FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Wipasa, J Xu, HJ Stowers, A Good, MF AF Wipasa, J Xu, HJ Stowers, A Good, MF TI Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FAS-MEDIATED APOPTOSIS; PLASMODIUM-FALCIPARUM; PROTECTIVE IMMUNITY; MONONUCLEAR-CELLS; INTERFERON-GAMMA; CD95 FAS/APO-1; TNF-ALPHA; IFN-GAMMA; IN-VIVO; DEATH AB Immunity induced by the 19-kDa fragment of merozoite surface protein 1 is dependent on CD4(+) Th cells. However, we found that adoptively transferred CFSE-labeled Th cells specific for an epitope on Plasmodium yoelii 19-kDa fragment of merozoite surface protein 1 (peptide (p)24), but not OVA-specific T cells, were deleted as a result of P. yoelii infection. As a result of infection, spleen cells recovered from infected p24-specific T cell-transfused mice demonstrated reduced response to specific Ag. A higher percentage of CFSE-labeled p24-specific T cells stained positive with annexin and anti-active caspase-3 in infected compared with uninfected mice, suggesting that apoptosis contributed to deletion of p24-specific T cells during infection. Apoptosis correlated with increased percentages of p24-specific T cells that stained positive for Fas from infected mice, suggesting that P. yoelii-induced apoptosis is, at least in part, mediated by Fas. However, bystander cells of other specificities also showed increased Fas expression during infection, suggesting that Fas expression alone is not sufficient for apoptosis. These data have implications for the development of immunity in the face of endemic parasite exposure. C1 Royal Brisbane Hosp, Queensland Inst Med Res, Cooperat Res Ctr Vaccine Technol, Brisbane, Qld 4029, Australia. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Good, MF (reprint author), Royal Brisbane Hosp, Queensland Inst Med Res, Cooperat Res Ctr Vaccine Technol, Brisbane, Qld 4029, Australia. NR 43 TC 53 Z9 58 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 OCT 1 PY 2001 VL 167 IS 7 BP 3903 EP 3909 PG 7 WC Immunology SC Immunology GA 496JH UT WOS:000172392100046 PM 11564808 ER PT J AU Crowe, JE Firestone, CY Murphy, BR AF Crowe, JE Firestone, CY Murphy, BR TI Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TEMPERATURE-SENSITIVE MUTANT; CYTOTOXIC T-CELLS; MATERNAL ANTIBODIES; COTTON RATS; INFLUENZA-VIRUS; G-GLYCOPROTEINS; RSV CHALLENGE; PULMONARY HISTOPATHOLOGY; SERONEGATIVE CHIMPANZEES; NEUTRALIZING ANTIBODIES AB A respiratory syncytial virus (RSV) vaccine will need to be administered by 1 mo of age to protect young infants; therefore, it will need to be effective in the presence of maternally acquired RSV Abs. In the present study, the immunogenicity and efficacy of two live attenuated RSV vaccine candidates of different level of attenuation were evaluated in mice passively immunized with varying quantities of RSV Abs. The replication of the RSV vaccines was suppressed in the lower, but not the upper, respiratory tract of the passively immunized mice. Immunization with either vaccine candidate was highly efficacious against challenge with wild-type RSV in both passively immunized and control mice. Nonetheless, a high level of immunity was seen even in passively/actively immunized animals that failed to develop a humoral immune response, suggesting that T cells mediated the immunity. Depletion of CD4(+) and CD8(+) T cells in passively/actively immunized and control animals at the time of challenge with wild-type RSV demonstrated that CD4(+) and CD8(+) T cells made significant independent contributions to the restriction of replication of RSV challenge virus in both the upper and lower respiratory tracts. Although passively acquired serum RSV Abs suppressed the primary systemic and mucosal Ab responses of IgM, IgG, and IgA isotypes, B lymphocytes were nevertheless primed for robust secondary Ab responses. Thus, immunity mediated by CD4(+) and CD8(+) T cells and Abs can be readily induced in mice by live RSV vaccine candidates in the presence of physiologic levels of RSV neutralizing Abs. C1 Vanderbilt Univ, Med Ctr, Dept Pediat, Div Pediat Infect Dis, Nashville, TN 37232 USA. NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Dept Pediat, Div Pediat Infect Dis, D-7235 MCN,1161 21st Ave S, Nashville, TN 37232 USA. RI Crowe, James/B-5549-2009 OI Crowe, James/0000-0002-0049-1079 NR 58 TC 47 Z9 47 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 OCT 1 PY 2001 VL 167 IS 7 BP 3910 EP 3918 PG 9 WC Immunology SC Immunology GA 496JH UT WOS:000172392100047 PM 11564809 ER PT J AU McInnes, IB Illei, GG Danning, CL Yarboro, CH Crane, M Kuroiwa, T Schlimgen, R Lee, E Foster, B Flemming, D Prussin, C Fleisher, TA Boumpas, DT AF McInnes, IB Illei, GG Danning, CL Yarboro, CH Crane, M Kuroiwa, T Schlimgen, R Lee, E Foster, B Flemming, D Prussin, C Fleisher, TA Boumpas, DT TI IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B7-2 CD86 EXPRESSION; T-CELLS; RHEUMATOID-ARTHRITIS; CYTOKINE PRODUCTION; T-HELPER-2 CELLS; HUMAN MONOCYTES; GROWTH-FACTOR; P-SELECTIN; INTERLEUKIN-10; PROLIFERATION AB Psoriatic arthritis (PsA) provides an ideal disease model in which to investigate the bioactivities of potentially therapeutic cytokines at multiple sites of tissue inflammation. We investigated the effects of IL-10, an antiinflammatory cytokine, given s.c. for 28 days in a double-blind, placebo-controlled study in PsA patients. Synovial/skin biopsies, peripheral blood leukocytes, articular magnetic resonance images, and clinical disease activity scores were obtained sequentially. Modest, but significant clinical improvement in skin, but not articular disease activity scores with only minor adverse effects was observed. Type 1, but not type 2 T cell cytokine production in vitro was suppressed in human rIL-10 compared with placebo recipients. Similarly, monokine production in vitro was reduced, whereas serum soluble TNFRII levels were elevated, indicating suppression of monocyte function. Decreased T cell and macrophage infiltration in synovial tissues was accompanied by reduced P-selectin expression. Moreover, suppressed synovial enhancement on magnetic resonance imaging and reduced alpha (v)beta (3) integrin expression on von Willebrand factor(+) vessels were observed. Together these data demonstrate that a short course of IL-10 modulates immune responses in vivo via diverse effects on endothelial activation, and leukocyte recruitment and effector function. Such biological changes may result in clinically meaningful improvement in disease activity. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA. RP McInnes, IB (reprint author), Univ Glasgow, Glasgow Royal Infirm, Ctr Rheumat Dis, 10 alexandra Parade, Glasgow G31 2ER, Lanark, Scotland. EM i.b.mcinnes@clinmed.gla.ac.uk OI Prussin, Calman/0000-0002-3917-3326 NR 52 TC 64 Z9 66 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2001 VL 167 IS 7 BP 4075 EP 4082 PG 8 WC Immunology SC Immunology GA 496JH UT WOS:000172392100067 PM 11564829 ER PT J AU Philipp, MT Bowers, LC Fawcett, PT Jacobs, MB Liang, FT Marques, AR Mitchell, PD Purcell, JE Ratterree, MS Straubinger, RK AF Philipp, MT Bowers, LC Fawcett, PT Jacobs, MB Liang, FT Marques, AR Mitchell, PD Purcell, JE Ratterree, MS Straubinger, RK TI Antibody response to IR6, a conserved immunodominant region of the VlsE lipoprotein, wanes rapidly after antibiotic treatment of Borrelia burgdorferi infection in experimental animals and in humans SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 14th International Conference on Lyme Disease and Other Tick-Borne Disorders CY APR, 2001 CL HARTFORD, CONNECTICUT ID B-CELL MEMORY; LYME-DISEASE; ERYTHEMA MIGRANS; ANTIGENIC VARIATION; RHESUS-MONKEY; SEQUENCE; TESTS; OSPA; CYTOKINES; INDUCTION AB Invariable region (IR)(6), an immunodominant conserved region of VISE, the antigenic variation protein of Borrelia burgdorferi, is currently used for the serologic diagnosis of Lyme disease in humans and canines. A longitudinal assessment of anti-IR, antibody levels in B. burgdorferi-infected rhesus monkeys revealed that this level diminished sharply after antibiotic treatment (within 25 weeks). In contrast, antibody levels to P39 and to whole-cell antigen extracts of B. burgdorferi either remained unchanged or diminished less. A longitudinal analysis in dogs yielded similar results. In humans, the anti-IR6 antibody titer diminished by a factor of greater than or equal to4 in successfully treated patients and by a factor of <4 in treatment-resistant patients. This result suggests that the quantification of anti-IR6 antibody titer as a function of time should be investigated further as a test to assess response to Lyme disease therapy or to determine whether a B. burgdorferi infection has been eliminated. C1 Tulane Univ, Hlth Sci Ctr, Tulane Reg Primate Res Ctr, Dept Parasitol, Covington, LA 70433 USA. Alfred I duPont Hosp Children, Wilmington, DE USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. Marshfield Labs, Clin Microbiol Sect, Marshfield, WI USA. Univ Leipzig, Fak Vet Med, Inst Immunol, D-7010 Leipzig, Germany. RP Philipp, MT (reprint author), Tulane Univ, Hlth Sci Ctr, Tulane Reg Primate Res Ctr, Dept Parasitol, 18703 3 Rivers Rd, Covington, LA 70433 USA. RI Straubinger, Reinhard/D-1719-2010; OI Straubinger, Reinhard/0000-0001-8382-7182 FU NCRR NIH HHS [RR-00164]; PHS HHS [CCU606604] NR 37 TC 74 Z9 74 U1 0 U2 6 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 OCT 1 PY 2001 VL 184 IS 7 BP 870 EP 878 DI 10.1086/323392 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 476LK UT WOS:000171228400008 PM 11550127 ER PT J AU Gangaidzo, IT Moyo, VM Mvundura, E Aggrey, G Murphree, NL Khumalo, H Saungweme, T Kasvosve, I Gomo, ZAR Rouault, T Boelaert, JR Gordeuk, VR AF Gangaidzo, IT Moyo, VM Mvundura, E Aggrey, G Murphree, NL Khumalo, H Saungweme, T Kasvosve, I Gomo, ZAR Rouault, T Boelaert, JR Gordeuk, VR TI Association of pulmonary tuberculosis with increased dietary iron SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 2nd International Conference on HIV and Iron CY APR, 2000 CL BRUGGE, BELGIUM ID MYCOBACTERIUM-TUBERCULOSIS; HUMAN-MONOCYTES; OVERLOAD; MACROPHAGES; GROWTH AB To determine whether increased dietary iron could be a risk factor for active tuberculosis, dietary iron history and human immunodeficiency virus (HIV) status were studied in 98 patients with pulmonary tuberculosis and in 98 control subjects from rural Zimbabwe. Exposure to high levels of dietary iron in the form of traditional beer is associated with increased iron stores in rural Africans. HIV seropositivity was associated with a 17.3-fold increase in the estimated odds of developing active tuberculosis (95% confidence interval [95% CI], 7.4-40.6; P<.001), and increased dietary iron was associated with a 3.5-fold increase (95% CI, 1.4-8.9; P =.009). Among patients treated for tuberculosis, HIV seropositivity was associated with a 3.8-fold increase in the estimated hazard ratio of death (95% CI, 1.0-13.8; P =.046), and increased dietary iron was associated with a 1.3-fold increase (95% CI, 0.4-6.4; P =.2). These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis. C1 Univ Zimbabwe, Sch Med, Dept Med, Harare, Zimbabwe. Univ Zimbabwe, Sch Med, Dept Chem Pathol, Harare, Zimbabwe. Nyadire Mission Hosp, Mutoko, Zimbabwe. Johns Hopkins Univ, Johns Hopkins Oncol Ctr, Baltimore, MD USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Sch Publ Hlth, Washington, DC 20037 USA. Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. Algemeen Ziekenhuis St Jan, Unit Renal & Infect Dis, Brugge, Belgium. RP Gangaidzo, IT (reprint author), Univ Zimbabwe, Sch Med, Dept Med, Box A178, Harare, Zimbabwe. FU NICHD NIH HHS [HD 3-3196] NR 15 TC 91 Z9 91 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 OCT 1 PY 2001 VL 184 IS 7 BP 936 EP 939 DI 10.1086/323203 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 476LK UT WOS:000171228400020 PM 11528590 ER PT J AU Warren, GW Van Ess, PJ Watson, AM Mattson, MP Blouin, RA AF Warren, GW Van Ess, PJ Watson, AM Mattson, MP Blouin, RA TI Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; FETAL-RAT HEPATOCYTES; TESTOSTERONE 16-ALPHA-HYDROXYLASE C-P-45016-ALPHA; CLOFIBRIC ACID INDUCTION; DOWN-REGULATION; GENE-EXPRESSION; NITRIC-OXIDE; MESSENGER-RNAS; ENDOTOXIN; LIVER AB Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity. C1 Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40536 USA. Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, Lexington, KY 40536 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NIA, Neurosci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Blouin, RA (reprint author), Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40536 USA. RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [AG14554]; NIEHS NIH HHS [ES07266]; NINDS NIH HHS [NS29001, NS35253] NR 44 TC 26 Z9 27 U1 1 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD OCT PY 2001 VL 21 IS 10 BP 821 EP 826 DI 10.1089/107999001753238060 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 491GD UT WOS:000172099900007 PM 11710994 ER PT J AU Albert, MR Foster, RA Vogel, JC AF Albert, MR Foster, RA Vogel, JC TI Murine epidermal label-retaining cells isolated by flow cytometry do not express the stem cell markers CD34, Sca-1, or Flk-1 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE differentiation; mouse; skin; stem cells ID PRIMARY HUMAN KERATINOCYTES; TRANSIT AMPLIFYING CELLS; BONE-MARROW; IN-VIVO; PROLIFERATIVE UNIT; HAIR FOLLICLE; GENE-THERAPY; MUSCLE REGENERATION; SURFACE PHENOTYPE; BASAL CELLS AB Keratinocyte stem cells are present in the murine epidermis, based on both in vitro and in vivo evidence, and better characterization of these cells remains an active goal. Because keratinocyte stem cells are believed to cycle slowly, a good method for identification is based on their ability to retain nucleoside analog, such as bromodeoxyuridine. Adult stem cells have been identified in other tissues, including hematopoietic, neural, and skeletal muscle, and stem cell surface markers have been characterized. We wanted to determine if cell-surface markers present on both hematopoietic and skeletal muscle stem cells (CD34, Sca-1, and Flk-1) were also present on keratinocyte stem cells, and could be used to identify them. The cell-surface expression of cells that retained bromodeoxyuridine label for at least 21 d was compared with that of nonlabel-retaining cells. Double-labeling for flow cytometric analysis was employed, and label-retaining cells were found to lack expression of the tested markers. beta1 integrin levels were also evaluated, and although high expression was found on label-retaining cells, it was not specific for these cells. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12 N238,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 56 TC 32 Z9 36 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2001 VL 117 IS 4 BP 943 EP 948 DI 10.1046/j.0022-202x.2001.01517.x PG 6 WC Dermatology SC Dermatology GA 486YT UT WOS:000171847500019 PM 11676836 ER PT J AU Kawamur, T Blauvelt, A AF Kawamur, T Blauvelt, A TI Comparative inhibition of R5 HIV infection in epidermal Langerhans cells by novel chemically modified RANTES analogues SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2001 VL 117 IS 4 MA C26 BP 1008 EP 1008 PG 1 WC Dermatology SC Dermatology GA 486YT UT WOS:000171847500066 ER PT J AU Lisziewicz, J Xu, J Trocio, J Whitman, L Varga, G Erbacher, P Fox, C Woodward, R Markham, P Arya, S Behr, JP Lori, F AF Lisziewicz, J Xu, J Trocio, J Whitman, L Varga, G Erbacher, P Fox, C Woodward, R Markham, P Arya, S Behr, JP Lori, F TI DermaVir: A Langerhans cell-mediated DNA immunization technology for the induction of cellular immune responses SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 Res Inst Genet & Human Therapy, RIGHT, Washington, DC USA. Fac Pharm, Lab Chim Genet, Illkirch Graffenstaden, France. Adv BioSci Labs Inc, Rockville, MD USA. Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 6 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2001 VL 117 IS 4 MA C28 BP 1008 EP 1008 PG 1 WC Dermatology SC Dermatology GA 486YT UT WOS:000171847500067 ER PT J AU Wu, M Fang, H Hwang, ST AF Wu, M Fang, H Hwang, ST TI Rapid chemokine-mediated binding of T cells to dendritic cells (DC) under dynamic conditions SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2001 VL 117 IS 4 MA C37 BP 1010 EP 1010 PG 1 WC Dermatology SC Dermatology GA 486YT UT WOS:000171847500075 ER PT J AU De Rosa, SC Mitra, DK Watanabe, N Herzenberg, LA Herzenberg, LA Roederer, M AF De Rosa, SC Mitra, DK Watanabe, N Herzenberg, LA Herzenberg, LA Roederer, M TI V delta and V delta 2 gamma delta T cells express distinct surface markers and might be developmentally distinct lineages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE intestinal intraepithelial lymphocytes; CD5; FACS ID INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; PERIPHERAL-BLOOD; FLOW-CYTOMETRY; HIV-INFECTION; RECEPTOR; SUBSETS; GLUTATHIONE; REPERTOIRE; ACTIVATION; INCREASE AB We report here that the two major types of gamma delta T cells found in human blood, V delta1 and V delta2, were found to have markedly different phenotypes. V delta2 cells had a phenotype typical of most up T cells in blood; i.e., they were CD5(+), CD28(+), and CD57(-). In contrast, V delta1 cells tended to be CD5(-/dull), CD28(-), and CD57(+). Furthermore, although V delta1 T cells appeared to be "naive" in that they were CD45RA(+), they were CD62L(-) and on stimulation uniformly produced interferon-gamma, indicating that they are in fact memory/effector cells. This phenotype for V delta1 cells was similar to that of intestinal intraepithelial lymphocytes, a subset that can develop in the absence of the thymus. We suggest that the V delta1 and V delta2 T cell subsets represent distinct lineages with different developmental pathways. The disruption of the supply of normal, thymus-derived T cells in HIV-infected individuals might be responsible for the shift in the V delta2/V delta1 ratio that occurs in the blood of individuals with HIV disease. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20814 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP De Rosa, SC (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5612, Bethesda, MD 20814 USA. RI Roederer, Mario/G-1887-2011 FU NCI NIH HHS [CA-42509, CA-81543-02]; NIAID NIH HHS [5T32 AI-07290] NR 34 TC 33 Z9 33 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2001 VL 70 IS 4 BP 518 EP 526 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 480NJ UT WOS:000171467500005 PM 11590187 ER PT J AU Schwieters, CD Clore, GM AF Schwieters, CD Clore, GM TI Internal coordinates for molecular dynamics and minimization in structure determination and refinement SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID MULTIBODY SYSTEM DYNAMICS; NMR STRUCTURE CALCULATION; SPATIAL OPERATOR ALGEBRA; TORSION ANGLE DYNAMICS; DIPOLAR COUPLINGS; ALGORITHM; FORMULATION; INTEGRATION; CONSTRAINTS; SIMULATION AB We present a software module which allows one to efficiently perform molecular dynamics and local minimization calculations in internal coordinates when incorporated into a molecular dynamics package. We have implemented a reference interface to the NIH version of the X-PLOR structure refinement package and we show that the module provides superior torsion-angle dynamics functionality relative to the native X-PLOR implementation. The module has been designed in a portable fashion so that interfacing it with other packages should be relatively easy. Other features of the module include the ability to define rather general internal coordinates, an accurate integration algorithm which can automatically adjust the integration step size, and a modular design, which facilitates extending and enhancing the module. C1 NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 39 TC 140 Z9 140 U1 0 U2 5 PU ACADEMIC PRESS INC 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 OCT PY 2001 VL 152 IS 2 BP 288 EP 302 DI 10.1006/jmre.2001.2413 PG 15 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 481XP UT WOS:000171546000011 PM 11567582 ER PT J AU Zhang, MD Purcell, RH Emerson, SU AF Zhang, MD Purcell, RH Emerson, SU TI Identification of the 5 ' terminal sequence of the SAR-55 and MEX-14 strains of hepatitis E virus and confirmation that the genome is capped SO JOURNAL OF MEDICAL VIROLOGY LA English DT Editorial Material DE cap-dependent RACE; conserved 5; termini; Burmese strain ID MOLECULAR-CLONING; ISOLATE; HEV AB Hepatitis E virus (HEV) is a nonenveloped virus with a genome of sing le-stranded, positive-sense RNA. The 5 ' terminal sequence of two HEV strains (SAR-55 and MEX-14) was determined by a 5 ' RNA ligase-mediated rapid amplification of cDNA ends (RACE) method designed to select capped RNAs. The 5 ' noncoding region of the SAR-55 and MEX-14 strains were amplified, confirming that the genomic RNA of HEV is capped. The 5 ' noncoding region of the SAR-55 strain had 25 nucleotides, which is two less than reported for the Burmese strain, and that of the MEX-14 strain had 24 nucleotides, which is 21 more than reported previously [Huang et al., 1992]. (C) 2001 Wiley-Liss, Inc. C1 NIAID, Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 12 TC 16 Z9 18 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2001 VL 65 IS 2 BP 293 EP 295 DI 10.1002/jmv.2032 PG 3 WC Virology SC Virology GA 467ZZ UT WOS:000170734800011 PM 11536235 ER PT J AU Mattson, MP Chan, SL AF Mattson, MP Chan, SL TI Dysregulation of cellular calcium homeostasis in Alzheimer's disease - Bad genes and bad habits SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Review DE amyloid; apoptosis; excitotoxicity; oxidative stress; presenilin; synaptic plasticity ID AMYLOID-BETA-PEPTIDE; LIPID-PEROXIDATION PRODUCT; MITOCHONDRIAL PERMEABILITY TRANSITION; PROTECTS HIPPOCAMPAL-NEURONS; CORTICAL SYNAPTIC TERMINALS; NA+/K+-ATPASE ACTIVITY; ISCHEMIC BRAIN INJURY; METHYL-D-ASPARTATE; PRECURSOR PROTEIN; GLUTAMATE TRANSPORT AB Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasticity, and the regulation of various metabolic pathways. The findings reviewed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer's disease (AD). Associations between the pathological hallmarks of AD (neurofibrillary tangles [NFT] and amyloid plaques) and perturbed cellular calcium homeostasis have been established in studies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the beta -amyloid precursor protein (APP) and presenilins on neuronal plasticity and survival have provided insight into the molecular cascades that result in synaptic dysfunction and neuronal degeneration in AD. Central to the neurodegenerative process is the inability of neurons to properly regulate intracellular calcium levels. Increased levels of amyloid beta -peptide (A beta) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnerable to apoptosis and excitotoxicity. Subtoxic levels of A beta may induce synaptic dysfunction by impairing multiple signal transduction pathways. Presenilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links between aberrant calcium regulation and altered APP processing are emerging. Environmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual activity (bad habits); in each case, the environmental factor impacts on neuronal calcium homeostasis. Low calorie diets and intellectual activity may guard against AD by stimulating production of neurotrophic factors and chaperone proteins, The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic strategies for eradicating this growing epidemic of the elderly. C1 NIA, Gerontol Res Ctr 4F02, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr 4F02, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 185 TC 117 Z9 119 U1 1 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD OCT PY 2001 VL 17 IS 2 BP 205 EP 224 DI 10.1385/JMN:17:2:205 PG 20 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 492EE UT WOS:000172154800012 PM 11816794 ER PT J AU Rashid, MA Cantrell, CL Gustafson, KR Boyd, MR AF Rashid, MA Cantrell, CL Gustafson, KR Boyd, MR TI Chondropsin D, a new 37-membered-ring macrolide lactam from the marine sponge Chondropsis species SO JOURNAL OF NATURAL PRODUCTS LA English DT Article AB Chondropsin D (2), a new 37-membered-ring macrolide lactam, was isolated as a minor constituent of an aqueous extract of the marine sponge Chondropsis sp. This sponge sample had previously been the source of chondropsins A (1) and B, two novel polyketide-derived macrolides with potent cytotoxic activity. The structure of 2 was initially deduced from analysis of spectral data. This assignment was supported by the observation that chondropsin A (1), which contains a 35-membered macrocyclic ring, could be converted to chondropsin D (2) by a base-catalyzed intramolecular transesterification reaction. Rearrangement of the methylated derivative of chondropsin A (3) to the corresponding methylated analogue of chondropsin D (4) confirmed the structure of 2. C1 NCI, Ctr Canc Res, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Ctr Canc Res, Mol Targets Drug Discovery Program, Bldg 1052,Room 121, Frederick, MD 21702 USA. EM Boyd@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01 CO-56000] NR 5 TC 20 Z9 22 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2001 VL 64 IS 10 BP 1341 EP 1344 DI 10.1021/np0101907 PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 487GE UT WOS:000171864700017 PM 11678663 ER PT J AU O'Keefe, BR AF O'Keefe, BR TI Biologically active proteins from natural product extracts SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; RIBOSOME-INACTIVATING PROTEINS; MULTIFUNCTIONAL EFFECTOR MOLECULES; LIPOPOLYSACCHARIDE-BINDING-PROTEIN; LEUKOCYTE ANTIMICROBIAL PEPTIDES; HERPES-SIMPLEX VIRUS; CYANOVIRIN-N; ANTIBACTERIAL PEPTIDES; INNATE IMMUNITY; INSECT IMMUNITY AB The term "biologically active proteins" is almost redundant. All proteins produced by living creatures are, by their very nature, biologically active to some extent in their homologous species. In this review, a subset of these proteins will be discussed that are biologically active in heterologous systems. The isolation and characterization of novel proteins from natural product extracts including those derived from microorganisms, plants, insects, terrestrial vertebrates, and marine organisms will be reviewed and grouped into several distinct classes based on their biological activity and their structure. C1 NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. RP O'Keefe, BR (reprint author), NCI, Canc Res Ctr, Mol Targets Drug Discovery Program, Frederick, MD 21702 USA. NR 179 TC 40 Z9 41 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2001 VL 64 IS 10 BP 1373 EP 1381 DI 10.1021/np0103362 PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 487GE UT WOS:000171864700027 PM 11678673 ER PT J AU Guo, ZH Lee, J Lane, M Mattson, MP AF Guo, ZH Lee, J Lane, M Mattson, MP TI Iodoacetate protects hippocampal neurons against excitotoxic and oxidative injury: involvement of heat-shock proteins and Bcl-2 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis; cerebral ischemia; glutamate; heat-shock proteins 70 and 90; membrane lipid peroxidation; mitochondrial transmembrane potential ID AMYLOID BETA-PEPTIDE; MANGANESE SUPEROXIDE-DISMUTASE; TRANSIENT FOREBRAIN ISCHEMIA; TROPHIC FACTOR WITHDRAWAL; MITOCHONDRIAL DYSFUNCTION; DIETARY RESTRICTION; LIPID-PEROXIDATION; INDUCED APOPTOSIS; NEURAL CELLS; PEROXYNITRITE PRODUCTION AB Mild metabolic stress may increase resistance of neurons in the brain to subsequent, more severe insults, as demonstrated by the ability of ischemic pre-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the present study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycolysis can protect neurons. Pre-treatment of cultured hippocampal neurons with IAA can protect them against cell death induced by glutamate, iron and trophic factor withdrawal. Surprisingly, protection occurred with concentrations of IAA (2-200 nm) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxidative insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds in the prevention and/or treatment of neurodegenerative conditions. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 NR 61 TC 28 Z9 28 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2001 VL 79 IS 2 BP 361 EP 370 DI 10.1046/j.1471-4159.2001.00564.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 483KJ UT WOS:000171634300015 PM 11677264 ER PT J AU Chalela, JA Kasner, SE McGarvey, M Alsop, DC Detre, JA AF Chalela, JA Kasner, SE McGarvey, M Alsop, DC Detre, JA TI Continuous arterial spin labeling perfusion magnetic resonance imaging findings in postpartum vasculopathy SO JOURNAL OF NEUROIMAGING LA English DT Article DE cerebral blood flow; vasculopathy; postpartum; stroke ID CEREBRAL BLOOD-FLOW; ANGIOPATHY; PREECLAMPSIA; HEMORRHAGE; ECLAMPSIA; STROKE AB Postpartum vasculopathy (PPV) is a rare heterogeneous nonatherosclerotic vasculopathy that occurs in the puerperium. It occurs spontaneously but may be triggered by vasoconstrictor substances. The angiographic findings vary and include narrowing of the intracranial arteries and vasospasm. The angiographic findings and the occurrence of ischemic infarcts suggest that cerebral blood flow (CBF) is impaired in PPV. The purpose of this study is to determine CBF in patients with PPV. The authors conducted a case study of 3 patients with clinical and laboratory criteria for PPV examined during a 2-year period. Clinical examination, computed tomography imaging, structural magnetic resonance imaging (MRI), cerebral angiography, and continuous arterial spin labeling perfusion (CASIL-PI) MRI were performed in all patients. Mean global CBF was determined, and perfusion maps were visually inspected. The CBF values and perfusion maps were correlated with the clinical symptoms and the neuroimaging findings. Three women were studied (22, 34, and 36 years old). The median time of presentation was 4 days postpartum. One presented with intracranial hemorrhage and diffuse arterial narrowing, the other 2 with stroke-like lesions, encephalopathy, and segmental narrowing mainly in the posterior circulation. CASL-PI was performed within 1 week of symptom onset in all 3 patients. Global mean CBF values were 51.8, 39.3, and 41.8 cc/100 g/min. Although global CBF was mildly diminished, it was above ischemic levels. Visual inspection of the CASL-PI perfusion maps did not reveal areas of focal hypoperfusion or hyperperfusion. In this series of patients with PPV, CBF was close to normal. Although angiography often reveals diffuse arterial narrowing, the CBF values encountered in this study do not support a state of generalized or focal oligoemia. Vasomotor tone may change intermittently in patients with PPV. C1 Hosp Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Chalela, JA (reprint author), NINCDS, NIH, 36 Convent Dr,Room 4A03,MSC 4129, Bethesda, MD 20892 USA. RI Kasner, Scott/C-6109-2011; Alsop, David/J-5764-2013 OI Alsop, David/0000-0002-8206-1995 NR 11 TC 5 Z9 5 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD OCT PY 2001 VL 11 IS 4 BP 444 EP 446 PG 3 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 477RQ UT WOS:000171298400017 PM 11677889 ER PT J AU Stanley, AV Wang, Y Vinores, MA Derevjanik, NL Shi, A Klein, DA Detrick, B Hooks, JJ AF Stanley, AV Wang, Y Vinores, MA Derevjanik, NL Shi, A Klein, DA Detrick, B Hooks, JJ TI Blood-retinal barrier breakdown in experimental coronavirus retinopathy: association with viral antigen, inflammation, and VEGF in sensitive and resistant strains SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE coronavirus; blood-retinal barrier; vascular endothelial growth factor; retinopathy ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; HERPES-SIMPLEX VIRUS; IMMUNOHISTOCHEMICAL LOCALIZATION; MONOCYTE MIGRATION; GALACTOSEMIC RATS; FACTOR EXPRESSION; ALDOSE REDUCTASE; HUMAN DIABETICS AB Intraocular coronavirus inoculation results in a biphasic retinal disease in susceptible mice (BALB/c) characterized by an acute inflammatory response, followed by retinal degeneration associated with autoimmune reactivity. Resistant mice (CD-1), when similarly inoculated, only develop the early phase of the disease. Blood-retinal barrier (BRB) breakdown occurs in the early phase in both strains, coincident with the onset of inflammation. As the inflammation subsides, the extent of retinal vascular leakage is decreased, indicating that BRB breakdown in experimental coronavirus retinopathy (ECOR) is primarily due to inflammation rather than to retinal cell destruction. Vascular endothelial growth factor (VEGF) is upregulated only in susceptible mice during the secondary (retinal degeneration) phase. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Wilmer Ophthalmol Inst, Baltimore, MD 21287 USA. NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. RP Stanley, AV (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Ophthalmol Inst, 825 Maumenee Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. NR 49 TC 10 Z9 10 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 OCT 1 PY 2001 VL 119 IS 2 BP 175 EP 182 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 483RX UT WOS:000171650600003 ER PT J AU Oram, MW Hatsopoulos, NG Richmond, BJ Donoghue, JP AF Oram, MW Hatsopoulos, NG Richmond, BJ Donoghue, JP TI Excess synchrony in motor cortical neurons provides redundant direction information with that from coarse temporal measures SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PRECISELY REPLICATING PATTERNS; SPIKE TRAINS; MOVEMENT DIRECTION; FAVORED PATTERNS; FIRING PATTERNS; VISUAL-CORTEX; RESPONSES; DYNAMICS; AREAS; CONNECTIVITY AB Previous studies have shown that measures of fine temporal correlation, such as synchronous spikes, across responses of motor cortical neurons carries more directional information than that predicted from statistically independent neurons. It is also known, however, that the coarse temporal measures of responses, such as spike count, are not independent. We therefore examined whether the information carried by coincident firing was related to that of coarsely defined spike counts and their correlation. Synchronous spikes were counted in the responses from 94 pairs of simultaneously recorded neurons in primary motor cortex (MI) while monkeys performed arm movement tasks. Direct measurement of the movement-related information indicated that the coincident spikes (1- to 5-ms; precision) carry similar to 10% of the information carried by a code of the two spike counts. Inclusion of the numbers of synchronous spikes did not add information to that available from the spike counts and their coarse temporal correlation. To assess the significance of the numbers of coincident spikes, we extended the stochastic spike count matched (SCM) model to include correlations between spike counts of the individual neural responses and slow temporal dependencies within neural responses (similar to 30 Hz bandwidth). The extended SCM model underestimated the numbers of synchronous spikes. Therefore as with previous studies, we found that there were more synchronous spikes in the neural data than could be accounted for by this stochastic model. However, the SCM model accounts for most (R-2 = 0.93 +/-0.05, mean SE) of the differences in the observed number of synchronous spikes to different directions of arm movement, indicating that synchronous spiking is directly related to spike counts and their broad correlation. Further, this model supports the information theoretic analysis that the synchronous spikes do not provide directional information beyond that available from the firing rates of the same pool of directionally tuned MI neurons. These results show that detection of precisely timed spike patterns above chance levels does not imply that those spike patterns carry information unavailable from coarser population codes but leaves open the possibility that excess synchrony carries other forms of information or serves other roles in cortical information processing not studied here. C1 Brown Univ, Dept Neurosci, Providence, RI 02912 USA. Univ St Andrews, Sch Psychol, St Andrews KY16 9JU, Fife, Scotland. NIMH, NIH, Bethesda, MD 20892 USA. RP Hatsopoulos, NG (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. RI Oram, Michael/A-2558-2010 NR 53 TC 80 Z9 81 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT PY 2001 VL 86 IS 4 BP 1700 EP 1716 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 482EN UT WOS:000171562000017 PM 11600633 ER PT J AU Sans, N Racca, C Petralia, RS Wang, YX McCallum, J Wenthold, RJ AF Sans, N Racca, C Petralia, RS Wang, YX McCallum, J Wenthold, RJ TI Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway SO JOURNAL OF NEUROSCIENCE LA English DT Article DE SAP97; GluR1; trafficking; ER-cis-Golgi; postsynaptic density; hippocampus ID DOMAIN-CONTAINING PROTEIN; TUMOR-SUPPRESSOR PROTEIN; GLUTAMATE RECEPTORS; RAT-BRAIN; POSTSYNAPTIC DENSITY; SURFACE EXPRESSION; DIFFERENTIAL DISTRIBUTION; GLUR1 SUBUNIT; K+ CHANNEL; C-TERMINUS AB The regulation of AMPA receptors at the postsynaptic membrane is a fundamental component of synaptic plasticity. In the hippocampus, the induction of long-term potentiation increases the delivery of GluR1, a major AMPA receptor subunit in hippocampal pyramidal neurons, to the synaptic plasma membrane through a mechanism that requires the PDZ binding domain of GluR1. Synapse-associated protein 97 (SAP97), a member of the membrane-associated guanylate kinase family, is believed to associate with AMPA receptors (AMPARs) containing the GluR1 subunit, but the functional significance of these interactions is unclear. We investigated the interaction of GluR1 with SAP97, the only PDZ protein known to interact with GluR1. We find that interactions involving SAP97 and GluR1 occur early in the secretory pathway, while the receptors are in the endoplasmic reticulum or cis-Golgi. In contrast, few synaptic receptors associate with SAP97, suggesting that SAP97 dissociates from the receptor complex at the plasma membrane. We also show that internalization of GUM, as triggered by NMDAR activation, does not require SAP97. These results implicate GluR1-SAP97 interactions in mechanisms underlying AMPA receptor targeting. C1 Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Sans, N (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 50,Room 4146, Bethesda, MD 20892 USA. NR 50 TC 185 Z9 190 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 1 PY 2001 VL 21 IS 19 BP 7506 EP 7516 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 475GL UT WOS:000171154000012 PM 11567040 ER PT J AU Weil, RJ Zhuang, ZP Pack, S Kumar, S Helman, L Fuller, BG Mackall, CL Oldfield, EH AF Weil, RJ Zhuang, ZP Pack, S Kumar, S Helman, L Fuller, BG Mackall, CL Oldfield, EH TI Intramedullary Ewing sarcoma of the spinal cord: consequences of molecular diagnostics - Case report SO JOURNAL OF NEUROSURGERY LA English DT Article DE Ewing sarcoma; chromosomal translocation; radiation therapy; chemotherapy; spinal cord ID PRIMITIVE NEUROECTODERMAL TUMORS; DIFFERENTIAL-DIAGNOSIS; CYTOGENETIC ANALYSIS; TRANSCRIPTION FACTOR; BINDING DOMAIN; FAMILY; GENE; EWS; HYBRIDIZATION; FUSION AB Molecular biological techniques have begun to transform modem medicine. These techniques have shown promise in the pathological diagnosis of difficult or uncommon tumors. Accurate molecular diagnosis of the small round-cell tumors, for example, is especially important because divergent therapies may be required to eradicate such disparate lesions as neuroblastoma, lymphoma, rhabdomyosarcoma, central primitive neuroectodermal tumors/medulloblastoma, or Ewing sarcoma (ES). The authors present an unusual case of a primary, extraosseous ES arising from the intramedullary spinal cord, in which molecular studies were required for specific diagnosis and therapeutic guidance. C1 NINCDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Dept Neurol Surg, Nashville, TN USA. RP Oldfield, EH (reprint author), NINCDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 29 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2001 VL 95 IS 2 SU S BP 270 EP 275 DI 10.3171/spi.2001.95.2.0270 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 479ZL UT WOS:000171434600021 PM 11599852 ER PT J AU Kashmiri, SVS AF Kashmiri, SVS TI Invited commentary - Multivalent single-chain antibodies for radioimaging of tumors SO JOURNAL OF NUCLEAR MEDICINE LA English DT Editorial Material ID ANTIGEN-BINDING PROTEIN; ESCHERICHIA-COLI; XENOGRAFTS; CC49; FV; IDENTIFICATION; RETENTION; FRAGMENT; DIABODY C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kashmiri, SVS (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 5B38, Bethesda, MD 20892 USA. NR 20 TC 6 Z9 6 U1 0 U2 0 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 OCT PY 2001 VL 42 IS 10 BP 1528 EP 1529 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 479YH UT WOS:000171431400023 PM 11585868 ER PT J AU Yao, ZS Garmestani, K Wong, KJ Park, LS Dadachova, E Yordanov, A Waldmann, TA Eckelman, WC Paik, CH Carrasquillo, JA AF Yao, ZS Garmestani, K Wong, KJ Park, LS Dadachova, E Yordanov, A Waldmann, TA Eckelman, WC Paik, CH Carrasquillo, JA TI Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE alpha-emitter; internalization; cellular retention; monoclonal antibody ID CHRONIC LYMPHOCYTIC-LEUKEMIA; T-CELLS; SURFACE; IN-111; T101; RADIOIMMUNOTHERAPY; BIODISTRIBUTION; ANTIGEN; Y-90; PHARMACOKINETICS AB Monoclonal antibodies (mAbs) labeled with alpha -emitting radionuclides such as At-211, Bi-212, Bi-213, and Pb-212 (which decays by beta -emission to its a-emitting daughter Bi-212) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. Methods: In this study, we attached various radionuclides that result in a-emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of I-125- and In-111-labeled T101. T101 was labeled with At-211, I-125 Bi-205.6, In-111, and Pb-203. CD5 antigen-positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for I h at 4 degreesC for surface labeling. Unbound activity was removed and I mL medium added. The cells were then incubated at 37 degreesC for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and nonprotein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. Results: All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, Bi-205.6, 203Pb, and In-111 radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, At-211 and I-125 were released from cells rapidly (At-211 < I-125) and most of the radioactivity in the supernatant was in a non-protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. Conclusion: At-211 catabolism and release from cells were somewhat similar to that of I-125, whereas Bi-205.6 and Pb-203 showed prolonged cell retention similar to that of In-111. These catabolism differences may be important in the selection of a-radionuclides for radioimmunotherapy. C1 NCI, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NCI, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Carrasquillo, JA (reprint author), Bldg 10,Room 1C-496,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; Dadachova, Ekaterina/I-7838-2013; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 40 TC 32 Z9 33 U1 0 U2 1 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 OCT PY 2001 VL 42 IS 10 BP 1538 EP 1544 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 479YH UT WOS:000171431400025 PM 11585870 ER PT J AU Dancey, JE Goin, J AF Dancey, JE Goin, J TI Intrahepatic Y-90-microspheres for hepatocellular carcinoma - Reply SO JOURNAL OF NUCLEAR MEDICINE LA English DT Letter ID MICROSPHERES; Y-90 C1 NCI, Bethesda, MD 20892 USA. Data Medix Corp, Media, PA USA. RP Dancey, JE (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 OCT PY 2001 VL 42 IS 10 BP 1588 EP 1589 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 479YH UT WOS:000171431400033 ER PT J AU Erichsen, HC Eck, P Levine, M Chanock, S AF Erichsen, HC Eck, P Levine, M Chanock, S TI Characterization of the genomic structure of the human vitamin C transporter SVCT1 (SLC23A2) SO JOURNAL OF NUTRITION LA English DT Article DE ascorbic acid transporter; gene; exon; intron; polymorphism ID SINGLE-NUCLEOTIDE POLYMORPHISMS; DEHYDROASCORBIC ACID; GENES; RECOMMENDATIONS; IDENTIFICATION; ASCORBATE; CLONING; HSVCT1; FAMILY AB Vitamin C (L-ascorbic acid), a critical cofactor for intracellular enzymatic reactions, functions as a scavenger of free oxygen radicals and is an essential micronutrient. Vitamin C is actively transported into cells by one of two closely related sodium-dependent transporters, SVCT1 or SVCT2. In this paper, we report the complete sequencing and gene structure of SLC23A2, the gene encoding SVCT1. The 1797-bp cDNA sequence (open reading frame) of the SLC23A2 gene was derived from a compact genomic sequence of 7966 bp [translation initiation codon (ATG) to poly A tail], which is divided into 14 exons. Furthermore, repetitive or masked elements constituted 17.98% of the gene; there were 4 Alu sequences and 5 MIR (Mammalian Interspersed Repetitive element) sequences. A search for common variants in SLC23A2, using current bioinformatic tools and direct resequencing of control populations, failed to identify common single nucleotide polymorphisms. The start of transcription was mapped to a position -47 relative to the ATG; the immediate 5' sequence was determined and analyzed for possible consensus binding sites for known transcription factors. Our findings will serve as the foundation for investigation of the regulation and expression of the tissue-specific sodium-dependent vitamin C transporter, SLC23A2. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. OI Eck, Peter/0000-0003-2371-9774 NR 23 TC 17 Z9 18 U1 1 U2 1 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2001 VL 131 IS 10 BP 2623 EP 2627 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 481DF UT WOS:000171504100004 PM 11584081 ER PT J AU Abnet, CC Borkowf, CB Qiao, YL Albert, PS Wang, E Merrill, AH Mark, SD Dong, ZW Taylor, PR Dawsey, SM AF Abnet, CC Borkowf, CB Qiao, YL Albert, PS Wang, E Merrill, AH Mark, SD Dong, ZW Taylor, PR Dawsey, SM TI A cross-sectional study of human serum sphingolipids, diet and physiologic parameters SO JOURNAL OF NUTRITION LA English DT Article DE sphinganine; sphingosine; humans; serum; fumonisin ID FUMONISIN EXPOSURE; SPHINGOSINE 1-PHOSPHATE; NUTRITIONAL-STATUS; BIOMARKER; LIVER; SPHINGANINE/SPHINGOSINE; INTERVENTION; METABOLISM; MEDIATOR; CERAMIDE AB Sphinganine and sphingosine, the two sphingoid base backbones of sphingolipids, are highly bioactive compounds that are of increasing interest to nutritionists because they occur in food and their metabolism can be altered by fungal toxins that contaminate some foods. Nonetheless, no studies of diet and sphinganine or sphingosine concentrations in serum have yet been reported. Here we describe a cross-sectional study of 265 residents of Linxian, People's Republic of China, which examines potential demographic, physiologic and dietary correlates of serum sphinganine and sphingosine in this population. Median concentrations of serum sphinganine and sphingosine were compared among strata for 29 different variables. For sphinganine, no significant differences were found. For sphingosine, significant differences were seen among strata of age, menstruation status, serum cholesterol, carotenoids, retinol, tocopherols, fresh and dried vegetable and fresh fruit consumption. Using multivariate linear regression with stepwise selection, we found that the significant predictors for serum sphingosine included total tocopherols, age, serum selenium and retinol, with a final R-2 = 0.22; for sphinganine, tooth loss was the sole correlate, with R-2 = 0.015. Analyses using ranked sphingolipid data or principal components analysis, to simplify the food variables, did not materially alter these results. This study represents the largest report of human serum sphingolipid concentrations to date and provides insight into potential explanatory variables that can be incorporated into future studies. C1 Natl Canc Inst, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Canc, Beijing, Peoples R China. Natl Canc Inst, Div Canc Treatment & Diag, Bethesda, MD USA. Emory Univ, Rollins Res Ctr, Dept Biochem, Atlanta, GA USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Abnet, CC (reprint author), Natl Canc Inst, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 NR 36 TC 12 Z9 12 U1 0 U2 3 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2001 VL 131 IS 10 BP 2748 EP 2752 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 481DF UT WOS:000171504100022 PM 11584099 ER PT J AU Lizak, MJ Mori, K Kador, PF AF Lizak, MJ Mori, K Kador, PF TI Determination of aldose reductase activity in the eye by localized magnetic resonance spectroscopy SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Proceedings Paper CT 5th Annual Meeting of the American-for-Ocular-Pharmacology-and-Therapeutics CY NOV, 2000 CL BIRMINGHAM, ALABAMA SP Amer Ocular Pharmacol & Therapeut ID BLOOD-RETINAL BARRIER; GALACTOSE-FED DOGS; DIABETIC-RETINOPATHY; INHIBITOR M79175; IN-VIVO AB The polyol pathway plays an important role in the formation of diabetic complications of the eye. Due to variations in the pharmacokinetic properties of aldose reductase inhibitors and variations in the degradation of the blood-ocular barrier, it is often difficult to determine the proper intraocular levels of aldose reductase inhibitor required for inhibition of aldose reductase activity in ocular tissues. Utilizing localized magnetic resonance spectroscopy (MRS), the present method can determine adequate inhibition of aldose reductase activity in the lens by noninvasively measuring polyol pathway activity in the eye. New Zealand White rabbits, under anesthesia, were administered an intravitreal injection of 3-fluoro-3-deoxy-D-glucose (3FDG). Localized MRS was then used to assess polyol pathway activity by determining the levels of 3-fuoro-3-deoxy-D-sorbitol (3FS) and 3-fluoro-3-deoxy-D-fructose (3FF) metabolite formation from 3FDG in the eye. MRS was able to follow the loss of 3FDG from the vitreous into the anterior segment of the eye and particularly into the lens and aqueous. The primary metabolism of 3FDG observed by MRS was the formation of 3FS in the lens that is catalyzed by aldose reductase. Production of 3FS was linear in time and decreased with the oral administration of an aldose reductase inhibitor. C1 NINCDS, NIH MRI Res Facil 1, NIH, Bethesda, MD 20892 USA. RP Lizak, MJ (reprint author), NINCDS, NIH MRI Res Facil 1, NIH, Bldg 10,Rm B1D-69,10 Ctr Dr, Bethesda, MD 20892 USA. EM LizakM@ninds.nih.gov NR 18 TC 3 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD OCT PY 2001 VL 17 IS 5 BP 475 EP 483 DI 10.1089/108076801753266857 PG 9 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 496RH UT WOS:000172409600008 PM 11765152 ER PT J AU Stavrou, T Bromley, CM Nicholson, HS Byrne, J Packer, RJ Goldstein, AM Reaman, GH AF Stavrou, T Bromley, CM Nicholson, HS Byrne, J Packer, RJ Goldstein, AM Reaman, GH TI Prognostic factors and secondary malignancies in childhood medulloblastoma SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE medulloblastoma; prognostic factors; nevoid basal cell carcinoma syndrome; secondary malignancies ID CELL CARCINOMA SYNDROME; RADIATION-INDUCED MENINGIOMA; LONG-TERM SURVIVAL; BRAIN-TUMORS; RECURRENT MEDULLOBLASTOMA; CRANIOSPINAL IRRADIATION; YOUNG-CHILDREN; COLLINS LAW; CHEMOTHERAPY; VINCRISTINE AB Purpose: Little is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed. Patients and Methods: The records of all patients with childhood medulloblastoma diagnosed at Children's National Medical Center in Washington, DC from 1969 through 1997 were reviewed. Results: The median follow-up time was 92 months (range 6-257 months), Overall survival was 59% at 5 years and 52% at 10 years. Univariate analysis showed that age at diagnosis, extent of surgical resection, presence of metastatic disease (M stage), ventriculoperitoneal shunt placement within 30 days from diagnosis, posterior fossa radiation therapy dose, and adjuvant chemotherapy significantly affected survival. Although based on small numbers, the risk of second neoplasms was significantly increased in this cohort. Multiple basal cell carcinomas developed in the areas of radiation therapy in two patients;, these patients also had nevoid basal cell carcinoma syndrome (NBCCS) diagnosed. One other patient died of glioblastoma multiforme 8 years after treatment of medulloblastoma. A meningioma developed in another patient 10 years after radiation therapy. Conclusion: As survival of medulloblastoma patients improves, increased surveillance regarding secondary malignancies is required, especially because radiation-induced tumors may occur many years after treatment. These two cases of NBCCS also illustrate the importance of considering the concomitant diagnosis of NBCCS in young patients with medulloblastoma. In those patients, alternative therapy should be considered to minimize radiation therapy-related sequelae. C1 Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Stavrou, T (reprint author), Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. NR 42 TC 57 Z9 60 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 OCT PY 2001 VL 23 IS 7 BP 431 EP 436 DI 10.1097/00043426-200110000-00008 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 481JK UT WOS:000171516000007 PM 11878577 ER PT J AU Kempner, ES AF Kempner, ES TI Effects of high-energy electrons and gamma rays directly on protein molecules SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE radiation; target theory; macromolecules; direct effects ID RADIATION TARGET ANALYSIS; INACTIVATION; TEMPERATURE; SIZE; FRAGMENTATION; SENSITIVITY; WEIGHT AB High-energy electrons and gamma rays ionize molecules at random along their trajectories. In each event, chemical bonds are ruptured, releasing radiolytic products that diffuse away. A solution of macromolecules is mostly water whose principal radiation products are H+ and OH-. These can diffuse to and react with macromolecules; this indirect action of radiation is responsible for 99.9% of the damage to proteins. In frozen samples, the ionizations still occur randomly and water is still the principle molecular target, but diffusion of radiation products is limited to only a very small distance. At very low temperatures, essentially all the radiation damage to macromolecules is due to primary ionizations occurring directly in those molecules. Therefore, proteins in frozen solutions are only 10(-3) to 10(-4) as sensitive to radiation as in the liquid state. Every molecule that suffered a direct ionization is destroyed; the only surviving molecules are those that escaped ionization. The survival of frozen proteins after irradiation is a direct measure of the mass of the active structures and independent of the presence of other proteins. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kempner, ES (reprint author), NIAMSD, Phys Biol Lab, NIH, Bldg 6,RM 140, Bethesda, MD 20892 USA. NR 33 TC 49 Z9 50 U1 2 U2 12 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-3549 J9 J PHARM SCI JI J. Pharm. Sci. PD OCT PY 2001 VL 90 IS 10 BP 1637 EP 1646 DI 10.1002/jps.1114 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 483TE UT WOS:000171651300019 PM 11745722 ER PT J AU Tsao, CC Coulter, SJ Chien, A Luo, G Clayton, NP Maronpot, R Goldstein, JA Zeldin, DC AF Tsao, CC Coulter, SJ Chien, A Luo, G Clayton, NP Maronpot, R Goldstein, JA Zeldin, DC TI Identification and localization of five CYP2Cs in murine extrahepatic tissues and their metabolism of arachidonic acid to regio- and stereoselective products SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID POTENTIAL FUNCTIONAL-SIGNIFICANCE; EPOXYEICOSATRIENOIC ACIDS; MOLECULAR-CLONING; CYTOCHROME-P-450 ENZYMES; EPITHELIAL-CELLS; EXPRESSION; EPOXYGENASE; SUBFAMILY; INFLAMMATION; ISOFORM AB The CYP2C subfamily has been extensively studied in humans with respect to the metabolism of clinically important drugs, and polymorphisms have been identified in these enzymes. In the present study, a murine model was used to determine the possible physiological functions and extrahepatic distribution of CYP2Cs. Using the reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immununohistochemistry, this report demonstrates that the mouse CYP2Cs are extensively distributed in extrahepatic tissues and localized to heart muscle, lung Clara and ciliated cells, kidney collecting ducts, the X-zone of female adrenals, reproductive organs, white blood cells, and eyes (in the optic nerve, rods, and cones). RT-PCR, subcloning, and sequencing of the products indicate that each CYP2C has a unique tissue distribution. Four cDNA fragments representing potentially new CYP2Cs were identified, each with its own organ-specific pattern of expression. Using a bacterial cDNA expression system, we found that recombinant proteins for each of the five full-length murine CYP2Cs metabolize arachidonic acid to different regio- and stereospecific products, including epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids. Regio- and stereospecific, metabolites of arachidonic acid have been reported to affect important physiological functions such as inflammation, neutrophil activation, ion transport, cellular proliferation, and vascular tone. Our results suggest that the presence of CYP2C enzymes in heart muscle, aorta, kidney, lung, adrenals, eyes, and reproductive organs could regulate important physiological and/or pathological processes in these tissues. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP NIEHS, Lab Pharmacol & Chem, POB 12233,A3-02, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012; OI Coulter, Sherry/0000-0002-2732-3470 NR 42 TC 41 Z9 41 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2001 VL 299 IS 1 BP 39 EP 47 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 474WB UT WOS:000171128900006 PM 11561061 ER PT J AU Rauser, L Savage, JE Meltzer, HY Roth, BL AF Rauser, L Savage, JE Meltzer, HY Roth, BL TI Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CONSTITUTIVELY ACTIVATED STATE; 2C RECEPTOR; SEROTONIN RECEPTOR; 5-HT2C RECEPTORS; CLINICAL POTENCY; BINDING-AFFINITY; PHOSPHOLIPASE-C; RAT AORTA; SCHIZOPHRENIA; CLOZAPINE AB Atypical antipsychotic drugs, which are distinguished from typical antipsychotic drugs by a lower incidence of extra-pyramidal side effects and less propensity to elevate serum prolactin levels (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone), have become the most widely used treatments for schizophrenia, although their precise mechanism of action remains controversial. It has been suggested that this group of atypical antipsychotic drugs is characterized by preferentially high affinities for 5-hydroxytryptamine (5-HT)(2A) serotonin receptors and relatively low affinities for D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic drugs (e.g., haloperidol, fluphenazine, chlorpromazine, and so on) by inverse agonist actions at the 5-HT2C-INI RNA edited isoform of the human 5-HT2C receptor transiently expressed in COS-7 cells. We have examined the relationship among 5-HT2C inverse agonist potency, efficacy, and atypical antipsychotic drug status in HEK-293 cells of a large number of typical and atypical antipsychotic drugs using human embryonic kidney (HEK)-293 cells stably transfected with the h5-HT2C-INI receptor. Inverse agonist actions at h5-HT2C-INI receptors were measured for both typical and atypical antipsychotic drugs. Thus, some typical antipsychotic drugs (chlorpromazine, mesoridazine, fluphenazine, and loxapine) were efficient inverse agonists, whereas several clinically effective atypical antipsychotic drugs (remoxapride, quetiapine, sulpiride, melperone, amperozide) were not. Additionally, several drugs without significant antipsychotic actions (M100907, ketanserin, mianserin, ritanserin, and amitriptyline) were potent inverse agonists at the 5-HT2C-INI isoform expressed in HEK-293 cells. Taken together, these results demonstrate that both typical and atypical antipsychotic drugs may exhibit inverse agonist effects at the 5-HT2C-INI isoform of the human 5-HT2C receptor and that no relationship exists between inverse agonist actions and atypicality. C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, RM W438,10900 Euclid Ave, Cleveland, OH 44106 USA. RI Roth, Bryan/F-3928-2010; Meltzer, Herbert/E-8131-2013 FU NIMH NIH HHS [KO2 MH01366, N01 MH80005] NR 48 TC 102 Z9 108 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2001 VL 299 IS 1 BP 83 EP 89 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 474WB UT WOS:000171128900011 PM 11561066 ER PT J AU Fedorova, I Hashimoto, A Fecik, RA Hedrick, MP Hanus, LO Boger, DL Rice, KC Basile, AS AF Fedorova, I Hashimoto, A Fecik, RA Hedrick, MP Hanus, LO Boger, DL Rice, KC Basile, AS TI Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GAP JUNCTION COMMUNICATION; ACID AMIDE HYDROLASE; RECEPTOR ANTAGONIST; LIPID OLEAMIDE; BRAIN LIPIDS; INDUCE SLEEP; ANANDAMIDE; CANNABINOIDS; INHIBITION; WITHDRAWAL AB While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)(1A), 5HT(2C), and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma -aminobutyric acid (GABA)(A) receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D-2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA USA. RP Basile, AS (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Room 121,MSC 0826, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA42056] NR 40 TC 52 Z9 54 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2001 VL 299 IS 1 BP 332 EP 342 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 474WB UT WOS:000171128900041 PM 11561096 ER PT J AU Tao, XL Cush, JJ Garret, M Lipsky, PE AF Tao, XL Cush, JJ Garret, M Lipsky, PE TI A phase I study of ethyl acetate extract of the Chinese antirheumatic herb Tripterygium wilfordii Hook F in rheumatoid arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE antirheumatic therapy; disease modifying antirheumatic drug; ethyl acetate extract; herbal remedies; Tripterygium wilfordii Hook F ID T2 AB Objective. To explore the efficacy and safety of ethyl acetate (EA) extracts of the Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) for treatment of patients with a variety of inflammatory and autoimmune diseases including rheumatoid arthritis (RA). Methods. The roots of TWHF were extracted sequentially by ethyl alcohol and ethyl acetate and the content of the extract documented. An open label, dose escalation Phase I study was performed in 1993 in 13 patients with established RA. Clinical manifestations and laboratory findings were examined before and every 4 weeks after starting treatment with the EA extract. Results. Three patients withdrew from the trial during the first 16 weeks of the dose escalation. These patients received a maximum dosage of 180 mg/day. There were no adverse effects or disease improvement observed in these patients. Nine of the remaining 10 patients tolerated the EA extract up to a dosage of 570 mg/day. There were no withdrawals related to adverse events in the trial except for one patient who developed diastolic hypertension at a dose of 180 mg/day of EA extract. Six of 10 patients treated with 180 mg/day of EA extract showed disease improvement. Eight of the 9 patients who received EA extract at doses > 360 mg/day experienced improvement in both clinical manifestations and laboratory findings. One patient met American College of Rheumatology criteria for remission. Conclusion. The EA extract of TWHF at dosages up to 570 mg/day appeared to be safe, and doses > 360 mg/day were associated with clinical benefit in patients with RA. C1 Univ Texas, SW Med Ctr, Harold C Simmons Arthrit Ctr, Dallas, TX USA. RP Lipsky, PE (reprint author), NIAMSD, Intramural Res Program, NIH, Bldg 10,9N228,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 95 Z9 103 U1 1 U2 2 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 OCT PY 2001 VL 28 IS 10 BP 2160 EP 2167 PG 8 WC Rheumatology SC Rheumatology GA 479JN UT WOS:000171401400005 PM 11669150 ER PT J AU Masi, AT Aldag, JC Sipes, J AF Masi, AT Aldag, JC Sipes, J TI Do elevated levels of serum C-reactive protein predict rheumatoid arthritis in men: Correlations with pre-RA status and baseline positive rheumatoid factors SO JOURNAL OF RHEUMATOLOGY LA English DT Letter C1 Univ Illinois, Coll Med, Peoria, IL 61656 USA. Natl Inst Hlth, Bethesda, MD USA. RP Masi, AT (reprint author), Univ Illinois, Coll Med, Peoria, IL 61656 USA. OI Masi, Alfonse/0000-0002-9695-6634 NR 9 TC 17 Z9 17 U1 0 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 OCT PY 2001 VL 28 IS 10 BP 2359 EP 2360 PG 2 WC Rheumatology SC Rheumatology GA 479JN UT WOS:000171401400035 PM 11669180 ER PT J AU Calderoni, D Wudarsky, M Bhangoo, R Dell, ML Nicolson, R Hamburger, SD Gochman, P Lenane, M Rapoport, JL Leibenluft, E AF Calderoni, D Wudarsky, M Bhangoo, R Dell, ML Nicolson, R Hamburger, SD Gochman, P Lenane, M Rapoport, JL Leibenluft, E TI Differentiating childhood-onset schizophrenia from psychotic mood disorders SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE mood disorders; psychosis; schizophrenia; children; diagnosis; prognosis ID MAJOR DEPRESSION; NONPSYCHOTIC CHILDREN; EMOTIONAL DISORDERS; HALLUCINATIONS; DIAGNOSIS; ADOLESCENTS; BIPOLAR; MANIA; PHENOMENOLOGY; FEATURES AB Objective: The authors systematically examined a sample of patients who were referred to an ongoing National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia (COS), but who received diagnoses of mood disorders at the NIMH, to analyze the reliability of these research-setting diagnoses and to characterize the patients clinically. Pilot data regarding the clinical course of these patients over a 2- to 7-year follow-up period were also obtained. Method: Thirty-three cases were selected from the 215 pediatric patients who had been screened in person from 1991 to 1999 for admission to the COS study. These 33 patients had been excluded from the COS study on the basis of a day-long evaluation, including a structured diagnostic interview, which yielded a diagnosis of a mood disorder rather than schizophrenia. This subgroup, together with six COS subjects (for a total N = 39), were included in a diagnostic reliability study in which they were reevaluated by three psychiatrists who were blind to the initial research diagnosis. In addition, pilot follow-up data regarding current function and treatment status were obtained for 25 of the 33 patients with mood disorders. Results: Overall, the interrater reliability of the three raters was excellent (kappa = 0.90). Global reliability between these raters and the NIMH research diagnoses was good (average kappa across diagnoses = 0.61), and agreement for those patients who had mood disorders was good (86% agreement; kappa = 0.60). Pilot follow-up data indicate that none of the subjects with a diagnosed mood disorder developed a clinical course resembling schizophrenia. Conclusions: Many of the patients referred to the NIMH COS study with clinical diagnoses of schizophrenia had psychotic mood disorders diagnosed on the basis of a comprehensive research evaluation including structured diagnostic interviews, and these research diagnoses were reliable. The diagnosis of COS is difficult and requires a time-consuming evaluation process. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, Room 4N208,10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. RI Nicolson, Robert/E-4797-2011 NR 39 TC 28 Z9 28 U1 5 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2001 VL 40 IS 10 BP 1190 EP 1196 DI 10.1097/00004583-200110000-00013 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 475XM UT WOS:000171195200012 PM 11589532 ER PT J AU Prasad, A Halcox, JPJ Waclawiw, MA Quyyumi, AA AF Prasad, A Halcox, JPJ Waclawiw, MA Quyyumi, AA TI Angiotensin type 1 receptor antagonism reverses unormal coronary vasomotion in atherosclerosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CONVERTING ENZYME-INHIBITION; NITRIC-OXIDE RELEASE; ENDOTHELIAL DYSFUNCTION; ARTERY DISEASE; SMOOTH-MUSCLE; VASCULAR HYPERTROPHY; INCREASES; HUMANS; HEART; TONE AB OBJECTIVES This study was performed to determine whether angiotensin type 1 (AT1) receptor inhibition improves abnormal coronary vasomotion and endothelial dysfunction in patients with atherosclerosis or its risk factors. BACKGROUND Endothelial dysfunction, an early feature of atherosclerosis, contributes to abnormal vasomotion during stress. Angiotensin II may contribute to endothelial dysfunction in atherosclerosis. METHODS In 25 patients, mean age 59 +/- 2 years, with atherosclerosis or its risk factors, we measured coronary vasomotion during flow-mediated dilation (FMD) in response to adenosine, cold pressor test (CPT) and exercise before and after AT1 receptor blockade with intracoronary losartan (5 mg). RESULTS Losartan did not alter resting coronary vascular tone, but epicardial FMD improved from 5.6 +/- 1.5% to 8.9 +/- 1.8% (p = 0.02). Abnormal epicardial vasomotion during CPT and exercise also improved with losartan from - 1.7 +/- 0.8% to 1.5 +/- 0.1% (p = 0.02) and - 0.6 +/- 0.9% to 3.4 +/- 1.2% (p = 0.009), respectively. Improvement in epicardial vasomotion was most prominent in segments with baseline endothelial dysfunction evidenced as constriction during stress. Microvascular dilation during adenosine, an endothelium-independent response, was unchanged with losartan. CONCLUSIONS Inhibition of the coronary vascular AT1 receptors in patients with atherosclerosis improves epicardial vasomotion during stress, probably by improving endothelial dysfunction. Whether AT1 receptor blockade will provide long-term therapeutic benefits in atherosclerosis needs further investigation. (C) 2001 by the American College of Cardiology C1 NHLBI, NIH, Cardiol Branch, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, NIH, Cardiol Branch, Bldg 10,Room 7B15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. OI Halcox, Julian/0000-0001-6926-2947 NR 43 TC 33 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT PY 2001 VL 38 IS 4 BP 1089 EP 1095 DI 10.1016/S0735-1097(01)01511-X PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 476TH UT WOS:000171244500028 PM 11583887 ER PT J AU Prasad, A Mincemoyer, R Quyyumi, AA AF Prasad, A Mincemoyer, R Quyyumi, AA TI Anti-ischemic effects of angiotensin-converting enzyme inhibition in hypertension SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; ENDOTHELIAL DYSFUNCTION; MYOCARDIAL-ISCHEMIA; ANGINA-PECTORIS; NITRIC-OXIDE; ACE-INHIBITION; CAPTOPRIL; EXERCISE; BRADYKININ; REVERSIBILITY AB OBJECTIVES We investigated whether augmentation of bradykinin (BK) bioavailability with angiotensin-converting enzyme (ACE) inhibition is associated with reduced exercise-induced myocardial ischemia in hypertension. BACKGROUND Bradykinin responses are depressed in hypertension, and endothelial dysfunction contributes to myocardial ischemia by promoting abnormal coronary vasomotion during stress. METHODS Fourteen hypertensive (HT) and 17 normotensive (NT), mildly symptomatic patients with coronary artery disease (CAD) and ST-segment depression during exercise were studied before and after seven days of oral enalapril (EN), which was titrated from 2.5 to 20 mg daily. Patients underwent two treadmill exercise tests and determination of forearm vasodilator response to BK. RESULTS Despite receiving a lower dose of EN (7.8 vs. 14.8 mg, p < 0.001), NT patients had a significant reduction in blood pressure compared to HT patients. Compared to pre-EN, the ischemic threshold, defined as the rate-pressure product at the onset of 1-mm ST depression (p = 0.045), the duration of exercise to 1-mm ST depression (180 +/- 54 s, p = 0.007) and the maximum exercise duration (94 +/- 18 s, p < 0.001) were greater after EN in HT patients, but not in NT subjects (all p greater than or equal to 0.3). Patients with a greater drop in blood pressure experienced no improvement in exercise-induced ischemia. Forearm blood flow responses to BK were improved with EN in all patients to a similar extent. Moreover, no correlation was observed between the basal response to BK or the magnitude of its improvement with EN and with either the dose of EN or the improvement in exercise ischemic threshold. CONCLUSIONS Exercise-induced myocardial ischemia is ameliorated in HT patients with CAD by ACE inhibition. (C) 2001 by the American College of Cardiology. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. NR 25 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT PY 2001 VL 38 IS 4 BP 1116 EP 1122 DI 10.1016/S0735-1097(01)01506-6 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 476TH UT WOS:000171244500032 PM 11583891 ER PT J AU Sitges, M Jones, M Shiota, T Prior, DL Qin, JX Tsujino, H Bauer, F Kim, YJ Deserranno, D Greenberg, NL Cardon, LA Zetts, AD Garcia, MJ Thomas, JD AF Sitges, M Jones, M Shiota, T Prior, DL Qin, JX Tsujino, H Bauer, F Kim, YJ Deserranno, D Greenberg, NL Cardon, LA Zetts, AD Garcia, MJ Thomas, JD TI Interaliasing distance of the flow convergence surface for determining mitral regurgitant volume: A validation study in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID COLOR DOPPLER FLOW; ORIFICE AREA; VALVULAR REGURGITATION; CLINICAL VALIDATION; QUANTIFICATION; ECHOCARDIOGRAPHY; VALVE; SIZE AB OBJECTIVES We aimed to validate a new flow convergence (FC) method that eliminated the need to locate the regurgitant orifice and that could be performed semiautomatedly. BACKGROUND Complex and time-consuming features of previously validated color Doppler methods for determining mitral regurgitant volume (MRV) have prevented their widespread clinical use. METHODS Thirty-nine different hemodynamic conditions in 12 sheep with surgically created flail leaflets inducing chronic mitral regurgitation were studied with two-dimensional (2D) echocardiography. Color Doppler M-mode images along the centerline of the accelerating flow towards the mitral regurgitation orifice were obtained. The distance between the two first aliasing boundaries (interaliasing distance [LAD]) was measured and the FC radius was mathematically derived according to the continuity equation (R-calc = LAD/(1 - rootv(1)/v(2)), v(1) and v(2) being the aliasing velocities). The conventional 2D FC radius was also measured (R-meas). Mitral regurgitant volume was then calculated according to the FC method using both R, and R-meas. Aortic and mitral electromagnetic (EM) flow probes and meters were balanced against each other to determine the reference standard MRV. RESULTS Mitral regurgitant volume calculated from R-calc and R-meas correlated well with EM-MRV (y = 0.83x + 5.17, r = 0.90 and y = 1.04x + 0.91, r = 0.91, respectively, p < 0.001 for both). However, both methods resulted in slight overestimation of EM-MRV (Delta was 3.3 +/- 2.1 ml for R-calc and 1.3 +/- 2.3 ml for R-meas). CONCLUSIONS Good correlation was observed between MRV derived from R-calc (IAD method) and EM-MRV, similar to that observed with R-meas (conventional FC method) and EM-MRV. The R-calc using the IAD method has an advantage over conventional R-meas in that it does not require spatial localization of the regurgitant orifice and can be performed semiautomatedly. (C) 2001 by the American College of Cardiology. C1 Cleveland Clin Fdn, Dept Cardiol, Cardiovasc Imaging Ctr, Cleveland, OH 44195 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Dept Cardiol, Cardiovasc Imaging Ctr, Desk F-15,9500 Euclid Ave, Cleveland, OH 44195 USA. NR 25 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT PY 2001 VL 38 IS 4 BP 1195 EP 1202 DI 10.1016/S0735-1097(01)01502-9 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 476TH UT WOS:000171244500044 PM 11583903 ER PT J AU Van Horn, L Ernst, N AF Van Horn, L Ernst, N TI A summary of the science supporting the new National Cholesterol Education Program dietary recommendations: What dietitians should know SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Editorial Material ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE; TRANS-FATTY-ACIDS; SERUM-CHOLESTEROL; HYPERCHOLESTEROLEMIC SUBJECTS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; PLASMA HOMOCYSTEINE; FISH CONSUMPTION; RANDOMIZED TRIAL C1 Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Van Horn, L (reprint author), Northwestern Univ, Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Ste 1102, Chicago, IL 60611 USA. NR 56 TC 15 Z9 15 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD OCT PY 2001 VL 101 IS 10 BP 1148 EP 1154 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 499BT UT WOS:000172551700011 PM 11678485 ER PT J AU Newman, AB Yanez, D Harris, T Duxbury, A Enright, PL Fried, LP AF Newman, AB Yanez, D Harris, T Duxbury, A Enright, PL Fried, LP CA Cardiovascular Study Res Grp TI Weight change in old age and its association with mortality SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE weight loss; weight gain; mortality ID BODY-MASS INDEX; CARDIOVASCULAR-HEALTH; 5-YEAR MORTALITY; RISK-FACTORS; US ADULTS; WOMEN; MEN; OVERWEIGHT; DISEASE; VARIABILITY AB OBJECTIVES: Previous studies of weight change and mortality in older adults have relied on self-reported weight loss, have not evaluated weight gain, or have had limited information on health status. Our objective was to determine whether 5% weight gain or loss in 3 years was predictive of mortality in a large sample of older adults. DESIGN: Longitudinal observational cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand seven hundred fourteen community-dwelling older adults, age 65 and older. MEASUREMENTS: Weight gain or loss of 5% in a 3-year period was examined in relationship to baseline health status and interim health events. Risk for subsequent mortality was estimated in those with weight loss or weight gain compared with the group whose weight was stable. RESULTS: Weight changes occurred in 34.6% of women and 27.3% of men, with weight loss being more frequent than gain. Weight loss was associated with older age, black race, higher weight, lower waist circumference, current smoking, stroke, any hospitalization, death of a spouse, activities of daily living disability, lower grip strength, and slower gait speed. Weight loss but not weight gain of 5% or more was associated with an increased risk of mortality that persisted after multivariate adjustment (Hazard ratio (HR) = 1.67, 95% CI = 1.29-2.15) and was similar in those with no serious illness in the period of weight change. Those with weight loss and low baseline weight had the highest crude mortality rate, although the HR for weight loss was similar for all tertiles of baseline weight and for those with or without a special diet, compared with those whose weight was stable. CONCLUSIONS: This study confirms that even modest decline in body weight is an important and independent marker of risk of mortality in older adults. C1 Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. Univ Washington, Seattle, WA 98195 USA. NIA, Bethesda, MD 20892 USA. Univ Alabama, Birmingham, AL USA. Univ Arizona, Tucson, AZ 85721 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Newman, AB (reprint author), Univ Pittsburgh, Sch Med, Div Geriatr Med, 3520 5th Ave,Suite 300, Pittsburgh, PA 15213 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85086] NR 35 TC 267 Z9 279 U1 3 U2 14 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2001 VL 49 IS 10 BP 1309 EP 1318 DI 10.1046/j.1532-5415.2001.49258.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 482VL UT WOS:000171597900006 PM 11890489 ER PT J AU Klein, EA Thompson, IM Lippman, SM Goodman, PJ Albanes, D Taylor, PR Coltman, C AF Klein, EA Thompson, IM Lippman, SM Goodman, PJ Albanes, D Taylor, PR Coltman, C TI Select: The next prostate cancer prevention trial SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; chemoprevention; selenium; vitamin E ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; KINASE-C ACTIVITY; VITAMIN-E; ALPHA-TOCOPHEROL; BETA-CAROTENE; COLORECTAL-CANCER; COLON-CANCER; LUNG-CANCER; FOLLOW-UP AB Purpose: Growing evidence implies that selenium and vitamin E may decrease the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized prospective double-blind study designed to determine whether selenium and vitamin E decrease the risk of prostate cancer in healthy men. Materials and Methods: The preclinical and epidemiological evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of the 2 agents were included in the current analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the SELECT schema. Results: Preclinical, epidemiological and phase III data imply that selenium and vitamin E have potential efficacy for prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial shows the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. Conclusions: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment in the study is planned to begin in 2001 with final results anticipated in 2013. C1 Cleveland Clin Fdn, Inst Urol, Sect Urol Oncol, Cleveland, OH 44195 USA. Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX USA. SW Oncol Grp, San Antonio, TX USA. MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX USA. Fred Hutchinson Canc Res Ctr, SW Oncol Grp, Ctr Stat, Seattle, WA 98104 USA. NCI, Div Clin Sci, Canc Prevent Studies Branch, Washington, DC USA. RP Cleveland Clin Fdn, Inst Urol, Sect Urol Oncol, 9500 Euclid Ave, Cleveland, OH 44195 USA. RI Albanes, Demetrius/B-9749-2015 NR 55 TC 173 Z9 179 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD OCT PY 2001 VL 166 IS 4 BP 1311 EP 1315 DI 10.1016/S0022-5347(05)65759-X PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 471VV UT WOS:000170950100023 PM 11547064 ER PT J AU Wassef, M Baxter, BT Chisholm, RL Dalman, RL Fillinger, MF Heinecke, J Humphrey, JD Kuivaniemi, H Parks, WC Pearce, WH Platsoucas, CD Sukhova, GK Thompson, RW Tilson, MD Zarins, CK AF Wassef, M Baxter, BT Chisholm, RL Dalman, RL Fillinger, MF Heinecke, J Humphrey, JD Kuivaniemi, H Parks, WC Pearce, WH Platsoucas, CD Sukhova, GK Thompson, RW Tilson, MD Zarins, CK TI Pathogenesis of abdominal aortic aneurysms: A multidisciplinary research program supported by the National Heart, Lung, and Blood Institute SO JOURNAL OF VASCULAR SURGERY LA English DT Review ID SMOOTH-MUSCLE CELLS; MATRIX METALLOPROTEINASES; ARTERIAL ENLARGEMENT; SACCULAR ANEURYSMS; POSTTRANSCRIPTIONAL REGULATION; REGIONAL DISTRIBUTION; ANTIGENIC PROTEINS; ELASTIN PRODUCTION; EXPRESSION; WALL C1 NHLBI, Vasc Biol Res Program, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. RP Wassef, M (reprint author), NHLBI, Vasc Biol Res Program, Div Heart & Vasc Dis, NIH, 2 Rockledge Ctr,Room 10196,6701 Rockledge Dr, Bethesda, MD 20892 USA. RI Chisholm, Rex/B-3418-2009; OI Chisholm, Rex/0000-0002-5638-3990; Kuivaniemi, Helena/0000-0001-5753-8766 FU NHLBI NIH HHS [HL60942] NR 55 TC 128 Z9 135 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2001 VL 34 IS 4 BP 730 EP 738 DI 10.1067/mva.2001.116966 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 489YK UT WOS:000172020400026 PM 11668331 ER PT J AU Lewis, BC Chinnasamy, N Morgan, RA Varmus, HE AF Lewis, BC Chinnasamy, N Morgan, RA Varmus, HE TI Development of an avian leukosis-sarcoma virus subgroup A pseudotyped lentiviral vector SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VESICULAR STOMATITIS-VIRUS; NONDIVIDING HUMAN-CELLS; MEDIATED GENE-TRANSFER; IN-VIVO; RETROVIRAL VECTORS; LEUKEMIA-VIRUS; TRANSDUCTION; DELIVERY; MICE AB We are using avian leukosis-sarcoma virus (ALSV) vectors to generate mouse tumor models in transgenic mice expressing TVA, the receptor for subgroup A ALSV. Like other classical retroviruses, ALSV requires cell division to establish a provirus after infection of host cells. In contrast, lentiviral vectors are capable of integrating their viral DNA into the genomes of nondividing cells. With the intention of initiating tumorigenesis in resting, TVA-positive cells, we have developed a system for the preparation of a human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector, pseudotyped with the envelope protein of ALSV subgroup A (EnvA). The HIV(ALSV-A) vector retains the requirement for TVA on the surface of target cells and can be produced at titers of 5 x 10(3) infectious units (IU)/ml. By inserting the central polypurine tract (cPPT) from the HIV-1 pol gene and removing the cytoplasmic tail of EnvA, the pseudotype can be produced at titers approaching 10(5) IU/ml and can be concentrated by ultracentrifugation to titers of 10(7) IU/ml. HIV(ALSV-A) also infects embryonic fibroblasts derived from transgenic mice in which TVA expression is driven by the beta -actin promoter. In addition, this lentivirus pseudotype efficiently infects these fibroblasts after cell cycle arrest, when they are resistant to infection by ALSV vectors. This system may be useful for introducing genes into somatic cells in adult TVA transgenic animals and allows evaluation of the effects of altered gene expression in differentiated cell types in vivo. C1 Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA. NCI, Div Basic Sci, Bethesda, MD 20892 USA. NHGRI, Clin Gene Therapy Branch, Bethesda, MD 20892 USA. RP Lewis, BC (reprint author), Mem Sloan Kettering Canc Ctr, Cell Biol Program, 1275 York Ave,Box 62, New York, NY 10021 USA. NR 37 TC 58 Z9 60 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2001 VL 75 IS 19 BP 9339 EP 9344 DI 10.1128/JVI.75.19.9339-9344.2001 PG 6 WC Virology SC Virology GA 470XX UT WOS:000170898600047 PM 11533197 ER PT J AU Tang, SX Murakami, T Agresta, BE Campbell, S Freed, EO Levin, JG AF Tang, SX Murakami, T Agresta, BE Campbell, S Freed, EO Levin, JG TI Human immunodeficiency virus type 1 N-terminal capsid mutants that exhibit aberrant core morphology and are blocked in initiation of reverse transcription in infected cells SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; AMINO-ACID SUBSTITUTIONS; CYCLOPHILIN-A; LIFE-CYCLE; GAG PROTEINS; POSTTRANSLATIONAL MODIFICATIONS; HIV-1 VIRIONS; WILD-TYPE; IN-VITRO; DOMAIN AB A group of conserved hydrophobic residues faces the interior of the coiled-coil-like structure within the N-terminal domain of the human immunodeficiency virus type 1 (HIV-1) capsid protein (CA). It has been suggested that these residues are important for maintaining stable structure and functional activity. To investigate this possibility, we constructed two HIV-1 clones, in which Trp23 or Phe40 was changed to Ala. We also constructed a third mutant, D51A, which has a mutation that destroys a salt bridge between Pro1 and Asp51. All three mutants are replication defective but produce virus particles. Mutant virions contain all of the viral proteins, although the amount and stability of CA are decreased and levels of virion-associated integrase are reduced. The mutations do not affect endogenous reverse transcriptase activity; however, the mutants are blocked in their ability to initiate reverse transcription in infected cells and no minus-strand strong-stop DNA is detected. The defect in reverse transcription is associated with striking defects in the morphology of mutant virus cores, as determined by transmission electron microscopy. Our data indicate that the mutations made in this study disrupt CA structure and prevent proper maturation of virus cores. We propose that this results in a defect in core stability or in an early postentry event preceding reverse transcription. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. NCI, HIV Drug Resistance Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Levin, JG (reprint author), NICHHD, Mol Genet Lab, NIH, Bldg 6B,Room 216, Bethesda, MD 20892 USA. NR 61 TC 96 Z9 97 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2001 VL 75 IS 19 BP 9357 EP 9366 DI 10.1128/JVI.75.19.9357-9366.2001 PG 10 WC Virology SC Virology GA 470XX UT WOS:000170898600049 PM 11533199 ER PT J AU Blaydes, SM Kogan, SC Truong, BTH Gilbert, DJ Jenkins, NA Copeland, NG Largaespada, DA Brannan, CI AF Blaydes, SM Kogan, SC Truong, BTH Gilbert, DJ Jenkins, NA Copeland, NG Largaespada, DA Brannan, CI TI Retroviral integration at the Epi1 locus cooperates with Nf1 gene loss in the progression to acute myeloid leukemia SO JOURNAL OF VIROLOGY LA English DT Article ID NEUROFIBROMATOSIS TYPE-1 GENE; C-MYB; MYELOMONOCYTIC LEUKEMIA; CONSTITUTIVE EXPRESSION; ERYTHROLEUKEMIA-CELLS; DIFFERENTIATION; CHILDREN; LEUKEMOGENESIS; MUTATIONS; DISEASE AB Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding, or progression to acute myeloid leukemia (AML). As it is known that children with neurofibromatosis type 1 syndrome have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML through reconstitution of lethally irradiated mice with hematopoietic stem cells homozygous for a loss-of-function mutation in the Nf1 gene (D. L. Largaespada, C. I. Brannan, N. A. Jenkins, and N. G. Copeland, Nat. Genet. 12:137-143, 1996). In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression to AML. Here, we describe the production of a unique tumor panel, created using the BXH-2 genetic background, for identification of these additional genetic lesions. Using this tumor panel, we have identified a locus, Epi1, which maps 30 to 40 kb downstream of the Myb gene and appears to be the most common site of somatic viral integration in BXH-2 mice. Our findings suggest that proviral integrations at Epi1 cooperate with loss of Nf1 to cause AML. C1 Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr Mammalian Genet, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Shands Canc Ctr, Gainesville, FL 32610 USA. Univ Calif San Francisco, Ctr Comprehens Canc, Dept Lab Med, San Francisco, CA 94143 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Minnesota, Ctr Canc, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Brannan, CI (reprint author), Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr Mammalian Genet, POB 100266, Gainesville, FL 32610 USA. RI Largaespada, David/C-9832-2014 FU NCI NIH HHS [CA75986, CA84221, U01 CA084221] NR 38 TC 21 Z9 21 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 OCT PY 2001 VL 75 IS 19 BP 9427 EP 9434 DI 10.1128/JVI.75.19.9427-9434.2001 PG 8 WC Virology SC Virology GA 470XX UT WOS:000170898600055 PM 11533205 ER PT J AU Peletskaya, EN Boyer, PL Kogon, AA Clark, P Kroth, H Sayer, JM Jerina, DM Hughes, SH AF Peletskaya, EN Boyer, PL Kogon, AA Clark, P Kroth, H Sayer, JM Jerina, DM Hughes, SH TI Cross-linking of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase to template-primer SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED DNA; ANGSTROM RESOLUTION; NONNUCLEOSIDE INHIBITOR; NUCLEIC-ACID; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; DRUG-RESISTANCE; HIV-1 RT; COMPLEX; DESIGN AB Cross-linking experiments were performed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants with unique cysteine residues at several positions (positions 65, 67, 70, and 74) in the fingers subdomain of the p66 subunit. Two approaches were used-photoaffinity cross-linking and disulfide chemical cross-linking (using an oligonucleotide that contained an N-2-modified dG with a reactive thiol group). In the former case, cross-linking can occur to any nucleotide in either DNA strand, and in the latter case, a specific cross-link is produced between the template and the enzyme. Neither the introduction of the unique cysteine residues into the fingers nor the modification of these residues with photocross-linking reagents caused a significant decrease in the enzymatic activities of RT. We were able to use this model system to investigate interactions between specific points on the fingers domain of RT and double-stranded DNA (dsDNA). Photoaffinity cross-linking of the template to the modified RTs with Cys residues in positions 65, 67, 70, and 74 of the fingers domain of the p66 subunit was relatively efficient. Azide-modified Cys residues produced 10 to 25% cross-linking, whereas diazirine modified residues produced 5 to 8% cross-linking. Disulfide cross-linking yields were up to 90%. Ail of the modified RTs preferentially photocross-linked to the 5' extended template strand of the dsDNA template-primer substrate. The preferred sites of interactions were on the extended template, 5 to 7 bases beyond the polymerase active site. HIV-1 RT is quite flexible. There are conformational changes associated with substrate binding. Cross-linking was used to detect intramolecular movements associated with binding of the incoming deoxynucleoside triphosphate (dNTP). Binding an incoming dNTP at the polymerase active site decreases the efficiency of cross-linking, but causes only modest changes in the preferred positions of cross-linking. This suggests that the interactions between the fingers of p66 and the extended template involve the "open" configuration of the enzyme with the fingers away from the active site rather than the closed configuration with the fingers in direct contact with the incoming dNTP. This experimental approach can be used to measure distances between any site on the surface of the protein and an interacting molecule. C1 NCI, ABL Basic Res Program, Frederick, MD 21702 USA. NCI, SAIC Frederick, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, NIH, Rockville, MD 20892 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539, Frederick, MD 21702 USA. NR 39 TC 19 Z9 19 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2001 VL 75 IS 19 BP 9435 EP 9445 DI 10.1128/JVI.75.19.9435-9445.2001 PG 11 WC Virology SC Virology GA 470XX UT WOS:000170898600056 PM 11533206 ER PT J AU Monaco, MCG Sabath, BF Durham, LC Major, EO AF Monaco, MCG Sabath, BF Durham, LC Major, EO TI JC virus multiplication in human hematopoietic progenitor cells requires the NF-1 class D transcription factor SO JOURNAL OF VIROLOGY LA English DT Article ID NUCLEAR FACTOR-I; ADENOVIRUS DNA-REPLICATION; TONSILLAR STROMAL CELLS; HUMAN CYTOMEGALO-VIRUS; AFFINITY BINDING-SITE; HUMAN POLYOMAVIRUS; B-LYMPHOCYTES; GENE FAMILY; GLIAL-CELLS; PROTEIN AB JCV, a small DNA virus of the polyomavirus family, has been shown to infect glial cells of the central nervous system, hematopoietic progenitor cells, and immune system lymphocytes. A family of DNA binding proteins called nuclear factor-1 (NF-1) has been linked with site-coding specific transcription of cellular and viral genes and replication of some viruses, including JC virus (JCV). It is unclear which NF-1 gene product must be expressed by cells to promote JCV multiplication. Previously, it was shown that elevated levels of NF-1 class D mRNA were expressed by human brain cells that are highly susceptible to JCV infection but not by JCV nonpermissive HeLa cells. Recently, we reported that CD34(+) precursor cells of the KG-1 line, when treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA), differentiated to cells with macrophage-like characteristics and lost susceptibility to JCV infection. These studies have now been extended by asking whether loss of JCV susceptibility by PMA-treated KG-1 cells is linked with alterations in levels of NF-1 class D expression. Using reverse transcription-PCR, we have found that PMA-treated KG-1 cells express mRNA that codes for all four classes of NF-I proteins, although different levels of RNA expression were observed in the hematopoietic cells differentiated into macrophages. Northern hybridization confirms that the expression of NF-1 class D gene is lower in JCV nonpermissive PMA-treated KG-1 cells compared with non-PMA-treated cells. Further, using gel mobility shift assays, we were able to show the induction of specific NF-I-DNA complexes in KG-1 cells undergoing PMA treatment. The binding increases in direct relation to the duration of PMA treatment. These results suggest that the binding pattern of NF-1 class members may change in hematopoietic precursor cells, such as KG-1, as they undergo differentiation to macrophage-like cells. Transfection of PMA-treated KG-1 cells with an NF-1 class D expression vector restored the susceptibility of these cells to JCV infection, while the transfection of PMA-treated KG-1 cells with NF-1 class A, B, and C vectors was not able to restore JCV susceptibility. These data collectively suggest that selective expression of NF-1 class D has a regulatory role in JCV multiplication. C1 NINCDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINCDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Room 5W21, Bethesda, MD 20892 USA. NR 49 TC 49 Z9 49 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 OCT PY 2001 VL 75 IS 20 BP 9687 EP 9695 DI 10.1128/JVI.75.20.9687-9695.2001 PG 9 WC Virology SC Virology GA 474JG UT WOS:000171102900015 PM 11559801 ER PT J AU Blaney, JE Johnson, DH Firestone, CY Hanson, CT Murphy, BR Whitehead, SS AF Blaney, JE Johnson, DH Firestone, CY Hanson, CT Murphy, BR Whitehead, SS TI Chemical mutagenesis of dengue virus type 4 yields mutant viruses which are temperature sensitive in Vero cells or human liver cells and attenuated in mice SO JOURNAL OF VIROLOGY LA English DT Article ID YELLOW-FEVER VIRUS; FRENCH NEUROTROPIC VACCINE; SERIAL PASSAGE; NS3 PROTEASE; KIDNEY-CELLS; INFECTION; CANDIDATE; STRAIN; LINES; FLAVIVIRUSES AB A recombinant live attenuated dengue virus type 4 (DEN4) vaccine candidate, 2A Delta 30, was found previously to be generally well tolerated in humans, but a rash and an elevation of liver enzymes in the serum occurred in some vaccinees. 