pathogens. (C) 2003 by The American Society of Hematology. C1 NIAID, LPD, NIH, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, LPD, NIH, 4 Ctr Dr,Rm 4-126, Bethesda, MD 20892 USA. OI Chaussabel, Damien/0000-0002-6131-7242 NR 45 TC 195 Z9 199 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2003 VL 102 IS 2 BP 672 EP 681 DI 10.1182/blood-2002-10-3232 PG 10 WC Hematology SC Hematology GA 699XY UT WOS:000184083500047 PM 12663451 ER PT J AU Aerbajinai, W Giattina, M Lee, YT Raffeld, M Miller, JL AF Aerbajinai, W Giattina, M Lee, YT Raffeld, M Miller, JL TI The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation SO BLOOD LA English DT Article ID MEDIATED APOPTOSIS; CELL-PROLIFERATION; POLYCYTHEMIA-VERA; EXPRESSION; PROTEIN; ERYTHROPOIETIN; BCL-X(L); HYPOXIA; NIP3; GENE AB Transcriptional profiles of cultured primary human erythroid cells were examined to identify those genes involved in the control of erythroid growth during the terminal phase of maturation. Our in silico screening strategy indicated that a hypoxia-inducible proapoptotic member of the Bcl-2 gene family called Nix is expressed during erythropoiesis. We next performed Northern blot analyses and determined that the 1.4-kb Nix transcript is expressed at lower levels in erythroleukemia cells than reticulocytes. Polymerase chain reaction (PCR)-based transcriptional patterning confirmed the increased expression of Nix during human erythropoiesis with a pattern similar to that of Bcl-xL and glycophorin A and opposite that of Bcl-2. Western blot analyses revealed Nix protein levels that were lower than expected due to increased proteosomal degradation. The expression of Nix and Bcl-xL proteins decreased relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) control on the removal of erythropoietin (EPO) from the culture medium. Immunocytochemical analyses demonstrated a similar perinuclear mitochondrial expression pattern for both proteins in hemoglobinized precursors. On the basis of these data, we propose that the proapoptotic factor Nix is a highly regulated effector of growth during terminal erythroid maturation. (C) 2003 by The American Society of Hematology. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9B17,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 53 Z9 58 U1 1 U2 7 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 JUL 15 PY 2003 VL 102 IS 2 BP 712 EP 717 DI 10.1182/blood-2002-11-3324 PG 6 WC Hematology SC Hematology GA 699XY UT WOS:000184083500052 PM 12663450 ER PT J AU Zhang, QS Bratton, GR Agarwal, RK Calise, D Kugel, G Wan, YS Kumar, AM AF Zhang, QS Bratton, GR Agarwal, RK Calise, D Kugel, G Wan, YS Kumar, AM TI Lead-induced cell signaling cascades in GTI-7 cells SO BRAIN RESEARCH BULLETIN LA English DT Article DE PKC; CaMKII; MEK1/2; ERK1/2; P90(RSK); CREB; GnRH ID GONADOTROPIN-RELEASING-HORMONE; EXCITATORY AMINO-ACIDS; GENE-EXPRESSION; INORGANIC LEAD; GNRH NEURONS; KINASE-C; LHRH NEURONS; REPRODUCTIVE TOXICITY; CYNOMOLGUS MONKEY; PULSE-GENERATOR AB The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90(RSK) and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90(RSK) activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90(RSK) pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90(RSK) pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Tufts Univ, Sch Vet Med, Dept Biomed Sci, North Grafton, MA 01536 USA. Texas A&M Univ, Coll Vet Med, Dept Anat & Publ Hlth, College Stn, TX 77843 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Dent Med, Dept Restorat Dent, Boston, MA 02111 USA. Providence Coll, Dept Biol, Providence, RI 02918 USA. RP Kumar, AM (reprint author), Tufts Univ, Sch Vet Med, Dept Biomed Sci, 200 Westboro Rd N, North Grafton, MA 01536 USA. FU NCRR NIH HHS [1 P20 RR16457] NR 62 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUL 15 PY 2003 VL 61 IS 2 BP 207 EP 217 DI 10.1016/S0361-9230(03)00127-8 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 699HW UT WOS:000184051800013 PM 12832008 ER PT J AU Alexander, HR AF Alexander, HR TI Hyperthermia and its modern use in cancer treatment SO CANCER LA English DT Editorial Material ID CONCURRENT CHEMOTHERAPY; PELVIC RADIATION; CELLS; PERFUSION; MELPHALAN; MELANOMA; EXTREMITIES; TUMORS C1 NCI, Ctr Canc Res, Surg Metab Sect, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Ctr Canc Res, Surg Metab Sect, NIH, 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. NR 28 TC 6 Z9 7 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 JUL 15 PY 2003 VL 98 IS 2 BP 219 EP 221 DI 10.1002/cncr.11471 PG 3 WC Oncology SC Oncology GA 697LJ UT WOS:000183944300002 PM 12872338 ER PT J AU Abou-Saif, A Gibril, F Ojeaburu, JV Bashir, S Entsuah, LK Asgharian, B Jensen, RT AF Abou-Saif, A Gibril, F Ojeaburu, JV Bashir, S Entsuah, LK Asgharian, B Jensen, RT TI Prospective study of the ability of serial measurements of serum chromogranin A and gastrin to detect changes in tumor burden in patients with gastrinomas SO CANCER LA English DT Article DE gastrinoma; pancreatic endocrine tumor; tumor marker; gastrin; chromogranin; islet tumor; Zollinger-Ellison syndrome ID ZOLLINGER-ELLISON-SYNDROME; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; MULTIPLE ENDOCRINE NEOPLASIA; NEURON-SPECIFIC ENOLASE; NEUROENDOCRINE TUMORS; METASTATIC GASTRINOMAS; PROGNOSTIC FACTORS; CARCINOID-TUMORS; MANAGEMENT; MARKER AB BACKGROUND. Assessment of tumor burden changes is essential for the management of patients with neumendocrine gastrointestinal (GI) tumors. Chromogranin A (CgA) is a tumor marker for such tumors; however, to the authors' knowledge, there is little information on whether serial assessments can assess changes in tumor burden. In this prospective study of patients with gastrinomas, serial changes in serum CgA levels were compared with changes in levels of the specific tumor marker gastrin to determine whether they reflected changes in tumor burden. METHODS. in 72 consecutive patients, the mean CgA and gastrin levels from three determinations were measured on each visit. Changes in markers were correlated with changes in tumor burden determined by imaging. By assessing daily changes, significance changes in CgA and gastrin levels were determined. RESULTS. During 103 follow-up visits (mean, 9.6 months), an increased tumor size occurred in 25% of patients, no change occurred in 62% of patients, and a decrease occurred in 13% of patients. In patients who had increasing tumor size, CgA levels increased numerically in 77% of patients, gastrin levels increased in 54% of patients, and the increases were significant in 60-80% of patients. In patients who had tumor stabilization, CgA levels in 63% of patients and gastrin levels in 73% of patients did not show a significant change. Decreased tumor size postresection showed a significant decrease in CgA and gastrin levels in all patients. The sensitivity of CgA and gastrin was as follows: sensitivity for detecting an increase, 62% for CgA and 31% for gastrin; sensitivity for detecting no change, 42% for CgA and 75% for gastrin; and sensitivity for detecting a decrease in tumor size, 85% for CgA and 85% for gastrin. The specificity varied from 53% to 99% for CgA and from 49% to 93% for gastrin. CONCLUSIONS. in patients with gastrinomas, serum CgA and gastrin levels varied considerably from day to day, and this must be taken into consideration. Both markers had low sensitivity and specificity for detecting tumor increases and stabilization. For large tumor decreases postresection, both markers had high sensitivity and specificity. The current results suggest that these markers do not have sufficient sensitivity to replace serial imaging studies for detecting important smaller changes in tumor burden in patients with gastrinomas. Published 2003 by the American Cancer Society. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. NR 63 TC 29 Z9 30 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 JUL 15 PY 2003 VL 98 IS 2 BP 249 EP 261 DI 10.1002/cncr.11473 PG 13 WC Oncology SC Oncology GA 697LJ UT WOS:000183944300006 PM 12872342 ER PT J AU Su, H Hu, N Shih, J Hu, Y Wang, QH Chuang, EY Roth, MJ Wang, CY Goldstein, AM Ding, T Dawsey, SM Giffen, C Emmert-Buck, MR Taylor, PR AF Su, H Hu, N Shih, J Hu, Y Wang, QH Chuang, EY Roth, MJ Wang, CY Goldstein, AM Ding, T Dawsey, SM Giffen, C Emmert-Buck, MR Taylor, PR TI Gene expression analysis of esophageal squamous cell carcinoma reveals consistent molecular profiles related to a family history of upper gastrointestinal cancer SO CANCER RESEARCH LA English DT Article ID ALLELIC LOSS; BARRETTS-ESOPHAGUS; SHANXI-PROVINCE; CHINA; OVEREXPRESSION; IDENTIFICATION; ARRAYS; TUMORS; ESCC AB Tumor and matched normal tissue from 19 esophageal squamous cell carcinoma patients from a high-risk area of China were analyzed with 7680 gene cDNA microarrays. Forty-one genes were differentially expressed (P<0.001; &GE;2-fold change) between tumor and matched normal samples (13 overexpressed and 28 underexpressed). Hierarchical clustering showed consistent molecular profiles across patients. Multidimensional scaling plots visually distinguished cases by family history status, which was confirmed statistically using a global permutation test (P=0.007); we then identified 152 genes of which the expression differed in tumors from family history positive versus negative cases (55 overexpressed and 97 underexpressed at P<0.001). These data indicate that molecular profiles in esophageal squamous cell carcinoma are highly consistent and that expression patterns in familial cases differ from those in sporadic cases. C1 NCI, Canc Prevent Studies Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Gen Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Shanxi Canc Hosp & Inst, Taiyuan 030013, Peoples R China. Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Taylor, PR (reprint author), NCI, Canc Prevent Studies Branch, NIH, 6116 Execut Blvd,Room 705, Bethesda, MD 20892 USA. NR 28 TC 51 Z9 55 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 JUL 15 PY 2003 VL 63 IS 14 BP 3872 EP 3876 PG 5 WC Oncology SC Oncology GA 705DE UT WOS:000184379800005 PM 12873975 ER PT J AU Woodson, K Tangrea, JA Pollak, M Copeland, TD Taylor, PR Virtamo, J Albanes, D AF Woodson, K Tangrea, JA Pollak, M Copeland, TD Taylor, PR Virtamo, J Albanes, D TI Serum insulin-like growth factor 1: Tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; FACTOR-BINDING PROTEINS; IGF-I; RISK AB Recent epidemiological studies suggest an association between higher blood levels of insulin-like growth factor I (IGF-I) and increased risk of prostate cancer. We evaluated the association between prediagnostic levels of IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) and prostate cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Within the same cohort (using different cases and controls who had sequential serum samples available) we also examined changes in serum IGF-I and IGFBP-3 levels over time by case status. The risk association study included incident prostate cancer cases (n=100) diagnosed at least 5 years after baseline blood draw (range, 5-12 years; median 9 years) and frequency-matched (4:1) controls. The sequential serum study included all of the prostate cancer cases (n=21) with prediagnostic (2-3 years before diagnosis) and diagnostic serum available, and pair-matched controls (1:1). An ELISA was used to quantitate serum levels of IGF-I and IGFBP-3 for both studies. The association between IGF-I or IGFBP-3 and prostate cancer risk was assessed using conditional logistic regression, and paired t tests were used to evaluate case-control differences in change in serum analytes over time. We found no significant association between either IGF-I or IGFBP-3 and prostate cancer risk. In a multivariate analysis, we observed an odds ratio of 0.52 (95% confidence interval, 0.23-1.16) for the fourth versus the first quartile of serum IGF-I. Serum IGF-I, but not IGFBP-3, increased significantly over time in cases (18% increase) but not controls (4% decrease; P=0.02). In contrast to previous reports, we found no evidence to support a causal association between serum IGF-I or IGFBP-3 and the risk of prostate cancer. It is possible that serum IGF-I may be serving as a tumor marker rather than an etiologic factor in prostate cancer. C1 NCI, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. McGill Univ, Jewish Gen Hosp, Canc Prevent Res Unit, Dept Med, Montreal, PQ H3T 1E2, Canada. McGill Univ, Jewish Gen Hosp, Dept Oncol, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada. NCI, Basic Res Lab, Canc Res Ctr, Frederick, MD 21701 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. RP Woodson, K (reprint author), NCI, Canc Prevent Studies Branch, Canc Res Ctr, 6116 Execut Blvd MSC 8314, Bethesda, MD 20892 USA. RI Pollak, Michael/G-9094-2011; Albanes, Demetrius/B-9749-2015 OI Pollak, Michael/0000-0003-3047-0604; FU NCI NIH HHS [N01 CN 45165] NR 21 TC 95 Z9 100 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 JUL 15 PY 2003 VL 63 IS 14 BP 3991 EP 3994 PG 4 WC Oncology SC Oncology GA 705DE UT WOS:000184379800026 PM 12873996 ER PT J AU Chen, ZS Robey, RW Belinsky, MG Shchaveleva, I Ren, XQ Sugimoto, Y Ross, DD Bates, SE Kruh, GD AF Chen, ZS Robey, RW Belinsky, MG Shchaveleva, I Ren, XQ Sugimoto, Y Ross, DD Bates, SE Kruh, GD TI Transport of methotrexate, methotrexate polyglutamates, and 17 beta-estradiol 17-(beta-D-glucuronide) by ABCG2: Effects of acquired mutations at R482 on methotrexate transport SO CANCER RESEARCH LA English DT Article ID CANCER RESISTANCE PROTEIN; ORGANIC ANION TRANSPORTER; MULTIDRUG-RESISTANCE; ANTICANCER AGENTS; CELL-LINES; MITOXANTRONE-RESISTANT; MEMBRANE-VESICLES; LEUKOTRIENE C-4; DRUG-RESISTANCE; PLASMA-MEMBRANE AB ABCG2 is a plasma membrane efflux pump that is able to confer resistance to several anticancer agents, including mitoxantrone, camptothecins, anthracyclines, and flavopiridol. The antimetabolite methotrexate (MTX) was inferred recently to be an additional substrate of the pump based on the analysis of ABCG2-overexpressing cell lines. However, the transport characteristics of the pump with regard to this agent have not been determined. In addition, physiological substrates of ABCG2 have not been identified. Here we examine the in vitro transport properties of the pump using membrane vesicles prepared from HEK293 cells transfected with ABCG2 expression vector. In so doing it is shown that MTX is a high capacity low affinity substrate of the pump, with K-m and V-max values of 1.34 +/- 0.18 mM and 687 +/- 87 pmol/mg/min, respectively. Unlike previously characterized multidrug resistance protein family members, ABCG2 is also able to transport MTX diglutamate and MTX triglutamate. However, addition of even one more glutamyl residue is sufficient to completely abrogate ABCG2-mediated transport. By contrast with the wild-type protein (ABCG2-R482), two ABCG2 variants that have been identified in drug selected cell lines, R482T and R482G, were unable to transport MTX to any extent. Similarly, folic acid was subject to efflux by the wild-type protein but not by the two mutants. However, transport of the reduced folate leucovorin was not detected for either the wild-type or the mutant proteins. Finally, it is shown that ABCG2 is capable of transporting E(2)17betaG with K-m and V-max values of 44.2 +/- 4.3 muM and 103 +/- 17 pmol/mg/min, respectively. These results indicate that ABCG2 is a component of the energy-dependent efflux system for certain folates and antifolates, but that its transport characteristics with respect to polyglutamates and reduced folates are not identical to those of multidrug resistance protein family members. In addition, it is demonstrated that R482 mutations observed in drug-resistant cell lines have profound effects on the in vitro transport properties of the pump. C1 Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. NCI, Bethesda, MD 20892 USA. Kagoshima Univ, Fac Med, Inst Canc Res, Kagoshima 8908520, Japan. Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Div Expt Chemotherapy, Tokyo 1708455, Japan. Univ Maryland, Sch Med, Dept Med, Div Hematol Oncol, Baltimore, MD 21201 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. RP Kruh, GD (reprint author), Fox Chase Canc Ctr, Div Med Sci, 7701 Burholme Ave, Philadelphia, PA 19111 USA. FU NCI NIH HHS [CA06927, CA73728] NR 50 TC 218 Z9 222 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 JUL 15 PY 2003 VL 63 IS 14 BP 4048 EP 4054 PG 7 WC Oncology SC Oncology GA 705DE UT WOS:000184379800035 PM 12874005 ER PT J AU Giorda, E Sibilio, L Martayan, A Moretti, S Venturo, I Mottolese, M Ferrara, GB Cappellacci, S Eibenschutz, L Catricala, C Grammatico, P Giacomini, P AF Giorda, E Sibilio, L Martayan, A Moretti, S Venturo, I Mottolese, M Ferrara, GB Cappellacci, S Eibenschutz, L Catricala, C Grammatico, P Giacomini, P TI The antigen processing machinery of class I human leukocyte antigens: Linked patterns of gene expression in neoplastic cells SO CANCER RESEARCH LA English DT Article ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; HUMAN-MELANOMA CELLS; HLA-A EXPRESSION; DOWN-REGULATION; CERVICAL-CANCER; HEAVY-CHAINS; HUMAN TUMORS; B ANTIGENS; IFN-GAMMA AB The ultimate outcome of an immune response (escape or surveillance) depends on a delicate balance of opposing signals delivered by activating and inhibitory immune receptors expressed by cytotoxic T lymphocytes and natural killer cells. In this light, loss and down-regulation of human leukocyte antigens (HLA) class I molecules, while important for keeping tumors below the T-cell detection levels, may incite recognition of missing self. Conversely, the maintenance of normal levels of expression (or even up-regulation) may be favorable to tumors, at least in certain cases. In this study, we took advantage of a previously characterized panel of 15 early passage tumor cell lines (mainly from melanoma and lung carcinoma lesions) enriched with class I-low phenotypes. These cells were systematically characterized by Northern and/or Western blotting (e.g., minitranscriptome/mini-proteome analysis) for the expression of HLA-A, -B, -C, beta(2)-microglobulin, and the members of the "antigen processing machinery" of class I molecules (LMP2, LMP7, TAP1, TAP2, tapasin, calreticulin, calnexin, and ERp57). In addition, we established four pairs of cultures, each comprising melanoma cells and normal melanocytes from the same patient. We found that similar to 97 % of the 185 tested gene products are expressed (although often weakly), and in many cases coordinately regulated in 18 of 19 tumor cell lines. Linked expression patterns could be hierarchically arranged by statistical methods and graphically described as a class I HLA "coordinome." Deviations (both down- and up-regulation) from the coordinome expression pattern inherited from the normal, paired melanocyte counterpart, were allowed but limited in magnitude, as if melanoma cells were trying to keep a "low profile" HLA phenotype. We conclude that irreversible HLA loss is a rare event, and class I expression in tumor cells almost invariably results from reversible gene regulatory (rather than gene disruption) events. C1 Regina Elena Canc Inst CRS, Immunol Lab, I-00158 Rome, Italy. Regina Elena Inst Canc Res, Pathol Lab, I-00144 Rome, Italy. Ist Fisioterap Ospitalieri, S Maria & S Gallicano Inst, I-00144 Rome, Italy. Univ Genoa, Dept Oncol & Genet, Ctr Adv Biotechnol, Natl Canc Inst,Lab Immunogenet, I-16132 Genoa, Italy. Univ Roma La Sapienza, S Camillo Forlanini Hosp, I-00149 Rome, Italy. RP Giacomini, P (reprint author), Regina Elena Canc Inst CRS, Immunol Lab, Via Messi Oro 156, I-00158 Rome, Italy. RI Giacomini, Patrizio/K-5217-2016 OI Giacomini, Patrizio/0000-0001-6109-1709 NR 47 TC 31 Z9 31 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 JUL 15 PY 2003 VL 63 IS 14 BP 4119 EP 4127 PG 9 WC Oncology SC Oncology GA 705DE UT WOS:000184379800046 PM 12874016 ER PT J AU Buckhaults, P Zhang, Z Chen, YC Wang, TL St Croix, B Saba, S Bardelli, A Morin, PJ Polyak, K Hruban, RH Velculescu, VE Shih, IM AF Buckhaults, P Zhang, Z Chen, YC Wang, TL St Croix, B Saba, S Bardelli, A Morin, PJ Polyak, K Hruban, RH Velculescu, VE Shih, IM TI Identifying tumor origin using a gene expression-based classification map SO CANCER RESEARCH LA English DT Article ID OVARIAN-CANCER ANTIGEN; MOLECULAR CLASSIFICATION; SERIAL ANALYSIS; IDENTIFICATION; PREDICTION; DIAGNOSIS; CA125; MUC16; MUCIN AB Identifying the primary site in cases of metastatic carcinoma of unknown origin has profound clinical importance in managing cancer patients. Although transcriptional profiling promises molecular solutions to this clinical challenge, simpler and more reliable methods for this purpose are needed. A training set of 11 serial analysis of gene expression (SAGE) libraries was analyzed using a combination of supervised and unsupervised computational methods to select a small group of candidate genes with maximal power to discriminate carcinomas of different tissue origins. Quantitative real-time PCR was used to measure their expression levels in an independent validation set of 62 samples of ovarian, breast, colon, and pancreatic adenocarcinomas and normal ovarian surface epithelial controls. The diagnostic power of this set of genes was evaluated using unsupervised cluster analysis methods. From the training set of 21,321 unique SAGE transcript tags derived from 11 libraries, five genes were identified with expression patterns that distinguished four types of adenocarcinomas. Quantitative real-time PCR expression data obtained from the validation set clustered tumor samples in an unsupervised manner, generating a self-organized map with distinctive tumor site-specific domains. Eighty-one percent (50 of 62) of the carcinomas were correctly allocated in their corresponding diagnostic regions. Metastases clustered tightly with their corresponding primary tumors. A classification map diagnostic of tumor types was generated based on expression patterns of five genes selected from the SAGE database. This expression map analysis may provide a reliable and practical approach to determine tumor type in cases of metastatic carcinoma of clinically unknown origin. C1 Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. NCI, Frederick, MD 21701 USA. NIA, Baltimore, MD 21224 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Shih, IM (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 418 N Bond St,B-315, Baltimore, MD 21231 USA. FU NCI NIH HHS [CA97527, P50-CA62924] NR 26 TC 68 Z9 69 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2003 VL 63 IS 14 BP 4144 EP 4149 PG 6 WC Oncology SC Oncology GA 705DE UT WOS:000184379800049 PM 12874019 ER PT J AU Lozano, J Xing, R Cai, ZZ Jensen, HL Trempus, C Mark, W Cannon, R Kolesnick, R AF Lozano, J Xing, R Cai, ZZ Jensen, HL Trempus, C Mark, W Cannon, R Kolesnick, R TI Deficiency of kinase suppressor of Ras1 prevents oncogenic Ras signaling in mice SO CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASE; EPIDERMAL-GROWTH-FACTOR; INTESTINAL EPITHELIAL-CELLS; TUMOR-NECROSIS-FACTOR; KSR-1 GENE ENCODES; HA-RAS; MOUSE SKIN; TRANSGENIC MOUSE; FACTOR RECEPTOR; MAP KINASE AB In Drosophila and Caenorhabditis elegans, kinase suppressor of ras (KSR) positively modulates Ras/Raf-mitogen-activated protein kinase (MAPK) signaling. The precise signaling mechanism of mammalian KSR1 and its role in Ras-mediated transformation, however, remain uncertain. To gain insight into KSR1 function in vivo, we generated mice homozygous null for KSR1. ksr1(-/-) mice are viable and without major developmental defects. However, an unusual disorganized hair follicle phenotype manifest in epidermal growth factor receptor knockout mice is recapitulated in ksr1(-/-) mice, providing genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals. Furthermore, ksr1(-/-) mice allow for the definition of KSR1-dependent and -independent mechanisms of c-Raf-1 activation. In embryonic fibroblasts, epidermal growth factor and 12-O-tetradecanoylphorbol-13-acetate activated the MAPK cascade to a similar extent, yet only c-Raf-1 activation by epidermal growth factor depended on KSR1. Moreover, whereas the genesis of polyomavirus middle T antigen (MT)-driven mammary cancer appears independent of KSR1, KSR1 is obligate for v-Ha-ras-mediated skin tumor formation. The growth of MT-driven mammary tumor was moderately slowed in ksr1(-/-) mice, however, consistent with a decreased rate of proliferation of ksir1(-/-) cells (T cells and embryonic fibroblasts). Nonetheless, all ksr1(-/-) animals succumbed to mammary cancer. In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1(-/-) background. Hence, MT-driven mammary tumor genesis, which is signaled through src and phosphatidylinositol 3'-kinase, appears KSR1 independent, whereas v-Ha-ras-mediated skin cancer, signaled through the Raf-1/MAPK cascade, requires KSR1. These results suggest KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis. C1 Mem Sloan Kettering Canc Ctr, Lab Signal Tranduct, Sloan Kettering Inst, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, Sloan Kettering Inst, New York, NY 10021 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Kolesnick, R (reprint author), Mem Sloan Kettering Canc Ctr, Lab Signal Tranduct, Sloan Kettering Inst, 1275 York Ave, New York, NY 10021 USA. RI Lozano, Jose/C-2760-2014 OI Lozano, Jose/0000-0002-8187-2833 FU NCI NIH HHS [CA42385] NR 39 TC 77 Z9 78 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 JUL 15 PY 2003 VL 63 IS 14 BP 4232 EP 4238 PG 7 WC Oncology SC Oncology GA 705DE UT WOS:000184379800061 PM 12874031 ER PT J AU Cao, JJ Thach, C Manolio, TA Psaty, BM Kuller, LH Chaves, PHM Polak, JF Sutton-Tyrrell, K Herrington, DM Price, TR Cushman, M AF Cao, JJ Thach, C Manolio, TA Psaty, BM Kuller, LH Chaves, PHM Polak, JF Sutton-Tyrrell, K Herrington, DM Price, TR Cushman, M TI C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly - The Cardiovascular Health Study SO CIRCULATION LA English DT Article DE inflammation; atherosclerosis; carotid arteries; stroke; risk factors ID ATHEROSCLEROTIC PLAQUE; ADHESION MOLECULE-1; RISK-FACTORS; DISEASE; ASSOCIATION; ATHEROGENESIS; INFLAMMATION; MACROPHAGES; MARKERS; WOMEN AB Background-Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT. Methods and Results-We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P < 0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT. Conclusions-We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke. C1 Henry Ford Hosp, Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. Merck Res Lab, Rahway, NJ USA. NHLBI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Univ Pittsburgh, Pittsburgh, PA USA. Johns Hopkins Univ, Baltimore, MD USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Vermont, Burlington, VT USA. RP Cushman, M (reprint author), Univ Vermont, Dept Med, 208 S Park Dr,Suite 2, Colchester, VT 05446 USA. FU NHLBI NIH HHS [N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85086] NR 32 TC 211 Z9 230 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 15 PY 2003 VL 108 IS 2 BP 166 EP 170 DI 10.1161/01.CIR.0000079160.07364.6A PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 701DL UT WOS:000184152900012 PM 12821545 ER PT J AU Stabile, E Burnett, MS Watkins, C Kinnaird, T Bachis, A la Sala, A Miller, JM Shou, M Epstein, SE Fuchs, S AF Stabile, E Burnett, MS Watkins, C Kinnaird, T Bachis, A la Sala, A Miller, JM Shou, M Epstein, SE Fuchs, S TI Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice SO CIRCULATION LA English DT Article; Proceedings Paper CT 75th Annual Scientific Session of the American-Heart-Association CY NOV 17-20, 2002 CL CHICAGO, ILLINOIS SP Amer Heart Assoc DE angiogenesis; lymphocytes; inflammation ID ENDOTHELIAL GROWTH-FACTOR; T-LYMPHOCYTES; ANGIOGENESIS; CELLS; RECEPTOR; MODEL AB Background-T lymphocytes, components of the immune and inflammatory systems, are involved in such normal processes as wound healing and host defense against infection and in such pathological processes as tumor growth and atherosclerotic plaque development. Angiogenesis is a mechanism common to each. Because CD4+ T lymphocytes are active in regulating humoral and cellular responses of the immune system, we determined whether CD4+ cells contribute to collateral vessel development by using the mouse ischemic hindlimb model. Methods and Results-One week after ischemia, CD4(-/-) mice showed reduced collateral flow induction, macrophage number, and vascular endothelial growth factor levels in the ischemic muscle compared with wild-type mice. There was also delayed recovery of hindlimb function and increased muscle atrophy/fibrosis. Spleen-derived purified CD4+ T cells infused into CD4(-/-) mice selectively localized to the ischemic limb and significantly increased collateral flow as well as macrophage number and vascular endothelial growth factor levels in the ischemic muscle. Muscle function and damage also improved. Conclusions-These results indicate an important role of CD4+ cells in collateral development, as demonstrated by a 25% decrease in blood flow recovery after femoral artery ligation. Our data also suggest that CD4+ T cells control the arteriogenic response to acute hindlimb ischemia, at least in part, by recruiting macrophages to the site of active collateral artery formation, which in turn triggers the development of collaterals through the synthesis of arteriogenic cytokines. C1 Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Lab Vasc Biol, Washington, DC 20010 USA. Georgetown Univ, Dept Neurosci, Washington, DC USA. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Stabile, E (reprint author), Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Lab Vasc Biol, Suite 4B 1,110 Irving St NW, Washington, DC 20010 USA. RI la Sala, Andrea/A-3228-2009; OI la Sala, Andrea/0000-0003-1268-6516; stabile, eugenio/0000-0001-9763-6010; stabile, eugenio/0000-0002-4544-3142 NR 18 TC 127 Z9 131 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 15 PY 2003 VL 108 IS 2 BP 205 EP 210 DI 10.1161/01.CIR.0000079225.50817.71 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 701DL UT WOS:000184152900018 PM 12821542 ER PT J AU Laquerriere, P Grandjean-Laquerriere, A Guenounou, M Laurent-Maquin, D Frayssinet, P Nardin, M AF Laquerriere, P Grandjean-Laquerriere, A Guenounou, M Laurent-Maquin, D Frayssinet, P Nardin, M TI Correlation between sintering temperature of hydroxyapatite particles and the production of inflammatory cytokines by human monocytes SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE hydroxyapatite particles; sintering temperature; human monocytes; inflammatory reaction; surface properties ID MACROPHAGES IN-VITRO; SURFACE-AREA; SIZE; PROLIFERATION; CELLS; BONE AB Osteolysis remains the most important problem in orthopaedic implant failure. Wear debris from the implant contains hydroxyapatite particles which have been shown to activate monocyte cells. Although the response of monocytes has been observed to be influenced by size and shape of the hydroxyapatite particles, little is known on the effect of surface properties on inflammatory cytokines production. In this study, human monocytes have been exposed to hydroxyapatite particles sintered at different temperatures (not sintered, sintered at 600 and 1180 degreesC). We show that the sintering temperature modifies the crystal size and the pH of zero charge of the particles. Moreover, interleukin 1-beta, tumor necrosis factor-alpha and interleukin-6 secretion were evaluated as a function of the sintering temperature because they play a key role in the osteoclast cells differentiation. The level of secretion was small compared to the production induced by zymosan particles. But we demonstrate in the present paper that the particles sintered at the highest temperature induced the most important production of the cytokines studied. (C) 2003 Elsevier Science B.V. All rights reserved. C1 UFR Sci, Lab Microscopie Electron, INSERM, ERM 0203,IFR 53, F-51685 Reims 2, France. UFR Pharm, Lab Immunol & Biotechnol, EA2070, IFR 53, F-51100 Reims, France. Urodelia, F-31470 St Lys, France. CNRS, Inst Chim Surfaces & Interfaces, UPR 9069, F-68057 Mulhouse, France. RP Laquerriere, P (reprint author), NIH, ORS, Div Bioengn & Phys Sci, Bldg 13,Room 3E73,13 South Dr, Bethesda, MD 20892 USA. RI Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 NR 28 TC 16 Z9 16 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD JUL 15 PY 2003 VL 30 IS 3 BP 207 EP 213 DI 10.1016/S0927-7765(03)00083-3 PG 7 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA 708BM UT WOS:000184546700004 ER PT J AU Nakaya, M Habas, R He, X Yamaguchi, TP AF Nakaya, M Habas, R He, X Yamaguchi, TP TI Regulation of cell and tissue polarity by Daam and Wnt signaling. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NCI, Canc & Dev Biol Lab, Ft Detrick, MD 21702 USA. Harvard Univ, Sch Med, Div Neurosci, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 77 BP 462 EP 462 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300085 ER PT J AU Covassin, L Bakis, M Weinstein, B Lawson, N AF Covassin, L Bakis, M Weinstein, B Lawson, N TI An allelic series of mutants in phospholipase C-gamma-1 reveals its requirement for arterial development in zebrafish. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Univ Massachusetts, Sch Med, Program Gene Funct & Express, Amherst, MA 01003 USA. NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 84 BP 463 EP 464 PG 2 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300091 ER PT J AU Lawson, N Covassin, L Diamond, B Mugford, J Weinstein, B AF Lawson, N Covassin, L Diamond, B Mugford, J Weinstein, B TI Dissecting the role of vascular endothelial growth factor during arterial development and differentiation. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Univ Massachusetts, Sch Med, Program Gene Funct Express, Worcester, MA 01605 USA. NICHD, Genet Mol Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 83 BP 463 EP 463 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300090 ER PT J AU Brody, T Stivers, C Russ, D Stevenson, C Odenwald, WF AF Brody, T Stivers, C Russ, D Stevenson, C Odenwald, WF TI A search for targets of the drosophila neuroblast temporal network. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD USA. NIH, CIT, Div Comp Biosci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 93 BP 465 EP 465 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300098 ER PT J AU Lee, WK Kim, YM Malik, N Ma, C Westphal, H AF Lee, WK Kim, YM Malik, N Ma, C Westphal, H TI Cloning and characterization of the 5'-flanking region for the Ehox gene. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NICHD, LMGD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 109 BP 469 EP 469 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300114 ER PT J AU Kuzin, A Stivers, C Brody, T Odenwald, W AF Kuzin, A Stivers, C Brody, T Odenwald, W TI Axon segmental border crossing in the Drosophila CNS is regulated by nerfin-1. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 281 BP 506 EP 506 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300260 ER PT J AU Miura, S Davis, S Klingensmith, J Mishina, Y AF Miura, S Davis, S Klingensmith, J Mishina, Y TI BMP signaling regulates mesoderm patterning in mouse embryogenesis. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 NIEHS, LRDT, Mol Dev Biol Grp, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 302 BP 510 EP 510 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300277 ER PT J AU Parisi, MJ Nuttall, R Lu, JN Chan, C Vainer, M Minor, J Lash, A Eastman, S Malley, J Naiman, D Oliver, B AF Parisi, MJ Nuttall, R Lu, JN Chan, C Vainer, M Minor, J Lash, A Eastman, S Malley, J Naiman, D Oliver, B TI Microarray analysis of sexual dimorphism in Drosophila. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Society-for-Development-Biology CY JUL 30-AUG 02, 2003 CL BOSTON, MASSACHUSETTS SP Soc Dev Biol C1 Natl Inst Hlth, Bethesda, MD USA. Incyte Genom, Palo Alto, CA USA. Natl Lib Med, Bethesda, MD USA. Novat Biosci, Palo Alto, CA USA. Johns Hopkins Univ, Baltimore, MD USA. RI Naiman, Daniel/A-3304-2010 OI Naiman, Daniel/0000-0001-6504-9081 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2003 VL 259 IS 2 MA 389 BP 528 EP 528 PG 1 WC Developmental Biology SC Developmental Biology GA 705AD UT WOS:000184373300349 ER EF