2A Delta 30, a non-temperature-sensitive (non-ts) virus, contains a 30-nucleotide deletion (Delta 30) in the 3 ' untranslated region (UTR) of the viral genome. In the present study, chemical mutagenesis of DEN4 was utilized to generate attenuating mutations which may be useful in further attenuation of the 2A Delta 30 candidate vaccine. Wild-type DEN4 2A virus was grown in Vero cells in the presence of 5-fluorouracil, and a panel of 1,248 clones were isolated. Twenty is mutant viruses were identified that were is in both simian Vero and human liver HuH-7 cells (n = 13) or only in HuH-7 cells (n = 7). Each of the 20 is mutant viruses possessed an attenuation phenotype, as indicated by restricted replication in the brains of 7-day-old mice. The complete nucleotide sequence of the 20 is mutant viruses identified nucleotide substitutions in structural and nonstructural genes as well as in the 5 ' and 3 ' UTRs, with more than one change occurring, in general, per mutant virus. A is mutation in the NS3 protein (nucleotide position 4995) was introduced into a recombinant DEN4 virus possessing the Delta 30 deletion, thereby creating rDEN4 Delta 30-4995, a recombinant virus which is is and more attenuated than rDEN4 Delta 30 virus in the brains of mice. We are assembling a menu of attenuating mutations that should be useful in generating satisfactorily attenuated recombinant dengue vaccine viruses and in increasing our understanding of the pathogenesis of dengue virus. C1 NIAID, LID, NIH, Bethesda, MD 20892 USA. RP Blaney, JE (reprint author), NIAID, LID, NIH, Bldg 7,Room 100,7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. NR 62 TC 48 Z9 48 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 OCT PY 2001 VL 75 IS 20 BP 9731 EP 9740 DI 10.1128/JVI.75.20.9731-9740.2001 PG 10 WC Virology SC Virology GA 474JG UT WOS:000171102900020 PM 11559806 ER PT J AU Fang, JY Mikovits, JA Bagni, R Petrow-Sadowski, CL Ruscetti, FW AF Fang, JY Mikovits, JA Bagni, R Petrow-Sadowski, CL Ruscetti, FW TI Infection of lymphoid cells by integration-defective human immunodeficiency virus type 1 increases de novo methylation SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; PROTEIN ZINC-FINGER; DNA METHYLATION; DE-NOVO; VIRAL-DNA; HISTONE DEACETYLASE; CPG ISLAND; HIV-1 INTEGRASE; P16(INK4A) GENE; LEUKEMIA-VIRUS AB DNA methylation, by regulating the transcription of genes, is a major modifier of the eukaryotic genome. DNA methyltransferases (DNMTs) are responsible for both maintenance and de novo methylation. We have reported that human immunodeficiency virus type 1 (HIV-1) infection increases DNMT1 expression and de novo methylation of genes such as the gamma interferon gene in CD4(+) cells. Here, we examined the mechanisms) by which HIV-1 infection increases the cellular capacity to methylate genes. While the RNAs and proteins of all three DNMTs (1, 3a, and 3b) were detected in Hut 78 lymphoid cells, only the expression of DNMT1 was significantly increased 3 to 5 days postinfection. This increase was observed with either wild-type HIV-1 or an integrase (IN) mutant, which renders HIV replication defective, due to the inability of the provirus to integrate into the host genome. Unintegrated viral DNA is a common feature of many retroviral infections and is thought to play a role in pathogenesis. These results indicate another mechanism by which unintegrated viral DNA affects the host. In addition to the increase in overall genomic methylation, hypermethylation and reduced expression of the p16(INK4A) gene, one of the most commonly altered genes in human cancer, were seen in cells infected with both wild-type and IN-defective HIV-1. Thus, infection of lymphoid cells with integration-defective HIV-1 can increase the methylation of CpG islands in the promoters of genes such as the p16(INK4A) gene, silencing their expression. C1 NCI, Basic Res Lab, CCR, Frederick, MD 21702 USA. SAIC Frederick, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. DCTP, Dev Therapeut Program, Frederick, MD 21702 USA. RP Ruscetti, FW (reprint author), NCI, Basic Res Lab, CCR, Bldg 567,Rm 253, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 88 TC 54 Z9 60 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 OCT PY 2001 VL 75 IS 20 BP 9753 EP 9761 DI 10.1128/JVI.75.20.9753-9761.2001 PG 9 WC Virology SC Virology GA 474JG UT WOS:000171102900022 PM 11559808 ER PT J AU Aung, S Rutigliano, JA Graham, BS AF Aung, S Rutigliano, JA Graham, BS TI Alternative mechanisms of respiratory syncytial virus clearance in perforin knockout mice lead to enhanced disease SO JOURNAL OF VIROLOGY LA English DT Article ID CD8(+) T-CELLS; MURINE CYTOMEGALOVIRUS-INFECTION; TUMOR-NECROSIS-FACTOR; MEDIATED CYTOTOXICITY; INTERFERON-GAMMA; IN-VIVO; HOMEOSTATIC REGULATION; IMMUNE-RESPONSES; FAS; PATHOGENESIS AB Virus-specific cytotoxic T lymphocytes are key effectors for the clearance of virus-infected cells and are required for the normal clearance of respiratory syncytial virus (RSV) in mice. Although perforin/granzyme-mediated lysis of infected cells is thought to be the major molecular mechanism used by CD8(+) cytotoxic T lymphocytes for elimination of virus, its role in RSV has not been reported. Here, we show that viral clearance in perforin knockout (PKO) mice is slightly delayed but that both PKO and wild-type mice clear virus by day 10, suggesting an alternative mechanism of RSV clearance. Effector T cells from the lungs of both groups of mice were shown to lyse Fas (CD95)-overexpressing target cells in greater numbers than target cells expressing low levels of Fas, suggesting that Fas ligand (CD95L) -mediated target cell lysis was occurring in vivo. This cell lysis was associated with a delay in RSV-induced disease in PKO mice compared to the time of disease onset for wild-type controls, which correlated with increased and prolonged production of gamma interferon and tumor necrosis factor alpha levels in PKO mice. We conclude that while perforin is not necessary for the clearance of primary RSV infection, the use of alternative CTL target cell killing mechanisms is less efficient and can lead to enhanced disease. C1 Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. RP Graham, BS (reprint author), NIH, Vaccine Res Ctr, Bldg 40,Room 2502,40 Convent Dr, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R01 AI033933, R01-AI-33933] NR 44 TC 51 Z9 51 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 OCT PY 2001 VL 75 IS 20 BP 9918 EP 9924 DI 10.1128/JVI.75.20.9918-9924.2001 PG 7 WC Virology SC Virology GA 474JG UT WOS:000171102900038 PM 11559824 ER PT J AU Xiang, Y Moss, B AF Xiang, Y Moss, B TI Correspondence of the functional epitopes of poxvirus and human interleukin-18-binding proteins SO JOURNAL OF VIROLOGY LA English DT Article ID MOLLUSCUM-CONTAGIOSUM VIRUS; BINDING-PROTEIN; IL-18 BINDING; APOPTOSIS; INHIBITION; MOLECULES; EVASION; HOMOLOG; FAMILY; CELLS AB Molluscum contagiosum virus, a human poxvirus that causes persistent small benign skin tumors, encodes a variety of putative immune defense proteins. Three such proteins, MC51L, MC53L, and MC54L, have 20 to 35% amino acid sequence identities with human interleukin-18 (hIL-18)-binding protein (hIL-18BP), a naturally occurring antagonist of the proinflammatory cytokine IL-18. We previously demonstrated that seven amino acids within the immunoglobulin-like domain of hIL-18BP were important for high-affinity binding to hIL-18. Model building indicated that MC54L, which has been shown to bind hIL-18, contains five of the seven amino acids at corresponding positions in its immunoglobulin-like domain, the exceptions being the conservative substitution of isoleucine for a leucine and the nonconservative substitution of valine for a phenylalanine. We found that individual alanine substitutions for these six identical or highly conserved amino acids of MC54L caused changes in affinity and binding free energy for hIL-18 that were quantitatively similar to those produced by mutagenesis of hIL-18BP. Furthermore, when the nonconserved valine of MC54L was mutated to phenylalanine, making it more like hIL-18BP, its affinity for hIL-18 increased more than 10-fold. In addition, the carboxyl-terminal half of MC54L, which has no similarity with ML-18BP, was dispensable for hIL-18 binding. Thus, despite their relatively low overall sequence identity, MC54L and hIL-18BP have similar hIL-18 binding sites and functional epitopes. On the other hand, MC51L and MC53L have nonconservative substitutions of three to six of the seven critical amino acids of hIL-18BP and neither protein bound hIL-18, suggesting that they may interact with unidentified ligands. 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 39 TC 42 Z9 43 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2001 VL 75 IS 20 BP 9947 EP 9954 DI 10.1128/JVI.75.20.9947-9954.2001 PG 8 WC Virology SC Virology GA 474JG UT WOS:000171102900041 PM 11559827 ER PT J AU Jylha, M Guralnik, JM Balfour, J Fried, LP AF Jylha, M Guralnik, JM Balfour, J Fried, LP TI Walking difficulty, walking speed, and age as predictors of self-rated health: The women's health and aging study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID DISABLED OLDER WOMEN; PHYSICAL PERFORMANCE; FUNCTIONAL STATUS; ELDERLY MEN; COMMUNITY; ADULTS; ASSOCIATION; DISABILITY; DEPRESSION; APPRAISAL AB Background. Older persons reporting disability are more likely to report poor self-rated health, but little work has been done to assess the independent relationships of reported walking difficulty and measured walking performance with self-rated health. This study examines the associations of walking difficulty, walking speed, and age with self-rated health in older women. Methods. The data are from the baseline of the Women's Health and Aging Study. Difficulty walking one quarter mile was used as a measure of mobility in the representative population aged 65 and older screened for the study (n = 3841) and in the one third most disabled study group (n = 1002). Maximal walking speed was measured in the study sample. Results. Increasing severity of walking difficulty (in the screened population and in the disabled study.-roup), slower walking speed (in the study.-roup), and younger age were all associated with fair or poor self-rated health, after simultaneous adjustment for these and other objective measures of physical performance and health. The associations of both measures of walking with self-rated health weakened with age. Conclusions. Both walking difficulty and walking speed are independent determinants of self-rated health. Adjusted for health and functioning, self-rated health tends to improve with age. C1 Univ Tampere, Tampere Sch Publ Hlth, FIN-33014 Tampere, Finland. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sch Med, Dept Epidemiol, Baltimore, MD 21205 USA. RP Jylha, M (reprint author), Univ Tampere, Tampere Sch Publ Hlth, FIN-33014 Tampere, Finland. FU NIA NIH HHS [N01-AG-1-2112] NR 35 TC 80 Z9 84 U1 2 U2 9 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 OCT PY 2001 VL 56 IS 10 BP M609 EP M617 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 480JU UT WOS:000171458900008 PM 11584033 ER PT J AU Simonsick, EM Newman, AB Nevitt, MC Kritchevsky, SB Ferrucci, L Guralnik, JM Harris, T AF Simonsick, EM Newman, AB Nevitt, MC Kritchevsky, SB Ferrucci, L Guralnik, JM Harris, T CA Health ABC Study Grp TI Measuring higher level physical function in well-functioning older adults: Expanding familiar approaches in the health ABC study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID PERFORMANCE-BASED MEASURES; SUBSEQUENT DISABILITY; EXERCISE; POPULATION; PREDICTOR; VALIDITY AB Background. To evaluate development and progression of functional limitation and retain comparability with established approaches, we raised the measurement ceiling of commonly used self-report and performance-based measures of function. This study evaluated the utility and concurrent validity of these expanded measures. Methods. The study population consisted of 3075 black and white men and women aged 70 to 79 years, with no reported mobility limitations or disability, participating in the Health, Aging, and Body Composition, or Health ABC study. Self-report measures were expanded by ascertaining case of performance and including more demanding levels of some tasks. A single foot stand and narrow walk supplemented an established performance battery. For walking endurance, we developed the Long Distance Corridor Walk (LDCW), which includes distance covered in 2 minutes and the time to walk 400 m. Results. The expanded self-report items identified one half of the men and one third of the women as exceptionally well functioning and 10% to 13% of men and 21% to 36% of women with lower capacity. The supplemented and re-scored performance battery discriminated function over the full range. The LDCW further differentiated walking capacity at the high end and also identified a subgroup with limitations. The self-report and performance measures were significantly, but weakly, correlated (0.13-0.35) and were independent predictors of walking endurance. Conclusions. Well-functioning persons in their 70s exhibit a broad range of functional capacity readily ascertained by expanded self-report and performance tests, Significant associations among these measures support their concurrent validity, but generally weak correlations indicate they tap different, but important, dimensions of physical function. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Natl Res Inst, INRCA, Geriatr Dept I Fraticini, Florence, Italy. RP Simonsick, EM (reprint author), NIA, Gerontol Res Ctr, Clin Invest Lab, 5600 Nathan Shock Dr,Box 06, Baltimore, MD 21224 USA. FU NIA NIH HHS [N01-AG-2103, N01-AG-2106, N01-AG-6-2102] NR 18 TC 166 Z9 167 U1 1 U2 11 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2001 VL 56 IS 10 BP M644 EP M649 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 480JU UT WOS:000171458900013 PM 11584038 ER PT J AU Miskulin, DC Athienites, NV Yan, G Martin, AA Ornt, DB Kusek, JW Meyer, KB Levey, AS AF Miskulin, DC Athienites, NV Yan, G Martin, AA Ornt, DB Kusek, JW Meyer, KB Levey, AS CA HEMO Study Grp TI Comorbidity assessment using the Index of Coexistent Diseases in a multicenter clinical trial SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the American-Society-of-Nephrology CY NOV 02-06, 1997 CL SAN ANTONIO, TEXAS SP Amer Soc Nephrol DE case-mix adjustment; risk assessment; randomized clinical trial; population sampling; dialysis; instrument ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; DIALYSIS PATIENTS; CO-MORBIDITY; RISK-FACTORS; HEMODIALYSIS-PATIENTS; MAINTENANCE DIALYSIS; PERITONEAL-DIALYSIS; MEDICAL SPECIALTIES; FUNCTIONAL STATUS AB Background. The Hemodialysis (HEMO) Study is a multicenter trial designed to determine whether hemodialysis dose and membrane flux affect survival. Comorbid conditions are also important determinants of survival, and thus, an accurate and reliable method to assess comorbidity was required. Comorbidity was being assessed at baseline and annually in the HEMO Study using the Index of Coexistent Disease (ICED). We describe the instrument. its implementation in the HEMO Study, and the results of comorbidity assessment in the first 1000 randomized patients in the trial. Methods. The ICED aggregated the presence and severity of 19 medical conditions and 11 physical impairments within two scales: the Index of Disease Severity (IDS) and the Index of Physical Impairment (IPI). The final ICED score was determined by an algorithm combining the peak scores for the IDS and IPI. The range of the ICED was from 0 to 3, reflecting increasing severity. Results. Study personnel at 15 clinical centers were trained to update and abstract data from the dialysis medical records. Availability of data, measures of construct validity, and measures of reliability were adequate; 99.8% and 60.6% of patients had comorbid conditions in at least one IDS or IPI category, respectively. The distribution of patients by ICED level was 0 (02%), 1 (34.9%). 2 (31.2%), and 3 (33.7%). In multivariable analysis, the following factors were significantly associated with more severe comorbidity: older age, diabetes and other causes of renal disease, a lower level of education, employment status (unemployed and retired), longer duration of dialysis, and lower serum creatinine. There was a significant variation in the severity of comorbidity among clinical centers after adjustment for other factors. The R-2 of the model was 25.3%, indicating that a substantial proportion of the variation in the ICED was not explained by these factors. Conclusions. We conclude that comorbidity assessment using the ICED is feasible in multicenter clinical trials of dialysis patients. There is a large burden of comorbidity in dialysis patients, which is not well explained by the cause of renal disease, demographic, and socioeconomic factors and common clinical and laboratory measurements. These variables should not be considered substitutes for comorbid conditions in case-mix adjustment. Comorbidity assessment is useful to describe the sample population, to improve the precision of the treatment effect, and to use possibly as an outcome measurement. C1 Tufts Univ New England Med Ctr, Div Nephrol, Boston, MA 02111 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Rochester, Rochester, NY USA. NIDDK, Bethesda, MD USA. RP Miskulin, DC (reprint author), Tufts Univ New England Med Ctr, Div Nephrol, Box 391,750 Washington St, Boston, MA 02111 USA. OI Meyer, Klemens/0000-0001-5253-4950 FU NIDDK NIH HHS [U01 DK 46114, U01DK 49252, U01DK 46143, U01DK 49241, U01DK 46109, UO1DK49242, U01DK 49254, U01DK 49249, U01DK 49264, U01DK 49261, U01DK 49240, U01DK 49244, U01DK 49271, U01DK 46126, U01DK 49243, U01DK 49259] NR 47 TC 131 Z9 133 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2001 VL 60 IS 4 BP 1498 EP 1510 DI 10.1046/j.1523-1755.2001.00954.x PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 474VF UT WOS:000171127000031 PM 11576365 ER PT J AU Hoyt, RF Clevenger, RR McGehee, JA AF Hoyt, RF Clevenger, RR McGehee, JA TI Introduction to microsurgery: An emerging discipline in biomedical research SO LAB ANIMAL LA English DT Article AB Using microsurgical techniques, biomedical researchers are able to perform procedures that would otherwise be impossible on small laboratory animals. The authors provide a primer on learning microsurgical technique, from correct posture and hand position, to understanding lenses and proper handling of surgical needles and suture material. C1 NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. RP Hoyt, RF (reprint author), NHLBI, LAMS, NIH, Serv Rd S,Bldg 14E,105B, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 2 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2001 VL 30 IS 9 BP 26 EP 35 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 482NX UT WOS:000171583100003 PM 11687781 ER PT J AU Hoyt, RF Clevenger, RR McGehee, JA AF Hoyt, RF Clevenger, RR McGehee, JA TI Microsurgical instrumentation and suture material SO LAB ANIMAL LA English DT Article C1 NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. RP Hoyt, RF (reprint author), NHLBI, LAMS, NIH, 14 Serv Rd S,14E,105B, Bethesda, MD 20892 USA. NR 9 TC 1 Z9 1 U1 1 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2001 VL 30 IS 9 BP 38 EP 45 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 482NX UT WOS:000171583100004 PM 11687782 ER PT J AU Engelholm, LH Nielsen, BS Netzel-Arnett, S Solberg, H Chen, XD Garcia, JML Lopez-Otin, C Young, MF Birkedal-Hansen, H Dano, K Lund, LR Behrendt, N Bugge, TH AF Engelholm, LH Nielsen, BS Netzel-Arnett, S Solberg, H Chen, XD Garcia, JML Lopez-Otin, C Young, MF Birkedal-Hansen, H Dano, K Lund, LR Behrendt, N Bugge, TH TI The urokinase plasminogen activator receptor-associated Protein/Endo180 is coexpressed with its interaction partners urokinase plasminogen activator receptor and matrix metalloprotease-13 during osteogenesis SO LABORATORY INVESTIGATION LA English DT Article ID MACROPHAGE MANNOSE RECEPTOR; PHOSPHOLIPASE A(2) RECEPTOR; INHIBITOR TYPE-1 COMPLEX; V COLLAGEN; DEFICIENT MICE; BONE-FORMATION; MEMBRANE-RECEPTOR; EPITHELIAL-CELLS; MOLECULAR SWITCH; BINDING SITE AB The urokinase plasminogen activator receptor-associated protein/Endo180 (uPARAP/Endo180) is a newly discovered member of the macrophage mannose receptor family that was reported to interact with ligand-bound urokinase plasminogen activator receptor (uPAR), matrix metalloprotease-13 (MMP-13), and collagen V on the cell surface. We have determined the sites of expression of this novel receptor during murine postimplantation development. uPARAP/Endo180 was expressed in all tissues undergoing primary ossification, including the developing bones of the viscerocranium and calvarium that ossify intramembranously, and developing long bones undergoing endochondral ossification. uPARAP/Endo180 mRNA was expressed by both immature osteoblasts and by mature osteocalcin-producing osteoblasts-osteocytes, and was coexpressed with MMP-13. Interestingly, osteoblasts also expressed uPAR. Besides bone-forming tissues, uPARAP/Endo180 expression was detected only in a mesenchymal condensation of the midbrain and in the developing lungs. The data suggest a function of this novel protease receptor in bone development, possibly mediated through its interactions with uPAR, MMP-13, or collagen V. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Proteases & Tissue Remodeling Unit, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Matrix Metalloprot Unit, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Finsen Lab, Copenhagen, Denmark. Univ Oviedo, Dept Morfol & Biol Celular, E-33006 Oviedo, Spain. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Proteases & Tissue Remodeling Unit, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. RI Lopez-Otin, Carlos/C-6657-2013 OI Lopez-Otin, Carlos/0000-0001-6964-1904 NR 71 TC 48 Z9 50 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2001 VL 81 IS 10 BP 1403 EP 1414 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 485CE UT WOS:000171735300009 PM 11598153 ER PT J AU Blagosklonny, MV Fojo, T Bhalla, KN Kim, JS Trepel, JB Figg, WD Rivera, Y Neckers, LM AF Blagosklonny, MV Fojo, T Bhalla, KN Kim, JS Trepel, JB Figg, WD Rivera, Y Neckers, LM TI The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy SO LEUKEMIA LA English DT Article DE oncogenes; Bcr-Abl; chemotherapy; cytoprotection; gendanamycin; HSP90 ID CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITOR; MYELOID-LEUKEMIA; POSITIVE CELLS; IN-VITRO; APOPTOSIS; RESISTANCE; INDUCTION; AGENTS; PROTEINS AB The Bcr-Abl fusion protein drives leukemogenesis and can render leukemia cells resistant to conventional chemotherapy. Geldanamycin (GA), a drug which destabilizes Hsp90-associated proteins, depletes cells of Bcr-Abl, an Hsp90 client, but not of Abl. Both HL60 cells transfected with Bcr-Abl and naturally Ph-positive K562 leukemia cells are resistant to most cytotoxic drugs, but were found to be sensitive to GA. Furthermore, GA sensitized Bcr-Abl-expressing cells to doxorubicin (DOX) and paclitaxel (PTX). In contrast, in parental HL60 cells, 90 nm GA inhibited PARP cleavage, nuclear fragmentation, and cell death caused by 500 ng/ml DOX. Like GA, STI 571 (an inhibitor of the Abl kinase) sensitized Bcr-Abl-expressing cells to DOX. Unlike GA, STI 571 did not antagonize the cytotoxic effects of DOX in parental HL60 cells. These results indicate that sensitization of Bcr-Abl-expressing cells, but not desensitization of HL60 cells, depends on inhibition of Bcr-Abl. Thus, GA differentially affects leukemia cells depending on their Bcr-Abl expression and selectively increases apoptosis in Bcr-Abl-expressing cells. C1 NCI, Dept Dev Therapeut, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Cell & Canc Biol, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Dev Therapeut, Med Branch, NIH, Rockville, MD USA. NCI, Dept Cell & Canc Biol, Med Branch, NIH, Rockville, MD USA. H Lee Moffitt Canc Ctr, Tampa, FL USA. RP Blagosklonny, MV (reprint author), NCI, Dept Dev Therapeut, Med Branch, NIH, Bldg 10,R12N226, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 37 TC 111 Z9 116 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2001 VL 15 IS 10 BP 1537 EP 1543 DI 10.1038/sj.leu.2402257 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 479UN UT WOS:000171422100008 PM 11587211 ER PT J AU Zimonjic, DB Keck-Waggoner, C Popescu, NC AF Zimonjic, DB Keck-Waggoner, C Popescu, NC TI Novel genomic imbalances and chromosome translocations involving c-myc gene in Burkitt's lymphoma SO LEUKEMIA LA English DT Article DE Burkitt's lymphoma; chromosome translocation; c-myc; comparative genomic hybridization; fluorescence in situ hybridization; spectral karyotyping ID CELL-LINES; CYTOGENETIC ANALYSIS; MOLECULAR-GENETICS; ABNORMALITIES; CANCER; REGION; ABERRATIONS; LEUKEMIA; TUMORIGENICITY; REARRANGEMENTS AB In this study, CA46 and ST486, two Epstein-Barr (EBV) negative cell lines derived from sporadic BL, were analyzed by multicolor spectral karyotyping, G-banding, fluorescence in situ hybridization with single-copy gene probes, and comparative genomic hybridization (CGH). In addition to reciprocal t(8;14)(q24;q32) translocation involving c-myc and IgH loci, we identified a t(7;8;14)(q11.2;q24;q32) translocation in CA 46 cells and t(8;14;18)(q24;q32;q23) in ST486 cells. Both rearrangements were not previously described in BL and resulted in transposition of myc sequences in a new genomic configuration. Several DNA imbalances mapped by CGH at the same sites in both lines, may reflect recurrent genomic changes that are relevant to pathogenesis of BL. We tested the tumorigenicity of these lines by injecting cells intraperitoneally in SCID mice. In two separate experiments, CA46 cells produced tumors 2 weeks after cell inoculation while ST486 cells induced only one tumor after a long latency period. Partial duplication of the long arm of chromosome 1 involving variable bands but always band 1q23 is the second most common alteration in BL and is known to be associated with aggressive tumors and poor prognosis. Duplication of the bands 1q23-24 commonly observed in EBV-negative lines was identified only in highly tumorigenic CA46 cells suggesting that this region harbor gene(s) associated with tumor cell invasiveness. C1 NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, 37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 34 TC 22 Z9 22 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2001 VL 15 IS 10 BP 1582 EP 1588 DI 10.1038/sj.leu.2402281 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 479UN UT WOS:000171422100013 PM 11587216 ER PT J AU Alavanja, MCR Field, RW Sinha, R Brus, CP Shavers, VL Fisher, EL Curtain, J Lynch, CF AF Alavanja, MCR Field, RW Sinha, R Brus, CP Shavers, VL Fisher, EL Curtain, J Lynch, CF TI Lung cancer risk and red meat consumption among Iowa women SO LUNG CANCER LA English DT Article DE lung cancer; red meat; case-control; Iowa women; diet ID HETEROCYCLIC AMINE CONTENT; DIETARY-CHOLESTEROL; UNITED-STATES; VARYING DEGREES; FAT; FOODS; DONENESS; URUGUAY; HEALTH; COHORT AB Objective: Some epidemiologic studies suggest that diets high in total fat, saturated fat, or cholesterol are associated with increased risk of lung cancer. Others suggest that diets high in red meat consumption, particularly well-done red meat, are a lung cancer risk factor, In Iowa, we had the opportunity to investigate concurrently the role of meat intake and macronutrients in lung cancer etiology. Methods: A population-based case-control study of both non-smoking and smoking women was conducted in Iowa. A 70-item food frequency questionnaire (FFQ) was completed by 360 cases and 574 frequency-matched controls. Odds ratios (ORs) and 95% confidence intervals (Cis) were calculated using logistic regression. Multivariate models included age, education, pack-years of smoking, yellow-green vegetable intake, fruit/fruit juice intake, nutrient density calories, previous non-malignant lung disease, alcohol consumption and body mass index (BMI). Results: When comparing the fifth (highest) to the first (lowest) quintile of consumption of total fat, saturated fat and cholesterol, we obtained odds ratios of 2.0 (1.3-3.1), 3.0 (1.9-4.7), and 2.0 (1.3-3.0) respectively. However, when red meat was entered into the model along with total fat, saturated fat or cholesterol, the excess risk for the macronutrients disappeared while an odds ratio of 3.3 (1.7-7.6) was obtained for red meat. The odds ratios for red meat consumption were similar among adenocarcinoma cases, OR = 3.0 (1.1-7.9) and non-adenocarcinoma cases, OR = 3.2 (1.3-8.3) and among life-time nonsmokers and ex-smokers OR = 2.8 (1.4-5.4), and current smokers, OR = 4.9 (1.1-22.3). Yellow-green vegetables were protective with an odds ratio of 0.4 (0.2-0.7). Conclusions: Consumption of red meat, was associated with an increased risk of lung cancer even after controlling for total fat, saturated fat, cholesterol, fruit, yellow-green vegetable consumption and smoking history, while yellow-green vegetables are associated with a decreased risk of lung cancer. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Alavanja, MCR (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS,Room 8000, Bethesda, MD 20892 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 38 TC 41 Z9 43 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 OCT PY 2001 VL 34 IS 1 BP 37 EP 46 DI 10.1016/S0169-5002(01)00227-6 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 484HN UT WOS:000171684300005 PM 11557111 ER PT J AU Wen, H AF Wen, H TI Mapping the velocity vector onto the spin vector: Two-dimensional velocity-selective spin excitation for MR flow imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; quantitative flow imaging; velocity-selective; two-dimensional; MR angiography ID MAGNETIC-RESONANCE ANGIOGRAPHY; PULSE; SUPPRESSION; SEQUENCE; SIGNAL AB This article presents a two-dimensional velocity-selective spin excitation (2D-VSP) method that enables quantitative imaging of motion in two directions in a single scan, without the need for image subtraction or combination. It Is based on the idea of mapping a 2D velocity vector directly onto the transverse magnetization vector, such that the signal intensity reflects the speed of motion, while the signal phase represents the direction of motion. Experimental demonstration is presented in conjunction with an analysis of the accuracy of this method. VSP methods are often limited by inconsistent static signal suppression under variable shim and RF conditions. By using adiabatic RF pulses in a 2D-VSP composite that possesses time-reversal symmetry, consistent background suppression of 30-fold or higher was demonstrated over experimental conditions of +/- 200 Hz off-resonance and 30% RF field variation. Published 2001 Wiley-Liss, Inc.(dagger). C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Cardiac Energet Lab, NIH, MSC 1061, Bethesda, MD 20892 USA. RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [ZIA HL004606-13] NR 30 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2001 VL 46 IS 4 BP 767 EP 772 DI 10.1002/mrm.1255 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476GJ UT WOS:000171217600016 PM 11590653 ER PT J AU Kobayashi, H Kawamoto, S Saga, T Sato, N Hiraga, A Ishimori, T Konishi, J Togashi, K Brechbiel, MW AF Kobayashi, H Kawamoto, S Saga, T Sato, N Hiraga, A Ishimori, T Konishi, J Togashi, K Brechbiel, MW TI Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE macromolecular; MRI; contrast agent; polyamidoamine dendrimer; polyethylene glycol ID DTPA-LABELED DEXTRAN; GD-DTPA; MOLECULAR-WEIGHT; MONOCLONAL-ANTIBODY; ENHANCING AGENT; IMMUNOGENICITY; ANGIOGRAPHY; PHARMACOKINETICS; BIODISTRIBUTION; FLEXIBILITY AB Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting In a longer half-life in circulation and lower Immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation-4 polyamidoamine dendrimer (G4D), 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG(2)-G4D-(1B4M-Gd)(62) (MW: 96 kD), PEG(1)-G4D-(1B4M-Gd)(63) (MW: 77 kD)), Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D-(1B4M-Gd)(64) (MW: 57 kD). PEG(2)-G4D-(1B4M-Gd)(62) remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, Increased excretion, and decreased accumulation in the organs. (C) 2001 Wiley-Liss, Inc. C1 Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Sakyo Ku, Kyoto 6068507, Japan. Dept Nucl Med & Diagnost Imaging, Kyoto, Japan. Kyoto Univ, Dept Radiol, Kyoto, Japan. Otsu Municipal Hosp, Dept Radiol, Otsu, Shiga, Japan. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. NR 40 TC 84 Z9 92 U1 3 U2 13 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2001 VL 46 IS 4 BP 781 EP 788 DI 10.1002/mrm.1257 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476GJ UT WOS:000171217600018 PM 11590655 ER PT J AU Kobayashi, H Kawamoto, S Saga, T Sato, N Hiraga, A Ishimori, T Akita, Y Mamede, MH Konishi, J Togashi, K AF Kobayashi, H Kawamoto, S Saga, T Sato, N Hiraga, A Ishimori, T Akita, Y Mamede, MH Konishi, J Togashi, K TI Novel liver macromolecular MR contrast agent with a polypropylenimine diaminobutyl dendrimer core: Comparison to the vascular MR contrast agent with the polyamidoamine dendrimer core SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; liver; dendrimer; contrast media ID GD-EOB-DTPA; MONOCLONAL-ANTIBODY; CLINICAL-EVALUATION; IN-VIVO; PHARMACOKINETICS; ENHANCEMENT; METASTASES; BIODISTRIBUTION; FLEXIBILITY; SYSTEM AB As MRI contrast agents, more hydrophobic molecules reportedly accumulate in the liver and thus are potentially useful as liver MRI contrast agents. In this study, a generation-4 polypropylenimine diaminobutane dendrimer (DAB-Am64), which is expected to be more hydrophobic than the generation-4 polyamidoamine dendrimer (PAMAM-G4D), was used to synthesize a conjugate with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M) [DAB-Am64-(1B4M-Gd)(64)] for complexing Gd(III) ions. This DAB conjugate quickly accumulated in the liver and its characteristics were studied and compared with those of a PAMAM conjugate [PAMAM-G4D-(1B4M-Gd)(64)], which is known to be a useful vascular MRI contrast agent, in regard to its availability as a liver MRI contrast agent. DAB-Am64-(1B4M-Gd)(64) accumulated significantly more in the liver and less in blood than PAMAM-G4D-(1B4M-Gd)(64) (P < 0.001). Contrast-enhanced MRI with DAB-Am64-(1B4M-Gd)(64) was able to homogeneously enhance liver parenchyma and visualize both portal and hepatic veins of 0.5 mm diameter in mice. In conclusion, DAB-Am64-(1B4M-Gd)(64) is a good candidate for a liver MRI contrast agent. (C) 2001 Wiley-Liss, Inc. C1 Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Sakyo Ku, Kyoto 6068507, Japan. Dept Nucl Med & Diagnost Imaging, Kyoto, Japan. Kyoto Univ, Dept Radiol, Kyoto, Japan. Otsu Municipal Hosp, Dept Radiol, Otsu, Shiga, Japan. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. RI Mamede, Marcelo/A-1751-2014 OI Mamede, Marcelo/0000-0001-5818-0954 NR 30 TC 61 Z9 62 U1 3 U2 9 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2001 VL 46 IS 4 BP 795 EP 802 DI 10.1002/mrm.1259 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476GJ UT WOS:000171217600020 PM 11590657 ER PT J AU Ellis, SJ Velayutham, M Velan, SS Petersen, EF Zweier, JL Kuppusamy, P Spencer, RGS AF Ellis, SJ Velayutham, M Velan, SS Petersen, EF Zweier, JL Kuppusamy, P Spencer, RGS TI EPR oxygen mapping (EPROM) of engineered cartilage grown in a hollow-fiber bioreactor SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE EPR; cartilage; chondrocytes; oximetry; oxygen mapping ID ELECTRON-PARAMAGNETIC-RESONANCE; IN-VIVO EPR; ARTICULAR-CARTILAGE; CHONDROCYTES; TISSUE; METABOLISM; CULTURE; PROTEOGLYCAN; SPECTROSCOPY; SENSITIVITY AB A novel electron paramagnetic resonance (EPR)-based oxygen mapping procedure (EPROM) is applied to cartilage grown in a single-, hollow-fiber bioreactor (HFBR) system. Chondrocytes harvested from the sterna of 17-day-old chick embryos were inoculated into an HFBR and produced hyaline cartilage over a period of 4 weeks. Tissue oxygen maps were generated according to the EPROM technique (Velan et al., Magn Reson Med 2000;43:804-809) by making use of the line-broadening effects of oxygen on the signal generated from nitroxide spin probes. In addition, the effect on oxygen consumption of the addition of cyanide to the tissue was investigated. Cyanide is a potent inhibitor of oxidative phosphorylation, and accordingly, given the constant provision of oxygen to the tissue, it would be expected to increase oxygen levels within the HFBR. The EPROM measurements showed a significant increase in oxygen concentration In the cartilage after the addition of cyanide. In contrast to other methods for studying oxygen in cartilage, EPROM can provide direct, noninvasive visualization of local concentrations in three dimensions. (C) 2001 Wiley-Liss, Inc. C1 NIA, Nucl Magnet Resonance Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol,EPR Ctr, Baltimore, MD 21205 USA. RP Spencer, RGS (reprint author), NIA, Nucl Magnet Resonance Unit, NIH, Gerontol Res Ctr, 4D-06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Velan, S. Sendhil/B-6374-2017 OI Velan, S. Sendhil/0000-0002-4096-0722 NR 47 TC 18 Z9 18 U1 0 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2001 VL 46 IS 4 BP 819 EP 826 DI 10.1002/mrm.1262 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476GJ UT WOS:000171217600023 PM 11590660 ER PT J AU Perez, P Santos, A Vaquero, JJ AF Perez, P Santos, A Vaquero, JJ TI Potential use of the undersampling technique in the acquisition of nuclear magnetic resonance signals SO MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE LA English DT Article DE undersampling; direct digital receiver; NMR and MRI systems; folding back noise; NMR signal acquisition; MRI signal processing ID CONVERTERS AB This communication reviews the use of undersampling techniques to acquire NMR signals. Undersampling transforms bandpass free induction decay (FID) signals, centered at high frequencies, into lowpass signals or bandpass signals centered at much lower frequencies. Consequently, the analog electronic stages that perform the demodulation can be eliminated, gaining in stability and reducing the phase distortion while maintaining an equivalent or better signal to noise ratio when an adequate sampling rate is chosen. The technique has been tested on a BRUKER BIOSPEC BMT 47/40, and the results show that undersampling could be used to process NMR and MRI signals, extending the range of applications of the 'digital radio' techniques to NMR and MRI apparatus. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Politecn Madrid, ETSI Telecomunicac, E-28040 Madrid, Spain. Natl Inst Hlth, Dept Nucl Med, Bethesda, MD USA. Hosp GU Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. RP Santos, A (reprint author), Univ Politecn Madrid, ETSI Telecomunicac, Ciudad Univ, E-28040 Madrid, Spain. RI Vaquero, Juan Jose/D-3033-2009; Santos, Andres/C-4012-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X; Santos, Andres/0000-0001-7423-9135 NR 30 TC 7 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1352-8661 J9 MAGN RESON MATER PHY JI Magn. Reson. Mat. Phys. Biol. Med. PD OCT PY 2001 VL 13 IS 2 BP 109 EP 117 DI 10.1007/BF02668159 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 486JV UT WOS:000171815400007 PM 11502425 ER PT J AU Zhou, L Rowley, DL Mi, QS Sefcovic, N Matthes, HWD Kieffer, BL Donovan, DM AF Zhou, L Rowley, DL Mi, QS Sefcovic, N Matthes, HWD Kieffer, BL Donovan, DM TI Murine inter-strain polymorphisms alter gene targeting frequencies at the mu opioid receptor locus in embryonic stem cells SO MAMMALIAN GENOME LA English DT Article ID INBRED MOUSE STRAINS; POSITRON EMISSION TOMOGRAPHY; MORPHINE-INDUCED ANALGESIA; GERM-LINE TRANSMISSION; MISMATCH-REPAIR; OPIATE RECEPTOR; HOMOLOGOUS RECOMBINATION; MESSENGER-RNA; KNOCKOUT MICE; SACCHAROMYCES-CEREVISIAE AB Chromosomal regions near the rim opioid receptor gene are implicated in morphine preference by quantitative trait loci studies. Differences in expression of the mu opioid receptor are expected to contribute to differences in inter-individual (humans) or strain-specific (mice) responses to painful stimuli, opiate drugs, and addictive behaviors. The search for relevant genetic elements is hindered by a lack of inter-strain (or inter-individual) genomic sequence information. This work describes 9.3 kb of DNA sequence surrounding exons 2 and 3 of the murine mu opioid receptor gene from both 129/Sv and C57BL/6 strains. While the exons are perfectly conserved, intronic sequences demonstrate approximately a 2.5% divergence between the strains. Polymorphism within these intronic regions may effect either primary transcript stability or C-terminal splicing. Homologous recombination frequencies of targeting vectors harboring mu opioid receptor gene sequences have also been compared in embryonic stem cells derived from these strains. Non-isogenic targeting reduces homologous recombination in both 129/Sv and C57BL/6 embryonic stem cells by greater than 15-fold. These findings are the first to examine C57BL/6 embryonic stem cells for non-isogenic targeting frequencies and to define polymorphisms that exist between these mouse strains which might contribute to opioid behaviors. C1 NIA, Comparat Med Sect, IRP, NIH, Baltimore, MD 21224 USA. NIA, Immunol Lab, IRP, NIH, Baltimore, MD 21224 USA. CNRS, UPR 9050, F-67400 Illkirch Graffenstaden, France. RP NIA, Comparat Med Sect, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM donovand@grc.nia.nih.gov NR 86 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2001 VL 12 IS 10 BP 772 EP 778 DI 10.1007/s00335-001-1003-8 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 479NX UT WOS:000171411400004 PM 11668392 ER PT J AU Kodjabachian, L Lemaire, P AF Kodjabachian, L Lemaire, P TI Siamois functions in the early blastula to induce Spemann's organiser SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Spemann's organiser; head organiser; trunk organiser; Siamois; glucocorticoid rcceptor; temporal competence; Xenopus ID EARLY XENOPUS-EMBRYOS; HOMEOBOX GENE; HEAD INDUCTION; ANTEROPOSTERIOR AXIS; MESODERM INDUCTION; CORTICAL ROTATION; NEURAL INDUCTION; MOLECULAR NATURE; EXPRESSION; WNT AB In Xenopus, the Spemann organiser is defined as a dorsal territory in the early gastrula that initiates development of the embryonic axis. It has been shown that the early zygotic transcription factor Siamois is essential for Spemann's organiser formation. By the onset of gastrulation, the organiser is patterned into a vegetal head organiser, which induces anterior structures upon transplantation, and a more animal trunk organiser, which induces a posterior neuraxis. However, it is unclear when these distinct organiser domains are initially specified. To shed light on this question, we analysed the temporal activity of Siamois, as this factor induces both head and trunk development, when ectopically expressed via mRNA injection. In this study, we expressed Siamois ectopically at different time points and analysed the extent of axial development. Using a hormone- inducible version of Siamois, we found evidence for a tight window of competence during which ventral cells can respond to Siamois by commencing both the head and the trunk genetic programmes. The competence to form Spemann's organiser was lost 2 h before gastrulation, although partial axis formation could still occur following delayed activation of Siamois. We demonstrate that this late response to Siamois involves a new role for this gene, which can indirectly repress ventral gene expression, in the absence of known organiser genes. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Mediterranee, Inst Biol Dev Marseille, Lab Genet & Physiol Dev, CNRS,INSERM, F-13288 Marseille 9, France. RP Kodjabachian, L (reprint author), NICHHD, Mol Genet Lab, NIH, Bldg 6B,Rm 420,9200 Rockville Pike, Bethesda, MD 20892 USA. RI Lemaire, Patrick/D-4237-2009; Lemaire, Patrick/B-5560-2012 OI Lemaire, Patrick/0000-0003-4925-2009 NR 53 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD OCT PY 2001 VL 108 IS 1-2 BP 71 EP 79 DI 10.1016/S0925-4773(01)00484-1 PG 9 WC Developmental Biology SC Developmental Biology GA 479TM UT WOS:000171419700006 PM 11578862 ER PT J AU McNeil, DE Brown, M Ching, A DeBaun, MR AF McNeil, DE Brown, M Ching, A DeBaun, MR TI Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: A cost-effective model SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE Beckwith-Wiedemann syndrome; cost-effectiveness analysis; Wilms tumor; cancer screening ID HEMIHYPERTROPHY; CANCER; ANIRIDIA; RISK; LIFE; CT AB Background. We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. Procedures. We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. Results. Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (<$50,000 per life year saved). Conclusions. Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy tor a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice. C1 NCI, Genet Epidemiol Branch, Div Genet Epidemiol, NIH,EPS, Bethesda, MD 20892 USA. NCI, Appl Res Branch, DCPC, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. RP DeBaun, MR (reprint author), NCI, Genet Epidemiol Branch, Div Genet Epidemiol, NIH,EPS, Room 7125,6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. FU NCI NIH HHS [N02 CP 91026] NR 21 TC 26 Z9 27 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD OCT PY 2001 VL 37 IS 4 BP 349 EP 356 DI 10.1002/mpo.1209 PG 8 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 480YK UT WOS:000171490600001 PM 11568898 ER PT J AU Jae-Heup, K Eizirik, E O'Brien, SJ Johnson, WE AF Jae-Heup, K Eizirik, E O'Brien, SJ Johnson, WE TI Structure and patterns of sequence variation in the mitochondrial DNA control region of the great cats SO MITOCHONDRION LA English DT Article DE mitochondrial DNA; control region; heteroplasmy; Panthera genus; felidae; phylogenetic analyses ID D-LOOP REGION; MAJOR NONCODING REGION; MTDNA CONTROL REGION; TANDEM REPEATS; NUCLEOTIDE-SEQUENCES; CONSERVED SEQUENCES; NUCLEAR GENOME; DOMESTIC CAT; EVOLUTION; HETEROPLASMY AB Mitochondrial DNA control region structure and variation were determined in the five species of the genus Panthera. Comparative analyses revealed two hypervariable segments, a central conserved region, and the occurrence of size and sequence heteroplasmy. As observed in the domestic cat, but not commonly seen in other animals, two repetitive sequence arrays (RS-2 with an 80-bp motif and RS-3 with a 6-10-bp motif) were identified. The 3' ends of RS-2 and RS-3 were highly conserved among species, suggesting that these motifs have different functional constraints. Control region sequences provided improved phylogenetic resolution grouping the sister taxa lion (Panthera leo) and leopard (Panthera pardus), with the jaguar (Panthera onca). Published by Elsevier Science B.V. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP Johnson, WE (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM johnsonw@ncifcrf.gov RI Eizirik, Eduardo/K-8034-2012; Johnson, Warren/D-4149-2016 OI Eizirik, Eduardo/0000-0002-9658-0999; Johnson, Warren/0000-0002-5954-186X NR 64 TC 28 Z9 29 U1 1 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD OCT PY 2001 VL 1 IS 3 BP 279 EP 292 DI 10.1016/S1567-7249(01)00027-7 PG 14 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 519BX UT WOS:000173706000006 PM 16120284 ER PT J AU Teruya-Feldstein, J Kingma, DW Weiss, A Sorbara, L Burd, PR Raffeld, M Mueller, BU Tosato, G Jaffe, ES AF Teruya-Feldstein, J Kingma, DW Weiss, A Sorbara, L Burd, PR Raffeld, M Mueller, BU Tosato, G Jaffe, ES TI Chemokine gene expression and clonal analysis of B cells in tissues involved by lymphoid interstitial pneumonitis from HIV-infected pediatric patients SO MODERN PATHOLOGY LA English DT Article DE chemokine; HIV; LIP; lymphoma; pediatric ID IMMUNODEFICIENCY-VIRUS-INFECTION; MULTILOCULAR THYMIC CYSTS; T-CELLS; INDUCIBLE PROTEIN-10; MALIGNANT-LYMPHOMA; CHILDREN; DISEASE; MALT; CYTOKINE; GAMMA AB Lymphoid interstitial pneumonitis (LIP), a frequent pulmonary complicationini HIV-infected pediatric patients, is characterized histologically by marked infiltration of lymphoid cells. We sought to evaluate the nature and pathogenesis of the lymphoid infiltrates and to examine the relationship of UP to pulmonary MALT lymphoma that has been described in pediatric HIV positive patients. To examine the potential contribution of chemokines and cytokines to the inflammatory cell recruitment in tissues involved by lymphoid interstitial pneumonitis from HIV-infected pediatric patients, RNA was extracted from paraffin-embedded tissues from five lung biopsies in four pediatric HIV-positive patients and from five control, normal lung biopsies in five HIV-negative patients and was analyzed by semiquantitative RT-PCR for the expression of cytokines (TNF-alpha, GM-CSF, IFN-gamma, IL-4, IL-6, IL-10, and IL-18) and chemokines (IL-10, Mig, regulated upon activation, normal T expressed and secreted [RANTES], and MIP1-alpha and beta) after normalization for G3PDH. Expression of IL-18 was increased, as well as expression of IFN-gamma -inducible chemokines IP-10 and Mig in LIP tissues compared with controls. RANTES and MIP1-alpha and -beta were also increased in pediatric UP lesions compared with controls. In contrast, expression of TNF-alpha, GM-CSF, IL-10, and IL-6 was variable in UP tissues and controls. In addition, clonality of the B-cell population was evaluated by VDJ-PCR. A polyclonal B-cell population was shown hi all five biopsies from five patients with LIP; and in one patient with concurrent LIP and MALT lymphoma, a band of increased intensity was observed in the LIP biopsy that was identical in size to the monoclonal band In the concurrent MALT lymphoma biopsy. These results provide evidence of high-level expression of certain chemokines in lymphoid interstitial pneumonitis tissues and suggest that chemokines and cytokines may play an important role in the recruitment of inflammatory cell infiltrates into these tissues. In addition, UP may represent an early stage of MALT lymphoma or an immunologic response to a chronic antigenic stimulus that may provide a milieu or microenvironment for the evolution of a monoclonal B-cell population. C1 NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Texas Childrens Canc Ctr, Houston, TX USA. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Hematopathol Sect, NIH, Bldg 10,Room 2N202,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. NR 30 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD OCT PY 2001 VL 14 IS 10 BP 929 EP 936 DI 10.1038/modpathol.3880414 PG 8 WC Pathology SC Pathology GA 481UU UT WOS:000171539500001 PM 11598160 ER PT J AU Shen, DF Herbort, CP Tuaillon, N Buggage, RR Egwuagu, CE Chan, CC AF Shen, DF Herbort, CP Tuaillon, N Buggage, RR Egwuagu, CE Chan, CC TI Detection of Toxoplasma gondii DNA in primary intraocular B-cell lymphoma SO MODERN PATHOLOGY LA English DT Article DE B-cell lymphoma; CNS lymphoma; microdissection; primary intraocular lymphoma; Toxoplasma gondii ID POLYMERASE-CHAIN-REACTION; EPSTEIN-BARR-VIRUS; LASER CAPTURE MICRODISSECTION; NERVOUS-SYSTEM LYMPHOMA; GENE REARRANGEMENT; DISTINCT AB Primary intraocular lymphoma, a variant of primary central nervous system lymphoma with ocular involvement, is a large B-cell non-Hodgkin's lymphoma. Some cases of primary intraocular lymphoma. have been reported to be associated with microorganisms including Epstein-Barr virus (EBV) and human herpes virus-8 (HHV-8), but not parasites. We analyzed 10 cases of primary intraocular lymphoma using microdissection and PCR Tumor and normal cells were microdissected from ocular tissue on slides and subjected to PCR for genes from Taxoplasma gondii, EBV, and HHV-8. We detected Taxoplasma gondii, not HHV-8 or EBV, DNA in the lymphoma. but not in normal cells of two cases that resembled ocular toxoplasmosis clinically. We speculate that Taxoplasma gondii may play a role in some forms of primary intraocular B-cell lymphoma. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Lausanne, Lausanne, Switzerland. Eye Ctr Source, Lausanne, Switzerland. RP Chan, CC (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD OCT PY 2001 VL 14 IS 10 BP 995 EP 999 PG 5 WC Pathology SC Pathology GA 481UU UT WOS:000171539500010 PM 11598169 ER PT J AU Miller, LD Park, KS Guo, QBM Alkharouf, NW Malek, RL Lee, NH Liu, ET Cheng, SY AF Miller, LD Park, KS Guo, QBM Alkharouf, NW Malek, RL Lee, NH Liu, ET Cheng, SY TI Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BETA-CATENIN; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; NEURONAL DIFFERENTIATION; TRANSCRIPTIONAL PROGRAM; LIPID-PEROXIDATION; BRAIN-DEVELOPMENT; PROTEIN-TURNOVER; HYPOTHYROID RATS; OXIDATIVE STRESS AB To investigate the transcriptional program underlying thyroid hormone (T3)-induced cell proliferation, cDNA microarrays were used to survey the temporal expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionally modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynthesis, transcriptional regulation, protein degradation, and detoxification in T3-induced cell proliferation. Clustering the genes by temporal expression patterns provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the expression of key regulators of the Wnt signaling pathway and suppressed the transcriptional downstream elements of the beta -catenin-T-cell factor complex. This was confirmed biochemically, as beta -catenin protein levels also decreased, leading to a decrease in the transcriptional activity of a beta -catenin-responsive promoter. These results indicate that T3-induced cell proliferation is accompanied by a complex coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway may be critical to this event. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Sect Mol Signaling & Oncogenesis, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Inst Genom Res, Dept Funct Genom, Rockville, MD 20850 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 2D24,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Liu, Edison/C-4141-2008; Miller, Lance/A-5633-2009 FU NHLBI NIH HHS [HL59781] NR 61 TC 69 Z9 71 U1 2 U2 3 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 OCT PY 2001 VL 21 IS 19 BP 6626 EP 6639 DI 10.1128/MCB.21.19.6626-6639.2001 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469XV UT WOS:000170842100025 PM 11533250 ER PT J AU Aoyagi, N Wassarman, DA AF Aoyagi, N Wassarman, DA TI Developmental and transcriptional consequences of mutations in Drosophila TAF(II)60 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; PROMOTER ELEMENT; IN-VIVO; GENE-EXPRESSION; TYROSINE KINASE; CELL FATE; TATA-BOX; PROTEIN; ACTIVATION; SPERMATOGENESIS AB In vitro, the TAF(II)60 component of the TFIID complex contributes to RNA polymerase II transcription initiation by serving as a coactivator that interacts with specific activator proteins and possibly as a promoter selectivity factor that interacts with the downstream promoter element. In vivo roles for TAF(II)60 in metazoan transcription are not as clear. Here we have investigated the developmental and transcriptional requirements for TAF(II)60 by analyzing four independent Drosophila melanogaster TAF(II)60 mutants. Loss-of-function mutations in Drosophila TAF(II)60 result in lethality, indicating that TAF(II)60 provides a nonredundant function in vivo. Molecular analysis of TAF(II)60 alleles revealed that essential TAF(II)60 functions are provided by two evolutionarily conserved regions located in the N-terminal half of the protein. TAF(II)60 is required at all stages of Drosophila development, in both germ cells and somatic cells. Expression of TAF(II)60 from a transgene ;rescued the lethality of TAF(II)60 mutants and exposed requirements for TAF(II)60 during imaginal development, spermatogenesis, and oogenesis. Phenotypes of rescued TAF(II)60 mutant flies implicate TAF(II)60 in transcriptional mechanisms that regulate cell growth and cell fate specification and suggest that TAF(II)60 is a limiting component of the machinery that regulates the transcription of dosage-sensitive genes. Finally, TAF(II)60 plays roles in developmental regulation of gene expression that are distinct from those of other TAF(II) proteins. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Wassarman, DA (reprint author), Univ Wisconsin, Sch Med, Dept Pharmacol, 1300 Univ Ave, Madison, WI 53706 USA. NR 60 TC 19 Z9 21 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2001 VL 21 IS 20 BP 6808 EP 6819 DI 10.1128/MCB.21.20.6808-6819.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500009 PM 11564865 ER PT J AU Connor, JH Weiser, DC Li, S Hallenbeck, JM Shenolikar, S AF Connor, JH Weiser, DC Li, S Hallenbeck, JM Shenolikar, S TI Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RABBIT SKELETAL-MUSCLE; EUKARYOTIC TRANSLATION INITIATION-FACTOR-2; LONG-TERM POTENTIATION; CATALYTIC SUBUNIT; GAMMA(1)34.5 PROTEIN; GLYCOGEN-METABOLISM; REGULATORY SUBUNIT; ALPHA-SUBUNIT; SMOOTH-MUSCLE; PHOSPHORYLATION AB The growth arrest and DNA damage-inducible protein, GADD34, was identified by its interaction with human inhibitor 1 (I-1), a protein kinase A (PKA)-activated inhibitor of type 1 protein serine/threonine phosphatase (PPI), in a yeast two-hybrid screen of a human brain cDNA library. Recombinant GADD34 (amino acids 233 to 674) bound both PKA-phosphorylated and unphosphorylated I-1(1-171). Serial truncations mapped the C terminus of I-1 (amino acids 142 to 171) as essential for GADD34 binding. In contrast, PKA phosphorylation was required for PPI binding and inhibition by the N-terminal I-1(1-80) fragment. Pulldowns of GADD34 proteins expressed in HEK293T cells showed that I-1 bound the central domain of GADD34 (amino acids 180 to 483). By comparison, affinity isolation of cellular GADD34/PP1 complexes showed that PPI bound near the C terminus of GADD34 (amino acids 483 to 619), a region that shows sequence homology with the virulence factors ICP34.5 of herpes simplex virus and NL-S of avian sarcoma virus. While GADD34 inhibited PP1-catalyzed dephosphorylation of phosphorylase a, the GADD34-bound PP1 was an active eIF-2 alpha phosphatase. In brain extracts from active ground squirrels, GADD34 bound both I-1 and PP1 and eIF-2 alpha was largely dephosphorylated. In contrast, the I-1/GADD34 and PP1/GADD34 interactions were disrupted in brain from hibernating animals, in which eIF-2 alpha was highly phosphorylated at serine-51 and protein synthesis was inhibited. These studies suggested that modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues. C1 Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NINCDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Shenolikar, S (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Box 3813, Durham, NC 27710 USA. OI Connor, John/0000-0002-8867-7256 FU NIDDK NIH HHS [R01 DK052054, DK52054] NR 68 TC 132 Z9 141 U1 0 U2 7 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 OCT PY 2001 VL 21 IS 20 BP 6841 EP 6850 DI 10.1128/MCB.21.20.6841-6850.2001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500012 PM 11564868 ER PT J AU Hamada, M Huang, Y Lowe, TM Maraia, RJ AF Hamada, M Huang, Y Lowe, TM Maraia, RJ TI Widespread use of TATA elements in the core promoters for RNA polymerases III, II, and I in fission yeast SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PHOSPHOSERINE TRANSFER-RNA; TRANSCRIPTION FACTOR; BINDING PROTEIN; SCHIZOSACCHAROMYCES-POMBE; EUKARYOTIC TRANSCRIPTION; STRUCTURAL FEATURES; VITRO TRANSCRIPTION; GENE-TRANSCRIPTION; INITIATOR ELEMENT; 5S-RNA GENES AB In addition to directing transcription initiation, core promoters integrate input from distal regulatory elements. Except for rare exceptions, it has been generally found that eukaryotic tRNA and rRNA genes do not contain TATA promoter elements and instead use protein-protein interactions to bring the TATA-binding protein (TBP), to the core promoter. Genomewide analysis revealed TATA elements in the core promoters of tRNA and 5S rRNA (Pol III), U1 to U5 snRNA (Pol II), and 37S rRNA (Pol I) genes in Schizosaccharomyces pombe. Using tRNA-dependent suppression and other in vivo assays, as well as in vitro transcription, we demonstrated an obligatory requirement for upstream TATA elements for tRNA and 5S rRNA expression in S. pombe. The Pol III initiation factor Brf is found in complexes with TFIIIC and Pol III in S. pombe, while TBP is not, consistent with independent recruitment of TBP by TATA. Template commitment assays are consistent with this and confirm that the mechanisms of transcription complex assembly and initiation by Pol III in S. pombe differ substantially from those in other model organisms. The results were extended to large-rRNA synthesis, as mutation of the TATA element in the Pol I promoter also abolishes rRNA expression in fission yeast. A survey of other organisms' genomes reveals that a substantial number of eukaryotes may use,widespread TATAs for transcription. These results indicate the presence of TATA-unified transcription systems in contemporary eukaryotes and provide insight into the residual need for TBP by all three Pols in other eukaryotes despite a lack of TATA elements in their promoters. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. RP Maraia, RJ (reprint author), 6 Ctr Dr,Rm 416, Bethesda, MD 20892 USA. NR 84 TC 47 Z9 47 U1 1 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 OCT PY 2001 VL 21 IS 20 BP 6870 EP 6881 DI 10.1128/MCB.21.20.6870-6881.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500015 PM 11564871 ER PT J AU Kameda, H Risinger, JI Han, BB Baek, SJ Barrett, JC Abe, T Takeuchi, T Glasgow, WC Eling, TE AF Kameda, H Risinger, JI Han, BB Baek, SJ Barrett, JC Abe, T Takeuchi, T Glasgow, WC Eling, TE TI Expression of Gab1 lacking the pleckstrin homology domain is associated with neoplastic progression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TUMOR-SUPPRESSOR GENE; HAMSTER EMBRYO CELLS; SHP-2 TYROSINE PHOSPHATASE; LINOLEIC-ACID METABOLITE; ACTIVATED PROTEIN-KINASE; DOCKING PROTEIN; EPITHELIAL MORPHOGENESIS; SIGNALING PATHWAY; EGF-RECEPTOR AB An in vitro transformation system of carcinogen-treated Syrian hamster embryo (SHE) cell cultures represents multistep genetic and nongenetic changes that develop during the neoplastic progression of normal cells to tumor cells in vivo. During this neoplastic progression, SHE cells demonstrate an altered response to epidermal growth factor (EGF). In the present report, we examined the role of the adapter protein Gab1 (Grb2-associated binder-1) in the neoplastic progression of SHE cells. We used two asbestos-transformed SHE cell clones in different neoplastic stages: a 10W+8 clone, which is immortal and retains the ability to suppress the tumorigenicity of tumor cells in cell-cell hybrid experiments, and a 10W-1 clone, which has lost this tumor suppressor ability. 10W+8 cells expressed full-length 100-kDa Gab1 and associated 5.2-kb mRNA. Upon repeated cell passaging, 10W-1 cells showed increasing expression of a novel 87-kDa form of Gab1 as well as 4.6-kb mRNA with diminishing expression of the original 100-kDa Gab1. cDNA encoding the 87-kDa Gab1 predicts a form of Gab1 lacking the amino-terminal 103 amino acids (Gab1(Delta1-103)), which corresponds to loss of most of the pleckstrin homology (PH) domain. Gab1(Delta1-103) retains the ability to be phosphorylated in an EGF-dependent manner and to associate with the EGF receptor and SHP-2 upon EGF stimulation. The endogenous expression of Gab1(Delta1-103) in 10W-1 cells appeared closely related to EGF-dependent colony formation in soft agar. Moreover, transfection and expression of Gab1(Delta1-103), but not Gab1, in 10W+8 cells enhanced their EGF-dependent colony formation in soft agar. These results demonstrate that Gab1 is a target of carcinogen-induced transformation of SHE cells and that the expression of a Gab1 variant lacking most of the PH domain plays a specific role in the neoplastic progression of SHE cells. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Saitama Med Ctr, Dept Internal Med, Kawagoe, Saitama 350, Japan. Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Takeuchi, Tsutomu/L-2327-2013; OI Takeuchi, Tsutomu/0000-0003-1111-8218; Baek, Seung/0000-0001-7866-7778 NR 46 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2001 VL 21 IS 20 BP 6895 EP 6905 DI 10.1128/MCB.21.20.6895-6905.2001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500017 PM 11564873 ER PT J AU Veri, MC DeBell, KE Seminario, MC DiBaldassarre, A Reischl, I Rawat, R Graham, L Noviello, C Rellahan, BL Miscia, S Wange, RL Bonvini, E AF Veri, MC DeBell, KE Seminario, MC DiBaldassarre, A Reischl, I Rawat, R Graham, L Noviello, C Rellahan, BL Miscia, S Wange, RL Bonvini, E TI Membrane raft-dependent regulation of phospholipase C gamma-1 activation in T lymphocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL ANTIGEN RECEPTOR; PROTEIN-TYROSINE KINASE; TEC FAMILY KINASES; SIGNAL-TRANSDUCTION; PLASMA-MEMBRANE; GENETIC-EVIDENCE; PHOSPHORYLATION; ZAP-70; LAT; LOCALIZATION AB Numerous signaling molecules associate with lipid rafts, either constitutively or after engagement of surface receptors. One such molecule, phospholipase C gamma -1 (PLC gamma1), translocates from the cytosol to lipid rafts during T-cell receptor (TCR) signaling. To investigate the role played by lipid rafts in the activation of this molecule in T cells, an influenza virus hemagglutinin A (HA)-tagged PLC gamma1 was ectopically expressed in Jurkat T cells and targeted to these microdomains by the addition of a dual-acylation signal. Raft-targeted PLC gamma1 was constitutively tyrosine phosphorylated and induced constitutive NF-AT-dependent transcription and interleukin-2 secretion in Jurkat cells. Tyrosine phosphorylation of raft-targeted PLC gamma1 did not require Zap-70 or the interaction with the adapters Lat and Slp-76, molecules that are necessary for TCR signaling. In contrast, the Src family kinase Lek was required. Coexpression in HEK 293T cells of PLC gamma1-HA with Lek or the Tec family kinase Rlk resulted in preferential phosphorylation of raft-targeted PLC gamma1 over wild-type PLC gamma1. These data show that localization of PLC gamma1 in lipid rafts is sufficient for its activation and demonstrate a role for lipid rafts as microdomains that dynamically segregate and integrate PLC gamma1 with other signaling components. C1 Ctr Biol Evaluat & Res, Immunobiol Lab, Div Monoclonal Antibodies, LIB,OTRR, Bethesda, MD 20892 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIA, Gerontol Res Ctr, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Univ G DAnnunzio, Ist Morfol Umana Normale, I-66100 Chieti, Italy. RP Bonvini, E (reprint author), Ctr Biol Evaluat & Res, Immunobiol Lab, Div Monoclonal Antibodies, LIB,OTRR, HFM-564,Bldg 29B,Rm 3NN10,29 Lincoln Dr,MSC-4555, Bethesda, MD 20892 USA. NR 49 TC 51 Z9 54 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2001 VL 21 IS 20 BP 6939 EP 6950 DI 10.1128/MCB.21.20.6939-6950.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500021 PM 11564877 ER PT J AU Bera, TK Bera, J Brinkmann, U Tessarollo, L Pastan, I AF Bera, TK Bera, J Brinkmann, U Tessarollo, L Pastan, I TI Cse1l is essential for early embryonic growth and development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEGREGATION GENE CSE1; APOPTOSIS SUSCEPTIBILITY GENE; CHROMOSOME-SEGREGATION; HUMAN HOMOLOG; NUCLEAR-LOCALIZATION; CELL-PROLIFERATION; YEAST; BINDING; PROTEIN; CLONING AB The CSE1L gene, the human homologue of the yeast chromosome segregation gene CSE1, is a nuclear transport factor that plays a role in proliferation as well as in apoptosis. CSE1 and CSE1L are essential genes in Saccharomyces cerevisiae and mammalian cells, as shown by conditional yeast mutants and mammalian cell culture experiments with antisense-mediated depletion of CSE1L. To analyze whether CSE IL is also essential in vivo and whether its absence can be compensated for by other genes or mechanisms, we have cloned the murine CSE1L gene (Cse1l) and analyzed its tissue- and development-specific expression: Csell was detected at embryonic day 7.0 (E7.0), E11.0, E15.0, and E17.0, and in adults, high expression was observed in proliferating tissues. Subsequently, we inactivated the Csell gene in embryonic stem cells to generate heterozygous and homozygous knockout mice. Mice heterozygous for Csell appear normal and are fertile. However, no homozygous pups were born after interbreeding of heterozygous mice. In 30 heterozygote interbreeding experiments, 50 Csell wild-type mice and 100 heterozygotes were born but no animal with both Csell alleles deleted was born. Embryo analyses showed that homozygous mutant embryos were already disorganized and degenerated by E5.5. This implicates with high significance (P < 0.0001, Pearson chi-square test) an embryonically lethal phenotype of homozygous murine CSE1 deficiency and suggests that Csell plays a critical role in early embryonic development. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, NIH, Frederick, MD 21702 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 18 TC 21 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2001 VL 21 IS 20 BP 7020 EP 7024 DI 10.1128/MCB.21.20.7020-7024.2001 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474NC UT WOS:000171112500028 PM 11564884 ER PT J AU Boehm, M Bonifacino, JS AF Boehm, M Bonifacino, JS TI Adaptins - The final recount SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CLATHRIN-ASSOCIATED PROTEIN; POLARIZED EPITHELIAL-CELLS; HERMANSKY-PUDLAK-SYNDROME; NEMATODE CAENORHABDITIS-ELEGANS; MANNOSE 6-PHOSPHATE RECEPTORS; SYNAPTIC VESICLE ENDOCYTOSIS; EAR HOMOLOGY DOMAIN; GAMMA-ADAPTIN; AP-3 ADAPTER; DROSOPHILA-MELANOGASTER AB Adaptins are subunits of adaptor protein (AP) complexes involved in the formation of intracellular transport vesicles and in the selection of cargo for incorporation into the vesicles. In this article, we report the results of a survey for adaptins from sequenced genomes including those of man, mouse, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, the plant Arabidopsis thaliana, and the yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. We find that humans, mice, and Arabidopsis thaliana have four AP complexes (AP-1, AP-2, AP-3, and AP-4), whereas D. melanogaster, C. elegans, S. cerevisiae, and S. pombe have only three (AP-1, AP-2, and AP-3). Additional diversification of AP complexes arises from the existence of adaptin isoforms encoded by distinct genes or resulting from alternative splicing of mRNAs. We complete the assignment of adaptins to AP complexes and provide information on the chromosomal localization, exon-intron structure, and pseudogenes for the different adaptins. In addition, we discuss the structural and evolutionary relationships of the adaptins and the genetic analyses of their function. Finally, we extend our survey to adaptin-related proteins such as the GGAs and stonins, which contain domains homologous to the adaptins. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 98 TC 290 Z9 333 U1 3 U2 18 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2001 VL 12 IS 10 BP 2907 EP 2920 PG 14 WC Cell Biology SC Cell Biology GA 481VC UT WOS:000171540300001 PM 11598180 ER PT J AU Puri, PL Iezzi, S Stiegler, P Chen, TT Schiltz, RL Muscat, GEO Giordano, A Kedes, L Wang, JYJ Sartorelli, V AF Puri, PL Iezzi, S Stiegler, P Chen, TT Schiltz, RL Muscat, GEO Giordano, A Kedes, L Wang, JYJ Sartorelli, V TI Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis SO MOLECULAR CELL LA English DT Article ID CELL-CYCLE ARREST; MEF2 TRANSCRIPTION FACTOR; MUSCLE GENE-EXPRESSION; RETINOBLASTOMA PROTEIN; TERMINAL DIFFERENTIATION; REPRESS TRANSCRIPTION; BINDING; RB; P300; ACETYLATION AB We describe a functional and biochemical link between the myogenic activator MyoD, the deacetylase HDAC1, and the tumor suppressor pRb. Interaction of MyoD with HDAC1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression. Prodifferentiation cues, mimicked by serum removal, induce both downregulation of HDAC1 protein and pRb hypophosphorylation. Dephosphorylation of pRb promotes the formation of pRb-HDAC1 complex in differentiated myotubes. pRb-HDAC1 association coincides with disassembling of MyoD-HDAC1 complex, transcriptional activation of muscle-restricted genes, and cellular differentiation of skeletal myoblasts. A single point mutation introduced in the HDAC1 binding domain of pRb compromises its ability to disrupt MyoD-HDAC1 interaction and to promote muscle gene expression. These results suggest that reduced expression of HDAC1 accompanied by its redistribution in alternative nuclear protein complexes is critical for terminal differentiation of skeletal muscle cells. C1 Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. Univ Roma La Sapienza, Gene Express Lab, Fdn Andrea Cesalpino, I-00161 Rome, Italy. NIAMSD, Muscle Biol Lab, Muscle Gene Express Grp, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. Univ Queensland, Ctr Cellular & Mol Biol, Ritchie Res Labs, St Lucia, Qld 4072, Australia. Univ So Calif, Inst Genet Mol, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. RP Puri, PL (reprint author), Salk Inst Biol Studies, Peptide Biol Lab, La Jolla, CA 92093 USA. RI Giordano, Antonio/F-1927-2010 OI Giordano, Antonio/0000-0002-5959-016X FU NCI NIH HHS [R01 CA058320] NR 34 TC 141 Z9 144 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT PY 2001 VL 8 IS 4 BP 885 EP 897 DI 10.1016/S1097-2765(01)00373-2 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 487ZE UT WOS:000171908900019 PM 11684023 ER PT J AU Shimada, J Suzuki, Y Kim, SJ Wang, PC Matsumura, M Kojima, S AF Shimada, J Suzuki, Y Kim, SJ Wang, PC Matsumura, M Kojima, S TI Transactivation via RAR/RXR-Sp1 interaction: Characterization of binding between Sp1 and GC box motif SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BOVINE ENDOTHELIAL-CELLS; RETINOIC ACID RECEPTOR; GROWTH-FACTOR-BETA; TRANSGLUTAMINASE GENE PROMOTER; TRANSCRIPTION FACTOR SP1; BREAST-CANCER CELLS; DNA-BINDING; PLASMINOGEN-ACTIVATOR; PHYSICAL INTERACTION; RESPONSE ELEMENT AB Modulation of Spl activity by nuclear receptors is a novel mechanism by which fat-soluble hormones regulate gene expression. We previously established that upon autoinduction of RARs by RA, RARs/RXRs physically interact with Spl, potentiate Spl binding to the GC box motifs, and thus enhance transactivation of the urokinase promoter, which lacks a canonical RAR-responsive element/RXR-responsive element. Here, we examined whether a similar mechanism might participate in transcriptional regulation of other key RA-inducible genes in endothelial cells and characterized binding between Spl and GC box motifs. Northern blot analyses showed that in addition to urokinase, after induction of RARs, RA upregulates GC-rich region-dependent mRNA expression of transglutaminase, TGF beta1, and types I and II TGF beta receptors. RA failed to alter the expression of Spl at both mRNA and protein levels. Reporter and gel shift assays and Western blot analyses suggested that either RA-treatment or RAR/RXR-over-expression enhances transactivation of these genes through a GC-rich region and strengthens the affinity of Spl to GC box motifs, accompanying a potential conformational change of Spl as reflected in its increased immunogenicity. Detailed analyses of the GC box motifs within the urokinase and other promoters indicate that interaction between RAR/RXR and Spl does not occur in the presence of nonfunctional GC box motifs containing five tandem purine or pyrimidine bases at the 3'-flanking region of hexanucleotide core sequence. These findings provide insight into the molecular mechanisms underlying RARE/RXRE-independent transactivation of RA-inducible gene promoters. C1 RIKEN, Lab Mol Cell Sci, Tsukuba Inst, Tsukuba, Ibaraki 3050074, Japan. Univ Tsukuba, Inst Appl Biochem, Tsukuba, Ibaraki 3050006, Japan. NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Kojima, S (reprint author), RIKEN, Lab Mol Cell Sci, Tsukuba Inst, Tsukuba, Ibaraki 3050074, Japan. RI Kojima, Soichi/N-7104-2015 OI Kojima, Soichi/0000-0002-5252-1612 NR 61 TC 82 Z9 82 U1 0 U2 0 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 OCT PY 2001 VL 15 IS 10 BP 1677 EP 1692 DI 10.1210/me.15.10.1677 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 477DL UT WOS:000171267800003 PM 11579201 ER PT J AU Kast, HR Nguyen, CM Sinal, CJ Jones, SA Laffitte, BA Reue, K Gonzalez, FJ Willson, TM Edwards, PA AF Kast, HR Nguyen, CM Sinal, CJ Jones, SA Laffitte, BA Reue, K Gonzalez, FJ Willson, TM Edwards, PA TI Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; HEPATIC CONTROL REGION; GENE LOCUS; TRANSGENIC MICE; PROTEIN GENE; IDENTIFICATION; BINDING; EXPRESSION; SPECIFICITY; RETINOIDS AB The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid-containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias. C1 Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. NIH, Lab Metab, Div Basic Sci, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA. RP Edwards, PA (reprint author), Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. FU NHLBI NIH HHS [HL-30568] NR 36 TC 208 Z9 217 U1 1 U2 7 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 OCT PY 2001 VL 15 IS 10 BP 1720 EP 1728 DI 10.1210/me.15.10.1720 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 477DL UT WOS:000171267800006 PM 11579204 ER PT J AU Ravichandran, LV Chen, H Li, YH Quon, MJ AF Ravichandran, LV Chen, H Li, YH Quon, MJ TI Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; RAT ADIPOSE-CELLS; NUCLEOTIDE PHOSPHODIESTERASE 3B; KINASE-B; STIMULATED TRANSLOCATION; INTACT-CELLS; NITRIC-OXIDE; SUBSTRATE-SPECIFICITY; SIGNAL-TRANSDUCTION; NEGATIVE REGULATOR AB PTP1B is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. Akt is a ser/thr kinase effector of insulin signaling that phosphorylates substrates at the consensus motif RXRXXS/T. Interestingly, PTP1B contains this motif (RYRDVS50), and wild-type PTP1B (but not mutants with substitutions for Ser(50)) was significantly phosphorylated by Akt in vitro. To determine whether PTP1B is a substrate for AM in intact cells, NIH-3T3(IR) cells transfected with either wild-type PTP1B or PTP1B-S50A were labeled with [P-32]-orthophosphate. Insulin stimulation caused a significant increase in phosphorylation of wild-type PTP1B that could be blocked by pretreatment of cells with wortmannin or cotransfection of a dominant inhibitory Akt mutant. Similar results were observed with endogenous PTP1B in untransfected HepG2 cells. Cotransfection of constitutively active Akt caused robust phosphorylation of wildtype PTP1B both in the absence and presence of insulin. By contrast, PTP1B-S50A did not undergo phosphorylation in response to insulin. We tested the functional significance of phosphorylation at Ser(50) by evaluating insulin receptor autophosphorylation in transfected Cos-7 cells. Insulin treatment caused robust receptor autophosphorylation that could be substantially reduced by coexpression of wild-type PTP1B. Similar results were obtained with coexpression of PTP1B-S50A. However, under the same conditions, PTP1B-S50D had an impaired ability to dephosphorylate the insulin receptor. Moreover, cotransfection of constitutively active Akt significantly inhibited the ability of wild-type PTP1B, but not PTP1B-S50A, to dephosphorylate the insulin receptor. We conclude that PTP1B is a novel substrate for Akt and that phosphorylation of PTP1B by Akt at Ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism for insulin signaling. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008 NR 58 TC 62 Z9 66 U1 0 U2 7 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 OCT PY 2001 VL 15 IS 10 BP 1768 EP 1780 DI 10.1210/me.15.10.1768 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 477DL UT WOS:000171267800011 PM 11579209 ER PT J AU Kinter, AL Biswas, P Alfano, M Justement, JS Mantelli, B Rizzi, C Gatti, AR Vicenzi, E Bressler, P Poli, G AF Kinter, AL Biswas, P Alfano, M Justement, JS Mantelli, B Rizzi, C Gatti, AR Vicenzi, E Bressler, P Poli, G TI Interleukin-6 and glucocorticoids synergistically induce human immunodeficiency virus type-1 expression in chronically infected U1 cells by a long terminal repeat independent post-transcriptional mechanism SO MOLECULAR MEDICINE LA English DT Article ID NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; MONOCYTE CHEMOTACTIC PROTEIN-1; MESSENGER-RNA ACCUMULATION; CENTRAL-NERVOUS-SYSTEM; HIV-1 INFECTION; GENE-EXPRESSION; DNA-BINDING; C-JUN; POSTTRANSCRIPTIONAL MECHANISMS AB Background: Glucocorticoids (GC) such as dexamethasone (Dex) can directly upregulate human immunodeficiency virus type-1 (HIV-1) replication in acutely infected cells and potentiate HIV expression from chronically infected promonocytic UI cells stimulated with tumor necrosis factor-alpha (TNF-alpha). We have here investigated the potential effect of Dex in UI cells stimulated with interleukin-6 (IL-6), a cytokine inducing virus expression by acting mostly at a post-transcriptional level on the virus life cycle. Materials and Methods: Virus production in culture supernatants was evaluated by reverse transcriptase (RT) activity. GC receptor expression was tested by both binding of [H-3]-Dexamethasone 21-mesylate and Northern blotting. Cell-associated HIV protein expression was analyzed by Western blotting, whereas both HIV and monocyte chemoattractant protein-1 (MCP-1) RNA accumulation were evaluated by Northern blotting. HIV transcription was tested by long terminal repeat (LTR) chloramphenicol acetyl transferase (CAT) assay after transient transfection of UI or U937 cells. Formation of activating protein-1 (AP-1) DNA binding complex in nuclear cell extracts was visualized by electrophoretic mobility shift assay (EMSA), whereas ERK1/2 mitogen-activated protein kinase (MAPK) phosporylation was studied by Western blotting. Results: IL-6 and Dex synergistically induced HIV expression in U I cells, and this effect was blocked by RU 486. No substantial HIV RNA accumulation was demonstrated in UI cells co-stimulated with IL-6 and Dex, whereas IL-6 upregulated the expression of MCP-I RNA, and this effect was inhibited by Dex. In contrast, Dex potentiated IL-6 induced activation of AP-1 and ERK1/2 MAPK phosphorylation, as revealed by EMSA. HIV-1 LTR driven transcription was observed in U1 cells stimulated with TNF-alpha and this effect was potentiated by Dex. In sharp contrast, no induction of LTR-directed CAT activity was observed in transfected UI cells (or in their parental uninfected U937 cells) stimulated with IL-6 and Dex either alone or in combination. Conclusions: High levels of virion production can be induced in latently infected cells by stimulation with IL-6 and Dex in the absence of activation of the HIV LTR or viral transcription in spite of activation of both ERK1/2 MAPK and AP-1. These findings suggest the existence of LTR-independent pathways influenced by cytokine and GC through which HIV can maintain substantial levels of protein expression and virion production. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD USA. San Raffaele Sci Inst, San Luigi AIDS Ctr, Clin Immunol Lab, Milan, Italy. San Raffaele Sci Inst, AIDS Immunopathogenesis Unit, Milan, Italy. Duke Univ, Med Ctr, Durham, NC USA. RP Poli, G (reprint author), DIBIT, Lab P2P3, Via Olgettina 58, I-20132 Milan, Italy. OI Vicenzi, Elisa/0000-0003-0051-3968 NR 93 TC 19 Z9 19 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD OCT PY 2001 VL 7 IS 10 BP 668 EP 678 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 496KU UT WOS:000172395400002 PM 11713366 ER PT J AU Kutty, G Ma, L Kovacs, JA AF Kutty, G Ma, L Kovacs, JA TI Characterization of the expression site of the major surface glycoprotein of human-derived Pneumocystis carinii SO MOLECULAR MICROBIOLOGY LA English DT Article ID ANTIGENIC VARIATION; GENES; TRANSCRIPTION; PNEUMONIA; FAMILY; RAT; IDENTIFICATION; PURIFICATION; VITRONECTIN; FIBRONECTIN AB The major surface glycoprotein (MSG) of Pneumocystis carinii, a pathogen responsible for pulmonary infection in AIDS and other immunocompromised patients, is an abundant surface protein that potentially allows the organism to evade host defences by antigenic variation. MSG is encoded by a multicopy gene family; in two specific forms of rat-derived P. carinii, regulation of MSG expression uses a single expression site, termed the upstream conserved sequence (UCS), through two related but distinct mechanisms. In the current study, the UCS of the from human-derived P. carinii was obtained using an RNA ligase-mediated rapid amplification of cDNA ends technique. Southern blot analysis demonstrated that the UCS was present in a single copy per genome, whereas multiple copies of the downstream MSG gene were present. Sequencing and restriction fragment length polymorphism analysis of polymerase chain reaction products amplified from pulmonary samples of patients with P. carinii pneumonia demonstrated that multiple MSG genes were expressed in a given host, and that different patterns of MSG expression were seen among different patients. Tandem repeats present in the single intron occurred with varying frequency in different patient isolates, potentially providing a new method for typing human isolates. Thus, human-derived P. carinii regulates MSG expression in a manner similar to P. carinii f. sp. carinii and, in immunosuppressed patients, in whom immune pressures that probably drive antigenic variation are functioning inadequately, P. carinii can express a broad repertoire of MSG variants. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 7D43,MSC 1662, Bethesda, MD 20892 USA. NR 46 TC 32 Z9 35 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2001 VL 42 IS 1 BP 183 EP 193 DI 10.1046/j.1365-2958.2001.02620.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 482PY UT WOS:000171585500017 PM 11679077 ER PT J AU Kajava, AV Cheng, N Cleaver, R Kessel, M Simon, MN Willery, E Jacob-Dubuisson, F Locht, C Steven, AC AF Kajava, AV Cheng, N Cleaver, R Kessel, M Simon, MN Willery, E Jacob-Dubuisson, F Locht, C Steven, AC TI Beta-helix model for the filamentous haemagglutinin adhesin of Bordetella pertussis and related bacterial secretory proteins SO MOLECULAR MICROBIOLOGY LA English DT Article ID PECTATE LYASE-C; ESCHERICHIA-COLI; RESPIRATORY-INFECTION; NUCLEOTIDE-SEQUENCE; TAILSPIKE PROTEIN; CRYSTAL-STRUCTURE; VIRULENCE FACTOR; HEMAGGLUTININ; MOTIF; ADHERENCE AB Bordetella pertussis establishes infection by attaching to epithelial cells of the respiratory tract. One of its adhesins is filamentous haemagglutinin (FHA), a 500-Angstrom -long secreted protein that is rich in beta -structure and contains two regions, R1 and R2, of tandem 19-residue repeats. Two models have been proposed in which the central shaft is (i) a hairpin made up of a pairing of two long antiparallel beta -sheets; or (ii) a beta -helix in which the polypeptide chain is coiled to form three long parallel beta -sheets. We have analysed a truncated variant of FHA by electron microscopy (negative staining, shadowing and scanning transmission electron microscopy of unstained specimens): these observations support the latter model. Further support comes from detailed sequence analysis and molecular modelling studies. We applied a profile search method to the sequences adjacent to and between R1 and R2 and found additional 'covert' copies of the same motifs that may be recognized in overt form in the R1 and R2 sequence repeats. Their total number is sufficient to support the tenet of the beta -helix model that the shaft domain - a 350 Angstrom rod - should consist of a continuous run of these motifs, apart from loop inserts. The N-terminus, which does not contain such repeats, was found to be weakly homologous to cyclodextrin transferase, a protein of known immunoglobulin-like structure. Drawing on crystal structures of known beta -helical proteins, we developed structural models of the coil motifs putatively formed by the R1 and R2 repeats. Finally, we applied the same profile search method to the sequence database and found several other proteins - all large secreted proteins of bacterial provenance - that have similar repeats and probably also similar structures. C1 NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. NIAMSD, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. Inst Pasteur, INSERM, U447, F-59019 Lille, France. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, Bldg 6,Room B2-34,MSC 2717, Bethesda, MD 20892 USA. RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 FU NCRR NIH HHS [RR 01777] NR 59 TC 111 Z9 115 U1 0 U2 7 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2001 VL 42 IS 2 BP 279 EP 292 DI 10.1046/j.1365-2958.2001.02598.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 491FV UT WOS:000172098700001 PM 11703654 ER PT J AU Park, HSM Wolfgang, M van Putten, JPM Dorward, D Hayes, SF Koomey, M AF Park, HSM Wolfgang, M van Putten, JPM Dorward, D Hayes, SF Koomey, M TI Structural alterations in a type IV pilus subunit protein result in concurrent defects in multicellular behaviour and adherence to host tissue SO MOLECULAR MICROBIOLOGY LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; HUMAN EPITHELIAL-CELLS; NEISSERIA-GONORRHOEAE; TWITCHING MOTILITY; ANTIGENIC VARIATION; VIBRIO-CHOLERAE; NATURAL TRANSFORMATION; MEDIATED ADHERENCE; MENINGITIDIS; PILIN AB The ability of bacteria to establish complex communities on surfaces is believed to require both bacterial-substratum and bacterial-bacterial interactions, and type IV pill appear to play a critical but incompletely defined role in both these processes. Using the human pathogen Neisseria gonorrhoeae, spontaneous mutants defective in bacterial self-aggregative behaviour but quantitatively unaltered in pilus fibre expression were isolated by a unique selective scheme. The mutants, carrying single amino acid substitutions within the conserved aminoterminal domain of the pilus fibre subunit, were reduced in the ability to adhere to a human epithelial cell line. Co-expression of the altered alleles in the context of a wild-type pilE gene confirmed that they were dominant negative with respect to aggregation and human cell adherence. Strains expressing two copies of the altered alleles produced twice as much purifiable pili but retained the aggregative and adherence defects. Finally, the defects in aggregative behaviour and adherence of each of the mutants were suppressed by a loss-of-function mutation in the twitching motility gene pilT. The correlations between self-aggregation and the net capacity of the microbial population to adhere efficiently demonstrates the potential significance of bacterial cell-cell interactions to colonization. C1 Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. NIAID, Microscopy Branch, Rocky Mt Labs, NIH, Hamilton, MN USA. Univ Oslo, Dept Microbiol, N-0316 Oslo, Norway. Biotechnol Ctr Oslo, N-0316 Oslo, Norway. RP Koomey, M (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. OI van Putten, Jos/0000-0002-4126-8172 FU NIAID NIH HHS [AI 27837]; NIGMS NIH HHS [2T32 GM 07315] NR 45 TC 27 Z9 28 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2001 VL 42 IS 2 BP 293 EP 307 DI 10.1046/j.1365-2958.2001.02629.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 491FV UT WOS:000172098700002 PM 11703655 ER PT J AU Bae, MA Pie, JE Song, BJ AF Bae, MA Pie, JE Song, BJ TI Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH2-terminal protein kinase-related cell death pathway SO MOLECULAR PHARMACOLOGY LA English DT Article ID CYTOCHROME P4502E1; PC12 CELLS; HEPATOTOXICITY; BINDING; STRESS; CYTOTOXICITY; ETHANOL; BCL-2; LIVER; LINE AB Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys --> Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor of CYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Pk 5 Bldg,Room 425, Rockville, MD 20852 USA. NR 39 TC 47 Z9 48 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 OCT PY 2001 VL 60 IS 4 BP 847 EP 856 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 477LJ UT WOS:000171284800027 PM 11562448 ER PT J AU Sanchez-Pernaute, R Harvey-White, J Cunningham, J Bankiewicz, KS AF Sanchez-Pernaute, R Harvey-White, J Cunningham, J Bankiewicz, KS TI Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats SO MOLECULAR THERAPY LA English DT Article DE L-DOPA; Parkinson's disease; AAV; rat model; AADC; gene therapy ID EXPRESSING TYROSINE-HYDROXYLASE; GTP-CYCLOHYDROLASE-I; PARKINSONS-DISEASE; L-DOPA; PRIMARY FIBROBLASTS; 6-HYDROXYDOPAMINE-TREATED RATS; EXTRACELLULAR DOPAMINE; BEHAVIORAL RECOVERY; AAV VECTOR; BRAIN AB In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment. C1 NINCDS, Mol Therapeut Sect, NIH, Bethesda, MD 20892 USA. Avigen Inc, Alameda, CA 94502 USA. RP Bankiewicz, KS (reprint author), Univ Calif San Francisco, Dept Neurosurg, Mission Ctr Bldg,Room 230,1855 Folsom St, San Francisco, CA 94103 USA. NR 45 TC 57 Z9 61 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD OCT PY 2001 VL 4 IS 4 BP 324 EP 330 DI 10.1006/mthe.2001.0466 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 479KH UT WOS:000171403200010 PM 11592835 ER PT J AU Weiss, MD Luciano, CA Quarles, RH AF Weiss, MD Luciano, CA Quarles, RH TI Nerve conduction abnormalities in aging mice deficient for myelin-associated glycoprotein SO MUSCLE & NERVE LA English DT Article DE axonopathy; Charcot-Marie-Tooth disease; electrophysiology; myelin-associated glycoprotein; neurofilaments ID MARIE-TOOTH-DISEASE; 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; PROTEIN ZERO GENE; AXONAL DEGENERATION; PERIPHERAL MYELIN; MOLECULAR-BASIS; MAG; NEUROPATHIES; MAINTENANCE; MUTATION AB Ultrastructural, biochemical, and electrophysiological analyses were done on 12-14-month-old mice deficient for myelin-associated glycoprotein (MAG) to further characterize the neuropathy that develops as they age. Electron microscopy demonstrated normal myelin compaction and axonal degeneration in a large number of myelinated nerve fibers. Western blots showed that the proteins of compact myelin, PO glycoprotein, and myelin basic protein were not significantly altered in the mutants; however, the Schwann cell protein, 2 ' ,3 ' -cyclic nucleotide 3 ' -phosphodiesterase, was reduced to less than half the control level. Also, both total and phosphorylated high-molecular-weight neurofilament proteins (TNFH and PNFH, respectively) were significantly decreased, as was the PNFH:TNFH ratio. Electrophysiological evaluation revealed a mild, but statistically significant, reduction of conduction velocity and a nonsignificant mild decrease in compound muscle action potential amplitudes. This constellation of findings in aging MAG-null mice is consistent with an axonopathy that resembles axonal Charcot-Marie-Tooth (CMT2) disease in many respects. Thus, mutation of a myelin-associated gene expressed by Schwann cells can induce axonal degeneration and cause a neuropathy with minimal signs of demyelination. (C) 2001 John Wiley & Sons, Inc. C1 NINCDS, Myelin & Brain Dev Sect, NIH, Bethesda, MD 20892 USA. NINCDS, Neurmuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Quarles, RH (reprint author), NINCDS, Myelin & Brain Dev Sect, NIH, Bldg 49,Room 2A28, Bethesda, MD 20892 USA. NR 36 TC 26 Z9 27 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD OCT PY 2001 VL 24 IS 10 BP 1380 EP 1387 DI 10.1002/mus.1159 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 477PR UT WOS:000171293900017 PM 11562920 ER PT J AU Petroff, MGV Kim, SH Pepe, S Dessy, C Marban, E Balligand, JL Sollott, SJ AF Petroff, MGV Kim, SH Pepe, S Dessy, C Marban, E Balligand, JL Sollott, SJ TI Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes SO NATURE CELL BIOLOGY LA English DT Article ID PIG VENTRICULAR MYOCYTES; SMOOTH-MUSCLE CELLS; CARDIAC MYOCYTES; ANGIOTENSIN-II; PHOSPHOINOSITIDE 3-KINASE; ENDOTHELIAL-CELLS; CALCIUM SPARKS; IN-VITRO; ACTIVATION; HEART AB Stretching of cardiac muscle modulates contraction through the enhancement of the Ca2+ transient, but how this occurs is still not known. We found that stretching of myocytes modulates the elementary Ca2+ release process from ryanodine-receptor Ca2+-release channels (RyRCs), Ca2+ sparks and the electrically stimulated Ca2+ transient. Stretching induces PtdIns-3-OH kinase (PI(3)K)-dependent phosphorylation of both Akt and the endothelial isoform of nitric oxide synthase (NOS), nitric oxide (NO) production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI(3)K. Exogenously generated NO reversibly increases Ca2+-spark frequency without cell stretching. We propose that myocyte NO produced by activation of the PI(3)K-Akt-endothelial NOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Univ Catholique Louvain, Sch Med, Dept Med, Unit Pharmacol & Therapeut,FATH 5349, B-1200 Brussels, Belgium. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. RP Sollott, SJ (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 49 TC 191 Z9 200 U1 2 U2 16 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2001 VL 3 IS 10 BP 867 EP 873 DI 10.1038/ncb1001-867 PG 7 WC Cell Biology SC Cell Biology GA 479GJ UT WOS:000171396400010 PM 11584267 ER PT J AU Zhang, PJ Hinshaw, JE AF Zhang, PJ Hinshaw, JE TI Three-dimensional reconstruction of dynamin in the constricted state SO NATURE CELL BIOLOGY LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAIN; RECEPTOR-MEDIATED ENDOCYTOSIS; ACETYLCHOLINE-RECEPTOR; CRYSTAL-STRUCTURE; VESICLE FORMATION; NERVE-TERMINALS; GTPASE; UNDERGOES; ASSEMBLES; DIVISION AB Members of the dynamin family of GTPases have unique structural properties that might reveal a general mechanochemical basis for membrane constriction. Receptor-mediated endocytosis, caveolae internalization and certain trafficking events in the Golgi all require dynamin for vesiculation(1). The dynamin-related protein Drp1 (Dlp1) has been implicated in mitochondria fission(2) and a plant dynamin-like protein phragmoplastin is involved in the vesicular events leading to cell wall formation(3). A common theme among these proteins is their ability to self-assemble into spirals and their localization to areas of membrane fission. Here we present the first three-dimensional structure of dynamin at a resolution of similar to 20 Angstrom, determined from cryo-electron micrographs of tubular crystals in the constricted state. The map reveals a T-shaped dimer consisting of three prominent densities: leg, stalk and head. The structure suggests that the dense stalk and head regions rearrange when GTP is added, a rearrangement that generates a force on the underlying lipid bilayer and thereby leads to membrane constriction. These results indicate that dynamin is a force-generating 'contrictase'. C1 NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hinshaw, JE (reprint author), NIDDKD, Lab Cell Biochem & Biol, NIH, Bldg 8,Room 419,MSC 0851,8 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 157 Z9 158 U1 0 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2001 VL 3 IS 10 BP 922 EP 926 DI 10.1038/ncb1001-922 PG 5 WC Cell Biology SC Cell Biology GA 479GJ UT WOS:000171396400018 PM 11584275 ER PT J AU MacDonald, TJ Brown, KM LaFleur, B Peterson, K Lawlor, C Chen, YD Packer, RJ Cogen, P Stephan, DA AF MacDonald, TJ Brown, KM LaFleur, B Peterson, K Lawlor, C Chen, YD Packer, RJ Cogen, P Stephan, DA TI Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease SO NATURE GENETICS LA English DT Article ID CHROMOSOME 17P DELETIONS; DNA-POLYMERASE-DELTA; GENE-EXPRESSION; GROWTH-FACTOR; CHILDHOOD MEDULLOBLASTOMA; MOLECULAR CLASSIFICATION; PROGNOSTIC-SIGNIFICANCE; BRAIN-TUMORS; RECEPTOR; CANCER AB Little is known about the genetic regulation of medulloblastoma dissemination, but metastatic medulloblastoma is highly associated with poor outcome. We obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or non-metastatic (M0) and identified 85 genes whose expression differed significantly between classes. Using a class prediction algorithm based on these genes and a leave-one-out approach, we assigned sample class to these tumors (M+ or M0) with 72% accuracy and to four additional independent tumors with 100% accuracy. We also assigned the metastatic medulloblastoma cell line Daoy to the metastatic class. Notably, platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors. Immunohistochemical validation on an independent set of tumors shows significant overexpression of PDGFRA in M+ tumors compared to MO tumors. Using in vitro assays, we show that platelet-derived growth factor alpha (PDGFA) enhances medulloblastoma migration and increases downstream MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK1 (p42 MAPK) and MAPK3 (p44 MAPK) phosphorylation in a dose-dependent manner. Neutralizing antibodies to PDGFRA blocks MAP2K1, MAP2K2 and MAPK1/3 phosphorylation, whereas U0126, a highly specific inhibitor of MAP2K1 and MAP2K2, also blocks MAPK1/3. Both inhibit migration and prevent PDGFA-stimulated migration. These results provide the first insight into the genetic regulation of medulloblastoma metastasis and are the first to suggest a role for PDGFRA and the RAS/MAPK signaling pathway in medulloblastoma metastasis. Inhibitors of PDGFRA and RAS proteins should therefore be considered for investigation as possible novel therapeutic strategies against medulloblastoma. C1 Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. Childrens Natl Med Ctr, Ctr Canc & Transplantat Biol, Washington, DC 20010 USA. George Washington Univ, Dept Genet, Washington, DC USA. Vanderbilt Univ, Dept Prevent Med, Div Biostat, Nashville, TN USA. NHGRI, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Neurosurg, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. RP MacDonald, TJ (reprint author), Childrens Natl Med Ctr, Res Ctr Genet Med, 111 Michigan Ave NW, Washington, DC 20010 USA. RI MacDonald, Tobey/D-4554-2013 NR 38 TC 296 Z9 304 U1 1 U2 13 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2001 VL 29 IS 2 BP 143 EP 152 DI 10.1038/ng731 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 478XP UT WOS:000171374100019 PM 11544480 ER PT J AU Hudson, TJ Church, DM Greenaway, S Nguyen, H Cook, A Steen, RG Van Etten, WJ Castle, AB Strivens, MA Trickett, P Heuston, C Davison, C Southwell, A Hardisty, R Varela-Carver, A Haynes, AR Rodriguez-Tome, P Doi, H Ko, MSH Pontius, J Schriml, L Wagner, L Maglott, D Brown, SDM Lander, ES Schuler, G Denny, P AF Hudson, TJ Church, DM Greenaway, S Nguyen, H Cook, A Steen, RG Van Etten, WJ Castle, AB Strivens, MA Trickett, P Heuston, C Davison, C Southwell, A Hardisty, R Varela-Carver, A Haynes, AR Rodriguez-Tome, P Doi, H Ko, MSH Pontius, J Schriml, L Wagner, L Maglott, D Brown, SDM Lander, ES Schuler, G Denny, P TI A radiation hybrid map of mouse genes SO NATURE GENETICS LA English DT Article ID HUMAN GENOME AB A comprehensive gene-based map of a genome is a powerful tool for genetic studies and is especially useful for the positional cloning and positional candidate approaches. The availability of gene maps for multiple organisms provides the foundation for detailed conserved-orthology maps showing the correspondence between conserved genomic segments, These maps make it possible to use cross-species information in gene hunts and shed light on the evolutionary forces that shape the genome. Here we report a radiation hybrid map of mouse genes, a combined project of the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, the Medical Research Council UK Mouse Genome Centre, and the National Center for Biotechnology Information. The map contains 11,109 genes, screened against the T31 RH panel(1) and positioned relative to a reference map containing 2,280 mouse genetic markers(2). It includes 3,658 genes homologous to the human genome sequence(3) and provides a framework for overlaying the human genome sequence to the mouse and for sequencing the mouse genome. C1 MIT, Whitehead Inst, Ctr Genome Res, Cambridge, England. McGill Univ, Ctr Hlth, Montreal Genome Ctr, Montreal, PQ, Canada. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD USA. MRC, UK Mouse Genome Ctr, Oxford, England. Mammalian Genet Unit, Oxford, England. European Mol Biol Lab, European Bioinformat INst, Cambridge, England. Japan Sci & Technol Corp, ERATO, Doi Bioasymmetry Project, Chiba 2617112, Japan. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. MIT, Dept Biol, Cambridge, MA USA. RP Hudson, TJ (reprint author), MIT, Whitehead Inst, Ctr Genome Res, Cambridge, England. EM tjhudson@med.mcgill.ca RI Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Hudson, Thomas/0000-0002-1376-4849; Schriml, Lynn/0000-0001-8910-9851 FU NHGRI NIH HHS [HG01806] NR 18 TC 46 Z9 48 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2001 VL 29 IS 2 BP 201 EP 205 DI 10.1038/ng1001-201 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 478XP UT WOS:000171374100028 PM 11586302 ER PT J AU Kondo, T Cortese, I Markovic-Plese, S Wandinger, KP Carter, C Brown, M Leitman, S Martin, R AF Kondo, T Cortese, I Markovic-Plese, S Wandinger, KP Carter, C Brown, M Leitman, S Martin, R TI Dendritic cells signal T cells in the absence of exogenous antigen SO NATURE IMMUNOLOGY LA English DT Article ID CLASS-II MOLECULES; MULTIPLE-SCLEROSIS; ACTIVATION; RECEPTOR; SURVIVAL; COMPLEX; PEPTIDE; DIFFERENTIATION; LYMPHOCYTES; EXPRESSION AB Interactions with self-major histocompatibility complex molecules on dendritic cells (DCs) are important for the survival of mature CD4(+)T cells. We have followed the DC-mediated signal from the T cell surface to the nucleus and identified a pattern of activation that correlates with increased in vitro survival. This response is induced exclusively by DCs and is likely associated with a modulation of the T cell activation threshold. We have also found that DC-mediated activation results in antigen-independent cytokine gene expression, which points to a new role for DCs in shaping the cytokine milieu. Such antigen-independent activation of T cells may play a role in protective immunity, but may also induce and perpetuate autoimmune states such as multiple sclerosis. C1 NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NR 39 TC 65 Z9 66 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2001 VL 2 IS 10 BP 932 EP 938 DI 10.1038/ni711 PG 7 WC Immunology SC Immunology GA 478TM UT WOS:000171361500012 PM 11561182 ER PT J AU Liu, WM Quinto, I Chen, XN Palmieri, C Rabin, RL Schwartz, OM Nelson, DL Scala, G AF Liu, WM Quinto, I Chen, XN Palmieri, C Rabin, RL Schwartz, OM Nelson, DL Scala, G TI Direct inhibition of Brurton's tyrosine kinase by IBtk, a Btk-binding protein SO NATURE IMMUNOLOGY LA English DT Article ID X-LINKED AGAMMAGLOBULINEMIA; B-CELL RECEPTOR; IMMUNODEFICIENT XID MICE; FACTOR-KAPPA-B; DEFICIENT EXPRESSION; SH3 DOMAIN; ACTIVATION; MUTATION; FAMILY; GENE AB Bruton's tyrosine kinase (Btk) is required for human and mouse B cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice. Unlike Src proteins, Btk lacks a negative regulatory domain at the COOH terminus and may rely on cytoplasmic Btk-binding proteins to regulates its kinase activity by trans-inhibitor mechanisms. Consistent with this possibility, IBtk, which we identified as an inhibitor of Btk, bound to the PH domain of Btk. IBtk downregulated Btk kinase activity, Btk-mediated calcium mobilization and nuclear factor-kappaB-driven transcription. These results define a potential mechanism for the regulation of Btk function in B cells. C1 Univ Catanzaro, Dept Clin & Expt Med, Sch Med, I-88100 Catanzaro, Italy. Univ Naples Federico II, Sch Med, Dept Biochem & Biomed Technol, I-80131 Naples, Italy. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Biol Imaging Facil, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Scala, G (reprint author), Univ Catanzaro, Dept Clin & Expt Med, Sch Med, I-88100 Catanzaro, Italy. RI SCALA, GIUSEPPE/A-3280-2009; Palmieri, Camillo/A-3195-2009 OI Palmieri, Camillo/0000-0001-6707-4723 FU Telethon [A.045] NR 52 TC 41 Z9 44 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2001 VL 2 IS 10 BP 939 EP 946 DI 10.1038/ni1001-939 PG 8 WC Immunology SC Immunology GA 478TM UT WOS:000171361500013 PM 11577348 ER PT J AU Hwang, PM Bunz, F Yu, J Rago, C Chan, TA Murphy, MP Kelso, GF Smith, RAJ Kinzler, KW Vogelstein, B AF Hwang, PM Bunz, F Yu, J Rago, C Chan, TA Murphy, MP Kelso, GF Smith, RAJ Kinzler, KW Vogelstein, B TI Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells SO NATURE MEDICINE LA English DT Article ID REACTIVE OXYGEN; ADRENODOXIN REDUCTASE; ANTICANCER AGENTS; ELECTRON LEAKAGE; GENE-EXPRESSION; DNA-DAMAGE; P53; MITOCHONDRIA; P21; PROTEIN AB Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (54U). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FIR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria. C1 Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Wellcome Trust Res Labs, Cambridge, England. Univ Otago, Dept Chem, Dunedin, New Zealand. RP Vogelstein, B (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RI Murphy, Michael/C-2120-2009 OI Murphy, Michael/0000-0003-1115-9618 FU NCI NIH HHS [CA 43460, R37 CA043460]; NIGMS NIH HHS [GM 07184, T32 GM007184] NR 39 TC 246 Z9 251 U1 0 U2 21 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2001 VL 7 IS 10 BP 1111 EP 1117 DI 10.1038/nm1001-1111 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 481NA UT WOS:000171524500031 PM 11590433 ER PT J AU De Vries, TJ Shaham, Y Homberg, JR Crombag, H Schuurman, K Dieben, J Vanderschuren, LJMJ Schoffelmeer, ANM AF De Vries, TJ Shaham, Y Homberg, JR Crombag, H Schuurman, K Dieben, J Vanderschuren, LJMJ Schoffelmeer, ANM TI A cannabinoid mechanism in relapse to cocaine seeking SO NATURE MEDICINE LA English DT Article ID EXTRACELLULAR DOPAMINE LEVELS; STRESS-INDUCED RELAPSE; NUCLEUS-ACCUMBENS; CB1 RECEPTOR; BEHAVIOR; RATS; AMYGDALA; HEROIN; WITHDRAWAL; ACTIVATION AB Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine(1), by re-exposure to stimuli previously associated with cocaine(2) or by exposure to stress(3). In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods', thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction(7,8). The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system(9,10) and has rewarding effects in preclinical models of drug abuse(8,11,12). We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use. C1 Vrije Univ Amsterdam, Neurosci Res Inst, Dept Med Pharmacol, Med Ctr, Amsterdam, Netherlands. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP De Vries, TJ (reprint author), Vrije Univ Amsterdam, Neurosci Res Inst, Dept Med Pharmacol, Med Ctr, Amsterdam, Netherlands. RI Homberg, Judith/D-2473-2010; shaham, yavin/G-1306-2014; De Vries, Taco/B-2831-2014; OI Vanderschuren, Louk/0000-0002-5379-0363; De Vries, Taco/0000-0002-0340-4946 NR 28 TC 276 Z9 285 U1 0 U2 6 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2001 VL 7 IS 10 BP 1151 EP 1154 DI 10.1038/nm1001-1151 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 481NA UT WOS:000171524500038 PM 11590440 ER PT J AU Lewandoski, M AF Lewandoski, M TI Conditional control of gene expression in the mouse SO NATURE REVIEWS GENETICS LA English DT Review ID SITE-SPECIFIC RECOMBINATION; EMBRYONIC STEM-CELLS; MEDIATED DNA RECOMBINATION; CARDIAC NEURAL CREST; TRANSGENIC MICE; MAMMALIAN-CELLS; IN-VIVO; VERTEBRATE DEVELOPMENT; TARGETED EXPRESSION; SOMATIC MUTAGENESIS AB One of the most powerful tools that the molecular biology revolution has given us is the ability to turn genes on and off at our discretion. In the mouse, this has been accomplished by using binary systems in which gene expression is dependent on the interaction of two components, resulting in either transcriptional transactivation or DNA recombination. During recent years, these systems have been used to analyse complex and multi-staged biological processes, such as embryogenesis and cancer, with unprecedented precision. Here, I review these systems and discuss certain studies that exemplify the advantages and limitations of each system. C1 NCI, Frederick Canc Res & Dev Ctr, Sect Genet Vertebrate Dev, Lab Canc & Dev Biol, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sect Genet Vertebrate Dev, Lab Canc & Dev Biol, Frederick, MD 21702 USA. NR 153 TC 482 Z9 497 U1 8 U2 48 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD OCT PY 2001 VL 2 IS 10 BP 743 EP 755 DI 10.1038/35093537 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 478TL UT WOS:000171361400010 PM 11584291 ER PT J AU Copeland, NG Jenkins, NA Court, DL AF Copeland, NG Jenkins, NA Court, DL TI Recombineering: A powerful new tool for mouse functional genomics SO NATURE REVIEWS GENETICS LA English DT Review ID BACTERIAL ARTIFICIAL CHROMOSOMES; ESCHERICHIA-COLI K12; BACTERIOPHAGE-LAMBDA RECOMBINATION; LINEAR DNA FRAGMENTS; BREAK REPAIR MODEL; HOMOLOGOUS RECOMBINATION; SYNTHETIC OLIGONUCLEOTIDES; GENE REPLACEMENT; SACCHAROMYCES-CEREVISIAE; TARGETING VECTORS AB Highly efficient phage-based Escherichia coli homologous recombination systems have recently been developed that enable genomic DNA in bacterial artificial chromosomes to be modified and subcloned, without the need for restriction enzymes or DNA ligases. This new form of chromosome engineering, termed recombinogenic engineering or recombineering, is efficient and greatly decreases the time it takes to create transgenic mouse models by traditional means, Recombineering also facilitates many kinds of genomic experiment that have otherwise been difficult to carry out, and should enhance functional genomic studies by providing better mouse models and a more refined genetic analysis of the mouse genome. C1 NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM copeland@ncifcrf.gov NR 79 TC 459 Z9 495 U1 5 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD OCT PY 2001 VL 2 IS 10 BP 769 EP 779 DI 10.1038/35093556 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 478TL UT WOS:000171361400012 PM 11584293 ER PT J AU Hyman, SE Malenka, RC AF Hyman, SE Malenka, RC TI Addiction and the brain: The neurobiology of compulsion and its persistence SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID LONG-TERM POTENTIATION; VENTRAL TEGMENTAL AREA; ELEMENT-BINDING PROTEIN; EXCITATORY AMINO-ACIDS; RAT NUCLEUS-ACCUMBENS; SYNAPTIC PLASTICITY; TRANSCRIPTION FACTOR; STRIATAL NEURONS; BEHAVIORAL SENSITIZATION; MOLECULAR MECHANISMS AB People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can Include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue, Addiction is characterized by a long-lasting risk of relapse, which is often Initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory. C1 NIMH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Nancy Pritzker Lab, Palo Alto, CA 94134 USA. RP Hyman, SE (reprint author), NIMH, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 112 TC 750 Z9 793 U1 5 U2 102 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD OCT PY 2001 VL 2 IS 10 BP 695 EP 703 DI 10.1038/35094560 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 480GQ UT WOS:000171454000016 PM 11584307 ER PT J AU Engel, AK Fries, P Singer, W AF Engel, AK Fries, P Singer, W TI Dynamic predictions: Oscillations and synchrony in top-down processing SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID SELECTIVE VISUAL-ATTENTION; PRIMATE MOTOR CORTEX; BAND EEG ACTIVITY; GAMMA-BAND; NEURONAL SYNCHRONIZATION; PREMOTOR CORTEX; COINCIDENCE DETECTOR; PREFRONTAL CORTEX; COGNITIVE SCIENCE; NEURAL MECHANISMS AB Classical theories of sensory processing view the brain as a passive, stimulus-driven device. By contrast, more recent approaches emphasize the constructive nature of perception, viewing it as an active and highly selective process. Indeed, there is ample evidence that the processing of stimuli is controlled by top-down influences that strongly shape the intrinsic dynamics of thalamocortical networks and constantly create predictions about forthcoming sensory events. We discuss recent experiments indicating that such predictions might be embodied in the temporal structure of both stimulus-evoked and ongoing activity, and that synchronous oscillations are particularly important in this process. Coherence among subthreshold membrane potential fluctuations could be exploited to express selective functional relationships during states of expectancy or attention, and these dynamic patterns could allow the grouping and selection of distributed neuronal responses for further processing. C1 Forschungszentrum Julich, Inst Med, Cellular Neurobiol Grp, D-52425 Julich, Germany. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Max Planck Inst Brain Res, Dept Neurophysiol, D-60528 Frankfurt, Germany. RP Engel, AK (reprint author), Forschungszentrum Julich, Inst Med, Cellular Neurobiol Grp, Postfach 1913, D-52425 Julich, Germany. EM a.k.engel@fz-juelich.de RI Fries, Pascal/E-3196-2010; X, Simon/F-4678-2011; Engel, Andreas/C-7781-2012; Singer, Wolf/D-6874-2012 OI Fries, Pascal/0000-0002-4270-1468; Engel, Andreas/0000-0003-4899-8466; NR 120 TC 1557 Z9 1580 U1 24 U2 220 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD OCT PY 2001 VL 2 IS 10 BP 704 EP 716 DI 10.1038/35094565 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 480GQ UT WOS:000171454000017 PM 11584308 ER PT J AU Ghribi, O Herman, MM Forbes, MS DeWitt, DA Savory, J AF Ghribi, O Herman, MM Forbes, MS DeWitt, DA Savory, J TI GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-X-L and inhibiting mitochondrial bax translocation SO NEUROBIOLOGY OF DISEASE LA English DT Article DE cytochrome c; Bax; Bcl-2; Bcl-X-L; caspase-3; GDNF; aluminum; endoplasmic reticulum ID PERMEABILITY TRANSITION PORE; NEUROTROPHIC FACTOR; CYTOCHROME-C; ENDOPLASMIC-RETICULUM; ALZHEIMERS-DISEASE; BRAIN-INJURY; INDUCED NEURODEGENERATION; OXIDATIVE STRESS; CELL; ACTIVATION AB Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-X-L, and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins. (C) 2001 Academic Press. C1 Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Biochem, Charlottesville, VA 22908 USA. Univ Virginia, Dept Mol Genet, Charlottesville, VA 22908 USA. NIMH, IRP, NIH, Bethesda, MD 20892 USA. Liberty Univ, Dept Biol & Chem, Lynchburg, VA 24506 USA. RP Ghribi, O (reprint author), Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. NR 34 TC 64 Z9 69 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2001 VL 8 IS 5 BP 764 EP 773 DI 10.1006/nbdi.2001.0429 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 486QH UT WOS:000171828100003 PM 11592846 ER PT J AU Barrett, T Xie, T Piao, Y Dillon-Carter, O Kargul, GJ Lim, MK Chrest, FJ Wersto, R Rowley, DL Juhaszova, M Zhou, L Vawter, MP Becker, KG Cheadle, C Wood, WH McCann, UD Freed, WJ Ko, MS Ricaurte, GA Donovan, DM AF Barrett, T Xie, T Piao, Y Dillon-Carter, O Kargul, GJ Lim, MK Chrest, FJ Wersto, R Rowley, DL Juhaszova, M Zhou, L Vawter, MP Becker, KG Cheadle, C Wood, WH McCann, UD Freed, WJ Ko, MS Ricaurte, GA Donovan, DM TI A murine dopamine neuron-specific cDNA library and microarray: Increased COXI expression during methamphetamine neurotoxicity SO NEUROBIOLOGY OF DISEASE LA English DT Article DE dopamine; cDNA library; cDNA microarray; methamphetamine; development; gene expression profile ID POSITRON-EMISSION-TOMOGRAPHY; CENTRAL-NERVOUS-SYSTEM; HEAT-SHOCK-PROTEIN; STRIATAL DOPAMINE; INDUCED HYPERTHERMIA; RAT-BRAIN; OXIDATIVE STRESS; C-11 WIN-35,428; MESSENGER-RNAS; MICE AB Due to brain tissue heterogeneity, the molecular genetic profile of any neurotransmitter-specific neuronal subtype is unknown. The purpose of this study was to purify a population of dopamine neurons, construct a cDNA library, and generate an initial gene expression profile and a microarray representative of dopamine neuron transcripts. Ventral mesencephalic dopamine neurons were purified by fluorescent-activated cell sorting from embryonic day 13.5 transgenic mice harboring a 4.5-kb rat tyrosine hydroxylase promoter-lacZ fusion. Nine-hundred sixty dopamine neuron cDNA clones were sequenced and arrayed for use in studies of gene expression changes during methamphetamine neurotoxicity. A neurotoxic dose of methamphetamine produced a greater than twofold up-regulation of the mitochondrial cytochrome c oxidase polypeptide I transcript from adult mouse substantial nigra at 12 h posttreatment. This is the first work to describe a gene expression profile for a neuronal subtype and to identify gene expression changes during methamphetamine neurotoxicity. (C) 2001 Academic Press. C1 NIA, Intramural Res Program, Res Resources Branch, NIH, Baltimore, MD 21224 USA. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Barrett, T (reprint author), NIA, Intramural Res Program, Res Resources Branch, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU NIDA NIH HHS [DA00206, DA13790] NR 63 TC 21 Z9 22 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2001 VL 8 IS 5 BP 822 EP 833 DI 10.1006/nbdi.2001.0423 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 486QH UT WOS:000171828100008 PM 11592851 ER PT J AU Bermejo, F Gabriel, R Vega, S Morales, JM Rocca, WA Anderson, DW AF Bermejo, F Gabriel, R Vega, S Morales, JM Rocca, WA Anderson, DW CA Neurological Disorders Central Sp TI Problems and issues with door-to-door, two-phase surveys: An illustration from central Spain SO NEUROEPIDEMIOLOGY LA English DT Article DE epidemiology; neurological disorders; prevalence; screening; survey ID COMMUNITY AB In 1994-1995, a screening and examination survey was conducted to ascertain the prevalence of dementia, Parkinson's disease and stroke in two urban communities and one rural community of central Spain. We use this survey to illustrate many nonclinical aspects of conducting two-phase prevalence surveys. Special emphasis is given to two common weaknesses in such surveys: screening nonparticipation and screening validation. Copyright (C) 2001 S. Karger AG, Basel. C1 Univ Hosp Octubre 12, Dept Neurol, Bethesda, MD USA. Hosp Princesa, Clin Epidemiol Unit, Arevalo, Avila, Spain. Hlth Ctr, Madrid, Spain. Minist Social Affairs, Madrid, Spain. Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. NINDS, Biostat Branch, Populat Studies Unit, Bethesda, MD USA. RP Anderson, DW (reprint author), NIH, Bldg 10,Rm 5S 203 10 Ctr Dr,MSC 1442, Bethesda, MD 20892 USA. NR 12 TC 58 Z9 59 U1 1 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0251-5350 J9 NEUROEPIDEMIOLOGY JI Neuroepidemiology PD OCT PY 2001 VL 20 IS 4 BP 225 EP 231 DI 10.1159/000054794 PG 7 WC Public, Environmental & Occupational Health; Clinical Neurology SC Public, Environmental & Occupational Health; Neurosciences & Neurology GA 491UN UT WOS:000172128600002 PM 11684897 ER PT J AU Maki, PM Resnick, SM AF Maki, PM Resnick, SM TI Effects of estrogen on patterns of brain activity at rest and during cognitive activity: A review of neuroimaging studies SO NEUROIMAGE LA English DT Review ID POSITRON-EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; SURGICALLY MENOPAUSAL WOMEN; DENDRITIC SPINE DENSITY; REPLACEMENT THERAPY; ALZHEIMERS-DISEASE; POSTMENOPAUSAL WOMEN; SEX-DIFFERENCES; GONADAL-STEROIDS; MENSTRUAL-CYCLE AB Animal and human studies provide evidence of systematic effects of estrogen on cerebral activity and cognitive function. In this article, we review studies of the activational effects of estrogen on cerebral activity during rest and during the performance of cognitive tasks in pre- and postmenopausal women. The goal is twofold-to better understand evidence suggesting that estrogen influences brain functioning and argue for the importance of considering hormone effects when designing neuroimaging studies. Hormone-related increases in blood flow during the resting state have been documented in healthy elderly women, elderly women with cerebrovascular disease, and middle-aged postmenopausal women with early menopause. There is no reliable influence of estrogen on blood flow during the resting state in women with Alzheimer's disease. Hormone therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing critical biological support for the view that estrogen might protect against age-associated changes in cognition and lower the risk of Alzheimer's disease. There is a paucity of studies examining changes in brain activation patterns across the menstrual cycle and a need for randomized studies of hormone therapy in postmenopausal women to confirm findings from observational studies. General procedural guidelines for controlling and investigating hormone effects in neuroimaging studies are discussed. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21231 USA. RP Maki, PM (reprint author), NIA, Gerontol Res Ctr, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21231 USA. NR 81 TC 85 Z9 88 U1 2 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2001 VL 14 IS 4 BP 789 EP 801 DI 10.1006/nimg.2001.0887 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 478EK UT WOS:000171329800001 PM 11554798 ER PT J AU Birn, RM Saad, ZS Bandettini, PA AF Birn, RM Saad, ZS Bandettini, PA TI Spatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response SO NEUROIMAGE LA English DT Article DE BOLD fMRI; linearity; stimulus duration; visual; motor ID FUNCTIONAL MRI; VISUAL-CORTEX; BALLOON MODEL; ADAPTATION; MOVEMENTS; CELLS; AREAS AB Recent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RI Bandettini, Peter/F-5871-2012 NR 20 TC 134 Z9 135 U1 1 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2001 VL 14 IS 4 BP 817 EP 826 DI 10.1006/nimg.2001.0873 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 478EK UT WOS:000171329800003 PM 11554800 ER PT J AU Ali, SO Denicoff, KD Altshuler, LL Hauser, P Li, XM Conrad, AJ Smith-Jackson, EE Leverich, GS Post, RM AF Ali, SO Denicoff, KD Altshuler, LL Hauser, P Li, XM Conrad, AJ Smith-Jackson, EE Leverich, GS Post, RM TI Relationship between prior course of illness and neuroanatomic structures in bipolar disorder - A preliminary study SO NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY LA English DT Article; Proceedings Paper CT 151st Annual Meeting of the American-Psychiatric-Association CY MAY 30-JUN 05, 1998 CL TORONTO, CANADA SP Amer Psychiat Assoc ID MAJOR DEPRESSION; MOOD DISORDERS; BRAIN CHANGES; MRI; SCHIZOPHRENIA; PERFORMANCE; REDUCTION; VOLUME AB Objective: In this preliminary study, we examined the relationships between prior course and severity of illness and size of the hippocampus, temporal lobes, and third and lateral ventricles in patients with bipolar disorder. Background: The few studies that have investigated relationships between course of illness measures and neuroanatomic structures in patients with bipolar disorder found divergent results. Method: Twenty-six outpatients, who met Diagnostic and Statistical Manual, Third Edition - Revised (DSM-III-R) criteria for bipolar disorder, received a magnetic resonance imaging (MRI) scan. from which volumes of the temporal lobes. hippocampi, third ventricle, and areas of the lateral ventricles were calculated. Prior course of illness variables were determined using the NIMH Life-Chart Method and were correlated to the volumetric measures of neuroanatomic structures using multiple regression analyses. Results: A longer duration of illness was paradoxically associated with a larger left temporal lobe volume whether patients with a history of substance abuse were removed from the analyses. Conclusions: Additional studies are needed to both replicate and further examine the association of prior course of illness and larger hippocampal and ventricular volumes in bipolar disorder. C1 NIMH, Biol Psychiat Branch, NIH, Psychol Sect, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Res Serv, Los Angeles, CA 90073 USA. Portland Vet Affairs Med Ctr, Dept Psychiat, Portland, OR USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. Natl Inst Genet, Los Angeles, CA USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Psychol Sect, 9000 Rockville Pike,Bldg 10,Room 3S239, Bethesda, MD 20892 USA. OI Ali, Syed/0000-0003-3131-3299 NR 31 TC 28 Z9 29 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-878X J9 NEUROPSY NEUROPSY BE JI Neuropsychiatr. Neuropsychol. Behav. Neurol. PD OCT-DEC PY 2001 VL 14 IS 4 BP 227 EP 232 PG 6 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 491QF UT WOS:000172119300005 PM 11725216 ER PT J AU Mentis, MJ Sunderland, T Lai, J Connolly, C Krasuski, J Levine, B Friz, J Sobti, S Schapiro, M Rapoport, SI AF Mentis, MJ Sunderland, T Lai, J Connolly, C Krasuski, J Levine, B Friz, J Sobti, S Schapiro, M Rapoport, SI TI Muscarinic versus nicotinic modulation of a visual task: A PET study using drug probes SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE PET scan; visual cortex; photic stimulation; regional blood flow; acetylcholine; anticholinesterase; muscarinic blocker; physostigmine; scopolamine; brain; oxygen isotopes; human ID CEREBRAL BLOOD-FLOW; CHOLINERGIC INNERVATION; ALZHEIMERS-DISEASE; HUMAN-BRAIN; CORTEX; ACETYLCHOLINE; SCOPOLAMINE; RECEPTOR; LOCALIZATION; STIMULATION AB Little is known about acetylcholine (ACh) modulation of central visual processing in humans. Receptor densities in visual brain regions are differentially distributed suggesting that receptor subtypes have different functions. Using PET, we have previously described the brain regions activated by a simple pattern-flash stimulus in healthy elderly subjects. To evaluate muscarinic and nicotinic contributions to ACh modulation of visual processing, we scanned elderly subjects watching the pattern-flash stimulus during no drug, during physostigmine augmentation, and during scopolamine antagonism of physostigmine's action. These manipulations of ACh significantly altered regional cerebral bloodflow (rCBF) in brain regions activated by the task. The pattern Of rCBF values across drug conditions suggested that muscarinic and nicotinic effects were dissociated. Muscarinic action predominated in striate cortex (Brodmann Area, BA 17) and lateral visual association areas (BA 18, 19), while nicotinic action predominated in the thalamus and inferior parietal regions (BA 39/40). Both muscarinic and nicotinic actions increased rCBF in some regions while decreasing it in others. A parsimonious reconciliation of these results with functional anatomy suggests that muscarinic action modulates visual attribute processing, while nicotinic action modulates arousal and selective attention to the visual task. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Mentis, MJ (reprint author), N Shore Univ Hosp, Ctr Neurosci, Boas Marks Res Ctr, 350 Community Dr, Manhasset, NY 11030 USA. NR 52 TC 45 Z9 46 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2001 VL 25 IS 4 BP 555 EP 564 DI 10.1016/S0893-133X(01)00264-0 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 471YV UT WOS:000170957000011 PM 11557169 ER PT J AU Miller, FG Rosenstein, DL AF Miller, FG Rosenstein, DL TI Does rapid tryptophan depletion induce depressive relapse? SO NEUROPSYCHOPHARMACOLOGY LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2001 VL 25 IS 4 BP 614 EP 614 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 471YV UT WOS:000170957000017 PM 11563388 ER PT J AU Yordanov, AT Garmestani, K Zhang, M Zhang, Z Yao, Z Phillips, KE Herring, B Horak, E Beitzel, MP Schwarz, UP Gansow, OA Plascjak, PS Eckelman, WC Waldmann, TA Brechbiel, MW AF Yordanov, AT Garmestani, K Zhang, M Zhang, Z Yao, Z Phillips, KE Herring, B Horak, E Beitzel, MP Schwarz, UP Gansow, OA Plascjak, PS Eckelman, WC Waldmann, TA Brechbiel, MW TI Preparation and in vivo evaluation of linkers for At-211 labeling of humanized anti-Tac SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE astatine; SAPS; radioimmunotherapy; monoclonal antibody; alpha-particle ID AT-211-LABELED MONOCLONAL-ANTIBODY; B-CELL LYMPHOMA; INTERLEUKIN-2 RECEPTOR; EMITTING RADIONUCLIDES; TISSUE DISTRIBUTION; ANTI-CD20 ANTIBODY; RADIOIMMUNOTHERAPY; THERAPY; INVIVO; I-131 AB The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for At-211 labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the a-chain of the IL-2 receptor (IL-2R alpha) shown to be a useful target for radioimmunotherapy are described. Synthesis of the organometallic linker precursors is accomplished by reaction of the corresponding bromo- or iodoaryl esters with bis(tributyltin) in the presence of a palladium catalyst. Subsequent conversion to the corresponding N-succinimidyl ester and labeling with At-211 of two new linkers, N-succinimidyl 4- [At-211]astato-3-methylbenzoate and N-succinimidyl N-(4-[At-211]astatophenethyl)succinamate (SAPS), together with the previously reported N-succinimidyl 4- [At-211]astatobenzoate and N-succinimidyl 3-[At-211]astato-4-methylbenzoate, are each conjugated to Hu-anti-Tac. The plasma survival times of these conjugates are compared to those of directly iodinated (I-125) Hu-anti-Tac. The N-succinimidyl N-(4-[At-211]astatophenethyl)succinamate compound (SAPS) emerged from this assay as the most viable candidate for At-211-labeling of Hu-anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4[I-125]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated (I-125) Hu-anti-Tac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NCI, Radiat Oncol Branch, Div Clin Sci, Dept Nucl Med, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radiat Oncol Branch, Div Clin Sci, Dept Nucl Med, Bethesda, MD 20892 USA. NR 47 TC 22 Z9 27 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2001 VL 28 IS 7 BP 845 EP 856 DI 10.1016/S0969-8051(01)00257-8 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 479QL UT WOS:000171415000013 PM 11578907 ER PT J AU Fujibuchi, W Anderson, JSJ Landsman, D AF Fujibuchi, W Anderson, JSJ Landsman, D TI PROSPECT improves cis-acting regulatory element prediction by integrating expression profile data with consensus pattern searches SO NUCLEIC ACIDS RESEARCH LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; GENOMIC SCALE; CELL-CYCLE; IDENTIFICATION; TRANSCRIPTION; INFORMATION AB Consensus pattern and matrix-based searches designed to predict cis-acting transcriptional regulatory sequences have historically been subject to large numbers of false positives. We sought to decrease false positives by incorporating expression profile data into a consensus pattern-based search method. We have systematically analyzed the expression phenotypes of over 6000 yeast genes, across 121 expression profile experiments, and correlated them with the distribution of 14 known regulatory elements over sequences upstream of the genes. Our method is based on a metric we term probabilistic element assessment (PEA), which is a ranking of potential sites based on sequence similarity in the upstream regions of genes with similar expression phenotypes. For eight of the 14 known elements that we examined, our method had a much higher selectivity than a naive consensus pattern search. Based on our analysis, we have developed a web-based tool called PROSPECT, which allows consensus pattern-based searching of gene clusters obtained from microarray data. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RP Landsman, D (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, 45 Ctr Dr, Bethesda, MD 20894 USA. RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 22 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 2001 VL 29 IS 19 BP 3988 EP 3996 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 480CC UT WOS:000171443100012 PM 11574681 ER PT J AU O'Bryan, JP Mohney, RP Oldham, CE AF O'Bryan, JP Mohney, RP Oldham, CE TI Mitogenesis and endocytosis: What's at the INTERSECTIoN? SO ONCOGENE LA English DT Article DE Eps15 homology; Src homology 3; GTPase; ubiquitination ID CLATHRIN-MEDIATED ENDOCYTOSIS; ACTIVATED PROTEIN-KINASE; COATED VESICLE FORMATION; GROWTH-FACTOR RECEPTORS; FAT-FACETS GENE; SIGNAL-TRANSDUCTION; EPS15 HOMOLOGY; DEUBIQUITINATING ENZYME; ADAPTER PROTEIN; TYROSINE KINASE AB Endocytosis is a regulated physiological process by which cell surface proteins are internalized along with extracellular factors such as nutrients, pathogens, peptides, toxins, etc. The process begins with the invagination of small regions of the plasma membrane which ultimately form intracellullar vesicles. These internalized vesicles may shuttle back to the plasma membrane to recycle the membrane components or they may be targeted for degradation. One role for endocytosis is in the attenuation of receptor signaling. For example, desensitization of activated membrane bound receptors such as G-protein coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs) occurs, in part, through endocytosis of the activated receptor. However, accumulating evidence suggests that endocytosis also mediates intracellular signaling. In this review, we discuss the experimental data that implicate endocytosis as a critical component in cellular signal transduction, both in the initiation of a signal as well as in the termination of a signal. Furthermore, we focus our attention on a recently described adaptor protein, intersectin (ITSN), which provides a link to both the endocytic and the mitogenic machinery of a cell. Thus, ITSN functions at a crossroad in the biochemical regulation of cell function. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP O'Bryan, JP (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,Bldg Rm 101-F336,MD F3-06, Res Triangle Pk, NC 27709 USA. NR 81 TC 38 Z9 39 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 1 PY 2001 VL 20 IS 44 BP 6300 EP 6308 DI 10.1038/sj.onc.1204773 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 483NF UT WOS:000171640600005 PM 11607832 ER PT J AU Rowland, JH Varricchio, CG Trimble, EL Gore-Langton, RE AF Rowland, JH Varricchio, CG Trimble, EL Gore-Langton, RE TI Clinical trials referral resource - Investigator-initiated health-related quality-of-life research SO ONCOLOGY-NEW YORK LA English DT Article C1 NCI, Bethesda, MD 20892 USA. RP Rowland, JH (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 2001 VL 15 IS 10 BP 1284 EP + PG 6 WC Oncology SC Oncology GA 489DM UT WOS:000171976800012 PM 11702958 ER PT J AU Baccaglini, L Schiffmann, R Brennan, MT Lancaster, HE Kulkarni, AB Brahim, JS AF Baccaglini, L Schiffmann, R Brennan, MT Lancaster, HE Kulkarni, AB Brahim, JS TI Oral and craniofacial findings in Fabry's disease: A report of 13 patients SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Association-for-Dental-Research CY 2000 CL BETHESDA, MARYLAND SP Amer Assoc Dental Res ID MAXILLARY SINUS; SIGNS AB Objective. Fabry's disease is an X-linked metabolic disease caused by the deficiency of the lysosomal enzyme alpha -galactosidase A. The purpose of this study was to assess oral and craniofacial findings in a cohort of patients with Fabry's disease to facilitate recognition of this condition and early treatment of its manifestations. Study design. This is a case series describing oral and craniofacial findings of 13 male patients diagnosed with Fabry's disease. Data were collected by means of a standardized questionnaire, clinical examination, panoramic and cephalometric radiographs, and magnetic resonance imaging. Results. A variety of abnormalities are described, including an increased prevalence of cysts/pseudocysts of the maxillary sinuses (PCMs) and the presence of maxillary prognathism. Conclusion. Given the high prevalence of oral and dental abnormalities, we recommend a thorough stomatologic evaluation of these patients. C1 Natl Inst Dent & Craniofacial Res, Clin Res Core, NIH, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, Funct Genomics Unit, NIH, Bethesda, MD USA. Indiana Univ, Sch Dent, Dept Oral Surg Med & Pathol, Indianapolis, IN USA. NINCDS, Clin Invest & Therapeut Sect, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Baccaglini, L (reprint author), Univ N Carolina, Sch Dent, Dept Dent Ecol, CB 7450, Chapel Hill, NC 27599 USA. NR 20 TC 25 Z9 25 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD OCT PY 2001 VL 92 IS 4 BP 415 EP 419 DI 10.1067/moe.2001.114833 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 486QF UT WOS:000171827900014 PM 11598576 ER PT J AU Little, RE Little, AS Chislovska, N Hulchiy, OP Monaghan, SC Gladen, BC AF Little, RE Little, AS Chislovska, N Hulchiy, OP Monaghan, SC Gladen, BC TI Hospital admissions during pregnancy in two urban areas of Ukraine SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID UNITED-STATES; COMPLICATIONS AB Hospital admissions are generally regarded as a marker of severe pregnancy complications, and a low ratio of antenatal admissions to deliveries is considered an indicator of maternal-fetal well-being. We investigated the reasons for hospital admissions in a sample of deliveries from Ukraine, a country of the former eastern bloc. All hospitalisations were traced among 3099 women who delivered live singletons of at least 20 weeks gestation in two urban areas of Ukraine and data were abstracted from their medical records. More than a third of the women were admitted to hospital during their pregnancy, and 91% of the admissions were for a pregnancy complication, primarily threatened abortion or early labour. Median length of stay for all admissions was 12 days. The ratio of admissions to deliveries was 52 per 100. The Ukrainian ratio of hospitalisations to deliveries is notably higher than any that have been published in studies from the United States and Australia, reflecting patterns of care that stress hospital-based treatment. This high ratio does not necessarily mean that Ukrainian women are sicker, although that may be the case. The comparison of hospitalisation to delivery ratios is meaningful only when other factors, such as resources, patterns of care, costs and access, are taken into account. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Oregon Independent Hlth Serv, Bend, OR USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. Inst Paediat Obstet & Gynecol, Kiev, Ukraine. Natl Med Univ, Kiev, Ukraine. RP Little, RE (reprint author), NIEHS, A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 3 Z9 4 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD OCT PY 2001 VL 15 IS 4 BP 323 EP 327 DI 10.1046/j.1365-3016.2001.0380a.x PG 5 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 491FU UT WOS:000172098600002 PM 11703679 ER PT J AU Cadet, JL AF Cadet, JL TI Molecular neurotoxicological models of Parkinsonism: focus on genetic manipulation of mice SO PARKINSONISM & RELATED DISORDERS LA English DT Article; Proceedings Paper CT 5th International Symposium on the Treatment of Parkinsons Disease CY SEP 30-OCT 01, 2000 CL KOBE, JAPAN DE Parkinson's disease; free radicals; knockout mice; transgenic ID DISMUTASE TRANSGENIC MICE; METHAMPHETAMINE-INDUCED NEUROTOXICITY; NEURONAL NITRIC-OXIDE; CUZN-SUPEROXIDE DISMUTASE; DNA-DAMAGING AGENTS; WILD-TYPE P53; SUBSTANTIA-NIGRA; DOPAMINERGIC NEUROTOXICITY; STRIATAL DOPAMINE; OXIDATIVE STRESS AB Parkinson's disease is a neurodegenerative disorder that affects mainly the nigrostriatal doparminergic system in humans. Several propositions have been put forward to explain the cellular and molecular pathobiology of this syndrome. Initial attempts were made through the use of various agents to manipulate the deleterious effects of toxins that destroy dopaminergic cells both in vitro and in vivo. These studies led to the idea that oxidative stress is an important factor in killing these cells. More recent attempts have made use of genetically modified mice to eliminate or over-express genes of interest. These experiments have suggested that the destruction of dopaminergic cells might be the result of the convergence of dependent and independent molecular pathways and that trigger cellular events might lead to the demise of these doparninergic cells. (C) 2001 Published by Elsevier Science Ltd. C1 NIDA, Intramural Res Program, Mol Neuropsychiat Sect, NIH, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Intramural Res Program, Mol Neuropsychiat Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 101 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 OCT PY 2001 VL 8 IS 2 BP 85 EP 90 DI 10.1016/S1353-8020(01)00021-9 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 476HP UT WOS:000171220400003 PM 11489672 ER PT J AU DeBaun, MR Gurney, JG AF DeBaun, MR Gurney, JG TI Environmental exposure and cancer in children - A conceptual framework for the pediatrician SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID ADENOCARCINOMA; VAGINA; STILBESTROL; REGISTRY AB Pediatricians frequently are asked to make recommendations regarding the protection of children from suspected carcinogenic agents. Information on health effects of suspected cancer causing environmental exposures is often incomplete, however. Informed recommendations require systematic assessments of the weight of evidence from available studies and placement of the studies into a conceptual framework that allows for available data to be reviewed in the context of epidemiology principles of causal inference. C1 Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. RP DeBaun, MR (reprint author), Washington Univ, Sch Med, Dept Pediat, 660 S Euclid Ave,Campus Box 8208, St Louis, MO 63110 USA. NR 15 TC 3 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD OCT PY 2001 VL 48 IS 5 BP 1215 EP + DI 10.1016/S0031-3955(05)70370-9 PG 9 WC Pediatrics SC Pediatrics GA 474AD UT WOS:000171081400011 PM 11579670 ER PT J AU Santosham, M Englund, JA McInnes, P Croll, J Thompson, CM Croll, L Glezen, WP Siber, GR AF Santosham, M Englund, JA McInnes, P Croll, J Thompson, CM Croll, L Glezen, WP Siber, GR TI Safety and antibody persistence following Haemophilus influenzae type b conjugate or pneumococcal polysaccharide vaccines given before pregnancy in women of childbearing age and their infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE antibody; Haemophilus influenzae type b conjugate; vaccine; pneumococcal polysaccharide vaccine; prepregnancy vaccination ID HIGH-RISK INFANTS; CAPSULAR POLYSACCHARIDE; MATERNAL IMMUNIZATION; SERUM ANTIBODIES; TOXOID CONJUGATE; IMMUNE GLOBULIN; CHILDREN AB Background. Immunization of healthy women before pregnancy is a potential approach to providing increased levels of maternal antibody to newborns to protect them from infections occurring during the perinatal period and first months of life. Methods. Healthy nonpregnant Pima Indian women of childbearing age were randomized to receive one of two Haemophilus influenzae type b (Hib) conjugate vaccines [HbOC or Hib-meningococcal outer membrane protein complex (OMP)] or a 23-valent pneumococcal polysaccharide vaccine (PnPs). Infants received Hib-OMP vaccine at 2, 4 and 12 months of age. Vaccine safety and immunogenicity was evaluated in the women and their infants. Results. Anti-polyribose ribitol phosphate antibody titers were significantly higher in women in both Hib conjugate vaccine groups than in the pneumococcal vaccine group throughout the 37-month observation period. Antibody responses to HbOC vaccine were significantly higher than those to Hib-OMP. A subsequent booster dose of each Hib conjugate vaccine induced reactions and antibody responses similar to those of the first dose. Infants born to mothers immunized with Hib vaccines compared with PnPs had significantly higher polyribose ribitol phosphate-specific IgG antibody titers at birth and 2 months of age but lower antibody responses to Hib-OMP at 6 months and similar titers before and after boosting with Hib-OMP at 1 year of age. By contrast women immunized with PnPs did not have significantly elevated concentrations of pneumococcal-specific antibody at delivery, and their infants had pneumococcal antibody titers similar to those of infants born to mothers who did not receive pneumococcal vaccine before pregnancy. Conclusion. Hib conjugate vaccine given to women before pregnancy significantly increased the proportion of infants who had protective Hib antibody levels at birth and 2 months of age. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Hlth, Ctr Amer Indian & Alaskan Nat Hlth, Baltimore, MD 21205 USA. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. NIAID, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. Wyeth Lederle Vaccines & Pediat, Pearl River, NY USA. RP Santosham, M (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Hlth, Ctr Amer Indian & Alaskan Nat Hlth, 615 N Wolfe St,B Suite E8132, Baltimore, MD 21205 USA. RI Sandall, Jane/D-4146-2009 OI Sandall, Jane/0000-0003-2000-743X NR 25 TC 23 Z9 24 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 OCT PY 2001 VL 20 IS 10 BP 931 EP 940 DI 10.1097/00006454-200110000-00005 PG 10 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 481PX UT WOS:000171529500003 PM 11642626 ER PT J AU Nicholson, JC McDuffie, JR Bonat, SH Russell, DL Boyce, KA McCann, S Michael, M Sebring, NG Reynolds, JC Yanovski, JA AF Nicholson, JC McDuffie, JR Bonat, SH Russell, DL Boyce, KA McCann, S Michael, M Sebring, NG Reynolds, JC Yanovski, JA TI Estimation of body fatness by air displacement plethysmography in African American and white children SO PEDIATRIC RESEARCH LA English DT Article ID X-RAY ABSORPTIOMETRY; FAT-FREE BODY; CROSS-CALIBRATION; MASS; VALIDATION; OBESITY; ADULTS; GIRLS; HYDRODENSITOMETRY; MATURATION AB The purpose of this study was to determine the ability of air displacement plethysmography (ADP) to estimate body fatness in prepubertal and early pubertal African American and white children. One hundred nineteen nonoverweight and overweight boys (N=56) and girls (N=63), age (mean +/- SD) 9.8 +/-1.7 y, body mass index 25.9 +/-7.6 kg/m(2) (range, 14.2-47.0 kg/m(2)), and mean percent body fat (%BF) by dual-energy x-ray absorptiometry (DXA) 39.2 +/- 11.7% (range, 12.2-57.5%), were studied. %BF by ADP was compared with DXA %BF estimates and with body fat by several field methods: skinfold thicknesses using the Slaughter et al. equations (Hum Biol 60: 709-723, 1988), bioelectrical impedance analysis (BIA) using the Houtkooper et al. equation (J Appl Physiol 72: 366-373, 1992), and a predictive equation using skinfold thicknesses, BIA, and weight (Goran et al.: Am J Clin Nutr 63: 299-305, 1996). All methods used to estimate %BF were significantly correlated with DXA (all p<0.0001), with r(2) ranging from 0.85 (skinfold measurements) to 0.95 (ADP). ADP using the Siri equation underestimated %BF by -1.9% (p<0.001); the Bland-Altman limits of agreement (defined as +/-2 SD) were +/-7.4%. %BF by ADP-Siri underestimated %BF by DXA by 3.0% for girls (p<0.001) and by 0.6% for boys (NS). Agreement between body fat estimation by ADP and DXA did not vary with age, race, or pubertal stage. Application of the age-adjusted Lohman model to ADP significantly increased the magnitude of the underestimation to -6.9% (p<0.0001). Prediction of %BF by the Slaughter skinfold thickness equation showed no significant mean bias for the overall data, but significantly underestimated %BF in girls (-3.7%) while overestimating %BF in boys (+2.4%) with wide limits of agreement (+/- 17.7%, p<0.01 versus ADP). %BF by the Houtkooper BIA equation or Goran model underestimated %BF to a significantly greater degree than ADP (Houtkooper, -8.1%; Goran, -10.1%; both p<0.0001 versus DXA or ADP). Determination of %BF from ADP using the Siri model slightly underestimates %BF as determined by DXA in girls, but appears to be superior to existing field methods both in accuracy and limits of agreement. Because of the ease with which it can be performed, ADP may prove useful for investigations of adiposity in children. C1 NICHHD, Unit Growth & Obes, DEB, NIH, Bethesda, MD 20892 USA. NIH, Div Nutr Res Coordinat, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Nutr, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, DEB, NIH, 100 Ctr Dr,Bldg 10,Room 10N262 MSC 1862, Bethesda, MD 20892 USA. FU NICHD NIH HHS [Z-001-HD-04-00641] NR 38 TC 55 Z9 55 U1 2 U2 3 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2001 VL 50 IS 4 BP 467 EP 473 DI 10.1203/00006450-200110000-00008 PG 7 WC Pediatrics SC Pediatrics GA 474EK UT WOS:000171092600008 PM 11568289 ER PT J AU Ohls, RK Ehrenkranz, RA Wright, LL Lemons, JA Korones, SB Stoll, BJ Stark, AR Shankaran, S Donovan, EF Close, NC Das, A AF Ohls, RK Ehrenkranz, RA Wright, LL Lemons, JA Korones, SB Stoll, BJ Stark, AR Shankaran, S Donovan, EF Close, NC Das, A CA Natl Inst Child Hlth Human Dev Neo TI Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: A multicenter, randomized, controlled trial SO PEDIATRICS LA English DT Article DE neonate; intravenous iron; donor exposure ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; ERYTHROID PROGENITORS; IRON SUPPLEMENTATION; PARENTERAL-NUTRITION; DOUBLE-BLIND; PREMATURITY; ANEMIA; LESS; EXPOSURE; EFFICACY AB Objectives. Infants of less than or equal to 1250 g birth weight receive multiple erythrocyte transfusions during their hospitalization. We hypothesized that early erythropoietin (Epo) and iron therapy would 1) decrease the number of transfusions received (infants 401-1000 g birth weight; trial 1) and 2) decrease the percentage of infants who received any transfusions (1001-1250 g birth weight; trial 2). Methods. A total of 172 infants in trial 1 and 118 infants in trial 2 were randomized to treatment (Epo, 400 U/kg 3 times weekly) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Complete blood and reticulocyte counts were measured weekly, and ferritin concentrations were measured monthly. Transfusions were administered according to protocol. Phlebotomy losses and transfusion data were recorded. Results. Treated and placebo/control infants in trial 1 received a similar number of transfusions (4.3 +/- 3.6 vs 5.2 +/- 4.2, respectively). A similar percentage of treated and control infants in trial 2 received at least 1 transfusion (37% vs 46%). Reticulocyte counts were higher in treated infants during each week of the study in both trials. Hematocrits were higher among treated infants from week 2 on in both trials. Ferritin concentrations were higher in placebo/controls than in treated infants at weeks 4 and 8 in trial 1 and at week 4 in trial 2. No adverse effects of Epo or supplemental iron occurred. Conclusion. The combination of early Epo and iron as administered in this study stimulated erythropoiesis in infants who were less than or equal to 1250 g at birth. However, the lack of impact on transfusion requirements fails to support routine use of early Epo. C1 Univ New Mexico, Sch Med, Dept Pediat, Albuquerque, NM 87131 USA. Yale Univ, Dept Pediat, New Haven, CT 06520 USA. Indiana Univ, Dept Pediat, Indianapolis, IN 46204 USA. Univ Tennessee, Dept Pediat, Memphis, TN USA. Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. Harvard Univ, Dept Pediat, Boston, MA 02115 USA. Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. George Washington Univ, Ctr Biostat, Dept Pediat, Washington, DC USA. Res Triangle Inst, Dept Pediat, Res Triangle Pk, NC 27709 USA. NICHHD, Dept Pediat, Bethesda, MD 20892 USA. RP Ohls, RK (reprint author), Univ New Mexico, Sch Med, Dept Pediat, 2211 Lomas St, Albuquerque, NM 87131 USA. FU NCRR NIH HHS [M01 RR 00750, M01 RR 00997, M01 RR 01032, M01 RR 02172, M01 RR 06022, M01 RR 08084, M01 RR02635]; NICHD NIH HHS [U10 HD27871, U01 HD19897, U01 HD36790, U10 HD21385, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27881, U10 HD34167] NR 37 TC 94 Z9 96 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 OCT PY 2001 VL 108 IS 4 BP 934 EP 942 DI 10.1542/peds.108.4.934 PG 9 WC Pediatrics SC Pediatrics GA 478AC UT WOS:000171319600036 PM 11581447 ER PT J AU Bowersox, J AF Bowersox, J CA NIH Consensus Dev Panel TI National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: Screening and Management, October 16-18, 2000 SO PEDIATRICS LA English DT Article DE phenylketonuria; hyperphenylalanimea; phenylketonuria screening; phenylalanine-restricted diet; maternal phenylketonuria; newborn screening; phenylalanine monitoring; phenylketonuria outcomes ID PHENYLALANINE-HYDROXYLASE DEFICIENCY; MATERNAL PHENYLKETONURIA; TREATED HYPERPHENYLALANINEMIA; NEUROLOGICAL DETERIORATION; DIETARY-TREATMENT; PHENOTYPE; GENOTYPE; PERFORMANCE; CHILDREN; ADULTS AB Objective. To provide health care providers, patients, and the general public with a responsible assessment of currently available data regarding screening for and management of phenylketonuria (PKU). Participants. A nonfederal, nonadvocate, 14-member panel representing the fields of pediatrics, genetics, human development, public policy, nursing, and molecular physiology and including patient representatives. In addition, 19 experts in pediatrics, medical genetics, psychology, pediatric neurology, biochemical and molecular genetics, and gene therapy presented data to the panel and to a conference audience of 312. Evidence. The literature was searched using Medline for January 1980 through July 2000, and an extensive bibliography of 3394 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. Consensus Process. The panel, answering predefined questions, developed its conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov. Conclusions. Genetic testing for PKU has been in place for almost 40 years and has been very successful in preventing severe mental retardation in thousands of children and adults. Metabolic control is necessary across the lifespan of individuals with PKU. A comprehensive, multidisciplinary, integrated system is needed to delivery of care to individuals with PKU. Greatly needed are consistency and coordination between screening, treatment, data collection, and patient support programs. There should be equal access to culturally sensitive, age-appropriate treatment programs. Ethically sound, specific policies for storage, ownership, and use in future studies of archived samples remaining from PKU testing should be established. Research into the pathophysiology of PKU and relationship to genetic, neural, and behavioral variation is strongly encouraged. Uniform policies must be established to remove financial barriers to the acquisition of medical foods and modified low-protein foods and to provide access to support services needed to maintain metabolic control in individuals with PKU. Research on nondietary alternative treatments for PKU is strongly encouraged. To achieve optimal statistical power and cross-cultural applicability, it will be beneficial to use data acquired via national and international collaboration. C1 NIH, Off Dis Prevent, Consensus Dev Panel, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Dept Pediat, Miami, FL USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Univ Washington, Ctr Human Dev & Disabil, Seattle, WA 98195 USA. Univ Iowa Hlth Care, Childrens Hosp Iowa, Dept Pediat, Div Gen Pediat & Adolescent Med, Iowa City, IA USA. Univ Texas, Sch Med, Dept Pediat, Houston, TX USA. Texas So Univ, Dept Biol, Houston, TX 77004 USA. Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. So Illinois Univ, Sch Nursing, Edwardsville, IL 62026 USA. Univ Minnesota, Inst Human Genet, Grad Program Genet Counseling, Minneapolis, MN 55455 USA. Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Univ Calif Irvine, Dept Pediat, Orange, CA 92668 USA. Univ Wisconsin, Madison, WI USA. RP Bowersox, J (reprint author), NIH, Off Dis Prevent, Consensus Dev Panel, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 150 Z9 155 U1 3 U2 22 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 OCT PY 2001 VL 108 IS 4 BP 972 EP 982 PG 11 WC Pediatrics SC Pediatrics GA 478AC UT WOS:000171319600042 ER PT J AU Vitiello, B AF Vitiello, B TI Psychopharmacology for young children: Clinical needs and research opportunities SO PEDIATRICS LA English DT Article DE children; preschoolers; psychopharmacology; research; mental ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PRESCHOOL-CHILDREN; DEVELOPMENTAL NEUROTOXICITY; PSYCHOTROPIC MEDICATIONS; BEHAVIOR PROBLEMS; METHYLPHENIDATE; DIAGNOSIS; AUTISM; ADHD; AGE AB In response to concerns about the increasing use of psychotropic medications in preschoolers, the National Institute of Mental Health and the Food and Drug Administration convened a workshop in October 2000 to examine the current state of knowledge regarding psychopharmacology for young children and discuss a variety of topics relevant to research in this age group, including safety, efficacy, investigational methods, and ethical aspects. The meeting gathered researchers, practitioners, ethicists, industry staff, and family and patient representatives. Efficacy and safety of psychotropics have not been systematically evaluated in preschoolers. The major limitation to this research is the diagnostic uncertainty surrounding most manifestations of psychopathology in early childhood. Research in developmental psychopathology is needed to clarify diagnosis and provide sensitive and specific methods for clinical trials. Possible approaches to expanding the research basis of this area of clinical practice, including a recently started study of methylphenidate in preschoolers, are reported here. C1 NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Child & Adolescent Treatment & Prevent Intervent, Room 7147,6001 Execut Blvd,MSC 9633, Bethesda, MD 20892 USA. NR 36 TC 54 Z9 54 U1 4 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2001 VL 108 IS 4 BP 983 EP 989 DI 10.1542/peds.108.4.983 PG 7 WC Pediatrics SC Pediatrics GA 478AC UT WOS:000171319600043 PM 11581454 ER PT J AU Buchacz, K Cervia, JS Lindsey, JC Hughes, MD Seage, GR Dankner, WM Oleske, JM Moye, J AF Buchacz, K Cervia, JS Lindsey, JC Hughes, MD Seage, GR Dankner, WM Oleske, JM Moye, J CA Pediat AIDS Clin Trials Grp 219 St TI Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children SO PEDIATRICS LA English DT Article DE HIV-1; protease inhibitor; growth; children ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED TRIAL; PRELIMINARY EXPERIENCES; SOMATIC GROWTH; LARGE COHORT; RITONAVIR; NELFINAVIR; ZIDOVUDINE; INDINAVIR; INFANTS AB Objective. To examine beneficial or detrimental effects of protease inhibitor (PI)-containing antiretroviral regimens on height and weight growth in children with human immunodeficiency virus (HIV) infection. Methods. A prospective cohort study was conducted of 906 HIV-infected children, from pediatric research clinics in the United States, who were between 3 months and 18 years of age and who had height and weight assessed in 1995 (before introduction of PIs in this population) and at least once more through 1999. Changes in age- and gender-adjusted height and weight growth associated with PI use were assessed. Results. Compared with a healthy reference population, children were more affected in height (mean z score: -0.90 [18th percentile]) than in weight (mean z score: -0.42 [34th percentile]) at baseline (1995). Two thirds of children received at least 1 PI during 1996 to 1999. In the multivariate mixed effects regression models adjusted for baseline log(10) CD4 cell count, baseline age, gender, and race/ethnicity, the use of PIs was associated with per-year gains of 0.13 z scores in height and 0.05 z scores in weight relative to the expected growth with non-PI-containing regimens (eg, after 1 year of PI use, a representative 6-year-old boy in our study would be approximately 0.7 cm taller and 0.1 kg heavier than if he had not received PIs). No significant differential effects of PIs on height or weight growth according to specific agents or children's sociodemographic or clinical characteristics were found. Conclusions. Although the use of PI-containing regimens was not associated with growth retardation, it was associated with only small annual increments in height and weight growth in HIV-infected children. C1 Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Long Isl Jewish Med Ctr, New Hyde Pk, NY 11042 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Parexel Int Corp, Durham, NC USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Buchacz, K (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave, Boston, MA 02115 USA. RI Oleske, James/C-1951-2016 OI Oleske, James/0000-0003-2305-5605 FU NIAID NIH HHS [AI27563, AI25883, AI41110] NR 34 TC 37 Z9 37 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 OCT PY 2001 VL 108 IS 4 AR e72 DI 10.1542/peds.108.4.e72 PG 7 WC Pediatrics SC Pediatrics GA 478AC UT WOS:000171319600015 PM 11581480 ER PT J AU Otto, M AF Otto, M TI Staphylococcus aureus and Staphylococcus epidermidis peptide pheromones produced by the accessory gene regulator agr system SO PEPTIDES LA English DT Review DE Staphylococcus; agr; pheromone ID VIRULENCE FACTOR EXPRESSION; GRAM-POSITIVE BACTERIA; PSEUDOMONAS-AERUGINOSA; INTERNAL THIOESTER; CELL COMMUNICATION; GLOBAL REGULATORS; HUMAN-COMPLEMENT; MUTANT; LOCUS; SAR AB The accessory gene regulator (agr) system of staphylococci regulates the expression of virulence factors in response to cell density. The extracellular signaling molecule encoded by this system is a thiolactone-containing pheromone peptide whose primary sequence varies among staphylococcal strains. A post-translational modification of the peptide is believed to be carried out by an enzyme with a novel function, AgrB. Staphylococcal pheromones show cross-inhibiting properties: Pheromones of self and pheromones of non-self induce and suppress the agr response, respectively, and have therefore been proposed as novel anti-staphylococcal drugs. As inhibition of agr leads to diminished expression of toxins, but to increased expression of colonization factors and biofilm formation, their therapeutic potential remains yet to be evaluated in depth. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Otto, M (reprint author), NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. OI Otto, Michael/0000-0002-2222-4115 NR 41 TC 57 Z9 63 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD OCT PY 2001 VL 22 IS 10 BP 1603 EP 1608 DI 10.1016/S0196-9781(01)00495-8 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 480ZE UT WOS:000171492600009 PM 11587788 ER PT J AU Zhang, J Kuehl, P Green, ED Touchman, JW Watkins, PB Daly, A Hall, SD Maurel, P Relling, M Brimer, C Yasuda, K Wrighton, SA Hancock, M Kim, RB Strom, S Thummel, K Russell, CG Hudson, JR Schuetz, EG Boguski, MS AF Zhang, J Kuehl, P Green, ED Touchman, JW Watkins, PB Daly, A Hall, SD Maurel, P Relling, M Brimer, C Yasuda, K Wrighton, SA Hancock, M Kim, RB Strom, S Thummel, K Russell, CG Hudson, JR Schuetz, EG Boguski, MS TI The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants SO PHARMACOGENETICS LA English DT Article DE PXR; SXR; CYP3A4; SNPs; polymorphism; pharmacogenomics ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ADULT-RAT HEPATOCYTES; NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVATION; SIGNALING PATHWAY; P-GLYCOPROTEIN; GENE; INDUCTION; RIFAMPICIN; CYP3A4 AB The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets. Pharmacogenctics 11:555-572 (C) 2001 Lippincott Williams & Wilkins. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Univ Maryland, Dept Mol & Cell Biol, Baltimore, MD 21201 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. Newcastle Univ, Dept Pharmacol Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Indiana Univ, Dept Clin Pharmacol, Indianapolis, IN 46204 USA. INSERM, Montpellier, France. St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Eli Lilly & Co, Dept Drug Metab, Indianapolis, IN 46285 USA. Vanderbilt Univ, Dept Clin Pharmacol, Nashville, TN USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. Res Genet, Huntsville, AL USA. RP Boguski, MS (reprint author), Rosetta Inpharmat Inc, 1304011 5th Ave NE, Kirkland, WA 98034 USA. EM mboguski@rii.com RI Strom, Stephen/A-6501-2008; Daly, Ann/H-3144-2011; Cline, Cynthia/F-7065-2012 OI Daly, Ann/0000-0002-7321-0629; FU NCI NIH HHS [CA51001, P30 CA21765]; NCRR NIH HHS [RR00046]; NIEHS NIH HHS [ES08658]; NIGMS NIH HHS [GM48349, GM31304, GM38149, GM60346, U01 GM61393, U01GM61374] NR 41 TC 213 Z9 230 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD OCT PY 2001 VL 11 IS 7 BP 555 EP 572 DI 10.1097/00008571-200110000-00003 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 483LF UT WOS:000171636300003 PM 11668216 ER PT J AU Dai, D Zeldin, DC Blaisdell, JA Chanas, B Coulter, SJ Ghanayem, BI Goldstein, JA AF Dai, D Zeldin, DC Blaisdell, JA Chanas, B Coulter, SJ Ghanayem, BI Goldstein, JA TI Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid SO PHARMACOGENETICS LA English DT Article DE CYP2C8 polymovrphisms; site-directed mutagenesis; paclitaxel; arachidonic acid ID PRIMARY CONGENITAL GLAUCOMA; HUMAN LIVER-MICROSOMES; S-MEPHENYTOIN; EPOXYEICOSATRIENOIC ACIDS; POOR METABOLIZER; GENETIC-DEFECT; MOLECULAR-CLONING; ESCHERICHIA-COLI; TAXOL METABOLISM; LUNG-CANCER AB Cytochrome P450 (CYP) 2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (Taxol). It is also the predominant P450 responsible for the metabolism of arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs) in human liver and kidney. In this study, we describe two new CYP2C8 alleles containing coding changes: CYP2C8*2 has an Ile(269)Phe substitution in exon 5 and CYP2C8*3 includes both Arg(139)Lys and Lys(399)Arg amino acid substitutions in exons 3 and 8. CYP2C8*2 was found only in African-Americans, while CYP2C8*3 occurred primarily in Caucasians. Neither occurred in Asians. The frequency of the CYP2C8*2 allele was 0.18 in African-Americans, and that of CYP2C8*3 was 0.13 in Caucasians. CYP2C8*1 (wild-type), CYP2C8*2 and CYP2C8*3 cDNAs were expressed in Escherichia coli, and the ability of these enzymes to metabolize both paclitaxel and arachidonic acid was assessed. Recombinant CYP2C8*3 was defective in the metabolism of both substrates. The turnover number of CYP2C8*3 for paclitaxel was 15% of CPY2C8*1. CYP2C8*2 had a two-fold higher K-m and two-fold lower intrinsic clearance for paclitaxel than CYP2C8*1. CYP2C8*3 was also markedly defective in the metabolism of arachidonic acid to 11,12- and 14,15-EET (turnover numbers 35-40% that of CYP2C8*1). Thus, CYP2C8*3 is defective in the metabolism of two important CYP2C8 substrates: the anticancer drug paclitaxel and the physiologically important compound arachidonic acid. This polymorphism has important clinical and physiological implications in individuals homozygous for this allele. Pharmacogenetics 11:597-607 (C) 2001 Lippincott Williams & Wilkins. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pulm & Pathobiol, Res Triangle Pk, NC 27709 USA. RP NIEHS, Lab Pharmacol & Chem, MD A303,POB 12233, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012; OI Coulter, Sherry/0000-0002-2732-3470 NR 53 TC 318 Z9 338 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD OCT PY 2001 VL 11 IS 7 BP 597 EP 607 DI 10.1097/00008571-200110000-00006 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 483LF UT WOS:000171636300006 PM 11668219 ER PT J AU Hecht, AM Horkay, F Geissler, E AF Hecht, AM Horkay, F Geissler, E TI Structure of polymer solutions containing fumed silica SO PHYSICAL REVIEW E LA English DT Article ID RIGID MATRIX; DYNAMICS; SCATTERING; GELS AB Small angle neutron scattering is employed to estimate the interactions in complex multicomponent systems. The method is applied to describe a ternary system, poly(dimethyl siloxane) toluene with silica filler particles. Contrast variation by solvent deuteration is used to distinguish the three different partial structure factors of filled polymer samples, S-pp(q), S-pf(q), and S-ff(q), where the subscripts p and f refer to polymer and filler. This procedure allows changes to be detected in the distribution of the polymer close to the solid surface. Independent dynamic light scattering measurements are used to validate the method, A comparison is made between the behavior of different filled poly(dimethyl siloxane) PDMS samples. It is found that the polymer distribution is perturbed in the vicinity of the solid surfaces. In the case of weak interactions, the solvent removes the polymer almost completely from the filler particles, while, when the interaction is strong, the surface remains covered. C1 Univ Grenoble 1, CNRS, UMR 5588, Spectrometrie Phys Lab, F-38402 St Martin Dheres, France. NIH, Bethesda, MD 20892 USA. RP Hecht, AM (reprint author), Univ Grenoble 1, CNRS, UMR 5588, Spectrometrie Phys Lab, Boite Postale 87, F-38402 St Martin Dheres, France. EM anne-marie.hecht@ujf-grenoble.fr; horkay@helix.nih.gov; erik.geissler@ufj-grenoble.fr NR 11 TC 9 Z9 10 U1 1 U2 4 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1063-651X J9 PHYS REV E JI Phys. Rev. E PD OCT PY 2001 VL 64 IS 4 AR 041402 DI 10.1103/PhysRevE.64.041402 PN 1 PG 6 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 483RE UT WOS:000171649000023 PM 11690021 ER PT J AU Witters, I Moerman, P Muenke, M Van Assche, FA Devriendt, K Legius, E Van Schoubroeck, D Fryns, JP AF Witters, I Moerman, P Muenke, M Van Assche, FA Devriendt, K Legius, E Van Schoubroeck, D Fryns, JP TI Semilobar holoprosencephaly in a 46,XY female fetus SO PRENATAL DIAGNOSIS LA English DT Article DE CNS malformation; holoprosencephaly; sex-reversal; prenatal diagnosis ID LEMLI-OPITZ-SYNDROME; MIDDLE INTERHEMISPHERIC FUSION; CHOLESTEROL; DIAGNOSIS; MUTATIONS; DEFECT AB We report the prenatal echographic diagnosis of holoprosencephaly (HPE) at 11 weeks' gestation. Fetopathological examination revealed an unusual variant of semilobar HPE with middle interhemispheric fusion associated with sex-reversal: 46,XY normal male karyotype, normal external and internal female genitalia and streak gonads. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium. Univ Louvain, Dept Obstet & Gynecol, Louvain, Belgium. Univ Louvain, Dept Pathol, Louvain, Belgium. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Fryns, JP (reprint author), Univ Louvain, Ctr Human Genet, Herestr 49, B-3000 Louvain, Belgium. NR 20 TC 4 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD OCT PY 2001 VL 21 IS 10 BP 839 EP 841 DI 10.1002/pd.151 PG 3 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 490LQ UT WOS:000172053700008 PM 11746125 ER PT J AU Tsai, CJ Nussinov, R AF Tsai, CJ Nussinov, R TI The building block folding model and the kinetics of protein folding SO PROTEIN ENGINEERING LA English DT Article DE anatomy; building block; folding kinetics; folding model; protein folding; two-state versus three-state ID TRANSITION-STATE; 2-STATE TRANSITION; ENERGY LANDSCAPES; BINDING CASCADES; SH3 DOMAIN; UNITS; ACYLPHOSPHATASE; INTERMEDIATE; CONSERVATION; STABILITY AB Here we show that qualitatively, the building blocks folding model accounts for three-state versus the two-state protein folding. Additionally, it is consistent with the faster versus slower folding rates of the two-state proteins. Specifically, we illustrate that the building blocks size, their mode of associations in the native structure, the number of ways they can combinatorially assemble, their population times and the way they are split in the iterative, step-by-step structural dissection which yields the anatomy trees, explain a broad range of folding rates. We further show that proteins with similar general topologies may have different folding pathways, and hence different folding rates. On the other hand, the effect of mutations resembles that of changes in conditions, shifting the population times and hence the energy landscapes. Hence, together with the secondary structure type and the extent of local versus non-local interactions, a coherent, consistent rationale for folding kinetics can be outlined, in agreement with experimental results. Given the native structure of a protein, these guidelines enable a qualitative prediction of the folding kinetics. We further describe these in the context of the protein folding energy landscape. Quantitatively, in principle, the diffusion-collision model for the building block association can be used. However, the folding rates of the building blocks and traps in their formation and association, need to be considered. C1 NCI, Intramural Res Support Program, SAIC Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sch Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Intramural Res Support Program, SAIC Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 43 TC 16 Z9 16 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD OCT PY 2001 VL 14 IS 10 BP 723 EP 733 DI 10.1093/protein/14.10.723 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 504UD UT WOS:000172873500002 PM 11739890 ER PT J AU Wulfkuhle, JD McLean, KC Paweletz, CP Sgroi, DC Trock, BJ Steeg, PS Petricoin, EF AF Wulfkuhle, JD McLean, KC Paweletz, CP Sgroi, DC Trock, BJ Steeg, PS Petricoin, EF TI New approaches to proteomic analysis of breast cancer SO PROTEOMICS LA English DT Review DE breast cancer; surface-enhanced laser desorption/ionization two-dimensional polyacrylamide gel electrophoresis; laser capture microdissection pharmacoproteomics; review ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; LASER CAPTURE MICRODISSECTION; MAMMARY EPITHELIAL-CELLS; PROTEIN EXPRESSION; POLYPEPTIDE EXPRESSION; DUCTAL CARCINOMA; RISK; HYPERPLASIA; PROGRESSION; DISEASE AB Proteomic based approaches are beginning to be utilized to study the natural history and treatment of breast cancer. A variety of proteomics approaches are under study, and are summarized herein. Two-dimensional gel electrophoresis (2D-PAGE) is still the foundation of most proteomics studies. We present an analysis of 2D-PAGE studies reported to date in breast cancer, including those examining normal/tumor differences and selected populations of breast cells. Newer technologies such as laser capture microdissection and highly sensitive mass spectrometry methods are currently being used together to identify greater numbers of lower abundance proteins that are differentially expressed between defined cell populations. Novel technologies still in developmental phases will enable identification of validated targets in small biopsy specimens, including high density protein arrays, antibody arrays and lysate arrays. Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) analysis enables the high throughput characterization of lysates from very few tumor cells and may be best suited for clinical biomarker studies. We present SELDI-TOF data herein to show the accuracy of the method in a small cohort of breast tumors, as well as its potential discriminatory capability. Such technologies are expected to supplement our armamentarium of mRNA-based assays, and provide critical information on protein levels and post-translational modifications. C1 US FDA, NCI,CBER, Div Therapeut Prod, Clin Proteom Program, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Pathol Lab, Womens Canc Sect, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. Georgetown Univ, Dept Chem, Washington, DC 20057 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02114 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Petricoin, EF (reprint author), US FDA, NCI,CBER, Div Therapeut Prod, Clin Proteom Program, Bldg 29A,Room 2B02,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 62 TC 151 Z9 154 U1 1 U2 13 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD OCT PY 2001 VL 1 IS 10 BP 1205 EP 1215 DI 10.1002/1615-9861(200110)1:10<1205::AID-PROT1205>3.3.CO;2-O PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486WF UT WOS:000171839400004 PM 11721633 ER PT J AU Knezevic, V Leethanakul, C Bichsel, VE Worth, JM Prabhu, VV Gutkind, JS Liotta, LA Munson, PJ Petricoin, EF Krizman, DB AF Knezevic, V Leethanakul, C Bichsel, VE Worth, JM Prabhu, VV Gutkind, JS Liotta, LA Munson, PJ Petricoin, EF Krizman, DB TI Proteomic profiling of the cancer microenvironment by antibody arrays SO PROTEOMICS LA English DT Article DE oral cavity cancer; antibody array; microenvironment ID LASER-CAPTURE MICRODISSECTION; ORGAN-SPECIFIC FIBROBLASTS; SQUAMOUS-CELL CARCINOMA; GENE-EXPRESSION; CDNA MICROARRAY; IN-VIVO; PROGRESSION; IMMUNOASSAY; FABRICATION; STATISTICS AB Critical changes in protein expression that enable tumors to initiate and progress originate in the local tissue microenvironment, and there are increasing indications that these microenviron mental alterations in protein expression play critical roles in shaping and directing this process. As a model to better understand how patterns of protein expression shape the tissue microenvironment, we analyzed protein expression in tissue derived from squamous cell carcinoma of the oral cavity through an antibody microarray approach for high-throughput proteomic analysis. Utilizing laser capture microdissection to procure total protein from specific microscopic cellular populations, we demonstrate that quantitative, and potentially qualitative, differences in expression patterns of multiple proteins within epithelial cells reproducibly correlate with oral cavity tumor progression. Furthermore, differential expression of multiple proteins was also found in stromal cells surrounding and adjacent to regions of diseased epithelium that directly correlated with tumor progression of the epithelium. Most of the proteins identified in both cell types are involved in signal transduction pathways, thus we hypothesize that extensive molecular communication involving complex cellular signaling between epithelium and stroma play a key role in driving oral cavity cancer progression. C1 NCI, Adv Technol Ctr 134F, Pathol Lab, NIH, Gaithersburg, MD 20877 USA. NCI, Canc Genome Anat Project, NIH, Bethesda, MD USA. SAIC, Frederick, MD USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. US FDA, CBER, Div Therapeut Prod, Tissue Proteom Unit, Bethesda, MD 20014 USA. RP Krizman, DB (reprint author), NCI, Adv Technol Ctr 134F, Pathol Lab, NIH, 8717 Grovement Circle, Gaithersburg, MD 20877 USA. RI Gutkind, J. Silvio/A-1053-2009 FU NCI NIH HHS [N01-CO-56000] NR 37 TC 220 Z9 228 U1 1 U2 8 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD OCT PY 2001 VL 1 IS 10 BP 1271 EP 1278 DI 10.1002/1615-9861(200110)1:10<1271::AID-PROT1271>3.3.CO;2-Y PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486WF UT WOS:000171839400009 PM 11721638 ER PT J AU Shekhar, A McCann, UD Meaney, MJ Blanchard, DC Davis, M Frey, KA Liberzon, I Overall, KL Shear, MK Tecott, LH Winsky, L AF Shekhar, A McCann, UD Meaney, MJ Blanchard, DC Davis, M Frey, KA Liberzon, I Overall, KL Shear, MK Tecott, LH Winsky, L TI Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders SO PSYCHOPHARMACOLOGY LA English DT Review DE stress; panic; obsessive-compulsive disorder; PTSD; startle; maternal grooming; mutant mice; ethological models; benzodiazepine ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; FEAR-POTENTIATED STARTLE; CORTICOTROPIN-RELEASING FACTOR; HIPPOCAMPAL GLUCOCORTICOID RECEPTORS; PITUITARY-ADRENAL AXIS; ELEVATED PLUS-MAZE; EARLY-LIFE EVENTS; PANIC DISORDER; BASOLATERAL AMYGDALA AB Rationale: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. Objectives: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. Methods: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. Results: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. Conclusions: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors. C1 NIMH, Bethesda, MD 20892 USA. Indiana Univ Penn, Indiana, PA USA. Johns Hopkins Univ, Baltimore, MD USA. McGill Univ, Montreal, PQ, Canada. Univ Hawaii, Honolulu, HI 96822 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Michigan, Ann Arbor, MI 48109 USA. VAMC, Ann Arbor, MI USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Winsky, L (reprint author), NIMH, 6001 Execut Blvd MSC 9641, Bethesda, MD 20892 USA. NR 151 TC 64 Z9 68 U1 11 U2 15 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2001 VL 157 IS 4 BP 327 EP 339 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 483UW UT WOS:000171655100001 PM 11605091 ER PT J AU De Roos, AJ Arab, L Renner, JB Craft, N Luta, G Helmick, CG Hochberg, MC Jordan, JM AF De Roos, AJ Arab, L Renner, JB Craft, N Luta, G Helmick, CG Hochberg, MC Jordan, JM TI Serum carotenoids and radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project SO PUBLIC HEALTH NUTRITION LA English DT Article DE carotenoids; knee osteoarthritis; radiographic osteoarthritis; antioxidants; biomarkers ID BETA-CAROTENE; ANTIOXIDANT VITAMINS; RISK-FACTORS; DISEASE; LUTEIN; MICRONUTRIENTS; PREVENTION; SUPPLEMENT; ARTHRITIS; PROTECT AB Objective: Antioxidant intake has been associated with less progression of radiographic knee osteoarthritis (OA), but studies of carotenoid biomarkers and OA have not been done. We examined associations between serum concentrations of nine naturally occurring carotenoids and radiographic knee OA. Design: The study design was matched case-control. Sera were analysed by high-performance liquid chromatography for nine carotenoids: lutein, zeaxanthin, alpha- and beta-cryptoxanthin, trans- and cis-lycopene, alpha-carotene, and trans- and cis-beta-carotene. Conditional logistic regression was used to estimate the association between tertiles of each carotenoid and radiographic knee OA, independent of body mass index, education, serum cholesterol, and the other carotenoids. Setting: Johnston County, North Carolina, United States of America. Subjects: Two-hundred cases with radiographic knee OA (Kellgren-Lawrence grades greater than or equal to2) and 200 controls (Kellgren-Lawrence grade=0) were randomly selected from the Johnston County Osteoarthritis Project, and were matched on age, gender and race. Results: Participants with serum levels of lutein or beta-cryptoxanthin in the highest tertile were approximately 70% less likely to have knee OA than controls (odds ratio (OR) [95% confidence interval (CI)] = 0.28 [0.11, 0.73] and 0.36 [0.14, 0.95], respectively). Those in the highest tertile of trans-beta-carotene (OR = 6.40 [1.86, 22.1]) and zeaxanthin (OR = 3.06 [1.19, 7.85]) were more likely to have knee OA. Conclusions: While certain carotenoids may protect against knee OA, others may increase the odds of knee OA. Further study of carotenoids and knee OA are warranted before clinical recommendations about these substances and knee OA can be made. C1 Univ N Carolina, Thurston Arthritis Res Ctr, Dept Epidemiol & Nutr, Sch Publ Hlth, Chapel Hill, NC 27599 USA. NCI, Bethesda, MD 20892 USA. Univ N Carolina, Thurston Arthritis Res Ctr, Dept Radiol, Sch Med, Chapel Hill, NC 27599 USA. Craft Technol Inc, Wilson, NC USA. Univ N Carolina, Sch Publ Hlth, Thurston Arthritis Res Ctr, Dept Biostat, Chapel Hill, NC 27599 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Jordan, JM (reprint author), Univ N Carolina, Thurston Arthritis Res Ctr, Dept Epidemiol & Nutr, Sch Publ Hlth, 3310 Doc J Thurston Jr Bldg,CB 7330, Chapel Hill, NC 27599 USA. FU NIAMS NIH HHS [5-P60-AR30701]; NIDDK NIH HHS [DK56350] NR 35 TC 12 Z9 12 U1 0 U2 2 PU C A B I PUBLISHING PI WALLINGFORD PA C/O PUBLISHING DIVISION, WALLINGFORD OX10 8DE, OXON, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD OCT PY 2001 VL 4 IS 5 BP 935 EP 942 DI 10.1079/PHN2001132 PG 8 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 520TY UT WOS:000173798500002 PM 11784406 ER PT J AU Smith, PJS Hengstenberg, A Jung, SK AF Smith, PJS Hengstenberg, A Jung, SK TI Measuring molecular flux in the diffusionary boundary layer of cells and tissues SO RADIATION RESEARCH LA English DT Meeting Abstract ID PROTON C1 NIH, Biocurrents Res Ctr, Marine Biol Lab, NCRR, Woods Hole, MA 02543 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2001 VL 156 IS 4 BP 436 EP 437 PG 2 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 478DE UT WOS:000171327000017 ER PT J AU Rogakou, EP Redon, C Pilch, DR Sedelnikova, O Bonner, WM AF Rogakou, EP Redon, C Pilch, DR Sedelnikova, O Bonner, WM TI Antibody to gamma-H2A-S((4C))Q detects DNA double-strand breaks SO RADIATION RESEARCH LA English DT Meeting Abstract C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2001 VL 156 IS 4 BP 442 EP 442 PG 1 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 478DE UT WOS:000171327000024 ER PT J AU Kolettas, E Muir, HI Barrett, JC Hardingham, TE AF Kolettas, E Muir, HI Barrett, JC Hardingham, TE TI Chondrocyte phenotype and cell survival are regulated by culture conditions and by specific cytokines through the expression of Sox-9 transcription factor SO RHEUMATOLOGY LA English DT Article DE chondrocytes; gene expression; cytokines; apoptosis; Sox9 ID II COLLAGEN GENE; HUMAN ARTICULAR-CARTILAGE; SRY-RELATED GENE; AUTOSOMAL SEX REVERSAL; TUMOR-SUPPRESSOR GENE; HAMSTER EMBRYO CELLS; GROWTH FACTOR-I; NEOPLASTIC PROGRESSION; CAMPOMELIC DYSPLASIA; MESSENGER-RNAS AB Objective. To investigate the effects of culture conditions, serum and specific cytokines such as insulin-like growth factor (IGF) 1 and interleukin (IL) 1 alpha on phenotype and cell survival in cultures of Syrian hamster embryonic chondrocyte-like cells (DES4(+).2). Methods. Proteins and RNA extracted from subconfluent and confluent early- and late-passage DES4(+).2 cells cultured in the presence or absence of serum and IL-1 alpha or IGF-1 or both cytokines together were analysed for the expression of chondrocyte-specific genes and for the chondrogenic transcription factor Sox-9 by Western and Northern blotting. Apoptosis was assessed by agarose get electrophoresis of labelled low-molecular weight DNA extracted from DES4(+).2 cells and another Syrian hamster embryonic chondrocyte-like cell line, 10W(+).1, cultured under the different conditions and treatments. Results. Early passage DES4(+).2 cells expressed chondrocyte-specific molecules such as collagen types alpha1(II) and alpha1(IX), aggrecan, biglycan and link protein and collagen types alpha1(I) and alpha1(X) mRNAs, suggesting a prehypertrophic chondrocyte-like phenotype. The expression of all genes investigated was cell density- and serum-dependent and was low to undetectable in cell populations from later passages. Early-passage DES4(+).2 and 10W(+).1 cells survived when cultured at low cell density, but died by apoptosis when cultured at high cell density in the absence of serum or IGF-1. IGF-1 and IL-1 alpha had opposite and antagonistic effects on the chondrocyte phenotype and survival. Whereas LL-lot acting alone suppressed cartilage-specific gene expression without significantly affecting cell survival, IGF-1 increased the steady-state mRNA levels and relieved the IL-1 alpha -induced suppression of all the chondrocyte-specific genes investigated, it also enhanced chondrocyte survival. Suppression of the chondrocyte phenotype by the inflammatory cytokine IL-1 alpha correlated with marked down-regulation of the transcription factor Sox-9, which was relieved by IGF-1. The expression of the Sox9 gene was closely correlated with the expression of the chondrocyte-specific genes under all conditions and treatments. Conclusions, The results suggest that the effects of cartilage anabolic and catabolic cytokines IGF-1 and IL-1 alpha on the expression of the chondrocyte phenotype are mediated by Sox-9. As Sox-9 appears to be essential for matrix production, the potent effect of IL-1 alpha in suppressing Sox-9 expression may limit the ability of cartilage to repair during inflammatory joint diseases. C1 Univ Manchester, Sch Biol Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kolettas, E (reprint author), Univ Ioannina, Sch Med, Physiol Lab, Cell & Mol Physiol Unit, GR-45110 Ioannina, Greece. NR 74 TC 55 Z9 58 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD OCT PY 2001 VL 40 IS 10 BP 1146 EP 1156 DI 10.1093/rheumatology/40.10.1146 PG 11 WC Rheumatology SC Rheumatology GA 485PY UT WOS:000171764600012 PM 11600745 ER PT J AU Arikawa-Hirasawa, E Yamada, Y AF Arikawa-Hirasawa, E Yamada, Y TI Roles of perlecan in development and disease: studies in knockout mice and human disorders SO SEIKAGAKU LA Japanese DT Article ID HEPARAN-SULFATE PROTEOGLYCAN; FIBROBLAST GROWTH-FACTOR; BASEMENT-MEMBRANES; EXPRESSION; CARTILAGE; FIBULIN-2; MATRICES; NIDOGEN; BINDS; GENE C1 Natl Inst Dent Craniofaical Res, Mol Biol Sect, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NR 18 TC 1 Z9 2 U1 0 U2 1 PU JAPANESE BIOCHEMICAL SOC PI TOKYO PA ISHIKAWA BLDG-3F, 25-16 HONGO-5-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0037-1017 J9 SEIKAGAKU JI Seikagaku PD OCT PY 2001 VL 73 IS 10 BP 1257 EP 1261 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 492EK UT WOS:000172155300009 PM 11725543 ER PT J AU Deng, CX Brodie, SG AF Deng, CX Brodie, SG TI Knockout mouse models and mammary tumorigenesis SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE cell cycle checkpoint; DNA damage repair; genetic stability; conditional knockout; breast cancer ID TUMOR-SUPPRESSOR GENE; CANCER SUSCEPTIBILITY GENE; EARLY EMBRYONIC LETHALITY; BREAST-CANCER; TRANSGENIC MICE; ATAXIA-TELANGIECTASIA; DNA-REPAIR; APC GENE; TARGETED DISRUPTION; THYMIC LYMPHOMA AB The generation of transgenic mice overexpressing activated forms of oncogenes has greatly advanced our understanding into their roles in mammary tumor initiation, promotion and progression. However, targeted disruption of tumor suppressor genes often results in lethality at stages prior to mammary tumor formation. This obstacle can now be overcome using several approaches including conditional knockouts that delete genes of interest in a spatial and temporal manner. This review summarizes recent studies on tumor suppressor genes, including APC, ATM, BRCA1, BRCA2, PTEN and p53, in knockout mouse models and our understanding of the possible mechanisms underlying mammary tumorigenesis. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 52 TC 32 Z9 33 U1 1 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2001 VL 11 IS 5 BP 387 EP 394 DI 10.1006/scbi.2001.0394 PG 8 WC Oncology SC Oncology GA 482DZ UT WOS:000171560700008 PM 11562181 ER PT J AU Monni, O Hyman, E Mousses, S Barlund, M Kallioniemi, A Kallioniemi, OP AF Monni, O Hyman, E Mousses, S Barlund, M Kallioniemi, A Kallioniemi, OP TI From chromosomal alterations to target genes for therapy: integrating cytogenetic and functional genomic views of the breast cancer genome SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE cDNA microarray; CGH microarray; tissue microarray; breast cancer; amplification ID CELL-LINES; EXPRESSION PATTERNS; HYBRIDIZATION ANALYSIS; COMPLEMENTARY-DNA; CDNA MICROARRAYS; AMPLIFICATION; TUMORS; CARCINOMAS; KINASE; CGH AB A vast number of recurrent chromosomal alterations have been implicated in cancer development and progression. However, most of the genes involved in recurrent chromosomal alterations in solid tumors remain unknown, despite the recent substantial progress in genomic research and availability of high-throughput technologies. For example, it is now possible to quickly identify large numbers of differentially expressed genes in cancer specimens using cDNA microarrays. Integration of this 'functional genomic view' of the cancer genome with the 'cytogenetic view' could lead to the identification of genes Playing a critical role in cancer development and progression. In this review, we illustrate how the combination of three different microarray technologies, cDNA, CGH, and tissue microarrays, makes it possible to directly identify genes involved in chromosomal rearrangements in cell line model systems and then rapidly explore their significance as potential diagnostic and therapeutic targets in human Primary breast cancer Progression. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Biomedicum Biochip Ctr, FIN-00014 Helsinki, Finland. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. Natl Inst Hlth Res Scholar, Howard Hughes Med Inst, Bethesda, MD 20814 USA. Tampere Univ, Canc Genet Lab, FIN-33521 Tampere, Finland. Tampere Univ Hosp, FIN-33521 Tampere, Finland. RP Kallioniemi, OP (reprint author), NHGRI, Canc Genet Branch, NIH, 49 Convent Dr,Room 4A24, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 33 TC 19 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2001 VL 11 IS 5 BP 395 EP 401 DI 10.1006/scbi.2001.0395 PG 7 WC Oncology SC Oncology GA 482DZ UT WOS:000171560700009 PM 11562182 ER PT J AU Brown, P AF Brown, P TI Creutzfeldt-Jakob disease: Blood infectivity and screening tests SO SEMINARS IN HEMATOLOGY LA English DT Article; Proceedings Paper CT Symposium on Current Issues in Hemostasis and Transfusion Medicine CY NOV, 2000 CL WASHINGTON, D.C. ID PRION PROTEIN; TRANSFUSION; SURVEILLANCE C1 NINCDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. RP Brown, P (reprint author), NINCDS, Cent Nervous Syst Studies Lab, NIH, Bldg 36,Room 4A-05,36 Convent Dr,MSC 4122, Bethesda, MD 20892 USA. NR 21 TC 18 Z9 19 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2001 VL 38 IS 4 SU 9 BP 2 EP 6 DI 10.1053/shem.2001.28832 PG 5 WC Hematology SC Hematology GA 511XP UT WOS:000173291100002 PM 11685719 ER PT J AU Steinberg, MH Rodgers, GP AF Steinberg, MH Rodgers, GP TI Pathophysiology of sickle cell disease: Role of cellular and genetic modifiers SO SEMINARS IN HEMATOLOGY LA English DT Review ID GAMMA-GLOBIN-GENE; HETEROCELLULAR HEREDITARY PERSISTENCE; STAGE SELECTOR ELEMENT; BETA-S-CHROMOSOMES; ENDOTHELIAL-CELLS; FETAL HEMOGLOBIN; TRANSCRIPTION FACTOR; VASCULAR ENDOTHELIUM; SEQUENCE VARIATIONS; CLUSTER HAPLOTYPES C1 Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Univ, Med Ctr, Ctr Excellence Sickle Cell Dis, Boston, MA USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Steinberg, MH (reprint author), 88 E Newton St, Boston, MA 02118 USA. NR 105 TC 47 Z9 51 U1 3 U2 9 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2001 VL 38 IS 4 BP 299 EP 306 DI 10.1053/shem.2001.27570 PG 8 WC Hematology SC Hematology GA 485FA UT WOS:000171741800001 PM 11605164 ER PT J AU Gladwin, MT Schechter, AN AF Gladwin, MT Schechter, AN TI Nitric oxide therapy in sickle cell disease SO SEMINARS IN HEMATOLOGY LA English DT Article ID ACUTE CHEST SYNDROME; PRIMARY PULMONARY-HYPERTENSION; BLOOD-FLOW; RIBONUCLEOTIDE REDUCTASE; ENDOTHELIAL ADHESIVENESS; S-NITROSOHEMOGLOBIN; OXYGEN-AFFINITY; RELAXING FACTOR; RISK-FACTORS; P-SELECTIN C1 Warren G Magnuson Clin Ctr, Crit Care Med Dept, Bethesda, MD 20892 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD USA. RP Gladwin, MT (reprint author), Warren G Magnuson Clin Ctr, Crit Care Med Dept, Bldg 10,Room 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 92 TC 47 Z9 51 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2001 VL 38 IS 4 BP 333 EP 342 DI 10.1053/shem.2001.27574 PG 10 WC Hematology SC Hematology GA 485FA UT WOS:000171741800005 PM 11605168 ER PT J AU Tisdale, J Sadelain, M AF Tisdale, J Sadelain, M TI Toward gene therapy for disorders of globin synthesis SO SEMINARS IN HEMATOLOGY LA English DT Review ID HUMAN BETA-GLOBIN; HEMATOPOIETIC STEM-CELLS; LOCUS-CONTROL REGION; DOMINANT CONTROL REGION; BONE-MARROW-CELLS; FIBRONECTIN FRAGMENT CH-296; COLONY-STIMULATING FACTOR; SELECTIVE AMPLIFIER GENE; I HYPERSENSITIVE SITE; LONG-TERM ENGRAFTMENT C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Gene Transfer & Gene Express Lab, New York, NY 10021 USA. RP Tisdale, J (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL-66952, HL-57612] NR 120 TC 25 Z9 27 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2001 VL 38 IS 4 BP 382 EP 392 DI 10.1053/shem.2001.27571 PG 11 WC Hematology SC Hematology GA 485FA UT WOS:000171741800011 PM 11605174 ER PT J AU McAfee, JG AF McAfee, JG TI The impact of recent advances in immunology and cancer therapy on nuclear medicine SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID COLONY-STIMULATING FACTOR; PULSED DENDRITIC CELLS; FACTOR GM-CSF; RHEUMATOID-ARTHRITIS; METASTATIC DISEASE; BREAST-CANCER; MIGRATION; ANTIGEN; IMMUNOTHERAPY; VACCINATION AB The explosive expansion of knowledge in immunology in recent decades has already affected the research and practice of nuclear medicine in several ways. New hematopoietic cells have been isolated and their functions discovered, including hematopoietic stem cells and dendritic cells (DCs). Many new humeral factors have been found that have potent effects on cells, including cytokines, growth factors, and specialized proteins. Radiolabeled compounds are needed to follow the pharmacodynamics of the humeral factors and to follow the migration of mobile cells in animals and humans. In this article, only DCs, cytokines, and growth factors used clinically are discussed. DCs are essential for defense against infectious diseases. Autologous DCs cultured for a week and pulsed with tumor antigens have already proved highly immunogenic compared with other methods for activating cytotoxic T cells, and preliminary studies suggest that DCs are more potent for tumor cell killing than monoclonal antibodies. DCs, unfortunately, also play an important role in causing certain human diseases. In allograft transplants, residual donor DCs are responsible for the cellular rejection; if they could be eliminated, rejection could be prevented. These cells are also detrimental in rheumatoid arthritis, other autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Cytokines such as interleukin-2 and such growth factors as granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, administered to patients with malignancies to alleviate the leukopenia of chemotherapy agents, frequently alter the tissue distribution of radiopharmaceuticals; these alterations may be confused with disease. Copyright (C) 2001 by W.B. Saunders Company. C1 NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. RP McAfee, JG (reprint author), NIH, Dept Nucl Med, Ctr Clin, Bldg 10,Room 1C401,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 50 TC 2 Z9 2 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 0001-2998 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD OCT PY 2001 VL 31 IS 4 BP 342 EP 349 DI 10.1053/snuc.2001.26198 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 490AJ UT WOS:000172025700013 PM 11710776 ER PT J AU Tan, AR Swain, SM AF Tan, AR Swain, SM TI Novel agents: Clinical trial design SO SEMINARS IN ONCOLOGY LA English DT Review ID PHASE-I TRIAL; ANTICANCER AGENTS; END-POINT; KINASE; O-6-BENZYLGUANINE; INHIBITION; QUERCETIN C1 NCI, Canc Therapeut Branch, Bethesda, MD 20889 USA. RP Swain, SM (reprint author), NCI, Canc Therapeut Branch, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 21 TC 4 Z9 5 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2001 VL 28 IS 5 SU 16 BP 148 EP 153 DI 10.1053/sonc.2001.28556 PG 6 WC Oncology SC Oncology GA 492JJ UT WOS:000172164400018 PM 11706406 ER PT J AU Jones, JM Gellert, M Yang, W AF Jones, JM Gellert, M Yang, W TI A Ku bridge over broken DNA SO STRUCTURE LA English DT Article ID DEPENDENT PROTEIN-KINASE; V(D)J RECOMBINATION; END; REPAIR; COMPLEX AB The Ku heterodimer is essential for the nonhomologous end-joining pathway of DNA double-strand break repair; it both protects the broken ends and recruits some of the many proteins required to complete repair. The recently determined structure of Ku provides insights into how it can both bind to the DNA ends and allow access by the other proteins required to rejoin them. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 5,Rm B1-03, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 19 TC 32 Z9 33 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2001 VL 9 IS 10 BP 881 EP 884 DI 10.1016/S0969-2126(01)00658-X PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 482XZ UT WOS:000171603700001 PM 11591342 ER PT J AU Bewley, CA AF Bewley, CA TI Solution structure of a cyanovirin-N : Man alpha 1-2Man alpha complex: Structural basis for high-affinity carbohydrate-mediated binding to gp120 SO STRUCTURE LA English DT Article DE NMR; dipolar couplings; HIV fusion; viral entry; lectin; oligomannose ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INACTIVATING PROTEIN; CYANOVIRIN-N; ENVELOPE GLYCOPROTEIN; DIPOLAR COUPLINGS; NMR; TYPE-1; CD4; OLIGOSACCHARIDE; INHIBITION AB Background: Cyanovirin-N (CVN) is a novel, 11 kDa cyanobacterial protein that potently inhibits viral entry by diverse strains of HIV through high-affinity carbohydrate-mediated interactions with the viral envelope glycoprotein gp120. CVN contains two symmetry-related carbohydrate binding sites of differing affinities that selectively bind to Man(8) D1 D3 and Man(9) with nanomolar affinities, the carbohydrates that also mediate CVN:gp120 binding. High-resolution structural studies of CVN in complex with a representative oligosaccharide are desirable for understanding the structural basis for this unprecedented specificity. Results: We have determined by multidimensional heteronuclear NMR spectroscopy the three-dimensional solution structure of CVN in complex with two equivalents of the disaccharide Man alpha1-2Man alpha, a high-affinity ligand which represents the terminal-accessible disaccharide present in Man(8) D1 D3 and Man(9). The structure reveals that the bound disaccharide adopts the stacked conformation, thereby explaining the selectivity for Mans D1 D3 and Man(9) over other oligomannose structures, and presents two novel carbohydrate binding sites that account for the differing affinities of the two sites. The high-affinity site comprises a deep pocket that nearly envelops the disaccharide, while the lower-affinity site comprises a semicircular cleft that partially surrounds the disaccharide. The similar to 40 Angstrom spacing of the two binding sites provides a simple model for CVN:gp120 binding. Conclusions: The CVN:Man alpha1-2Man alpha. complex provides the first high-resolution structure of a mannose-specific protein-carbohydrate complex with nanomolar affinity and presents a new carbohydrate binding motif, as well as a new class of carbohydrate binding protein, that facilitates divalent binding via a monomeric protein. C1 NIDDKD, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. NR 41 TC 100 Z9 103 U1 3 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2001 VL 9 IS 10 BP 931 EP 940 DI 10.1016/S0969-2126(01)00653-0 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 482XZ UT WOS:000171603700007 PM 11591348 ER PT J AU Horne, MK AF Horne, MK TI Secondary prophylaxis with low molecular weight heparin: The dose? SO THROMBOSIS AND HAEMOSTASIS LA English DT Letter ID DEEP-VEIN THROMBOSIS; LONG-TERM TREATMENT; SUBCUTANEOUS HEPARIN; VENOUS THROMBOSIS; RANDOMIZED TRIAL; WARFARIN; ACENOCOUMAROL; PREVENTION C1 NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Serv Hematol, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Serv Hematol, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD OCT PY 2001 VL 86 IS 4 BP 1129 EP 1129 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 484LJ UT WOS:000171691400040 PM 11686343 ER PT J AU Horne, MK Williams, SB Gahl, WA Rick, ME AF Horne, MK Williams, SB Gahl, WA Rick, ME TI Evaluation of the Xylum clot signature analyzer in normal subjects and patients with the Hermansky-Pudlak syndrome SO THROMBOSIS RESEARCH LA English DT Article ID HEMOSTASIS AB Laboratory evaluation of platelet function is compromised by the unphysiologic conditions inherent in standard platelet aggregometry [1]. In an attempt to mimic physiology more closely, Gorog and Ahmed [2] developed an instrument that tested anticoagulated whole blood perfused through a plastic tube under controlled pressure. As the blood flowed, the tube was punched with a needle to simulate a vessel wound. "Bleeding" from the tube was detected by a marked drop in intraluminal pressure. When the "bleeding" stopped, intraluminal pressure returned to baseline. More recently, engineers at Xylum (Scarsdale, NY) adapted this "tube bleeding time" for use with mn-anticoagulated blood, thereby eliminating a major distortion of physiology. This technique was incorporated in an instrument, the "Clot Signature Analyzer" (CSA), which also measures the clotting time (CT) of whole non-anticoagulated blood passing through a second tube containing a collagen fiber [3]. Both tests are sensitive to potent inhibitors of platelet function and severe platelet abnormalities such as Glanzmann's thrombasthenia [4-6]. Although reference ranges have been determined for the measurements made by the CSA, the reproducibility of the tests and the effect of thrombocytopenia on the results have not been published. We felt that these were important issues to explore in order to judge the suitability of the instrument for clinical use. We also had an opportunity to apply the instrument to the evaluation of a group of patients with the Hermansky-Pudlak syndrome (HPS), a disorder of oculocutaneous albinism and absent platelet dense granules, to determine how sensitive the CSA is to this specific form of relatively mild platelet dysfunction [7-9]. C1 WG Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Dept Clin Pathol, Serv Hematol, Rm 2C306,Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD OCT 1 PY 2001 VL 104 IS 1 BP 57 EP 63 DI 10.1016/S0049-3848(01)00340-1 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 478QD UT WOS:000171356100007 PM 11583739 ER PT J AU Qu, W Kasprzak, KS Kadiiska, M Liu, J Chen, H Maciag, A Mason, RP Waalkes, MP AF Qu, W Kasprzak, KS Kadiiska, M Liu, J Chen, H Maciag, A Mason, RP Waalkes, MP TI Mechanisms of arsenic-induced cross-tolerance to nickel cytotoxicity, genotoxicity, and apoptosis in rat liver epithelial cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE nickel; arsenic; lipid peroxidation; free radical; DNA damage; apoptosis; GSH ID LIPID-PEROXIDATION PRODUCTS; OXIDATIVE DAMAGE; REACTIVE OXYGEN; CULTURED-CELLS; DNA; CARCINOGENICITY; GLUTATHIONE; INHIBITION; SUBSULFIDE; MANGANESE AB The purpose of the present study was to investigate the mechanism of cross-tolerance to nickel in arsenic-transformed cells. Chronic arsenite-exposed (CAsE) cells (TRL 1215 cells, which had been continuously exposed to 0.5 muM arsenite for 20 or more weeks) and control TRL 1215 cells were both exposed to nickel for 24 h, and cell viability was determined by metabolic integrity. The LC50 for nickel was 608 +/- 32 muM in CAsE cells as compared to 232 +/- 16 muM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 muM nickel for 4 h and cellular-free radical production was measured using ESR spectrometry. Hydroxyl radical generation was decreased in CAsE cells. Thiobarbituric acid reactive substances, indicative of lipid peroxidation, and 8-oxo-2'-deoxyguanosine, indicative of oxidative DNA damage, were reduced in CAsE cells. Flow cytometric analysis using Annexin/FITC revealed that nickel-induced apoptosis was reduced in CAsE cells. CAsE cells showed generalized resistance to oxidant-induced toxicity as evidenced by a marked reduction in sensitivity to hydrogen peroxide. Interestingly, intracellular reduced glutathione (GSH) levels were significantly increased in CAsE cells, and when GSH was depleted, CAsE cells lost their nickel resistance. The mechanism of arsenic-induced cross-tolerance to cytotoxicity, genotoxicity, and apoptosis induced by nickel appears related to a generalized resistance to oxidant-induced injury, probably based, at least in part, in increased cellular GSH levels. C1 NIEHS, NCI, Chief Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NCI, Met Sect, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Chief Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 40 TC 18 Z9 19 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2001 VL 63 IS 2 BP 189 EP 195 DI 10.1093/toxsci/63.2.189 PG 7 WC Toxicology SC Toxicology GA 477XW UT WOS:000171310400007 PM 11568362 ER PT J AU Rao, GN Morris, RW Seely, JC AF Rao, GN Morris, RW Seely, JC TI Beneficial effects of NTP-2000 diet on growth, survival, and kidney and heart diseases of Fischer 344 rats in chronic studies SO TOXICOLOGICAL SCIENCES LA English DT Article DE diet; nephropathy; cardiomyopathy; body weight; survival; group housing; individual housing; Fischer 344 rat ID CORN-OIL GAVAGE; F344/N RATS; TUMOR INCIDENCES; BODY-WEIGHT; CARCINOGENICITY; TOXICOLOGY; NEOPLASMS; PROTEIN; MICE AB Diet is one of the most important environmental factors influencing growth, survival, and appearance of age-associated diseases in rodents. NIH-07 open formula rodent diet was the selected diet for the National Toxicology Program studies from 1980 to 1994. After a number of experimental diets were evaluated, a new one designated as NTP-2000 was selected for rodents in NTP studies beginning in 1994. This report summarizes the results of dosed feed and inhalation studies for differences in growth, survival, and severity of kidney and heart lesions in Fischer 344 rats fed NTP-2000 or NIH-07 diets. In the dosed feed studies, male rats group housed and fed the NTP-2000 diet grew slightly slower, attained maximum body weight later, and lost less body weight by the end of the 2-year studies compared to the groups fed NIH-07. Female rats group housed and fed the NTP-2000 diet in dosed feed studies had significantly slower growth, with lower maximum body weight compared to the groups fed the NIH-07 diet. In the inhalation studies, male rats individually housed and fed the NTP-2000 diet had slightly higher maximum body weight and significantly higher final body weight, with lower loss of weight when compared to similarly housed groups fed the NIH-07 diet. In inhalation studies, female rats fed the NTP-2000 diet and individually housed had significantly slower growth. The NTP-2000 diet significantly increased the survival of male and female rats, with a dramatic increase in survival of males in inhalation studies. This diet also caused significant decreases in severity of nephropathy and cardiomyopathy, and the decrease was marked in males. These observations indicate that diets balanced for nutrients, such as the NTP-2000, could markedly improve the health and increase survival of the rats used in chronic studies. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Analyt Sci Inc, Durham, NC 27713 USA. Expt Pathol Labs, Res Triangle Pk, NC 27709 USA. RP Rao, GN (reprint author), NIEHS, Environm Toxicol Program, MD B3-08,POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 24 Z9 25 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 OCT PY 2001 VL 63 IS 2 BP 245 EP 255 DI 10.1093/toxsci/63.2.245 PG 11 WC Toxicology SC Toxicology GA 477XW UT WOS:000171310400013 PM 11568368 ER PT J AU Liu, J Corton, C Dix, DJ Liu, YP Waalkes, MP Klaassen, CD AF Liu, J Corton, C Dix, DJ Liu, YP Waalkes, MP Klaassen, CD TI Genetic background but not metallothionein phenotype dictates sensitivity to cadmium-induced testicular injury in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE cadmium; testicular toxicity; strain-difference; metallothionein; testicular hemorrhage; atrophy; metallothionein-deficient mice ID INBRED STRAINS; RESISTANCE; TOXICITY; EXPRESSION; NECROSIS; TESTES; MOUSE; RATS; SUSCEPTIBILITY; PROTEIN AB Sensitivity to cadmium (Cd)-induced testicular injury varies greatly among mouse strains. For instance, 129/SvJ (129) mice are highly sensitive while C57BL/6J (C57) mice are refractory to Cd-induced testicular injury. Metallothionein (MT), a Cd-binding protein, is thought to be responsible for the strain susceptibility to Cd toxicity. In this study, MT-I/II knockout (MT-null) an wi type 129 mice were used to determine the role of NIT in Cd-induced testicular injury. Two additional strains of mice (C57 and the C57 x 129 F1cross) were also used to help define the role of genetic background in Cd toxicity. Mice were given 5-20 mu mol/kg ip CdCl2 and testicular injury was examined 24 h later by histopathology and testicular hemoglobin concentration. Cd produced dose-dependent testicular injury in all strains of mice, except for C57 mice, in which testicular injury could not be produced. MT-null mice were more sensitive than C57 x 129 mice but were equally sensitive as 129 mice to Cd-induced testicular injury. Fourteen days after 15 mu mol/kg ip Cd administration, testicular atrophy was evident in MT-null, 129, and C57 x 129 mice but was absent in C57 mice. The resistance of C57 mice to Cd-induced testicular injury could not be attributed solely to a decreased uptake of Cd-109 nor to a greater amount of testicular MT. Microarray analysis revealed a higher expression of glutathione peroxidase in the testes of C57 mice, as well as genes encoding antioxidant components and DNA damage/repair, but their significance to Cd-induced injury is not immediately clear. Thus, this study demonstrates that it is genetic strain, not MT genotype, that is mechanistically important in determining susceptibility to Cd-induced testicular injury. (C) 2001 Academic Press. C1 Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. NIEHS, NCI, Res Triangle Pk, NC 27709 USA. Ctr Hlth Res, CIIT, Res Triangle Pk, NC 27709 USA. US EPA, Reprod Toxicol Div, Natl Hlth & Enviornm Effects Res Lab, Res Triangle Pk, NC 27711 USA. RP Liu, J (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. FU NIEHS NIH HHS [ES-01142] NR 39 TC 37 Z9 42 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 1 PY 2001 VL 176 IS 1 BP 1 EP 9 DI 10.1006/taap.2001.9262 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 482HT UT WOS:000171571300001 PM 11578143 ER PT J AU Burke, B Mounkes, LC Stewart, C AF Burke, B Mounkes, LC Stewart, C TI The nuclear envelope in muscular dystrophy and cardiovascular diseases SO TRAFFIC LA English DT Review DE cardiomyopathy; emerin; lamina-associated polypeptides; lipodystrophy; muscular dystrophy; nuclear envelope; nuclear lamins; nuclear membranes ID FAMILIAL PARTIAL LIPODYSTROPHY; LAMIN-A/C GENE; INTEGRAL MEMBRANE-PROTEINS; CAUSE AUTOSOMAL-DOMINANT; CELL-CYCLE; DILATED CARDIOMYOPATHY; MISSENSE MUTATIONS; DUNNIGAN VARIETY; PORE COMPLEXES; CDNA CLONING AB Considerable interest has been focused on the nuclear envelope in recent years following the realization that several human diseases are linked to defects in genes encoding nuclear envelope specific proteins, most notably A-type lamins and emerin. These disorders, described as laminopathies or nuclear envelopathies, include both X-linked and autosomal dominant forms of Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy with conduction system defects, limb girdle muscular dystrophy 1B with atrioventricular conduction disturbances, and Dunnigan-type familial partial lipodystrophy. Certain of these diseases are associated with nuclear structural abnormalities that can be seen in a variety of cells and tissues. These observations clearly demonstrate that A-type lamins in particular play a central role, not only in the maintenance of nuclear envelope integrity but also in the large-scale organization of nuclear architecture. What is not obvious, however, is why defects in nuclear envelope proteins that are found in most adult cell types should give rise to pathologies associated predominantly with skeletal and cardiac muscle and adipocytes. The recognition of these various disorders now raises the novel possibility that the nuclear envelope may have functions that go beyond housekeeping and which impact upon cell-type specific nuclear processes. C1 Univ Calgary, Dept Cell Biol & Anat, Calgary, AB T21 4N1, Canada. NCI, Frederick Canc Res & Dev Ctr, Lab Canc & Dev Biol, Frederick, MD 21701 USA. RP Burke, B (reprint author), Univ Calgary, Dept Cell Biol & Anat, 3330 Hosp Dr NW, Calgary, AB T21 4N1, Canada. NR 77 TC 28 Z9 28 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD OCT PY 2001 VL 2 IS 10 BP 675 EP 683 DI 10.1034/j.1600-0854.2001.21001.x PG 9 WC Cell Biology SC Cell Biology GA 478ZM UT WOS:000171379500001 PM 11576443 ER PT J AU Dittmar, K Procter, JL Cipolone, K Njoroge, JM Miller, J Stroncek, DF AF Dittmar, K Procter, JL Cipolone, K Njoroge, JM Miller, J Stroncek, DF TI Comparison of DATs using traditional tube agglutination to gel column and affinity column procedures SO TRANSFUSION LA English DT Article ID ANTIGLOBULIN-TEST AB BACKGROUND: Detection of immunoglobulin or complement bound to RBCs by using the DAT is valuable in the diagnosis of immune-mediated hemolytic anemia. Traditionally, the DAT has been performed by tube agglutination using anti-IgG or anti-C3d. The purpose of this study was to compare the tube agglutination DAT to gel microcolumn, affinity microcolumn, and flow cytometric DATs on RBCs coated in vitro and on patient RBC samples. STUDY DESIGN AND METHODS: RBCs from 84 patients were assessed by tube agglutination DAT, one gel microcolumn DAT, and two affinity microcolumn DATs. One affinity microcolumn assay was unmodified and one was modified by the addition of polyspecific antiglobulin or anti-IgG as a secondary antibody. RBCs from 15 of the 84 patients underwent analysis by flow cytometry with fluorescence-labeled anti-IgG. The assays were also compared by using D+ RBCs sensitized with serially adjusted concentrations of anti-D. RESULTS: Both tube agglutination and gel microcolumn DATs were positive in 49 patient samples; both assays were negative in 20 samples, and the results were discordant in 15. Gel microcolumn DATs were more likely than were tube agglutination DATs to detect IgG on RBCs. Affinity microcolumn DATs were less likely than gel microcolumn or tube agglutination DATs to detect IgG on RBCs. Flow cytometry results were the same as gel microcolumn results in 12 of 15 patient samples and the same as tube agglutination results in 13 of 15. Tube agglutination and both affinity microcolumn assays reacted with RBCs coated with anti-D that was diluted 1-in-100. The gel microcolumn and flow cytometry assays reacted with RBCs coated with anti-D diluted 1-in-400. There was no correlation between tube agglutination and gel microcolumn DATs in detecting bound C3d. CONCLUSION: Detection of IgG bound to RBCs was not consistent with the methods described. Gel microcolumn DATs were more sensitive than tube agglutination and affinity microcolumn DATs. Given the varied results of these assays, reference laboratories should not rely on a single method for DATs. More comprehensive testing should be performed when the tube agglutination DAT is negative in a patient with suspected immune-mediated hemolytic anemia. Further comparisons are necessary to determine the proficiency of flow cytometric assays. C1 NIDDKD, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIDDKD, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bldg 10,Room 1C711,10 Ctr Dr,MSC-1184, Bethesda, MD 20892 USA. NR 16 TC 18 Z9 20 U1 0 U2 1 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2001 VL 41 IS 10 BP 1258 EP 1262 DI 10.1046/j.1537-2995.2001.41101258.x PG 5 WC Hematology SC Hematology GA 485XW UT WOS:000171789600016 PM 11606825 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI The CHASE domain: a predicted ligand-binding module in plant cytokinin receptors and other eukaryotic and bacterial receptors SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID DICTYOSTELIUM-DISCOIDEUM; PROTEINS; DATABASE; LIGHT; PAS AB A novel, 200-230 amino acid extracellular domain was identified in the plant cytokinin receptor Cre1, in the receptor-histidine kinase DhkA and the adenylyl cyclase Acg from the slime mold Dictyostelium discoideum, and in a variety of other receptor-like proteins from bacteria and eukaryotes. The domain is predicted to bind diverse low molecular weight ligands, such as the cytokinin-like adenine derivatives or peptides, and mediate signal transduction through the respective receptors. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Anantharaman, V (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. OI Anantharaman, Vivek/0000-0001-8395-0009 NR 16 TC 83 Z9 87 U1 0 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2001 VL 26 IS 10 BP 579 EP 582 DI 10.1016/S0968-0004(01)01968-5 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 484XN UT WOS:000171715000002 PM 11590000 ER PT J AU Mounkes, LC Burke, B Stewart, CL AF Mounkes, LC Burke, B Stewart, CL TI The A-type lamins - Nuclear structural proteins as a focus for muscular dystrophy and cardiovascular diseases SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Article ID FAMILIAL PARTIAL LIPODYSTROPHY; CAUSE AUTOSOMAL-DOMINANT; DILATED CARDIOMYOPATHY; A/C GENE; MISSENSE MUTATIONS; CONDUCTION-SYSTEM; DUNNIGAN VARIETY; C2 DOMAIN; EXPRESSION; MEMBRANE AB Mutations in the lamin A (LMNA) gene are associated with the tissue-specific diseases Emery-Dreifuss muscular dystrophy (EDMD), limb girdle muscular dystrophy (LGMD-1B), dilated cardiomyopathy with conduction system disease (DCM-CD), and Dunnigan's familial partial lipodystrophy (FPLD). Lamins A and C, the products of the LMNA gene, are nuclear intermediate filament proteins and are the major structural components of the lamina network that underlies and supports the nuclear envelope. Nuclear fragility and mislocalization of the nuclear envelope protein emerin are two defects induced by a lack of the A-type lamins. These observations reveal that organization and structural integrity of the nucleus are critical factors in the origins of certain dystrophic and cardiovascular diseases. (Trends Cardiovasc Med 2001; 11:280-285). (C) 2001, Elsevier Science Inc. C1 NCI, Lab Canc & Dev Biol, FCRDC, Frederick, MD 21702 USA. Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. RP Stewart, CL (reprint author), NCI, Lab Canc & Dev Biol, FCRDC, POB B, Frederick, MD 21702 USA. NR 47 TC 33 Z9 35 U1 1 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD OCT PY 2001 VL 11 IS 7 BP 280 EP 285 DI 10.1016/S1050-1738(01)00126-8 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492QB UT WOS:000172178100005 PM 11709282 ER PT J AU Nichols, BJ Lippincott-Schwartz, J AF Nichols, BJ Lippincott-Schwartz, J TI Endocytosis without clathrin coats SO TRENDS IN CELL BIOLOGY LA English DT Editorial Material ID GOLGI-APPARATUS; MIGRATING CELLS; PLASMA-MEMBRANE; CHOLERA-TOXIN; CAVEOLAE; MECHANISMS; RECEPTOR; INTERNALIZATION; TRANSPORT; DYNAMIN AB Endocytosis is involved in an enormous variety of cellular processes. To date, most studies on endocytosis in mammalian cells have focused on pathways that start with uptake through clathrin-coated pits. Recently, new techniques and reagents have allowed a wider range of endocytic pathways to begin to be characterized. Various non-clathrin endocytic mechanisms have been identified, including uptake through caveolae, macropinosomes and via a separate constitutive pathway. Many markers for clathrin-independent endocytosis are found in detergent-resistant membrane fractions, or lipid rafts. We will discuss these emerging new findings and their implications for the nature of lipid rafts themselves, as well as for the potential roles of non-clathrin endocytic pathways in remodeling of the plasma membrane and in regulating the membrane composition of specific intracellular organelles. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Nichols, BJ (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. NR 56 TC 306 Z9 314 U1 0 U2 22 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 OCT PY 2001 VL 11 IS 10 BP 406 EP 412 DI 10.1016/S0962-8924(01)02107-9 PG 7 WC Cell Biology SC Cell Biology GA 480FX UT WOS:000171452300008 PM 11567873 ER PT J AU Frucht, DM Fukao, T Bogdan, C Schindler, H O'Shea, JJ Koyasu, S AF Frucht, DM Fukao, T Bogdan, C Schindler, H O'Shea, JJ Koyasu, S TI IFN-gamma-production by antigen-presenting cells: mechanisms emerge SO TRENDS IN IMMUNOLOGY LA English DT Editorial Material ID MOUSE PERITONEAL-MACROPHAGES; INTERFERON-GAMMA; DENDRITIC CELLS; B-CELLS; T-CELLS; MYCOBACTERIAL INFECTION; ALVEOLAR MACROPHAGES; RECEPTOR EXPRESSION; MURINE MACROPHAGES; IMMUNE INTERFERON AB The suggestion that antigen-presenting cells (APCs) produce interferon gamma (IFN-gamma) is controversial because it conflicts with the initial paradigm in which the production of IFN-gamma was restricted to lymphoid cells. However, some answers to this skepticism have been provided by recent findings of high-level production and intracellular expression of IFN-gamma by interleukin-12 (IL-12)-stimulated macrophages and dendritic cells. New data are now emerging to explain the mechanism of production of IFN-gamma vby APCs. As in lymphoid cells, IL-12-induced IFN-gamma production in APCs requires signal transducer and activator of transcription 4 (STAT4), although the precise molecular events that govern the transcription of the gene encoding IFN-gamma are enigmatic still. Understanding these processes in lymphoid, and now nonlymphoid, cells remains an important challenge. C1 Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan. NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Inst Clin Microbiol Immunol & Hyg, D-91054 Erlangen, Germany. RP Koyasu, S (reprint author), Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan. RI Fukao, Taro/I-3246-2014; Koyasu, Shigeo/J-5583-2015 OI Koyasu, Shigeo/0000-0001-9585-3038 NR 45 TC 280 Z9 290 U1 3 U2 21 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 OCT PY 2001 VL 22 IS 10 BP 556 EP 560 DI 10.1016/S1471-4906(01)02005-1 PG 5 WC Immunology SC Immunology GA 485YM UT WOS:000171791100010 PM 11574279 ER PT J AU Fry, TJ Mackall, CL AF Fry, TJ Mackall, CL TI Interleukin-7: master regulator of peripheral T-cell homeostasis? SO TRENDS IN IMMUNOLOGY LA English DT Review ID RECEPTOR-DEFICIENT MICE; BONE-MARROW TRANSPLANT; RECOMBINANT HUMAN IL-7; IN-VIVO; LYMPHOPROLIFERATIVE DISORDERS; TRANSGENIC MICE; LYMPHOCYTES-T; SERUM LEVELS; GAMMA-CHAIN; PROLIFERATION AB Recent evidence has implicated interleukin-7 (IL-7) as a master regulator of T-cell homeostasis, based upon its essential role in the homeostatic expansion of naive T-cell populations in response to low-affinity antigens (Ags) and its capacity to enhance dramatically the expansion of peripheral T-cell populations in response to high-affinity Ags. Furthermore, T-cell-depleted humans have a unique inverse relationship between the peripheral CD4(+) T-cell count and the level of circulating IL-7. Together, these data suggest that increased amounts of IL-7 become available following T-cell depletion, thus, enhancing the high- and low-affinity Ag-driven expansion of the population of residual, mature T cells and boosting thymic regenerative capacity, as a means to restore T-cell homeostasis. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Room 13N240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 65 TC 213 Z9 217 U1 1 U2 2 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 OCT PY 2001 VL 22 IS 10 BP 564 EP 571 DI 10.1016/S1471-4906(01)02028-2 PG 8 WC Immunology SC Immunology GA 485YM UT WOS:000171791100012 PM 11574281 ER PT J AU Barry, CE AF Barry, CE TI Mycobacterium smegmatis: an absurd model for tuberculosis? Response SO TRENDS IN MICROBIOLOGY LA English DT Letter C1 NIH, Host Def Lab, Rockville, MD 20852 USA. RP Barry, CE (reprint author), NIH, Host Def Lab, Twinbrook 2,Room 239,MSC 8180,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012 NR 12 TC 14 Z9 15 U1 0 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD OCT PY 2001 VL 9 IS 10 BP 473 EP 474 DI 10.1016/S0966-842X(01)02169-2 PG 2 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 483WG UT WOS:000171658400008 ER PT J AU Emerson, SU Purcell, RH AF Emerson, SU Purcell, RH TI Recombinant vaccines for hepatitis E SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID NON-B HEPATITIS; E VIRUS HEV; OPEN READING FRAME-2; NON-A; UNITED-STATES; MOLECULAR-CLONING; CAPSID PROTEIN; INSECT CELLS; E INFECTION; EPIDEMIC AB Hepatitis E virus causes epidemics of acute hepatitis in many developing countries. It infrequently causes disease in developed countries, but avirulent strains might circulate. Some evidence suggests that hepatitis E might be a zoonosis. There is probably only a single serotype. A candidate vaccine consisting of baculovirus-expressed recombinant capsid protein protected macaques from hepatitis E - it passed phase I clinical trials and is currently scheduled for phase II/III clinical trials. C1 NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 49 TC 50 Z9 57 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD OCT PY 2001 VL 7 IS 10 BP 462 EP 466 DI 10.1016/S1471-4914(01)02106-2 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 484XM UT WOS:000171714900006 PM 11597521 ER PT J AU Piatigorsky, J AF Piatigorsky, J TI Dual use of the transcriptional repressor (CtBP2)/ribbon synapse (RIBEYE) gene: how prevalent are multifunctional genes? SO TRENDS IN NEUROSCIENCES LA English DT Article ID ANTIFREEZE GLYCOPROTEIN; LENS CRYSTALLINS; NITRIC-OXIDE; EVOLUTION; HEMOGLOBIN; PROTEINS; COMPONENT; RIBBON; GENOME AB Vertebrates have ribbon synapses in the retina and in other sensory structures that are specialized for rapid, tonic release of synaptic vesicles'. The lamellar sheets of the ribbon situated at right angles to the plasma membrane are lined with synaptic vesicles that undergo exocytosis under the influence of Ca(2+). Synaptic ribbons act as a conveyer belt to accelerate the release of this ready supply of synaptic vesicles at the presynaptic membranes. Although the protein composition of the terminals of ribbon synapses is generally similar to that of ordinary synapses in nervous tissue, much less is known about the composition of the ribbons themselves. RIM, a universal component of presynaptic active zones that interacts with rab3 on the synaptic vesicle, has been localized to the ribbons(2). In addition, the kinesin motor protein, KIF3A, is associated with the ribbons and other organelles in presynaptic nerve terminals(3). Recently, a similar to 120 kDa protein called RIBEYE has been identified in purified ribbons of bovine retina. The RIBEYE cDNA was cloned and its gene identified in the database. 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@intra.nei.nih.gov NR 20 TC 9 Z9 9 U1 0 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 OCT PY 2001 VL 24 IS 10 BP 555 EP 557 DI 10.1016/S0166-2236(00)01894-4 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 480GA UT WOS:000171452600004 PM 11576649 ER PT J AU Ronsmans, C Endang, A Gunawan, S Zazri, A McDermott, J Koblinsky, M Marshall, T AF Ronsmans, C Endang, A Gunawan, S Zazri, A McDermott, J Koblinsky, M Marshall, T TI Evaluation of a comprehensive home-based midwifery programme in South Kalimantan, Indonesia SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE audit; evaluation; home-birth; Indonesia; maternal mortality; midwife; safe motherhood; unmet obstetric need ID MATERNAL MORTALITY; SAFE MOTHERHOOD; CARE; BANGLADESH; DECLINE; IMPACT; MATLAB AB We report the findings of an evaluation of a programme in three districts in South Kalimantan, Indonesia, which consisted of the training, deployment and supervision of a large number of professional midwives in villages, an information, education and communication (IEC) strategy to increase use of village midwives for birth, and a district-based maternal and perinatal audit (MPA). Before the programme, the midwives had limited ability to manage obstetric complications, and 90% of births took place at home. Only 37% were attended by a skilled attendant. By 1998-99, 510 midwives were posted in the districts and skilled attendance at delivery had increased to 59%. Through in-service training, continuous supervision and participation in the audit system midwives also gained confidence and skills in the management of obstetric complications. Despite this, the proportion admitted to hospital for a Caesarean section declined from 1.7 to 1.4% and the proportion admitted to hospital with a complication requiring a life-saving intervention declined from 1.1% to 0.7%. The strategy of a midwife in every village has dramatically increased skilled birth attendance, but does not yet provide specialized obstetric care for all women needing it. The high cost of emergency obstetric interventions may well be the most important obstacle to the use of hospital care. C1 Univ London London Sch Hyg & Trop Med, Infect Dis Epidemiol Unit, Maternal Hlth Program, Dept Infect & Trop Dis, London WC1E 7HT, England. Univ Indonesia, Sch Publ Hlth, Jakarta, Indonesia. MotherCare, Arlington, VA USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. NGO Networks Hlth, Washington, DC USA. RP Ronsmans, C (reprint author), Univ London London Sch Hyg & Trop Med, Infect Dis Epidemiol Unit, Maternal Hlth Program, Dept Infect & Trop Dis, Keppel St, London WC1E 7HT, England. NR 34 TC 40 Z9 41 U1 1 U2 6 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD OCT PY 2001 VL 6 IS 10 BP 799 EP 810 DI 10.1046/j.1365-3156.2001.00780.x PG 12 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 480RH UT WOS:000171475600009 PM 11679128 ER PT J AU Miyoshi, N Takeshita, T Misik, V Riesz, P AF Miyoshi, N Takeshita, T Misik, V Riesz, P TI Monomerization of photo sensitizers by ultrasound irradiation in surfactant micellar solutions SO ULTRASONICS SONOCHEMISTRY LA English DT Article DE monomer; aggregate; pheophorbide-a derivatives; surfactant micellar solutions AB The absorption and fluorescence properties of pheophorbide-a. Sodium salt of pheophorbide-a and its long chain (C(20)H(39)) ester (Pheophytine) were investigated in air-saturated micellar aqueous solutions before and after ultrasound irradiation ( 48 kHz. 10 min). The absorption spectra changed depending on the surfactant; cetyltrimethyl ammonium bromide (CTAB) or sodium dodecyl sulfate concentrations. The formation of different molecular species in various micellar solutions was estimated from the analysis of the absorption spectra. The absorption bands resulted from an aggregated form of the chromophore present in 50 mM phosphate buffer and in pre-micellar solutions. The specific bands of the aggregate disappeared with a simultaneous increase of the bands of monomer in normal micellar solution. The fluorescence spectra., the lifetimes and the fraction of each component (with a characteristic lifetime) of the chromophore in the micellar solutions changed significantly before and after ultrasound irradiation although the changes in absorption spectra were small. The fluorescence emission band at 710 nm due to the aggregate almost disappeared in the pre-micellar solution after ultrasound irradiation. The fraction of the short-lifetime component estimated for the aggregates decreased 55% in H(2)O or 85% in 2 mM CTAB, however the long-lifetime components increased after the ultrasound treatment. From these fluorescence properties, it was concluded that the aggregated molecules were converted to a stable monomeric form by ultrasound. Extrapolation of these data to in vivo situations suggests that pretreatment of certain photosensitizers, with ultrasound in micellar solutions may lead to increased efficiency of photodynamic therapy since only the monomers are photodynamically active. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Fukui Med Univ, Dept Pathol, Matsuoka, Fukui 9101193, Japan. Hamamatsu Photon KK, Syst Div, Hamamatsu, Shizuoka 43131, Japan. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Miyoshi, N (reprint author), Fukui Med Univ, Dept Pathol, Matsuoka, Fukui 9101193, Japan. EM nmiyoshi@fmsrsa.fukui-med.ac.jp NR 9 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD OCT PY 2001 VL 8 IS 4 BP 367 EP 371 DI 10.1016/S1350-4177(00)00079-1 PG 5 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 461XN UT WOS:000170389300007 PM 11510221 ER PT J AU Gelmann, EP Chia, D Pinsky, PF Andriole, GL Crawford, ED Reding, D Hayes, RB Kramer, BS Woodrum, DL Gohagan, JK Levin, DL AF Gelmann, EP Chia, D Pinsky, PF Andriole, GL Crawford, ED Reding, D Hayes, RB Kramer, BS Woodrum, DL Gohagan, JK Levin, DL CA PLCO Screening Trial Investigators TI Relationship of demographic and clinical factors to free and total prostate-specific antigen SO UROLOGY LA English DT Article ID PSA RATIO IMPROVES; REFERENCE RANGES; AFRICAN-AMERICAN; FREE/TOTAL PSA; CANCER; MEN; AGE; DENSITY; BENIGN; TESTOSTERONE AB Objectives. To characterize the role of demographic and clinical parameters in the measurements of prostate-specific antigen (PSA), free PSA (fPSA), and percent free PSA (%fPSA). Methods. This was a cohort study of volunteers to a randomized screening trial. A central laboratory determined PSA and fPSA for the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A baseline evaluation of free and total PSA was done for 7183 white, black, Asian, Hispanic, and other male volunteers, aged 55 to 74 years. Comparisons were made across racial and ethnic groups and across a set of clinical parameters from a baseline questionnaire. Results. The median levels of serum PSA were less than 2.1 ng/mL in each age-race grouping of the study participants. The levels of free and total PSA were higher in black (n = 868, 12%) participants than in white (n = 4995, 70%) and Asian (n = 849, 11.8%) participants. Individuals who identified themselves as ethnically Hispanic (n = 339, 4.7%) had median PSA levels higher than whites who were not Hispanic. The free and total PSA levels increased with age, particularly among men 70 to 74 years old. However, the %fPSA levels showed less variation among the four racial groups or by age. The free and total PSA levels were higher among those who had a history of benign prostatic disease. Conclusions. Demographic (age and race/ethnicity) and clinical (history of benign prostatic disease) variables had a moderate effect on the measures of PSA and fPSA and very little effect on %fPSA. (C) 2001, Elsevier Science Inc. C1 Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Tissue Typing Lab, Los Angeles, CA USA. NCI, Early Detect Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Washington Univ, Div Urol, St Louis, MO 63130 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, MN USA. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NIH, Off Med Applicat Res, Bethesda, MD 20892 USA. Beckman Coulter Inc, San Diego, CA USA. NCI, Div Canc Prevent Biometry Res Grp, Bethesda, MD 20892 USA. RP Gelmann, EP (reprint author), Georgetown Univ, Vincent T Lombardi Canc Res Ctr, 3800 Reservoir Rd, Washington, DC 20007 USA. NR 27 TC 21 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD OCT PY 2001 VL 58 IS 4 BP 561 EP 566 DI 10.1016/S0090-4295(01)01305-X PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 482HH UT WOS:000171570400014 PM 11597539 ER PT J AU Winter, DL Hanlon, AL Raysor, SL Watkins-Bruner, D Pinover, WH Hanks, GE Tricoli, JV AF Winter, DL Hanlon, AL Raysor, SL Watkins-Bruner, D Pinover, WH Hanks, GE Tricoli, JV TI Plasma levels of IGF-1, IGF-2, and IGFBP-3 in white and African-American men at increased risk of prostate cancer SO UROLOGY LA English DT Article ID GROWTH-FACTOR-I; FACTOR BINDING PROTEIN-3; UNITED-STATES; FACTOR AXIS; CELL-LINES; RECEPTOR; HORMONE; BLACK; INSULIN-LIKE-GROWTH-FACTOR-1; BINDING-PROTEIN-3 AB Objectives. To further investigate the relationship between the plasma levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone, testosterone, and demographic factors, particularly race, within a group of men at increased risk of prostate cancer development. Methods. Enzyme-linked immunosorbent assays or an immunosorbent assay was used to quantitate the plasma levels of IGF-1, IGF-2, IGFBP-3, growth hormone, and testosterone. The study group consisted of 169 men (85 African-American, 84 white) aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were African-American. The relationships between the plasma levels and the categorical covariates were assessed using the nonparametric Wilcoxon test and between the continuous variables using Spearman's correlation coefficient. Results. The mean plasma levels of IGFBP-3 were significantly lower in African-American (2657 ng/mL) than in white (2965 ng/mL) men (P = 0.0062). The plasma levels of IGF-2 were also lower in the African-American (503.5 ng/mL) than in the white (549.1 ng/mL) men (P = 0.0084). Overall, the IGF-1 plasma levels correlated positively with the IGF-2, IGFBP-3, and growth hormone levels and the IGF-2 plasma levels correlated negatively with the testosterone levels. Conclusions. Our results demonstrate that lower plasma levels of IGFBP-3 and IGF-2 are associated with race in a population of men at increased risk of developing prostate cancer. The ability of these markers to predict earlier disease onset is currently under investigation. (C) 2001, Elsevier Science Inc. C1 Fox Chase Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. RP Tricoli, JV (reprint author), NCI, Canc Diag Program, 6130 Execut Blvd,Execut Plaza N,Suite 6035A, Rockville, MD 20852 USA. NR 32 TC 30 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD OCT PY 2001 VL 58 IS 4 BP 614 EP 618 DI 10.1016/S0090-4295(01)01273-0 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 482HH UT WOS:000171570400027 PM 11597555 ER PT J AU Khaled, AR Durum, SK AF Khaled, AR Durum, SK TI From cytosol to mitochondria: The Bax translocation story SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE apoptosis; Bax; Bcl-2; cell death ID INDUCED CONFORMATIONAL CHANGE; PROGRAMMED CELL-DEATH; BCL-X-L; INTRACELLULAR PH; APOPTOSIS; PROTEIN; DIMERIZATION; FAMILY; LOCALIZATION; BCL-X(L) AB The balance between life and death of a cell regulates essential developmental processes in multicellular organisms. Apoptotic cell death is a complex, stepwise program involving multiple protein components that trigger and execute the demise of the cell. Of the many triggers of apoptosis, most are not well understood, but some key components have been identified, such as those of the Bcl-2 family, which function as anti-apoptotic or pro-apoptotic factors. Bax, a pro-apoptotic member of this family, has been shown to serve as a component of many apoptotic triggering cascades and its mechanism of action is the focus of intense study. Herein we discuss current, differing ideas on the function of Bax and its structure, and suggest novel mechanisms for how this death protein targets mitochondria, triggering apoptosis. C1 NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NR 29 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD SEP 30 PY 2001 VL 34 IS 5 BP 391 EP 394 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 477PW UT WOS:000171294300001 ER PT J AU Ikemoto, S Sharpe, LG AF Ikemoto, S Sharpe, LG TI A head-attachable device for injecting nanoliter volumes of drug solutions into brain sites of freely moving rats SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE intracranial drug self-administration; microinjection; operant reinforcement; reward; nucleus accumbens core and shell; dopamine; D-amphetamine ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; D-AMPHETAMINE; ANTAGONISTS; SYSTEM AB We describe a head-mounted micropump-injection system designed for the infusion of nanoliter volumes of drug solutions into discrete brain regions of the freely moving rats. Using a miniature step motor, the micropump-injection system can be readily constructed from commercially available supplies. In calibrating the micropump-injection system, we found that it will deliver a reliable volume of 50 nl per infusion over a 1-h period, with an infusion given every 1 min. From in vivo testing, we also found that rats readily self-administered up to 100 infusions of D-amphetamine into the nucleus accumbens at regular intervals, suggesting that this system can deliver constant volumes of infusions over time in freely moving rats. It (1) attaches easily to an implanted guide, (2) is compact and durable, (3) weighs only 10 g, and (4) is well tolerated with no apparent discomfort to the animal. This system overcomes some of the weaknesses of currently used intracranial self-administration systems. Published by Elsevier Science B.V. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 13 TC 36 Z9 36 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 30 PY 2001 VL 110 IS 1-2 BP 135 EP 140 DI 10.1016/S0165-0270(01)00428-9 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 482VM UT WOS:000171598000016 PM 11564533 ER PT J AU Schlessinger, D Van Zant, G AF Schlessinger, D Van Zant, G TI Does functional depletion of stem cells drive aging? SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE immortal cells; ovarian follicles; hematopoiesis; lifespan ID IN-VIVO; SERIAL TRANSPLANTATION; CALORIC RESTRICTION; OOCYTE APOPTOSIS; DENTATE GYRUS; BONE-MARROW; MOUSE; MICE; EXPRESSION; BRAIN AB The regenerative power of stem cells has raised issues about their relation to aging. We focus on the question of whether a decline in the function of stem cells may itself be a significant feature of aging. The question is implicitly two-fold: does functional depletion of stem cells affect the accumulation of aging-related deficits, and -- whether or not depletion is significant -- can activation of stem cells alleviate deficits? Two types of system are considered: 1) the exhaustible pool of ovarian follicles. The depletion of follicles leads to the aging-related phenomenon of menopause: and 2) the reserve of hematopoietic stem cells. Substantial numbers are sustained throughout life, but in mouse models. endogenous replicative activity has been shown to decline sharply with age. We discuss the possible implications of these observations for the rate of aging and the prospects for intervention. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Genet Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21218 USA. Univ Kentucky, Med Ctr, Markey Canc Ctr, Div Hematol Oncol, Lexington, KY 40536 USA. RP Schlessinger, D (reprint author), NIA, Genet Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21218 USA. NR 73 TC 43 Z9 45 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD SEP 30 PY 2001 VL 122 IS 14 BP 1537 EP 1553 DI 10.1016/S0047-6374(01)00299-8 PG 17 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 468ZT UT WOS:000170788600004 PM 11511395 ER PT J AU Sutherland, KA Collins, PL Peeples, ME AF Sutherland, KA Collins, PL Peeples, ME TI Synergistic effects of gene-end signal mutations and the M2-1 protein on transcription termination by respiratory syncytial virus SO VIROLOGY LA English DT Article ID MESSENGER-RNA; SEQUENTIAL TRANSCRIPTION; ELONGATION-FACTOR; N-PROTEIN; P-PROTEIN; GENOME; POLYADENYLATION; REPLICATION; POLYMERASE; EXPRESSION AB Individual mononegavirus genes terminate with a short cis-acting element, the gene-end (GE) signal, that directs polyadenylation and termination and might also influence the efficiency of reinitiation at the next downstream gene. The 12-13 nucleotide (nt) GE signals of human respiratory syncytial virus (RSV) consist of a conserved pentanucleotide (3'-UCAAU, negative sense), followed by a 3-nt middle region that is AU-rich but otherwise not conserved, followed by a 4-or 5-nt poly(U) region that is thought to generate the poly(A) tail of the encoded mRNA by reiterative copying. Most of the naturally occurring differences in the GE signals of the various RSV genes occur in the "middle" and "poly(U)" regions. We mutated a copy of the fusion protein (F) GE signal that was positioned at the end of the promoter-proximal gene of a tricistronic minigenome and evaluated the effect of these mutations on RSV transcription in a plasmid-initiated, intracellular assay. Mutations confirmed the importance of the middle region's AU-rich nature and 3-nt length, and the poly(U) tract's 4-nt minimum functional length, with maximal termination efficiency observed at five U residues. Nt assignments other than U at position 13 also affected the efficiency of termination, showing that this position is part of the functional 13-nt GE signal. These results indicate that differences in nt assignments in the middle and poly(U) regions of the GE signal, which occur frequently In nature, affect the efficiency of termination. Unexpectedly, the ability of certain mutations to inhibit termination was completely dependent on coexpression of the M2-1 protein, and in many other cases the inhibitory effect of the mutation was greatly enhanced in the presence of M2-1. Thus, M2-1 appears to have the effect of altering the polymerase such that it ignores suboptimal GE signals. Interestingly, certain mutations that greatly decreased the efficiency of termination in the absence of M2-1 did not have much effect on the expression of the second gene, implying that correct termination and/or polyadenylation at the upstream gene is not obligatory for reinitiation at the next downstream gene. (C) 2001 Academic Press. C1 Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Peeples, ME (reprint author), Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, 1653 W Congress Pkwy, Chicago, IL 60612 USA. FU NIAID NIH HHS [AI47213] NR 34 TC 21 Z9 23 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2001 VL 288 IS 2 BP 295 EP 307 DI 10.1006/viro.2001.1105 PG 13 WC Virology SC Virology GA 479WG UT WOS:000171426100012 PM 11601901 ER PT J AU Vargha-Khadem, F Gadian, DG Mishkin, M AF Vargha-Khadem, F Gadian, DG Mishkin, M TI Dissociations in cognitive memory: the syndrome of developmental amnesia SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Royal-Society Discussion Meeting on Episodic Memory CY JAN 24-25, 2001 CL ROYAL SOC, LONDON, ENGLAND SP Royal Soc HO ROYAL SOC DE recognition; episodic memory; semantic memory; hippocampus; premature birth; event-related potentials ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; RECOGNITION MEMORY; HIPPOCAMPAL DAMAGE; SEMANTIC MEMORY; ACQUISITION; RECOLLECTION; ORGANIZATION; PATIENT; LESIONS; INJURY AB The dearth of studies on amnesia in children has led to the assumption that when damage to the medial temporal lobe system occurs early in life, the compensatory capacity of the immature brain rescues memory functions. An alternative view is that such damage so interferes with the development of learning and memory that it results not in selective cognitive impairments but in general mental retardation. Data will be presented to counter both of these arguments. Results obtained from a series of 11 amnesic patients with a history of hypoxic ischaemic damage sustained perinatally or during childhood indicate that regardless of age at onset of hippocampal pathology, there is a pronounced dissociation between episodic memory, which is severely impaired, and semantic memory, which is relatively preserved. A second dissociation is characterized by markedly impaired recall and relatively spared recognition leading to a distinction between recollection-based versus familiarity-based judgements. These findings are discussed in terms of the locus and extent of neuropathology associated with hypoxic ischaemic damage, the neural basis of 'remembering' versus 'knowing', and a hierarchical model of cognitive memory. C1 UCL, Inst Child Hlth, Cognit Neurosci Unit, London, England. UCL, Inst Child Hlth, Radiol & Phys Unit, London, England. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Vargha-Khadem, F (reprint author), UCL, Inst Child Hlth, Cognit Neurosci Unit, London, England. EM f.khadem@ich.ucl.ac.uk RI Gadian, David/C-4961-2008; Vargha-Khadem, Faraneh/C-2558-2008 NR 34 TC 65 Z9 67 U1 2 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD SEP 29 PY 2001 VL 356 IS 1413 BP 1435 EP 1440 DI 10.1098/rstb.2001.0951 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 479ZV UT WOS:000171436000010 PM 11571034 ER PT J AU Sereti, I Herpin, B Metcalf, JA Stevens, R Baseler, MW Hallahan, CW Kovacs, JA Davey, RT Lane, HC AF Sereti, I Herpin, B Metcalf, JA Stevens, R Baseler, MW Hallahan, CW Kovacs, JA Davey, RT Lane, HC TI CD4 T cell expansions are associated with increased apoptosis rates of T lymphocytes during IL-2 cycles in HIV infected patients SO AIDS LA English DT Article DE apoptosis; cytokines; immune activation; immune-based therapy; interleukin 2; T cell turnover ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED TRIAL; SUBCUTANEOUS INTERLEUKIN-2; IMMUNE ACTIVATION; INTRAVENOUS INTERLEUKIN-2; DISEASE PROGRESSION; TYPE-1 INFECTION; ANNEXIN-V; IN-VIVO AB Objective and design: In an attempt to determine the mechanisms underlying the CD4 T cell expansions in patients receiving intermittent interleukin (IL)-2, a cohort of 10 HIV infected patients were studied during a 5-day cycle of IL-2 to measure rates of apoptosis, the expression of activation markers in CD4 and CD8 T cell subsets and the serum levels of proinflammatory cytokines. All patients were receiving highly active antiretroviral therapy. Methods: Peripheral blood mononuclear cells were tested pre- and at the completion of IL-2 treatment with annexin V/7-AAD for the measurement of apoptosis. Phenotypic analyses of T lymphocytes were performed in parallel. Serum levels of interferon (IFN)gamma, granulocyte-macrophage colony stimulating factor, IL-6 and tumor necrosis factor (TNF)alpha were tested by enzyme-linked immunosorbent assay. Results: IL-2 increased the spontaneous apoptosis rates of CD4 and CD8 T lymphocytes (P = 0.003). Expression of HLA-DR, CD38 and CD95 increased on both CD4 and CD8 T lymphocytes whereas CD25 induction was observed exclusively on CD4 T cells. Significant increases of serum IL-6 and TNF alpha levels were noted in all patients whereas viral loads remained unchanged. Conclusion: Administration of IL-2 for 5 days in HIV infected patients leads to enhanced apoptosis of both CD4 and CD8 T cells despite an eventual increase of the CD4 T cell count. A profound activation state with induction of activation markers on T cells and high levels of TNF alpha and IL-6 accompanies the increased apoptosis during the IL-2 cycle. These data suggest that the CD4 expansions seen in the context of intermittent IL-2 therapy are the net result of increases in both cell proliferation and cell death. (C) 2001 Lippincott Williams & Wilkins. C1 NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lane, HC (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11S-231,10 Ctr Dr MSC 1876, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 45 TC 48 Z9 48 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 28 PY 2001 VL 15 IS 14 BP 1765 EP 1775 DI 10.1097/00002030-200109280-00004 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 478XY UT WOS:000171375100004 PM 11579237 ER PT J AU Fry, TJ Mackall, CL AF Fry, TJ Mackall, CL TI What limits immune reconstitution in HIV infection? Divergent tools converge on thymic function SO AIDS LA English DT Editorial Material DE thymus; immune reconstitution; HIV; interleukin 7 ID ADULTS; REPERTOIRE; CD4(+); AGE C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Fry, TJ (reprint author), NCI, Pediat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 15 TC 13 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 28 PY 2001 VL 15 IS 14 BP 1881 EP 1882 DI 10.1097/00002030-200109280-00019 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 478XY UT WOS:000171375100019 PM 11579252 ER PT J AU Tsao, LI Su, TP AF Tsao, LI Su, TP TI Hibernation-induction peptide and cell death: [D-Ala(2),D-Leu(5)]enkephalin blocks Bax-related apoptotic processes SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE [D-Ala(2),D-Leu(5)]enkephalin (DADLE) methamphetamine; Bax ID CYTOCHROME-C; BCL-2 AB The psychostimulant methamphetamine, both in vivo and in vitro. caused a mitochondrial cytochrome c release, the translocation of Bax from cytosol into mitochondrion, and the oligomerization of Bax. These effects by methamphetamine were blocked by a neuroprotective and hibernation-induction delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin (DADLE). These results suggest that methamphetamine causes apoptosis by affecting the dynamics of Bax and that the neuroprotective property of DADLE may be due partly to its ability to potently block Bax-related apoptotic processes. Published by Elsevier Science B.V. C1 NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Cellular Neurobiol Res Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 8 TC 18 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 28 PY 2001 VL 428 IS 1 BP 149 EP 151 DI 10.1016/S0014-2999(01)01346-2 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 483UE UT WOS:000171653600019 PM 11779032 ER PT J AU Zeldin, DC AF Zeldin, DC TI Epoxygenase pathways of arachidonic acid metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID CYTOSOLIC EPOXIDE HYDROLASE; ENDOGENOUS EPOXYEICOSATRIENOIC ACIDS; SPONTANEOUSLY HYPERTENSIVE RATS; GLOMERULAR MESANGIAL CELLS; ARTERIAL SMOOTH-MUSCLE; MOLECULAR-CLONING; 8,9-EPOXYEICOSATRIENOIC ACID; EPITHELIAL-CELLS; 5,6-EPOXYEICOSATRIENOIC ACID; MICROSOMAL CYTOCHROME-P450 C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Pulm Pathobiol Lab, NIH, 111 T W Alexander Dr Bldg 101,Rm D236, Res Triangle Pk, NC 27709 USA. NR 92 TC 357 Z9 368 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 28 PY 2001 VL 276 IS 39 BP 36059 EP 36062 DI 10.1074/jbc.R100030200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475XF UT WOS:000171194500001 PM 11451964 ER PT J AU Banks, GC Deterding, LJ Tomer, KB Archer, TK AF Banks, GC Deterding, LJ Tomer, KB Archer, TK TI Hormone-mediated dephosphorylation of specific histone H1 isoforms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; TRANSCRIPTION IN-VIVO; TUMOR VIRUS PROMOTER; GENE-EXPRESSION; CHROMATIN STRUCTURE; LINKER HISTONES; CELL-CYCLE; CHROMOSOME CONDENSATION; POSITIONED NUCLEOSOMES; GLOBULAR DOMAIN AB We have previously shown a connection between histone H1 phosphorylation and the transcriptional competence of the hormone inducible mouse mammary tumor virus (MMTV) promoter. Prolonged exposure of mouse cells to dexamethasone concurrently dephosphorylated histone H1 and rendered the MMTV promoter refractory to hormonal stimulation and, therefore, transcriptionally unresponsive. Using electrospray mass spectrometry, we demonstrate here that prolonged dexamethasone treatment differentially effects a subset of the six somatic H1 isoforms in mouse cells. H1 isoforms H1.0, H1.1, and H1.2 are non-responsive to hormone whereas prolonged dexamethasone treatment effectively dephosphorylated the H1.3, H1.4, and H1.5 isoforms. The protein kinase inhibitor staurosporine, shown to dephosphorylate historic H1 and down-regulate MMTV in cultured cells, appears only to completely dephosphorylate the H1.3 isoform. These results suggest that dephosphorylation of specific histone H1 isoforms may contribute to the previously observed decrease in transcriptional competence of the MMTV promoter through the modulation of chromatin structure. In a broader sense, this work advances the hypothesis that post-translational modifications of individual histone H1 isoforms directly influence the transcriptional activation/repression of specific genes. C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, MD E4-06, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 44 TC 40 Z9 40 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 28 PY 2001 VL 276 IS 39 BP 36467 EP 36473 DI 10.1074/jbc.M104641200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475XF UT WOS:000171194500057 PM 11479299 ER PT J AU Tokita, K Katsuno, T Hocart, SJ Coy, DH Llinares, M Martinez, J Jensen, RT AF Tokita, K Katsuno, T Hocart, SJ Coy, DH Llinares, M Martinez, J Jensen, RT TI Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN NEUROKININ-1 RECEPTOR; PROTEIN-COUPLED RECEPTORS; NEUROMEDIN-B RECEPTOR; SWISS 3T3 CELLS; BOMBESIN RECEPTOR; BINDING-SITES; AGONIST-BINDING; LIGAND-BINDING; AMINO-ACID; EXTRACELLULAR DOMAINS AB Few gastrointestinal hormones/neurotransmitters have high affinity peptide receptor antagonists, and little is known about the molecular basis of their selectivity or affinity. The receptor mediating the action of the mammalian bombesin (Bn) peptide, gastrin-releasing peptide receptor (GRPR), is an exception, because numerous classes of peptide antagonists are described. To investigate the molecular basis for their high affinity for the GRPR, two classes of peptide antagonists, a statine analogue, JMV594 ([D-Phe(6),Stat(13)]Bn(6-14)), and a pseudopeptide analogue, JMV641 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu psi (CHOH-CH2)-(CH2)(2)-CH3), were studied. Each had high affinity for the GRPR and >3,000-fold selectivity for GRPR over the closely related neuromedin B receptor (NMBR). To investigate the basis for this, we used a chimeric receptor approach to make both GRPR loss of affinity and NMBR gain of affinity chimeras and a site-directed mutagenesis approach. Chimeric or mutated receptors were transiently expressed in Balb/c 3T3. Only substitution of the fourth extracellular (EC) domain of the GRPR by the comparable NMBR domain markedly decreased the affinity for both antagonists. Substituting the fourth EC domain of NMBR into the GRPR resulted in a 300-fold gain in affinity for JMV594 and an 11-fold gain for JMV641. Each of the 11 amino acid differences between the GRPR and NMBR in this domain were exchanged. The substitutions of Thr(297) in GRPR by Pro from the comparable position in NMBR, Phe(302) by Met, and Ser(305) by Thr decreased the affinity of each antagonist. Simultaneous replacement of Thr(297), Phe(302), and Ser(305) in GRPR by the three comparable NMBR amino acids caused a 500-fold decrease in affinity for both antagonists. Replacing the comparable three amino acids in NMBR by those from GRPR caused a gain in affinity for each antagonist. Receptor modeling showed that each of these three amino acids faced inward and was within 5 Angstrom of the putative binding pocket. These results demonstrate that differences in the fourth EC domain of the mammalian Bn receptors are responsible for the selectivity of these two peptide antagonists. They demonstrate that Thr(297), Phe(302), and Ser(305) of the fourth EC domain of GRPR are the critical residues for determining GRPR selectivity and suggest that both receptor-ligand cation-pi interactions and hydrogen bonding are important for their high affinity interaction. C1 NIDDK, DDB, NIH, Bethesda, MD 20892 USA. Tulane Univ, Hlth Sci Ctr, Peptide Res Labs, Dept Med, New Orleans, LA 70112 USA. Univ Montpellier, Fac Pharm, F-34060 Montpellier, France. RP Jensen, RT (reprint author), NIDDK, DDB, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. OI Martinez, Jean/0000-0002-9267-4621 NR 75 TC 30 Z9 32 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 28 PY 2001 VL 276 IS 39 BP 36652 EP 36663 DI 10.1074/jbc.M104566200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475XF UT WOS:000171194500080 PM 11463790 ER PT J AU Wheeler, MD Nakagami, M Bradford, BU Uesugi, T Mason, RP Connor, HD Dikalova, A Kadiiska, M Thurman, RG AF Wheeler, MD Nakagami, M Bradford, BU Uesugi, T Mason, RP Connor, HD Dikalova, A Kadiiska, M Thurman, RG TI Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; LIPID-PEROXIDATION; KUPFFER CELLS; MITOCHONDRIAL GLUTATHIONE; DIETARY-FAT; FISH-OIL; ETHANOL; HEPATOCYTES; DISEASE; EXPOSURE AB Mitochondria are thought to play a major role in hepatic oxidative stress associated with alcohol-induced liver injury. Thus, the hypothesis that delivery of the mitochondrial isoform of superoxide dismutase (Mn-SOD) via recombinant adenovirus would reduce alcohol-induced liver injury was tested. Rats were given recombinant adenovirus containing Mn-SOD (Ad.SOD2) or beta -galactosidase (Ad.lacZ) and then fed alcohol enterally for 4 weeks. Mn-SOD expression and activity of Ad.SOD2 in liver mitochondria of infected animals was increased nearly 3-fold compared with Ad.lacZ-infected controls. Mitochondrial glutathione levels in Ad.lacZ-infected animals were decreased after 4 weeks of chronic ethanol, as expected, but were unchanged in Ad.SOD2-infected animals. Alanine aminotransferase was elevated significantly by ethanol, an effect that was prevented by Ad.SOD2. Moreover, pathology (e.g. the sum of steatosis, inflammation, and necrosis) was elevated dramatically by ethanol in Ad.lacZ-treated rats. This effect was also blunted in animals infected with Ad.SOD2. Neutrophil infiltration was increased about 3-fold in livers from both Ad.lacZ- and Ad.SOD2-infected rats by ethanol treatment. Moreover, ESR-detectable free radical adducts in bile were increased about 8-fold by ethanol. Using C-13-labeled ethanol, it was determined that nearly 60% of total adducts were due to the a-hydroxyethyl radical adduct. This increase in radical formation was blocked completely by Ad.SOD2 infection. Furthermore, apoptosis of hepatocytes was increased about 5-fold by ethanol, an effect also blocked by Ad.SOD2. Interestingly, tumor necrosis factor-alpha mRNA was elevated to the same extent in both Ad.lacZ- and Ad.SOD2-infected animals follows ethanol exposure. These data suggest that hepatocyte mitochondrial oxidative stress is involved in alcohol-induced liver damage and likely follows Kupffer cell activation, cytokine production, and neutrophil infiltration. These results also support the hypothesis that mitochondrial oxidant production is a critical factor in parenchymal cell death caused by alcohol. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Wheeler, MD (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. NR 58 TC 128 Z9 130 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 28 PY 2001 VL 276 IS 39 BP 36664 EP 36672 DI 10.1074/jbc.M105352200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475XF UT WOS:000171194500081 PM 11477087 ER PT J AU Hall, MC Wang, H Erie, DA Kunkel, TA AF Hall, MC Wang, H Erie, DA Kunkel, TA TI High affinity cooperative DNA binding by the yeast Mlh1-Pms1 heterodimer SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE mismatch repair; Mlh1; Pms1; MutL homologs; DNA binding; recombination ID DIRECTED MISMATCH REPAIR; ATOMIC-FORCE MICROSCOPY; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; CROSSING-OVER; PROTEIN MUTS; HELICASE-II; COMPLEX; HYDROLYSIS; MEIOSIS AB We demonstrate here that the Saccharomyces cerevisiae Mlh1-Pms1 heterodimer required for DNA mismatch repair and other cellular processes is a DNA binding protein. Binding was evaluated using a variety of single and double-stranded DNA molecules. Mlh1-Pms1 bound short substrates with low affinity and showed a slight preference for single-stranded DNA. In contrast, Mlh1-Pms1 exhibited a much higher affinity for long DNA molecules, suggesting that binding is cooperative. High affinity binding required a duplex DNA length greater than 241 base-pairs. The rate of association with DNA was rapid and dissociation of protein-DNA complexes following extensive dilution was very slow. However, in competition experiments, we observed a rapid active transfer of Mlh1-Pms1 from labeled to unlabeled DNA. Binding was non-sequence specific and highly sensitive to salt type and concentration, suggesting that Mlh1-Pms1 primarily interacts with the DNA backbone via ionic contacts. Cooperative binding was observed visually by atomic force microscopy as long, continuous tracts of Mlh1-Pms1 protein bound to duplex DNA. These images also showed that Mlh1-Pms1 simultaneously interacts with two different regions of duplex DNA. Taken together, the atomic force microscope images and DNA binding assays provide strong evidence that Mlh1-Pms1 binds duplex DNA with positive cooperativity and that there is more than one DNA binding site on the heterodimer. These DNA binding properties of Mlh1-Pms1 may be relevant to its participation in DNA mismatch repair, recombination and cellular responses to DNA damage. C1 NIEHS, Labs Mol Genet & Struct Biol, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kunkel, TA (reprint author), NIEHS, Labs Mol Genet & Struct Biol, Res Triangle Pk, NC 27709 USA. RI Wang, Hong/F-3164-2014 OI Wang, Hong/0000-0003-0165-3559 FU NIEHS NIH HHS [ES09895] NR 37 TC 43 Z9 44 U1 1 U2 7 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 28 PY 2001 VL 312 IS 4 BP 637 EP 647 DI 10.1006/jmbi.2001.4958 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 481TP UT WOS:000171536600006 PM 11575920 ER PT J AU Evdokimov, AG Anderson, DE Routzahn, KM Waugh, DS AF Evdokimov, AG Anderson, DE Routzahn, KM Waugh, DS TI Unusual molecular architecture of the Yersinia pestis cytotoxin YopM: A leucine-rich repeat protein with the shortest repeating unit SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Yersinia pestis; YopM; leucine-rich repeat; contact-dependent secretion; type III secretion ID CRYSTAL-STRUCTURE; III SECRETION; TYROSINE PHOSPHATASE; BACTERIAL PATHOGENS; VIRULENCE FACTOR; HOST-CELLS; BINDING; DISRUPTION; TARGETS; PROGRAM AB Many Gram-negative bacterial pathogens employ a contact-dependent (type III) secretion system to deliver effector proteins into the cytosol of animal or plant cells. Collectively, these effectors enable the bacteria to evade the immune response of the infected organism by modulating host-cell functions. YopM, a member of the leucine-rich repeat protein superfamily, is an effector produced by the bubonic plague bacterium, Yersinia pestis, that is essential for virulence. Here, we report crystal structures of YopM at 2.4 and 2.1 Angstrom resolution. Among all leucine-rich repeat family members whose atomic coordinates have been reported, the repeating unit of YopM has the least canonical secondary structure. In both crystals, four YopM monomers form a hollow cylinder with an inner diameter of 35 Angstrom. The domain that targets YopM for translocation into eukaryotic cells adopts a well-ordered, alpha -helical conformation that packs tightly against the proximal leucine-rich repeat module. A similar alpha -helical domain can be identified in virulence-associated leucine-rich repeat proteins produced by Salmonella typhimurium and Shigella flexneri, and in the conceptual translation products of several open reading frames in Y. pestis. C1 NCI, Crystallog Lab, Prot Engn Sect, Frederick, MD 21702 USA. RP Evdokimov, AG (reprint author), NCI, Crystallog Lab, Prot Engn Sect, POB B, Frederick, MD 21702 USA. NR 52 TC 111 Z9 118 U1 1 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 28 PY 2001 VL 312 IS 4 BP 807 EP 821 DI 10.1006/jmbi.2001.4973 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 481TP UT WOS:000171536600020 PM 11575934 ER PT J AU Rackoff, J Yang, QF DePetrillo, PB AF Rackoff, J Yang, QF DePetrillo, PB TI Inhibition of rat PC12 cell calpain activity by glutathione, oxidized glutathione and nitric oxide SO NEUROSCIENCE LETTERS LA English DT Article DE calpain; glutathione; inhibitor; nitric oxide ID OXIDATIVE STRESS; LIVER; PROTEOLYSIS; DISULFIDES; APOPTOSIS; INJURY; PAPAIN AB Calpain, a calcium activated neutral protease, is involved in mediating neurotoxicity resulting from conditions of oxidative stress and free radical formation, such as hypoxia and ischemia. Nitric oxide (NO) may also be involved in modulating the cytotoxic effects of oxidative stress. We investigated the roles of reduced glutathione (GSH), oxidized glutathione (GSSG), and NO in modulating calpain activity in PC12 cells. Cell extracts were treated with GSSG, GSH, or the NO-donor S-nitroso-N-acetylpenicillamine. Calpain activity was determined by means of a fluorescent assay. Non-linear regression analysis was used to determine the type of inhibition (competitive, uncompetitive, or non-competitive). GSH displayed uncompetitive inhibition, with K-i = 7.0 +/- 2.0 mM (Mean +/- SEM) while GSSG exhibited competitive inhibition with K-i = 2.5 +/- 0.3 mM. NO was an irreversible inhibitor of calpain activity. These results suggest that both GSH and GSSG may be important physiological modulators of calpain activity. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Div Intramural Clin & Biochem Res,NIH, Bethesda, MD 20892 USA. RP DePetrillo, PB (reprint author), NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Div Intramural Clin & Biochem Res,NIH, 10-3C103,10 Ctr Dr,MSC 1256, Bethesda, MD 20892 USA. NR 20 TC 7 Z9 7 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 SEP 28 PY 2001 VL 311 IS 2 BP 129 EP 132 DI 10.1016/S0304-3940(01)02161-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 478DQ UT WOS:000171328000016 PM 11567795 ER PT J AU Haxby, JV Gobbini, MI Furey, ML Ishai, A Schouten, JL Pietrini, P AF Haxby, JV Gobbini, MI Furey, ML Ishai, A Schouten, JL Pietrini, P TI Distributed and overlapping representations of faces and objects in ventral temporal cortex SO SCIENCE LA English DT Article ID INFEROTEMPORAL CORTEX; PERCEPTION; AREA; RECOGNITION; COMPONENTS; EXPERTISE; STIMULI; SPACE AB The functional architecture of the object vision pathway in the human brain was investigated using functional magnetic resonance imaging to measure patterns of response in ventral temporal cortex white subjects viewed faces, cats, five categories of man-made objects, and nonsense pictures. A distinct pattern of response was found for each stimulus category. The distinctiveness of the response to a given category was not due simply to the regions that responded maximally to that category, because the category being viewed also could be identified on the basis of the pattern of response when those regions were excluded from the analysis. Patterns of response that discriminated among A categories were found even within cortical regions that responded maximally to only one category. These results indicate that the representations of faces and objects in ventral temporal cortex are widely distributed and overlapping. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Pisa, Dept Human & Environm Sci, I-56126 Pisa, Italy. Univ Pisa, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. RP Haxby, JV (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RI Furey, Maura/H-5273-2013 NR 35 TC 1652 Z9 1675 U1 22 U2 168 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 28 PY 2001 VL 293 IS 5539 BP 2425 EP 2430 DI 10.1126/science.1063736 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PD UT WOS:000171237200038 PM 11577229 ER PT J AU Litt, MD Simpson, M Gaszner, M Allis, CD Felsenfeld, G AF Litt, MD Simpson, M Gaszner, M Allis, CD Felsenfeld, G TI Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus SO SCIENCE LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; INSULATOR; EXPRESSION; GENE AB Methylation of histories at specific residues plays an important role in transcriptional regulation. Chromatin immunoprecipitation of dimethytated lysine 9 on histone H3 across 53 kilobases of the chicken beta -globin locus during erythropoiesis shows an almost complete anticorrelation between regions of elevated lysine 9 methylation and acetylation. Lysine 9 is methylated most over constitutive condensed chromatin and developmentally inactive globin genes. In contrast, lysine 4 methylation of histone H3 correlates with H3 acetylation. These results lead us to propose a mechanism by which the insulator in the beta -globin locus can protect the globin genes from being silenced by adjacent condensed chromatin. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 21 TC 472 Z9 484 U1 2 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 28 PY 2001 VL 293 IS 5539 BP 2453 EP 2455 DI 10.1126/science.1064413 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PD UT WOS:000171237200047 PM 11498546 ER PT J AU Fan, Y Shi, LM Kohn, KW Pommier, Y Weinstein, JN AF Fan, Y Shi, LM Kohn, KW Pommier, Y Weinstein, JN TI Quantitative structure-antitumor activity relationships of camptothecin analogues: Cluster analysis and genetic algorithm-based studies SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DNA-TOPOISOMERASE-I; TUMOR-CELL-LINES; MOLECULAR-DYNAMICS SIMULATIONS; DRUG DISCOVERY DATABASES; FUNCTION APPROXIMATION; EXPRESSION DATABASE; ELLIPTICINE ANALOGS; CANCER; DERIVATIVES; MECHANISM AB Topoisomerase 1 (top1) inhibitors are proving useful against a range of refractory tumors, and there is considerable interest in the development of additional top1 agents. Despite crystallographic studies, the binding site and ligand properties that lead to activity are poorly understood. Here we report a unique approach to quantitative structure-activity relationship (QSAR) analysis based on the National Cancer Institute's (NCI) drug databases. In 1990, the NCI established a drug discovery program in which compounds are tested for their ability to inhibit the growth of 60 different human cancer cell lines in culture. More than 70 000 compounds have been screened, and patterns of activity against the 60 cell lines have been found to encode rich information on mechanisms of drug action and drug resistance. Here, we use hierarchical clustering to define antitumor activity patterns in a data set of 167 tested camptothecins (CPTs) in the NCI drug database. The average pairwise Pearson correlation coefficient between activity patterns for the CPT set was 0.70. Coherence between chemical structures and their activity patterns was observed. QSAR studies were carried out using the mean 50% growth inhibitory concentrations (GI(50)) for 60 cell lines as the dependent variables. Different statistical methods, including stepwise linear regression, principal component regression (PCR), partial least-squares regression (PLS), and fully cross-validated genetic function approximation (GFA) were applied to construct quantitative structure-antitumor relationship models. For our data set, the GFA method performed better in terms of correlation coefficients and cross-validation analysis. A number of molecular descriptors were identified as being correlated with antitumor activity. Included were partial atomic charges and three interatomic distances that define the relative spatial dispositions of three significant atoms (the hydroxyl hydrogen of the E-ring, the lactone carbonyl oxygen of the E-ring, and the carbonyl oxygen of the D-ring). The cross-validated r(2) for the final GFA model was 0.783, indicating a predictive QSAR model. C1 NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Weinstein, JN (reprint author), NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NR 48 TC 147 Z9 150 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 27 PY 2001 VL 44 IS 20 BP 3254 EP 3263 DI 10.1021/jm0005151 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 476EU UT WOS:000171213900007 PM 11563924 ER PT J AU Eichhorn, EJ Krause-Steinrauf, H Lavori, PW AF Eichhorn, EJ Krause-Steinrauf, H Lavori, PW TI Effects of beta-blocker therapy in severe chronic heart failure. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Texas, SW Med Ctr, Dallas, TX 75216 USA. NHLBI, Bethesda, MD 20817 USA. Vet Affairs Med Ctr, Menlo Pk, CA 94025 USA. RP Eichhorn, EJ (reprint author), Univ Texas, SW Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75216 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 27 PY 2001 VL 345 IS 13 BP 999 EP 999 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 475NF UT WOS:000171170000019 ER PT J AU Mullan, PB Quinn, JE Gilmore, PM McWilliams, S Andrews, H Gervin, C McCabe, N McKenna, S White, P Song, YH Maheswaran, S Liu, E Haber, DA Johnston, PG Harkin, DP AF Mullan, PB Quinn, JE Gilmore, PM McWilliams, S Andrews, H Gervin, C McCabe, N McKenna, S White, P Song, YH Maheswaran, S Liu, E Haber, DA Johnston, PG Harkin, DP TI BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents SO ONCOGENE LA English DT Article DE BRCA1; GADD45; antimicrotubule agents; G2/M arrest; cell death ID DNA-DAMAGE RESPONSE; TRANSCRIPTION-COUPLED REPAIR; POLYMERASE-II HOLOENZYME; GENE-EXPRESSION; PROTEIN; PHOSPHORYLATION; ASSOCIATION; ACTIVATION; CHECKPOINT; INDUCTION AB BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds. C1 Queens Univ Belfast, Canc Res Ctr, Dept Oncol, Belfast BT9 7AB, Antrim, North Ireland. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA 02114 USA. NIH, Div Clin Sci, Bethesda, MD 20892 USA. RP Harkin, DP (reprint author), Queens Univ Belfast, Belfast City Hosp, Canc Res Ctr, Dept Oncol, Univ Floor,Lisburn Rd, Belfast BT9 7AB, Antrim, North Ireland. RI Liu, Edison/C-4141-2008 NR 40 TC 116 Z9 120 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 27 PY 2001 VL 20 IS 43 BP 6123 EP 6131 DI 10.1038/sj.onc.1204712 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 476BL UT WOS:000171206300003 PM 11593420 ER PT J AU Schmidt, M Koller, R Haviernik, P Bies, J Maciag, K Wolff, L AF Schmidt, M Koller, R Haviernik, P Bies, J Maciag, K Wolff, L TI Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15(INK4b) normally associated with differentiation SO ONCOGENE LA English DT Article DE c-Myb; p15(INK4b); myeloid leukemia ID CELL-CYCLE INHIBITORS; TERMINAL DIFFERENTIATION; GENE FAMILY; BALB/C MICE; APOPTOSIS; INACTIVATION; METHYLATION; P16(INK4A); INDUCTION; PROTEIN AB Deregulated expression of the proto-oncogene c-myb, which results from provirus integration, is thought to be responsible for transformation in a set of murine leukemia virus (MuLV)-induced myeloid leukemias (MML). We reported recently that this transcription factor promotes proliferation by directly transactivating c-myc and inhibits cell death through its up-regulation of Bcl-2 (Schmidt et al., 2000). To understand more about how these cells become transformed we looked at how they deal with cellular pathways inducing growth arrest. Specifically, we were interested in the expression of the tumor suppressor gene Cdkn2b (p15(INK4b)) in MML because this gene is expressed during myeloid differentiation and its inactivation by methylation has been shown to be important for the development of human acute myeloid leukemia. mRNA levels for p15(INK4b) and another INK4 gene p16(INK4b) were examined in monocytic Myb tumors and were compared with expression of the same genes in c-myc transformed monocytic tumors that do not express c-Myb. The Cdkn2a (p16(INK4b)) gene was generally not expressed in either tumor type, an observation explained by methylation or deletion in the promoter region. Although Cdkn2b (p15(INK4b)) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1. Surprisingly, in the majority of the Myb tumors there was no p15(INK4b) transcription and neither deletion nor methylation could explain this result. Additional experiments demonstrated that, in the presence of constitutive c-Myb expression, the induction of p15(INK4b) mRNA that accompanies differentiation of MI cells to monocytes does not occur. Therefore, the transcriptional regulator c-Myb appears to prevent activation of a growth arrest pathway that normally accompanies monocyte maturation. C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Canc Res Inst, Mol Virol Lab, Bratislava, Slovakia. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. OI , /0000-0003-0803-4312 NR 45 TC 11 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 27 PY 2001 VL 20 IS 43 BP 6205 EP 6214 DI 10.1038/sj.onc.1204821 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 476BL UT WOS:000171206300012 PM 11593429 ER PT J AU Kondo, M Ji, L Kamibayashi, C Tomizawa, Y Randle, D Sekido, Y Yokota, J Kashuba, V Zabarovsky, E Kuzmin, I Lerman, M Roth, J Minna, JD AF Kondo, M Ji, L Kamibayashi, C Tomizawa, Y Randle, D Sekido, Y Yokota, J Kashuba, V Zabarovsky, E Kuzmin, I Lerman, M Roth, J Minna, JD TI Overexpression of candidate tumor suppressor gene FUS1 isolated from the 3p21.3 homozygous deletion region leads to G1 arrest and growth inhibition of lung cancer cells SO ONCOGENE LA English DT Article DE tumor suppressor gene; growth inhibition; lung cancer ID HUMAN-CHROMOSOME 3P21.3; LOCUS; IDENTIFICATION; SEARCH AB Recently we identified FUS1 as a candidate tumor suppressor gene (TSG) in the 120 kb 3p21.3 critical region contained in nested lung and breast cancer homozygous deletions. Mutation of FUS1 is infrequent in lung cancers which we have confirmed in 40 other primary lung cancers. In addition, we found no evidence for FUS1 promoter region methylation. Because haplo-insufficiency or low expression of Fus1 may play a role in lung tumorigenesis, we tested the effect of exogenously induced overexpression of Fus1 protein and found 60-80% inhibition of colony formation for non-small cell lung cancer lines NCI-H1299 (showing allele loss for FUS1) and NCI-H322 (containing only a mutated FUS1 allele) in vitro. By contrast, a similar level of expression of a tumor-acquired mutant form of FUS1 protein did not significantly suppress colony formation. Also, induced expression of Fus1 under the control of an Ecdysone regulated promoter decreased colony formation 75%, increased the doubling time twofold, and arrested H1299 cells in G1. In conclusion, our data are consistent with the hypothesis that FUS1 may function as a 3p21.3 TSG, warranting further studies of its function in the pathogenesis of human cancers. C1 Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Sect Thorac Mol Oncol, Houston, TX 77030 USA. Nagoya Univ, Sch Med, Dept Clin Prevent Med, Nagoya, Aichi 466, Japan. Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan. Karolinska Inst, MTC, Stockholm, Sweden. Karolinska Inst, CGR, Stockholm, Sweden. Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD USA. RP Minna, JD (reprint author), Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, 6000 Harry Hines Blvd,NB8-206, Dallas, TX 75390 USA. RI Zabarovsky, Eugene/A-6645-2010; KONDO, Masashi/I-7378-2014; Sekido, Yoshitaka/P-9756-2015 FU NCI NIH HHS [P50 CA70907, CA 71618] NR 21 TC 58 Z9 65 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 27 PY 2001 VL 20 IS 43 BP 6258 EP 6262 DI 10.1038/sj.onc.1204832 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 476BL UT WOS:000171206300019 PM 11593436 ER PT J AU Foley, DJ Masaki, K Redline, S AF Foley, DJ Masaki, K Redline, S TI Relationship between apolipoprotein E epsilon 4 and sleep-disordered breathing at different ages SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID JAPANESE-AMERICAN MEN C1 NIA, Bethesda, MD 20892 USA. Univ Hawaii, Honolulu, HI 96822 USA. Univ Hosp Cleveland, Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. RP Foley, DJ (reprint author), NIA, Bethesda, MD 20892 USA. NR 5 TC 45 Z9 47 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 SEP 26 PY 2001 VL 286 IS 12 BP 1447 EP 1447 DI 10.1001/jama.286.12.1447 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 475UX UT WOS:000171188600013 PM 11572727 ER PT J AU Hediger, ML Ruan, WJ Overpeck, MD Kuczmarski, R AF Hediger, ML Ruan, WJ Overpeck, MD Kuczmarski, R TI Breastfeeding and risk of overweight - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. US Hlth Resources & Serv Adm, Maternal & Child Hlth Bur, Rockville, MD 20857 USA. Ctr Dis Control & Prevent, Div Hlth Examinat Stat, Natl Ctr Hlth Stat, Hyattsville, MD USA. RP Hediger, ML (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 26 PY 2001 VL 286 IS 12 BP 1449 EP 1450 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 475UX UT WOS:000171188600016 ER PT J AU Sanchez, AM Schreiber, GB Bethel, J McCurdy, PR Glynn, SA Williams, AE Gilcher, R AF Sanchez, AM Schreiber, GB Bethel, J McCurdy, PR Glynn, SA Williams, AE Gilcher, R CA Retrovirus Epidemiology Donor Stud TI Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-B ANTIGEN; HEREDITARY HEMOCHROMATOSIS; UNITED-STATES; TRANSFUSION; EXCLUSION; ANTIBODY; IMPACT AB Context Despite changes in eligibility policies, practical barriers limit blood donations from individuals with hemochromatosis. Increased knowledge of hemochromatosis donor characteristics may help foster further changes that will promote more donations. Objectives To estimate the prevalence of donors diagnosed as having hemochromatosis and to compare rates of unreported deferrable risks for transfusion-transmissible viral infections (TTVIs), positive screening test results for TTVIs, and donation patterns between hemochromatosis patient donors and donors reporting no medical conditions necessitating phlebotomy (non-health-related donors). Design An anonymous mail survey conducted in 1998 as part of the ongoing Retrovirus Epidemiology Donor Study. Setting and Participants Among a stratified probability sample of 92581 blood donors from 8 geographically diverse US blood centers, 52650 (57%) responded. Main Outcome Measures Prevalence of hemochromatosis among blood donors; prevalence of unreported deferrable risks and positive screening test results for TTVIs among hemochromatosis patient donors vs non-health-related donors. Results One hundred ninety-seven respondents (0.4%) identified themselves as hemochromatosis patients and 50079 (95.1%) as non-health-related donors. An estimated 0.8% of all donations were from hemochromatosis patients, 45.8% of whom reported that they had donated blood to treat their illness. The proportion of repeat donors was higher in hemochromatosis patients than in non-health-related donors (83.5% vs 76.5%; P = .03). Among repeat donors, 68.7% of hemochromatosis patients reported donating at least 3 times in the past year compared with 49.1% of non-health-related donors (P<.001). The prevalence of unreported deferrable risks for TTVIs was similar in hemochromatosis patients (2.0%) and non-health-related donors (3.1%) as was the overall prevalence of positive screening test results (1.3% of hemochromatosis patients vs 1.6% of non-health-related donors). Conclusions Although significant numbers of hemochromatosis patients reported donating blood for therapeutic reasons, our findings suggest that this population does not present a greater risk to blood safety than other donors. C1 WESTAT Corp, Rockville, MD 20850 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. Oklahoma Blood Inst, Sylvan N Goldman Ctr, Oklahoma City, OK USA. RP Sanchez, AM (reprint author), WESTAT Corp, WB 266,1650 Res Blvd, Rockville, MD 20850 USA. FU NHLBI NIH HHS [N01-HB-97077, N01-HB-97079, N01-HB-97080, N01-HB-97082, N01-HB-97078, N01-HB-97081, N01-HB-47114] NR 39 TC 20 Z9 20 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 26 PY 2001 VL 286 IS 12 BP 1475 EP 1481 DI 10.1001/jama.286.12.1475 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 475UX UT WOS:000171188600025 PM 11572740 ER PT J AU Zweckstetter, M Bax, A AF Zweckstetter, M Bax, A TI Single-step determination of protein substructures using dipolar couplings: Aid to structural genomics SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BACKBONE CONFORMATION; EMPIRICAL CORRELATION; CHEMICAL-SHIFTS; NMR; BIOMOLECULES; ALIGNMENT; ALPHA C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zweckstetter, M (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 57 Z9 57 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 26 PY 2001 VL 123 IS 38 BP 9490 EP 9491 DI 10.1021/ja016496h PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 475NC UT WOS:000171169700051 PM 11562251 ER PT J AU Rathore, D McCutchan, TF Garboczi, DN Toida, T Hernaiz, MJ LeBrun, LA Lang, SC Linhardt, RJ AF Rathore, D McCutchan, TF Garboczi, DN Toida, T Hernaiz, MJ LeBrun, LA Lang, SC Linhardt, RJ TI Direct measurement of the interactions of glycosaminoglycans and a heparin decasaccharide with the malaria circumsporozoite protein SO BIOCHEMISTRY LA English DT Article ID REGION-II-PLUS; PLASMODIUM-FALCIPARUM; SPOROZOITE INVASION; CELL-ADHESION; CHONDROITIN SULFATE; BINDING; THROMBOSPONDIN; HEPATOCYTES; OLIGOSACCHARIDES; PROTEOGLYCANS AB Circumsporozoite (CS) protein is a predominant surface antigen of malaria sporozoites, the infective form of the parasite, and has been used for making anti-malaria vaccines. For the first time we have examined the interaction of CS protein with various glycosaminoglycans in real time using surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Heparin was the best binder among the glycosaminoglycans tested and bound to CS protein with nanomolar affinity. Using purified and structurally defined small heparin oligosaccharides, we identified a decasaccharide to be the minimum sized CS protein-binding sequence. In an indirect competition assay, this decasaccharide blocked the CS protein interaction with HepG2 cells with an ID50 Of less than 60 nM. The decasaccharide has a structure commonly found in hepatic heparan sulfate, and the same sequence has recently been shown to bind specifically to apolipoprotein E. Examination of porcine liver heparan sulfate in this indirect competition assay showed that it and heparin were the only glycosaminoglycans that could effectively block CS protein interaction with HepG2 cells in culture. These data support the hypothesis that the invasion of liver cells by the parasite shares a common mechanism with the hepatic uptake of lipoprotein remnants from the blood. C1 Univ Iowa, Dept Med, Iowa City, IA 52242 USA. Univ Iowa, Dept Nat Prod Chem, Iowa City, IA 52242 USA. Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. Univ Iowa, Dept Chem & Biochem Engn, Iowa City, IA 52242 USA. NIAID, Parasit Dis Lab, Growth & Dev Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunogenet Lab, Struct Biol Sect, NIH, Rockville, MD 20852 USA. Chiba Univ, Sch Pharm, Dept Analyt Chem, Chiba, Japan. RP Linhardt, RJ (reprint author), Univ Iowa, Dept Med, PHAR S 342, Iowa City, IA 52242 USA. FU NHLBI NIH HHS [HL52622]; NIGMS NIH HHS [GM38060] NR 30 TC 55 Z9 57 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 25 PY 2001 VL 40 IS 38 BP 11518 EP 11524 DI 10.1021/bi0105476 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 476BA UT WOS:000171205300025 PM 11560500 ER PT J AU Chen, Y Matsushita, M Nairn, AC Damuni, Z Cai, DC Frerichs, KU Hallenbeck, JM AF Chen, Y Matsushita, M Nairn, AC Damuni, Z Cai, DC Frerichs, KU Hallenbeck, JM TI Mechanisms for increased levels of phosphorylation of elongation factor-2 during hibernation in ground squirrels SO BIOCHEMISTRY LA English DT Article ID PROTEIN PHOSPHATASE 2A; FACTOR-II KINASE; TRANSLATIONAL CONTROL; RABBIT RETICULOCYTES; CATALYTIC DOMAIN; GENE-EXPRESSION; IDENTIFICATION; BRAIN; PURIFICATION; CELLS AB Previously, eEF-2 phosphorylation has been identified as a reversible mechanism involved in the inhibition of the elongation phase of translation. In this study, an increased level of phosphorylation of eukaryotic elongation factor-2 (eEF-2) was observed in the brains and livers of hibernating ground squirrels. In brain and liver from hibernators, eEF-2 kinase activity was increased relative to that of active animals. The activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF-2, was also decreased in brain and liver from hibernators. This was associated with an increase in the level of inhibitor 2 of PP2A (I-2(PP2A)), although there was an increase in the level of the catalytic subunit of PP2A (PP2A/C) in hibernating brains and livers. These results indicate that eEF-2 phosphorylation represents a specific and previously uncharacterized mechanism for inhibition of the elongation phase of protein synthesis during hibernation. Increased levels of eEF-2 phosphorylation in hibernators appear to be a component of the regulated shutdown of cellular functions that permits hibernating animals to tolerate severe reductions in cerebral blood flow and oxygen delivery capacity. C1 NINCDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Brigham & Womens Hosp, Div Neurosurg, Boston, MA 02115 USA. RP Hallenbeck, JM (reprint author), NINCDS, Stroke Branch, NIH, Bldg 36,Room 4A03,36 Convent Dr,MSC 3128, Bethesda, MD 20892 USA. OI Nairn, Angus/0000-0002-7075-0195 FU NIGMS NIH HHS [GM50402] NR 43 TC 54 Z9 55 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 SEP 25 PY 2001 VL 40 IS 38 BP 11565 EP 11570 DI 10.1021/bi010649w PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 476BA UT WOS:000171205300031 PM 11560506 ER PT J AU Kass, DA Shapiro, EP Kawaguchi, M Capriotti, AR Scuteri, A deGroof, RC Lakatta, EG AF Kass, DA Shapiro, EP Kawaguchi, M Capriotti, AR Scuteri, A deGroof, RC Lakatta, EG TI Improved arterial compliance by a novel advanced glycation end-product crosslink breaker SO CIRCULATION LA English DT Article DE ALT-711; arteries; compliance; aging; glycosylation end products, advanced; hypertension ID BLOOD-PRESSURE MONITOR; PULSE PRESSURE; AORTIC COMPLIANCE; RADIAL TONOMETRY; HEART-FAILURE; IN-VIVO; HYPERTENSION; STIFFNESS; RISK; SPHYGMOMANOMETER AB Background-Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. Methods and Results-Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures > 60 mm Hg and systolic pressures > 140 min Hg to once-daily ALT-711 (210 mg; n=62) or placebo (n=31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (-5.3 versus -0.6 min Hg at day 56; P=0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (P=0.056). Mean pressure declined similarly in both groups (-4 mm Hg; P <0.01 for each group, P=0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711-treated subjects versus no change with placebo (P=0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (P <0.05 at day 56, P=0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group. Conclusions-ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension. C1 Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21287 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Alteon Inc, Ramsey, NJ 07446 USA. RP Kass, DA (reprint author), Johns Hopkins Med Inst, Div Cardiol, 600 N Wolfe St,Halsted 500, Baltimore, MD 21287 USA. NR 39 TC 451 Z9 479 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 25 PY 2001 VL 104 IS 13 BP 1464 EP 1470 DI 10.1161/hc3801.097806 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 477CM UT WOS:000171265600015 PM 11571237 ER PT J AU Moore, DF Scott, LTC Gladwin, MT Altarescu, G Kaneski, C Suzuki, K Pease-Fye, M Ferri, R Brady, RO Herscovitch, P Schiffmann, R AF Moore, DF Scott, LTC Gladwin, MT Altarescu, G Kaneski, C Suzuki, K Pease-Fye, M Ferri, R Brady, RO Herscovitch, P Schiffmann, R TI Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease - Reversal by enzyme replacement therapy SO CIRCULATION LA English DT Article DE cerebrovascular disorders; nitric oxide; tomography; regional blood flow; cerebrovascular circulation ID QUANTITATIVE-ANALYSIS; POTASSIUM CHANNELS; ARTERIOLES AB Background-Fabry disease is an X-linked lysosomal deficiency of a-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure. Methods and Results-Using [O-15] H2O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of a-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels. Conclusions-These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy. C1 Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, PET Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. Univ Vermont, Dept Neurol, Burlington, VT USA. Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. RP Schiffmann, R (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Kaneski, Christine/0000-0003-1453-2502 NR 27 TC 176 Z9 183 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 25 PY 2001 VL 104 IS 13 BP 1506 EP 1512 DI 10.1161/hc3801.096352 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 477CM UT WOS:000171265600022 PM 11571244 ER PT J AU Kikonyogo, A Bouamr, F Vana, ML Xiang, Y Aiyar, A Carter, C Leis, J AF Kikonyogo, A Bouamr, F Vana, ML Xiang, Y Aiyar, A Carter, C Leis, J TI Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RSV; Gag; virus particle assembly ID VESICULAR STOMATITIS-VIRUS; MURINE LEUKEMIA-VIRUS; WW DOMAIN; IMMUNODEFICIENCY-VIRUS; MATRIX PROTEIN; RELEASE; IDENTIFICATION; MYRISTYLATION; EXPRESSION; MUTATIONS AB The late assembly (L) domain of retrovirus Gag, required in the final steps of budding for efficient exit from the host cell, is thought to mediate its function through interaction with unknown cellular factors. Here, we report the identification of the Nedd4-like family of E3 ubiquitin protein ligases as proteins that specifically interact with the Rous sarcoma virus (RSV) L domain in vitro and in vivo. We screened a chicken embryo cDNA expression library by using a peptide derived from the RSV p2b sequence, isolating two unique partial cDNA clones. Neither clone interacted with a peptide containing mutations known to disrupt in vivo RSV L domain function or with human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus (EIAV) L domain-derived peptides. The WW domain region of one of the clones, late domain-interacting protein 1 (LDI-1), but not the C2 domain, bound RSV Gag and inhibited RSV Gag budding from human 293 cells in a dominant-negative manner, functionally implicating LDI-1 in RSV particle budding from cells. RSV Gag can be coimmune precipitated from cell extracts with an antisera directed at an exogenously expressed hemagglutinin (HA)-tagged LDI-1 or endogenous Nedd4 proteins. These findings mechanistically link the cellular ubiquitination pathway to retrovirus budding. C1 Northwestern Univ, Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. NIAID, Mol Virol Lab, Bethesda, MD 20892 USA. RP Leis, J (reprint author), Northwestern Univ, Sch Med, Dept Microbiol & Immunol, Ward Bldg,Room 4-065,303 E Chicago Ave, Chicago, IL 60611 USA. FU NCI NIH HHS [K01 CA082177, K01 CA082177-03, CA82177, CA52047, R01 CA052047]; NIGMS NIH HHS [GM48294, R01 GM048294, GM58271] NR 43 TC 165 Z9 165 U1 3 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2001 VL 98 IS 20 BP 11199 EP 11204 DI 10.1073/pnas.201268998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100042 PM 11562473 ER PT J AU Allander, T Emerson, SU Engle, RE Purcell, RH Bukh, J AF Allander, T Emerson, SU Engle, RE Purcell, RH Bukh, J TI A virus discovery method incorporating DNase treatment and its application to the identification of two bovine parvovirus species SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; HEPATITIS AGENT; B HEPATITIS; NON-A; CDNA; AMPLIFICATION; SERUM; CLONING; DISEASE; GENOMES AB Identification of previously unrecognized viral agents in serum or plasma samples is of great medical interest but remains a major challenge, primarily because of abundant host DNA. The current methods, library screening or representational difference analysis (RDA), are very laborious and require selected sample sets. We have developed a simple and reproducible method for discovering viruses in single serum samples that is based on DNase treatment of the serum followed by restriction enzyme digestion and sequence-independent single primer amplification (SISPA) of the fragments, and have evaluated its performance on known viruses. Both DNA viruses and RNA viruses at a concentration of approximate to 10(6) genome equivalents per ml were reproducibly identified in 50 mul of serum. While evaluating the method, two previously unknown parvoviruses were discovered in the bovine sera used as diluent. The near complete genome sequence of each virus was determined; their classification as two species (provisionally named bovine parvoviruses 2 and 3) was confirmed by phylogenetic analysis. Both viruses were found to be frequent contaminants of commercial bovine serum. DNase treatment of serum samples may prove to be a very useful tool for virus discovery. The DNase-SISPA method is suitable for screening of a large number of samples and also enables rapid sequence determination of high-titer viruses. C1 NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, Mol Hepatitis Sect, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, 7 Ctr Dr,MSC 0740,Bldg 7,Room 201, Bethesda, MD 20892 USA. FU NCI NIH HHS [CO-56000] NR 23 TC 192 Z9 213 U1 4 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 SEP 25 PY 2001 VL 98 IS 20 BP 11609 EP 11614 DI 10.1073/pnas.211424698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100112 PM 11562506 ER PT J AU Mengozzi, M Malipatlolla, M De Rosa, SC Herzenberg, LA Herzenberg, LA Roederer, M AF Mengozzi, M Malipatlolla, M De Rosa, SC Herzenberg, LA Herzenberg, LA Roederer, M TI Naive CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CD62L; CCR5; B7; CD3; proliferation ID IMMUNODEFICIENCY-VIRUS TYPE-1; BLOOD MONONUCLEAR-CELLS; CD28 COSTIMULATION; IN-VITRO; PREFERENTIAL REPLICATION; DIFFERENTIAL REGULATION; INFECTION; EXPRESSION; LYMPHOCYTES; CCR5 AB Stimulation with antibodies to CD3 and CD28 coimmobilized on beads can be used to significantly expand T cells ex vivo. With CD4 T cells from HIV-infected patients, this expansion usually is accompanied by complete suppression of viral replication, presumed to be caused by down-regulation of the viral coreceptor CCR5 and up-regulation of CCR5 ligands. Here we show that this suppression occurs in total CD4 T cells acutely infected with R5 HIV, but not in purified CD62L(-) memory CD4 T cells. The lack of complete suppression in these memory cells, typically comprising 10-40% of total CD4 T cells, occurs despite high levels of CCR5 ligand secretion and down-regulation of CCR5. Significantly, adding back naive or CD62L(+) memory CD4 T cells inhibits the viral replication in the CD62L(-) cells, with the naive cells capable of completely repressing the virus. Although this inhibition was previously thought to be specific to bead-bound anti-CD3/CD28 stimulation, we show that the same suppression is obtained with sufficiently strong antiCD3/B7.1 stimulation. Our results show that inhibitory mechanisms, expressed predominantly by strongly stimulated naive CD4 T cells and mediated independently of CCR5-binding chemokines, play a role in the inhibition of R5 HIV replication in CD4 T cells upon CD28 costimulation. C1 Stanford Univ, Dept Genet, Stanford, CA 94305 USA. RP Roederer, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 FU NCI NIH HHS [CA-42509-14, CA-81543-02] NR 29 TC 13 Z9 13 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 SEP 25 PY 2001 VL 98 IS 20 BP 11644 EP 11649 DI 10.1073/pnas.211205098 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100118 PM 11562498 ER PT J AU Thompson, PM Vidal, C Giedd, JN Gochman, P Blumenthal, J Nicolson, R Toga, AW Rapoport, JL AF Thompson, PM Vidal, C Giedd, JN Gochman, P Blumenthal, J Nicolson, R Toga, AW Rapoport, JL TI Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHILDHOOD; CORTEX; DEFICITS; DENSITY; MRI; DYSFUNCTION; MORPHOLOGY; DISORDER AB Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks, as well as early (pre/perinatal) and late (usually adolescent) developmental brain abnormalities. With the use of brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia; surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were rescanned prospectively with MRI, at 2-year intervals at three time points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (i) controlled for medication and IQ effects, (it) replicated in independent groups of males and females, and (fit) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia. Aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and nongenetic patterns of deficits. C1 Univ Calif Los Angeles, Sch Med, Lab Neuroimaging,Div Brain Mapping, Dept Neurol,Reed Neurol Res Ctr, Los Angeles, CA 90095 USA. NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Thompson, PM (reprint author), Univ Calif Los Angeles, Sch Med, Lab Neuroimaging,Div Brain Mapping, Dept Neurol,Reed Neurol Res Ctr, Room 4238,710 Westwood Plaza, Los Angeles, CA 90095 USA. RI Giedd, Jay/A-3080-2008; Nicolson, Robert/E-4797-2011; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NCRR NIH HHS [P41 RR013642, P41 RR13642]; NIMH NIH HHS [P20 MH/DA52176]; NINDS NIH HHS [NS38753]; NLM NIH HHS [LM/MH05639] NR 56 TC 493 Z9 499 U1 10 U2 43 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2001 VL 98 IS 20 BP 11650 EP 11655 DI 10.1073/pnas.201243998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100119 PM 11573002 ER PT J AU Quattrone, A Pascale, A Nogues, X Zhao, WQ Gusev, P Pacini, A Alkon, DL AF Quattrone, A Pascale, A Nogues, X Zhao, WQ Gusev, P Pacini, A Alkon, DL TI Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-BINDING PROTEIN; GAP-43 MESSENGER-RNA; AU-RICH ELEMENTS; 3'-UNTRANSLATED REGION; PC12 CELLS; NEURITE OUTGROWTH; TUMOR-ANTIGEN; MEMORY; DIFFERENTIATION; INCREASES AB The view that memory is encoded by variations in the strength of synapses implies that long-term biochemical changes take place within subcellular microdomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however, cannot be fully explained by a purely transcriptional control of gene expression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding proteins act posttranscriptionally by binding to adenine- and uridine-rich elements (ARES) in the 3 ' untranslated region of a set of target mRNAs, and by increasing mRNA cytoplasmic stability and/or rate of translation. Here we show that neuronal ELAV-like genes undergo a sustained up-regulation in hippocampal pyramidal cells only of mice and rats that have learned a spatial discrimination paradigm. This learning-specific increase of ELAV-like proteins was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulated mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant downregulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-induced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage. C1 Johns Hopkins Univ, Blanchette Rockefeller Neurosci Inst, W Virginia Univ, Rockville, MD 20850 USA. NINCDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. Univ Bordeaux 1, Cognit Neurosci Lab, F-33405 Talence, France. Univ Florence, Dept Anat Histol & Forens Med, Lab Funct Morphol, I-50134 Florence, Italy. RP Quattrone, A (reprint author), Johns Hopkins Univ, Blanchette Rockefeller Neurosci Inst, W Virginia Univ, Acad & Res Bldg,9601 Med Ctr Dr, Rockville, MD 20850 USA. RI QUATTRONE, Aldo/A-6734-2016; OI QUATTRONE, Aldo/0000-0003-2001-957X; Quattrone, Alessandro/0000-0003-3333-7630 NR 35 TC 99 Z9 101 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2001 VL 98 IS 20 BP 11668 EP 11673 DI 10.1073/pnas.191388398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100122 PM 11573004 ER PT J AU Misner, DL Jacobs, S Shimizu, Y de Urquiza, AM Solomin, L Perlmann, T De Luca, LM Stevens, CF Evans, RM AF Misner, DL Jacobs, S Shimizu, Y de Urquiza, AM Solomin, L Perlmann, T De Luca, LM Stevens, CF Evans, RM TI Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RETINOID-BINDING-PROTEINS; CENTRAL-NERVOUS-SYSTEM; ACID RECEPTORS; DIFFERENTIAL EXPRESSION; DOCOSAHEXAENOIC ACID; MOUSE EMBRYOS; X-RECEPTOR; BRAIN; MICE; POTENTIATION AB Despite its long history, the central effects of progressive depletion of vitamin A in adult mice has not been previously described. An examination of vitamin-deprived animals revealed a progressive and ultimately profound impairment of hippocampal CA1 longterm potentiation and a virtual abolishment of long-term depression. Importantly, these losses are fully reversible by dietary vitamin A replenishment in vivo or direct application of all trans-retinoic acid to acute hippocampal slices. We find retinoid responsive transgenes to be highly active in the hippocampus, and by using dissected explants, we show the hippocampus to be a site of robust synthesis of bioactive retinoids. In aggregate, these results demonstrate that vitamin A and its active derivatives function as essential competence factors for long-term synaptic plasticity within the adult brain, and suggest that key genes required for long-term potentiation and long-term depression are retinoid dependent. These data suggest a major mental consequence for the hundreds of millions of adults and children who are vitamin A deficient. C1 Salk Inst Biol Studies, Howard Hughes Med Inst, Gene Express Lab, La Jolla, CA 92037 USA. Salk Inst Biol Studies, Howard Hughes Med Inst, Mol Neurobiol Lab, La Jolla, CA 92037 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Ludwig Inst Canc Res, S-17177 Stockholm, Sweden. RP Evans, RM (reprint author), Salk Inst Biol Studies, Howard Hughes Med Inst, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU PHS HHS [27183] NR 45 TC 176 Z9 184 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2001 VL 98 IS 20 BP 11714 EP 11719 DI 10.1073/pnas.191369798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100130 PM 11553775 ER PT J AU Vazquez, G Lievremont, JP Bird, GS Putney, JW AF Vazquez, G Lievremont, JP Bird, GS Putney, JW TI Human Trp3 forms both inositol trisphosphate receptor-dependent and receptor-independent store-operated cation channels in DT40 avian B lymphocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SMOOTH-MUSCLE CELLS; CAPACITATIVE CALCIUM-ENTRY; STIMULATES CA2+ INFLUX; 1,4,5-TRISPHOSPHATE RECEPTORS; HUMAN HOMOLOG; DEPLETION; GENE; EXPRESSION; ACTIVATION; CURRENTS AB Mammalian Trp proteins are candidates for plasma membrane calcium channels regulated by receptor activation or by intracellular calcium store depletion [capacitative calcium entry (CCE)]. One extensively investigated member of the Trp family, the human Trp3 (hTrp3), behaves as a receptor-activated, calcium-permeable, nonselective cation channel when expressed in cell lines and does not appear to be activated by store depletion. Nonetheless, there is good evidence that Trp3 can be regulated by interacting with inositol trisphosphate receptors (IP(3)Rs), reminiscent of the conformational coupling mode of CCE. To investigate the role of Trp3 in CCE, and its regulation by IP3R, we transiently expressed hTrp3 in the wild-type DT40 chicken B lymphocyte cell line and its variant lacking IP3R. Expression of hTrp3 in either wild-type or IP3R-knockout cells did not increase basal membrane permeability, but resulted in a substantially greater divalent cation entry after thapsigargin-induced store depletion. This hTrp3-dependent divalent cation entry was significantly greater in the wild type than in IP3R-knockout cells. Thus, it appears that in this cell line, hTrp3 forms channels that are store-operated by both IP3R-dependent and IP3R-independent mechanisms. Trp3, or one of its structural relatives, is a candidate for the store-operated, nonselective cation channels observed in smooth muscle cells and other cell types. C1 Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Vazquez, G (reprint author), Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 125 Z9 135 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2001 VL 98 IS 20 BP 11777 EP 11782 DI 10.1073/pnas.201238198 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 476PC UT WOS:000171237100141 PM 11553786 ER PT J AU Berezhkovskii, AM Makhnovskii, YA Weiss, GH AF Berezhkovskii, AM Makhnovskii, YA Weiss, GH TI Trapping of Brownian particles by random spheres of different radii SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DIFFUSION-CONTROLLED REACTIONS; WIENER SAUSAGE; STATIC TRAPS; SINKS; KINETICS; SIZE AB We analyze the survival of a Brownian particle moving among randomly distributed spherical traps of two different radii. All of the results known in the case of identical traps, the mean-field Smoluchowski solution, the lowest order correction of this solution, the cumulant expansion, and the long-time behavior, are generalized to the case of two types of traps. Our approach is readily extended to deal with trapping spheres having more than two different radii. (C) 2001 American Institute of Physics. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Berezhkovskii, AM (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X NR 23 TC 4 Z9 4 U1 1 U2 2 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 22 PY 2001 VL 115 IS 12 BP 5376 EP 5380 DI 10.1063/1.1396673 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 472YZ UT WOS:000171013700006 ER PT J AU Weiss, SC Emanuel, LL Fairclough, DL Emanuel, EJ AF Weiss, SC Emanuel, LL Fairclough, DL Emanuel, EJ TI Adequacy of treatment in terminally ill patients - Reply SO LANCET LA English DT Letter C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Chicago, IL USA. AMC Canc Res Ctr, Ctr Res Methodol & Biometr, Denver, CO USA. RP Weiss, SC (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 22 PY 2001 VL 358 IS 9286 BP 1015 EP 1015 DI 10.1016/S0140-6736(01)06143-8 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 474YR UT WOS:000171135300052 ER PT J AU Dawson, K Aviles-Hernandez, A Cushman, SW Malide, D AF Dawson, K Aviles-Hernandez, A Cushman, SW Malide, D TI Insulin-regulated trafficking of dual-labeled glucose transporter 4 in primary rat adipose cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE GLUT4; GFP; glucose transport; insulin response; confocal microscopy; adipose tissue ID GREEN-FLUORESCENT PROTEIN; 3T3-L1 ADIPOCYTES; PLASMA-MEMBRANE; STIMULATED TRANSLOCATION; 3T3L1 ADIPOCYTES; GLUT4; SURFACE; MECHANISM; LOCALIZATION; COMPARTMENTS AB In isolated rat adipose cells, physiologically relevant insulin target cells, glucose transporter 4 (GLUT4) subcellular trafficking can be assessed by transfection of exofacially HA-tagged GLUT4. To simultaneously visualize the transfected GLUT4, we fused GFP with HA-GLUT4. With the resulting chimeras, GFP-HA-GLUT4 and HA-GLUT4-GFP, we were able to visualize for the first time the cell-surface localization, total expression, and intracellular distribution of GLUT4 in a single cell. Confocal microscopy reveals that the intracellular proportions of both GFP-HA-GLUT4 and HA-GLUT4-GFP are properly targeted to the insulin-responsive aminopeptidase-positive vesicles. Dynamic studies demonstrate close similarities in the trafficking kinetics between the two constructs and with native GLUT4. However, while the basal subcellular distribution of HA-GLUT4-GFP and the response to insulin are indistinguishable from those of HA-GLUT4 and endogenous GLUT4, most of the GFP-HA-GLUT4 is targeted to the plasma membrane with little further insulin response. Thus, HA-GLUT4-GFP will be useful to study GLUT4 trafficking in vivo while GFP on the N-terminus interferes with intracellular retention. C1 NIDDK, EDMNS, DB, NIH, Bethesda, MD 20892 USA. RP Cushman, SW (reprint author), NIDDK, EDMNS, DB, NIH, Bldg 8,Room 326,8 Ctr Dr MSC 0842, Bethesda, MD 20892 USA. NR 38 TC 47 Z9 51 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 21 PY 2001 VL 287 IS 2 BP 445 EP 454 DI 10.1006/bbrc.2001.5620 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 476BE UT WOS:000171205700023 PM 11554749 ER PT J AU Ahmed, FAKM Hegazy, K Chaudhary, P Sharma, SC AF Ahmed, FAKM Hegazy, K Chaudhary, P Sharma, SC TI Neuroprotective effect of alpha(2) agonist (brimonidine) on adult rat retinal ganglion cells after increased intraocular pressure SO BRAIN RESEARCH LA English DT Article DE neuroprotection; brimonidine; adrenoceptor; alpha(2)-agonist; cell death; retinal ganglion cell; hypertensive eye ID OPEN-ANGLE GLAUCOMA; BALTIMORE EYE SURVEY; HYPERTENSIVE EYES; GLUTAMATE; DEATH; PREVALENCE; BODY AB Brimonidine, a selective alpha (2)-adrenoceptor agonist, has recently been shown to be neuroprotective as it significantly improves survival of retinal ganglion cells (RGCs) after calibrated optic nerve injury in rats. In the present study, we examined the effect of brimonidine (alpha (2)-adrenoceptor agonist) on RGC survival after increased intraocular pressure (IOP) in adult rats. RM were prelabeled by bilateral tectal injection of 5% Fluoro-Gold (FG). Two days later, unilaterally IOP was increased 2.2-2.5 times (28-30.5 mmHg) that of the normal pressure (12.5-14.5 mmHg) by cauterization of three episcleral veins. The elevated IOP was maintained throughout the duration of the experiment. Rats were treated intraperitoneally with brimonidine (1 mg/kg) or phosphate-buffered saline (PBS) once per week beginning either before (group A) or after (group B) increasing the IOP. Another group of rats was left as the control with elevated IOP but without any brimonidine/PBS treatment. Rats were euthanized at 3, 4 and 5 weeks after IOP elevation. Identifiable RM were counted and compared between control and experimental groups. Brimonidine significantly protected RGCs from elevated IOP-induced cell death. In control rats with three-vein cauterization, there was 5-6% cell death per week. Almost all RGCs were protected following brimonidine treatment for 3 weeks both in groups A and B. At 4 weeks, there was 4.5% cell death in group A and 6.5% in group B. At 5 weeks, cell death was 5.9% in group A and 6.2% in group B. The difference in cell death in groups A and B was insignificant. No significant differences were observed between PBS-treated and control groups. No significant changes in elevated IOP was found after brimonidine or PBS treatment when compared with the nontreated control group. Although pressure remained elevated throughout the length of the experiment, 3 weeks later the amount of cell death gradually increased in brimonidine-treated animals. (C) 2001 Elsevier Science B.V. All rights reserved. C1 New York Med Coll, Dept Ophthalmol, Valhalla, NY 10595 USA. RP Ahmed, FAKM (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 6,Room 2A04,6 Ctr Dr,MSC 2730, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY 11295] NR 35 TC 44 Z9 47 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 21 PY 2001 VL 913 IS 2 BP 133 EP 139 DI 10.1016/S0006-8993(01)02759-7 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 478VL UT WOS:000171366000002 PM 11549376 ER PT J AU Karimullah, K George, DT DePetrillo, PB AF Karimullah, K George, DT DePetrillo, PB TI The time-course of electrocardiographic interbeat interval dynamics in alcoholic subjects after short-term abstinence SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE heart rate; electrocardiography; alcohol-related disorders; fractal; toxicology ID HEART-RATE-VARIABILITY; RESPIRATORY SINUS ARRHYTHMIA; SPECTRAL-ANALYSIS; SERIES; NONSTATIONARITY; CONSUMPTION; RECOVERY; GENDER; PERIOD; MEN AB Alcohol dependence has been correlated with decreases in heart rate variability. However, the time course of recovery of heart rate variability after cessation of alcohol consumption is unknown. We used electrocardiogram (ECG) data serially obtained from a population of detoxifying alcoholic subjects to determine the Hurst exponent of the ECG interbeat interval time series. Higher values of the Hurst exponent are associated with decreased heart rate variability when H less than or equal to 0.5. We tested a series of response-surface models relating the Hurst exponent (H) thus obtained to the following independent variables: the time interval T (days since last use of alcohol), A (age in years at time of admission), and gender. The best-fit model was: H(T) = (KA + HmT + HfT)/(1 + T), F = 5.2, P(F) less than or equal to 0.01. Model parameters were: K = 0.008 +/- 0.002 (mean +/- SEM); asymptotic H-values for males and females: H-m = 0.24 +/- 0.02 and H-f = 0.16 +/- 0.03, respectively, significantly different at P less than or equal to 0.05. Age was the strongest predictor of initial H-values in this alcoholic population sample. (C) 2001 Published by Elsevier Science B.V. C1 NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP DePetrillo, PB (reprint author), NIAAA, Clin Studies Lab, Unit Clin & Biochem Pharmacol, Intramural Res Program,NIH, NIH 10-3C103,10 Ctr Dr MSC 1256, Bethesda, MD 20892 USA. NR 31 TC 3 Z9 3 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 21 PY 2001 VL 427 IS 3 BP 227 EP 233 DI 10.1016/S0014-2999(01)01247-X PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 479AU UT WOS:000171382400007 PM 11567653 ER PT J AU Germain, RN AF Germain, RN TI The T cell receptor for antigen: Signaling and ligand discrimination SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID PEPTIDE-MHC COMPLEXES; IMMUNOLOGICAL SYNAPSE; BINDING-SITE; CLASS-I; TYROSINE KINASES; MEMBRANE DOMAINS; LIPID RAFTS; ACTIVATION; CD4; TRANSDUCTION C1 NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bldg 10,Rm 11N311,10 Ctr Dr,MSC-1892, Bethesda, MD 20892 USA. NR 68 TC 48 Z9 52 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 21 PY 2001 VL 276 IS 38 BP 35223 EP 35226 DI 10.1074/jbc.R100025200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 474LU UT WOS:000171109300001 PM 11435448 ER PT J AU Lawson, VA Priola, SA Wehrly, K Chesebro, B AF Lawson, VA Priola, SA Wehrly, K Chesebro, B TI N-terminal truncation of prion protein affects both formation and conformation of abnormal protease-resistant prion protein generated in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOUSE NEUROBLASTOMA-CELLS; NEURO-BLASTOMA CELLS; CULTURED-CELLS; BIOCHEMICAL-PROPERTIES; INSERTIONAL MUTATION; SCRAPIE AGENT; PRP 27-30; CONVERSION; SUSCEPTIBILITY; INHIBITION AB Transmissible spongiform encephalopathy diseases are characterized by conversion of the normal protease-sensitive host prion protein, PrP-sen, to an abnormal protease-resistant form, PrP-res. In the current study, deletions were introduced into the flexible tail of PrP-sen (23-124) to determine if this region was required for formation of PrP-res in a cell-free assay. PrP-res formation was significantly reduced by deletion of residues 34-94 relative to full-length hamster PrP. Deletion of another nineteen amino acids to residue 113 further reduced the amount of PrP-res formed. Furthermore, the presence of additional proteinase K cleavage sites indicated that deletion to residue 113 generated a protease-resistant product with an altered conformation. Conversion of PrP deletion mutants was also affected by post-translational modifications to PrP-sen. Conversion of unglycosylated PrP-sen appeared to alter both the amount and the conformation of protease-resistant PrP-res produced from N-terminally truncated PrP-sen. The N-terminal region also affected the ability of hamster PrP to block mouse PrP-res formation in scrapie-infected mouse neuroblastoma cells. Thus, regions within the flexible N-terminal tail of PrP influenced interactions required for both generating and disrupting PrP-res formation. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. OI Lawson, Victoria/0000-0002-7362-7176 NR 54 TC 65 Z9 67 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 21 PY 2001 VL 276 IS 38 BP 35265 EP 35271 DI 10.1074/jbc.M103799200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 474LU UT WOS:000171109300010 PM 11466311 ER PT J AU Bandyopadhyay, G Sajan, MP Kanoh, Y Standaert, ML Quon, MJ Reed, BC Dikic, I Farese, RV AF Bandyopadhyay, G Sajan, MP Kanoh, Y Standaert, ML Quon, MJ Reed, BC Dikic, I Farese, RV TI Glucose activates protein kinase C-zeta/lambda through proline-rich tyrosine kinase-2, extracellular signal-regulated kinase, and phospholipase D - A novel mechanism for activating glucose transporter translocation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT SKELETAL-MUSCLE; INSULIN-INDUCED ACTIVATION; MEMBRANE GLUT4 CONTENT; PHOSPHATIDYLINOSITOL 3-KINASE; ACUTE HYPERGLYCEMIA; GLUCOSE-TRANSPORTER-4 TRANSLOCATION; POTENTIAL ROLE; ADIPOCYTES; ZETA; LAMBDA AB Insulin controls glucose uptake by translocating GLUT4 and other glucose transporters to the plasma membrane in muscle and adipose tissues by a mechanism that appears to require protein kinase C (PKC)-zeta/lambda operating downstream of phosphatidylinositol 3-kinase. In diabetes mellitus, insulin-stimulated glucose uptake is diminished, but with hyperglycemia, uptake is maintained but by uncertain mechanisms. Presently, we found that glucose acutely activated PKC-zeta/lambda in rat adipocytes and rat skeletal muscle preparations by a mechanism that was independent of phosphatidylinositol 3-kinase but, interestingly, dependent on the apparently sequential activation of the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; components of the extracellular signal-regulated kinase (ERK) pathway, including, GRB2, SOS, RAS, RAN, MEK1 and ERK1/2; and, most interestingly, phospholipase D, thus yielding increases in phosphatidic acid, a known activator of PKC-zeta/lambda. This activation of PKC-zeta/lambda, moreover, appeared to be required for glucose-induced increases in GLUT4 translocation and glucose transport in adipocytes and muscle cells. Our findings suggest the operation of a novel pathway for activating PKC-zeta/lambda and glucose transport. C1 Univ S Florida, Coll Med, James A Haley Vet Hosp, Res Serv, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Internal Med, Tampa, FL 33612 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA. Ludwig Inst Canc Res, S-75124 Uppsala, Sweden. RP Farese, RV (reprint author), Univ S Florida, Coll Med, James A Haley Vet Hosp, Res Serv, VAR 151,13000 Bruce B Downs Blvd, Tampa, FL 33612 USA. RI Quon, Michael/B-1970-2008; Farese, Robert/B-3605-2015; Dikic, Ivan/O-4650-2015 OI Dikic, Ivan/0000-0001-8156-9511 FU NIDDK NIH HHS [R01 DK065969] NR 36 TC 57 Z9 58 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 21 PY 2001 VL 276 IS 38 BP 35537 EP 35545 DI 10.1074/jbc.M106042200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 474LU UT WOS:000171109300045 PM 11463795 ER PT J AU Randerath, K Zhou, GD Somers, RL Robbins, JH Brooks, PJ AF Randerath, K Zhou, GD Somers, RL Robbins, JH Brooks, PJ TI A P-32-Postlabeling assay for the oxidative DNA lesion 8,5 '-cyclo-2 '-deoxyadenosine in mammalian tissues - Evidence that four type II I-compounds are dinucleotides containing the lesion in the 3 ' nucleotide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT-LIVER DNA; XERODERMA-PIGMENTOSUM; EXCISION-REPAIR; FERRIC NITRILOTRIACETATE; DIETARY RESTRICTION; PYRIMIDINE DIMERS; RENAL CARCINOGEN; FENTON REACTIONS; DAMAGE; ADDUCTS AB 8,5 ' -Cyclopurine-2 ' -deoxynuelcotides, which are strong blocks to mammalian DNA and RNA polymerases, represent a novel class of oxidative DNA lesion in that they are specifically repaired by nucleotide excision repair but not by base excision repair or direct enzymatic reversion. Previous studies using thin layer chromatography of P-32-postlabeled DNA digests have detected several bulky oxidative lesions of unknown structure, called I-compounds, in DNA from normal mammalian organs. We investigated whether any of these type II I-compounds contained 8,5 ' -cyclo-2 ' -deoxyadenosine (cA). Two previously detected type II I-compounds were found to be dinucleotides of the sequence pAp-cAp and pCp-cAp. Furthermore, a modification of the technique resulted in detection of two additional I-compounds, pTp-cAp and pGp-eAp. Each I-compound isolated from neonatal rat liver DNA matched authentic P-32-labeled cA-containing chromatographic standards under nine different chromatographic conditions. Their levels increased significantly after normal birth. The P-32-postlabeling technique used here is capable of detecting 1-5 lesions/diploid mammalian cell. Thus, it should now be possible to detect changes of cA levels resulting from low level ionizing radiation and other conditions associated with oxidative stress, and to assess cA levels in tissues from patients with the genetic disease xeroderma pigmentosum who are unable to carry out nucleotide excision repair. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pharmacol, Div Toxicol, Houston, TX 77030 USA. Glen Res Corp, Sterling, VA 20164 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Brooks, PJ (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA32157]; NIA NIH HHS [AG07550]; NIEHS NIH HHS [ES04917] NR 72 TC 50 Z9 50 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 21 PY 2001 VL 276 IS 38 BP 36051 EP 36057 DI 10.1074/jbc.M105472200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 474LU UT WOS:000171109300110 PM 11454870 ER PT J AU Wei, Y Zhang, TY Xu, GQ Ito, Y AF Wei, Y Zhang, TY Xu, GQ Ito, Y TI Application of analytical and preparative high-speed counter-current chromatography for separation of lycopene from crude extract of tomato paste SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE tomato paste; counter-current chromatography; lycopene ID BETA-CAROTENE; PURIFICATION; CANCER; VEGETABLES; PROSTATE AB Lycopene was isolated from 100 mg of crude extract of tomato paste containing about 9% of lycopene. Analytical high-speed counter-current chromatography (HSCCC) was first used for the systematic selection of the two-phase solvent system. Then preparative HSCCC separation was performed with a nonaqueous solvent system composed of n-hexane-dichloromethane-acetonitrile at an optimum volume ratio of 10:3.5:6.5. This yielded 8.6 mg of lycopene at over 98.5% purity as determined by HPLC analysis. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Inst New Technol, Beijing Res Ctr Separat & Purificat Technol Nat P, Beijing 100035, Peoples R China. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3334,50 South Dr,MSC 8014, Bethesda, MD 20892 USA. NR 20 TC 60 Z9 68 U1 9 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 21 PY 2001 VL 929 IS 1-2 BP 169 EP 173 DI 10.1016/S0021-9673(01)01177-3 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 476CL UT WOS:000171208600017 PM 11594399 ER PT J AU Murphy, EC Zhurkin, VB Louis, JM Cornilescu, G Clore, GM AF Murphy, EC Zhurkin, VB Louis, JM Cornilescu, G Clore, GM TI Structural basis for SRY-dependent 46-X,Y sex reversal: Modulation of DNA bending by a naturally occurring point mutation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE SRY-DNA complex; 46X,Y sex reversal; DNA bending mutation; multidimensional NMR ID PHOSPHORYL TRANSFER COMPLEX; SITE-SPECIFIC RECOMBINATION; RESIDUAL DIPOLAR COUPLINGS; QUANTITATIVE J-CORRELATION; NMR STRUCTURES; 3-DIMENSIONAL STRUCTURES; ORIENTED MACROMOLECULES; STRUCTURE REFINEMENT; PROTEIN COMPLEXES; MOLECULAR-BASIS AB The HMG-box domain of the human male sex-determining factor SIZY, hSRY(HMG) (comprising residues 57-140 of the full-length sequence), binds DNA sequence-specifically in the minor groove, resulting in substantial DNA bending. The majority of point mutations resulting in 46X,Y sex reversal are located within this domain. One clinical de novo mutation, M64I in the full-length hSRY sequence, which corresponds to M9I in the present hSRYHMG construct, acts principally by reducing the extent of DNA bending. To elucidate the structural consequences of the M9I mutation, we have solved the 3D solution structures of wild-type and M9I hSRY(HMG) complexed to a DNA 14mer by NMR, including the use of residual dipolar couplings to derive long-range orientational information. We show that the average bend angle (derived from an ensemble of 400 simulated annealing structures for each complex) is reduced by similar to 13 degrees from 54(+/-2)degrees in the wild-type complex to 41(+/-2)degrees in the M9I complex. The difference in DNA bending can be localized directly to changes in roll and tilt angles in the ApA base-pair step involved in interactions with residue 9 and partial intercalation of Ile13. The larger bend angle in the wild-type complex arises as a direct consequence of steric repulsion of the sugar of the second adenine by the bulky S-delta atom of Met9, whose position is fixed by a hydrogen bond with the guanidino group of Arg17. In the M9I mutant, this hydrogen bond can no longer occur, and the less bulky C(gamma)m methyl group of Ile9 braces the sugar moieties of the two adenine residues, thereby decreasing the roll and tilt angles at the ApA step by similar to8 degrees and similar to5 degrees, respectively, and resulting in an overall difference in bend angle of similar to 13 degrees between the two complexes. To our knowledge, this is one of the first examples where the effects of a clinical mutation involving a protein-DNA complex have been visualized at the atomic level. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; Cornilescu, Gabriel/H-3113-2011 OI Clore, G. Marius/0000-0003-3809-1027; Cornilescu, Gabriel/0000-0002-1204-8904 NR 86 TC 89 Z9 91 U1 1 U2 7 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 21 PY 2001 VL 312 IS 3 BP 481 EP 499 DI 10.1006/jmbi.2001.4977 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 476DK UT WOS:000171210800005 PM 11563911 ER PT J AU Demarest, JF Jack, N Cleghorn, FR Greenberg, ML Hoffman, TL Ottinger, JS Fantry, L Edwards, J O'Brien, TR Cao, K Mahabir, B Blattner, W Bartholomew, C Weinhold, KJ AF Demarest, JF Jack, N Cleghorn, FR Greenberg, ML Hoffman, TL Ottinger, JS Fantry, L Edwards, J O'Brien, TR Cao, K Mahabir, B Blattner, W Bartholomew, C Weinhold, KJ TI Immunologic and virologic analyses of an acutely HIV type 1-infected patient with extremely rapid disease progression SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; PRIMARY IMMUNE-RESPONSE; LOW VIRAL LOAD; NEUTRALIZING ANTIBODY; CHEMOKINE RECEPTORS; CELL RESPONSES; DIVERSE HUMAN; INFECTION; AIDS AB The immunologic and virologic factors that impact on the rate of disease progression after acute infection with human immunodeficiency virus (HIV) type 1 are poorly understood. A patient with an extraordinarily rapid disease course leading to AIDS-associated death within 6 months of infection was studied intensively for the presence of anti-HIV immune reactivities as well as changes in the genetic and biologic properties of virus isolates. Although altered humoral responses were evident, the most distinctive immunologic feature was a nearly complete absence of detectable HIV-specific CTL responses. In addition to a rapid decline in CD3(+)CD4(+) cells, elevated percentages of CD8(+)CD45RA(+) and CD8(+)CD57(+) cells and diminished CD8(+)CD45R0(+) and CD8(+)CD28(+) cells were evident. Primary viral isolates recovered throughout the course of infection exhibited limited sequence diversity. Cloned viral envelopes were found to have unusually broad patterns of coreceptor usage for cell-cell fusion, although infectivity studies yielded no evidence of infection via these alternative receptors. The infectivity studies demonstrated that these isolates and their envelopes maintained an R5 phenotype throughout the course of disease. The absence of demonstrable anti-HIV CTL reactivities, coupled with a protracted course of seroconversion, highlights the importance of robust HIV-specific immune responses in the control of disease progression. C1 Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Univ W Indies, Caribbean Epidemiol Ctr, Port Of Spain, Trinid & Tobago. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Univ Maryland, Med Syst, Amer Red Cross, Natl Histocompatibil Testing Lab, Baltimore, MD 21201 USA. Minist Hlth Govt Trinidad & Tobago, Port Of Spain, Trinid & Tobago. RP Weinhold, KJ (reprint author), Duke Univ, Med Ctr, Dept Surg, POB 2926, Durham, NC 27710 USA. RI Cao, Kai/I-4448-2013 FU NCI NIH HHS [N01-CP-40521, N01-CP-40547]; NIAID NIH HHS [R01-AI-29852, P30-AI-28662, AI-07392, P01-AI-40237] NR 70 TC 20 Z9 20 U1 1 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP 20 PY 2001 VL 17 IS 14 BP 1333 EP 1344 DI 10.1089/08892220152596597 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 481CC UT WOS:000171501500005 PM 11602044 ER PT J AU Hampl, M Tanaka, T Albert, PS Lee, JW Ferrari, N Fine, HA AF Hampl, M Tanaka, T Albert, PS Lee, JW Ferrari, N Fine, HA TI Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites SO HUMAN GENE THERAPY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; PLATELET FACTOR-IV; TUMOR-GROWTH; IN-VIVO; CELL APOPTOSIS; ANGIOGENESIS; ANGIOSTATIN; INHIBITION; ENDOSTATIN AB Malignant ascites is a common complication of advanced intraabdominal neoplasms for which standard treatments are suboptimal. Evidence suggests that tumor-mediated angiogenesis and enhanced vascular permeability in the peritoneal wall due to high levels of vascular endothelial growth factor play a fundamental role in the pathogenesis of malignant ascites. To explore the advantage of viral vector-mediated "targeted antiangiogenic therapy" in ascites formation, we constructed and administered adenoviral vectors encoding several different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone or in combination intraperitoneally in mice with peritoneal carcinomatosis from breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our data demonstrated statistically significant downregulation of ascites formation, tumor growth, vascularity, and prolongation of animal survival after intraperitoneal treatment with antiangiogenic adenoviral vectors in three different ascites tumor models. Combined treatment proved to be more effective than treatment with one vector alone. Reduced ascites formation was accompanied by decreased microvascular density in the peritoneal wall and increased apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant decrease in the level of VEGF secreted by tumor cells both in vitro and in TA3 ascites tumor-bearing animals in vivo. These data suggest that adenoviral vector-mediated delivery of genes encoding antiangiogenic proteins may represent a potentially new treatment modality for malignant ascites. C1 NCI, Neurooncol Branch, NINDS, NIH, Bethesda, MD 20892 USA. Jikei Univ, Sch Med, Dept Neurosurg, Tokyo 1058461, Japan. NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NCI, Neurooncol Branch, NINDS, NIH, 10 Ctr Dr,Bldg 10,Rm 12S245, Bethesda, MD 20892 USA. NR 60 TC 28 Z9 38 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD SEP 20 PY 2001 VL 12 IS 14 BP 1713 EP 1729 DI 10.1089/104303401750476221 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 475UH UT WOS:000171186100002 PM 11560766 ER PT J AU Charo, J Sundback, M Geluk, A Ottenhoff, T Kiessling, R AF Charo, J Sundback, M Geluk, A Ottenhoff, T Kiessling, R TI DNA immunization of HLA transgenic mice with a plasmid expressing mycobacterial heat shock protein 65 results in HLA class I- and II-restricted T cell responses that can be augmented by cytokines SO HUMAN GENE THERAPY LA English DT Article ID GENETIC IMMUNIZATION; IMMUNE-RESPONSE; TUBERCULOSIS; PROTECTION; VACCINES; VACCINATION; RECOGNITION; RESISTANCE; INJECTION; INFECTION AB Infection with Mycobacterium tuberculosis (MTB) remains a major cause of morbidity and mortality worldwide. An effective vaccination strategy is the immunization with plasmid DNA (pDNA), expressing an antigen (Ag) from a pathogen in vivo, which results in specific immune response against the encoded protein as well as the pathogen itself or cells infected with it. To test the ability to induce HLA-restricted T cell immune response against a mycobacterial antigen in humans by pDNA vaccination, we have used transgenic mice that express HLA class I (A*0201/Kb) or HLA class II (DRB1*0301) molecules. pDNA immunization with mycobacterial heat shock protein 65 (Mhsp65)-expressing plasmid (P3M.65) resulted in HLA-II-restricted, Ag-specific T cell-mediated immune responses characterized by proliferation and cytokine production. These T cell responses could be further augmented by the coinjection of P3M.65 and plasmid expressing murine GMCSF. Furthermore, coimmunizing HLA-I transgenic mice with P3M.65 and a plasmid expressing murine IFN-gamma induced a specific cytotoxic T lymphocyte response restricted by HLA-A2. These results represent the first evidence of a concomitant in vivo induction of HLA class I- as well as class II-restricted T cell responses by pDNA immunization, which is induced or augmented by the codelivery of cytokine-expressing plasmids, supporting its potential use in clinical trials. C1 Karolinska Hosp, Canc Ctr Karolinska, S-17176 Stockholm, Sweden. Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Leiden Univ, Med Ctr, Dept Immunohematol, NL-2300 RC Leiden, Netherlands. Leiden Univ, Med Ctr, Blood Bank, NL-2300 RC Leiden, Netherlands. RP Charo, J (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. RI Charo, Jehad/K-4433-2013 OI Charo, Jehad/0000-0002-5409-9160 NR 32 TC 16 Z9 16 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD SEP 20 PY 2001 VL 12 IS 14 BP 1797 EP 1804 DI 10.1089/104303401750476285 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 475UH UT WOS:000171186100008 PM 11560772 ER PT J AU Lee, KH Song, SU Hwang, TS Yi, Y Oh, IS Lee, JY Choi, KB Choi, MS Kim, SJ AF Lee, KH Song, SU Hwang, TS Yi, Y Oh, IS Lee, JY Choi, KB Choi, MS Kim, SJ TI Regeneration of hyaline cartilage by cell-mediated gene therapy using transforming growth factor beta 1-producing fibroblasts SO HUMAN GENE THERAPY LA English DT Article ID FACTOR-BETA; ARTICULAR-CARTILAGE; PROTEOGLYCAN SYNTHESIS; RABBIT; STIMULATION AB Transforming growth factor beta (TGF-beta) has been considered as a candidate for gene therapy of orthopedic diseases. The possible application of cell-mediated TGF-beta gene therapy as a new treatment regimen for degenerative arthritis was investigated. In this study, fibroblasts expressing active TGF-beta1 were injected into the knee joints of rabbits with artificially made cartilage defects to evaluate the feasibility of this therapy for orthopedic diseases. Two to 3 weeks after the injection there was evidence of cartilage regeneration, and at 4 to 6 weeks the cartilage defect was completely filled with newly grown hyaline cartilage. Histological analyses of the regenerated cartilage suggested that it was well integrated with the adjacent normal cartilage at the sides of the defect and that the newly formed tissue was indeed hyaline cartilage. Our findings suggest that cell-mediated TGF-beta1 gene therapy may be a novel treatment for orthopedic diseases in which hyaline cartilage damage has occurred. C1 Inha Univ, Coll Med, Clin Res Ctr, Inchon 400711, South Korea. Inha Univ, Coll Med, Dept Orthoped Surg, Inchon 400711, South Korea. Inha Univ, Coll Med, Dept Pathol, Inchon 400711, South Korea. TissueGene Inc, Gaithersburg, MD 20877 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Lee, KH (reprint author), Inha Univ, Coll Med, Clin Res Ctr, 7-206,3 Ga, Inchon 400711, South Korea. NR 22 TC 50 Z9 59 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD SEP 20 PY 2001 VL 12 IS 14 BP 1805 EP 1813 DI 10.1089/104303401750476294 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 475UH UT WOS:000171186100009 PM 11560773 ER PT J AU Quader, STA Bello-DeOcampo, D Williams, DE Kleinman, HK Webber, MM AF Quader, STA Bello-DeOcampo, D Williams, DE Kleinman, HK Webber, MM TI Evaluation of the chemopreventive potential of retinoids using a novel in vitro human prostate carcinogenesis model SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE prostate cancer; human cell lines; chemoprevention; retinoids; invasion; progression ID EPITHELIAL-CELL LINES; CANCER CELLS; CARCINOMA-CELLS; N-(4-HYDROXYPHENYL)RETINAMIDE; APOPTOSIS; PC-3 AB The prevalence of prostatic intraepithelial neoplasia (PIN) and latent prostatic carcinoma, representing multiple steps in carcinogenesis and progression to invasive carcinoma, makes them relevant targets for prevention. A unique family of human prostate epithelial cell lines, which mimic steps in prostate carcinogenesis and progression, were used to evaluate the chemopreventive potential of all-trans-retinoic acid (RA) and N-(4-hydroxyphenyl)retinamide (4-BPR). The effects of RA and 4-HPR on anchorage-dependent growth of an immortalized, non-tumorigenic cell line RWPE-1 and two tumorigenic cell lines, WPE1-NB14 and WPE1-NB11, derived from RWPE-1 by exposure to N-methyl-N-nitrosourea (MNU), were examined. Both tumorigenic cell lines grow more rapidly than the parent RWPE-1 cell line in monolayer culture. Further, while RWPE-1 cells do not form colonies in agar, both tumorigenic cell lines do, with a colony forming efficiency (CFE) of 1.85 and 2.04% for WPE1-NB14 and WPE1-NB11 cells, respectively. Both RA and 4-HPR inhibited anchorage-dependent growth of all cell lines and anchorage-independent growth of WPE1-NB14 and WPE1-NB11 cells, in a dose-dependent manner, however, 10 times more RA than 4-HPR was required to produce the same effect. RWPE-1 cells are not invasive but WPE1-NB11 cells are significantly more invasive than WPE1-NB14 cells. Both RA and 4-HPR inhibited invasion in vitro by WPE1-NB11 and WPE1-NB14 cells where the more malignant WPE1-NB11 cells showed greater inhibition of invasion by 4-HPR than by RA. Overall, 4-HPR was more effective than RA in inhibiting growth and invasion but the response varied amongst the cell lines. These three cell lines mimic progressive steps in carcinogenesis and progression, from immortalized, non-tumorigenic RWPE-1 cells, to the less malignant WPE1-NB14 to the more malignant WPE1-NB11 cells, and provide powerful models for studies on secondary and tertiary prevention, i.e. promotion and progression stages, respectively, of prostate cancer. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. NIDCR, Cell Biol Sect, NIH, Bethesda, MD USA. RP Webber, MM (reprint author), Michigan State Univ, Dept Zool, S350 Plant Biol Bldg, E Lansing, MI 48824 USA. NR 21 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD SEP 20 PY 2001 VL 496 IS 1-2 SI SI BP 153 EP 161 DI 10.1016/S1383-5718(01)00230-3 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 463NH UT WOS:000170481900018 PM 11551491 ER PT J AU Noonan, FP Recio, JA Takayama, H Duray, P Anver, MR Rush, WL De Fabo, EC Merlino, G AF Noonan, FP Recio, JA Takayama, H Duray, P Anver, MR Rush, WL De Fabo, EC Merlino, G TI Neonatal sunburn and melanoma in mice - Severe sunburn in newborn, but not adult, mice is linked with melanoma in later life. SO NATURE LA English DT Article ID FACTOR SCATTER FACTOR; MALIGNANT-MELANOMA C1 George Washington Univ, Sch Med, Dept Dermatol, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. George Washington Univ, Sch Med, Dept Immunol, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. Armed Forces Inst Pathol, Dept Dermatopathol, Washington, DC 20306 USA. RP Noonan, FP (reprint author), George Washington Univ, Sch Med, Dept Dermatol, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. NR 13 TC 224 Z9 228 U1 0 U2 1 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 20 PY 2001 VL 413 IS 6853 BP 271 EP 272 DI 10.1038/35095108 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 473KB UT WOS:000171040500027 PM 11565020 ER PT J AU Hostetter, TH AF Hostetter, TH TI Prevention of end-stage renal disease due to type 2 diabetes. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CONTROLLED TRIAL; NEPHROPATHY; ENALAPRIL; MELLITUS C1 NIDDKD, Bethesda, MD 20892 USA. RP Hostetter, TH (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 16 TC 93 Z9 95 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 20 PY 2001 VL 345 IS 12 BP 910 EP 912 DI 10.1056/NEJM200109203451209 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 473JW UT WOS:000171039600009 PM 11565525 ER PT J AU Emanuel, EJ Miller, FG AF Emanuel, EJ Miller, FG TI The ethics of placebo-controlled trials - A middle ground. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CISPLATIN-INDUCED NAUSEA; HIGH-DOSE METOCLOPRAMIDE; ACTIVE-CONTROL TRIALS; CLINICAL RESEARCH; ONDANSETRON GR-38032F; SEROTONIN ANTAGONIST; CHEMOTHERAPY; EFFICACY; EMESIS; DECLARATION C1 NIH, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 42 TC 186 Z9 192 U1 1 U2 17 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 20 PY 2001 VL 345 IS 12 BP 915 EP 919 DI 10.1056/NEJM200109203451211 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 473JW UT WOS:000171039600011 PM 11565527 ER PT J AU Carrington, M Gao, XJ O'Brien, S AF Carrington, M Gao, XJ O'Brien, S TI MHC class I molecules and progression to AIDS. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Frederick, MD 21702 USA. RP Carrington, M (reprint author), NCI, Frederick, MD 21702 USA. NR 2 TC 0 Z9 1 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 SEP 20 PY 2001 VL 345 IS 12 BP 925 EP 925 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 473JW UT WOS:000171039600022 ER PT J AU Chen, XF Thakkar, H Tyan, F Gim, S Robinson, H Lee, C Pandey, SK Nwokorie, C Onwudiwe, N Srivastava, RK AF Chen, XF Thakkar, H Tyan, F Gim, S Robinson, H Lee, C Pandey, SK Nwokorie, C Onwudiwe, N Srivastava, RK TI Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer SO ONCOGENE LA English DT Article DE TRAIL; apoptosis; prostate cancer; mitochondria; Akt; PTEN ID PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTORS; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; CYTOCHROME-C; CELL-DEATH; FREQUENT INACTIVATION; TUMORICIDAL ACTIVITY; NEGATIVE REGULATION; SURVIVAL SIGNALS AB TRAIL/Apo-2L is a member of the tumor necrosis factor superfamily and has recently been shown to induce apoptosis in cancer cells, but not in normal cells. In nude mice injected with human tumors, TRAIL reduces the size of these tumors without side effects. Akt promotes cell survival and block apoptosis. Some prostate cancer cells express high levels of Akt due to lack of active lipid phosphatase PTEN, a negative regulator of PI-3 kinase pathway, which may be responsible for drug resistance. The objective of this paper is to investigate the intracellular molecules that regulate TRAIL resistance. We have examined caspase-8 activity, BID cleavage, Akt activity, mitochondrial membrane potential (AT.) and apoptosis in prostate cancer (LNCap, PC-3, PC-3M and DU145) cells treated with or without TRAIL. PC-3, PC-3M and DU145 cells are sensitive to TRAIL, whereas LNCap cells are resistant. LNCap cells express the highest level of constitutively active Akt, which is directly correlated with TRAIL resistance. TRAIL activates caspase-8 in all the cell lines. Downregulation of constitutively active Akt by PI-3 kinase inhibitors (wortmannin and LY-294002), dominant negative Akt or PTEN, renders LNCap cells sensitive to TRAIL. Inhibition of TRAIL sensitivity occurs at the level of BID cleavage. Inhibition of protein synthesis by cycloheximide also causes LNCap cells sensitive to TRAIL. Overexpression of Bcl-2 or Bcl-X-L inhibits TRAIL-induced Delta Psi (m) and apoptosis. Overexpression of constitutively active Akt in PC-3M cells (express very low levels of constitutively active Akt) restores TRAIL resistance. These data suggest that elevated Akt activity protects LNCap cells from TRAIL-induced apoptosis, and the PI-3 kinase/Akt pathway may inhibit apoptotic signals by inhibiting processing of BID. Thus, constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Srivastava, RK (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Greenebaum Canc Ctr, 20 N Pine St, Baltimore, MD 21201 USA. NR 87 TC 229 Z9 237 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 20 PY 2001 VL 20 IS 42 BP 6073 EP 6083 DI 10.1038/sj.onc.1204736 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 473QF UT WOS:000171056300015 PM 11593415 ER PT J AU Kuttler, F Ame, P Clark, H Haughey, C Mougin, C Cahn, JY Dang, CV Raffeld, M Fest, T AF Kuttler, F Ame, P Clark, H Haughey, C Mougin, C Cahn, JY Dang, CV Raffeld, M Fest, T TI c-myc box II mutations in Burkitt's lymphoma-derived alleles reduce cell-transformation activity and lower response to broad apoptotic stimuli SO ONCOGENE LA English DT Article DE Burkitt's lymphoma; c-Myc; apoptosis; staurosporine; TNF alpha ID TRANSCRIPTIONAL ACTIVATION DOMAIN; TRANSACTIVATION DOMAIN; CYCLE; FIBROBLASTS; PROTEIN; GENE; BINDING; ARREST; REGION; GROWTH AB In addition to c-myc rearrangement, over 50% of Burkitt's lymphoma cases present clustered mutations in exon 2, where many of the functional activities of c-Myc protein are based. This report describes the functional consequences induced by tumour-derived c-myc mutations located in c-myc box II. Two mutated alleles were studied, focusing on the P138C mutation, and compared to wild-type c-myc. The c-Myc transformation, transactivation and apoptosis activities were explored based on cells over-expressing c-Myc. While the transcriptional activation activity was not affected, our experiments exploring the anchorage-independent growth capacity of c-Myc-transfected Rat1a cells showed that c-Myc box II mutants were less potent than wild-type c-Myc in promoting cell transformation. Considering the possibility that these mutations could be interfering with the ability of c-Myc to promote apoptosis, we tested c-Myc-transfected Rat1a fibroblasts under several conditions: serum deprivation-, staurosporine- and TNF alpha -induced cell death. Interestingly, the mutated alleles were characterized by an overall decrease in ability to mediate apoptosis. Our study indicates that point mutations located in c-Myc box II can decrease the ability of the protein to promote both transformation and apoptosis without modifying its transactivating activity. C1 Univ Hosp Jean Minjoz, Inst Etud & Transfert Genes, Dept Haematol & Cell Biol, F-25030 Besancon, France. NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. RP Fest, T (reprint author), Univ Hosp Jean Minjoz, Inst Etud & Transfert Genes, Dept Haematol & Cell Biol, F-25030 Besancon, France. RI Ame-Thomas, Patricia/C-3131-2017 OI Ame-Thomas, Patricia/0000-0001-8042-9250 NR 37 TC 13 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 20 PY 2001 VL 20 IS 42 BP 6084 EP 6094 DI 10.1038/sj.onc.1204827 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 473QF UT WOS:000171056300016 PM 11593416 ER PT J AU Schiffmann, R AF Schiffmann, R TI Skin manifestations of Fabry disease - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 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 SEP 19 PY 2001 VL 286 IS 11 BP 1315 EP 1315 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 473DJ UT WOS:000171024500022 ER PT J AU Owen, J Yost, N Berghella, V Thom, E Swain, M Dildy, GA Miodovnik, M Langer, O Sibai, B McNellis, D AF Owen, J Yost, N Berghella, V Thom, E Swain, M Dildy, GA Miodovnik, M Langer, O Sibai, B McNellis, D CA Natl Inst Child Hlth Human Dev Mat TI Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ULTRASONOGRAPHIC CERVICAL LENGTH; TRANSVAGINAL ULTRASONOGRAPHY; PREMATURE DELIVERY; GESTATIONAL-AGE; UTERINE CERVIX; PREDICTION; PREVENTION; PREGNANCY; CERCLAGE; INCOMPETENCE AB Context Although shortened cervical length has been consistently associated with spontaneous preterm birth, it is not known when in gestation this risk factor becomes apparent. Objective To determine whether sonographic cervical findings between 16 weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and whether serial evaluations up to 23 weeks 6 days' gestation improve prediction in high-risk women. Design, Setting, and Participants Blinded observational study performed between March 1997 and November 1999 at 9 university-affiliated medical centers in the United States in 183 women with singleton gestations who previously had experienced a spontaneous birth before 32 weeks' gestation. Observation Certified sonologists performed 590 endovaginal sonographic examinations at 2-week intervals. Cervical length was measured from the external os to the functional internal os along a closed endocervical canal. Funneling and dynamic cervical shortening were also recorded. Main Outcome Measure Spontaneous preterm birth before 35 weeks' gestation, analyzed by selected cutoff values of cervical length. Results Forty-eight women (26%) experienced spontaneous preterm birth before 35 weeks' gestation. A cervical length of less than 25 mm at the initial sonographic examination was associated with a relative risk (RR) for spontaneous preterm birth of 3.3.(95% confidence interval [CI], 2.1-5.0; sensitivity=19%; specificity=98%; positive predictive value=75%). After controlling for cervical length, neither funneling (P=.24) nor dynamic shortening (P=.054) were significant independent predictors of spontaneous preterm birth. However, using the shortest ever observed cervical length on serial evaluations, after any dynamic shortening, the RR of a cervical length of less than 25 mm for spontaneous preterm birth increased to 4.5 (95% CI, 2.7-7.6; sensitivity=69%; specificity=80%; positive predictive value=55%). Compared with a single cervical measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements at up to 23 weeks 6 days significantly improved the prediction of spontaneous preterm birth in a receiver operating characteristic curve analysis (P=.03). Conclusions Cervical length assessed by endovaginal sonography between 16 weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations, predicts spontaneous preterm birth before 35 weeks' gestation in high-risk women. C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35249 USA. Univ Texas, SW Med Ctr, Dept Obstet & Gynecol, Dallas, TX 75235 USA. Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. George Washington Univ, Ctr Biostat, Bethesda, MD USA. Wake Forest Univ, Dept Obstet & Gynecol, Winston Salem, NC 27109 USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH 45221 USA. Univ Texas, Dept Obstet & Gynecol, San Antonio, TX 78285 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN USA. NICHHD, Bethesda, MD 20892 USA. RP Owen, J (reprint author), Univ Alabama, Dept Obstet & Gynecol, 619 19th St S,OHB 458, Birmingham, AL 35249 USA. OI Berghella, Vincenzo/0000-0003-2854-0239 FU NICHD NIH HHS [HD21414, HD27860, HD27869, HD27905, HD34116, HD34136, HD34201, HD34208, HD36801] NR 32 TC 190 Z9 199 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 19 PY 2001 VL 286 IS 11 BP 1340 EP 1348 DI 10.1001/jama.286.11.1340 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 473DJ UT WOS:000171024500027 PM 11560539 ER PT J AU Levinsky, NG Yu, W Ash, A Moskowitz, M Gazelle, G Saynina, O Emanuel, EJ AF Levinsky, NG Yu, W Ash, A Moskowitz, M Gazelle, G Saynina, O Emanuel, EJ TI Influence of age on medicare expenditures and medical care in the last year of life SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ILL HOSPITALIZED ADULTS; SERIOUSLY ILL; DEATH; MORBIDITY; DECISIONS AB Context Expenditures for Medicare beneficiaries in the last year of life decrease with increasing age. The cause of this phenomenon is uncertain. Objectives To examine this pattern in detail and evaluate whether decreases in aggressiveness of medical care explain the phenomenon. Design, Setting, and Patients Analysis of sample Medicare data for beneficiaries aged 65 years or older from Massachusetts (n=34131) and California (n=19064) who died in 1996. Main Outcome Measure Medical expenditures during the last year of life, analyzed by age group, sex, race, place and cause of death, comorbidity, and use of hospital services. Results For Massachusetts and California, respectively, Medicare expenditures per beneficiary were $35300 and $27800 among those aged 65 through 74 years vs $22000 and $21600 for those aged 85 years or older. The pattern of decreasing Medicare expenditures with age is pervasive, persisting throughout the last year of life in both states for both sexes, for black and white beneficiaries, for persons with varying levels of comorbidity, and for those receiving hospice vs conventional care, regardless of cause and site of death. The aggressiveness of medical care in both Massachusetts and California also decreased with age, as judged by less frequent hospital and intensive care unit admissions and by markedly decreasing use of cardiac catheterization, dialysis, ventilators, and pulmonary artery monitors, regardless of cause of death. Decrease in the cost of hospital services accounts for approximately 80% of the decrease in Medicare expenditures with age in both states. Conclusions Medicare expenditures in the last year of life decrease with age, especially for those aged 85 years or older. This is in large part because the aggressiveness of medical care in the last year of life decreases with increasing age. C1 Boston Univ, Med Ctr, Sch Med, Dept Med,Sect Gen Internal Med,Hlth Care Res Unit, Boston, MA 02118 USA. US Dept Vet Affairs, Hlth Econ Resource Ctr Hlth Sci, Res Serv, Menlo Pk, CA USA. US Dept Vet Affairs, Hlth Econ Resource Ctr Hlth Sci, Dev Serv, Menlo Pk, CA USA. US Dept Vet Affairs, Ctr Cooperat Studies Hlth Serv, Menlo Pk, CA USA. Harvard Vanguard Med Associates, Palliat & Support Med Program, Boston, MA USA. Natl Bur Econ Res, Palo Alto, CA USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Levinsky, NG (reprint author), Boston Univ, Med Ctr, Sch Med, Dept Med,Sect Gen Internal Med,Hlth Care Res Unit, 715 Albany St, Boston, MA 02118 USA. NR 14 TC 121 Z9 121 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 19 PY 2001 VL 286 IS 11 BP 1349 EP 1355 DI 10.1001/jama.286.11.1349 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 473DJ UT WOS:000171024500028 PM 11560540 ER PT J AU Steeg, PS AF Steeg, PS TI Collapsin response mediator protein-1: a lung cancer invasion suppressor gene with nerve SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID AXON GUIDANCE; SEMAPHORIN 3A; NEUROPILIN-1; RECEPTORS; FAMILY; CELLS C1 NCI, Womens Canc Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD USA. RP Steeg, PS (reprint author), NIH, Bldg 10,Rm 2A33, Bethesda, MD 20892 USA. NR 14 TC 6 Z9 7 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 19 PY 2001 VL 93 IS 18 BP 1364 EP 1365 DI 10.1093/jnci/93.18.1364 PG 2 WC Oncology SC Oncology GA 473GZ UT WOS:000171033300001 PM 11562379 ER PT J AU Alper, O Bergmann-Leitner, ES Bennett, TA Hacker, NF Stromberg, K Stetler-Stevenson, WG AF Alper, O Bergmann-Leitner, ES Bennett, TA Hacker, NF Stromberg, K Stetler-Stevenson, WG TI Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID EXTRACELLULAR-MATRIX PROTEINS; PHOSPHOINOSITIDE 3-OH KINASE; BASEMENT-MEMBRANE; TUMOR-CELLS; ALPHA-6-BETA-4 INTEGRIN; TYROSINE KINASE; EGF RECEPTOR; FACTOR-ALPHA; CANCER; EXPRESSION AB Background: Most (70%-100%) ovarian carcinomas express high levels of the epidermal growth factor receptor (EGFR). To examine the relationship between EGFR and the invasive phenotype, we assessed integrin expression, adhesion, matrix metalloproteinase (MMP) activity, and migration in ovarian cancer cells in which EGFR expression was modified. Methods: NIH:OVCAR-8 human ovarian carcinoma cells were transfected with an expression vector containing the human EGFR complementary DNA in an antisense orientation (EGFR-antisense cells) or the vector alone (vector control cells). We compared vector control and EGFR-antisense cells for cell morphology and adhesion by light microscopy, expression of alpha (6)- and alpha (3)-integrin subunits by flow cytometry, MMP and tissue inhibitor of MMP (TIMP) activity by zymography, and migration by a wound migration assay. In some experiments, EGFR kinase activity in parental cells was inhibited by treatment with PD153035. All statistical tests were two-sided. Results: EGFR-antisense cells were morphologically distinct from vector control cells and had a selective decrease in adhesion to laminin-1 that was not observed with vector control cells (P =.008) or on other extracellular matrix substrates. Compared with vector control cells, cell surface alpha (6)-integrin expression decreased by approximately 80% (difference = 78.7%; 95% confidence interval [CI] = 77.8% to 79.6), MMP-9 activity decreased by approximately 50%, and TIMP activity increased by, approximately 50% in EGFR-antisense cells. Vector control cells were highly motile (5.51 arbitrary distance unit; 95% CI = 4.98 to 6.04), whereas the EGFR-antisense cells were not (0.99 arbitrary distance units; 95% CI = 0.38 to 1.60). The morphology and integrin profile of NIH:OVCAR-8 parental cells treated with PD153035 were similar to those of the EGFR-antisense cells. Conclusions: Reduced EGFR expression in ovarian carcinoma cells decreased their adhesion to laminin-1, expression of the alpha (6)-integrin subunit (a well-characterized laminin-1 receptor), and MMP-9 activity. These data support the hypothesis that EGFR overexpression in ovarian cancer cells results in multiple phenotypic changes that enhance the invasive phenotype. C1 Georgetown Univ, Dept Oncol, Washington, DC USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Royal Hosp Women, Gynaecol Canc Ctr, Randwick, NSW, Australia. US FDA, Div Therapeut Prot, Ctr Biol Evaluat & Res, NIH, Bethesda, MD 20014 USA. RP Stetler-Stevenson, WG (reprint author), NIH, Bldg 10,Rm 2A33,MSC 1500, Bethesda, MD 20892 USA. RI Bergmann-Leitner, Elke/B-3548-2011; Stetler-Stevenson, William/H-6956-2012 OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Stetler-Stevenson, William/0000-0002-5500-5808 NR 49 TC 101 Z9 111 U1 0 U2 3 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 19 PY 2001 VL 93 IS 18 BP 1375 EP 1384 DI 10.1093/jnci/93.18.1375 PG 10 WC Oncology SC Oncology GA 473GZ UT WOS:000171033300008 PM 11562388 ER PT J AU Warren, KE Patronas, N Aikin, AA Albert, PS Balis, FM AF Warren, KE Patronas, N Aikin, AA Albert, PS Balis, FM TI Comparison of one-, two-, and three-dimensional measurements of childhood brain tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SOLID TUMORS AB Background. End points for assessing drug activity in brain tumors are determined by measuring the change in tumor size by magnetic resonance imaging (MRI) relative to a pretreatment or best-response scan. Traditionally, two-dimensional (2D) tumor measurements have been used, but one-dimensional (1D) measurements have recently been proposed as an alternative. Because software to estimate three-dimensional (3D) tumor volume from digitized MRI images is available, we compared all three methods of tumor measurement for childhood brain tumors and clinical outcome. Methods: Tumor size from 130 MRI scans from 32 patients (32 baseline and 98 follow-up scans, for a total of 130 scans; median, three scans per patient; range, two to 18 scans) was measured by each method. Tumor-response category (partial response, minor response, stable disease, or progressive disease) was determined from the percentage change in tumor size between the baseline or best-response scan and follow-up scans. Time to clinical progression was independently determined by chart review. All statistical tests were two-sided. Results: Concordances between ID and 2D, ID and 3D, and 2D and 3D were 83% (95% confidence interval [CI] = 67% to 99%), 61% (95 % CI = 47% to 75%), and 66% (95% CI = 52% to 80%), respectively, on follow-up scans. Concordances for ID and 3D and for 2D and 3D were statistically significantly lower than the concordance for ID and 2D (P<.001 and P =.003, respectively). Concordance among 1D, 2D, and 3D methods in detecting partial response was high; there was less concordance in classifying tumors in the minor response and progressive-disease categories. Median times to progression measured by the 1D, 2D, and 3D methods were 154, 105, and 112 days, respectively, compared with 114 days based on neurologic symptoms and signs (P =.09 for overall comparison). Conclusions: Detection of partial responses was not influenced by the measurement method, but estimating time to disease progression may be method dependent for childhood brain tumors. C1 NCI, Neurooncol Branch, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Ctr Clin, Dept Radiol, Bethesda, MD USA. Ctr Clin, Biometr Res Branch, Bethesda, MD USA. RP Warren, KE (reprint author), NIH, Bldg 10,Rm 12S245,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 7 TC 61 Z9 62 U1 0 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 19 PY 2001 VL 93 IS 18 BP 1401 EP 1405 DI 10.1093/jnci/93.18.1401 PG 5 WC Oncology SC Oncology GA 473GZ UT WOS:000171033300011 PM 11562391 ER PT J AU Signorello, LB Ye, WM Fryzek, JP Lipworth, L Fraumeni, JF Blot, WJ McLaughlin, JK Nyren, O AF Signorello, LB Ye, WM Fryzek, JP Lipworth, L Fraumeni, JF Blot, WJ McLaughlin, JK Nyren, O TI Nationwide study of cancer risk among hip replacement patients in Sweden SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RHEUMATOID-ARTHRITIS; PROSTATE-CANCER; GASTRIC-CANCER; ASPIRIN; COHORT AB Background. Orthopedic implants and their fixatives contain materials with carcinogenic potential. Whether these implants are linked to subsequent cancer development remains unknown, mainly because large-scale, long-term follow-up data are scarce. Methods: We conducted a nationwide cohort study in Sweden to examine cancer incidence among 116 727 patients who underwent hip replacement surgery during the period from 1965 through 1994. Through record linkage to the Swedish Cancer Register, we identified all incident cancers through 1995 in this population (693 954 person-years of observation). For each cancer type, the observed number of cases was divided by that expected in the general Swedish population to produce standardized incidence ratios (SIRs). Results: Relative to the general population, the cohort had no overall cancer excess (SIR = 1.01; 95% confidence interval [CI] = 0.99 to 1.03). However, we observed elevated SIRs for prostate cancer (SIR = 1.16; 95% CI = 1.11 to 1.22) and melanoma (SIR = 1.15; 95% CI = 1.01 to 1.30) and a reduction in stomach cancer risk (SIR = 0.83; 95% CI = 0.75 to 0.92). Long-term follow-up (greater than or equal to 15 years) revealed an excess of multiple myeloma (SIR = 1.86; 95% CI = 1.01 to 3.11) and a statistically nonsignificant increase in bladder cancer (SIR = 1.42; 95% CI = 0.98 to 1.99). There was no material increase in risk for bone or connective tissue cancer for either men or women in any follow-up period. Conclusions: In this, the largest study to date, hip implant patients had similar rates of most types of cancer to those in the general population. Although the excesses of melanoma, multiple myeloma, and prostate and bladder cancers may be due to chance, confounding, or detection bias and should be interpreted cautiously, they warrant further investigation because of the ever-increasing use of hip implants at younger ages. C1 Int Epidemiol Inst, Rockville, MD 20850 USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP McLaughlin, JK (reprint author), Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. RI Ye, Weimin/A-5939-2008 NR 40 TC 39 Z9 39 U1 0 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 19 PY 2001 VL 93 IS 18 BP 1405 EP 1410 DI 10.1093/jnci/93.18.1405 PG 6 WC Oncology SC Oncology GA 473GZ UT WOS:000171033300012 PM 11562392 ER PT J AU Fisher, B Dignam, JJ AF Fisher, B Dignam, JJ TI Re: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID SURGICAL-ADJUVANT-BREAST; CANCER; TAMOXIFEN C1 Natl Surg Adjuvant Breast & Bowel Project, Allegheny Ctr 4, Pittsburgh, PA 15212 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. RP Fisher, B (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Allegheny Ctr 4, Suite 602, Pittsburgh, PA 15212 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 19 PY 2001 VL 93 IS 18 BP 1421 EP 1422 DI 10.1093/jnci/93.18.1421 PG 2 WC Oncology SC Oncology GA 473GZ UT WOS:000171033300017 ER PT J AU Chikhale, EG Balbo, A Galdzicki, Z Rapoport, SI Shetty, HU AF Chikhale, EG Balbo, A Galdzicki, Z Rapoport, SI Shetty, HU TI Measurement of myo-inositol turnover in phosphatidylinositol: Description of a model and mass spectrometric method for cultured cortical neurons SO BIOCHEMISTRY LA English DT Article ID RAT-BRAIN; 1-2-CYCLIC PHOSPHATE; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; DOWNS-SYNDROME; MYOINOSITOL; LITHIUM; CHROMATOGRAPHY; PHOSPHOLIPIDS; METABOLISM AB Rates of myo-inositol (Ins) incorporation and turnover in phosphatidylinositol (PtdIns) were determined in cultured mouse cortical neurons. Cells were incubated with deuterium-labeled myo-inositol (Ins*) in culture medium free of unlabeled Ins. The time-dependent changes in the specific activity of cytosolic Ins* and membrane PtdIns* were measured by mass spectrometry. PtdIns turnover was modeled incorporating values for Ins* flux, cytosolic dilution, PtdIns concentration, and rate of incorporation into PtdIns. Recycled Ins diluted the labeled precursor pool, and a time course was obtained for this cytosolic process. The specific activity of the precursor pool at the plateau of the time-course curve was 0.43 +/- 0.04 (mean SD). The incorporation of the tracer into PtdIns was linear between 4 and 10 h incubation of the neurons. After factoring in the extent of dilution of the tracer in the precursor pool, the rate of Ins incorporation into PtdIns was found to be 315 +/- 51 nmol (g of protein)(-1) h(-1). The half-life of Ins in PtdIns was calculated for each point on the linear incorporation curve and then corrected for the tracer reincorporation. The half-life of Ins in PtdIns was 6.7 +/- 0.2 h, which translates into a basal turnover rate of 10.3%/h in this in vitro system. The mathematical model and the stable isotope method described here should allow assessment of the dynamics of PtdIns signaling altered in certain diseases or by agents. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. US FDA, Off New Drug Chem, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Shetty, HU (reprint author), NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Room 6N 202,10 Ctr Dr Msc 1582, Bethesda, MD 20892 USA. NR 43 TC 7 Z9 7 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 18 PY 2001 VL 40 IS 37 BP 11114 EP 11120 DI 10.1021/bi010817k PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473GP UT WOS:000171032400024 PM 11551209 ER PT J AU Louis, JM Georgescu, RE Tasayco, ML Tcherkasskaya, O Gronenborn, AM AF Louis, JM Georgescu, RE Tasayco, ML Tcherkasskaya, O Gronenborn, AM TI Probing the structure and stability of a hybrid protein: The human - E-coli thioredoxin chimera SO BIOCHEMISTRY LA English DT Article ID DE-NOVO DESIGN; NMR SOLUTION STRUCTURE; ESCHERICHIA-COLI; 3-DIMENSIONAL STRUCTURE; CRYSTAL-STRUCTURE; HYDROPHOBIC CORE; 2 FRAGMENTS; BETA-SHEET; RESOLUTION; COMPLEMENTATION AB The structure and stability of a hybrid protein composed of N-terminal human and C-terminal E. coli thioredoxin domains were investigated by NMR, fluorescence, and circular dichroism spectroscopy. We demonstrate that the chimeric protein is correctly folded and exhibits the common thioredoxin architecture. However, the stability of the hybrid protein toward thermal and chemical denaturation is clearly reduced when compared with both parent proteins. Altogether, our data indicate that the interface between the two folding units of thioredoxin is tolerant toward changes in exact interdigitation of side chains, allowing for the formation of the unique overall thioredoxin fold. Further, the gene encoding the human-E. coli chimera was tested in vivo whether it supports the assembly of filamentous phages. No complementation of a thioredoxin-deficient E. coli mutant for the replication of the phages M13 or fd was observed, suggesting that parts of the overall protein structure in the N-terminal domain are crucial for this activity. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. CUNY City Coll, Dept Chem, New York, NY 10031 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RI Georgescu, Roxana/B-9943-2011; OI Gronenborn, Angela M/0000-0001-9072-3525 NR 62 TC 10 Z9 10 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 18 PY 2001 VL 40 IS 37 BP 11184 EP 11192 DI 10.1021/bi010745x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473GP UT WOS:000171032400032 PM 11551217 ER PT J AU Mukamal, KJ Jadhav, PP D'Agostino, RB Massaro, JM Mittleman, MA Lipinska, I Sutherland, PA Matheney, T Levy, D Wilson, PWF Ellison, RC Silbershatz, H Muller, JE Tofler, GH AF Mukamal, KJ Jadhav, PP D'Agostino, RB Massaro, JM Mittleman, MA Lipinska, I Sutherland, PA Matheney, T Levy, D Wilson, PWF Ellison, RC Silbershatz, H Muller, JE Tofler, GH TI Alcohol consumption and hemostatic factors Analysis of the Framingham Offspring cohort SO CIRCULATION LA English DT Article DE alcohol; fibrinogen; fibrinolysis; thrombosis; plasminogin activators; von Willebrand factor ID CORONARY HEART-DISEASE; PLASMINOGEN-ACTIVATOR INHIBITOR; ACUTE MYOCARDIAL-INFARCTION; VON-WILLEBRAND-FACTOR; RISK-FACTORS; PLASMA-FIBRINOGEN; FACTOR-VIII; FIBRINOLYTIC-ACTIVITY; PLATELET-AGGREGATION; BODY-WEIGHT AB Background-Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results. Methods and Results-We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by higher levels of plasminogen activator inhibitor antigen-1 and tissue plasminogen activator antigen. Wine drinkers had lower plasminogen activator inhibitor antigen-1 levels than other drinkers, particularly at 3 to 21 drinks weekly, but beverage type did not otherwise consistently affect the results. Conclusions-Light-to-moderate alcohol consumption is associated with lower levels of coagulatory factors, but higher intake is associated with impaired fibrinolytic potential. These findings are consistent with the hypothesis that a balance between hemostatic and fibrinolytic activity may contribute to the complex relation of alcohol use with coronary heart disease. C1 Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Boston Univ, Dept Math & Stat, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Royal N Shore Hosp, Div Cardiol, Sydney, NSW, Australia. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,Libby-303, Boston, MA 02215 USA. FU NHLBI NIH HHS [R01-HL-48157]; NIAAA NIH HHS [K23-AA00299] NR 49 TC 126 Z9 136 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 SEP 18 PY 2001 VL 104 IS 12 BP 1367 EP 1373 DI 10.1161/hc3701.096067 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 474XB UT WOS:000171131200009 PM 11560851 ER PT J AU Long, YQ Lee, SL Lin, CY Enyedy, IJ Wang, SM Li, P Dickson, RB Roller, PP AF Long, YQ Lee, SL Lin, CY Enyedy, IJ Wang, SM Li, P Dickson, RB Roller, PP TI Synthesis and evaluation of the sunflower derived trypsin inhibitor as a potent inhibitor of the type II transmembrane serine protease, matriptase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; DATA-BANK; ACTIVATOR; CLONING; COMPLEX; PURIFICATION; LOCALIZATION; PROTEINS; CELLS AB We report here the synthesis of a 14-amino acid long bicyclic peptide, previously isolated from sunflower seeds. This peptide, termed sunflower trypsin inhibitor (SFTI-1), is one of the most potent naturally occurring small-molecule trypsin inhibitors. In addition to inhibiting trypsin, the synthetic SFTI-1 is also a very potent inhibitor, with a K-i of 0.92 nM, of the recently identified epithelial serine protease, termed 'matriptase'. Published by Elsevier Science Ltd. C1 NCI, Med Chem Lab, FCRDC, Frederick, MD 21702 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. RP Roller, PP (reprint author), NCI, Med Chem Lab, FCRDC, 376-208,POB B, Frederick, MD 21702 USA. RI Wang, Shaomeng/E-9686-2010 NR 23 TC 61 Z9 63 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 17 PY 2001 VL 11 IS 18 BP 2515 EP 2519 DI 10.1016/S0960-894X(01)00493-0 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 469HL UT WOS:000170808400025 PM 11549459 ER PT J AU Morales, M McCollum, N Kirkness, EF AF Morales, M McCollum, N Kirkness, EF TI 5-HT3-receptor subunits A and B are co-expressed in neurons of the dorsal root ganglion SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE dorsal horn; nociception; peripheral nervous system; serotonin receptors; spinal cord ID 5-HT3 RECOGNITION SITES; RAT SPINAL-CORD; RECEPTOR SUBUNIT; FUNCTIONAL EXPRESSION; RADIOLIGAND BINDING; ADMINISTERED SEROTONIN; NERVOUS-SYSTEM; H-3 ZACOPRIDE; BRAIN; IDENTIFICATION AB The type 3 serotonin (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT), Many pharmacological, behavioral, and electrophysiological studies indicate heterogeneous properties for this receptor. Although the basis for this heterogeneity is unknown, one possible explanation for these findings resides in the subunit composition of the receptor, Two 5-HT3-receptor subunits have been cloned: the 5-HT3-receptor subunit A (5-HT3A) and the 5-HT3-receptor subunit B (5-HT3B). Recombinant co-expression of 5-HT3A and 5-HT3B subunits produces a functional heteromeric 5-HT3A/3B receptor with pharmacological and electrophysiological properties different from those displayed by the 5-HT3A homomeric receptor. In the present report, we used in situ hybridization histochemistry to demonstrate that the 5-HT3B subunit is expressed in rat dorsal root ganglion (DRG) neurons. We determined with cellular resolution that 5-HT3B subunit mRNA was expressed in 43.2 +/- 2.8% of the total population of DRG neurons. By comparison, the 5-HT3A subunit was more widely expressed, with 70.0 +/- 2.8% of the total population of DRG neurons expressing this subunit. Further analyses showed that most of the neurons containing mRNA for the 5-HT3B subunit (91.5 +/- 3.4%) also expressed the 5-HT3A subunit. In contrast, nearly half the population of neurons expressing 5-HT3A subunit lacked (52.8 +/- 5.9%) transcripts for the 5-HT3B subunit. These results provide the first evidence indicating that the 5-HT3B subunit of the 5-HT3 receptor is expressed in DRG and suggest that sensory neurons have the capacity to synthesize at least two structurally different 5-HT3 receptors: a heteromeric 5-HT3A/3B receptor and a homomeric 5-HT3A receptor. Consequently, 5-HT3 receptors with different properties might be present in peripheral and central axons of the DRG. These findings open the possibility that distinct types of 5-HT3 receptors may be involved in perception and/or processing of sensory information. J. Comp. Neurol. 438:163-172, 2001. Published 2001 Wiley-Liss, Inc.dagger. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Inst Genome Res, Rockville, MD 20850 USA. RP Morales, M (reprint author), NIDA, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NINDS NIH HHS [NS34702] NR 52 TC 37 Z9 40 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 17 PY 2001 VL 438 IS 2 BP 163 EP 172 DI 10.1002/cne.1307 PG 10 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 468FF UT WOS:000170746900004 PM 11536186 ER PT J AU Colgan, R Powers, JH AF Colgan, R Powers, JH TI Appropriate antimicrobial prescribing: Approaches that limit antibiotic resistance SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID UPPER RESPIRATORY-INFECTIONS; ACUTE BRONCHITIS; STREPTOCOCCUS-PNEUMONIAE; UNITED-STATES; PHYSICIANS; EXPECTATIONS; ERYTHROMYCIN; CHILDREN; ADULTS; COUGH AB Since the introduction of antimicrobial agents, there has been an association between antibiotic use and the development of antimicrobial resistance. Antibiotic therapy eradicates not only pathogenic organisms but also the protective normal flora. This so-called "selective pressure" results in colonization with bacteria that are resistant to the original therapy. The result has been an increase over the past two decades in antibiotic resistance among common bacteria[ causes of outpatient infections. Several studies have demonstrated that a substantial portion of the antibiotics prescribed in the outpatient setting are given for viral illnesses or bacterial diseases where the benefit of antibacterial therapy is marginal. The reasons for prescribing antibiotics in these situations are related to medical and social factors. Physicians should be familiar with the clinical situations in which they should provide antibiotics and those in which they may safely be withheld. Physicians should understand the motivations of patients who are seeking antibiotics and provide education, empathy and alternative treatments. C1 Univ Maryland, Sch Med, Dept Family Med, Baltimore, MD 21201 USA. NIH, Bethesda, MD 20892 USA. RP Colgan, R (reprint author), Univ Maryland, Sch Med, Dept Family Med, 29 S Paca St, Baltimore, MD 21201 USA. NR 29 TC 22 Z9 24 U1 1 U2 2 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD SEP 15 PY 2001 VL 64 IS 6 BP 999 EP 1004 PG 6 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 475UU UT WOS:000171188200011 PM 11578036 ER PT J AU Peters, U Poole, C Arab, L AF Peters, U Poole, C Arab, L TI Does tea affect cardiovascular disease? A meta-analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; cerebrovascular accident; coronary disease; meta-analysis; myocardial infarction; tea ID CORONARY HEART-DISEASE; DOSE-RESPONSE DATA; MYOCARDIAL-INFARCTION; OXIDIZED LDL; COFFEE-DRINKING; RISK-FACTORS; GREEN TEA; FLAVONOIDS; WOMEN; CONSUMPTION AB This meta-analysis of tea consumption in relation to stroke, myocardial infarction, and all coronary heart disease is based on 10 cohort studies and seven case-control studies. The study-specific effect estimates for stroke and coronary heart disease were too heterogeneous to be summarized (homogeneity p < 0.02 for stroke, p < 0.001 for coronary heart disease). Only the relative risk estimates for myocardial infarction (seven studies) appeared reasonably homogeneous (homogeneity p = 0.20). The incidence rate of myocardial infarction is estimated to decrease by 11% with an increase in tea consumption of 3 cups per day (fixed-effects relative risk estimate = 0.89, 95% confidence interval: 0.79, 1.01) (1 cup = 237 ml). However, evidence of bias toward preferential publication of smaller studies that suggest protective effects urges caution in interpreting this result. The geographic region where the studies were conducted appeared to explain much of the heterogeneity among coronary heart disease, myocardial infarction, and probably stroke results. With increasing tea consumption, the risk increased for coronary heart disease in the United Kingdom and for stroke in Australia, whereas the risk decreased in other regions, particularly in continental Europe. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Arab, L (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, CB 7400, Chapel Hill, NC 27599 USA. NR 45 TC 212 Z9 221 U1 1 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2001 VL 154 IS 6 BP 495 EP 503 DI 10.1093/aje/154.6.495 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 473BQ UT WOS:000171019800002 PM 11549554 ER PT J AU Hessol, NA Schneider, M Greenblatt, RM Bacon, M Barranday, Y Holman, S Robison, E Williams, C Cohen, M Weber, K AF Hessol, NA Schneider, M Greenblatt, RM Bacon, M Barranday, Y Holman, S Robison, E Williams, C Cohen, M Weber, K CA Womens Interagency Human Immunod TI Retention of women enrolled in a prospective study of human immunodeficiency virus infection: Impact of race, unstable housing, and use of human immunodeficiency virus therapy SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; HIV; prospective studies; women ID COHORT; HIV AB Even though women and people of color represent an increasing proportion of US acquired immunodeficiency syndrome (AIDS) cases, few research studies include adequate representation of these populations. Here the authors describe recruitment and retention of a diverse group of human immunodeficiency virus (HIV)-infected and at risk HIV-uninfected women in a prospective study operating in six sites across the United States. Methods used to minimize loss to follow-up in this cohort are also described. For the first 10 study visits that occurred during a 5-year period between 1994 and 1999, the retention rate of participants was approximately 82%. In adjusted Cox analysis, factors associated with retention among all women were older age, African-American race, stable housing, HIV-Infected serostatus, past experience in studies of HIV/AIDS, and site of enrollment. In an adjusted Cox analysis of HIV-infected women, African-American race, past experience in studies of HIV/AIDS, site of enrollment, and reported use of combination or highly active antiretroviral HIV therapy at the last visit were significantly associated with retention. In adjusted Cox analysis of HIV-uninfected study participants, only the site of enrollment was significantly associated with study retention. These results show that women with and at risk for HIV infection, especially African-American women, can be successfully recruited and retained in prospective studies. C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94122 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. Cook Cty Hosp, Core Ctr, Chicago, IL 60612 USA. RP Hessol, NA (reprint author), Univ Calif San Francisco, Dept Med, 405 Irving St,2nd Floor, San Francisco, CA 94122 USA. FU NCRR NIH HHS [MO1-RR-00079, MO1-RR-00083]; NIAID NIH HHS [U01-AI-35004, U01-AI-31834, U01-AI-34989, U01-AI-34993, U01-AI-34994, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 11 TC 73 Z9 73 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2001 VL 154 IS 6 BP 563 EP 573 DI 10.1093/aje/154.6.563 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 473BQ UT WOS:000171019800010 PM 11549562 ER PT J AU Clegg, LX Potosky, AL Harlan, LC Hankey, BF Hoffman, RM Stanford, JL Hamilton, AS AF Clegg, LX Potosky, AL Harlan, LC Hankey, BF Hoffman, RM Stanford, JL Hamilton, AS TI Comparison of self-reported initial treatment with medical records: Results from the prostate cancer outcomes study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE medical records; prostatic neoplasms; questionnaires; recall; therapeutics ID WOMEN; AGREEMENT; INFORMATION; RELIABILITY; DISEASE; COHORT AB Medical records are generally accepted as the most accurate source of information documenting cancer treatments. However, as the health care system becomes more decentralized and more cancer care is delivered in outpatient settings, it is increasingly difficult and expensive to review records from the many surgeons and medical/radiation oncologists who administer cancer therapies in the community setting. Using 1994-1995 data, the authors compared initial treatment for prostate cancer self-reported (from a mailed questionnaire or telephone/in-person interview) by 3,196 US men in the population-based Prostate Cancer Outcomes Study with information obtained from medical records. Agreement between self-reports and medical records varied by type of treatment. Generally, agreement was excellent for more invasive procedures such as prostatectomy or radiation (kappa values > 0.8), with decreasing agreement for hormone shots and pills (kappa values < 0.7). If the medical record abstract is assumed to be the "gold standard," the estimated sensitivity was generally high (>80%) for prostatectomy and radiation but low (68%) for hormone pills, although the estimated specificity was 90% or greater for all treatments. These results can serve as a useful guide to researchers contemplating the use of surveys as an alternative to medical record abstraction to ascertain treatment in studies of patient outcomes. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Hlth Sci Ctr, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. Dept Vet Affairs Med Ctr, Med Serv, Albuquerque, NM USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. RP Clegg, LX (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 EXecut Blvd,Suite 504,MSC 8316, Bethesda, MD 20892 USA. NR 15 TC 24 Z9 24 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2001 VL 154 IS 6 BP 582 EP 587 DI 10.1093/aje/154.6.582 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 473BQ UT WOS:000171019800012 PM 11549564 ER PT J AU Green, MJ Biesecker, BB McInerney, AM Mauger, D Fost, N AF Green, MJ Biesecker, BB McInerney, AM Mauger, D Fost, N TI An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetic counseling; genetic testing; genetic education; informed consent; ethics; BRCA1/BRCA2 ID INFORMED CONSENT; DECISION-MAKING; OVARIAN-CANCER; INFORMATION; BRCA1; FAMILIES; WRITTEN; RISK AB As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P < .0001). Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group (P =.048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P =.0002; odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing. (C) 2001 Wiley-Liss, Inc. C1 Penn State Univ, Coll Med, Dept Humanities, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Gen Internal Med Sect, Hershey, PA 17033 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Penn State Univ, Coll Med, Dept Hlth Evaluat Sci, Hershey, PA 17033 USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. RP Green, MJ (reprint author), Penn State Univ, Coll Med, Dept Humanities, H134,500 Univ Dr, Hershey, PA 17033 USA. FU NCI NIH HHS [1R03 CA 70638, 1 R01 CA84770] NR 47 TC 76 Z9 76 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 15 PY 2001 VL 103 IS 1 BP 16 EP 23 DI 10.1002/ajmg.1500 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 467NQ UT WOS:000170711000003 PM 11562929 ER PT J AU Green, MJ McInerney, AM Biesecker, BB Fost, N AF Green, MJ McInerney, AM Biesecker, BB Fost, N TI Education about genetic testing for breast cancer susceptibility: Patient preferences for a computer program or genetic counselor SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetic testing; breast cancer; genetics education; BRCA1/BRCA2; genetic counseling; informed consent; computers; patient education ID INFORMATION AB The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling. (C) 2001 Wiley-Liss, Inc. C1 Penn State Univ, Coll Med, Dept Humanities, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Gen Internal Med Sect, Hershey, PA 17033 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. RP Green, MJ (reprint author), Penn State Univ, Coll Med, Dept Humanities, H134,500 Univ Dr, Hershey, PA 17033 USA. FU NCI NIH HHS [1 R01 CA84770, 1 R03 CA70638] NR 28 TC 38 Z9 38 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 15 PY 2001 VL 103 IS 1 BP 24 EP 31 DI 10.1002/ajmg.1501 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 467NQ UT WOS:000170711000004 PM 11562930 ER PT J AU Nemesure, B He, QM Mendell, N Wu, SY Hejtmancik, JF Hennis, A Leske, MC AF Nemesure, B He, QM Mendell, N Wu, SY Hejtmancik, JF Hennis, A Leske, MC CA Barbados Family Study Grp TI Inheritance of open-angle glaucoma in the Barbados Family Study SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE open-angle glaucoma; segregation; Mendelian inheritance ID BALTIMORE EYE SURVEY; CLINICAL-FEATURES; CHROMOSOME 1Q; RISK-FACTORS; JUVENILE; GENE; LOCUS; ADULT; PREVALENCE; REGION AB The majority of genetic studies on open-angle glaucoma (OAG) have been conducted in primarily white populations, with investigations of inheritance patterns largely based on self-reported information. The Barbados Family Study of Open-Angle Glaucoma (BFSG) is the first study to investigate the transmission pattern(s) for OAG in a predominantly black population, based on standardized examinations. Each BFSG participant received a comprehensive examination including anthropometric and other measurements, best-corrected visual acuity, perimetry, tonometry, lens gradings, fundus photography, venipuncture, an extensive interview including ocular, medical and family history information and a comprehensive ophthalmologic evaluation. Conservative criteria were used to define glaucoma status, including the presence of both visual field defects and optic disc damage. The study included 207 OAG-affected probands (median age: 68 years) and 1,056 of their relatives (median age: 47 years). Among the relatives examined 10% (n = 106) had OAG and 13% (n = 141) had probable OAG. Segregation analyses were performed to determine the mode of inheritance for glaucoma in these families. The results indicate that transmission of OAG or probable OAG is most likely due to a major codominant gene. Both age and gender are shown to be significant factors as well; with an increase in risk being associated with each year of age over 54 years and an increase in risk for all ages and genotypes observed in males. These analyses do not, however, preclude the possible existence of an environmental component or other genetic determinants in OAG. Further evidence for the existence of a major gene may be obtained by additional follow-up of the relatively young cohort of relatives, as well as ongoing linkage analyses. (C) 2001 Wiley-Liss, Inc. C1 SUNY Stony Brook, Med Ctr, Sch Med, Dept Prevent Med, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. NEI, Bethesda, MD 20892 USA. Univ W Indies, Sch Clin Med & Res, Mona, Barbados. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Nemesure, B (reprint author), SUNY Stony Brook, Med Ctr, Sch Med, Dept Prevent Med, Stony Brook, NY 11794 USA. FU NCRR NIH HHS [1 P41 RR03655]; NEI NIH HHS [EYO11000] NR 50 TC 26 Z9 26 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 JI Am. J. Med. Genet. PD SEP 15 PY 2001 VL 103 IS 1 BP 36 EP 43 DI 10.1002/ajmg.1498 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 467NQ UT WOS:000170711000006 PM 11562932 ER PT J AU Nowaczyk, MJM Farrell, SA Sirkin, WL Velsher, L Krakowiak, PA Waye, JS Porter, FD AF Nowaczyk, MJM Farrell, SA Sirkin, WL Velsher, L Krakowiak, PA Waye, JS Porter, FD TI Smith-Lemli-Opitz (RHS) syndrome: Holoprosencephaly and homozygous IVS8-1G -> C genotype SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Smith-Lemli-Opitz syndrome; 7-dehydrocholesterol; prenatal diagnosis; DHCR7 mutations; holoprosencephaly ID LEMLI-OPITZ-SYNDROME; SONIC HEDGEHOG; REDUCTASE GENE; MUTATIONS; RECEPTOR; DIAGNOSIS AB Smith-Lemli-Opitz syndrome (RHS) (SLOS, OMIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 30-hydroxysterol Delta (7)-Delta (8)- reductase gene, DHCR7. We report a fetus with holoprosencephaly and multiple congenital anomalies who was homozygous for the IVS8-1G -->C mutation. Following termination of pregnancy, both the elevated amniotic fluid 7-dehydrocholesterol level and the DHCR7 mutations were demonstrated. Two other newborn infants with IVS8-1G -->C/IVS8-1G -->X genotype are described. This report illustrates a severe phenotypic extreme of SLOS associated with a null genotype, underscores the complex relationship between SLOS and holoprosencephaly, and discusses the possible pathogenetic mechanisms of the development of holoprosencephaly in SLOS. (C) 2001 Wiley-Liss, Inc. C1 McMaster Univ, Med Ctr, Dept Pathol & Lab Med, Hamilton, ON L8S 4J9, Canada. Hamilton Reg Lab Program, Hamilton, ON, Canada. Credit Valley Hosp, Div Genet, Mississauga, ON, Canada. N York Gen Hosp, Dept Pathol, N York, ON, Canada. N York Gen Hosp, Dept Clin Genet, N York, ON, Canada. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD USA. RP Nowaczyk, MJM (reprint author), McMaster Univ, Med Ctr, Dept Pathol & Lab Med, Room 3N16,1200 Main St W, Hamilton, ON L8S 4J9, Canada. NR 22 TC 22 Z9 24 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 JI Am. J. Med. Genet. PD SEP 15 PY 2001 VL 103 IS 1 BP 75 EP 80 DI 10.1002/1096-8628(20010915)103:1<75::AID-AJMG1502>3.0.CO;2-R PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 467NQ UT WOS:000170711000012 PM 11562938 ER PT J AU Guidry, UC Mendes, LA Evans, JC Levy, D O'Connor, GT Larson, MG Gottlieb, DJ Benjamin, EJ AF Guidry, UC Mendes, LA Evans, JC Levy, D O'Connor, GT Larson, MG Gottlieb, DJ Benjamin, EJ TI Echocardiographic features of the right heart in sleep-disordered breathing - The Framingham Heart Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cohort study; echocardiography; epidemiology; obesity; right ventricle; sleep-disordered breathing ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; RIGHT-VENTRICULAR DYSFUNCTION; OBSTRUCTIVE LUNG-DISEASE; APNEA SYNDROME; PULMONARY-HYPERTENSION; INDEPENDENT PREDICTOR; CARDIAC-FUNCTION; HYPERTROPHY; OBESITY; ASSOCIATION AB The effect of sleep-disordered breathing (SDB) on right heart structure and function is controversial. Studies of patients referred for evaluation of possible sleep apnea have yielded conflicting results, and the impact of SDB on the right heart has not been investigated In the general population. We examined the echocardiographic features of subjects with SDB at the Framingham Heart Study site of the Sleep Heart Health Study. Of 1,001 polysomnography subjects, 90 with SDB defined as a respiratory disturbance index (RDI) score >90th percentile (mean RDI = 42) were compared with 90 low-RDI subjects (mean RDI = 5) matched for age, sex, and body mass index. Right heart measurements, made without knowledge of clinical status, were compared between groups. The majority of the subjects were male (74%). After multivariable adjustment, right ventricle (RV) wall thickness was significantly greater (p = 0.005) in subjects with SDB (0.78 +/- 0.02 cm) than in the low-RDI subjects (0.68 +/- 0.02 cm). Right atria] dimensions, RV dimensions, and RV systolic function were not found to be significantly different between subjects with SDB and the low-RD[ subjects. We conclude that in this community-based study of SDB and right heart echocardiographic features, RV wall thickness was increased in subjects with SDB. Whether the RV hypertrophy observed in persons with SDB Is associated with increased morbidity and mortality remains unknown. C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Cardiol, Sect Prevent Med, Boston, MA 02118 USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Clin Epidemiol, Boston, MA 02115 USA. RP O'Connor, GT (reprint author), Boston Univ, Sch Med, Ctr Pulm, Room R304,715 Albany St, Boston, MA 02118 USA. OI O'Connor, George/0000-0002-6476-3926 FU NHLBI NIH HHS [N01-HC-38038, U01-HL53941]; NINDS NIH HHS [5-R01-NS-17950] NR 52 TC 80 Z9 82 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 15 PY 2001 VL 164 IS 6 BP 933 EP 938 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 480DD UT WOS:000171446000006 PM 11587973 ER PT J AU Taveira-DaSilva, AM Hedin, C Stylianou, MP Travis, WD Matsui, K Ferrans, VJ Moss, J AF Taveira-DaSilva, AM Hedin, C Stylianou, MP Travis, WD Matsui, K Ferrans, VJ Moss, J TI Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE lymphangioleiomyomatosis; respiratory function tests; histology; outcome measures ID LONGITUDINAL DATA-ANALYSIS; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; STANDARDS; ADULTS AB Lymphangioleiomyomatosis (LAM) is a rare disease, occurring in women, characterized by cystic degeneration of the lungs, abdominal tumors, and proliferation of abnormal smooth muscle cells. Lung function abnormalities consist of impairment of the diffusion capacity (DLCO) and airflow obstruction. The objective of this study was to correlate the functional impairment with histologic measures of disease severity to identify predictors of disease outcome. Lung function of 143 patients and lung biopsies of 74 of these patients were reviewed for evidence of airway disease and scoring,of disease severity. A positive response to bronchodilators was associated with more severe airflow obstruction, a predominantly solid pattern of LAM lesions in the lung biopsy, and greater rate of decline in expiratory flow. Airway inflammation, present in 61% of the lung specimens, was not associated with reversible airway obstruction and did not correlate with the severity of airflow obstruction. DLCO correlated best with the LAM histologic score (LHS), a demonstrated predictor of outcome. We conclude that reversible airway obstruction is found in LAM patients with accelerated loss of lung function and a predominantly solid pattern of LAM lesions. Impairment of DLCO correlates with LHS, a predictor of survival and time to lung transplantation. C1 NHLBI, Pulm Crit Care Med Branch, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Pulm & Mediastinal Dept, Washington, DC 20306 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, Off Biostat Res, NIH, Bldg 10,Room 6D-03,MSC 1590, Bethesda, MD 20892 USA. NR 16 TC 65 Z9 66 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 15 PY 2001 VL 164 IS 6 BP 1072 EP 1076 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 480DD UT WOS:000171446000032 PM 11587999 ER PT J AU Singh, VK Ganesh, L Cunningham, ML Shane, BS AF Singh, VK Ganesh, L Cunningham, ML Shane, BS TI Comparison of the mutant frequencies and mutation spectra of three non-genotoxic carcinogens, oxazepam, phenobarbital, and Wyeth 14,643, at the lambda cII locus in Big Blue (R) transgenic mice SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE oxazepam; phenobarbital; Wyeth 14; 643; cII assay; mutation spectra ID HYPOLIPIDEMIC PEROXISOME PROLIFERATORS; UNSCHEDULED DNA-SYNTHESIS; CELL-PROLIFERATION; IN-VIVO; LIVER; LACI; HEPATOCYTES; INDUCTION; INVIVO; RISK AB Oxazepam (OX), a widely used benzodiazepine anxiolytic, phenobarbital (PHE), a drug used for convulsive disorders, and Wyeth 14,643 (WY; [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid), a hypolipidemic agent, are all hepatocarcinogenic in B6C3F1 mice. They have been classified as "non-genotoxic" carcinogens since they are non-DNA reactive in in vitro assays and are either negative or weakly positive in Salmonella typhimurium (Ames assay). Male B6C3F1 Big Blue((R)) transgenic mice were fed 2500 ppm of OX or PHE or 500 ppm of WY in their diet, while a control group of mice received diet alone for 180 days. The mutant frequency (MF) of cII in the control mice, after correction for clonality, was 6.2 +/- 2.8 X 10(-5). The MF values for mice fed OX, PHE, and WY were 10.0 +/- 3.6 X 10(-5) (P < 0.05), 7.9 +/- 1.3 X 10(-5) (P = 0.1) and 17.4 +/- 4.2 X 10(-5) (P < 0.01), respectively. The mutation spectrum (MS) at cII from the PBE-fed mice was significantly different (P < 0.05) from that of the control mice even though the MF was not, whereas the MS spectra of mice fed OX (P = 0.4) and WY (P = 0.7) were not significantly different. The PHE-derived spectrum differed from the spontaneous spectrum in the lower occurrence of G:C >C:G transversions (17 vs 1.6%) and the higher incidence of A:T >T:A transversions (3.4 vs 9.5%). Prior to correction for clonal expansion, each treated group exhibited a high incidence of frameshift mutations at the homopolymeric run of guanines at bp 179-184 (OX 21%, PHE 21%, WY 16% of the total mutations); this was not the case with the control group (6%). Even after clonal correction, more than 10% of the mutations were frameshifts in the treated mice, while 5% were frameshifts in the control mice. Despite this hypersensitive region of the gene, our findings suggest that the cII locus is less sensitive than the lac1 locus to mutation induction by non-DNA reactive carcinogens. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIEHS, Integrated Lab Syst, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Louisiana State Univ, Inst Environm Studies, Baton Rouge, LA 70803 USA. RP Shane, BS (reprint author), NIEHS, Integrated Lab Syst, Environm Toxicol Program, Bldg 4401,Mail Drop EC-17,79 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA72534] NR 37 TC 17 Z9 17 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2001 VL 62 IS 6 BP 685 EP 692 DI 10.1016/S0006-2952(01)00722-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 463HB UT WOS:000170470100004 PM 11551513 ER PT J AU Winterer, G Egan, MF Radler, T Coppola, R Weinberger, DR AF Winterer, G Egan, MF Radler, T Coppola, R Weinberger, DR TI Event-related potentials and genetic risk for schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Review DE schizophrenia; genetic risk; endophenotype; event-related potentials; topography; P300 ID P300 SUBCOMPONENT ABNORMALITIES; HUMAN ELECTROENCEPHALOGRAM EEG; BIPOLAR AFFECTIVE-DISORDER; EYE TRACKING DYSFUNCTION; TO-NOISE RATIO; INTRACEREBRAL POTENTIALS; AUDITORY ODDBALL; VISUAL-STIMULI; TEMPORAL-LOBE; RARE TARGET AB Background: Event-related potentials (ERPs) during an auditory oddball task were investigated in patients with schizophrenia and in their healthy siblings to explore the question of whether abnormalities of two-dimensional topographic scalp-distribution of P300 amplitude and latency relate to genetic risk for schizophrenia. We also examined the P50, N100, and P200-waves, elicited during the same task. Methods: We investigated 42 schizophrenic patients, 62 of their healthy siblings, and 34 unrelated normal control subjects with a standard auditory oddball paradigm and 16 electroencephalogram electrodes. Amplitudes and latencies of the ERPs P50, N100, P200, and P300 were topographically analyzed. Results: In the patients, P300 amplitude was significantly decreased in the range of 54%-58% over the left parietotemporal area. Siblings did not show decreased P300 amplitudes when compared with normal subjects. P300 latencies were unchanged in both groups. No significant group differences were observed for the other event-related potentials. Conclusions: In line with previous studies, the P300 amplitude in schizophrenic patients was decreased over the left temporoparietal area; however, we found no evidence for a genetic trait effect in the event-related potential abnormality. Possible reasons for these largely negative findings are discussed. Biol Psychiatry 2001; 50:407-417 (C) 2001 Society of Biological Psychiatry. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Winterer, G (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4S229A MSC, Bethesda, MD 20892 USA. NR 102 TC 47 Z9 50 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2001 VL 50 IS 6 BP 407 EP 417 DI 10.1016/S0006-3223(01)01072-1 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 473GL UT WOS:000171032100002 PM 11566157 ER PT J AU Bolan, CD Leitman, SF Griffith, LM Wesley, RA Procter, JL Stroncek, DF Barrett, AJ Childs, RW AF Bolan, CD Leitman, SF Griffith, LM Wesley, RA Procter, JL Stroncek, DF Barrett, AJ Childs, RW TI Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; PERIPHERAL-BLOOD; ANTI-A; LYMPHOCYTE INFUSION; CYCLOSPORIN-A; HOST-DISEASE; GRAFT; SYSTEM; ERYTHROPOIETIN AB Delayed donor red cell engraftment and pure red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible hematopoietic stem cell transplantation (SCT) performed by means of myeloablative conditioning. To evaluate these events following reduced-intensity nonmyeloablative SCT (NST), consecutive series of patients with major ABO incompatibility undergoing either NST (fludarabine/cyclophosphamide conditioning) or myeloablative SCT (cyclophosphamide/high-dose total body irradiation) were compared. Donor red blood cell (RBC) chimerism (initial detection of donor RBCs in peripheral blood) was markedly delayed following NST versus myeloablative SCT (median, 114 versus 40 days; P < .0001) and strongly correlated with decreasing host antidonor isohemagglutinin levels. Antidonor isohemagglutinins declined to clinically insignificant levels more slowly following NST than myeloablative SCT (median, 83 versus 44 days; P=.03). Donor RBC chimerism was delayed more than 100 days in 9 of 14 (64%) and PRCA occurred in 4 of 14 (29%) patients following NST, while neither event occurred in 12 patients following myeloablative SCT. Conversion to full donor myeloid chimerism following NST occurred significantly sooner in cases with, compared with cases without, PRCA (30 versus 98 days; P = .008). Cyclosporine withdrawal appeared to induce graft-mediated immune effects against recipient isohemagglutinin-producing cells, resulting in decreased antidonor ischemagglutinin levels and resolution of PRCA following NST. These data indicate that significantly delayed donor erythropoiesis is (1) common following major ABO-incompatible NST and (2) associated with prolonged persistence of host antidonor isohemagglutinins. The clinical manifestations of these events are affected by the degree and duration of residual host hematopoiesis. (C) 2001 by The American Society of Hematology. C1 NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. NHLBI, Biostat Branch, Off Director, Warren G Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. RP Bolan, CD (reprint author), NHLBI, Dept Transfus Med, NIH, Bldg 10,Rm 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. NR 57 TC 87 Z9 90 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1687 EP 1694 DI 10.1182/blood.V98.6.1687 PG 8 WC Hematology SC Hematology GA 471UV UT WOS:000170947800012 PM 11535498 ER PT J AU Nagai, M Brennan, MB Sakai, JA Mora, CA Jacobson, S AF Nagai, M Brennan, MB Sakai, JA Mora, CA Jacobson, S TI CD8(+) T cells are an in vivo reservoir for human T-cell lymphotropic virus type I SO BLOOD LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; HTLV-I; LEUKEMIA PATIENTS; MYELOPATHY; RETROVIRUS; RECEPTOR; TAX; LYMPHOCYTES; INFECTION; PROTEIN AB It is thought that human T-cell lymphotropic virus type I (HTLV-I) preferentially infects CD4(+) T cells in vivo. However, observations of high HTLV-I proviral load in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis suggest that HTLV-I may infect other cell types in addition to CD4(+) T cells. To identify in vivo T-cell tropisms of HTLV-I, real-time quantitative polymerase chain reaction (PCR) and intracellular protein staining were used. A high amount of HTLV-I proviral DNA was detected from purified CD8(+) T cells by quantitative PCR (between 1.64 and 62.83 copies of HTLV-I provirus per 100 isolated CD8(+) T cells). CD8(+) T cells expressed HTLV-I-related antigens (HTLV-I Tax and p19 protein) after a short time in cultivation. These results demonstrate that CD8(+) T cells are also infected with HTLV-I and express HTLV-I antigens at levels that are comparable to HTLV-I-infected CD4(+) cells. Therefore, CD8(+) cells are an additional viral reservoir in vivo for HTLV-I and may contribute to the pathogenesis of HTLV-I-mediated disorders. C1 NINDS, Virol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Virol Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Rm 5B-16,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 40 TC 103 Z9 104 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1858 EP 1861 DI 10.1182/blood.V98.6.1858 PG 4 WC Hematology SC Hematology GA 471UV UT WOS:000170947800036 PM 11535522 ER PT J AU Lee, YT Miller, LD Gubin, AN Makhlouf, F Wojda, U Barrett, AJ Liu, ET Miller, JL AF Lee, YT Miller, LD Gubin, AN Makhlouf, F Wojda, U Barrett, AJ Liu, ET Miller, JL TI Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays SO BLOOD LA English DT Article ID GENE-EXPRESSION; CELLS; CLASSIFICATION; IDENTIFICATION; APOPTOSIS; LEUKEMIA; PROTEIN; GROWTH AB Because abnormal erythroid differentiation is the most common manifestation of the myelodysplastic syndromes (MDS), it was hypothesized that erythroid gene expression may be used to illustrate myelodysplastic transcription patterns. Ten normal bone marrow aspirates (NBM) were first analyzed using an erythroid-focused cDNA array to define steady-state transcription levels. Proliferation and differentiation gene subsets were identified by statistically significant differences between NBM and erythroleukemia gene expression. Next, cDNAs from 5 separate MDS aspirates were studied: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (RAEB-T), and RAEB-T/secondary MDS. A distinct pattern of significantly increased proliferation-associated and reduced differentiation-associated gene activity was established for MDS. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Sect Mol Signalling & Oncogenesis, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NHLBI, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9B17, Bethesda, MD 20892 USA. RI Liu, Edison/C-4141-2008; Miller, Lance/A-5633-2009; Wojda, Urszula/M-6079-2015 OI Wojda, Urszula/0000-0002-4525-2004 NR 26 TC 28 Z9 31 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1914 EP 1921 DI 10.1182/blood.V98.6.1914 PG 8 WC Hematology SC Hematology GA 471UV UT WOS:000170947800043 PM 11535529 ER PT J AU Joshi, SS Lynch, JC Pavletic, SZ Tarantolo, SR Pirruccello, SJ Kessinger, A Bishop, MR AF Joshi, SS Lynch, JC Pavletic, SZ Tarantolo, SR Pirruccello, SJ Kessinger, A Bishop, MR TI Decreased immune functions of blood cells following mobilization with granulocyte colony-stimulating factor: association with donor characteristics SO BLOOD LA English DT Article ID VERSUS-HOST DISEASE; BONE-MARROW TRANSPLANTATION; PERIPHERAL-BLOOD; STEM-CELLS; G-CSF; T-CELLS; MONONUCLEAR-CELLS; HEMATOLOGIC MALIGNANCIES; ALLOANTIGEN STIMULATION; PROGENITOR CELLS AB In this study, mononuclear cells (MNCs) from granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cell (BSC) harvests from 104 healthy donors were analyzed for their immunological functions and compared with MNCs from 28 steady-state nonmobilized donors. The relationships between donor characteristics (age, gender, weight, and HLA type) and immune functions of the harvests were also analyzed. There was a significant (P < .01) decrease in natural killer and lymphokine-activated killer (LAK) cell-mediated cytotoxicity for G-CSF-mobilized effector cells compared with nonmobilized cells. Similarly, there was a significant (P < .005) decrease in both T-cell and B-cell mitogen response in G-CSF-mobilized cells compared with nonmobilized cells. There was dose-dependent inhibition of LAK cell-mediated cytotoxicity, but this effect was not seen with other immune function assays. Changes in immune function did not appear to be determined by frequency of cellular phenotypes or expression of effector function genes seen in a reverse-transcription polymerase chain reaction. There was a significant relationship between expression of certain HLA alleles (A1, A3, A24, B44, B62, DR15, DR17; all P < .01) and increased immune function, such as cytotoxicity and/or mitogen response. A decrease in immune function with the HLA-DR13 expression was also observed (P < .01). Since the G-CSF increases the number of MNCs, the increase in effector cells might compensate for decreased immune functions of these cells in vivo when transplanted into patients. These results suggest a decreased immune function in G-CSF-mobilized BSC harvests and warrant further studies to correlate these data with clinical outcome. C1 NCI, Dept Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Dept Anat & Cell Biol, Omaha, NE 68182 USA. Univ Nebraska, Med Ctr, Dept Prevent & Social Med, Omaha, NE 68182 USA. Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE 68182 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68182 USA. RP Bishop, MR (reprint author), NCI, Dept Expt Transplantat & Immunol, NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. NR 38 TC 27 Z9 29 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1963 EP 1970 DI 10.1182/blood.V98.6.1963 PG 8 WC Hematology SC Hematology GA 471UV UT WOS:000170947800050 PM 11535536 ER PT J AU Hisada, M Biggar, RJ Greene, MH Fraument, JF Travis, LB AF Hisada, M Biggar, RJ Greene, MH Fraument, JF Travis, LB TI Solid tumors after chronic lymphocytic leukemia SO BLOOD LA English DT Article ID KIDNEY CANCER; RISK AB Prior reports indicate that patients with chronic lymphocytic leukemia (CLL) may be at increased risk of subsequent neoplasms. This study quantified the risk of second cancers among 16 367 patients with CLL in the population-based Surveillance, Epidemiology and End Results Program. Overall, the observed/expected ratio (O/E) was 1.20 (95% confidence Interval [CI], 1.15-1.26). Second cancer risks for patients who received chemotherapy only as the first course of treatment (O/E = 1.21) were similar to risks for those who received no treatment initially (O/E = 1.19). Significant excesses were found for Kaposi sarcoma (O/E = 5.09), malignant melanoma (O/E = 3.18), and cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66). Increased risks were also found for brain cancer among men (O/E = 1.91) and for cancers of the stomach (O/E = 1.76) and bladder (O/E = 1.52) among women. Additional investigations of cancers after CLL are needed to explore the role of immunologic impairment and/or other etiologic influences. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Hisada, M (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8008, Rockville, MD 20852 USA. NR 23 TC 97 Z9 101 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1979 EP 1981 DI 10.1182/blood.V98.6.1979 PG 3 WC Hematology SC Hematology GA 471UV UT WOS:000170947800052 PM 11535538 ER PT J AU Cheson, BD Bennett, JM Kantarjian, H Schiffer, CA Nimer, SD Lowenberg, B Stone, RM Mittelman, M Sanz, GF Wijermans, PW Greenberg, PL AF Cheson, BD Bennett, JM Kantarjian, H Schiffer, CA Nimer, SD Lowenberg, B Stone, RM Mittelman, M Sanz, GF Wijermans, PW Greenberg, PL CA Int Working Grp Standarize Respons TI Response: Myelodysplastic syndromes standardized response criteria: further definition SO BLOOD LA English DT Letter ID COLONY-STIMULATING FACTOR; WORKING GROUP; ERYTHROPOIETIN; ANEMIA C1 NCI, Bethesda, MD 20892 USA. RP Cheson, BD (reprint author), NCI, Execut Plaza N,Room 741, Bethesda, MD 20892 USA. NR 8 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2001 VL 98 IS 6 BP 1985 EP 1985 DI 10.1182/blood.V98.6.1985 PG 1 WC Hematology SC Hematology GA 471UV UT WOS:000170947800054 PM 11535540 ER PT J AU Andrus, JP Herzenberg, LA Herzenberg, LA De Rosa, SC AF Andrus, JP Herzenberg, LA Herzenberg, LA De Rosa, SC TI Effects of legislation restricting pack sizes of paracetamol on self poisoning - Paracetamol should be packaged with its antidote SO BRITISH MEDICAL JOURNAL LA English DT Letter ID ACETAMINOPHEN C1 Stanford Univ, Sch Med, Dept Genet, Beckman Ctr B007, Stanford, CA 94305 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Andrus, JP (reprint author), Stanford Univ, Sch Med, Dept Genet, Beckman Ctr B007, Stanford, CA 94305 USA. NR 5 TC 2 Z9 2 U1 1 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD SEP 15 PY 2001 VL 323 IS 7313 BP 634 EP 634 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 474CT UT WOS:000171087300040 PM 11575321 ER PT J AU Bates, S Kang, M Meadows, B Bakke, S Choyke, P Merino, M Goldspiel, B Chico, I Smith, T Chen, C Robey, R Bergan, R Figg, WD Fojo, T AF Bates, S Kang, M Meadows, B Bakke, S Choyke, P Merino, M Goldspiel, B Chico, I Smith, T Chen, C Robey, R Bergan, R Figg, WD Fojo, T TI A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar) SO CANCER LA English DT Article DE renal cell carcinoma; P-glycoprotein antagonist; drug resistance reversal; pharmacokinetic interaction ID RENAL-CELL CARCINOMA; SDZ PSC 833; MULTIDRUG-RESISTANCE MODULATOR; ACUTE MYELOGENOUS LEUKEMIA; ALTERED PHARMACOKINETICS; SOLID TUMORS; TISSUE DISTRIBUTION; DRUG-INTERACTIONS; TC-99M SESTAMIBI; CANCER PATIENTS AB BACKGROUND. PSC 833 is a second- generation P-glycoprotein (Pgp). antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CM for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable, Improved methods for predicting pharmacokinetic interactions should improve future studies. (C) 2001 American Cancer Society. C1 NCI, Canc Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. NCI, Dept Pathol, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIH, Clin Ctr Pharm, Bethesda, MD 20892 USA. Novartis Pharmaceut, E Hanover, NJ USA. NIH, Dept Nucl Med, Bethesda, MD USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. RP Bates, S (reprint author), NCI, Canc Therapeut Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 45 TC 51 Z9 55 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2001 VL 92 IS 6 BP 1577 EP 1590 DI 10.1002/1097-0142(20010915)92:6<1577::AID-CNCR1484>3.0.CO;2-H PG 14 WC Oncology SC Oncology GA 478UG UT WOS:000171363300028 PM 11745237 ER PT J AU Kantarjian, HM Talpaz, M Santini, V Murgo, A Cheson, B O'Brien, SM AF Kantarjian, HM Talpaz, M Santini, V Murgo, A Cheson, B O'Brien, SM TI Homoharringtonine - History, current research, and future directions SO CANCER LA English DT Review DE homoharringtonine; leukemia; cancer; hematologic; myelodysplastic syndrome ID CHRONIC MYELOGENOUS LEUKEMIA; PHASE-I TRIAL; PERFORMANCE LIQUID-CHROMATOGRAPHY; CONTINUOUS INFUSION; CELL-DIFFERENTIATION; REMISSION INDUCTION; MYELOID-LEUKEMIA; INTERFERON-ALPHA; HARRINGTONINE; RESISTANT AB BACKGROUND. Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S. METHODS. The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors. RESULTS. HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-a and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy. CONCLUSIONS. HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued. (C) 2001 American Cancer Society. C1 MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. RP Kantarjian, HM (reprint author), MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Box 428, Houston, TX 77030 USA. NR 103 TC 107 Z9 119 U1 3 U2 18 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2001 VL 92 IS 6 BP 1591 EP 1605 DI 10.1002/1097-0142(20010915)92:6<1591::AID-CNCR1485>3.0.CO;2-U PG 15 WC Oncology SC Oncology GA 478UG UT WOS:000171363300029 PM 11745238 ER PT J AU Varricchio, CG Stevens, J AF Varricchio, CG Stevens, J TI Funding ideas for new research SO CANCER LA English DT Article; Proceedings Paper CT Meeting on the Cancer Related Fatique: New Directions for Research CY FEB 19-20, 2000 CL TEXAS UNIV, HOUSTON, TEXAS HO TEXAS UNIV C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Amer Canc Soc, Res Dept, Atlanta, GA 30329 USA. RP Varricchio, CG (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,EPN 300, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2001 VL 92 IS 6 SU S BP 1737 EP 1743 DI 10.1002/1097-0142(20010915)92:6+<1737::AID-CNCR1506>3.0.CO;2-0 PG 7 WC Oncology SC Oncology GA 480LE UT WOS:000171462200015 PM 11598896 ER PT J AU Honjo, Y Hrycyna, CA Yan, QW Medina-Perez, WY Robey, RW van de Laar, A Litman, T Dean, M Bates, SE AF Honjo, Y Hrycyna, CA Yan, QW Medina-Perez, WY Robey, RW van de Laar, A Litman, T Dean, M Bates, SE TI Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells SO CANCER RESEARCH LA English DT Article ID CANCER RESISTANCE PROTEIN; ABC HALF-TRANSPORTER; HUMAN P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; MITOXANTRONE-RESISTANT; DROSOPHILA-MELANOGASTER; CROSS-RESISTANCE; CARCINOMA CELLS; PLASMA-MEMBRANE; TOPOTECAN AB A disparity was noted in the transport of rhodamine 123 among nine MXR/BCRP/ABCP-overexpressing cells studied; all demonstrated mitoxantrone transport, whereas only two effluxed rhodamine 123. When the MXR/BCRP/ABCP gene was sequenced in the cell lines studied, differences were noted at amino acid 482, predicted to be at the start of the third transmembrane domain. Sequencing genomic DNA revealed wild-type MXR/BCRP/ABCP to have an arginine at position 482. Cells having a threonine or glycine at position 482 were able to efflux rhodamine 123, whereas cells having an arginine were not. A vaccinia virus expression system confirmed that rhodamine as well as doxorubicin efflux is observed with R482T or R482G but not with the wild-type R482; all three MXR/BCRP/ABCP forms transported mitoxantrone. Cross-resistance studies suggest that, compared with wild-type MXR/BCRP/ABCP, cells having an R482T mutation have higher anthracycline resistance, whereas an R482G mutation seems to confer relatively less resistance to SN-38 and topotecan. These results suggest that amino acid 482 has a crucial role in MXR/BCRP/ABCP function and that mutation of a single amino acid residue significantly changes substrate specificity, thus altering the drug resistance phenotype. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. Univ Copenhagen, Panum Inst, Dept Med Physiol, DK-2200 Copenhagen, Denmark. NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bldg 10,Room 12M226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 21 TC 300 Z9 315 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2001 VL 61 IS 18 BP 6635 EP 6639 PG 5 WC Oncology SC Oncology GA 474LK UT WOS:000171108400004 PM 11559526 ER PT J AU Robles, AI Bemmels, NA Foraker, AB Harris, CC AF Robles, AI Bemmels, NA Foraker, AB Harris, CC TI APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis SO CANCER RESEARCH LA English DT Article ID CELL-LINES; EXPRESSION PATTERNS; GENE-EXPRESSION; ARREST; DEATH AB The expression of genes involved in p53-mediated apoptosis was studied using cDNA microarray after treating isogenic cell lines with either ionizing radiation or doxorubicin. Most of the known p53 transcriptional activation target genes clustered in a functional category defined by early and p53-dependent induction, regardless of the type of stress. Apoptotic protease activating factor-1 (APAF-1) emerged from this analysis as a novel p53 target gene. Genomic sequences upstream of the APAF-1 transcription start site contain a classic p53-responsive element that bound to p53. Consistently, p53 directly induced APAF-1 gene expression. Furthermore, DNA damage-mediated induction of APAF-1 mRNA and protein expression, accompanied by apoptosis, were strictly dependent on wildtype p53 function. These data are consistent with the hypothesis that APAF-1 is an essential downstream effector of p53-mediated apoptosis. C1 NCI, Canc Res Ctr, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Canc Res Ctr, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 2C05, Bethesda, MD 20892 USA. NR 24 TC 137 Z9 146 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2001 VL 61 IS 18 BP 6660 EP 6664 PG 5 WC Oncology SC Oncology GA 474LK UT WOS:000171108400008 PM 11559530 ER PT J AU Im, YH Kim, HT Kim, IY Factor, VM Hahm, KB Anzano, M Jang, JJ Flanders, K Haines, DC Thorgeirsson, SS Sizeland, A Kim, SJ AF Im, YH Kim, HT Kim, IY Factor, VM Hahm, KB Anzano, M Jang, JJ Flanders, K Haines, DC Thorgeirsson, SS Sizeland, A Kim, SJ TI Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis SO CANCER RESEARCH LA English DT Article ID HUMAN PROSTATE-CANCER; TGF-BETA; CELLS; INACTIVATION; INHIBITION; REPRESSION; KINASE AB The transforming growth factor-13 (TGF-13) receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. In many cancers, expression of TGF-beta type 11 receptor (T betaR-II) is markedly decreased. In the present study, we show that the hepatocytes isolated from 15-day-old, but not 9-month-old, mice heterozygous for the deletion of the T betaR-II gene are slightly less sensitive to the growth-inhibitory effect of TGF-beta when compared with wild-type littermates of same age. In addition, the proliferation index of hepatocytes as indicated by bromodeoxyuridine incorporation is mildly increased in the heterozygous mice. These subtle changes in cellular phenotype did not result in either gross or microscopic abnormality of the liver. The treatment of these mice with the chemical carcinogen, diethyinitrosamine, results in a significantly enhanced tumorigenesis in the liver when compared with the wild-type littermates. Our results demonstrate the gene-dosage effect of T betaR-11 and indicate that the reduced expression of T betaR-11 in mice increases susceptibility to tumorigenesis in the liver. C1 NCI, Lab Cell Regulat & Carcinogensis, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. SAIC, Frederick Canc Res & Dev Ctr, Pathol Histotechnol Lab, Frederick, MD 21702 USA. Royal Melbourne Hosp, Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogensis, NIH, Bldg 41,Room B1106, Bethesda, MD 20892 USA. RI Jang, JaJune/F-6647-2011 NR 19 TC 39 Z9 41 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2001 VL 61 IS 18 BP 6665 EP 6668 PG 4 WC Oncology SC Oncology GA 474LK UT WOS:000171108400009 PM 11559531 ER PT J AU Worley, BS van den Broeke, LT Goletz, TJ Pendleton, CD Daschbach, EM Thomas, EK Marincola, FM Helman, LJ Berzofsky, JA AF Worley, BS van den Broeke, LT Goletz, TJ Pendleton, CD Daschbach, EM Thomas, EK Marincola, FM Helman, LJ Berzofsky, JA TI Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations SO CANCER RESEARCH LA English DT Article ID CLEAR-CELL-SARCOMA; TUMOR ALVEOLAR RHABDOMYOSARCOMA; HUMAN SYNOVIAL SARCOMA; MALIGNANT-MELANOMA; SOFT PARTS; CYTOTOXIC LYMPHOCYTES; BINDING MOTIFS; SOLID TUMORS; GENE FUSION; WT1 GENES AB Synovial sarcoma (SS), clear cell sarcoma (CCS), and desmoplastic small round cell tumor (DSRCT) are soft-tissue malignancies occurring primarily in adolescents and young adults. These tumors contain specific chromosomal translocations that fuse the 5 ' region of one gene with the 3 ' region of another, resulting in the formation of characteristic fusion proteins. These translocations are unique to tumor cells and may be required for persistence, thereby serving as targets for immunotherapy. It was hypothesized that the fusion breakpoint sequences associated with SS. CCS, and DSRCT can serve as tumor-specific neoantigens. To test this, peptides corresponding to the fusion breakpoints were designed and assessed for ability to bind to various class I HLA molecules. Two peptides derived from the SS breakpoint specifically bind the HLA-B7 antigen, and a 10-amino acid minimal epitope was identified for this interaction. Specific binding of a SS peptide and a CCS peptide to HLA-B27 molecule was also observed. Finally, a peptide designed from the DSRCT breakpoint specifically binds the HLA-A3 molecule, and a 9-amino acid optimal epitope was identified for this interaction. The physiological/immunological relevance of these peptide/MHC interactions was demonstrated by the induction of SS-specific CTLs from normal donor lymphocytes using in vitro stimulation with autologous, peptide-pulsed dendritic cells and by the ability of these CTLs to lyse human SS tumor cells endogenously expressing the full-length fusion protein. These results suggest that sequences in the fusion region of sarcoma-associated chimeras can bind class I HLA molecules and serve as neoantigens. These may be useful for the development of novel immunotherapies for sarcoma patients with appropriate HLA molecules and tumors bearing these translocations. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Pediat Branch, Bethesda, MD 20892 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12,MSC 1578,10 Ctr Dr, Bethesda, MD 20892 USA. NR 46 TC 48 Z9 49 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2001 VL 61 IS 18 BP 6868 EP 6875 PG 8 WC Oncology SC Oncology GA 474LK UT WOS:000171108400041 PM 11559563 ER PT J AU Nam, SW Clair, T Kim, YS McMarlin, A Schiffmann, E Liotta, LA Stracke, ML AF Nam, SW Clair, T Kim, YS McMarlin, A Schiffmann, E Liotta, LA Stracke, ML TI Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor SO CANCER RESEARCH LA English DT Article ID MOTILITY-STIMULATING PROTEIN; FIBROBLAST GROWTH-FACTOR; HUMAN-MELANOMA CELLS; BASEMENT-MEMBRANE; CANCER METASTASIS; ENDOTHELIAL-CELLS; IN-VITRO; EXPRESSION; IDENTIFICATION; CLONING AB Autotaxin [ATX (NPP-2)], originally isolated as a tumor motility-stimulating protein, has recently been shown to augment tumor aggressiveness. Specifically, atx-transfected, ras-transformed NIH3T3 cell lines have been shown to be more invasive, tumorigenic, and metastatic than mock-transfected ras-transformed control cells. In addition, the atx-transfected ras-transformed cell lines appeared to produce tumors that were much more hyperemic than those formed by appropriate control cells. This observation led to the present study, in which we demonstrate that ATX modulates angiogenesis both directly and indirectly. We have used a marine in vivo angiogenesis model in which treated Matrigel plugs are injected s.c. into athymic nude BALB/c mice. Using the same transfected cell lines as before, we found that mixing atx-transfected ras-transformed NIH3T3 cells into the Matrigel resulted in greater new blood vessel formation than control cells. Similarly, mixing purified ATX into the Matrigel resulted in new blood vessel formation within the plug, similar to that produced by vascular endothelial growth factor. Mechanistically, ATX is not a strong chemoattractant for human endothelial cells (HUVECs); however, it strongly stimulates motility in human coronary artery smooth muscle cells. In addition, ATX stimulates HUVECs grown on Matrigel to form tubules, much like vascular endothelial growth factor. Both of these normal cell types are shown to express and secrete ATX. In HUVECS, ATX expression is up-regulated by basic fibroblast growth factor in a time-dependent manner. This up-regulation also extends to secretion of enzymatically active protein, as demonstrated by Western blot analysis and quantification of type-1 phosphodiesterase activity. These results establish the presence of ATX in HUVECs and coronary artery smooth muscle cells and specify ATX as a novel angiogenic factor, suggesting that ATX could contribute to the metastatic cascade through multiple mechanisms, perhaps by supporting an invasive microenvironment for both normal and tumor cells. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Nam, SW (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33, Bethesda, MD 20892 USA. NR 23 TC 152 Z9 157 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2001 VL 61 IS 18 BP 6938 EP 6944 PG 7 WC Oncology SC Oncology GA 474LK UT WOS:000171108400051 PM 11559573 ER PT J AU Augenbraun, M Corey, L Reichelderfer, P Wright, DJ Burns, D Koelle, DM Robison, E Cohen, M AF Augenbraun, M Corey, L Reichelderfer, P Wright, DJ Burns, D Koelle, DM Robison, E Cohen, M CA Women's Hlth Studies 002 Study Grp TI Herpes simplex virus shedding and plasma human immunodeficiency virus RNA levels in coinfected women SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID GENITAL HERPES; HIV-INFECTION; ACQUIRED IMMUNODEFICIENCY; RISK FACTOR; CD4+ CELL; TYPE-1; LOAD; MEN; TRANSCRIPTION; ACTIVATION AB Asymptomatic herpes simplex virus (HSV) shedding was described in a cohort of human immunodeficiency virus (HIV)-infected women, and the association of HSV shedding with changes in plasma HIV RNA load was investigated. Genital, rectal, and oral swabs were obtained daily during a 4-week period for polymerase chain reaction and culture, and concomitant plasma specimens were drawn 3 times weekly for determination of HIV RNA load. During the study, 70% and 79% of subjects shed HSV from the oral cavity and genital area, respectively. Shedding of HSV occurred for a mean of 3.2 days for oral shedding and 5.4 days for genital shedding. Mean plasma HIV RNA loads during periods of HSV shedding and nonshedding and for periods 3 days after the cessation of shedding were compared; no significant differences were found (P=.74). In women who shed HSV, as evaluated by detection of virus, plasma HIV RNA load did not fluctuate with HSV shedding. C1 Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Washington, Seattle, WA 98195 USA. NICHHD, NIH, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. Cook Cty Hosp, Chicago, IL 60612 USA. RP Augenbraun, M (reprint author), SUNY Hlth Sci Ctr, Dept Med, Box 37,450 Clarkson Ave, Brooklyn, NY 11203 USA. RI Koelle, David/Q-6529-2016 OI Koelle, David/0000-0003-1255-9023 FU NCI NIH HHS [CA-70017]; NIAID NIH HHS [AI-30731]; NICHD NIH HHS [HD-33162, U1-HD-32632]; PHS HHS [A1-34989, U01-A131834, U01-A134993, U01-A134994, U01-A135004, U01-A142590] NR 28 TC 20 Z9 20 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2001 VL 33 IS 6 BP 885 EP 890 DI 10.1086/322654 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 472PZ UT WOS:000170994700023 PM 11512094 ER PT J AU Potterf, SB Mollaaghababa, R Hou, L Southard-Smith, EM Hornyak, TJ Arnheiter, H Pavan, WJ AF Potterf, SB Mollaaghababa, R Hou, L Southard-Smith, EM Hornyak, TJ Arnheiter, H Pavan, WJ TI Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase SO DEVELOPMENTAL BIOLOGY LA English DT Article DE neural crest; development; melanocyte; DCT; mouse embryo; pigmentation; MITF; KIT; SOX10 ID TYROSINASE-RELATED PROTEIN; WAARDENBURG-SYNDROME; MOUSE TYROSINASE; HIRSCHSPRUNG-DISEASE; GENE; EXPRESSION; MITF; MUTATION; CELLS; MICROPHTHALMIA AB SOX10 is a high-mobility-group transcription factor that plays a critical role in the development of neural crest-derived melanocytes. At E11.5, mouse embryos homozygous for the Sox10(Dom) mutation entirely lack neural crest-derived cells expressing the lineage marker KIT, MITF, or DCT. Moreover, neural crest cell cultures derived from homozygous embryos do not give rise to pigmented cells. In contrast, in Sox10(Dom) heterozygous embryos, melanoblasts expressing KIT and MITF do occur, albeit in reduced numbers, and pigmented cells eventually develop in nearly normal numbers both in culture and in vivo. Intriguingly, however, Sox10(Dom)/+ melanoblasts transiently lack Det expression both in culture and in vivo, suggesting that during a critical developmental period SOX10 may serve as a transcriptional activator of Dct. Indeed, we found that SOX10 and DCT colocalized in early melanoblasts and that SOX10 is capable of transactivating the Dct promoter in vitro. Our data suggest that during early melanoblast development SOX10 acts as a critical transactivator of Dct, that MITF, on its own, is insufficient to stimulate Dct expression, and that delayed onset of Dct expression is not deleterious to the melanocyte lineage. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Henry Ford Hlth Syst, Dermatol Res, Detroit, MI 48202 USA. NINCDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RI Southard-Smith, Michelle/C-3488-2012; OI Hou, Ling/0000-0003-0705-8099 FU NIDDK NIH HHS [R01 DK060047, R01 DK060047-01A1, R01 DK060047-02, R01 DK060047-03] NR 46 TC 96 Z9 99 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 2001 VL 237 IS 2 BP 245 EP 257 DI 10.1006/dbio.2001.0372 PG 13 WC Developmental Biology SC Developmental Biology GA 476CQ UT WOS:000171209000001 PM 11543611 ER PT J AU Raben, N Lu, N Nagaraju, K Rivera, Y Lee, A Yan, B Byrne, B Meikle, PJ Umapathysivam, K Hopwood, JJ Plotz, PH AF Raben, N Lu, N Nagaraju, K Rivera, Y Lee, A Yan, B Byrne, B Meikle, PJ Umapathysivam, K Hopwood, JJ Plotz, PH TI Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy SO HUMAN MOLECULAR GENETICS LA English DT Article ID DISEASE TYPE-II; RECOMBINANT ADENOASSOCIATED VIRUS; CORRECTS GLYCOGEN ACCUMULATION; ADENOVIRUS-MEDIATED TRANSFER; SKELETAL-MUSCLE; POMPE-DISEASE; INTRAMUSCULAR INJECTION; INTRACELLULAR-TRANSPORT; TARGETED DISRUPTION; TRANSGENIC MICE AB Both enzyme replacement and gene therapy of lysosomal storage disorders rely on the receptor-mediated uptake of lysosomal enzymes secreted by cells, and for each lysosomal disorder it is necessary to select the correct cell type for recombinant enzyme production or for targeting gene therapy. For example, for the therapy of Pompe disease, a severe metabolic myopathy and cardiomyopathy caused by deficiency of acid alpha -glucosidase (GAA), skeletal muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Using knockout mice with this disease and transgenes containing cDNA for the human enzyme under muscle or liver specific promoters controlled by tetracycline, we have demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising <5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110 kDa precursor form. Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early. C1 NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Dept Med, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Gene Therapy Ctr, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Pediat, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Mol Genet, Gainesville, FL 32610 USA. Womens & Childrens Hosp, Dept Chem Pathol, Adelaide, SA 5006, Australia. RP Raben, N (reprint author), NIAMS, Arthrit & Rheumatism Branch, NIH, 9000 Rockville Pike,Clin Ctr Bldg 10-9B244, Bethesda, MD 20892 USA. RI Meikle, Peter/B-4023-2009 NR 42 TC 51 Z9 55 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2001 VL 10 IS 19 BP 2039 EP 2047 DI 10.1093/hmg/10.19.2039 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 484MH UT WOS:000171693800003 PM 11590121 ER PT J AU Lally, KM Mocellin, S Ohnmacht, GA Nielsen, MB Bettinotti, M Panelli, MC Monsurro, V Marincola, FM AF Lally, KM Mocellin, S Ohnmacht, GA Nielsen, MB Bettinotti, M Panelli, MC Monsurro, V Marincola, FM TI Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE immunotherapy; tumor antigens; MAGE; vaccines; epitope spreading ID CD8(+) T-CELLS; MELANOMA PATIENTS; PERIPHERAL-BLOOD; GENE-EXPRESSION; REACTIVE CTL; PEPTIDE; LYMPHOCYTES; IDENTIFICATION; RECOGNITION; MART-1 AB The basis of intra-tumoral and systemic T cell reactivity toward cancer remains unclear. In particular the role that peripheral stimuli, whether endogenous or exogenous, play in shaping acquired immune response toward cancer remains poorly understood. In this study we document the surfacing of systemic immune reactivity toward a cryptic epitope from the MAGE-12 gene (MAGE-12:170-178), after temporary regression of a single melanoma metastasis, in response to gp100/PMe117-specific vaccination. This emergence was unlikely related to unusually high expression of MAGE-12 by the tumor, by the influence of analog epitopes to MAGE-12:170-178. Because MAGE-12 was unlikely to be expressed at sites other than the tumor, the demonstration of MAGE-12:170-178 reactivity in post- but not pre-vaccination circulating lymphocytes suggests that the systemically observed immune response was influenced by events induced by the vaccine at tumor site or draining lymph nodal areas. Possibly, as suggested by pre-clinical models, immunologic ignorance is the default response toward cancer in humans unless unusual stimulatory conditions occur in peripheral tissues. Surfacing of MAGE-12 specificity occurred in association with loss of gp100/PMel 17 targeted by the vaccine. This finding suggests that vaccinations might have effects beyond their intrinsic specificity and may trigger broader immune responses through epitope spreading by inducing changes within the tumor microenvironment. This may have important practical implication for the development of immunization strategies. Published 2001 Wiley-Liss,Inc.dagger C1 NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Div Clin Sci, NIH, Bldg 10,Room 2B42,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. NR 31 TC 43 Z9 44 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2001 VL 93 IS 6 BP 841 EP 847 DI 10.1002/ijc.1420 PG 7 WC Oncology SC Oncology GA 463ME UT WOS:000170479300012 PM 11519046 ER PT J AU Radko, SP Stastna, M Chrambach, A AF Radko, SP Stastna, M Chrambach, A TI Polydispersity of liposome preparations as a likely source of peak width in capillary zone electrophoresis SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE polydispersity; liposomes ID PARTICLES; SEPARATIONS AB Negatively charged liposomes consisting of phosphatidylcholine/phosphatidylglycerol/cholesterol in various ratios when subjected to capillary zone electrophoresis (CZE) in Tris-HCl (pH 8) buffer of different concentrations have been shown previously to exhibit a size-dependent migration rate at low ionic strength. The present study, focusing on the peak width under those conditions, shows that the polydispersity of liposomes correlated with, and appears to be a dominant source of, the peak width of the liposomes in CZE in a buffer of low ionic strength (2 to 5 mM Tris-HCl buffer, pH 8) at moderate electric field strengths (200 V cm(-1) or less). This finding, beyond allowing for the analysis of liposome polydispersity by CZE, suggests that the size-dependent fractionation of liposome preparations by a preparative electrophoretic technique such as free-flow electrophoresis is potentially feasible. (C) 2001 Published by Elsevier Science B.V. C1 NICHHD, Lab Cellular & Mol Biophys, Sect Macromol Anal, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Lab Cellular & Mol Biophys, Sect Macromol Anal, NIH, Bldg 10,Room 9D50, Bethesda, MD 20892 USA. RI Stastna, Miroslava/G-9266-2014 NR 12 TC 17 Z9 18 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4347 J9 J CHROMATOGR B JI J. Chromatogr. B PD SEP 15 PY 2001 VL 761 IS 1 BP 69 EP 75 DI 10.1016/S0378-4347(01)00301-2 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 472BD UT WOS:000170962400007 PM 11585133 ER PT J AU Marcus, PM AF Marcus, PM TI Lung cancer screening: An update SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROJECT AB Two prominent and timely issues in lung cancer screening are discussed in this article. First, findings from extended mortality follow-up of participants enrolled as part of the Mayo Lung Project are reviewed. These findings suggest that overdiagnosis -the identification, through screening, of clinically unimportant lung cancer lesions-may occur when screening for lung cancer. Second, the question of whether sufficient evidence exists to advocate mass lung cancer screening with low radiation dose spiral computed tomography (CT) is discussed. Given the absence of lung cancer mortality data for spiral CT, it is concluded that such activities should not be advocated at this point in time. The Lung Screening Study, an ongoing randomized controlled trial of lung cancer screening with spiral CT, also is described. (C) 2001 by American Society of Clinical Oncology. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,Ste 344, Bethesda, MD 20892 USA. NR 12 TC 38 Z9 38 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2001 VL 19 IS 18 SU S BP 83S EP 86S PG 4 WC Oncology SC Oncology GA 475GY UT WOS:000171155400017 PM 11560979 ER PT J AU Swain, SM AF Swain, SM TI Tamoxifen for patients with estrogen receptor-negative breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL-ADJUVANT-BREAST; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; THERAPY; ALPHA; BETA; RISK C1 NCI, Bethesda, MD 20892 USA. RP Swain, SM (reprint author), Natl Naval Med Res Inst, Canc Therapeut Branch, 8901 Wisconsin Ave,Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM swains@mail.nih.gov NR 28 TC 15 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2001 VL 19 IS 18 SU S BP 93S EP 97S PG 5 WC Oncology SC Oncology GA 475GY UT WOS:000171155400019 PM 11560981 ER PT J AU Wickerham, DL AF Wickerham, DL TI Ductal carcinoma-in-situ SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL-ADJUVANT-BREAST; INTRADUCTAL CARCINOMA; PATHOLOGICAL FINDINGS; RADIATION-THERAPY; PROTOCOL B-17; CANCER; TAMOXIFEN; TRIAL; CHEMOTHERAPY; LUMPECTOMY C1 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. RP Wickerham, DL (reprint author), 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, E Commons Profess Bldg, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10CA12027, U10CA37377] NR 19 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2001 VL 19 IS 18 SU S BP 98S EP 100S PG 3 WC Oncology SC Oncology GA 475GY UT WOS:000171155400020 PM 11560982 ER PT J AU Chen, LC Zhang, ZJ Myers, AC Huang, SK AF Chen, LC Zhang, ZJ Myers, AC Huang, SK TI Cutting edge: Altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AIRWAY HYPERREACTIVITY; ALLERGIC RESPONSES; MURINE MODEL; MAST-CELL; ASTHMA; INHIBITION; EXPRESSION; IL-5; LUNG AB Clara cell secretory protein (CC10) is a steroid-inducible protein, and its in vivo function is currently unclear. The role of CC10 in modulation of pulmonary allergic inflammation was examined in mice deficient for the CC10 gene. Wild-type and homozygous CC10-deficient mice were sensitized with an Ag, OVA, and challenged with either OVA or saline. When compared with that seen in wild-type mice, a significantly higher level of pulmonary eosinophilia was found in Ag-sensitized and challenged CC10-deficient mice. Significantly increased levels of Th2 cytokines IL-4, IL-5, IL-9, and IL-13 were also found in CC10-deficient mice. In addition, an increased level of eotaxin, but not RANTES, was also seen in CC10-deficient mice. No significant difference was observed in the level of a Th1 cytokine, IFN-gamma, between different groups of mice. These results provided the first in vivo evidence that CC10 plays a role in the modulation of pulmonary allergic inflammation. C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA. Chang Gung Childrens Hosp, Div Allergy Asthma & Rheumatol, Dept Pediat, Taoyuan, Taiwan. NICHHD, NIH, Bethesda, MD 20892 USA. RP Huang, SK (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. RI Huang, Shau-Ku/F-5509-2010 FU PHS HHS [R01-40274] NR 25 TC 68 Z9 72 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 SEP 15 PY 2001 VL 167 IS 6 BP 3025 EP 3028 PG 4 WC Immunology SC Immunology GA 496JG UT WOS:000172392000001 PM 11544284 ER PT J AU Suzuki, Y Rahman, M Mitsuya, H AF Suzuki, Y Rahman, M Mitsuya, H TI Diverse transcriptional response of CD4(+) T cells to stromal cell-derived factor (SDF)-1: Cell survival promotion and priming effects of SDF-1 on CD4+T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; NEURONAL APOPTOSIS; FACTOR-I; ACTIVATION; PROTEIN; CHEMOTAXIS; INHIBITOR; PATHWAY; KINASE; GENE AB Stromal cell-derived factor (SDF)-1 is a ligand for the chemokine receptor CXCR4 which is broadly expressed in lymphocytes, but the effects of SDF-1 on T cells are largely unknown. When examined using complementary DNA microarray, up-regulation of genes which are associated with DNA repair, detoxification, apoptosis, cell morphology, cell adhesion, and signal transduction was seen in CD4(+) T cells upon SDF-1 exposure. SDF-1 was shown to promote CD4(+) T cell survival through the phosphatidylinositol 3-kinase (PI3K)- and mitogen-activated protein kinase (MAPK)-cascades without cell cycle progression. The proapoptotic Bcl-2 antagonistic of cell death protein was also seen inactivated by the SDF-1-mediated activation of MAPK-extracellular signal-regulated kinases (MEK)-extracellular signal-regulated kinase-ribosomal S6 kinases- and PI3K-pathways. Moreover, the genes known to be associated with cell survival were up-regulated upon SDF-1 exposure and were linked to the MAPK-MEK and PI3K-pathways. Thus, SDF-1 promotes cell survival by two mechanisms: posttranslational inactivation of the cell death machinery and an increased transcription of cell survival-related genes. SDF-1 also primed resting CD4(+) T cells for cytokine- and TCR-mediated stimuli. These data suggest that the SDF-1-mediated cell survival combined with its priming function would set T cells to respond to immunologic challenges. C1 NCI, Expt Retrovirol Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, Canc Res Ctr, NIH, Bldg 10,Room 5A11,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 114 Z9 119 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2001 VL 167 IS 6 BP 3064 EP 3073 PG 10 WC Immunology SC Immunology GA 496JG UT WOS:000172392000007 PM 11544290 ER PT J AU Wang, JH Guan, E Roderiquez, G Norcross, MA AF Wang, JH Guan, E Roderiquez, G Norcross, MA TI Synergistic induction of apoptosis in primary CD4(+) T cells by macrophage-tropic HIV-1 and TGF-beta 1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GROWTH-FACTOR-BETA; CASPASE-ACTIVATED DNASE; FAS LIGAND EXPRESSION; TGF-BETA; UP-REGULATION; CCR5 EXPRESSION; CYTOCHROME-C; HOST FACTORS; B-CELLS AB Depletion of CD4(+) T lymphocytes is a central immunological characteristic of HIV-1 infection. Although the mechanism of such CD4(+) cell loss following macrophage-tropic (R5) HIV-1 infection remains unclear, interactions between viral and host cell factors are thought to play an important role in the pathogenesis of HIV-1 disease. Based on the observation that TGF-beta1 enhanced expression of HIV chemokine coreceptors, the role of this host factor in virus effects was investigated using PBLs cultured in a nonmitogen-added system in the absence or presence of TGF-beta1. Most CD4 cells in such cultures had the phenotype CD25(-)CD69(-)DR(-)Ki67(-) and were CD45RO(bright)CD45(dim). Cultured cells had increased expression of CCR5 and CXCR4 and supported both HIV-1 entry and completion of viral reverse transcription. Virus production by cells cultured in the presence of IL-2 was inhibited by TGF-beta1, and this inhibition was accompanied by a loss of T cells from the culture and an increase in CD4(+) T cell apoptosis. Whereas R5X4 and X4 HIV-1 infection was sufficient to induce T cell apoptosis, R5 HIV-1 failed to induce apoptosis of PBLs in the absence of TGF-beta1 despite the fact that R5 HIV-1 depletes CD4(+) T cells in vivo. Increased apoptosis with HIV and TGF-beta1 was associated with reduced levels of Bcl-2 and increased expression of apoptosis-inducing factor, caspase-3, and cleavage of BID, c-IAP-1, and X-linked inhibitor of apoptosis. These results show that TGF-beta1 promotes depletion of CD4(+) T cells after R5 HIV-1 infection by inducing apoptosis and suggest that TGF-beta1 might contribute to the pathogenesis of HIV-1 infection in vivo. C1 NIH, Div Therapeut Prot, Ctr Biol Evaluat & Res, US FDA,Lab Gene Regulat, Bethesda, MD 20892 USA. RP Wang, JH (reprint author), NIH, Div Therapeut Prot, Ctr Biol Evaluat & Res, US FDA,Lab Gene Regulat, Bldg 29B,Room 4E12,8000 Rockville Pike, Bethesda, MD 20892 USA. NR 71 TC 18 Z9 19 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2001 VL 167 IS 6 BP 3360 EP 3366 PG 7 WC Immunology SC Immunology GA 496JG UT WOS:000172392000043 PM 11544326 ER PT J AU Wellems, TE Plowe, CV AF Wellems, TE Plowe, CV TI Chloroquine-resistant malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID UNCOMPLICATED FALCIPARUM-MALARIA; PARASITE PLASMODIUM-FALCIPARUM; PFMDR1 GENE; DIGESTIVE VACUOLE; DRUG SENSITIVITY; 2 MUTATIONS; INVITRO; REVERSAL; ANTIMALARIALS; MECHANISM AB The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum, the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite's digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in greater than or equal to4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax, which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency. C1 NIAID, LPD, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. RP Wellems, TE (reprint author), NIAID, LPD, NIH, 4 Ctr Dr,Bldg 4,Rm 126, Bethesda, MD 20892 USA. NR 73 TC 375 Z9 383 U1 5 U2 35 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2001 VL 184 IS 6 BP 770 EP 776 DI 10.1086/322858 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 472PE UT WOS:000170992000014 PM 11517439 ER PT J AU Bridge, H Cumming, BG AF Bridge, H Cumming, BG TI Responses of macaque V1 neurons to binocular orientation differences SO JOURNAL OF NEUROSCIENCE LA English DT Article DE orientation disparity; positional disparity; energy model; cortical area V1; awake macaque; electrophysiology ID CAT STRIATE CORTEX; VISUAL-CORTEX; DEPTH DISCRIMINATION; COMPLEX CELLS; DISPARITY; SELECTIVITY; PERCEPTION; POSITION; AREA AB Interocular differences in orientation occur during binocular viewing of a surface slanted in depth. These orientation disparities could be exploited by the visual system to provide information about surface slant, but gradients of positional disparity provide an equally effective means to the same end. We examined the encoding of orientation disparities in V1 neurons that were recorded from two awake fixating monkeys. Monocular orientation selectivity was measured separately in each eye. Although the preferred monocular orientation in the left and right eyes was highly correlated (r = 0.98), 19 of 61 cells showed a significant interocular difference in preferred orientation (IDPO). By itself, an IDPO does not imply a specific binocular selectivity for orientation differences. We therefore examined the response to 25 binocular combinations of orientations by pairing each of five orientations in one eye with five in the other. Forty-four of 64 neurons showed responses that reflected the monocular orientation tuning selectivity; the preferred orientation disparity changed when the monocular orientation was changed in either eye. The remaining third (20 of 64) responded to a consistent orientation disparity in a way that was not simply predictable from monocular orientation selectivity. However, nearly all of these neurons were selective for positional disparity, and several characteristics of the responses suggest that the apparent selectivity for orientation disparities was just a consequence of the positional disparity sensitivity. Neither the data presented here nor previous data from the cat (Blakemore et al., 1972; Nelson et al., 1977) support the idea that a population of neurons early in the visual system has a separate encoding scheme for orientation disparities. C1 Univ Oxford, Physiol Lab, Oxford OX1 3PT, England. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Bridge, H (reprint author), Univ Oxford, Physiol Lab, S Parks Rd, Oxford OX1 3PT, England. NR 29 TC 39 Z9 39 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 15 PY 2001 VL 21 IS 18 BP 7293 EP 7302 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 471HM UT WOS:000170922800033 PM 11549739 ER PT J AU Wehr, TA Aeschbach, D Duncan, WC AF Wehr, TA Aeschbach, D Duncan, WC TI Evidence for a biological dawn and dusk in the human circadian timing system SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SUPRACHIASMATIC NUCLEUS; TEMPERATURE RHYTHMS; SLEEP PROPENSITY; MELATONIN; PHOTOPERIOD; PACEMAKER; PHASE; PINEAL; WAKEFULNESS; HAMSTER AB 1. Because individuals differ in the phase angle at which their circadian rhythms are entrained to external time cues, averaging group data relative to clock time sometimes obscures abrupt changes that are characteristic of waveforms of the rhythms in individuals. Such changes may have important implications for the temporal organization of human circadian physiology. 2. To control for variance in phase angle of entrainment, we used dual internal reference points - onset and offset of the nocturnal period of melatonin secretion - to calculate average profiles of circadian rhythm. data from five previously published studies. 3. Onset and/or offset of melatonin secretion were found to coincide with switch-like transitions between distinct diurnal and nocturnal periods of circadian rhythms in core body temperature, sleepiness, power in the theta band of the wake EEG, sleep propensity and rapid eye movement (REM) sleep propensity. 4. Transitions between diurnal and nocturnal periods of sleep-wake and cortisol circadian rhythms were found to lag the other transitions by 1-3 h. 5. When the duration of the daily light period was manipulated experimentally, melatonin-onset-related transitions in circadian rhythms appeared to be entrained to the light-to-dark transition, while melatonin-offset-related transitions appeared to be entrained to the dark-to-light transition. 6. These results suggest a model of the human circadian timing system in which two states, one diurnal and one nocturnal, alternate With one another, and in which transitions between the states are switch-like and are separately entrained to dawn and dusk. 7. This description of the human circadian system is similar to the Pittendrigh-Daan model of the rodent cireadian system, and it suggests that core features of the system in other mammals are conserved in humans. C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Wehr, TA (reprint author), NIMH, Sect Biol Rhythms, Bldg 10,Rm 3S-231,10 Ctr Dr MSC1390, Bethesda, MD 20892 USA. NR 39 TC 83 Z9 84 U1 3 U2 9 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2001 VL 535 IS 3 BP 937 EP 951 DI 10.1111/j.1469-7793.2001.t01-1-00937.x PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 480XJ UT WOS:000171488300025 PM 11559786 ER PT J AU Djimde, A Doumbo, OK Steketee, RW Plowe, CV AF Djimde, A Doumbo, OK Steketee, RW Plowe, CV TI Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria SO LANCET LA English DT Article ID MUTATIONS AB Drug-resistant falciparum malaria is increasing in Africa and so methods to map resistance on a broad scale are needed. A molecular marker for chloroquine resistance, pfcrt T76, can be used for surveillance of clinical chloroquine resistance. The prevalence of pfcrt T76 and the prevalence of clinical chloroquine resistance and therapeutic failure were measured at sentinel sites and used to calculate age-adjusted genotype-resistance Indices (GRIs) and genotype-failure Indices (GFIs). We found stable GRIs and GFIs at different sites In Mail, West Africa. This model permits mapping of chloroquine resistance using molecular tools in rapid and simple cross-sectional surveys. C1 Univ Maryland, Sch Med, Ctr Vaccine Dev, Malaria Sect, Baltimore, MD 21201 USA. Univ Mali, Fac Med Pharm & Dent, Dept Epidemiol & Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. NIAID, Malaria Genet Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Malaria Epidemiol Branch, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA USA. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Malaria Sect, Baltimore, MD 21201 USA. FU NIAID NIH HHS [N01-AI-85346, 5P50AI39469] NR 5 TC 110 Z9 111 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 15 PY 2001 VL 358 IS 9285 BP 890 EP 891 DI 10.1016/S0140-6736(01)06040-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 474CP UT WOS:000171087000013 PM 11567708 ER PT J AU Chen, H Liu, J Zhao, CQ Diwan, BA Merrick, BA Waalkes, MP AF Chen, H Liu, J Zhao, CQ Diwan, BA Merrick, BA Waalkes, MP TI Association of c-myc overexpression and hyperproliferation with arsenite-induced malignant transformation SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; arsenic-induced malignant transformation; hyperproliferation; c-myc activation ID CELL NUCLEAR ANTIGEN; DNA METHYLATION; GENE-EXPRESSION; GROWTH-FACTORS; HA-RAS; HEPATOCELLULAR-CARCINOMA; CHRONIC STIMULATION; SKIN NEOPLASIA; MESSENGER-RNA; CYCLIN D1 AB Numerous studies link arsenic exposure to human cancers in a variety of tissues, including the liver. However, inorganic arsenic has never been unequivocally shown to be an animal carcinogen, and its carcinogenic mechanism remains undefined. Our previous studies indicate that chronic (greater than or equal to 18 weeks), low-level (125 to 500 nM) exposure to arsenite induces malignant transformation in the normally nontumorigenic rat liver epithelial cell line (TRL 1215), and these chronic arsenic-exposed (CAsE) cells produce invasive and metastatic tumors upon inoculation into nude mice. In addition, a prior microarray screening analysis of aberrant gene expression showed several oncogenes were overexpressed in CAsE cells exposed to 500 nM arsenite, including a prominent overexpression of the protooncogene c-myc, as well as genes related to cell proliferation. Thus, to better understand the mechanism of arsenic carcinogenesis, we studied the role of c-myc overexpression in arsenite-induced cell transformation. The upregulation of c-myc was confirmed by RT-PCR at the transcription level and by Western blot analysis for the translation product. Further analysis showed that arsenite produced significant increases in the steady-state expression of c-myc in a time- and concentration-dependent manner during the malignant transformation process. The level of c-myc expression was highly correlated (r = 0.988) with tumor formation after inoculation of CAsE cells into nude mice and was also highly correlated (r = 0.997) with genomic DNA hypomethylation. CAsE cells showed a high cell proliferation rate in a fashion related to the level of arsenic exposure. The expression of c-myc was highly correlated with cellular hyperproliferation (r = 0.961). Consistent with the enhanced proliferation both proliferating cell nuclear antigen and cyclin DI were overexpressed in CAsE cells. In summary, a prominent overexpression of c-myc, a gene frequently activated during hepatocarcinogenesis, is strongly correlated with several events possibly associated with arsenic-induced malignant transformation, including hyperproliferation, DNA hypomethylation and tumor formation upon inoculation into nude mice. These correlations provide convincing evidence c-myc overexpression is mechanistically important in arsenic-induced malignant transformation in this model system. C1 NIEHS, NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Chen, H (reprint author), NIEHS, NCI, Comparat Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 51 TC 84 Z9 89 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2001 VL 175 IS 3 BP 260 EP 268 DI 10.1006/taap.2001.9253 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 479ND UT WOS:000171409700009 PM 11559025 ER PT J AU McKenna, IM Ramakrishna, G Diwan, BA Kang, Y Shiao, YH Wakefield, LM Powell, DA Anderson, LM Jakowlew, SB AF McKenna, IM Ramakrishna, G Diwan, BA Kang, Y Shiao, YH Wakefield, LM Powell, DA Anderson, LM Jakowlew, SB TI Heterozygous inactivation of TGF-beta 1 increases the susceptibility to chemically induced mouse lung tumorigenesis independently of mutational activation of K-ras SO TOXICOLOGY LETTERS LA English DT Article DE transforming growth factor-beta 1; lung tumorigenesis; K-ras mutations ID GROWTH-FACTOR-BETA; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; CANCER CELLS; II RECEPTOR; EPITHELIAL-CELLS; GENE-MUTATIONS; P53 MUTATIONS; TUMOR-CELLS; A/J MICE AB Mice heterozygous for deletion of the transforming growth factor beta1 (TGF-beta1) gene show an enhanced rate of lung tumorigenesis following carcinogen treatment. Since the growth inhibitory activity of TGF-beta1 in epithelial cells is associated with K-ras p21, and K-ras mutations commonly occur in chemically-induced mouse lung tumors, we postulated that tumors in heterozygous TGF-beta1 mice might be more likely to have K-ras mutations compared with tumors in wildtype TGF-beta1 mice. Urethane-induced lung tumors in AJBL6 TGF-beta1 + / - and + / + mice were examined for K-ras mutations by polymerase chain reaction/single strand conformation polymorphism analysis and sequencing. Mutation frequencies were similar in both genotypes: 12/18 + / - tumors (67%) and 10/16 + / + tumors (62%). Mutations occurred in 80% + / - and 75% + / + carcinomas, but in only 50% of the adenomas of both TGF-P I genotypes. Codon 61 A --> G transition mutations were predominant, occurring in 61% + / - and 44% + / + tumors. Three + / - (17%) and three + / + (19%) tumors showed codon 12 mutations, mostly G -->A transitions. Two + tumors had both codon 61 and codon 12 mutations. Interestingly, carcinomas with mutations in codon 61 were larger than those with codon 12 changes. It appears that the mechanism of enhanced susceptibility of TGF-beta1 + / - mice to urethane-induced lung carcinogenesis does not involve selective development of tumors with K-ras mutations. Published by Elsevier Science Ireland Ltd. C1 US EPA, Off Pollut Prevent & Tox Subst, Washington, DC 20460 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Med Branch, Dept Cell & Canc Biol, NCI, Rockville, MD 20850 USA. NCI, Comp & Stat Serv, Data Management Serv, Frederick, MD 21702 USA. RP McKenna, IM (reprint author), NCI, Div Canc Biol, Lab Cell Regulat & Carcinogenesis, 6130 Execut Blvd,EPN 5000, Bethesda, MD 20892 USA. NR 45 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 15 PY 2001 VL 123 IS 2-3 BP 151 EP 158 DI 10.1016/S0378-4274(01)00393-9 PG 8 WC Toxicology SC Toxicology GA 493NU UT WOS:000172230200006 PM 11641043 ER PT J AU Barro, M Mandiola, P Chen, DY Patton, JT Spencer, E AF Barro, M Mandiola, P Chen, DY Patton, JT Spencer, E TI Identification of sequences in rotavirus mRNAs important for minus strand synthesis using antisense oligonucleotides SO VIROLOGY LA English DT Article ID 3'-TERMINAL CONSENSUS SEQUENCE; CELL-FREE SYSTEM; MESSENGER-RNA; GUANYLYLTRANSFERASE ACTIVITY; OPEN CORES; REPLICATION; POLYMERASE; PARTICLES; PROTEIN; GENOME AB The core of the rotavirion consists of three proteins, including the viral RNA polymerase, and 11 segments of double-stranded (ds)RNA. The RNA polymerase of disrupted (open) cores Is able to catalyze the synthesis of dsRNA from exogenous viral mRNAs in vitro. In this study, we have identified sequences in exogenous viral mRNAs important for RNA replication using antisense oligonucleotides. The results showed that oligonucleotides complementary to the highly conserved 3'-terminal sequence of rotavirus mRNAs prevented all but basal levels of dsRNA synthesis. Notably, we observed that the addition of oligonucleotides which were complementary to nonconserved sequences present either at the 5'- or 3'-end of a viral mRNA effectively inhibited its replication without interfering with the replication of other viral mRNAs present in the same replication assay. Thus, the nonconserved sequences in rotavirus mRNAs contain gene-specific information that promotes RNA replication. The fact that antisense oligonucleotides Inhibited dsRNA synthesis indicates that the strandedness (single- versus double-stranded) and secondary structure of the viral mRNA template are factors that affect the efficiency of minus strand synthesis. (C) 2001 Academic Press. C1 Univ Santiago Chile, Dept Ciencias Biol, Virol Lab, Santiago, Chile. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Spencer, E (reprint author), Univ Santiago Chile, Dept Ciencias Biol, Virol Lab, Casilla 40 Correo 33, Santiago, Chile. RI Patton, John/P-1390-2014 NR 31 TC 12 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2001 VL 288 IS 1 BP 71 EP 80 DI 10.1006/viro.2001.1054 PG 10 WC Virology SC Virology GA 472YC UT WOS:000171011700008 PM 11543659 ER PT J AU Sodhi, A Montaner, S Miyazaki, H Gutkind, JS AF Sodhi, A Montaner, S Miyazaki, H Gutkind, JS TI MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1 alpha in rasV12 upregulation of VEGF SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE hypoxia inducible factor-1; vascular endothelial growth factor; ras; MAPK; Akt kinase; neovascularization ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR PROTEIN; FACTOR 1-ALPHA HIF-1-ALPHA; TRANSCRIPTIONAL ACTIVITY; FACTOR EXPRESSION; FACTOR-I; ANGIOGENESIS; INDUCTION; ALPHA; CELLS AB Oncogenic ras upregulates the expression of VEGF through the activation of the transcriptional enhancer hypoxia inducible factor-1 alpha (HIF-1 alpha) by a still poorly understood mechanism. Here, we demonstrate that both the Raf/MEK/MAPK and the PI3 kinase/Akt signaling pathways potently and additively stimulate the expression from a hypoxia response element (HRE) within the 5'flanking region of the VEGF promoter. Interestingly, while MAPK appears to specifically upregulate the transactivation activity of HIF-1 alpha through direct phosphorylation of its regulatory/inhibitory domain, GSK-3, a downstream target of Akt, directly phosphorylates the HIF-1 alpha oxygen-dependent degradation domain. These results suggest a novel mechanism whereby two divergent signaling pathways emerging from Ras may cooperatively but independently regulate the activity of a HIF-1 alpha, thereby promoting the expression of a potent angiogenic mediator. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 29 TC 121 Z9 124 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 14 PY 2001 VL 287 IS 1 BP 292 EP 300 DI 10.1006/bbrc.2001.5532 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 472YM UT WOS:000171012600047 PM 11549290 ER PT J AU Nukaya, M Takahashi, Y Gonzalez, FJ Kamataki, T AF Nukaya, M Takahashi, Y Gonzalez, FJ Kamataki, T TI Aryl hydrocarbon receptor-mediated suppression of expression of the low-molecular-weight prekininogen gene in mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID AH RECEPTOR; MOUSE; KININOGEN; BINDING; INDUCTION; DIOXINS; LIVER AB Differential mRNA display showed that a cDNA band disappeared after treatment of mice with 3-methylcholanthrene (MC). The cDNA encoded low-molecular-weight (LMW) prekininogen, known to be the precursor of a potent vasodilator, bradykinin. MC is generally known to bind to aryl hydrocarbon receptor (AhR) as an initial event to cause effects in vivo. In accordance with the results, Northern blot analysis for LMW prekininogen mRNA using total RNAs from wild-type and AhR-null mice indicated that the suppression of the mRNA expression by MC was seen in wild-type mice but not in AhR-null mice. The expression of LMW prekininogen mRNA was almost completely lost within I h after treatment of mice with MC, while a clear increase of CYP1A2 mRNA, as a positive control, was noted 4 h after the treatment. The plasma concentration of bradykinin released from LMW prekininogen was decreased by MC in wild-type mice, but not in AhR-null mice. Based on these results, we conclude that AhR inhibits bradykinin synthesis in mice via suppression of the expression of LMW prekininogen. Possible mechanism(s) responsible for hypertension caused by treatment of mice with MC is also discussed. (C) 2001 Academic Press. C1 Hokkaido Univ, Grad Sch Pharmaceut Sci, Div Pharmacobiodynam, Lab Drug Metab,Kita Ku, Sapporo, Hokkaido 0600812, Japan. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Kamataki, T (reprint author), Hokkaido Univ, Grad Sch Pharmaceut Sci, Div Pharmacobiodynam, Lab Drug Metab,Kita Ku, N12W6, Sapporo, Hokkaido 0600812, Japan. NR 26 TC 3 Z9 3 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 14 PY 2001 VL 287 IS 1 BP 301 EP 304 DI 10.1006/bbrc.2001.5581 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 472YM UT WOS:000171012600048 PM 11549291 ER PT J AU Reitinger, S Mullegger, J Lepperdinger, G AF Reitinger, S Mullegger, J Lepperdinger, G TI Xenopus kidney hyaluronidase-1 (XKH1), a novel type of membrane-bound hyaluronidase solely degrades hyaluronan at neutral pH SO FEBS LETTERS LA English DT Article DE hyaluronan; hyaluronidase; PH-20; kidney ID EXPRESSION; PURIFICATION; PROTEIN; PATTERN; LAEVIS; VENOM; BEE AB In search for Xenopus laevis hyaluronidase genes, a cDNA encoding a putative PH-20-like enzyme was isolated. In the adult frog, this mRNA was only found to be expressed in the kidney and therefore named XKH1. When expressed by means of cRNA injection into frog oocytes, XKH1 solely exhibited at physiologic ionic strength hyaluronidase activity at neutral pH and in weakly acidic solutions. The enzyme was inactive below pH 5.4. In addition to hyaluronic acid hydrolysis, chondroitin sulfate also was degraded at low yield as assessed by fluorophore-assisted carbohydrate electrophoresis analysis of the degradation products. The enzyme is sorted to the outer surface of the cell membrane of XKH1 expressing oocytes. From there, it could not be removed by phospholipase C nor was secreted hyaluronidase activity detectable. We conclude that XKH1 represents a membrane-bound hyaluronan-degrading enzyme exclusively expressed in cells of the adult frog kidney where it either may be involved in the reorganization of the extracellular architecture or in supporting physiological demands for proper renal functions. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Austrian Acad Sci, Inst Mol Biol, A-5020 Salzburg, Austria. RP Lepperdinger, G (reprint author), NICHHD, NIH, LMG, SVD, Bethesda, MD 20892 USA. NR 16 TC 7 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 14 PY 2001 VL 505 IS 2 BP 213 EP 216 DI 10.1016/S0014-5793(01)02813-7 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 474UT UT WOS:000171125800003 PM 11566178 ER PT J AU Nakamura, K Bindokas, VP Kowlessur, D Elas, M Milstein, S Marks, JD Halpern, HJ Kang, UJ AF Nakamura, K Bindokas, VP Kowlessur, D Elas, M Milstein, S Marks, JD Halpern, HJ Kang, UJ TI Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; GTP-CYCLOHYDROLASE-I; LEWY-BODY-DISEASE; GLUTATHIONE DEPLETION; PREFERENTIAL RESISTANCE; MITOCHONDRIAL-FUNCTION; TYROSINE-HYDROXYLASE; PARKINSONS-DISEASE; HYDROGEN-PEROXIDE; ENDOTHELIAL-CELLS AB Increased oxidative stresses are implicated in the pathogenesis of Parkinson's disease, and dopaminergic neurons may be intrinsically susceptible to oxidative damage. However, the selective presence of tetrahydrobiopterin (BH4) makes dopaminergic neurons more resistant to oxidative stress caused by glutathione depletion. To further investigate the mechanisms of BH4 protection, we examined the effects of BH4 on superoxide levels in individual living mesencephalic neurons. Dopaminergic neurons have intrinsically lower levels of superoxide than nondopaminergic neurons. In addition, inhibiting BH4 synthesis increased superoxide in dopaminergic neurons, while BH4 supplementation decreased superoxide in nondopaminergic cells. BH4 is also a cofactor in catecholamine and NO production. In order to exclude the possibility that the antioxidant effects of BH4 are mediated by dopamine and NO, we used fibroblasts in which neither catecholamine nor NO production occurs. In fibroblasts, BH4 decreased baseline reactive oxygen species, and attenuated reactive oxygen species increase by rotenone and antimycin A. Physiologic concentrations of BH4 directly scavenged superoxide generated by potassium superoxide in vitro. We hypothesize that BH4 protects dopaminergic neurons from ordinary oxidative stresses generated by dopamine and its metabolites and that environmental insults or genetic defects may disrupt this intrinsic capacity of dopaminergic neurons and contribute to their degeneration in Parkinson's disease. C1 Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. Univ Chicago, Comm Neurobiol, Chicago, IL 60637 USA. Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA. Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. Univ Chicago, Dept Pediat, Ctr EPR Imaging In Vivo Physiol, Chicago, IL 60637 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Kang, UJ (reprint author), Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. RI Elas, Martyna/E-3584-2017 OI Elas, Martyna/0000-0001-6296-2844 FU NIMH NIH HHS [MH11986]; NINDS NIH HHS [R01 NS038547, R01 NS038547-02, R01 NS038547-03, R01 NS038547-04, R01 NS038547-05, R01 NS038547-05S1] NR 55 TC 69 Z9 71 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 34402 EP 34407 DI 10.1074/jbc.M103766200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600008 PM 11447224 ER PT J AU Hsi, LC Wilson, L Nixon, J Eling, TE AF Hsi, LC Wilson, L Nixon, J Eling, TE TI 15-Lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor gamma via the MAPK signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KINASE-MEDIATED PHOSPHORYLATION; HUMAN COLORECTAL-CANCER; HUMAN BREAST-CANCER; PPAR-GAMMA; PROTEIN-KINASE; IN-VITRO; MAMMALIAN LIPOXYGENASES; PROSTATE ADENOCARCINOMA; OXIDIZED LDL; COLON-CANCER AB Human colon tumors have elevated levels of 15-lipoxygenase-1 (15-LO-1), suggesting that 15-LO-1 may play a role in the development of colorectal cancer. Also, 15-LO-1 metabolites can up-regulate epidermal growth factor signaling pathways, which results in an increase in mitogenesis. However, metabolites of 15-LO-1 can serve as ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), and activation of this receptor causes most colon cancer cell lines to undergo a differentiative response and reverse their malignant phenotype. Hence, the role 15-LO-1 plays in colon cancer is not clear. To clarify the role of 15-LO-1 in carcinogenesis, the effect of 15-LO-1 and its metabolites on epidermal growth factor signaling and PPAR gamma was investigated. In HCT-116 cells, exogenously added 15-LO-1 metabolites, 13-(S)-hydroxyoctadecadienoic acid, 13-(S)-hydroxyoctadecadienoic acid, and 13-(S)-hydroperoxyoctadecadienoic acid, up-regulated the MAPK signaling pathway, and an increase in PPAR gamma phosphorylation was observed. Furthermore, in stable overexpressing 15-LO-1 HCT-116 cells, which produce endogenous 15-LO-1 metabolites, an up-regulation in mitogen-activated protein kinase and PPAR gamma phosphorylation was observed. Incubation with a MAPK inhibitor ablated MAPK and PPAR gamma phosphorylation. The 15-LO-1 up-regulates MAPK activity and increases PPAR gamma phosphorylation, resulting in a down-regulation of PPAR gamma activity. Thus, 15-LO-1 metabolites may not only serve as ligands for PPAR gamma but can down-regulate PPAR gamma activity via the MAPK signaling pathway. C1 NIEHS, NIH, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, NIH, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, POB 12233, Res Triangle Pk, NC 27709 USA. NR 37 TC 72 Z9 75 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 34545 EP 34552 DI 10.1074/jbc.M100280200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600028 PM 11447213 ER PT J AU Garcia-Diaz, M Bebenek, K Kunkel, TA Blanco, L AF Garcia-Diaz, M Bebenek, K Kunkel, TA Blanco, L TI Identification of an intrinsic 5 '-deoxyribose-5-phosphate lyase activity in human DNA polymerase lambda - A possible role in base excision repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APURINIC-APYRIMIDINIC ENDONUCLEASE; MAMMALIAN-CELLS; PHOSPHATE LYASE; ESCHERICHIA-COLI; BETA; MECHANISM; BINDING; FAMILY; DOMAIN; SITE AB Base excision repair (BER) is a major repair pathway in eukaryotic cells responsible for repair of lesions that give rise to abasic (AP) sites in DNA. Pivotal to this process is the 5'-deoxyribose-5-phosphate lyase (dRP Iyase) activity of DNA polymerase beta (Pol beta). DNA polymerase lambda (Pol lambda) is a recently identified eukaryotic DNA polymerase that is homologous to Pol beta. We show here that human Pol lambda exhibits dRP, lyase, but not AP lyase, activity in vitro and that this activity is consistent with a beta -elimination mechanism. Accordingly, a single amino acid substitution (K310A) eliminated more than 90% of the wild-type dRP lyase activity, thus suggesting that LyS(310) of Pol lambda is the main nucleophile involved in the reaction. The dRP lyase activity of Pol A, in coordination with its polymerization activity, efficiently repaired uracil-containing DNA in an in vitro reconstituted BER reaction. These results suggest that Pol lambda may participate in "single-nucleotide" base excision repair in mammalian cells. C1 Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Blanco, L (reprint author), Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Campus U Autonoma Madrid,Cantoblanco, Madrid 28049, Spain. RI Blanco, Luis/I-1848-2015 NR 47 TC 173 Z9 179 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 34659 EP 34663 DI 10.1074/jbc.M106336200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600043 PM 11457865 ER PT J AU Yeh, GC Daschner, PJ Lopaczynska, J MacDonald, CJ Ciolino, HP AF Yeh, GC Daschner, PJ Lopaczynska, J MacDonald, CJ Ciolino, HP TI Modulation of glucose-6-phosphate dehydrogenase activity and expression is associated with aryl hydrocarbon resistance in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; POSTTRANSCRIPTIONAL MECHANISM; NUTRITIONAL REGULATION; HUMAN-ERYTHROCYTES; OXIDANT STRESS; DNA-ADDUCTS; IN-VITRO; REDUCTASE; DEHYDROEPIANDROSTERONE; CARCINOGENESIS AB The mutagenic effect of environmental carcinogens has been well documented in animal models and in human studies but the mechanisms involved in preventing carcinogen insult have not been fully elucidated. In this study we examined the molecular and biochemical changes associated with carcinogen resistance in a series of aryl hydrocarbon-resistant MCF-7 cell lines developed by exposure to benzo[a]pyrene (BP). The cell lines were designated as AH(R40), AH(R100), and AH(R200) to denote their increasing fold resistance to BP compared with wild type cells. These cell lines were also resistant to another aryl hydrocarbon (AH), dimethylbenz[a]anthracene, but not to pleiotropic drugs (doxorubicin, vinblastine, and taxol). The resistant cell lines showed an increase in the level of the primary intracellular antioxidant, reduced glutathione, corresponding to increasing AH resistance. However, there was no change in glutathione reductase activity. The generation of reduced glutathione requires NADPH, and we therefore examined the activity and expression of the rate-limiting enzyme in NADPH production, glucose-6-phosphate dehydrogenase (G6PD). An increase in G6PD specific activity was associated with increasing aryl hydrocarbon resistance. This was due to an increased expression of G6PD in resistant cells, which was demonstrated by increases in both protein and mRNA levels. However, there was no increase in the transcription rate of G6PD in the resistant cell. lines, indicating that the increase G6PD expression is due to a post-transcriptional modulation, which was confirmed by actinomycin D chase experiments. These results demonstrate that modulation of G6PD expression and activity is an important mechanism in AH resistance. C1 NCI, Frederick Canc Res & Dev Ctr, NIH,Cellular Defense & Carcinogenesis Sect, Basic Res Lab, Frederick, MD 21702 USA. RP Yeh, GC (reprint author), NCI, Frederick Canc Res & Dev Ctr, NIH,Cellular Defense & Carcinogenesis Sect, Basic Res Lab, Bldg 560,Rm 12-05, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 37 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 34708 EP 34713 DI 10.1074/jbc.M105680200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600050 PM 11463792 ER PT J AU Shalev, A Valasek, L Pise-Masison, CA Radonovich, M Phan, L Clayton, J He, H Brady, JN Hinnebusch, AG Asano, K AF Shalev, A Valasek, L Pise-Masison, CA Radonovich, M Phan, L Clayton, J He, H Brady, JN Hinnebusch, AG Asano, K TI Saccharomyces cerevisiae protein Pci8p and human protein eIF3e/Int-6 interact with the eIF3 core complex by binding to cognate eIF3b subunits SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION-FACTOR EIF3; MAMMARY-TUMOR VIRUS; TRANSLATION INITIATION; RNA-BINDING; NUCLEAR-BODIES; YEAST; GENE; INT-6; HOMOLOG; IDENTIFICATION AB Mammalian, plant, and Schizosaccharomyces pombe eukaryotic initiation factor-3 (eIF3) contains a protein homologous to the product of int-6 (eIF3e), a frequent integration site of mouse mammary tumor viruses. By contrast, Saccharomyces cerevisiae does not encode a protein closely related to eIF3e/Int-6. Here, we characterize a novel S. cerevisiae protein (Pci8p, Yi1071cp) that contains a PCI (proteasome-COP9 signalosome-eIF3) domain conserved in eIF3e/Int-6. We show that both Pci8p, and human eIF3e/Int-6 expressed in budding yeast interact with the yeast eIF3 complex in vivo and in vitro by binding to a discrete segment of its eIF3b subunit Prt1p and that human eIF3e/Int-6 interacts with the human eIF3b segment homologous to the Pci8p-binding, site of yeast Prt1p. These results refine our understanding of subunit interactions in the eIF3 complex and suggest structural similarity between human eIF3e/Int-6 and yeast Pci8p. However, deletion of PCI8 had no discernible effect on cell growth or translation initiation as judged by polysome analysis, suggesting that Pci8p is not required for the essential function of eIF3 in translation initiation. Motivated by the involvement of Int-6 in transcriptional control, we investigated the effects of deleting PCI8 on the total mRNA expression profile by oligonucleotide microarray analysis and found reduced mRNA levels for a subset of heat shock proteins in the pci8 Delta mutant. We discuss possible dual functions of Pci8p and Int-6 in transcriptional and translational control. C1 Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Asano, K (reprint author), Kansas State Univ, Div Biol, 109 Ackert Hall, Manhattan, KS 66506 USA. RI Valasek, Leos/I-5743-2014 NR 47 TC 28 Z9 34 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 34948 EP 34957 DI 10.1074/jbc.M102161200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600081 PM 11457827 ER PT J AU Brosh, RM Harmakar, P Sommers, JA Yang, Q Wang, XW Spillare, EA Harris, CC Bohr, VA AF Brosh, RM Harmakar, P Sommers, JA Yang, Q Wang, XW Spillare, EA Harris, CC Bohr, VA TI p53 modulates the exonuclease activity of Werner syndrome protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LYMPHOBLASTOID CELL-LINES; SINGLE-STRANDED-DNA; WILD-TYPE; P53-MEDIATED APOPTOSIS; HELICASE ACTIVITY; BINDING DOMAIN; GROWTH-CONTROL; SYNDROME GENE; WRN PROTEIN; MUTANT P53 AB Werner syndrome (WS) is characterized by the early onset of symptoms of premature aging, cancer, and genomic instability. The molecular basis of the defects is not understood but presumably relates to the DNA helicase and exonuclease activities of the protein encoded by the WRN gene that is mutated in the disease. The attenuation of p53-mediated apoptosis in WS cells and reported physical interaction between WRN and the tumor suppressor p53 suggest that p53 and WRN functionally interact in a pathway necessary for the normal cellular response. In this study, we have demonstrated that p53 inhibits the exonuclease activity of the purified full-length recombinant WRN protein. p53 did not have an effect on a truncated amino-terminal WRN fragment that retains exonuclease activity but lacks the physical interaction domain for p53 located in the carboxyl terminus. Two naturally occurring p53 mutants found in human cancer displayed a reduced ability to inhibit WRN exonuclease activity. In cells arrested in S phase with hydroxyurea, WRN exits the nucleolus and colocalizes with p53 in the nucleoplasm. The regulation of WRN function by p53 is likely to play an important role in the maintenance of genomic integrity and prevention of cancer and other clinical symptoms associated with WS. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 21892 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Wang, Xin/B-6162-2009 NR 50 TC 77 Z9 81 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 35093 EP 35102 DI 10.1074/jbc.M103332200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600099 PM 11427532 ER PT J AU Song, MS Pham, PT Olson, M Carter, JR Franden, MA Schaaper, RM McHenry, CS AF Song, MS Pham, PT Olson, M Carter, JR Franden, MA Schaaper, RM McHenry, CS TI The delta and delta ' subunits of the DNA polymerase III holoenzyme are essential for initiation complex formation and processive elongation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMOSOMAL REPLICATION MACHINE; ESCHERICHIA-COLI; SLIDING CLAMPS; GAMMA-SUBUNIT; ACCESSORY PROTEINS; LAGGING-STRAND; READING FRAME; BETA-SUBUNIT; PRIMED DNA; TAU AB delta and delta' are required for assembly of the processivity factor beta (2) onto primed DNA in the DNA polymerase III holoenzyme-catalyzed reaction. We developed protocols for generating highly purified preparations of delta and delta'. In holoenzyme reconstitution assays, delta' could not be replaced by delta, tau, or gamma, even when either of the latter were present at a 10,000-fold molar excess. Likewise, delta could not be replaced by delta', tau, or gamma. Bacterial strains bearing chromosomal knockouts of either the holA(delta) or holB(delta') genes were not viable, demonstrating that both delta and delta' are essential. Western blots of isolated initiation complexes demonstrated the presence of both delta and delta'. However, in the absence of chi psi and single-stranded DNA-binding protein, a stable initiation complex lacking delta delta' was isolated by gel filtration. Lack of delta-delta' decreased the rate of elongation about 3-fold, and the extent of processive replication was significantly decreased. Adding back delta-delta' but not chi psi, delta, or delta' alone restored the diminished activity, indicating that in addition to being key components required for the beta loading activity of the DnaX complex, delta delta' is present in initiation complex and is required for processive elongation. C1 Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80262 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP McHenry, CS (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, 4200 E 9th Ave, Denver, CO 80262 USA. FU NIGMS NIH HHS [GM35695] NR 50 TC 18 Z9 18 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 35165 EP 35175 DI 10.1074/jbc.M100389200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600107 PM 11432857 ER PT J AU Maeda, K Yoshimura, K Shibayama, S Habashita, H Tada, H Sagawa, K Miyakawa, T Aoki, M Fukushima, D Mitsuya, H AF Maeda, K Yoshimura, K Shibayama, S Habashita, H Tada, H Sagawa, K Miyakawa, T Aoki, M Fukushima, D Mitsuya, H TI Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; HIGHLY POTENT; CHEMOKINE RECEPTOR; TYPE-1 INFECTION; IN-VITRO; REPLICATION; VARIANTS; THERAPY; CORECEPTOR AB Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (M-r 484) specifically blocked the binding of macrophage inflammatory protein-1 alpha (MIP-1 alpha) to CCR5 (IC50 0.002 muM) and MIP-1 alpha -elicited cellular Ca2+ mobilization (IC50 similar to 0.02 muM). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/ macrophage tropic (R5) HIV-1 at IC50 values of 0.03 to 0.06 muM. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection. C1 Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan. Ono Pharmaceut Co Ltd, Minase Res Inst, Dept Med Chem, Osaka 6188585, Japan. Ono Pharmaceut Co Ltd, Minase Res Inst, Exploratory Res Labs, Osaka 6188585, Japan. NCI, Expt Retrovirol Sect, Med Branch, NIH, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Internal Med 2, 1-1-1 Honjo, Kumamoto 8600811, Japan. NR 44 TC 114 Z9 118 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 35194 EP 35200 DI 10.1074/jbc.M105670200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600110 PM 11454872 ER PT J AU Shen, CH Clark, DJ AF Shen, CH Clark, DJ TI DNA sequence plays a major role in determining nucleosome positions in yeast CUP1 chromatin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METALLOTHIONEIN GENE-TRANSCRIPTION; MOUSE SATELLITE DNA; BETA-GLOBIN GENE; HISTONE OCTAMER; IN-VITRO; BINDING PROTEIN; TRANSCRIBING POLYMERASE; REMODELING COMPLEX; SWI/SNF COMPLEX; CORE PARTICLE AB The role of DNA sequence in determining nucleosome positions in vivo was investigated by comparing the positions adopted by nucleosomes reconstituted on a yeast plasmid in vitro using purified core histones with those in native chromatin containing the same DNA, described previously. Nucleosomes were reconstituted on a 2.5 kilobase pair DNA sequence containing the yeast TRP1ARS1 plasmid with CUP1 as an insert (TAC-DNA). Multiple, alternative, overlapping nucleosome positions were mapped on TAC-DNA. For the 58 positioned nucleosomes identified, the relative positioning strengths and the stabilities to salt and temperature were determined. These positions were, with a few exceptions, identical to those observed in native, remodeled TAC chromatin containing an activated CUP1 gene. Only some of these positions are utilized in native, unremodeled chromatin. These observations suggest that DNA sequence is likely to play a very important role in positioning nucleosomes in vivo. We suggest that events occurring in yeast CUP1 chromatin determine which positions are occupied in vivo and when they are occupied. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 50,Rm 3148, Bethesda, MD 20892 USA. NR 56 TC 30 Z9 30 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2001 VL 276 IS 37 BP 35209 EP 35216 DI 10.1074/jbc.M104733200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473DK UT WOS:000171024600112 PM 11461917 ER PT J AU Yang, FQ Ma, Y Ito, Y AF Yang, FQ Ma, Y Ito, Y TI Separation and purification of isoflavones from a crude soybean extract by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE soybean; counter-current chromatography; isoflavones; daidzin; glycitin; genistin; acetyldaidzin; glycitein; acetylgenistin; daidzein ID PHYTOESTROGENS; CANCER; DIET; RISK; APPARATUS; BONE; MEN AB A set of isoflavones with a broad range of polarity including daidzin, glycitin, genistin, acetyldaidzin, glycitein, acetylgenistin and daidzein was separated from a crude soybean extract by high-speed counter-current chromatography using a two-step operation. Three solvent systems were used: chloroform-methanol-water (4:3:2, v/v); chloroform-methanol-n-butanol-water (4:3:0.5:2, v/v); and methyl tert.-butyl ether-tetrahydrofuran-0.5% aqueous trifluoroacetic acid (2:2:0.15:4, v/v). The first solvent system was used for separating less polar isoflavones and the second for more polar isoflavones by eluting the lower organic phase. Genistin and glycitin, which were only partially resolved in the chloroform system, were separated by the third solvent system. Each isolated component showed 98-99% purity as determined by high-performance liquid chromatography analysis. Their structures were identified by LC-MS. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 23 TC 29 Z9 40 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 14 PY 2001 VL 928 IS 2 BP 163 EP 170 DI 10.1016/S0021-9673(01)01144-X PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 474GN UT WOS:000171098100005 PM 11587334 ER PT J AU Matsuda, T Bebenek, K Masutani, C Rogozin, IB Hanaoka, F Kunkel, TA AF Matsuda, T Bebenek, K Masutani, C Rogozin, IB Hanaoka, F Kunkel, TA TI Error rate and specificity of human and murine DNA polymerase eta SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA polymerase eta; replication fidelity; frameshifts; tandem mutations; mismatch extension ID REVERSE-TRANSCRIPTASE; XERODERMA-PIGMENTOSUM; TRANSLESION SYNTHESIS; REPLICATION FIDELITY; MUTATIONAL SPECTRA; ESCHERICHIA-COLI; THYMINE DIMER; BYPASS; BETA; IOTA AB We describe here the error specificity of mammalian DNA polymerase eta (pol eta), an enzyme that performs translesion DNA synthesis and may participate in somatic hypermutation of immunoglobulin genes. Both mouse and human pol eta lack intrinsic proofreading exonuclease activity and both copy undamaged DNA inaccurately. Analysis of more than 1500 single-base substitutions by human pol eta indicates that error rates for all 12 mismatches are high and variable depending on the composition and symmetry of the mismatch and its location. pol eta also generates tandem base substitutions at an unprecedented rate, and kinetic analysis indicates that it extends a tandem double mismatch about as efficiently as other replicative enzymes extend single-base mismatches. This ability to use an aberrant primer terminus and the high rate of single and double-base substitutions support the idea that pol eta may forego strict shape complementarity in order to facilitate highly efficient lesion bypass. Relaxed discrimination is further indicated by pol eta infidelity for a wide variety of nucleotide deletion and addition errors. The nature and location of these errors suggest that some may be initiated by strand slippage, while others result from additional mechanisms. C1 NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 5650871, Japan. Japan Sci & Technol Corp, CREST, Suita, Osaka 5650871, Japan. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. Russian Acad Sci, Inst Cytol & Genet, Siberian Branch, Novosibirsk 630090, Russia. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Kunkel, TA (reprint author), NIEHS, Genet Mol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RI Masutani, Chikahide/I-6160-2014 NR 43 TC 126 Z9 127 U1 2 U2 10 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 14 PY 2001 VL 312 IS 2 BP 335 EP 346 DI 10.1006/jmbi.2001.4937 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 474FK UT WOS:000171095500003 PM 11554790 ER PT J AU Duelli, R Maurer, MH Staudt, R Sokoloff, L Kuschinsky, W AF Duelli, R Maurer, MH Staudt, R Sokoloff, L Kuschinsky, W TI Correlation between local glucose transporter densities and local 3-O-methylglucose transport in rat brain SO NEUROSCIENCE LETTERS LA English DT Article DE glucose transporter; Glut1; Glut3; local cerebral transport rates; autoradiography; 3-O-methylglucose ID GLUT3; NEURONS; PROTEINS; BARRIER AB The present study addresses the question whether local glucose transport kinetics are correlated with local glucose transporter densities in the brain. In 47 brain structures the local rate constants for 3- O-[C-14] methylglucose (3-O-MG) transport, K-1 and k(2), were quantified, and local glucose Glut1 and Glut3 transporter densities were determined by immuno-autoradiographic methods. Statistically significant correlations were found between the rate constants for glucose transport and the transporter densities. The correlations were tighter for Glut1 than for Glut3. Inasmuch as 3-O-MG is transported by the same transporter as glucose, these results indicate that the local densities of glucose transporters determine local glucose transport rates in the brain. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Heidelberg, Dept Physiol & Pathophysiol, D-69120 Heidelberg, Germany. NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. RP Duelli, R (reprint author), Univ Heidelberg, Dept Physiol & Pathophysiol, Neuenheimer Feld 326, D-69120 Heidelberg, Germany. NR 19 TC 14 Z9 15 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 SEP 14 PY 2001 VL 310 IS 2-3 BP 101 EP 104 DI 10.1016/S0304-3940(01)02060-2 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 473XB UT WOS:000171073300008 PM 11585577 ER PT J AU Wu, WC Wang, Y Su, CK Chai, CY AF Wu, WC Wang, Y Su, CK Chai, CY TI The nNOS/cGMP signal transducing system is involved in the cardiovascular responses induced by activation of NMDA receptors in the rostral ventrolateral medulla of cats SO NEUROSCIENCE LETTERS LA English DT Article DE nitric oxide; rostral ventrolateral medulla; 7-nitroindazole; ODQ; N-methyl-D-aspartate ID SOLUBLE GUANYLATE-CYCLASE; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE; CEREBRAL-CORTEX; ELECTRODES; GLUTAMATE; RELEASE; RATS AB Nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS). NO stimulates the soluble form of guanylyl cyclase (sGC) and induces accumulation of cyclic guanosine monophosphate (cGMP). The purpose of this study was to examine whether the cardiovascular responses induced by N-methyl-D-aspartate (NMDA) in the rostral ventrolateral medulla (RVLM) depend on the actions of NOS and sGC. In anesthetized cats,the extracellular NO level was measured by in vivo voltammetry using a nafion/porphyrine/o-phenylenediamine-coated carbon-fiber electrode. Microinjection of NMDA into the RVLM produced hypertension and bradycardia associated with NO formation. These NMDA-induced responses were attenuated by prior injections of 7-nitroindazole, a neuronal NO synthase (nNOS) inhibitor, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a sGC inhibitor. These findings suggest that NO is involved in the NMDA-induced cardiovascular responses in the RVLM. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan. NIDA, Baltimore, MD USA. RP Chai, CY (reprint author), Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan. OI Su, Chun-Kuei/0000-0002-5211-3520 NR 20 TC 25 Z9 25 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 SEP 14 PY 2001 VL 310 IS 2-3 BP 121 EP 124 DI 10.1016/S0304-3940(01)02100-0 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 473XB UT WOS:000171073300013 PM 11585582 ER PT J AU Chu, DQ Legon, S Smith, DM Costa, SKP Cuttitta, F Brain, SD AF Chu, DQ Legon, S Smith, DM Costa, SKP Cuttitta, F Brain, SD TI The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) blocks vasodilatation in inflamed rat skin: involvement of adrenomedullin in addition to CGRP SO NEUROSCIENCE LETTERS LA English DT Article DE adrenomedullin; calcitonin gene-related peptide; interleukin-1 beta; skin; microvasculature; vasodilator ID NECROSIS-FACTOR-ALPHA; CELLS; EXPRESSION; RECEPTORS; SECRETION; ACID AB The neuropeptide calcitonin gene-related peptide (CGRP) is a potent microvascular vasodilator in rat skin and effects are antagonised by CGRP(8-37), In this study, CGRP(8-37) significantly (P < 0.05) inhibited the time-dependent (3-5 h) increase in skin blood flow measured in the anaesthetised rat, after intradermal administration of the inflammatory cytokine interleukin-1 beta (3 pmol/site), indicating the involvement of CGRP1 receptors. The CGRP-related peptide adrenomedullin (ADM) is also a potent vasodilator in rat skin,with effects antagonised by CGRP(8-37) We show that ADM mRNA expression is increased in rat skin after treatment with IL-1 beta and that the IL-1p-induced blood flow is blocked by a selective ADM antibody (P < 0.05). Thus ADM is expressed locally in the inflamed cutaneous microvasculature where it can, in addition to, or as an alternative to CGRP, contribute to IL-1 beta -induced vasoactive effects. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Kings Coll London, Ctr Cardiovasc Biol & Med, London SE1 1UL, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Metab Med, London W12 0NN, England. NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Brain, SD (reprint author), Kings Coll London, Ctr Cardiovasc Biol & Med, New Hunts House,Guys Campus, London SE1 1UL, England. EM sue.brain@kcl.ac.uk RI Costa, Soraia/K-7227-2012; Brain, Susan/L-3681-2013 NR 18 TC 15 Z9 17 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 SEP 14 PY 2001 VL 310 IS 2-3 BP 169 EP 172 DI 10.1016/S0304-3940(01)02132-2 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 473XB UT WOS:000171073300025 PM 11585594 ER PT J AU Greenwald, P AF Greenwald, P TI From carcinogenesis to clinical interventions for cancer prevention SO TOXICOLOGY LA English DT Article DE scientific community; carcinogenesis; chemopreventive; cancer ID S-TRANSFERASE ACTIVITY; COOKED FOODS; DIETARY FACTORS; BENZYL ISOTHIOCYANATE; HYDROXYLASE-ACTIVITY; INDUCED NEOPLASIA; TEA EXTRACTS; INHIBITION; MUTAGENS; BEEF AB During the last three decades, the scientific community has made immense progress in acquiring the knowledge needed to prevent cancer. Pioneering research helped to identify potential causes of cancer, particularly environmental factors such as diet, and provided insight regarding their mechanisms-of-action. Concurrently, promising inhibitors of cancer that appeared able to either arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified and systematically evaluated for their potential as chemopreventive agents. Numerous agents determined to be safe and effective in preclinical trials have been and continue to be tested in Phase I, II, and III clinical interventions for cancers at various sites, including breast, colon, prostate, esophagus, mouth, lung, cervix, endometrium, ovary, liver, bladder, and skin. The development of valid intermediate biomarkers that can serve as surrogate endpoints For clinical disease is urgently needed to accelerate advances in clinical trials for cancer prevention. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Greenwald, P (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,Suite 2040, Bethesda, MD 20892 USA. NR 46 TC 20 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 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 14 PY 2001 VL 166 IS 1-2 BP 37 EP 45 DI 10.1016/S0300-483X(01)00443-7 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 470VA UT WOS:000170890800006 PM 11518609 ER PT J AU Kedzierski, L Black, CG Stowers, AW Goschnick, MW Kaslow, DC Coppel, RL AF Kedzierski, L Black, CG Stowers, AW Goschnick, MW Kaslow, DC Coppel, RL TI Comparison of the protective efficacy of yeast-derived and Escherichia coli-derived recombinant merozoite surface protein 4/5 against lethal challenge by Plasmodium yoelii SO VACCINE LA English DT Article DE Plasmodium yoelii; immunisation; antibodies; merozoite surface protein 4/5 ID SACCHAROMYCES-CEREVISIAE; MALARIA PARASITE; FALCIPARUM; MICE; IMMUNIZATION; EXPRESSION; INFECTION; BERGHEI; MEROZOITE-SURFACE-PROTEIN-4; IDENTIFICATION AB The gene encoding the Plasmodium yoelii homologue of P. falciparum merozoite surface proteins 4 (MSP4) and 5 (MSP5) has been expressed in Escherichia coli and Saccharomyces cerevisiae. The protein contains a single epidermal growth factor (EGF)-like domain and is expressed in a form lacking the predicted N-terminal signal and glycosyl phosphatidylinositol (GPI) attachment sequences. The recombinant protein derived from E. coli (EcMSP4/5) was highly effective at protecting mice against lethal challenge with 10(5) parasites of the P. yoelii YM strain. In contrast, the protective efficacy of yeast-derived MSP4/5 (yMSP4/5) was considerably less. The antibody titres in both groups were significantly different with mice immunised with yeast-derived protein showing significantly lower pre-challenge antibody responses. There was a significant inverse correlation between antibody levels as measured by ELISA and peak parasitaemia. Mice immunised with EcMSP4/5 produced anti-PyMSP4/5 antibodies predominantly of the IgG2a and IgG2b isotypes, whereas, mice immunised with yMSP4/5 mainly produced antibodies of the IgG1 isotype. The differences in antibody titres and subtype distribution may account for the observed differences in protective efficacy of these protein preparations. Levels of protective efficacy of MSP4/5 were compared with that obtained using P. yoelii MSPI produced in S. cerevisiae. Levels of protection induced by E. coh derived MSP4/5 were superior to those induced by MSPI which in turn were better than those induced by yeast-derived MSP4/5. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, Rockville, MD 20852 USA. RP Coppel, RL (reprint author), Monash Univ, Dept Microbiol, POB 53, Clayton, Vic 3800, Australia. RI Coppel, Ross/A-6626-2008; Black, Casilda/B-1519-2008 OI Coppel, Ross/0000-0002-4476-9124; Black, Casilda/0000-0002-0424-4593 NR 28 TC 19 Z9 19 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 14 PY 2001 VL 19 IS 32 BP 4661 EP 4668 DI 10.1016/S0264-410X(01)00244-4 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 473HR UT WOS:000171035500011 PM 11535314 ER PT J AU Clements-Mann, ML Dudas, R Hoshino, Y Nehring, P Sperber, E Wagner, M Stephens, I Karron, R Deforest, A Kapikian, AZ AF Clements-Mann, ML Dudas, R Hoshino, Y Nehring, P Sperber, E Wagner, M Stephens, I Karron, R Deforest, A Kapikian, AZ TI Safety and immunogenicity of live attenuated quadrivalent human-bovine (UK) reassortant rotavirus vaccine administered with childhood vaccines to infants SO VACCINE LA English DT Article DE rotavirus vaccine; human-bovine reassortant rotavirus vaccine; pediatric vaccine; live attenuated virus vaccine; diarrheal vaccine; rotavirus antibody; rotavirus immune responses; rotavirus vaccine immunity ID INFLUENZAE TYPE-B; ACELLULAR PERTUSSIS VACCINES; VENEZUELAN INFANTS; MULTICENTER TRIAL; YOUNG-CHILDREN; UNITED-STATES; EFFICACY; SEROTYPE-1; CANDIDATES; DIARRHEA AB The safety and immunogenicity of an orally administered, live rotavirus vaccine comprised of four strains, each with a titer of 10(5.3) or 10(5.8) pfu, and each having 10 genes from the UK bovine strain and the VP7 gene from human rotavirus serotype 1, 2, 3, or 4, were evaluated in adults, young children and infants in randomized, double-blind phase 1 trials. Three doses of rotavirus vaccine or placebo given with childhood immunizations to infants at 2, 4, and 6 months of age were well tolerated and did not inhibit antibody responses to childhood vaccines which included DTP, Hib, hepatitis B and OPV. Serum rotavirus antibody responses were detected in 12 of 20 infants after 1 dose, and in 19/19 of the vaccinees after three doses. Neutralizing antibody responses were detected more often against the bovine rotavirus UK strain (95%) than to human rotavirus VP7 serotypes 1 (37%), 2 (32%), 3 (32%) or 4 (32%). The efficacy of this quadrivalent rotavirus vaccine needs to be evaluated further. (C) 2001 Published by Elsevier Science Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. St Christophers Hosp Children, Philadelphia, PA 19134 USA. Johns Hopkins Univ, Sch Med, Sch Publ Hlth, Dept Int Hlth,Ctr Immunizat Res, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Kapikian, AZ (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM akapikian@nih.niaid.gov FU NIAID NIH HHS [N01-AI-15095] NR 44 TC 38 Z9 45 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 14 PY 2001 VL 19 IS 32 BP 4676 EP 4684 DI 10.1016/S0264-410X(01)00242-0 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 473HR UT WOS:000171035500013 PM 11535316 ER PT J AU Kim, HS Barak, D Harden, TK Boyer, JL Jacobson, KA AF Kim, HS Barak, D Harden, TK Boyer, JL Jacobson, KA TI Acyclic and cyclopropyl analogues of adenosine bisphosphate antagonists of the P2Y(1) receptor: Structure-activity relationships and receptor docking SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE-C; NUCLEOTIDE DERIVATIVES; PLATELET-AGGREGATION; PURINERGIC RECEPTOR; POTENT; AGONISTS; RECOGNITION; ACTIVATION; EXPRESSION; ADP AB The activation of P2Y(1) receptors in platelets contributes to platelet aggregation, and selective antagonists are sought as potential antithrombotic agents. We reported (Kim et al. J. bled. Chem. 2000, 43, 746-755) that acyclic analogues of adenine nucleotides, containing two phosphate groups on a symmetrically branched aliphatic chain, attached at the 9-position of adenine, are moderately potent P2Y(1) receptor antagonists. In this study we have varied the chain structure, to include asymmetric substitution, olefinic, and cyclopropyl groups. These antagonists inhibited the stimulation of phospholipase C in turkey erythrocyte membranes induced by 30 nM 2-MeS-ADP in the micromolar range. In the series of symmetrically branched aliphatic groups substituted with two phosphate groups, the optimal antagonist potency occurred with the 2-methylpropyl group. A 2-chloro-N-6-methyladenine derivative, 2-[2-(2-chloro-6-methylaminopurin-9-yl)methyl]propane-1,3-bisoxy(diammoniumphosphate) (7), was a full antagonist at the P2Y(1) receptor with an IC50 value of 0.48 muM. Esterification of one of the phosphate groups or substitution with O-acetyl greatly reduced the antagonist potency at the P2Y(1) receptor. Removal of a methylene group of 7 or inclusion of an olefinic or cyclopropyl group also reduced potency. A pair of enantiomeric glycerol derivatives demonstrated a 5-fold stereoselectivity for the S-isomer. Stereoisomerically defined analogues of 7 containing a cyclopropyl group in place of the branched carbon were less potent than 7 as antagonists, with IC50 values of 2-3 muM. No agonist activity was observed for these analogues. A new rhodopsin-based molecular model of the P2Y(1) receptor indicated that the optimal docked orientation of the two monophosphate moieties relative to the adenine N-6 (compared to a rigid, bicyclic analogue) was consistent with the dependence of antagonist potency on chain length. The 3 ' -phosphate was predicted to occupy a restricted space, deeper in the binding cleft than the 5 ' -phosphate location. In summary, modification of the flexible spacer chain linking bisphosphate groups to the adenine moiety provided many moderately potent antagonists. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [HL54889]; NIGMS NIH HHS [GM38213] NR 38 TC 65 Z9 67 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 13 PY 2001 VL 44 IS 19 BP 3092 EP 3108 DI 10.1021/jm010082h PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 472RN UT WOS:000170998900008 PM 11543678 ER PT J AU Robarge, MJ Husbands, SM Kieltyka, A Brodbeck, R Thurkauf, A Newman, AH AF Robarge, MJ Husbands, SM Kieltyka, A Brodbeck, R Thurkauf, A Newman, AH TI Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D-3 receptor subtype SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SUBSTITUTED 3-ALPHA-TROPANE ANALOGS; HUMAN COCAINE FATALITIES; WILD-TYPE MICE; COMPETITIVE ANTAGONIST; HIGH-AFFINITY; D3 RECEPTOR; ANTIPSYCHOTIC AGENT; POTENT; AGONISTS; BRAIN AB The dopamine D-3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D-3 agonists and antagonists. In an attempt to design a novel class of D-3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D-3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D-3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D-2, D-3, or D-4 receptor cDNAs. D-3 binding affinities ranged from K-i = 1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D-3/D-2 selectivity of 64 and a D-3/D-4 selectivity of 1300. Structure-activity relationships for this class of ligands at D-3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D-3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine. C1 Neurogen Corp, Branford, CT 06405 USA. NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), Neurogen Corp, Branford, CT 06405 USA. RI Husbands, Stephen/D-5926-2011; OI Husbands, Stephen/0000-0002-9928-6322 NR 46 TC 67 Z9 69 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 13 PY 2001 VL 44 IS 19 BP 3175 EP 3186 DI 10.1021/jm010146o PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 472RN UT WOS:000170998900017 PM 11543687 ER PT J AU Schmitz, D Schuchmann, S Fisahn, A Draguhn, A Buhl, EH Petrasch-Parwez, E Dermietzel, R Heinemann, U Traub, RD AF Schmitz, D Schuchmann, S Fisahn, A Draguhn, A Buhl, EH Petrasch-Parwez, E Dermietzel, R Heinemann, U Traub, RD TI Axo-axonal coupling: A novel mechanism for ultrafast neuronal communication SO NEURON LA English DT Article ID RAT HIPPOCAMPAL SLICES; ACTION-POTENTIAL PROPAGATION; HIGH-FREQUENCY OSCILLATIONS; CA1 PYRAMIDAL NEURONS; FIELD BURST ACTIVITY; GAP-JUNCTIONS; SYNAPTIC-INTERACTIONS; CHEMICAL SYNAPSES; INITIAL SEGMENT; BRAIN NEURONS AB We provide physiological, pharmacological, and structural evidence that axons of hippocampal principal cells are electrically coupled, with prepotentials or spikelets forming the physiological substrate of electrical coupling as observed in cell somata. Antidromic activation of neighboring axons induced somatic spikelet potentials in neurons of CA3, CA1, and dentate gyrus areas of rat hippocampal slices. Somatic invasion by these spikelets was dependent on the activation of fast Na+ channels in the postjunctional neuron. Antidromically elicited spikelets; were suppressed by gap junction blockers and low intracellular pH. Paired axo-somatic and somato-dendritic recordings revealed that the coupling potentials appeared in the axon before invading the soma and the dendrite. Using confocal laser scanning microscopy we found that putative axons of principal cells were dye coupled. Our data thus suggest that hippocampal neurons are coupled by axo-axonal junctions, providing a novel mechanism for very fast electrical communication. C1 Humboldt Univ, Charite, Inst Physiol, D-10117 Berlin, Germany. NICHHD, LCMN, NIH, Bethesda, MD 20892 USA. Univ Leeds, Sch Biomed Sci, Leeds LS2 9NQ, W Yorkshire, England. Ruhr Univ Bochum, Dept Neuroanat, D-4630 Bochum, Germany. Univ Birmingham, Sch Med, Div Neurosci, Birmingham B15 2TT, W Midlands, England. RP Schmitz, D (reprint author), Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, 513 Parnassus Ave, San Francisco, CA 94143 USA. NR 55 TC 274 Z9 280 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 13 PY 2001 VL 31 IS 5 BP 831 EP 840 DI 10.1016/S0896-6273(01)00410-X PG 10 WC Neurosciences SC Neurosciences & Neurology GA 472YV UT WOS:000171013300015 PM 11567620 ER PT J AU Murphy, PM AF Murphy, PM TI Chemokines and the molecular basis of cancer metastasis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article RP Murphy, PM (reprint author), NIH, Bethesda, MD 20892 USA. NR 4 TC 288 Z9 332 U1 0 U2 20 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 13 PY 2001 VL 345 IS 11 BP 833 EP 835 DI 10.1056/NEJM200109133451113 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 471BK UT WOS:000170906800013 PM 11556308 ER PT J AU Jhee, KH Niks, D McPhie, P Dunn, MF Miles, EW AF Jhee, KH Niks, D McPhie, P Dunn, MF Miles, EW TI The reaction of yeast cystathionine beta-synthase is rate-limited by the conversion of aminoacrylate to cystathionine SO BIOCHEMISTRY LA English DT Article ID COLI TRYPTOPHAN SYNTHASE; ULTRAVIOLET VISIBLE SPECTROSCOPY; O-ACETYLSERINE SULFHYDRYLASE; ESCHERICHIA-COLI; CATALYTIC MECHANISM; L-SERINE; ALPHA(2)BETA(2) COMPLEX; HEME PROTEIN; MUTATIONS; DISEASE AB Our studies of the reaction mechanism of cystathionine beta -synthase from Saccharomyces cerevisiae (yeast) are facilitated by the spectroscopic properties of the pyridoxal phosphate coenzyme that forms a series of intermediates in the reaction Of L-serine and L-homocysteine to form L-cystathionine. To characterize these reaction intermediates, we have carried out rapid-scanning stopped-flow and single-wavelength stopped-flow kinetic measurements under pre-steady-state conditions, as well as circular dichroism and fluorescence spectroscopy under steady-state conditions. We find that the gem-diamine and external aldimine of aminoacrylate are the primary intermediates in the forward half-reaction with L-serine and that the external aldimine of aminoacrylate or its complex with L-homocysteine is the primary intermediate in the reverse half-reaction with L-cystathionine. The second forward half-reaction of aminoacrylate with L-homocysteine is rapid. No primary kinetic isotope effect was obtained in the forward half-reaction with L-serine. The results provide evidence (1) that the formation of the external aldimine of L-Serine is faster than the formation of the aminoacrylate intermediate, (2) that aminoacrylate is formed by the concerted removal of the alpha -proton and the hydroxyl group Of L-serine, and (3) that the rate of the overall reaction is rate-limited by the conversion of aminoacrylate to L-cystathionine. We compare our results with cystathionine beta -synthase with those of related investigations of tryptopban synthase and O-acetylserine sulfhydrylase. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. RP Miles, EW (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM55749] NR 37 TC 25 Z9 25 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 11 PY 2001 VL 40 IS 36 BP 10873 EP 10880 DI 10.1021/bi011087j PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 470NC UT WOS:000170877200017 PM 11535064 ER PT J AU Faxon, D Lenfant, C AF Faxon, D Lenfant, C TI Timing is everything - Motivating patients to call 9-1-1 at onset of acute myocardial infarction SO CIRCULATION LA English DT Editorial Material ID REACT TRIAL; DELAY; INTERVENTION C1 Amer Heart Assoc, Dallas, TX 75231 USA. NHLBI, Bethesda, MD 20892 USA. RP Faxon, D (reprint author), Amer Heart Assoc, 7272 Greenville Ave, Dallas, TX 75231 USA. NR 11 TC 54 Z9 55 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 11 PY 2001 VL 104 IS 11 BP 1210 EP 1211 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 472TC UT WOS:000171000200010 PM 11551867 ER PT J AU Ornato, JP Hand, MM AF Ornato, JP Hand, MM TI Warning signs of a heart attack SO CIRCULATION LA English DT Editorial Material C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Emergency Med, Richmond, VA 23298 USA. NHLBI, Natl Heart Attack Alert Program, NIH, Bethesda, MD 20892 USA. RP Ornato, JP (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Emergency Med, Richmond, VA 23298 USA. NR 0 TC 11 Z9 13 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 11 PY 2001 VL 104 IS 11 BP 1212 EP 1213 DI 10.1161/hc2501.093258 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 472TC UT WOS:000171000200011 PM 11551868 ER PT J AU Galperin, MY Nikolskaya, AN Koonin, EV AF Galperin, MY Nikolskaya, AN Koonin, EV TI Novel domains of the prokaryotic two-component signal transduction systems SO FEMS MICROBIOLOGY LETTERS LA English DT Review DE signal transduction; genome sequencing; conserved motif; domain organization; histidine kinase; phosphorylation; phosphodiesterase; cyclic nucleotide ID ESCHERICHIA-COLI; BORDETELLA-PERTUSSIS; NUCLEOTIDE-SEQUENCE; ACETOBACTER-XYLINUM; CELLULOSE SYNTHESIS; RESPONSE REGULATOR; BACILLUS-SUBTILIS; PROTEIN FAMILIES; COG DATABASE; GAF DOMAIN AB The archetypal two-component signal transduction systems include a sensor histidine kinase and a response regulator, which consists of a receiver CheY-like domain and a DNA-binding domain. Sequence analysis of the sensor kinases and response regulators encoded in complete bacterial and archaeal genomes revealed complex domain architectures for many of them and allowed the identification of several novel conserved domains, such as PAS, GAF, HAMP, GGDEF, EAL, and HD-GYP. All of these domains are widely represented in bacteria, including 19 copies of the GGDEF domain and 17 copies of the EAL domain encoded in the Escherichia coli genome. In contrast, these novel signaling domains are much less abundant in bacterial parasites and in archaea, with none at all found in some archaeal species. This skewed phyletic distribution suggests that the newly discovered complexity of signal transduction systems emerged early in the evolution of bacteria, with subsequent massive loss in parasites and some horizontal dissemination among archaea. Only a few proteins containing these domains have been studied experimentally, and their exact biochemical functions remain obscure; they may include transformations of novel signal molecules, such as the recently identified cyclic diguanylate. Recent experimental data provide the first direct evidence of the participation of these domains in signal transduction pathways, including regulation of virulence genes and extracellular enzyme production in the human pathogens Bordetella pertussis and Borrelia burgdorferi and the plant pathogen Xanthomonas campestris. Gene-neighborhood analysis of these new domains suggests their participation in a variety of processes, from mercury and phage resistance to maintenance of virulence plasmids. It appears that the real picture of the complexity of phosphorelay signal transduction in prokaryotes is only beginning to unfold. (C) 2001 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. OI Galperin, Michael/0000-0002-2265-5572 NR 63 TC 416 Z9 443 U1 4 U2 41 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD SEP 11 PY 2001 VL 203 IS 1 BP 11 EP 21 DI 10.1111/j.1574-6968.2001.tb10814.x PG 11 WC Microbiology SC Microbiology GA 474BL UT WOS:000171084400002 PM 11557134 ER PT J AU Ni, N Tesconi, M Tabibi, ES Gupta, S Yalkowsky, SH AF Ni, N Tesconi, M Tabibi, ES Gupta, S Yalkowsky, SH TI Use of pure t-butanol as a solvent for freeze-drying: a case study SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea; lyophilization; tertiary butyl alcohol AB 1-(2-Chloroethyl)-3-sarcosinamide-1-nitrosourea, (SarCNU) (NSC-364432) is a new antitumor drug that is of interest to the National Cancer Institute. It is intended for use as an intravenous injection. Although SarCNU is sufficiently soluble in water to obtain the desired dosage, it is highly unstable. Its T-90 in aqueous solution at room temperature is less than 6 h. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent freeze-drying medium. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. The reconstituted solutions are stable for 4 and 13 h, respectively. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. Chiron Corp, Emeryville, CA 94608 USA. NCI, Pharmaceut Resources Branch, DTP, DCTD,NIH, Bethesda, MD 20892 USA. RP Ni, N (reprint author), Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. FU NCI NIH HHS [CM 77109] NR 9 TC 28 Z9 28 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARM JI Int. J. Pharm. PD SEP 11 PY 2001 VL 226 IS 1-2 BP 39 EP 46 DI 10.1016/S0378-5173(01)00757-8 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 476XW UT WOS:000171254900004 PM 11532568 ER PT J AU Dalakas, MC Mian, L Fujii, M Jacobowitz, DM AF Dalakas, MC Mian, L Fujii, M Jacobowitz, DM TI Stiff person syndrome - Quantification, specificity, and intrathecal synthesis of GAD(65) antibodies SO NEUROLOGY LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; GABAERGIC NEURONS; AUTOANTIBODIES; IDENTIFICATION; EPILEPSY AB Objective: To characterize the specificity of anti-GAD(65) antibodies in patients with stiff person syndrome (SPS), quantify antibody titers, and examine antibody production within the CNS. Methods: The authors studied 18 patients with SPS and positive serum immunoreactivity to gamma-aminobutyric acid (GABA)-ergic neurons. The reactivity of serum and CSF to purified GAD antigen was examined by Western blots, and the anti-GAD(65) antibody titers in serum and CSF were quantified by ELISA and compared with 70 disease controls (49 with other autoimmune disorders and 11 with insulin-dependent diabetes mellitus). The intrathecal synthesis of anti-GAD(65) IgG was calculated, and the functional significance of the antibodies was examined by measuring the GABA levels in the CSF. Results: The serum and CSF of all selected patients with SPS had high anti-GAD(65) titers (from 7.0 to 215 mug/mL in serum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recombinant GAD(65) on Western blots and with GABA-ergic neurons on rat cerebellum. Among controls, only the serum of eight patients with insulin-dependent diabetes mellitus had low anti-GAD(65) antibody titers (from 200 to 1760 ng/mL) but no reactivity to recombinant GAD(65). The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD(65)-specific IgG index in 11 (85%) of 13. The mean level of GABA in the CSF was lower in patients with SPS than in controls. Conclusions: In patients with SPS, there is marked intrathecal antibody response against neuronal GAD(65) epitopes, indicating a clonal B cell activation in the CNS. Anti-GAD(65) antibodies at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis. 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,MSC 1382, Bethesda, MD 20892 USA. NR 28 TC 106 Z9 107 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 2001 VL 57 IS 5 BP 780 EP 784 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 470TE UT WOS:000170886600007 PM 11552003 ER PT J AU Sohn, YH Kaelin-Lang, A Jung, HY Hallett, M AF Sohn, YH Kaelin-Lang, A Jung, HY Hallett, M TI Effect of levetiracetam on human corticospinal excitability SO NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; REFRACTORY PARTIAL SEIZURES; STATISTICAL PROCESS-CONTROL; UCB L059; ANTIEPILEPTIC DRUGS; DOUBLE-BLIND; ANTICONVULSANT LEVETIRACETAM; CORTICAL EXCITABILITY; SILENT PERIOD AB Objective: To investigate whether levetiracetam. (LTC) alters corticospinal excitability in humans. Background: Although the antiepileptic activity of LTC is well recognized, its mechanism of action has yet to be determined. Transcranial magnetic stimulation (TMS) has been used to investigate the pharmacologic effects of various antiepileptic drugs on human corticospinal excitability. Methods: The authors performed TMS before and after double-blind administration of 3000 mg LTC or placebo in six healthy volunteers. TMS measurements included resting and active motor threshold (MT), recruitment curve of motor-evoked potential amplitudes, intracortical inhibition, and facilitation using the paired-pulse technique and silent period. F-wave and compound muscle action potential (CMAP) were also measured. Results: In recruitment curve measurements, motor-evoked potential amplitude was reduced for LTC with high stimulation intensity (130% and 140% of resting MT) compared with placebo (p < 0.05 and p < 0.01), but not with relatively low stimulation intensity (110% and 120%). The changes in other TMS measurements as well as F-wave and CHAP after LTC did not differ significantly from those observed after placebo administration. Conclusion: These results suggest that LTC reduces the corticospinal neuronal response to magnetic stimulation, preferentially affecting less excitable neurons. The lack of change in F-wave and CHAP suggests that this effect is mainly derived from the motor cortex. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Coll Med, Dept Neurol, Seoul, South Korea. Yonsei Univ, Coll Med, Brain Res Inst, Seoul, South Korea. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Rm 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 41 TC 45 Z9 48 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 2001 VL 57 IS 5 BP 858 EP 863 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 470TE UT WOS:000170886600021 PM 11552017 ER PT J AU Warach, S AF Warach, S TI New imaging strategies for patient selection for thrombolytic and neuroprotective therapies SO NEUROLOGY LA English DT Article ID ISCHEMIC LESION VOLUMES; DIFFUSION-WEIGHTED MRI; ACUTE HUMAN STROKE; INTRACEREBRAL HEMORRHAGE; CEREBRAL-ISCHEMIA; CONTROLLED TRIAL; PERFUSION MRI; EVOLUTION; PENUMBRA; ECASS AB Ischemic stroke trials have traditionally sought to limit the range of disease studied according to several dimensions based on clinical examination and CT scan results. It has been proposed that the optimal sample for stroke trials would include a positive imaging diagnosis of a pathology rationally linked to the drug's mechanisms of action and that this would improve the likelihood of positive results. This principle has been supported by the results of the Prolyse in Acute Cerebral Thromoembolism Il (PROACT II) study. Whereas trials of iv thrombolysis between 3 and 6 hours after symptom onset in a general sample of patients were not positive, selection of a subgroup by angiography was an effective strategy in this time period for PROACT Il. This study contradicted the hypothesis that treatment of stroke beyond 3 hours would not be successful. MRI with diffusion and perfusion has been an appealing imaging modality because it provides pretreatment angiography, perfusion, and lesion volume information during a brief, non-invasive assessment. Current literature supports the validity of MRI as a marker for clinical severity and clinical improvement. The diffusion-perfusion mismatch, the MRI marker for the ischemic penumbra, is a very strong predictor of lesion volume growth. Several acute trials in progress use a positive imaging diagnosis for the basis of selection. As the field of stroke clinical trials examines opportunities for improving trial design, positive imaging diagnoses in patient selection are likely to assume an increasingly useful role. C1 Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Warach, S (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, 36 Convent Dr,MSC 4129,Room 4A03, Bethesda, MD 20892 USA. NR 25 TC 50 Z9 50 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 2001 VL 57 IS 5 SU 2 BP S48 EP S52 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 471PP UT WOS:000170938000010 PM 11552055 ER PT J AU Li, YF Hess, S Pannell, LK Tabor, CW Tabor, H AF Li, YF Hess, S Pannell, LK Tabor, CW Tabor, H TI In vivo mechanism-based inactivation of S-adenosylmethionine decarboxylases from Escherichia coli, Salmonella typhimurium, and Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROENZYME FORM; TRANSAMINATION; BIOSYNTHESIS; POLYAMINES; PYRUVATE; ENZYMES AB S-adenosylmethionine decarboxylase (AdoMetDC), a key enzyme in the biosynthesis of spermidine and spermine, is first synthesized as a proenzyme, which is cleaved posttranslationally to form alpha and beta subunits. The a subunit contains a covalently bound pyruvoyl group derived from serine that is essential for activity. With the use of an Escherichia coli overexpression system, we have purified, AdoMetDCs encoded by the E. coli, Saccharomyces cerevisiae, and Salmonella typhimurium genes. Unexpectedly we found by mass spectrometry that these enzymes had been modified posttranslationally in vivo by a mechanism-based "suicide" inactivation. A large percentage of the alpha subunit of each enzyme had been modified in vivo to give peaks with masses m/z = 57 +/- 1 and m/z = 75 +/- 1 daltons higher than the parent peak. AdoMetDC activity decreased markedly during overexpression concurrently with the increase of the additional peaks for the alpha subunit. Sequencing of a tryptic fragment by tandem mass spectrometry showed that Cys-140 was modified with a +/- 75 +/- 1 adduct, which is probably derived from the reaction product, Comparable modification of the a subunit was also observed in in vitro experiments after incubation with the substrate or with the reaction product, which is consistent with the in vitro alkylation of E. coli AdoMetDC reported by Diaz and Anton. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, Struct Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM tabor@helix.nih.gov RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 23 TC 18 Z9 19 U1 4 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10578 EP 10583 DI 10.1073/pnas.181341198 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800017 PM 11526206 ER PT J AU Flynn, JM Levchenko, I Seidel, M Wickner, SH Sauer, RT Baker, TA AF Flynn, JM Levchenko, I Seidel, M Wickner, SH Sauer, RT Baker, TA TI Overlapping recognition determinants within the ssrA degradation tag allow modulation of proteolysis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ClpAP; ClpXP; peptide recognition; protein degradation; SspB ID DEPENDENT CLP PROTEASE; GREEN FLUORESCENT PROTEIN; ESCHERICHIA-COLI; SUBSTRATE RECOGNITION; SPECIFICITY COMPONENT; MOLECULAR CHAPERONE; MU-TRANSPOSASE; BINDING; MACHINE; PURIFICATION AB The ssrA tag, an 11-aa peptide added to the C terminus of proteins stalled during translation, targets proteins for degradation by ClpXP and ClpAP. Mutational analysis of the ssrA tag reveals independent, but overlapping determinants for its interactions with ClpX, ClpA, and SspB, a specificity-enhancing factor for ClpX. ClpX interacts with residues 9-11 at the C terminus of the tag, whereas OpA recognizes positions 8-10 in addition to residues 1-2 at the N terminus. SspB interacts with residues 1-4 and 7, N-terminal to the ClpX-binding determinants, but overlapping the ClpA determinants. As a result, SspB and ClpX work together to recognize ssrA-tagged substrates efficiently, whereas SspB inhibits recognition of these substrates by ClpA. Thus, dissection of the recognition signals within the ssrA tag provides insight into how multiple proteins function in concert to modulate proteolysis. C1 MIT, Dept Biol, Cambridge, MA 02139 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Baker, TA (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. OI , /0000-0002-1719-5399 FU NIAID NIH HHS [AI-16892, R01 AI016892] NR 39 TC 162 Z9 162 U1 4 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10584 EP 10589 DI 10.1073/pnas.191375298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800018 PM 11535833 ER PT J AU Zhang, HL Barcelo, JM Lee, B Kohlhagen, G Zimonjic, DB Popescu, NC Pommier, Y AF Zhang, HL Barcelo, JM Lee, B Kohlhagen, G Zimonjic, DB Popescu, NC Pommier, Y TI Human mitochondrial topoisomerase I SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CALF THYMUS MITOCHONDRIA; HUMAN-LEUKEMIA CELLS; DNA TOPOISOMERASE; SACCHAROMYCES-CEREVISIAE; SEQUENCE; MOUSE; IDENTIFICATION; LOCALIZATION; COMPLEXES; NUCLEAR AB Tension generated in the circular mitochondrial genome during replication and transcription points to the need for mtDNA topoisomerase activity. Here we report a 601-aa polypeptide highly homologous to nuclear topoisomerase 1. The N-terminal domain of this novel topoisomerase contains a mitochondrial localization sequence and lacks a nuclear localization signal. Therefore, we refer to this polypeptide as top1mt. The pattern of top1mt expression matches the requirement for high mitochondrial activity in specific tissues. top1mt is a type IB topoisomerase that requires diva lent metal (Ca2+ or Mg2+) and alkaline pH for optimum activity. The TOP1mt gene is highly homologous to the nuclear TOP1 gene and consists of 14 exons. IL IS localized on human chromosome 8q24.3. C1 NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bldg 37,Room 4E28,37 Convent Dr, Bethesda, MD 20892 USA. NR 47 TC 99 Z9 102 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10608 EP 10613 DI 10.1073/pnas.191321998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800022 PM 11526219 ER PT J AU Gupta, R Hamasaki-Katagiri, N Tabor, CW Tabor, H AF Gupta, R Hamasaki-Katagiri, N Tabor, CW Tabor, H TI Effect of spermidine on the in vivo degradation of ornithine decarboxylase in Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID S-ADENOSYLMETHIONINE DECARBOXYLASE; YEAST; EXPRESSION; POLYAMINE; ANTIZYME; PROTEIN; GENE; SPE1 AB As part of our studies on the regulation of polyamine biosynthesis in Saccharomyces cerevisiae, we have investigated the effect of spermidine on the degradation of ornithine decarboxylase in this organism. We have found that in S. cerevisiae, as in other eukaryotic cells, the rate of degradation of ornithine decarboxylase, measured either enzymatically or immunologically, is increased by the addition of spermidine to a yeast culture. It is noteworthy that this effect of added spermidine is found even when the experiments are conducted with strains in which the ornithine decarboxylase is overexpressed several hundred-fold more than the wild-type level. The effect of added spermidine in the overexpressed SPE1 strains is best seen in spe2 mutants in which the initial intracellular spermidine is very low or absent, Experiments with cycloheximide show that new protein synthesis is required to effect the breakdown of the ornithine decarboxylase. These results indicate that S. cerevisiae contains an antizyme-like mechanism for the control of the level of ornithine decarboxylase by spermidine, even though, as contrasted with other eukaryotic cells, no specific antizyme homologue has been detected either in in vitro experiments or in the S. cerevisiae genome. C1 Natl Inst Diabet & Digest Dis, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), Natl Inst Diabet & Digest Dis, Lab Biochem Genet, NIH, Bldg 8,Room 223,8 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 19 Z9 20 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10620 EP 10623 DI 10.1073/pnas.181341298 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800024 PM 11535806 ER PT J AU Kushimoto, T Basrur, V Valencia, J Matsunaga, J Vieira, WD Ferrans, VJ Muller, J Appella, E Hearing, VJ AF Kushimoto, T Basrur, V Valencia, J Matsunaga, J Vieira, WD Ferrans, VJ Muller, J Appella, E Hearing, VJ TI A model for melanosome biogenesis based on the purification and analysis of early melanosomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pigment; melanin; tyrosinase; melanoma ID II OCULOCUTANEOUS ALBINISM; TYROSINASE GENE FAMILY; MAMMALIAN TYROSINASE; MEMBRANE-PROTEINS; LOCUS PROTEIN; PIGMENTATION; IDENTIFICATION; TRANSPORT; SIGNALS; PMEL-17 AB Melanosome biogenesis and function were studied after purification of early stage melanosomes and characterization of specific proteins sorted to that organelle. Melanosomes were isolated from highly pigmented human MNT1 melanoma cells after disruption and initial separation by sucrose density gradient centrifugation. Low-density sucrose fractions were found by electron microscopy to be enriched in stage I and stage II melanosomes, and these fractions were further separated and purified by free flow electrophoresis. Tyrosinase and dopachrome tautomerase (DCT) activities were found exclusively in stage II melanosomes, even though DCT (and to some extent tyrosinase) proteins were sorted to stage I melanosomes. Western immunoblotting revealed that these catalytic proteins, as well as TYRP1, MART1, and GP100, were cleaved and inactivated in stage I melanosomes. Proteolytic cleavage was critical for the refolding of GP100 within the melanosomal milieu, and subsequent reorganization of amorphous stage I melanosomes into fibrillar, ovoid, and highly organized stage II melanosomes appears to stabilize the catalytic functions of melanosomal enzymes and allows melanin biosynthesis to begin. These results provide a better understanding of the structural features seen during melanosome biogenesis, and they yield further clues as to the physiological regulation of pigmentation. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 41 TC 144 Z9 148 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10698 EP 10703 DI 10.1073/pnas.191184798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800038 PM 11526213 ER PT J AU Staunton, JE Slonim, DK Coller, HA Tamayo, P Angelo, MJ Park, J Scherf, U Lee, JK Reinhold, WO Weinstein, JN Mesirov, JP Lander, ES Golub, TR AF Staunton, JE Slonim, DK Coller, HA Tamayo, P Angelo, MJ Park, J Scherf, U Lee, JK Reinhold, WO Weinstein, JN Mesirov, JP Lander, ES Golub, TR TI Chemosensitivity prediction by transcriptional profiling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTICANCER DRUG SCREEN; MOLECULAR CLASSIFICATION; CELL LINES; EXPRESSION; CANCER; PHARMACOLOGY; DISCOVERY AB in an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCl-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible. C1 Whitehead MIT, Ctr Genome Res, Cambridge, MA 02139 USA. NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Lander, ES (reprint author), Whitehead MIT, Ctr Genome Res, Cambridge, MA 02139 USA. EM lander@wi.mit.edu; golub@genome.wi.mit.edu NR 16 TC 439 Z9 459 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10787 EP 10792 DI 10.1073/pnas.191368598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800053 PM 11553813 ER PT J AU Campbell, S Fisher, RJ Towler, EM Fox, S Issaq, HJ Wolfe, T Phillips, LR Rein, A AF Campbell, S Fisher, RJ Towler, EM Fox, S Issaq, HJ Wolfe, T Phillips, LR Rein, A TI Modulation of HIV-like particle assembly in vitro by inositol phosphates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE retrovirus assembly; phosphatidylinsitol phosphates ID TYPE-1 GAG PROTEIN; MASS CHANGES; DOMAIN; 1,3,4,5,6-PENTAKISPHOSPHATE; IDENTIFICATION; DELETION; MEMBRANE; BINDING; CELLS AB HIV-1 Gag protein assembles into 100- to 120-nm diameter particles in mammalian cells. Recombinant HIV-1 Gag protein assembles in a fully defined system in vitro into particles that are only 25-30 nm in diameter and that differ significantly in other respects from authentic particles. However, particles with the size and other properties of authentic virions were obtained in vitro by addition of inositol phosphates or phosphatidylinsitol phosphates to the assembly system. Thus, the interactions between HIV-1 Gag protein molecules are altered by binding of inositol derivatives; this binding is apparently essential for normal HIV-1 particle assembly. This requirement is not seen in a deleted Gag protein lacking residues 16-99 within the matrix domain. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Frederick, MD 21702 USA. RP Campbell, S (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RI Fisher, Robert/B-1431-2009 NR 21 TC 116 Z9 120 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2001 VL 98 IS 19 BP 10875 EP 10879 DI 10.1073/pnas.191224698 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 472CZ UT WOS:000170966800068 PM 11526217 ER PT J AU Rosas, SLB Caballero, OL Dong, SM Carvalho, MDGDC Sidransky, D Jen, J AF Rosas, SLB Caballero, OL Dong, SM Carvalho, MDGDC Sidransky, D Jen, J TI Methylation status in the promoter region of the human PGP9.5 gene in cancer and normal tissues SO CANCER LETTERS LA English DT Article DE PGP9.5; methylation; promoter; HeLa cell; lung cancer cell line ID C-TERMINAL HYDROLASE; CELL LUNG-CANCER; CPG ISLANDS; DNA METHYLATION; HUMAN NEOPLASIA; HYPERMETHYLATION; INACTIVATION; EXPRESSION; MARKERS; LINES AB PGP 9.5 is a neurospecific peptide that functions to remove ubiquitin from ubiquitinated cellular proteins, thereby preventing them from targeted degradation by the proteasome-dependent pathway or regulating their localization, activity or structure. Using the serial analysis of gene expression method (SAGE), we initially found that the PGP9.5 transcript and protein was highly expressed in more than 50% of primary lung cancers and nearly all lung cancer cell lines but was not detectable in the normal lung. This increased expression could be the result of transcriptional regulation accompanied by methylation changes at the CpG island of the promoter region. We studied the methylation status of the cytosines at the promoter region of human PGP9.5 using sodium bisulfite genomic sequencing in normal and neoplastic cells. Although no methylation of PGP9.5 promoter was observed in the normal lung, normal cervical tissue, and lung cancer cell lines, this region was densely methylated in the HeLa cell line. Exposure to HeLa cells to the demethylating agent, 5-aza-2 ' -deoxycytidine, led to re-expression of PGP9.5. This data suggested that while other mechanisms may be involved in the frequent overexpression of PGP9.5 gene in lung tumors and lung cancer cell lines, promoter methylation may play a role in the transcriptional suppression of PGP9.5 gene expression in the cervical tissue-derived HeLa cell line. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Div Head & Neck Surg, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Controle Expressao Genica, BR-21941900 Rio De Janeiro, RJ, Brazil. RP Jen, J (reprint author), NCI, Div Canc Epidemiol & Genet, Lab Populat Genet, NIH, Bldg 41,Room D702, Bethesda, MD 20892 USA. OI carvalho, maria da gloria/0000-0001-5890-8095 NR 29 TC 29 Z9 30 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 SEP 10 PY 2001 VL 170 IS 1 BP 73 EP 79 PG 7 WC Oncology SC Oncology GA 457FK UT WOS:000170126300010 ER PT J AU Tong, T Fan, WH Zhao, HC Jin, SQ Fan, FY Blanck, P Alomo, I Rajasekaran, B Liu, YS Holbrook, NJ Zhan, QM AF Tong, T Fan, WH Zhao, HC Jin, SQ Fan, FY Blanck, P Alomo, I Rajasekaran, B Liu, YS Holbrook, NJ Zhan, QM TI Involvement of the MAP kinase pathways in induction of GADD45 following UV radiation SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE GADD45; MAP kinases; DNA damage; transcription factor; gene regulation ID P53-REGULATED PROTEIN GADD45; P53-MEDIATED G(1) ARREST; CELL-CYCLE CHECKPOINT; TUMOR-SUPPRESSOR P53; DNA-DAMAGING AGENTS; C-JUN; SIGNAL-TRANSDUCTION; MAMMALIAN-CELLS; GROWTH ARREST; ACTIVATION AB The p53-regulated stress-inducible gene GADD45 has been shown to participate in cellular response to DNA damage, including cell cycle checkpoint, apoptosis, and DNA repair. However, the regulation of GADD45 expression is complex and may involve both p53-dependent and -independent pathways. Recent findings have demonstrated that the p53-independent induction of GADD45 is mainly regulated by the transcription factors Oct-l and NF-YA, which directly bind to their consensus motifs located at the GADD45 promoter region. Here, we report that mitogen-activated protein (MAP) kinases are involved in the induction of the GADD45 promoter after DNA damage. Inhibition of JNK1 and ERK kinase activities either by expression of the dominant negative mutant JNK1 or by treatment with a selective chemical inhibitor of ERK (PD098059) substantially abrogates the UV induction of the GADD45 promoter. In contrast, a p38 kinase inhibitor (SB203580) has little effect on GADD45 induction by UV. In addition, the GADD45 promoter is strongly activated following expression of JNKl; Raf-1, which is an upstream activator of the ERK pathway; or MEK1, an upstream activator of both the ERK and the JNK pathways. Activation of the GADD45 promoter by MAP kinases does not require normal p53 function. Interestingly, the MAP kinase-regulatory effect appears to be mediated via OCT-1 and CAAT motifs since disruption of these sites abrogates activation of the GADD45 promoter by MAP kinases. Therefore, these findings indicate that the MAP kinase pathways are involved in the regulation of the p53-independent induction of the GADD45 promoter, probably via interaction with transcription factors that directly bind to OCT-1 and CAAT motifs. (C) 2001 Academic Press. C1 Univ Pittsburgh, Sch Med, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Inst Canc, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. NIA, Gene Express & Aging Sect, Baltimore, MD 21224 USA. Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. RP Zhan, QM (reprint author), Univ Pittsburgh, Sch Med, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. RI Liu, Yusen/E-3527-2011 NR 39 TC 52 Z9 54 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2001 VL 269 IS 1 BP 64 EP 72 DI 10.1006/excr.2001.5312 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 472TP UT WOS:000171001300008 PM 11525640 ER PT J AU Ranginwale, M Smith, S Flom, J Chie, L Kanovsky, M Chung, D Friedman, FK Robinson, RC Brandt-Rauf, PW Yamaizumi, Z Michl, J Pincus, MR AF Ranginwale, M Smith, S Flom, J Chie, L Kanovsky, M Chung, D Friedman, FK Robinson, RC Brandt-Rauf, PW Yamaizumi, Z Michl, J Pincus, MR TI Differences in patterns of activation of MAP kinases induced by oncogenic ras-p21 and insulin in oocytes SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID N-TERMINAL KINASE; SIGNAL-TRANSDUCTION; XENOPUS OOCYTES; PROTEIN-KINASE; JUN PROTEINS; CHEMOTHERAPEUTIC-AGENTS; RAS PROTEINS; MATURATION; GENE; JNK AB Oncogenic ras (Val 12-containing)-p21 protein induces oocyte maturation by a pathway that is blocked by peptides from effector domains of ras-p21, i.e., residues 35-47 (that block Val 12-p21-activated raf) and 96-110 and 115-126, which do not affect the ability of insulin-activated cellular p21 to induce maturation. Oncogenic p21 binds directly to jun-N-terminal kinase (JNK), which is blocked by the p21 96-110 and 115-126 peptides. This finding predicts that oncogenic p21, but not insulin, induces maturation by early and sustained activation of JNK. We now directly confirm this prediction by showing that oncogenic p21 induces activating phosphorylation of JNK (JNK-P) and of ERK (MAP kinase) (MAPK-P), whose levels correlate with oocyte maturation. p21 peptides 35-47 and 96-110 block formation of JNK-P and MAK-P, further confirming this correlation and suggesting, unexpectedly, that raf-MEK-MAPK and JNK-jun pathways strongly interact on the oncogenic p21 pathway. In contrast, insulin activates only low levels of JNK-P, and, surprisingly, we find that insulin induces only low levels of MAPK-P, indicating that insulin and activated normal p21 utilize MAP kinase-independent signal transduction pathways. (C) 2001 Academic Press. C1 New York Harbor VA Hlth Care Syst, Dept Pathol & Lab Med, Brooklyn, NY 11209 USA. New York Harbor VA Hlth Care Syst, Mol & Cellular Cardiol Program, Brooklyn, NY 11209 USA. Long Isl Univ, Dept Chem, Brooklyn, NY 11201 USA. Long Isl Univ, Dept Biol, Brooklyn, NY 11201 USA. SUNY Hlth Sci Ctr, Dept Pathol, Brooklyn, NY 11203 USA. SUNY Hlth Sci Ctr, Dept Anat & Cell Biol, Brooklyn, NY 11203 USA. SUNY Hlth Sci Ctr, Dept Microbiol & Immunol, Brooklyn, NY 11203 USA. NIH, Bethesda, MD 20817 USA. Columbia Univ Coll Phys & Surg, Div Environm Sci, New York, NY 10032 USA. NCI, Tokyo, Japan. RP Pincus, MR (reprint author), New York Harbor VA Hlth Care Syst, Dept Pathol & Lab Med, 800 Poly Pl, Brooklyn, NY 11209 USA. RI Friedman, Fred/D-4208-2016 FU NCI NIH HHS [CA 42500] NR 25 TC 18 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2001 VL 269 IS 1 BP 162 EP 169 DI 10.1006/excr.2001.5311 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 472TP UT WOS:000171001300017 PM 11525649 ER PT J AU Deng, XL Wang, Y Chou, J Cadet, JL AF Deng, XL Wang, Y Chou, J Cadet, JL TI Methamphetamine causes widespread apoptosis in the mouse brain: evidence from using an improved TUNEL histochemical method SO MOLECULAR BRAIN RESEARCH LA English DT Article DE methamphetamine; TUNEL; apoptosis; ischemia ID POSITRON-EMISSION-TOMOGRAPHY; DISMUTASE TRANSGENIC MICE; INDUCED NEUROTOXICITY; DNA FRAGMENTATION; P53-KNOCKOUT MICE; C-11 WIN-35,428; DOPAMINE; CELLS; RAT; AMPHETAMINES AB Terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) histochemistry is a sensitive method to expose DNA strand breaks in apoptotic cells. but it is difficult to conduct on slide-mounted sections. By using a 80 degreesC/0.5% Triton X-100 pretreatment, we have developed a TUNEL histochemical approach with high specificity and sensitivity using sections from ischemic rat brains. Thereafter. methamphetamine (METH)-induced neuronal death was investigated in mice brains. The results showed that a single injection of 40 mg/kg METH caused neuronal death in several brain areas including the striatum, cortex (frontal, parietal, and piriform), indusium griseum, medial habenular nucleus. and hippocampus. These results further confirmed the presence of METH-induced deleterious effects in nondopaminergic neurons. The significance of these findings is also discussed. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIDA, NIH, IRP, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, NIH, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 35 TC 76 Z9 77 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD SEP 10 PY 2001 VL 93 IS 1 BP 64 EP 69 DI 10.1016/S0169-328X(01)00184-X PG 6 WC Neurosciences SC Neurosciences & Neurology GA 483XQ UT WOS:000171661500008 ER PT J AU Bergsagel, PL Kuehl, WM AF Bergsagel, PL Kuehl, WM TI Chromosome translocations in multiple myeloma SO ONCOGENE LA English DT Article DE primary translocation; secondary translocation; MGUS; myeloma ID IN-SITU HYBRIDIZATION; GROWTH-FACTOR RECEPTOR-3; POLYMERASE CHAIN-REACTION; PLASMA-CELL MALIGNANCIES; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; SOMATIC HYPERMUTATION; C-MYC; BURKITT-LYMPHOMA; DNA-REPAIR AB Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-switched plasma cells (PC), usually arises from a common benign PC tumor called Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases with the stage of disease: 50% in MGUS, 60-65% in intramedullarly MM, 70-80% in extramedullary MM, and > 90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many partners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p2l (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3 ' enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malignant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell. C1 Cornell Univ, Weill Med Coll, Dept Med, Div Hematol & Oncol, Ithaca, NY 14853 USA. NCI, Dept Genet, Med Branch, Bethesda, MD 20892 USA. RP Bergsagel, PL (reprint author), Cornell Univ, Weill Med Coll, Dept Med, Div Hematol & Oncol, Ithaca, NY 14853 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 NR 68 TC 273 Z9 280 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 10 PY 2001 VL 20 IS 40 BP 5611 EP 5622 DI 10.1038/sj.onc.1204641 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 470TP UT WOS:000170887500004 PM 11607813 ER PT J AU Fisher, EJ Chaloner, K Cohn, DL Grant, LB Alston, B Brosgart, CL Schmetter, B El-Sadr, WM Sampson, J AF Fisher, EJ Chaloner, K Cohn, DL Grant, LB Alston, B Brosgart, CL Schmetter, B El-Sadr, WM Sampson, J CA Terry Beirn Community Programs Cli TI The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial SO AIDS LA English DT Article DE adefovir dipivoxil; AIDS; antiretroviral therapy; clinical trials; cytomegalovirus; HIV; nephrotoxicity ID ORGANIC ANION TRANSPORTER-1; ANTIVIRAL ACTIVITY; INFECTED ADULTS; VIRUS; ANALOGS; CIDOFOVIR; THERAPY AB Objective: Efficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease. Design: Randomized, double-blind, placebo-controlled multicenter trial. Setting: Fifteen clinical trial units providing HIV primary care. Participants: Adults with CD4 cell count less than or equal to 100 X 10(6)/l, or 101-200 X 10(6)/l with prior nadir less than or equal to 50 X 10(6)/l. Interventions: Oral adefovir or placebo 120 mg once daily. Main outcome measures: Survival, cytomegalovirus (CMV) disease, plasma HIV-RNA, CD4 cell count, grade 4 drug toxicity, permanent drug discontinuation due to toxicity. Results: Among the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (P = 0.88), and four and eight experienced CMV disease (P = 0.25). Mean change in logo plasma HIV-RNA in the adefovir and placebo groups, respectively, was 0.09 and -0.03 copies/ml at 6 months (P = 0.22) and 0.06 and -0.02 at 12 months (P = 0.87). Changes in CD4 cell counts were not different between groups. At 12 months the cumulative percent with proximal renal tubular dysfunction (PRTD) was 17% in the adefovir group and 0.4% in the placebo group (P < 0.0001, log rank test). Median time to resolution of PRTD was 15 weeks among patients assigned adefovir, and 16 lo of patients did not resolve completely 41 weeks after onset. More drug discontinuations occurred in the adefovir group than in the placebo group. Conclusions: No virologic or immunologic benefit was observed when adefovir was added to background antiretroviral therapy in advanced HIV disease, and adefovir was associated with considerable nephrotoxicity. This study does not support the use of adefovir for treatment of advanced HIV disease in pretreated patients. (C) 2001 Lippincott Williams & Wilkins. C1 Richmond AIDS Consortium, Richmond, VA 23298 USA. Univ Minnesota, Minneapolis, MN USA. Denver Community Program Clin Res AIDS, Denver, CO USA. NIAID, NIH, Bethesda, MD 20892 USA. Gilead Sci Inc, Foster City, CA 94404 USA. Social & Sci Syst Inc, Rockville, MD USA. Harlem Hosp Med Ctr, New York, NY USA. Res & Educ Grp, Portland, OR USA. RP Fisher, EJ (reprint author), Richmond AIDS Consortium, POB 980049, Richmond, VA 23298 USA. RI Chaloner, Kathryn/B-5090-2013 NR 17 TC 68 Z9 74 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 7 PY 2001 VL 15 IS 13 BP 1695 EP 1700 DI 10.1097/00002030-200109070-00013 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 480QE UT WOS:000171472800013 PM 11546945 ER PT J AU Yu, Q La Rose, JH Zhang, HL Pommier, Y AF Yu, Q La Rose, JH Zhang, HL Pommier, Y TI Antisense inhibition of Chk2/hCds1 expression attenuates DNA damage-induced S and G2 checkpoints and enhances apoptotic activity in HEK-293 cells SO FEBS LETTERS LA English DT Article DE cell cycle checkpoint; Chk2; hCds1; apoptosis; 293 cells; p53 ID PROTEIN-KINASE; ADENOVIRUS E1A; FISSION YEAST; P53 FUNCTION; G(2) DELAY; CHK1; PATHWAYS; CDS1; ACTIVATION; PHASE AB The cellular response to DNA damage involves checkpoint controls that delay cell cycle progression in order to provide time for repair of damaged DNA. Chk2/hCds1 is a recently identified homolog of the yeast Cds1 kinase that is involved in cell cycle checkpoint response to DNA damage. To investigate the functions of Chk2/hCds1 in response to DNA damage in mammalian cells, we established a stable human kidney embryonic cell line (HEK-293) that expresses antisense Chk2/hCds1 (Chk2AS) under the control of an inducible promoter. Cells that express Chk2AS display defective S-phase delay in response to DNA replication-mediated DNA damage induced by the topoisomerase I inhibitor camptothecin. The defective G2 checkpoint was also observed in Chk2AS cells exposed to the DNA damaging agent VP-16 or gamma -radiation. Enhanced apoptosis was observed in Chk2AS cells after exposure to gamma -radiation or camptothecin. No p53 activation was observed after DNA damage in HEK-293 or Chk2AS cells. Our results indicate that perturbation of Chk2/hCds1 expression adversely affects the S- and G2-phase checkpoints following DNA damage or DNA replication block, and suggest that reduced expression of Chk2/hCds1 might promote a p53-independent apoptotic response. (C) 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bldg 37,Rm 4E28, Bethesda, MD 20892 USA. NR 32 TC 61 Z9 65 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 7 PY 2001 VL 505 IS 1 BP 7 EP 12 DI 10.1016/S0014-5793(01)02756-9 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 474BJ UT WOS:000171084200002 PM 11557032 ER PT J AU Sauna, ZE Smith, MM Muller, M Ambudkar, SV AF Sauna, ZE Smith, MM Muller, M Ambudkar, SV TI Evidence for the vectorial nature of drug (substrate)-stimulated ATP hydrolysis by human P-glycoprotein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CATALYTIC TRANSITION-STATE; MULTIDRUG-RESISTANCE; TRANSPORT; NUCLEOTIDE; MECHANISM; CELLS; SITES; PHOSPHORYLATION; RECONSTITUTION; PURIFICATION AB P-glycoprotein (Pgp), the ATP-binding cassette multidrug transporter, exhibits a drug (substrate)-stimulatable ATPase activity, and vanadate (Vi) inhibits this activity by stably trapping the nucleoside diphosphate in the Pgp-ADP-Vi conformation. We recently demonstrated that Vi-induced 8-azido-[alpha-(32)p]ADP trapping into Pgp in the absence of substrate occurs both in the presence of 8-azido-[alpha-P-32]ATP (following 8-azido-ATP hydrolysis) or 8-azido-[alpha-P-32]ADP (without hydrolysis) and, the transition state intermediates generated under either condition are functionally indistinguishable. In this study, we compare the effect of substrates on Vi-induced 8-azido.[alpha-P-32]ADP trapping into Pgp under both non-hydrolysis and hydrolysis conditions. We demonstrate that whereas substrates stimulate the Vi-induced trapping of 8-azido-[alpha-P-32]ADP under hydrolysis conditions, they strongly inhibit Vi-induced trapping under non-hydrolysis conditions. This inhibition is concentration-dependent, follows first order kinetics, and is effected by drastically decreasing the affinity of nucleoside diphosphate for Pgp during trapping. However, substrates do not affect the binding of nucleoside diphosphate in the absence of Vi, indicating that the substrate-induced conformation exerts its effect at a step distinct from nucleoside diphosphate-binding. Our results demonstrate that during the catalytic cycle of Pgp, although the transition state, Pgp.ADP.P-i (Vi), can be generated both via the hydrolysis of ATP or by directly providing ADP to the system, in the presence of substrate the reaction is driven in the forward direction, i.e. hydrolysis of ATP. These data suggest that substrate-stimulated ATP hydrolysis by Pgp is a vectorial process. C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Ambudkar, Suresh/B-5964-2008 NR 36 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33301 EP 33304 DI 10.1074/jbc.C100369200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200003 PM 11451943 ER PT J AU Taggart, CC Lowe, GJ Greene, CM Mulgrew, AT O'Neill, SJ Levine, RL McElvaney, NG AF Taggart, CC Lowe, GJ Greene, CM Mulgrew, AT O'Neill, SJ Levine, RL McElvaney, NG TI Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEUKOCYTE PROTEASE INHIBITOR; RESPIRATORY EPITHELIAL SURFACE; STABLE PROTEINASE-INHIBITOR; ALPHA-1-PROTEINASE INHIBITOR; LEUKOPROTEASE INHIBITOR; PSEUDOMONAS-AERUGINOSA; CYSTEINE PROTEASES; HUMAN-NEUTROPHIL; ELASTASE; METALLOPROTEINASES AB A number of serine proteases, matrix metalloproteases, and cysteine proteases were evaluated for their ability to cleave and inactivate the antiprotease, secretory leueoprotease inhibitor (SLPI). None of the serine proteases or the matrix metalloproteases examined cleaved the SLPI protein. However, incubation with cathepsins B, L, and S resulted in the cleavage and inactivation of SLPI. All three cathepsins initially cleaved SLPI between residues Thr(67) and Tyr(68). The proteolytic cleavage of SLPI by all three cathepsins resulted in the loss of the active site of SLPI and the inactivation of SLPI anti-neutrophil elastase capacity. Cleavage and inactivation were catalytic with respect to the cathepsins, so that the majority of a 400-fold excess of SLPI was inactivated within 15 min by cathepsins L and S. Analysis of epithelial lining fluid samples from individuals with emphysema indicated the presence of cleaved SLPI in these samples whereas only intact SLPI was observed in control epithelial lining fluid samples. Active cathepsin L was shown to be present in emphysema epithelial lining fluid and inhibition of this protease prevented the cleavage of recombinant SLPI added to emphysema epithelial lining fluid. Taken together with previous data that demonstrates that cathepsin L inactivates alpha (1)-antitrypsin, these findings indicate the involvement of cathepsins in the diminution of the lung antiprotease screen possibly leading to lung destruction in emphysema. C1 Beaumont Hosp, Royal Coll Surg Ireland, Educ & Res Ctr, Dept Med,Pulm Res Div, Dublin 9, Ireland. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP McElvaney, NG (reprint author), Beaumont Hosp, Royal Coll Surg Ireland, Educ & Res Ctr, Dept Med,Pulm Res Div, Dublin 9, Ireland. RI McElvaney, Noel/A-6809-2010; Greene, Catherine/D-3513-2012; Taggart, Clifford/G-4492-2014; Levine, Rodney/D-9885-2011 OI Greene, Catherine/0000-0003-2549-2569; NR 38 TC 105 Z9 107 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33345 EP 33352 DI 10.1074/jbc.M103220200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200010 PM 11435427 ER PT J AU Baek, SJ Horowitz, JM Eling, TE AF Baek, SJ Horowitz, JM Eling, TE TI Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter - Basal transcription is mediated by Sp1 and Sp3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; FUNCTIONAL INTERACTIONS; REPRESS TRANSCRIPTION; MORPHOGENETIC PROTEIN; BINDING PROTEINS; CARCINOMA-CELLS; RB PROTEIN; SP-FAMILY; EXPRESSION AB Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is known to be associated with anti-tumorigenic activity and belongs to the transforming growth factor-beta superfamily. In the present study, we cloned the promoter region (-3500 to +41) and investigated the transcriptional regulatory mechanisms of the basal expression of the human NAG-1 gene. Several potential transcription factor-binding sites in this region were identified. Based on the results from clones of nested deletions, the construct between -133 and +41 base pairs contains three Sp1-binding sites (Sp1-A, Sp1-B, and Sp1-C, which confer basal transcription specific activity of NAG-1 expression. When the Spi-C site was mutated (GG to TT), a 60-80% decrease in promoter activity was observed in HCT-116 cells. Gel shift, cotransfection, and chromatin immunoprecipitation assays showed that the Sp transcription factors bind to the Spl-binding sites and transactivate NAG-1 expression. In addition, chicken ovalbumin upstream promoter transcription factor I can interact with the C-terminal region of Sp1 and Sp3 proteins and induce NAG-1 promoter activity through SpI and Sp3 transcription factors. These results identify the critical regulatory regions for the human NAG-1 basal promoter. Furthermore, the results suggest that the level of expression of the NAG-1 gene will depend on the availability of Sp proteins and on co-factors such as chicken ovalbumin upstream promoter-transcription factor 1. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Coll Vet Med, Dept Anat Phys Sci & Radiol, Raleigh, NC 27606 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Baek, Seung/0000-0001-7866-7778 NR 41 TC 99 Z9 100 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33384 EP 33392 DI 10.1074/jbc.M101814200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200015 PM 11445565 ER PT J AU Pessach, I Leto, TL Malech, HL Levy, R AF Pessach, I Leto, TL Malech, HL Levy, R TI Essential requirement of cytosolic phospholipase A(2) for stimulation of NADPH oxidase-associated diaphorase activity in granulocyte-like cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; SUPEROXIDE-GENERATING SYSTEM; GTP-GAMMA-S; HUMAN-NEUTROPHILS; CONFORMATIONAL-CHANGES; ACTIN POLYMERIZATION; SUBUNIT P47(PHOX); H+ CHANNEL; PERMEABILIZED NEUTROPHILS; INDEPENDENT ACTIVATION AB We have previously established a model of cytosolic phospholipase A(2) (cPLA(2))-deficient differentiated PLB-985 cells (PLB-D cells) and demonstrated that cPLA(2)-generated arachidonic acid (AA) is essential for NADPH oxidase activation. In this study we used this model to investigate the physiological role of cPLA2 in regulation of NADPH oxidase-associated diaphorase activity. A novel diaphorase activity assay, using 4-iodonitrotetrazolium. violet as an electron acceptor, was used in permeabilized neutrophils and PLB-985 cells differentiated toward the granulocytic or monocytic phenotypes. Phorbol 12-myristate 13-acetate, guanosine 5'-3-O-(thio)triphosphate (GTP gammaS), or FMLP stimulated a similar diphenylene iodonium-sensitive diaphorase activity pattern in neutrophils and in differentiated parent PLB-985 cells. This diaphorase activity was not detected in undifferentiated cells, but developed during differentiation. Furthermore, diaphorase activity could not be stimulated in permeabilized neutrophils from X-linked CGD patients and in differentiated gp91(phox)-targeted PLB-985 cells that lacked normal expression of gp91(phox), but was restored to these cells following transduction with retrovirus encoding gp91(phox). The differentiated PLB-D cells showed no diaphorase activity when stimulated by either GTP gammaS or FMLP, and only partial activation when stimulated with phorbol 12-myristate 13-acetate. Diaphorase activity in response to either agonists was fully restored by the addition of 10 muM free AA. The permeabilized cell 4-iodonitrotetrazolium violet reduction assay offers a unique tool for the evaluation of NADPH oxidase-associated diaphorase activity in stimulated whole cells. These results establish an essential and specific physiological requirement of cPLA(2)-generated AA in activation of electron transfer through the FAD reduction center of NADPH oxidase. C1 Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Biochem, Infect Dis Lab, IL-84105 Beer Sheva, Israel. Soroka Med Ctr, IL-84105 Beer Sheva, Israel. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Levy, R (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Biochem, Infect Dis Lab, IL-84105 Beer Sheva, Israel. NR 52 TC 29 Z9 29 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33495 EP 33503 DI 10.1074/jbc.M011417200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200029 PM 11432850 ER PT J AU Couty, JP Geras-Raaka, E Weksler, BB Gershengorn, MC AF Couty, JP Geras-Raaka, E Weksler, BB Gershengorn, MC TI Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-SEQUENCES; SPINDLE CELLS; EXPRESSION; ONCOGENE; HUMAN-HERPESVIRUS-8; DISEASE; HHV-8; GENE AB Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) encodes a chemokine-like G protein-coupled receptor (KSHV-GPCR) that is implicated in the pathogenesis of Kaposi's sarcoma (KS). Since endothelial cells appear to be targets for the virus, we developed an in vitro mouse lung endothelial cell model in which KSHV-GPCR is stably expressed and KSHV-GPCR signaling was studied. In mouse lung endothelial cells: 1) HSHV-GPCR does not exhibit basal signaling through the phosphoinositide-specific phospholipase C pathway but inositol phosphate production is stimulated by growth-related oncogene a (Gro-alpha) via a pertussis toxin (PTX) -insensitive pathway; 2) KSHV-GPCR signals basally through a PTX-sensitive pathway leading to a lowering of intracellular cAMP level that can be lowered further by Gro alpha and increased by interferon gamma -inducible protein 10; 3) KSHV-GPCR stimulates phosphatidylinositol 3-kinase via a PTX-insensitive mechanism; and 4) KSHV-GPCR activates nuclear factor-kappaB (NF-kappaB) by a PTX-sensitive GB gamma subunit-mediated pathway. These data show that KSHV-GPCR couples to at least two G proteins and initiates signaling via at least three cascades in endothelial cells thereby increasing the complexity of regulation of endothelial cell function by KSHV-GPCR that may occur during viral infection. C1 Cornell Univ, Weill Med Coll, Dept Med, Div Mol Med, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Med, Div Hematol Oncol, New York, NY 10021 USA. Cornell Univ, Weill Grad Sch Med Sci, Program Physiol Biophys & Mol Med, New York, NY 10021 USA. RP Gershengorn, MC (reprint author), NIDDK, Div Intramural Res, NIH, Bldg 10,Rm 9N222,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 74 Z9 78 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33805 EP 33811 DI 10.1074/jbc.M104631200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200070 PM 11448967 ER PT J AU Van Goor, F Zivadinovic, D Martinez-Fuentes, AJ Stojilkovic, SS AF Van Goor, F Zivadinovic, D Martinez-Fuentes, AJ Stojilkovic, SS TI Dependence of pituitary hormone secretion on the pattern of spontaneus voltage-gated calcium influx - Cell type-specific action potential secretion coupling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROLACTIN SECRETION; CYTOPLASMIC CALCIUM; POTASSIUM CHANNELS; CA2+ OSCILLATIONS; RAT LACTOTROPES; PULSE-GENERATOR; NERVE-TERMINALS; EXOCYTOSIS; SOMATOTROPHS; GONADOTROPHS AB In excitable cells, voltage-gated calcium influx provides an effective mechanism for the activation of exocytosis. In this study, we demonstrate that although rat anterior pituitary lactotrophs, somatotrophs, and gonadotrophs exhibited spontaneous and extracellular calcium-dependent electrical activity, voltage-gated calcium influx triggered secretion only in lactotrophs and somatotrophs. The lack of action potential-driven secretion in gonadotrophs was not due to the proportion of spontaneously firing cells or spike frequency. Gonadotrophs exhibited calcium signals during prolonged depolarization comparable with signals observed in somatotrophs and lactotrophs. The secretory vesicles in all three cell types also had a similar sensitivity to voltage-gated calcium influx. However, the pattern of action potential calcium influx differed among three cell types. Spontaneous activity in gonadotrophs was characterized by high amplitude, sharp spikes that had a limited capacity to promote calcium influx, whereas lactotrophs and somatotrophs fired plateau-bursting action potentials that generated high amplitude calcium signals. Furthermore, a shift in the pattern of firing from sharp spikes to plateau-like spikes in gonadotrophs triggered luteinizing hormone secretion. These results indicate that the cell type-specific action potential secretion coupling in pituitary cells is determined by the capacity of their plasma membrane oscillator to generate threshold calcium signals. C1 NICHHD, Sect Cellular Signaling, ERRB, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, ERRB, NIH, Bldg 49,Rm 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. NR 52 TC 68 Z9 68 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33840 EP 33846 DI 10.1074/jbc.M105386200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200075 PM 11457854 ER PT J AU Neuss, M Monticone, R Lundberg, MS Chesley, AT Fleck, E Crow, MT AF Neuss, M Monticone, R Lundberg, MS Chesley, AT Fleck, E Crow, MT TI The apoptotic regulatory protein ARC (apoptosis repressor with caspase recruitment domain) prevents oxidant stress-mediated cell death by preserving mitochondrial function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; PERMEABILITY TRANSITION; KINASE; CYTOTOXICITY; ACTIVATION; INHIBITORS; INTERACTS; RECEPTOR; NECROSIS; PATHWAY AB ARC is an apoptotic regulatory protein expressed almost exclusively in myogenic cells. It contains a caspase recruitment domain (CARD) through which it has been shown to block the activation of some initiator caspases. Because ARC also blocks caspase-independent events associated with apoptosis, such as hypoxia-induced cytochrome c release, we examined its role in cell death triggered by exposure to hydrogen peroxide (H2O2) in the myogenic cell line, H9c2. Cell death in this model was caspase-independent and characterized by dose-dependent reduction in ARC expression accompanied by disruption of the mitochondrial membrane potential (Delta psi (m)) and loss of plasma membrane integrity, typical of necrotic cell death. Ectopic expression of ARC prevented both H2O2-induced mitochondrial dysfunction and cell death without affecting the stress kinase response, suggesting that ARCs protective effects were downstream of early signaling events and not due to quenching of H2O2. ARC was also effective in blocking H2O2-induced loss of membrane integrity and/or disruption of Delta psi (m) in two human cell lines in which it is not normally expressed. These results demonstrate that, in addition to its ability to block caspase-dependent and -independent events in apoptosis, ARC also prevents necrosis-like cell death via the preservation of mitochondrial function. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. German Heart Inst, Dept Med Cardiol, D-13353 Berlin, Germany. RP Crow, MT (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 37 TC 88 Z9 91 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 33915 EP 33922 DI 10.1074/jbc.M104080200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200085 PM 11438535 ER PT J AU Collingwood, TN Urnov, FD Chatterjee, VKK Wolffe, AP AF Collingwood, TN Urnov, FD Chatterjee, VKK Wolffe, AP TI Chromatin remodeling by the thyroid hormone receptor in regulation of the thyroid-stimulating hormone alpha-subunit promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-SPECIFIC EXPRESSION; TUMOR VIRUS PROMOTER; BETA-A GENE; NUCLEAR RECEPTOR; POSITIONED NUCLEOSOMES; TRANSCRIPTION FACTOR; IN-VIVO; HYPERSENSITIVE SITES; BASAL TRANSCRIPTION; NEGATIVE REGULATION AB The chromatin architecture of a promoter is an important determinant of its transcriptional response. For most target genes, the thyroid hormone receptor (TR) activates gene expression in response to thyroid hormone (T-3). In contrast, the thyroid-stimulating hormone a-subunit (TSH alpha) gene promoter is down-regulated by TR in the presence of T-3. Here we utilize the capacity for the Xenopus oocyte to chromatinize exogenous nuclear-injected DNA to analyze the chromatin architecture of the TSHa promoter and how this changes upon TR-mediated regulation. Interestingly, in the oocyte, the TSH alpha promoter was positively regulated by T-3. In the inactive state, the promoter contained six loosely positioned nucleosomes. The addition of TR/retinoid X receptor together had no effect on the chromatin structure, but the inclusion of T-3 induced strong positioning of a dinucleosome in the TSHa proximal promoter that was bordered by regions that were hypersensitive to cleavage by methidiumpropyl EDTA. We identified a novel thyroid response element that coincided with the proximal hypersensitive region. Furthermore, we examined the consequences of mutations in TR that impaired coactivator recruitment. In a comparison with the Xenopus TR betaA promoter, we found that the effects of these mutations on transactivation and chromatin remodeling were significantly more severe on the TSH alpha promoter. C1 NIH, Mol Embryol Lab, Bethesda, MD 20892 USA. Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. RP Collingwood, TN (reprint author), Sangamo Biosci, 501 Canal Blvd,Suite A100, Richmond, CA 94804 USA. NR 64 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 7 PY 2001 VL 276 IS 36 BP 34227 EP 34234 DI 10.1074/jbc.M105172200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471CP UT WOS:000170910200125 PM 11454868 ER PT J AU Shapiro, BA Bengali, D Kasprzak, W Wu, JC AF Shapiro, BA Bengali, D Kasprzak, W Wu, JC TI RNA folding pathway functional intermediates: Their prediction and analysis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE RNA; folding pathways; genetic algorithms; PSTVd; hok/sok ID PROGRAMMED CELL-DEATH; PARALLEL GENETIC ALGORITHM; HOK MESSENGER-RNA; SECONDARY STRUCTURE; PLASMID R1; VIROID REPLICATION; SPINDLE; CLEAVAGE; SEQUENCE; IMPROVES AB The massively parallel genetic algorithm (GA) for RNA structure prediction uses the concepts of mutation, recombination, and survival of the fittest to evolve a population of thousands of possible RNA structures toward a solution structure. As described below, the properties of the algorithm are ideally suited to use in the prediction of possible folding pathways and functional intermediates of RNA molecules given their sequences. Utilizing Stem Trace, an interactive visualization tool for RNA structure comparison, analysis of not only the solution ensembles developed by the algorithm, but also the stages of development of each of these solutions, can give strong insight into these folding pathways. The GA allows the incorporation of information from biological experiments, making it possible to test the influence of particular interactions between structural elements on the dynamics of the folding pathway. These methods are used to reveal the folding pathways of the potato spindle tuber viroid (PSTVd) and the host killing mechanism of Escherichia coli plasmid R1, both of which are successfully explored through the combination of the GA and Stem Trace. We also present novel intermediate folds of each molecule, which appear to be phylogenetically supported, as determined by use of the methods described below. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NCI Frederick,NIH, Frederick, MD 21702 USA. SAIC, Intramural Res Support Program, NCI Frederick, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Lab Expt & Computat Biol, Ctr Canc Res, NCI Frederick,NIH, Bldg 469,Room 150, Frederick, MD 21702 USA. NR 39 TC 48 Z9 49 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 7 PY 2001 VL 312 IS 1 BP 27 EP 44 DI 10.1006/jmbi.2001.4931 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473MF UT WOS:000171047500004 PM 11545583 ER PT J AU Exner, DV Domanski, MJ Cohn, JN AF Exner, DV Domanski, MJ Cohn, JN TI Race and responsiveness to drugs for heart failure. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Calgary, Calgary, AB T2N 4N1, Canada. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Exner, DV (reprint author), Univ Calgary, Calgary, AB T2N 4N1, Canada. NR 3 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 6 PY 2001 VL 345 IS 10 BP 767 EP 768 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 468RX UT WOS:000170772900016 ER PT J AU Goffeney, N Bulte, JWM Duyn, J Bryant, LH van Zijl, PCM AF Goffeney, N Bulte, JWM Duyn, J Bryant, LH van Zijl, PCM TI Sensitive NMR detection of cationic-polymer-based gene delivery systems using saturation transfer via proton exchange SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LASER-POLARIZED XENON; CONTRAST AGENTS; MONOCLONAL-ANTIBODIES; CHEMICAL-EXCHANGE; MAMMALIAN-CELLS; RELAXOMETRY; MRI; DENDRIMERS; RECEPTOR; TUMORS C1 Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NINDS, NIH, Ctr Clin, Lab Diagnost Radiol Res,Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD 21205 USA. RP van Zijl, PCM (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, 217 Traylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Bulte, Jeff/A-3240-2008; van Zijl, Peter/B-8680-2008; Duyn, Jozef/F-2483-2010 OI Bulte, Jeff/0000-0003-1202-1610; FU NCRR NIH HHS [RR11115]; NINDS NIH HHS [NS31490] NR 24 TC 121 Z9 122 U1 5 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 5 PY 2001 VL 123 IS 35 BP 8628 EP 8629 DI 10.1021/ja0158455 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 467XN UT WOS:000170729200035 PM 11525684 ER PT J AU Braddock, DT Cai, ML Baber, JL Huang, Y Clore, GM AF Braddock, DT Cai, ML Baber, JL Huang, Y Clore, GM TI Rapid identification of medium- to large-scale interdomain motion in modular proteins using dipolar couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODEL-FREE APPROACH; ORIENTED MACROMOLECULES; STRUCTURAL INFORMATION; NMR; RELAXATION; ALIGNMENT; MAGNITUDE; DYNAMICS; ABSENCE; TENSOR C1 NIDDK, Labs Chem Phys & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Labs Chem Phys & Mol Biol, NIH, Bldg 5,Room B1-301, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 20 TC 42 Z9 42 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 5 PY 2001 VL 123 IS 35 BP 8634 EP 8635 DI 10.1021/ja016234f PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 467XN UT WOS:000170729200038 PM 11525687 ER PT J AU Cai, ML Huang, Y Clore, GM AF Cai, ML Huang, Y Clore, GM TI Accurate orientation of the functional groups of asparagine and glutamine side chains using one- and two-bond dipolar couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID STEREOSPECIFIC ASSIGNMENT; IMPROVED SENSITIVITY; NMR STRUCTURES; MACROMOLECULES; PROTEINS; ENHANCEMENT C1 NIDDK, Labs Chem Phys & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Labs Chem Phys & Mol Biol, NIH, Bldg 5,Room B1-301, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 20 TC 9 Z9 9 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 5 PY 2001 VL 123 IS 35 BP 8642 EP 8643 DI 10.1021/ja0164475 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 467XN UT WOS:000170729200042 PM 11525691 ER PT J AU Stefanek, M Hartmann, L Nelson, W AF Stefanek, M Hartmann, L Nelson, W TI Risk-reduction mastectomy: Clinical issues and research needs SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID BILATERAL PROPHYLACTIC MASTECTOMY; BRCA2 MUTATION CARRIERS; BREAST-CANCER DETECTION; OVARIAN-CANCER; SCREENING MAMMOGRAPHY; HEREDITARY BREAST; DECISION-MAKING; RANDOMIZED TRIAL; FAMILY HISTORY; DEATH RATES AB Risk-reduction mastectomy (RRM), also known as bilateral prophylactic mastectomy, is a controversial clinical option for women who are at increased risk of breast cancer. Highrisk women, including women with a strong family history of breast cancer and BRCA1/2 mutation carriers, have several clinical options: risk-reduction surgery (bilateral mastectomy and bilateral oophorectomy), surveillance (mammography, clinical breast examination, and breast self-examination), and chemoprevention (tamoxifen). We review research in a number of areas central to our understanding of RRM, including recent data on 1) the effectiveness of RRM in reducing breast cancer risk, 2) the perception of RRM among women at increased risk and health-care providers, 3) the decision-making process for follow-up care of women at high risk, and 4) satisfaction and psychological status after surgery. We suggest areas of future research to better guide high-risk women and their health-care providers in the decision-making process. C1 NCI, Div Canc Control & Populat Sci, Behav Res Program, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Div Med Oncol, Rochester, MN 55905 USA. RP Stefanek, M (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, NIH, 6130 Execut Blvd,EPN 4066, Bethesda, MD 20892 USA. NR 79 TC 37 Z9 38 U1 4 U2 8 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 5 PY 2001 VL 93 IS 17 BP 1297 EP 1306 DI 10.1093/jnci/93.17.1297 PG 10 WC Oncology SC Oncology GA 467ZU UT WOS:000170734300008 PM 11535704 ER PT J AU Lal, A Peters, H St Croix, B Haroon, ZA Dewhirst, MW Strausberg, RL Kaanders, JHAM van der Kogel, AJ Riggins, GJ AF Lal, A Peters, H St Croix, B Haroon, ZA Dewhirst, MW Strausberg, RL Kaanders, JHAM van der Kogel, AJ Riggins, GJ TI Transcriptional response to hypoxia in human tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENE-EXPRESSION; CARBONIC-ANHYDRASES; GLYCOLYTIC-ENZYMES; ENDOTHELIAL-CELLS; ANGIOGENESIS; GROWTH; TENASCIN; CANCER; PROTEIN; PROGRESSION AB Background: The presence of hypoxic regions within solid tumors is associated with a more malignant tumor phenotype and worse prognosis. To obtain a blood supply and protect against cellular damage and death, oxygen-deprived cells in tumors alter gene expression, resulting in resistance to therapy. To investigate the mechanisms by which cancer cells adapt to hypoxia, we looked for novel hypoxia-induced genes. Methods: The transcriptional response to hypoxia in human glioblastoma cells was quantified with the use of serial analysis of gene expression. The time course of gene expression in response to hypoxia in a panel of various human tumor cell lines was measured by real-time polymerase chain reaction. Hypoxic regions of human carcinomas were chemically marked with pimonidazole. Immunohistochemistry and an situ hybridization were used to examine gene expression in the tumor's hypoxic regions. Results: From the 24504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected-all induced, to a greater extent than vascular endothelial growth factor, a hypoxia-induced mitogen that promotes blood vessel growth. These genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. In tumors, gene expression was limited to hypoxic regions. Induced genes included hexabrachion (an extracellular matrix glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an angiopoietin-related gene. Conclusions: We have identified the genes that are transcriptionally activated within hypoxic malignant cells, a crucial first step in understanding the complex interactions driving hypoxia response. Within our catalogue of hypoxia-responsive genes are novel candidates for hypoxia-driven angiogenesis. C1 Duke Univ, Med Ctr, Canc Genom Lab, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Genet, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA. Univ Nijmegen, Inst Radiotherapy, NL-6526 ED Nijmegen, Netherlands. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21218 USA. NCI, Off Director, Canc Genom Off, Bethesda, MD 20892 USA. RP Riggins, GJ (reprint author), Duke Univ, Med Ctr, Canc Genom Lab, Dept Pathol, Box 3156, Durham, NC 27710 USA. RI Kaanders, Hans/A-7432-2014; Kogel, A.J./L-4441-2015 FU PHS HHS [S98-146] NR 41 TC 225 Z9 230 U1 0 U2 7 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 5 PY 2001 VL 93 IS 17 BP 1337 EP 1343 DI 10.1093/jnci/93.17.1337 PG 7 WC Oncology SC Oncology GA 467ZU UT WOS:000170734300013 PM 11535709 ER PT J AU Bosch, FX Munoz, N De Sanjose, S Franco, ELF Lowy, DR Schiffman, M Franceschi, S Kjaer, SK Meijer, CJLM Frazer, IH Cuzick, J AF Bosch, FX Munoz, N De Sanjose, S Franco, ELF Lowy, DR Schiffman, M Franceschi, S Kjaer, SK Meijer, CJLM Frazer, IH Cuzick, J TI Re: Cervical carcinoma and human papillomavirus: On the road to preventing a major human cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Serv Epidemiol REgistre Canc, Inst Catala Oncol, E-08907 Barcelona, Spain. Hosp Llobregat, Barcelona, Spain. Int Agcy Res Canc, F-69372 Lyon, France. McGill Univ, Montreal, PQ H3A 2T5, Canada. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NCI, Environm Epidemiol Branch, Rockville, MD USA. Danish Canc Soc, Copenhagen, Denmark. Free Univ Amsterdam Hosp, NL-1081 HV Amsterdam, Netherlands. Ctr Immunol & Canc Res, Brisbane, Qld, Australia. Imperial Canc Res Fund, London WC2A 3PX, England. RP Bosch, FX (reprint author), Serv Epidemiol REgistre Canc, Inst Catala Oncol, Av Gran Via S-N,Km 2-7, E-08907 Barcelona, Spain. RI de Sanjose Llongueras, Silvia/H-6339-2014; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012 OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412 NR 7 TC 9 Z9 10 U1 0 U2 4 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 5 PY 2001 VL 93 IS 17 BP 1349 EP 1350 DI 10.1093/jnci/93.17.1349 PG 2 WC Oncology SC Oncology GA 467ZU UT WOS:000170734300017 PM 11535713 ER PT J AU Sharrett, AR Ballantyne, CM Coady, SA Heiss, G Sorlie, PD Catellier, D Patsch, W AF Sharrett, AR Ballantyne, CM Coady, SA Heiss, G Sorlie, PD Catellier, D Patsch, W TI Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions - The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Article DE lipoproteins; apolipoproteins; coronary disease; follow-up studies ID MYOCARDIAL-INFARCTION; ARTERY DISEASE; FOLLOW-UP; MEN; PLASMA; PREVENTION; HYPERTRIGLYCERIDEMIA; RADIOIMMUNOASSAY; QUANTITATION; ASSOCIATION AB Background-Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse. Methods and Results-After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. Conclusions-Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men. C1 NHLBI, Epidemiol & Biometry Program, NIH, DECA, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Landeskrankenanstalten Salzburg, Dept Lab Med, Salzburg, Austria. RP Sharrett, AR (reprint author), NHLBI, Epidemiol & Biometry Program, NIH, DECA, 2 Rockledge Ctr,Room 8164,6701 Rockledge Dr,MSC 7, Bethesda, MD 20892 USA. RI Ballantyne, Christie/A-6599-2008 FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 28 TC 519 Z9 549 U1 2 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 4 PY 2001 VL 104 IS 10 BP 1108 EP 1113 DI 10.1161/hc3501.095214 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 471HE UT WOS:000170922100008 PM 11535564 ER PT J AU Hilioti, Z Chung, YS Mochizuki, Y Hardy, CFJ Cohen-Fix, O AF Hilioti, Z Chung, YS Mochizuki, Y Hardy, CFJ Cohen-Fix, O TI The anaphase inhibitor Pds1 binds to the APC/C-associated protein Cdc20 in a destruction box-dependent manner SO CURRENT BIOLOGY LA English DT Article ID PROMOTING COMPLEX; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; MITOSIS; CYCLIN; PROTEOLYSIS; INITIATION; EXIT; DEGRADATION; REGULATOR AB An essential aspect of progression through mitosis is the sequential degradation of key mitotic regulators in a process that is mediated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase [1]. In mitotic cells, two forms of the APC/C exist, ApC/C-Cdc10 and ApC/C-Cdh1, which differ in their associated WD-repeat proteins (Cdc20 and Cdh1, respectively), time of activation, and substrate specificity [2, 3]. How the WD-repeat proteins contribute to APC/C's activation and substrate specificity is not clear. Many APC/C substrates contain a destruction box element that is necessary for their ubiquitination [4-6]. One such APC/C substrate, the budding yeast anaphase inhibitor Pds1 (securin), is degraded prior to anaphase initiation in a destruction box and APC/ C-Cdc20-dependent manner [3, 7]. Here we find that Pds1 interacts directly with Cdc20 and that this interaction requires Pds1's destruction box. Our results suggest that Cdc20 provides a link between the substrate and the core APC/C and that the destruction box is essential for efficient Cdc20-substrate interaction. We also find that Pds1 does not interact with Cdh1. Finally, the effect of spindle assembly checkpoint activation, known to inhibit APC/C function [8], on the Pds1-Cdc20 interaction is examined. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Cohen-Fix, O (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM56788] NR 22 TC 90 Z9 96 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 4 PY 2001 VL 11 IS 17 BP 1347 EP 1352 DI 10.1016/S0960-9822(01)00399-2 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469WN UT WOS:000170839200021 PM 11553328 ER PT J AU Kawahara, A Dawid, IB AF Kawahara, A Dawid, IB TI Critical role of biklf in erythroid cell differentiation in zebrafish SO CURRENT BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; GENE; PROMOTER; HEMATOPOIESIS; GATA-1; EMBRYOGENESIS; EXPRESSION; ELEMENTS; GLOBIN; EKLF AB Hematopoietic cells arise from ventral mesoderm in different vertebrates, but the mechanisms through which various factors contribute to the hematopoietic processes, including erythrogenesis, remain incompletely understood. The Kruppel-like transcription factor Biklf is preferentially expressed in blood islands throughout zebrafish embryogenesis, marking the region of future erythropoiesis [1]. In this paper, we show that expression of biklf is significantly suppressed in the blood-less mutants vampire and m683 in which primitive hematopoiesis is impaired. Knockdown of biklf using morpholino-based antisense oligonucleotides (bikif-MO) led to a potent reduction in the number of circulating blood cells and deficiency in hemoglobin production. Consistently, we found that the expression of beta (e3)globin is strongly suppressed in biklf-MO-injected embryos, while gata1 expression is partly inhibited at the 10-somite stage. In addition, analysis of reporter constructs driven by the GATA1 and beta -globin promoters showed that Biklf can positively regulate both genes. These results indicate that Biklf is required for erythroid cell differentiation in zebrafish. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 19 TC 33 Z9 33 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 4 PY 2001 VL 11 IS 17 BP 1353 EP 1357 DI 10.1016/S0960-9822(01)00398-0 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469WN UT WOS:000170839200022 PM 11553329 ER PT J AU Yamaguchi, TP AF Yamaguchi, TP TI Heads or tails: Wnts and anterior-posterior patterning SO CURRENT BIOLOGY LA English DT Review ID MOUSE EMBRYO; SPEMANN ORGANIZER; PRIMITIVE-STREAK; XENOPUS EMBRYOS; AXIS FORMATION; BETA-CATENIN; FOREBRAIN DEVELOPMENT; SIGNAL-TRANSDUCTION; MESODERMAL LINEAGES; AVIAN GASTRULATION AB Cell-cell communication is critical during embryogenesis for organizing the vertebrate body plan. Members of the Wnt family of secreted signaling molecules possess axis-inducing and posteriorizing activity when overexpressed. Wnt signals are modulated extracellularly by a diverse group of secreted Wnt antagonists and cofactors. Recent work has revealed that inhibition of posteriorly localized Wnt signaling by anteriorly localized Wnt antagonists is critical for inducing the anterior structures, forebrain and heart, from neural ectoderm and mesoderm, respectively. This review centers on the role that Writs and Wnt antagonists play in the patterning of the vertebrate anterior-posterior axis. C1 NCI, Frederick Canc Res & Dev Ctr, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Yamaguchi, TP (reprint author), NCI, Frederick Canc Res & Dev Ctr, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NR 113 TC 108 Z9 110 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 4 PY 2001 VL 11 IS 17 BP R713 EP R724 DI 10.1016/S0960-9822(01)00417-1 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469WN UT WOS:000170839200015 PM 11553348 ER PT J AU Ravi, G Lee, K Ji, XD Kim, HS Soltysiak, KA Marquez, VE Jacobson, KA AF Ravi, G Lee, K Ji, XD Kim, HS Soltysiak, KA Marquez, VE Jacobson, KA TI Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID A(3) ADENOSINE RECEPTORS; BIOLOGICAL-ACTIVITY; DIFFERENTIATION; DERIVATIVES; AGONISTS; NEURONS; ANALOGS; LIGANDS; TARGETS; CELLS AB 6-Oxopurine derivatives containing a northern (N) methanocarba modification (i.e., fused cyclopropane and cyclopentane rings in place of the ribose) were synthesized and the adenosine receptor affinity measured. Guanine or hypoxanthine was coupled at the 7-position, or 1,3-diblitylxanthine was coupled at the 9-position. The pseudoribose ring was also substituted at the 5 ' -position with an N-methyluronamide or with phosphate groups. Published by Elsevier Science Ltd. C1 NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Frederick, MD 21702 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 16 TC 16 Z9 16 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 3 PY 2001 VL 11 IS 17 BP 2295 EP 2300 DI 10.1016/S0960-894X(01)00450-4 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 466CW UT WOS:000170627600016 PM 11527718 ER PT J AU Flynn, BL Flynn, GP Hamel, E Jung, MK AF Flynn, BL Flynn, GP Hamel, E Jung, MK TI The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ANTIMITOTIC NATURAL-PRODUCTS; ANTINEOPLASTIC AGENTS; HALOCYCLIZATION REACTIONS; UNSATURATED SULFIDES; COLCHICINE SITE; PRODRUG; PHOSPHATE; POTENT; CELLS AB A number of analogues of combretastatin A-4 (1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed. a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[b]thiophenes 3 5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than I but exhibit comparable activity to the most active of the benzo[b]thiophenes 3 5. A structure-activity relationship or these compounds is considered. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Australian Natl Univ, Fac, Dept Chem, Canberra, ACT 0200, Australia. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,NIH, Ft Detrick, MD 21702 USA. NCI, Sci Applicat Int Corp, NIH, Frederick, MD 21701 USA. RP Flynn, BL (reprint author), Australian Natl Univ, Fac, Dept Chem, Canberra, ACT 0200, Australia. FU NCI NIH HHS [N01-CO-56000] NR 22 TC 99 Z9 100 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 3 PY 2001 VL 11 IS 17 BP 2341 EP 2343 DI 10.1016/S0960-894X(01)00436-X PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 466CW UT WOS:000170627600025 PM 11527727 ER PT J AU Davodeau, F Difilippantonio, M Roldan, E Malissen, M Casanova, JL Couedel, C Morcet, JF Merkenschlager, M Nussenzweig, A Bonneville, M Malissen, B AF Davodeau, F Difilippantonio, M Roldan, E Malissen, M Casanova, JL Couedel, C Morcet, JF Merkenschlager, M Nussenzweig, A Bonneville, M Malissen, B TI The tight interallelic positional coincidence that distinguishes T-cell receptor J alpha usage does not result from homologous chromosomal pairing during V alpha J alpha rearrangement SO EMBO JOURNAL LA English DT Article DE DNA recombination; homologous chromosomal pairing; T cell; T-cell receptor; V alpha repertoire ID CONSERVED SEQUENCE BLOCK; GENE REARRANGEMENT; ALLELIC EXCLUSION; TCR-ALPHA; SWITCH RECOMBINATION; CHAIN GENES; THYMOCYTES; LOCUS; CLONES; REGION AB The T-cell receptor (TCR) a locus is thought to undergo multiple cycles of secondary rearrangements that maximize the generation of alpha beta T cells. Taking advantage of the nucleotide sequence of the human V alpha and J alpha segments, we undertook a locus-wide analysis of TCR alpha gene rearrangements in human alpha beta T-cell clones. In most clones, V alphaJ alpha rearrangements occurred on both homologous chromosomes and, remarkably, resulted in the use of two neighboring J alpha segments. No such interallelic coincidence was found for the position of the two rearranged V alpha segments, and there was only a loose correlation between the 5' or 3' chromosomal position of the V alpha and J alpha segments used in a given rearrangement. These observations question the occurrence of extensive rounds of secondary V alpha-->J alpha rearrangements and of a coordinated and polarized usage of the V alpha and J alpha libraries. Fluorescence in situ hybridization analysis of developing T cells in which TCR alpha rearrangements are taking place showed that the interallelic positional coincidence in J alpha usage cannot be explained by the stable juxtaposition of homologous J alpha clusters. C1 Inst Biol, INSERM, U463, F-44035 Nantes 01, France. Univ Med, Ctr Immunol Marseille Luminy, CNRS, INSERM, F-13288 Marseille, France. Fac Med Necker Enfants Malad, Lab Genet Humaine Malad Infect, F-75015 Paris, France. Hammersmith Hosp, Imperial Coll Sch Med, MRC, Clin Sci Ctr,Lymphocyte Dev Grp, London W12 0NN, England. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Bonneville, M (reprint author), Inst Biol, INSERM, U463, 9 Quai Moncousu, F-44035 Nantes 01, France. RI Davodeau, Francois/M-1888-2015 FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 33 Z9 35 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 3 PY 2001 VL 20 IS 17 BP 4717 EP 4729 DI 10.1093/emboj/20.17.4717 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 471BX UT WOS:000170907900011 PM 11532936 ER PT J AU Brown, FD Rozelle, AL Yin, HL Balla, T Donaldson, JG AF Brown, FD Rozelle, AL Yin, HL Balla, T Donaldson, JG TI Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Arf6; membrane traffic; phosphatidylinositol 4,5-bisphosphate; PIP2; PIP 5-kinase ID ADP-RIBOSYLATION FACTOR-6; PLASMA-MEMBRANE; 4-PHOSPHATE 5-KINASE; IN-VIVO; PHOSPHOLIPASE-C; GOLGI MEMBRANES; EXCHANGE FACTOR; ACTIN; ARF6; VESICLES AB ADP ribosylation factor (Arf) 6 regulates the movement of membrane between the plasma membrane (PM) and a nonclathrin-derived endosomal compartment and activates phosphatidylinositol 4-phosphate 5-kinase (PIP 5-kinase), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show that PIP2 visualized by expressing a fusion protein of the pleckstrin homology domain from PLC delta and green fluorescent protein (PH-GFP), colocalized with Arf6 at the PM and on tubular endosomal structures. Activation of Arf6 by expression of its exchange factor EFA6 stimulated protrusion formation, the uptake of PM into macropinosomes enriched in PIP2, and recycling of this membrane back to the PM. By contrast, expression of Arf6 Q67L, a GTP hydrolysis-resistant mutant, induced the formation of PIP2 positive actin-coated vacuoles that were unable to recycle membrane back to the PM. PM proteins, such as beta1-integrin, plakoglobin, and major histocompatibility complex class I, that normally traffic through the Arf6 endosomal compartment became trapped in this vacuolar compartment. Overexpression of human PIP 5-kinase a mimicked the effects seen with Arf6 Q67L. These results demonstrate that PIP 5-kinase activity and PIP2 turnover controlled by activation and inactivation of Arf6 is critical for trafficking through the Arf6 PM-endosomal recycling pathway. C1 NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Physiol, Dallas, TX 75390 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, Bldg 50,Rm 2503, Bethesda, MD 20892 USA. OI Balla, Tamas/0000-0002-9077-3335 FU NIGMS NIH HHS [GM51112, GM61203] NR 47 TC 304 Z9 308 U1 7 U2 14 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 3 PY 2001 VL 154 IS 5 BP 1007 EP 1017 DI 10.1083/jcb.200103107 PG 11 WC Cell Biology SC Cell Biology GA 470ML UT WOS:000170875700010 PM 11535619 ER PT J AU Rhen, T Crews, D AF Rhen, T Crews, D TI Distribution of androgen and estrogen receptor mRNA in the brain and reproductive tissues of the leopard gecko, Eublepharis macularius SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE androgens; estrogens; hypothalamus; sex behavior; temperature-dependent sex determination ID DEPENDENT SEX DETERMINATION; SITU HYBRIDIZATION ANALYSIS; LIZARD PODARCIS-HISPANICA; SNAKE THAMNOPHIS-SIRTALIS; FEMALE WHIPTAIL LIZARDS; CNEMIDOPHORUS-UNIPARENS; PHEROMONAL DISCRIMINATION; EFFERENT CONNECTIONS; AGGRESSIVE-BEHAVIOR; OLFACTORY BULBS AB Incubation temperature during embryonic development determines gonadal sex in the leopard gecko, Eublepharis macularius. In addition, both incubation temperature and gonadal sex influence behavioral responses to androgen and estrogen treatments in adulthood. Although these findings suggest that temperature and sex steroids act upon a common neural substrate to influence behavior, it is unclear where temperature and hormone effects are integrated. To bogie to address this question, we identified areas of the leopard gecko brain that express androgen receptor {AR) and estrogen receptor {ER) mRNA. We gonadectomized adult female and male geckos from an incubation temperature that produces a female-biased sex ratio and another temperature that produces a male-biased sex ratio. Females and males from both temperatures were then treated with equivalent levels of various sex steroids. Region-specific patterns of AR mRNA expression and ER mRNA expression were observed upon hybridization of radiolabeled (S-35) cRNA probes to thin sections of reproductive tissues (male hemipenes and female oviduct) and brain. Labeling for AR mRNA was very intense in the epithelium, but not within the body, of the male hemipenes. In contrast, expression of ER mRNA was prominent in most of the oviduct but not in the luminal epithelium. Within the brain, labeling for AR mRNA was conspicuous in the anterior olfactory nucleus, the lateral septum, the medial preoptic area, the periventricular preoptic area, the external nucleus of the amygdala, the anterior hypothalamus, the ventromedial hypothalamus, the premammillary nucleus, and the caudal portion of the periventricular nucleus of the hypothalamus. Expression of ER mRNA was sparse in the septum and was prominent in the ventromedial hypothalamus, the caudal portion of the periventricular nucleus of the hypothalamus, and a group of cells near the torus semicircularis. Many of these brain regions have been implicated in the regulation of hormone-dependent, sex-typical reproductive and agonistic behaviors in other vertebrates. Consequently, these nuclei are likely to control such behaviors in the leopard gecko and also are candidate neural substrates for mediating temperature effects on behavior. J. Comp. Neurol. 437:385-397, 2001 (C). 2001 Wiley-Liss, Inc. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Sch Biol Sci, Sect Integrat Biol, Austin, TX 78712 USA. RP Rhen, T (reprint author), NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. FU NIMH NIH HHS [MH-57874, MH-11369] NR 47 TC 31 Z9 32 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 3 PY 2001 VL 437 IS 4 BP 385 EP 397 DI 10.1002/cne.1290 PG 13 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 459NM UT WOS:000170256900001 PM 11503141 ER PT J AU Nakamura, K Kitani, A Strober, W AF Nakamura, K Kitani, A Strober, W TI Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T lymphocytes, suppressor-effector; CD4-positive T lymphocytes; receptors, interleukin 2; transforming growth factors; autoimmune diseases ID IMMUNOLOGICAL SELF-TOLERANCE; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; INTESTINAL INFLAMMATION; IN-VITRO; AUTOIMMUNE-DISEASE; INDUCTION; COLITIS; ACTIVATION; RECEPTOR; THROMBOSPONDIN-1 AB CD4(+)CD25(+) T cells have been identified as a population of immunoregulatory T cells, which mediate suppression of CD4(+)CD25(-) T cells by cell-cell contact and not secretion of suppressor cytokines. In this study, we demonstrated that CD4(+)CD25(+) T cells do produce high levels of transforming growth factor (TGF)-beta1 and interleukin (IL)-10 compared with CD4(+)CD25(-) T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-beta1 (but not other cytokines), is further enhanced by costimulation via cytotoxic T lymphocyte-associated antigen (CTLA)-4. As in prior studies, we found that CD4(+)CD25(+) T cells suppress proliferation of CD4(+)CD25(-) T cells; however, we observed here that such suppression is abolished by the presence of anti-TGF-beta. In addition, we found that CD4(+)CD25(+) T cells suppress B cell immunoglobulin production and that anti-TGF-beta again abolishes such suppression. Finally, we found that stimulated CD4(+)CD25(+) T cells but not CD4(+)CD25(-) T cells express high and persistent levels of TGF-beta1 on the cell surface. This, plus the fact that we could find no evidence that a soluble factor mediates suppression, strongly suggests that CD4+CD25+ T cells exert immunosuppression by a cell-cell interaction involving cell surface TGF-beta1. C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bldg 10,Rm 11N238,10 Ctr Dr, Bethesda, MD 20892 USA. NR 31 TC 1057 Z9 1150 U1 0 U2 20 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 3 PY 2001 VL 194 IS 5 BP 629 EP 644 DI 10.1084/jem.194.5.629 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 470LP UT WOS:000170873700010 PM 11535631 ER PT J AU Nabhan, JF Hamdan, FF Ribeiro, P AF Nabhan, JF Hamdan, FF Ribeiro, P TI A Schistosoma mansoni Pad1 homologue stabilizes c-Jun SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Schistosoma mansoni; c-Jun; AP-1; Pad1; Jab1; proteasome ID 26-S PROTEASOME; 26S PROTEASOME; FISSION YEAST; IN-VIVO; DEUBIQUITINATING ENZYMES; DROSOPHILA-MELANOGASTER; REGULATORY COMPLEX; DEGRADATION; SUBUNIT; LOCALIZATION AB We report the cloning and functional analysis of a Pad1 homologue (Sn-LPOH) from Schistosoma mansoni. SmPOH encodes a protein of approximate to 35 kDa with high amino acid identities to yeast Pad1 (65%) and its human homologue, POH1 (78%). Members of the Pad1 family are subunits of the 26S proteasome and have been implicated as positive modulators of transcription in yeast. Recombinant SmPOH expressed in COS7 cells exhibited a punctate pattern of distribution throughout the cytoplasm and nucleus, predominantly in the nuclear periphery, a distribution consistent with that of the cellular proteasome. Transient overexpression of SmPOH in COS7 cells caused a dose-dependent stimulation in AP-1 transcriptional activity, as determined by a reporter gene assay. This effect was associated with a pronounced increase in the levels of cellular c-Jun. In vitro degradation assays further demonstrated that SmPOH specifically decreased the rate of c-Jun degradation in a dose dependent manner. Taken together, these results suggest that SmPOH, and possibly other related Pad1 proteins, function as positive modulators of transcription by increasing the stability of cellular c-Jun, making elevated amounts of this protein available for transactivation of AP-1-responsive genes. (C) 2001 Elsevier Science B.V. All rights reserved. C1 McGill Univ, Inst Parasitol, St Anne De Bellevue, PQ H9X 3V9, Canada. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ribeiro, P (reprint author), McGill Univ, Inst Parasitol, 21111 Lakeshore Rd, St Anne De Bellevue, PQ H9X 3V9, Canada. NR 32 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD SEP 3 PY 2001 VL 116 IS 2 BP 209 EP 218 DI 10.1016/S0166-6851(01)00321-8 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 472VA UT WOS:000171004600010 PM 11522353 ER PT J AU Sullivan, DC AF Sullivan, DC TI Research recommendations from a lung cancer screening workshop SO ACADEMIC RADIOLOGY LA English DT Article C1 NCI, Div Canc Treatment Diag & Ctr, NIH, Rockville, MD 20852 USA. RP Sullivan, DC (reprint author), NCI, Div Canc Treatment Diag & Ctr, NIH, Execut Pk N,Room 800,6130 Execut Blvd, Rockville, MD 20852 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 2001 VL 8 IS 9 BP 942 EP 943 DI 10.1016/S1076-6332(03)80779-1 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 468KU UT WOS:000170757500017 PM 11724050 ER PT J AU Granstrand, P Nylander-French, LA Lacks, G Holmstrom, M French, JE AF Granstrand, P Nylander-French, LA Lacks, G Holmstrom, M French, JE TI Absence of proinflammatory cytokine gene expression in nasal biopsies from wood surface-coating industry workers SO ACTA OTO-LARYNGOLOGICA LA English DT Article DE acrylates; cytokines; inflammation; nasal biopsy; occupational exposure ID ALLERGIC RHINITIS; MESSENGER-RNA; INTERLEUKIN-5; INFLAMMATION; CHALLENGE; CAPSAICIN; AIRWAYS; INFLUX; LAVAGE; MUCOSA AB Symptoms of nasal, pharyngeal and ocular discomfort have been reported among workers in the wood surface-coating industry. Symptoms were reported more often by workers using ultraviolet radiation-curable acrylate coatings (UV coatings), which contain potential chemical sensitizers, than by those using acid-curing coatings. Furthermore, increased levels of eosinophil cationic protein (ECP) and albumin, but not tryptase, in nasal lavage from workers exposed to UV coatings have been observed. To further examine whether air contaminants present in the UV-coating industry are causing the observed increase in symptoms, the inflammatory process in the nasal mucosa of workers exposed to UV coatings was investigated. Clinical and biochemical endpoints were selected to distinguish between specific and non-specific hypersensitivity and to test the hypothesis that the symptoms were consistent with Type IV hypersensitivity. The nasal lavage and nasal biopsy were performed under local anesthetic at the workplace during working hours after a minimum of 2 h of work in both the exposed and control groups. Albumin and ECP, and the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8), were used as inflammatory markers. P. multi-probe ribonuclease protection assay was used to attempt to detect cytokine variation in human nasal biopsies. The cytokine genes analyzed were TNF-alpha, GM-CSF, interferon-gamma, IL-2, IL-4 and IL-5. L32 and GAPDH were used as control genes for mRNA expression levels. Mucosal inflammation symptoms correlated with increased levels of albumin, but not with increased levels of ECP, secreted proinflammatory cytokines or cytokine gene mRNA expression. We conclude that the symptoms are non-specific and do not correlate with occupational exposure to UV coatings under the conditions of this investigation. C1 Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. Huddinge Univ Hosp, Dept Otorhinolaryngol, S-14186 Huddinge, Sweden. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Nylander-French, LA (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, CB 7400 Rosenau Hall, Chapel Hill, NC 27599 USA. NR 25 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD SEP PY 2001 VL 121 IS 6 BP 743 EP 749 DI 10.1080/00016480152583692 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 481ZG UT WOS:000171549900012 PM 11678174 ER PT J AU Knepper, MA Masilamani, S AF Knepper, MA Masilamani, S TI Targeted proteomics in the kidney using ensembles of antibodies SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 7th International Symposium on Functional Genomics - A New Approach to Understanding Cardiovascular and Renal Dysfunction CY AUG 19-20, 2000 CL STOCKHOLM UNIV, STOCKHOLM, SWEDEN HO STOCKHOLM UNIV DE aldosterone; ENaC; hypertension; vasopressin ID THICK ASCENDING LIMB; CORTICAL COLLECTING DUCT; NA-CL COTRANSPORTER; HENLES LOOP; VASOPRESSIN; RAT; EXPRESSION; ABUNDANCE; TRANSPORT; PROTEINS AB Building on extensive physiological characterization of sodium transport mechanisms along the renal tubule over the past 30 years, complementary DNAs for almost all of the major transporters and channels responsible for renal tubular sodium reabsorption have been cloned over the past 10 years. The consequence is the generation of a broad range of cDNA and antibody probes which can be used to investigate physiological mechanisms on a molecular level. An ensemble of such probes can be exploited for comprehensive analysis of integrative physiological processes, approaches which are referred to as 'physiological genomics' or 'physiological proteomics'. In this review, we describe a targeted proteomic approach to comprehensive analysis of sodium transporter and water channel protein abundance along the renal tubule using an ensemble of rabbit polyclonal antibodies directed to the major sodium transporters and water channels expressed in each renal tubule segment. We discuss preparation and characterization of the antibodies, strategies for quantification of transporter protein abundance, and provide examples of the application of antibody-based targeted proteomics analysis of kidney tissue, revealing the effects of elevations of circulating aldosterone levels and circulating vasopressin levels on sodium transporter, sodium channel, and water channel abundance in kidney. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 27 TC 30 Z9 34 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD SEP PY 2001 VL 173 IS 1 BP 11 EP 21 DI 10.1046/j.1365-201X.2001.00880.x PG 11 WC Physiology SC Physiology GA 477YK UT WOS:000171314000003 PM 11678722 ER PT J AU Schnermann, J AF Schnermann, J TI Sodium transport deficiency and sodium balance in gene-targeted mice SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 7th International Symposium on Functional Genomics - A New Approach to Understanding Cardiovascular and Renal Dysfunction CY AUG 19-20, 2000 CL STOCKHOLM UNIV, STOCKHOLM, SWEDEN HO STOCKHOLM UNIV DE aquaporin 1; Bartter's syndrome; glomerular filtration rate; knockout mice; Na channel; Na,K,2Cl-cotransporter; Na/H exchanger; pseudohypoaldosteronism ID HYPERPROSTAGLANDIN-E SYNDROME; GLOMERULAR-FILTRATION RATE; LUNG LIQUID CLEARANCE; AQUAPORIN-1 NULL MICE; RENAL COLLECTING DUCT; THICK ASCENDING LIMB; NA-CL COTRANSPORTER; BARTTERS-SYNDROME; PROXIMAL TUBULE; PSEUDOHYPOALDOSTERONISM TYPE-1 AB Animals with induced or natural null mutations in renal NaCl and water transporter genes provide a powerful tool to study the physiological mechanisms that enable the kidney to optimize the match between glomerular filtration rate and tubular reabsorption. Deficiencies in the Na/H exchanger NHE3 and in the water channel aquaporin 1 (AQP1) cause reductions in proximal fluid absorption which are accompanied by proportionate decrements in glomerular filtration rate (GFR). Compensation of the transport defect by a reduction in filtered load is so efficient that clinically symptomatic Na losses are not observed in either NHE3 or AQP1 deficient animals. On the other hand, severe syndromes of salt wasting are caused by loss of function of the Na,K,2Cl-cotransporter (NKCC2) in the thick ascending limb, or of the epithelial Na channel (ENaC) the collecting duct indicating that the severity of Na dysregulation is unrelated to the basal absorption of NaCl in a given nephron segment. In these states, the increased delivery of Na to downstream segments is not monitored by a sensor linked to the site of filtrate formation. In the absence of adaptations in the filtered load intrarenal compensation of a circumscribed NaCl malabsorption by adjustment of NaCl transport in other nephron segments is sometimes insufficient, particularly in the immature kidney of the newborn. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. NR 47 TC 15 Z9 16 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD SEP PY 2001 VL 173 IS 1 BP 59 EP 66 DI 10.1046/j.1365-201X.2001.00885.x PG 8 WC Physiology SC Physiology GA 477YK UT WOS:000171314000008 PM 11678727 ER PT J AU Dawson, DA AF Dawson, DA TI Converting actual to standard drinks SO ADDICTION LA English DT Letter C1 NIAAA, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Div Biometry & Epidemiol, NIH, 6000 Execut Blvd,Suite 514 MSC 7003, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD SEP PY 2001 VL 96 IS 9 BP 1361 EP 1361 DI 10.1046/j.1360-0443.2001.969136116.x PG 1 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 473BL UT WOS:000171019400016 PM 11672501 ER PT J AU Robinson, MR Salit, RB Bryant-Greenwood, PK Zeichner, SL Wood, LV Jaffe, ES Van Waes, C Magrath, IT AF Robinson, MR Salit, RB Bryant-Greenwood, PK Zeichner, SL Wood, LV Jaffe, ES Van Waes, C Magrath, IT TI Burkitt's/Burkitt's-like lymphoma presenting as bacterial sinusitis in two HIV-infected children SO AIDS PATIENT CARE AND STDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BURKITT-LYMPHOMA; MALIGNANCIES; THERAPY AB Two children (ages 12 and 13 years) with transfusion-acquired human immunodeficiency virus (HIV) infection presented with facial pain and rhinorrhea. Radiographic imaging showed extensive paranasal sinus disease, presumed to be bacterial sinusitis, and the patients were treated with broad-spectrum oral antibiotics. Both patients were unresponsive to oral agents and were switched to intravenous antibiotics. Despite aggressive antimicrobial therapy, one patient (case 1) developed increased periorbital swelling and proptosis, and the other patient (case 2) developed symptoms of nasopharyngeal obstruction. Repeat imaging showed progression of the infiltrative process extending from the paranasal sinuses into the orbit (case 1), and nasopharynx (case 2). Surgical exploration and tissue biopsies were performed on both patients and the histopathology was consistent with Burkitt's/Burkitt's-like lymphoma. Combination systemic and intrathecal chemotherapy resulted in a complete remission in both patients. These reports illustrate the fact that Burkitt's/Burkitt's-like lymphoma in the paranasal sinuses may initially masquerade as an acute bacterial sinusitis. The ability of the tumor to extend rapidly from the sinuses into the orbit and nasopharynx reinforces the importance of early diagnosis and treatment. Burkitt's/Burkitt's-like lymphoma in the paranasal sinuses has not been previously described in HIV-infected children. C1 NEI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD USA. NCI, Lymphoma Biol Sect, Pediat Branch, NIH, Bethesda, MD 20892 USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10N112,10 Ctr Dr MSC 1863, Bethesda, MD 20892 USA. NR 28 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD SEP PY 2001 VL 15 IS 9 BP 453 EP 458 DI 10.1089/108729101753145439 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 480DL UT WOS:000171446700002 PM 11587630 ER PT J AU Sices, HJ Leusink, MD Pacheco, A Kristie, TM AF Sices, HJ Leusink, MD Pacheco, A Kristie, TM TI Rapid genetic selection of inhibitor-resistant protease mutants: Clinically relevant and novel mutants of the HIV protease SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CROSS-RESISTANCE; PROTEOLYSIS; VARIANTS; PATTERNS; CASPASES; DESIGN; NOTCH AB Site-specific proteolysis is an important regulatory mechanism in many basic cellular processes as well as playing critical roles in the life cycle of viruses and other pathogenic organisms. For the human immunodeficiency virus (HIV) the encoded protease is required for the replication of the virus and has been the target of novel antiviral therapeutics. However, the emergence of inhibitor-resistant viral strains has become an increasingly significant clinical problem. Using a bacteriophage-based genetic selection, a bank of inhibitor-resistant mutants in this protease has been isolated that includes mutations that correlate with resistant clinical isolates. The rapid selection of such mutations has implications for the prediction of relevant mutations and may be applicable to other viral systems. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIH, Viral Dis Lab, Bldg 4,Room 133,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2001 VL 17 IS 13 BP 1249 EP 1255 DI 10.1089/088922201750461302 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 471HN UT WOS:000170923900004 PM 11559424 ER PT J AU Murphy, EL Wu, Y Ownby, HE Smith, JW Ruedy, RK Thomson, RA Ameti, DI Wright, DJ Nemo, GJ AF Murphy, EL Wu, Y Ownby, HE Smith, JW Ruedy, RK Thomson, RA Ameti, DI Wright, DJ Nemo, GJ CA NHLBI REDS Investigators TI Delayed hypersensitivity skin testing to mumps and Candida albicans antigens is normal in middle-aged HTLV-I- and -II-Infected U.S. cohorts SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID T-CELL LEUKEMIA; BLOOD-DONORS; VIRUS; CARRIERS; SUPPRESSION; DISEASES; PPD AB It has been reported that human T cell lymphotropic virus (HTLV)-I-infected persons in Japan have decreased delayed hypersensitivity skin test reactivity to tuberculin purified protein derivative (PPD), but HTLV-I- or -II-infected persons do not generally develop opportunistic infections. We administered standardized intradermal testing with PPD, mumps, and Candida albicans antigens to 31 HTLV-I, 48 HTLV-II, and 143 seronegative subjects in the United States. Reactivity at 48 hr was compared among the three groups. Response rates to PPD were very low in all subjects. Fifty-five percent of seronegative subjects did not react to mumps antigen, compared with 55% of HTLV-I [adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.27-2.33] and 38% of HTLV-II (OR = 0.73, 95% CI 0.33-1.64). Fifty-one percent of seronegatives did not react to Candida albicans antigen, compared with 34% of HTLV-I (OR = 0.37, 95% CI 0.15-0.93) and 46% of HTLV-II (OR = 0.71, 95% CI 0.34-1.52). Anergy was present in 33% of seronegatives, 28% of HTLV-I (OR = 0.60, 95% CI 0.20-1.78), and 19% of HTLV-II (OR = 0.56, 95% CI 0.22-1.44). HTLV-I- and -II-infected persons appear to have intact delayed hypersensitivity skin test responses to mumps and Candida albicans antigens. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. WESTAT Corp, Rockville, MD 20850 USA. Amer Red Cross, Blood Serv SE Michigan, Detroit, MI USA. Oklahoma Blood Inst, Oklahoma City, OK USA. NHLBI, Bethesda, MD 20892 USA. RP Murphy, EL (reprint author), Univ Calif San Francisco, Box 0884, San Francisco, CA 94143 USA. FU NHLBI NIH HHS [N01-HB-97077, N01-HB-47114, N01-HB-97080, N01-HB-97082, N01-HB-97081, N01-HB-97078, N01-HB-97079] NR 21 TC 6 Z9 6 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2001 VL 17 IS 13 BP 1273 EP 1277 DI 10.1089/088922201750461339 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 471HN UT WOS:000170923900007 PM 11559427 ER PT J AU Enoch, MA White, KV Harris, CR Rohrbaugh, JW Goldman, D AF Enoch, MA White, KV Harris, CR Rohrbaugh, JW Goldman, D TI Alcohol use disorders and anxiety disorders: Relation to the P300 event-related potential SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism; anxiety; auditory; EEG; ERP ID BRAIN POTENTIALS; INDIVIDUAL-DIFFERENCES; PERSONALITY-TYPES; AUDITORY-STIMULI; ALPHA-EEG; RISK; DETERMINANTS; HERITABILITY; PROBABILITY; ATTENTION AB Background: The robust association of alcoholism with reduced P300 event-related potential amplitude has been largely established in severely affected alcoholics and their offspring. Few studies have examined the relationship of increased arousal, anxiety, and P300. In this study,we sought to determine whether P300 group differences could be discerned in well functioning individuals with less severe forms of alcohol use disorders and anxiety disorders. We were particularly interested in looking at the subgroup of alcohol use disorders accompanied by anxiety disorders. This subgroup has previously been found to have diminished a amplitude in the resting EEG. Methods: Male and female community volunteers (99 unrelated index participants and 78 relatives) and 21 unrelated volunteers from an anxiety disorder clinic were interviewed by using the Schedule for Affective Disorders and Schizophrenia, Lifetime version. Blind-rated lifetime psychiatric diagnoses were assigned according to DSM-III-R criteria. Auditory and visual P300 event-related potentials were elicited with an oddball paradigm and were recorded at the midparietal (Pz) site. Results: As expected, auditory P300 amplitudes were significantly reduced in participants with alcohol use disorders and significantly increased in participants with lifetime anxiety disorders. However, more detailed analysis revealed that, in an apparent paradox, auditory P300 amplitudes were lowest in individuals with comorbid alcohol use and anxiety disorders and highest in individuals with anxiety disorders alone. Visual P300 amplitudes followed the same trends but were generally not significant. Conclusions: Even in a sample of largely community-ascertained individuals, auditory P300 amplitude is reduced in alcoholics, particularly those with anxiety disorders, and is highest in nonalcoholics with anxiety disorders. C1 NIAAA, DICBR, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. RP Enoch, MA (reprint author), NIAAA, DICBR, Neurogenet Lab, NIH, 12420 Parklawn Dr,Pk 5Bldg Room 451,MSC 8110, Bethesda, MD 20892 USA. EM maenoch@dicbr.niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 50 TC 28 Z9 31 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2001 VL 25 IS 9 BP 1293 EP 1300 PG 8 WC Substance Abuse SC Substance Abuse GA 473LE UT WOS:000171044800008 PM 11584148 ER PT J AU Dawson, DA Das, A Faden, VB Bhaskar, B Krulewitch, CJ Wesley, B AF Dawson, DA Das, A Faden, VB Bhaskar, B Krulewitch, CJ Wesley, B TI Screening for high- and moderate-risk drinking during pregnancy: A comparison of several TWEAK-based screeners SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article ID ALCOHOL-CONSUMPTION; PRENATAL EXPOSURE; IDENTIFICATION; GROWTH; AGE; TERATOGENICITY; QUESTIONS; PATTERN; WOMEN AB Purpose: This study investigated the use of the TWEAK and nine alternative screeners for predicting high-risk and moderate-risk drinking during pregnancy. Method: The analysis was based on self-reports from 404 lifetime drinkers who presented for an initial visit at nine prenatal clinics in Washington, DC. Data were collected anonymously by having women directly enter their responses onto an audio, computer-assisted interview that was programmed onto a laptop computer. Pregnancy risk drinking status was based on both average daily volume of intake and frequency of drinking 3+ drinks in a day. Each of the alternative screeners was constructed by adding one additional risk indicator to the TWEAK, and three different scoring options were explored. Results: Using thresholds of 2 points for high-risk drinking and 1 point for moderate-risk drinking, the TWEAK demonstrated a sensitivity and specificity of 70.6% and 73.2% for high-risk drinking and a sensitivity and specificity of 65.6% and 63.7% for any (high- or moderate-) risk drinking during pregnancy. None of the alternative screeners resulted in significant improvement, but the addition of current smoking status showed enough promise to warrant further testing in larger samples. Conclusions: Despite some loss in sensitivity and specificity, the TWEAK, in its original or a modified form, can be extended to measures of high-risk drinking that incorporate infrequent heavy intake and can be used to test for moderate- as well as high-risk drinking. Because identification of moderate-risk drinkers substantially increases the pool of women targeted for intervention, cost implications must be considered in designing appropriate interventions. C1 NIAAA, DBE, NIH, Bethesda, MD 20892 USA. Res Triangle Inst, Rockville, MD USA. Univ Maryland, Baltimore, MD 21201 USA. Howard Univ, Sch Med, Washington, DC 20059 USA. RP Dawson, DA (reprint author), NIAAA, DBE, NIH, Willco Bldg Suite 514,6000 Execut Blvd MSC 7003, Bethesda, MD 20892 USA. NR 41 TC 22 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2001 VL 25 IS 9 BP 1342 EP 1349 DI 10.1111/j.1530-0277.2001.tb02357.x PG 8 WC Substance Abuse SC Substance Abuse GA 473LE UT WOS:000171044800015 PM 11584155 ER PT J AU Pfeffer, MA Domanski, M Verter, J Dunlap, M Flaker, GC Gersh, B Hsia, J Goldberg, AD Limacher, MC Maggioni, AP Rosenberg, Y Rouleau, JL Warnica, JW Wasserman, AG Braunwald, E AF Pfeffer, MA Domanski, M Verter, J Dunlap, M Flaker, GC Gersh, B Hsia, J Goldberg, AD Limacher, MC Maggioni, AP Rosenberg, Y Rouleau, JL Warnica, JW Wasserman, AG Braunwald, E CA PEACE Investigators TI The continuation of the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial SO AMERICAN HEART JOURNAL LA English DT Editorial Material ID VENTRICULAR ENLARGEMENT TRIAL; MYOCARDIAL-INFARCTION; DYSFUNCTION; CAPTOPRIL; SURVIVAL C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Partners Healthcare Syst, Boston, MA USA. NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. George Washington Univ, Div Cardiovasc, Rockville, MD USA. Cleveland Vet Adm Med Ctr, Cleveland, OH USA. Univ Missouri, Columbia, MO USA. Mayo Clin, Div Cardiovasc, Rochester, MN USA. Gainesville Vet adm Med Ctr, Gainesville, FL USA. Henry Ford Hosp, Detroit, MI 48202 USA. iANMCO Res Ctr, Florence, Italy. Toronto Gen Hosp, Toronto, ON, Canada. Foothills Prov Gen Hosp, Calgary, AB T2N 2T9, Canada. RP Pfeffer, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. NR 11 TC 12 Z9 12 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2001 VL 142 IS 3 BP 375 EP 377 DI 10.1067/mhj.2001.117603 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 468WD UT WOS:000170780400001 PM 11526345 ER PT J AU Steinberg, JS Martins, J Sadanandan, S Goldner, B Menchavez, E Domanski, M Russo, A Tullo, N Hallstrom, A AF Steinberg, JS Martins, J Sadanandan, S Goldner, B Menchavez, E Domanski, M Russo, A Tullo, N Hallstrom, A CA AVID Investigators TI Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study SO AMERICAN HEART JOURNAL LA English DT Article ID INFARCT AMIODARONE TRIAL; CARDIOVERTER-DEFIBRILLATOR; VENTRICULAR-TACHYCARDIA; MYOCARDIAL-INFARCTION; CLINICAL-EXPERIENCE; CARDIAC-ARREST; HIGH-RISK; THERAPY; SURVIVAL; SHOCKS AB Background Previous retrospective or observational series suggest that many patients with an implantable cardioverter-defibrillator (ICD) will be treated with antiarrhythmic drugs (AADs) to modify the frequency or manifestation of recurrent ventricular arrhythmias. The relative clinical benefit, however, is uncertain, and deleterious interactions can occur. The objective of this clinical investigation was to study the need for, and effects of, concomitant AAD use with the ICD in a prospectively defined cohort. Methods All patients randomly assigned to the ICD arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) study were followed for the addition of class I or III AADs ("crossover") after hospital discharge. Addition of AADs was strictly regulated by AVID protocol. The timing and reasons for crossover and the effects on ventricular arrhythmia recurrence were analyzed. Patients were excluded if they required AADs before hospital discharge after index arrhythmias or if they had no ventricular arrhythmia before initiation of AADs. Results After a median follow-up of 135 days, 81 (18%) of the 461 eligible patients required AADs and formed the crossover group. The primary reason for crossover was frequent ICD shocks in 64% of patients. The most common AAD selected was amiodarone (in 42%). Independent predictors of crossover were lower ejection fraction, absence of ventricular fibrillation, or presence of nonsyncopal ventricular tachycardia at presentation, prior unexplained syncope, female sex, and history of cigarette smoking. Before AAD use, the 1-year arrhythmia event rate was 90%; after AAD, the event rate was only 64% (P=.0001). The time to first event was extended from 3.9 +/- 0.7 months to 11.2 +/- 1.8 months. There were 1.4 +/- 3.7 fewer ICD therapy events (P =.005) after crossover, predominantly accounted for by reduction in shocks rather than anti-tachycardia pacing therapies. Conclusions The majority of patients who receive ICDs for sustained ventricular tachycardia or ventricular fibrillation can be treated without AADs. Most commonly, AADs are added to combat frequent ICD shocks, which are successfully reduced by AAD therapy. C1 St Lukes Roosevelt Hosp, Div Cardiol, New York, NY 10025 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. N Shore Univ Hosp, Manhasset, NY USA. NHLBI, Bethesda, MD 20892 USA. Univ Penn Hlth Syst, Presbyterian Med Ctr, Philadelphia, PA USA. St Joseph Hosp & Med Ctr, Paterson, NJ USA. Univ Washington, Seattle, WA 98195 USA. RP Steinberg, JS (reprint author), St Lukes Roosevelt Hosp, Div Cardiol, 1111 Amsterdam Ave, New York, NY 10025 USA. FU NHLBI NIH HHS [N0-1-HC-25117] NR 28 TC 30 Z9 33 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2001 VL 142 IS 3 BP 520 EP 529 DI 10.1067/mhj.2001.117129 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 468WD UT WOS:000170780400021 PM 11526368 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, CE Everhart, JE TI Leptin concentrations in the United States: relations with demographic and anthropometric measures SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE leptin; anthropometry; ethnicity; population; epidemiology; obesity; Third National Health and Nutrition Examination Survey; NHANES III; United States ID BODY-FAT DISTRIBUTION; SERUM LEPTIN; PLASMA LEPTIN; AFRICAN-AMERICAN; WEIGHT-GAIN; INSULIN-RESISTANCE; CIGARETTE-SMOKING; MEXICAN-AMERICANS; CAUCASIAN WOMEN; ADIPOSE-TISSUE AB Background: Leptin is a peptide that is strongly correlated with adiposity and is a potential determinant of obesity and its complications. Objective: Leptin concentrations from a representative sample of the US population were examined in relation to demographic and anthropometric measures. Design: Fasting serum leptin concentrations were measured in 6303 women and men aged greater than or equal to 20 y in the third National Health and Nutrition Examination Survey. Anthropometric measures included body mass index, 4 skinfold thicknesses, and 4 body circumferences. Ethnic groups included non-Hispanic whites and blacks and Mexican Americans. Results: The mean serum leptin concentration was much higher in women (12.7 mug/L) than in men (4.6 mug/L). In a multivariate analysis, leptin concentrations were associated with the sum of 4 skinfold thicknesses, waist and hip circumferences, ethnicity, and age. These measures explained most of the variance in leptin concentrations in women (R-2 = 0.69) and in men (R-2 = 0.67). Triceps skinfold thickness, when substituted for the sum of skinfold thicknesses, performed nearly as well in women (R-2 = 0.68) and men (R-2 = 0.67). Leptin concentrations were slightly but significantly higher in non-Hispanic blacks than in non-Hispanic whites of both sexes when these anthropometric measures and age were controlled for; Mexican Americans had concentrations that were intermediate compared with the concentrations of non-Hispanic whites and blacks. Conclusions: In this large, representative sample of the US population, demographic and anthropometric measures predicted serum leptin concentrations in women and men. C1 Social & Sci Syst Inc, Bethesda, MD 20814 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 7101 Wisconsin Ave,Suite 1300, Bethesda, MD 20814 USA. FU NIDDK NIH HHS [N01-DK-6-2220] NR 32 TC 136 Z9 140 U1 0 U2 5 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2001 VL 74 IS 3 BP 295 EP 301 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 467GB UT WOS:000170693100006 PM 11522551 ER PT J AU Lanza, E Schatzkin, A Daston, C Corle, D Freedman, L Ballard-Barbash, R Caan, B Lance, P Marshall, J Iber, F Shike, M Weissfeld, J Slattery, M Paskett, E Mateski, D Albert, P AF Lanza, E Schatzkin, A Daston, C Corle, D Freedman, L Ballard-Barbash, R Caan, B Lance, P Marshall, J Iber, F Shike, M Weissfeld, J Slattery, M Paskett, E Mateski, D Albert, P CA PPT Study Grp TI Implementation of a 4-y, high-fiber, high-fruit-and-vegetable, low-fat dietary intervention: results of dietary changes in the Polyp Prevention Trial SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary intervention; nutrition intervention; dietary change; dietary fiber intake; dietary fat intake; fruit and vegetable intake; clinical trial; plasma cholesterol; serum carotenoids; body weight; Polyp Prevention Trial ID COLORECTAL ADENOMATOUS POLYPS; WOMENS HEALTH TRIAL; COLON-CANCER; RANDOMIZED TRIAL; BREAST-CANCER; ANTIOXIDANT VITAMINS; RISK POPULATION; BETA-CAROTENE; WEIGHT-LOSS; LIFE-STYLE AB Background: The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber (4.30 g/MJ), high-ftuit-and-vegetable (0.84 servings/MJ), low-fat (20% of energy from fat) diet on the recurrence of adenomatous polyps in the large bowel. Objective: Our goal was to determine whether the PPT intervention plan could effect change in 3 dietary goals and to examine the intervention's effect on the intake of other food groups and nutrients. Design: Participants with large-bowel adenomatous polyps diagnosed in the past 6 mo were randomly assigned to either the intervention (n=1037) or the control (n=1042) group and remained in the trial for 4 y. Three dietary assessment instruments were used to measure dietary change: food-frequency questionnaires (in 100% of the sample), 4-d food records (in a 20% random cohort), and 24-h dietary recalls (in a 10% random sample). Results: Intervention participants made and sustained significant changes in all PPT goals as measured by the dietary assessment instruments; the control participants' intakes remained essentially the same throughout the trial. The absolute differences between the intervention and control groups over the 4-y period were 9.7% of energy from fat (95% CI: 9.0%, 10.3%), 1.65 g dietary fiber/MJ (95% CI: 1.53, 1.74), and 0.27 servings of fruit and vegetables/MJ (95% CI: 0.25, 0.29). Intervention participants also reported significant changes in the intake of other nutrients and food groups. The intervention group also had significantly higher serum carotenoid concentrations and lower body weights than did the control group. Conclusion: Motivated, free-living individuals, given appropriate support, can make and sustain major dietary changes over a 4-y period. C1 NCI, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. Kaiser Fdn Res Inst, Oakland, CA USA. SUNY Buffalo, Buffalo, NY USA. Univ Arizona, Tucson, AZ USA. Edward Hines Jr Hosp, Vet Adm Med Ctr, Hines, IL USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Utah, Salt Lake City, UT USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Lanza, E (reprint author), 11601 Havenner Court,Fairfax Stn, Fairfax, VA 22039 USA. NR 59 TC 114 Z9 116 U1 1 U2 6 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2001 VL 74 IS 3 BP 387 EP 401 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 467GB UT WOS:000170693100020 PM 11522565 ER PT J AU Sherman, ME Solomon, D Schiffman, M AF Sherman, ME Solomon, D Schiffman, M CA ALTS Grp TI Qualification of ASCUS - A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Traige Study SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 23-31, 2000 CL NEW ORLEANS, LOUISIANA SP US & Canadian Acad Pathol DE Bethesda System; ASCUS; atypical squamous cells of undetermined significance; papillomavirus; screening; ALTS; ASCUS LSIL Triage Study; cervix; atypical; metaplasia ID ATYPICAL SQUAMOUS CELLS; UNDETERMINED SIGNIFICANCE; INTRAEPITHELIAL LESIONS; PAPANICOLAOU SMEARS; PROGRESSION; QUALIFIERS; DIAGNOSIS; BIOPSY; RISK AB Cytologic detection of high-grade squamous intraepithelial lesions (HSILs) is critical to cervical cancer prevention. Therefore, identifying "equivocal HSIL" (ASCUS [atypical squamous cells of undetermined significance]-H) may be useful. Accordingly, we compared findings associated with "equivocal low-grade SIL" (ASCUS-L), ASCUS-H and HSIL using data from the ASCUS LSIL (low-grade squamous intraepithelial lesion) Triage Study. The frequency of oncogenic human papillomavirus (HPV) DNA detection and underlying lesions cervical intraepithelial neoplasia (CIN) 2 or worse or CIN 3 or worse in women with ASCUS-H was intermediate between that of ASCUS-L and HSIL. Oncogenic HPV DNA was associated with 85.6% of ASCUS-H ThinPreps and 69.8% of ASCUS-H smears. Histopathologic lesions CIN 2 or worse were associated with 40.5% of ASCUS-H ThinPreps and 27.2% of ASCUS-H smears (mostly CIN 3). Nevertheless, numerically more lesions CIN 2 or worse were preceeded by ASCUS-L than by ASCUS-H because ASCUS-L was more common. ASCUS-H is an uncommon interpretation that derives clinical usefulness from its high positive predictive value for lesions CIN 2 or worse. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. RP Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7080, Rockville, MD 20852 USA. FU NCI NIH HHS [CN-55157, CN-55155, CN-55105, CN-55158, CN-55154, CN-55159, CN-55156, CN-55153] NR 23 TC 106 Z9 113 U1 2 U2 2 PU AMER SOC CLIN PATHOLOGISTS PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2001 VL 116 IS 3 BP 386 EP 394 PG 9 WC Pathology SC Pathology GA 467XF UT WOS:000170728500012 PM 11554167 ER PT J AU Schneider, LS Tariot, PN Lyketsos, CG Dagerman, KS Davis, KL Davis, S Hsiao, JK Jeste, DV Katz, IR Olin, JT Pollock, BG Rabins, PV Rosenheck, RA Small, GW Lebowitz, B Lieberman, JA AF Schneider, LS Tariot, PN Lyketsos, CG Dagerman, KS Davis, KL Davis, S Hsiao, JK Jeste, DV Katz, IR Olin, JT Pollock, BG Rabins, PV Rosenheck, RA Small, GW Lebowitz, B Lieberman, JA TI National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) - Alzheimer disease trial methodology SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article ID TARDIVE-DYSKINESIA; BEHAVIORAL SYMPTOMS; OLDER PATIENTS; DOUBLE-BLIND; DEMENTIA; PLACEBO; PSYCHOSIS; RISPERIDONE; HALOPERIDOL; RELIABILITY AB The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented. C1 Univ N Carolina, NIMH, Clin Antipsychot Trials Intervent Effectiveness P, Chapel Hill, NC 27599 USA. RP Schneider, LS (reprint author), Univ So Calif, Keck Sch Med, 1975 Zonal Ave,KAM-400, Los Angeles, CA 90033 USA. FU NIMH NIH HHS [N01 MH 90001] NR 43 TC 111 Z9 114 U1 6 U2 12 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD FAL PY 2001 VL 9 IS 4 BP 346 EP 360 DI 10.1176/appi.ajgp.9.4.346 PG 15 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 484PF UT WOS:000171698200004 PM 11739062 ER PT J AU Olin, JT Fox, LS Pawluczyk, S Taggart, NA Schneider, LS AF Olin, JT Fox, LS Pawluczyk, S Taggart, NA Schneider, LS TI A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article ID DEMENTIA; AGITATION; SCALE AB The authors performed a C-week, randomized, double-blind, placebo-controlled, parallel-group trial of carbamazepine (400 mg/day) with 21 agitated subjects (16 completers) who had been treated unsuccessfully with antipsychotics, There was greater improvement for the carbamazepine group on the Clinical Global Impression of Change (P=0.055) and the Brief Psychiatric Rating Scale (BPRS) Hostility item (P=0.009), with a trend toward worsening on the BPRS Hallucination item (P=0.067). Overall, carbamazepine showed modest clinical benefit in these subjects, who had not responded to antipsychotics, and particular benefit for hostility The effect on global ratings was similar to those found in an earlier report in nursing home residents. C1 NIMH, Psychopharmacol Program, Adult & Geriatr Treatment & Prevent Intervent Bra, Bethesda, MD 20892 USA. RP Olin, JT (reprint author), NIMH, Psychopharmacol Program, Adult & Geriatr Treatment & Prevent Intervent Bra, 6001 Execut Blvd,Rm 7160 MSC 9635, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG 05142]; NIMH NIH HHS [MH 48759, MH 01368] NR 18 TC 58 Z9 58 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD FAL PY 2001 VL 9 IS 4 BP 400 EP 405 DI 10.1176/appi.ajgp.9.4.400 PG 6 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 484PF UT WOS:000171698200008 PM 11739066 ER PT J AU Hayslett, JA Eichner, JE Yeh, JLL Wang, WY Henderson, J Devereux, RB Welty, TK Fabsitz, RR Howard, BV Lee, ET AF Hayslett, JA Eichner, JE Yeh, JLL Wang, WY Henderson, J Devereux, RB Welty, TK Fabsitz, RR Howard, BV Lee, ET TI Hypertension treatment patterns in American indians: The strong heart study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; epidemiology; Indians; North American; drug therapy; combination; diabetes mellitus ID AMBULATORY CARE DATA; AGED 45-74 YEARS; CARDIOVASCULAR-DISEASE; CLINICAL HYPERTENSION; NATIVE-AMERICANS; ALASKA NATIVES; POPULATIONS; PROTEINURIA; PREVALENCE; RATES AB Pharmacologic treatment patterns for hypertensive American Indians from 13 communities in Arizona, Oklahoma, South Dakota, and North Dakota were assessed. Participants (2254 women and 1384 men, aged 48 to 79 years) completed a clinical examination between July 1993 and December 1995. The mean of two blood pressure (BP) measurements and detailed medication histories were obtained. The observed prevalence of hypertension was 46.7% (n = 1698). In participants taking antihypertensive medications (n = 1114), four principal drug classes were evaluated: diuretics, calcium channel blocking agents, beta -blocking agents, and angiotensin-converting enzyme (ACE) inhibitors. Among treated hypertensive participants, 71.4%, 24.6%, and 4.0% received one, two, and three medications, respectively. Among single drug regimens, ACE inhibitors (n = 340) were used most often (49.4%), with calcium channel blocking agents and diuretics accounting for 24.2% and 19.9%, respectively. Although multiple drug class therapies varied, the combination of a diuretic and ACE inhibitor (n = 120) accounted for 47.4% of dual therapy use. Hypertension control (SBP < 140 mm Hg, DBP < 90 mm Hg) rates were highest for those on dual therapies (65.4%), followed by participants on single (53.8%) and triple (43.6%) therapies. Among monotherapies, diuretics exhibited the best overall hypertension control rate in both diabetics (63.0%) and nondiabetics (68.0%), versus 47% to 61% for other remaining agents. The frequent use of ACE inhibitors, used singly or in combination, reflects the high prevalence of diabetes among American Indians. ACE inhibitors, combined with diuretics, were particularly useful in achieving BP control in this population. Am J Hypertens 2001:14:950-956 (C) 2001 American Journal of Hypertension, Ltd. C1 Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, Oklahoma City, OK 73190 USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. RP Eichner, JE (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, POB 26901, Oklahoma City, OK 73190 USA. FU NHLBI NIH HHS [U01HL-41652, U01HL-41654, U01 HL041652, U01-HL-41642] NR 17 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD SEP PY 2001 VL 14 IS 9 BP 950 EP 956 DI 10.1016/S0895-7061(01)02146-X PN 1 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 473KY UT WOS:000171044100016 PM 11587163 ER PT J AU Biesecker, BB Peters, KF AF Biesecker, BB Peters, KF TI Process studies in genetic counseling: Peering into the black box SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetic counseling; process studies process analysis; counseling research; genetic counseling definition; genetic counseling goals; psychoeducational process ID SATISFACTION; OUTCOMES; INFORMATION; IMPACT AB Genetic counseling is a dynamic psychoeducational process. Yet we know very little about its interior. Process research explores what transpires between providers and their clients and can serve to provide insight into unknown practice dimensions. The few process studies that have been conducted in genetic counseling provide a glimpse into the Black Box, but more of this type of research is needed to examine the contents. To achieve success with process studies a contemporary definition of genetic counseling is proposed. Thoughtfully designed process studies in genetic counseling will provide the data to refine the definition and identify the components of counseling, the communication process between provider and client, the therapeutic interventions used by counselors, and the needs, attitudes and expectations of clients. Overall, process studies will contribute to a more accurate understanding of the practice of genetic counseling. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, NHGRI, Counseling Training Program, Baltimore, MD 21218 USA. RP Biesecker, BB (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,Room 3C710, Bethesda, MD 20892 USA. NR 57 TC 71 Z9 72 U1 0 U2 12 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD FAL PY 2001 VL 106 IS 3 BP 191 EP 198 DI 10.1002/ajmg.10004 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 482UY UT WOS:000171596700004 PM 11778979 ER PT J AU Guttmacher, AE Jenkins, J Uhlmann, WR AF Guttmacher, AE Jenkins, J Uhlmann, WR TI Genomic medicine: Who will practice it? A call to open arms SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetics; genomics; health care delivery; genetic counseling; genetic testing ID CLINICAL GENETICS SERVICES; TIME ANALYSIS; INFORMATION; ECONOMICS AB The Human Genome Project and other recent developments will broaden and increase the importance of genetics in health care. "Clinical genetics" will become "genomic medicine" and will no longer be almost the sole purview of genetic specialists-medical geneticists, genetic counselors, and genetic advanced practice nurses. The changing use of genetics in health care will require the acquisition of new knowledge, skills, and attitudes by many health care professionals who are not genetic specialists. Such health care professionals will not only be necessary to the widespread integration of genetics into clinical care, but they will make unique contributions to this integration that will add to the quality of genomic medicine. This new use of genetics in health care will also allow, even require, new ways of working for genetic specialists, who will continue to occupy unique and vital roles. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Med Genet Clin, Ann Arbor, MI USA. RP Guttmacher, AE (reprint author), NHGRI, NIH, Bldg 31,Room 4B09, Bethesda, MD 20892 USA. NR 13 TC 63 Z9 67 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 JI Am. J. Med. Genet. PD FAL PY 2001 VL 106 IS 3 BP 216 EP 222 DI 10.1002/ajmg.10008 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 482UY UT WOS:000171596700007 PM 11778982 ER PT J AU Mitchell, BD Hsueh, WC King, TM Pollin, TI Sorkin, J Agarwala, R Schaffer, AA Shuldiner, AR AF Mitchell, BD Hsueh, WC King, TM Pollin, TI Sorkin, J Agarwala, R Schaffer, AA Shuldiner, AR TI Heritability of life span in the old order Amish SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Amish; longevity; heritability ID HUMAN LONGEVITY; CAENORHABDITIS-ELEGANS; PEDIGREE ANALYSIS; CENTENARIANS; POPULATION; TWINS; EXTENSIONS; FAMILIES; MODELS; GENE AB Although a familial contribution to human longevity is recognized, the nature of this contribution is largely unknown. We have examined the familial contribution to life span in the Old Order Amish (OOA) population of Lancaster County, Pennsylvania. Analyses were conducted on 1,655 individuals, representing all those born prior to 1890 and appearing in the mos. widely available genealogy, surviving until at least age 30 years, and with known date of death. Mean age at death (+/-SD) in this population was 70.7 +/- 15.6 years, and this did not change appreciably over time. Parental and offspring ages at death were significantly correlated, as were ages of death among siblings. Offspring longevity was correlated with longevity of both parents, and in more or less additive fashion. For example, mean offspring age at death was 69.4 +/- 15.3 years in individuals for whom both parents died before the age of 75 years (n = 280) and increased to 73.5 +/- 16.0 years in individuals for whom neither parent died before the age of 75 years (n = 311). These differences were highly significant (P = 0.006). We estimated heritability of life span to be 25% +/- 5%, suggesting that the additive effects of genes account for one quarter of the total variability in life span in the OOA. We conclude that longevity is moderately heritable in the OOA, that the genetic effects are additive, and that genetic influences on longevity are likely to be expressed across a broad range of ages. Published 2001 Wiley-Liss, Inc. C1 Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. SW Fdn Biomed Res, San Antonio, TX 78284 USA. Univ Texas, Sch Med, Dept Internal Med, Houston, TX USA. Vet Adm Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Mitchell, BD (reprint author), Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, 660 W Redwood St,Room 492, Baltimore, MD 21201 USA. RI Schaffer, Alejandro/F-2902-2012; OI Mitchell, Braxton/0000-0003-4920-4744 FU NCI NIH HHS [K07-CA67960]; NCRR NIH HHS [1P41 RR03655]; NIA NIH HHS [R01-AG18728]; NIAMS NIH HHS [R01-AR46838]; NIDDK NIH HHS [K24-DK02673, R01-DK54261] NR 32 TC 91 Z9 93 U1 0 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 1 PY 2001 VL 102 IS 4 BP 346 EP 352 DI 10.1002/ajmg.1483 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 465XQ UT WOS:000170615600008 PM 11503162 ER PT J AU Chen, Z Meloni-Ehrig, A Palumbos, JC Guan, XY Carroll, KL Dent, KM Carey, JC AF Chen, Z Meloni-Ehrig, A Palumbos, JC Guan, XY Carroll, KL Dent, KM Carey, JC TI Pure trisomy 10p resulting from an extra ring chromosome: Characterization by methods of advanced molecular cytogenetics SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE multiple congenital anomalies; spectral karyotyping; chromosome microdissection; fluorescence in-situ hybridization ID MICRODISSECTION; DUPLICATION; PROBES; FISH AB With the use of advanced molecular cytogenetic techniques, we have identified an extra ring chromosome consisting of the entire short arm of chromosome 10 (10p) in a 9-month-old girl with multiple congenital anomalies. This case represents another cytogenetic mechanism leading to the formation of pure complete trisomy 10p, which has not been reported previously. Pure trisomy 10p is rare. This case will further delineate those features associated with trisomy 10p. (C) 2001 Wiley-Liss, Inc. C1 Univ Utah, Hlth Sci Ctr, Sch Med, Dept Pediat,Div Med Genet,Cytogenet Lab,SOM, Salt Lake City, UT 84132 USA. Univ Utah, Hlth Sci Ctr, Cytogenet FISH Core Lab, Salt Lake City, UT USA. Univ Utah, Hlth Sci Ctr, Dept Orthoped, Salt Lake City, UT USA. NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Univ Utah, Hlth Sci Ctr, Sch Med, Dept Pediat,Div Med Genet,Cytogenet Lab,SOM, Room 1C204, Salt Lake City, UT 84132 USA. NR 8 TC 14 Z9 14 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 JI Am. J. Med. Genet. PD SEP 1 PY 2001 VL 102 IS 4 BP 379 EP 382 DI 10.1002/ajmg.1470 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 465XQ UT WOS:000170615600013 PM 11503167 ER PT J AU Nowaczyk, MJM Nakamura, LM Eng, B Porter, FD Waye, JS AF Nowaczyk, MJM Nakamura, LM Eng, B Porter, FD Waye, JS TI Frequency and ethnic distribution of the common DHCR7 mutation in Smith-Lemli-Opitz syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Smith-Lemli-Opitz syndrome; DHCR7 mutations; carrier frequency; population genetics ID DELTA-7-STEROL REDUCTASE GENE; 7-DEHYDROCHOLESTEROL; PHENOTYPE AB Smith-Lemli-Opitz syndrome (SLOS) is an inherited multiple malformation syndrome caused by enzymatic deficiency of 3 beta -hydroxysterol-Delta (7)-reductase (DHCR7). SLOS is thought to be most common among European Caucasians, with an incidence of 1 in 20,000 to 1 in 30,000 births. To define the carrier rate and ethnic distribution of SLOS, we screened DNA samples from 2,978 unrelated individuals for the most common SLOS mutation (IVS8-1G-->C). Twenty-four heterozygotes of the IVS8-1G-->C mutation were detected in 2,978 individuals of European Caucasian and Black backgrounds. For European Caucasians, the carrier rate for SLOS may be as high as 1 in 30, suggesting an incidence of 1 in 1,700 to 1 in 13,400. This high number is supported by the recent observation of newborn and prenatal incidence of 1 in 22,000 in the Caucasian population. Ours is the first report of the IVS8-1G-->C mutation in persons of African ancestry. Published 2001 Wiley-Liss, Inc. C1 McMaster Univ, Med Ctr, Dept Pathol & Mol Med, Hamilton, ON L8S 4JP, Canada. McMaster Univ, Dept Paediat, Hamilton, ON, Canada. McMaster Univ, Dept Biol, Hamilton, ON, Canada. Hamilton Reg Lab Med Program, Hamilton, ON, Canada. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Nowaczyk, MJM (reprint author), McMaster Univ, Med Ctr, Dept Pathol & Mol Med, Room 3N16,1200 Main St W, Hamilton, ON L8S 4JP, Canada. NR 16 TC 34 Z9 34 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 1 PY 2001 VL 102 IS 4 BP 383 EP 386 DI 10.1002/ajmg.1441 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 465XQ UT WOS:000170615600014 PM 11503168 ER PT J AU Grady, C AF Grady, C TI Clinical research: The power of the nurse SO AMERICAN JOURNAL OF NURSING LA English DT Editorial Material C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD SEP PY 2001 VL 101 IS 9 BP 11 EP 11 PG 1 WC Nursing SC Nursing GA 528WG UT WOS:000174266900002 PM 11570376 ER PT J AU Regan, CL Levine, R Baird, DD Ewell, MG Martz, KL Sibai, BM Rokach, J Lawson, JA FitzGerald, GA AF Regan, CL Levine, R Baird, DD Ewell, MG Martz, KL Sibai, BM Rokach, J Lawson, JA FitzGerald, GA TI No evidence for lipid peroxidation in severe preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE preeclampsia; oxidant stress; lipid peroxidation; isoprostane; pregnancy ID PREGNANCY-INDUCED HYPERTENSION; IN-VIVO; OXIDATIVE STRESS; VITAMIN-E; PROSTACYCLIN; ISOPROSTANE; THROMBOXANE; TRIAL; BIOSYNTHESIS; GENERATION AB OBJECTIVE: This study was undertaken to address the role of oxidative stress in preeclampsia. STUDY DESIGN: We measured urinary 8,12-iso-iPF(2 alpha)-VI, a chemically stable, free-radical catalyzed product, in a case control study of severe preeclampsia nested within the trial of Calcium for Preeclampsia Prevention. Cases included 29 women who developed severe preeclampsia and from whom urine had been obtained 10 to 20 weeks before the diagnosis of preeclampsia, 3 to 9 weeks before, and 1 day before through delivery. Controls did not develop hypertension or proteinuria and were matched to cases by center, gestational age at each of 3 corresponding urine collections, and date of enrollment. RESULTS. Urinary 8,12-iso-iPF2 alpha -VI did not differ significantly between cases and controls before or at diagnosis of preeclampsia, nor did it vary with gestational age. CONCLUSIONS: These results call into question the importance of oxidative stress in the disease and the biochemical rationale for clinical trials of antioxidants to prevent and treat preeclampsia. C1 Univ Penn, Ctr Expt Therapeut, Philadelphia, PA 19104 USA. NICHHD, Epidemiol Branch, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. EMMES Corp, Potomac, MD USA. Univ Tennessee, Coll Med, Dept Obstet & Gynecol, Memphis, TN USA. Claude Pepper Inst, Melbourne, FL USA. Florida Inst Technol, Dept Chem, Melbourne, FL 32901 USA. RP FitzGerald, GA (reprint author), Univ Penn, Ctr Expt Therapeut, 811 BRB II-III,421 Curie Blvd, Philadelphia, PA 19104 USA. RI FitzGerald, Garret/A-4222-2010; OI Baird, Donna/0000-0002-5544-2653 FU NHLBI NIH HHS [HL 57847]; NICHD NIH HHS [N01-HD-1-3121, N01-HD-1-3122, N01-HD-1-3123, N01-HD-1-3124, N01-HD-1-3125, N01-HD-1-3126, N01-HD-2-3154, N01-HD-5-3246]; NIDDK NIH HHS [DK 44730]; PHS HHS [NIH 639302] NR 25 TC 63 Z9 64 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2001 VL 185 IS 3 BP 572 EP 578 DI 10.1067/mob.2001.116754 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 475LC UT WOS:000171164600009 PM 11568780 ER PT J AU Cohen, GR Curet, LB Levine, RJ Ewell, MG Morris, CD Catalano, PM Clokey, D Klebanoff, MA AF Cohen, GR Curet, LB Levine, RJ Ewell, MG Morris, CD Catalano, PM Clokey, D Klebanoff, MA TI Ethnicity, nutrition, and birth outcomes in nulliparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE nutrition; vitamin; mineral; ethnicity; race; birth outcomes; birth weight; gestational age at delivery; preterm; small for gestational age; intrauterine growth restriction ID UNITED-STATES; PRETERM DELIVERY; RISK-FACTORS; MATERNAL RISK; WEIGHT; INFANTS; MOTHERS; CALCIUM AB OBJECTIVE: Ethnic differences in birth outcomes are well established, but it is not clear whether differences in nutrition may partly explain unaccounted differences in birth outcomes. Our purpose was to evaluate the relationship of nutrition to ethnic differences in birth outcomes. STUDY DESIGN: This was a multicenter, prospective study of 4589 healthy nulliparous women who were enrolled in the Calcium for Preeclampsia Prevention trial conducted from 1992 to 1995. Main outcome measures were birth weight, gestational age at delivery, preterm birth, and small for gestational age birth after the data were controlled for maternal characteristics and intake of total calories, protein, carbohydrate, fat, and 13 vitamin and mineral constituents that were obtained from a 24-hour recall at 13 to 21 weeks' gestation. RESULTS: Black and non-Hispanic white women differed significantly in birth outcomes, with odds ratios of 2.06 (95% confidence interval, 1.48-2.86) for small for gestational age and 1.38 (95% confidence interval, 0.98-1.95) for preterm birth, after adjustment for maternal characteristics. These odds ratios were hardly changed by the further adjustment for all nutritional variables, even though there were substantial nutritional differences between black and white women. Differences in birth outcomes between Hispanic and non-Hispanic white women were small. Hispanic women who spoke only Spanish were better nourished than those Hispanic women who spoke English, but this had only a modest effect on birth outcomes. CONCLUSION: Nutritional variation among women in the United States does not appear to have a significant role in the explanation of ethnic differences in birth outcomes. C1 Emmes Corp, Polomar, MD USA. Univ New Mexico, Ctr Hlth Sci, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Div Med Informat & Outcomes Res, Portland, OR 97201 USA. Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. RP Levine, RJ (reprint author), 6100 Bldg,Room 7B03 MSC 7510, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-1-3121, N01-HD-1-3123, N01-HD-1-3122, N01-HD-1-3124, N01-HD-1-3125, N01-HD-1-3126, N01-HD-2-3154, N01-HD-5-3246] NR 26 TC 20 Z9 20 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2001 VL 185 IS 3 BP 660 EP 667 DI 10.1067/mob.2001.116755 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 475LC UT WOS:000171164600024 PM 11568795 ER PT J AU McKeeby, JL Li, XM Zhuang, ZP Vortmeyer, AO Huang, S Pirner, M Skarulis, MC James-Newton, L Marx, SJ Lubensky, IA AF McKeeby, JL Li, XM Zhuang, ZP Vortmeyer, AO Huang, S Pirner, M Skarulis, MC James-Newton, L Marx, SJ Lubensky, IA TI Multiple leiomyomas of the esophagus, lung, and uterus in multiple endocrine neoplasia type 1 SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; UTERINE LEIOMYOMAS; MEN1 GENE; SOMATIC MUTATIONS; PITUITARY-TUMORS; MARKERS AB Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary neuroendocrine tumors. Nonendocrine mesenchymal tumors, such as lipomas, collagenomas, and angiofibromas have also been reported. MEN1-associated neuroendocrine and some mesenchymal tumors have documented MEN1 gene alterations on chromosome 11q13. To test whether the MEN1 gene is involved in the pathogenesis of multiple smooth muscle tumors, we examined the 11q13 loss of heterozygosity (LOH) and clonality patterns in 15 leiomyomata of the esophagus, lung, and uterus from five patients with MEN1. Forty sporadic uterine leiomyomata were also studied for 11q13 LOH. LOH analysis was performed using four polymorphic DNA markers at the MEN1 gene locus; D11S480, PYGM, D11S449, and INT-2. 11q13 LOH was detected in 10 of 12 (83%) MEN1-associated esophageal and uterine smooth muscle rumors. in contrast, LOH at the MEN1 gene locus was demonstrated only in 2 of 40 (5%) sporadic uterine tumors. LOH at 11q13 was not documented in three lung smooth muscle tumors from a single patient with MEN1. Ten tumors from two female patients were additionally assessed for clonality by X-chromosome inactivation analysis. The results demonstrated different clonality patterns in multiple tumors in the same organ in each individual patient. The data indicate that leiomyomata of the esophagus and uterus in MEN1 patients arise as independent clones, develop through MEN1 gene alterations, and are an integral part of MEN1. However, the MEN1 gene Is not a significant contributor to the tumorigenesis of sporadic uterine leiomyomata. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Lubensky, IA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 33 Z9 37 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2001 VL 159 IS 3 BP 1121 EP 1127 DI 10.1016/S0002-9440(10)61788-9 PG 7 WC Pathology SC Pathology GA 470LA UT WOS:000170872400039 PM 11549605 ER PT J AU Panebra, A Ma, SX Zhai, LW Wang, XT Rhee, SG Khurana, S AF Panebra, A Ma, SX Zhai, LW Wang, XT Rhee, SG Khurana, S TI Regulation of phospholipase C-gamma(1) by the actin-regulatory protein villin SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE phosphatidylinositol 4,5-bisphosphate; tyrosine phosphorylation; cytoskeleton ID INTESTINAL BRUSH-BORDERS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; BINDING PROTEINS; PROXIMAL TUBULE; ALPHA-ACTININ; GROWTH-FACTOR; IN-VIVO; F-ACTIN; C-SRC; GELSOLIN AB The actin-regulatory protein villin is tyrosine phosphorylated and associates with phospholipase C-gamma (1) (PLC-gamma (1)) in the brush border of intestinal epithelial cells. To study the mechanism of villin-associated PLC-gamma (1) activation, we reconstituted in vitro the tyrosine phosphorylation of villin and its association with PLC-gamma (1). Recombinant villin was phosphorylated in vitro by the nonreceptor tyrosine kinase c-src or by expression in the TKX1 competent cells that carry an inducible tyrosine kinase gene. Using in vitro binding assays, we demonstrated that tyrosine-phosphorylated villin associates with the COOH-terminal Src homology 2 (SH2) domain of PLC-gamma (1). The catalytic activity of PLC-gamma (1) was inhibited by villin in a dose-dependent manner with half-maximal inhibition at a concentration of 12.4 muM. Villin inhibited PLC-gamma (1) activity by sequestering the substrate phosphatidylinositol 4,5-bisphosphate (PIP2), since increasing concentrations Of PIP2 reversed the inhibitory effects of villin on PLC activity. The inhibition of PLC-gamma (1) activity by villin was reversed by the tyrosine phosphorylation of villin. Further, we demonstrated that tyrosine phosphorylation of villin abolished villin's ability to associate with PIP2. In conclusion, tyrosine-phosphorylated villin associates with the COOH-terminal SH2 domain of PLC-gamma (1), and activates PLC-gamma (1) catalytic activity. Villin regulates PLC-gamma (1) activity by modifying its own ability to bind PIP2. This study provides biochemical proof of the functional relevance of tyrosine, phosphorylation of villin and identifies the molecular mechanisms involved in the activation of PLC-gamma (1) by villin. C1 Univ Tennessee, Ctr Hlth Sci, Dept Physiol, Memphis, TN 38163 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Khurana, S (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Physiol, 894 Union Ave,Nash 402, Memphis, TN 38163 USA. FU NIDDK NIH HHS [DK-54755] NR 40 TC 26 Z9 27 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP PY 2001 VL 281 IS 3 BP C1046 EP C1058 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 464XM UT WOS:000170558700034 PM 11502583 ER PT J AU Prabhakar, NR Fields, RD Baker, T Fletcher, EC AF Prabhakar, NR Fields, RD Baker, T Fletcher, EC TI Intermittent hypoxia: cell to system SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE protein kinases; gene expression; carotid body chemoreceptors; respiratory plasticity; blood pressure control ID CHRONIC EPISODIC HYPOXIA; BLOOD-PRESSURE ELEVATION; DEPENDENT REGULATION; RATS AB This symposium was organized to present research dealing with the effects of intermittent hypoxia on cardiorespiratory systems and cellular mechanisms. The pattern of neural impulse activity has been shown to be critical in the induction of genes in neuronal cells and involves distinct signaling pathways. Mechanisms associated with different patterns of intermittent hypoxia might share similar mechanisms. Chronic intermittent hypoxia selectively augments carotid body sensitivity to hypoxia and causes long-lasting activation of sensory discharge. Intermittent hypoxia also activates hypoxia-inducible factor-1. Reactive oxygen species are critical in altering carotid body function and hypoxia-inducible factor-1 activation caused by intermittent hypoxia. Blockade of serotonin function in the spinal cord prevents long-term facilitation in respiratory motor output elicited by episodic hypoxia and requires de novo protein synthesis. Chronic intermittent hypoxia leads to sustained elevation in arterial blood pressure and is associated with upregulation of catecholaminergic and renin-angiotensin systems and downregulation of nitric oxide synthases. C1 Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Vet Med, Dept Comparat Biosci, Madison, WI 53706 USA. Univ Louisville, Dept Med, Div Resp Crit Care & Environm Med, Louisville, KY 40292 USA. RP Prabhakar, NR (reprint author), Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA. NR 24 TC 79 Z9 90 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD SEP PY 2001 VL 281 IS 3 BP L524 EP L528 PG 5 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 464XH UT WOS:000170558300002 PM 11504675 ER PT J AU Dmitrieva, N Michea, L Burg, M AF Dmitrieva, N Michea, L Burg, M TI p53 Protects renal inner medullary cells from hypertonic stress by restricting DNA replication SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cell cycle arrest; apoptosis; sodium chloride ID NUCLEOTIDE EXCISION-REPAIR; LASER-SCANNING CYTOMETRY; IRRADIATED HUMAN FIBROBLASTS; CYCLE CHECKPOINT FUNCTION; C-TERMINAL DOMAIN; ATAXIA-TELANGIECTASIA; EPITHELIAL-CELLS; OXIDATIVE STRESS; APOPTOSIS; DAMAGE AB We previously found that p53 upregulation by hypertonicity protected renal inner medullary collecting duct (mIMCD3) cells from apoptosis. The purpose of the present study was to investigate the mechanism by which p53 protects the cells. We now find that hypertonicity (NaCl added to a total of 500 mosmol) inhibits DNA replication and delays G(1)-S transition as concluded from analysis of cell cycle distributions and bromodeoxyuridine (BrDU) incorporation rates. Lowering of p53 with p53 antisense oligonucleotide attenuated such effects of hypertonicity, resulting in an increased number of apoptotic cells in S phase and cells with >4 N DNA. Results with synchronized cells are similar, showing that cells in the early S phase are more sensitive to hypertonicity. Immunocytochemistry revealed that p53 becomes phosphorylated on Ser(15) and translocates to the nucleus in S both in isotonic and hypertonic conditions. Caffeine (2 mM) greatly reduces the p53 level and Ser(15) phosphorylation, followed by a remarkable increase of DNA replication rate, by failure of hypertonicity to inhibit it, and by reduction of cell number during hypertonicity. Finally, inhibition of DNA replication by the DNA polymerase inhibitor aphidicolin significantly improves cell survival, confirming that keeping cells in G(1) and decreasing the rate of DNA replication is protective and that these actions of p53 most likely are what normally help protect cells against hypertonicity. C1 NHLBI, Bethesda, MD 20892 USA. RP Dmitrieva, N (reprint author), NIH, Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 42 TC 39 Z9 41 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD SEP PY 2001 VL 281 IS 3 BP F522 EP F530 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 471BN UT WOS:000170907100018 PM 11502601 ER PT J AU Zarate, CA Tohen, M Fletcher, K AF Zarate, CA Tohen, M Fletcher, K TI Cycling into depression from a first episode of mania: A case-comparison study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article AB Objective: The characteristics of patients who cycle from mania to major depression and the frequencies of these cycles remain poorly understood. Method: This study compared 28 patients with a first episode of mania who cycled into a major depressive episode without recovery from their index episode and 148 patients with first-episode mania who did not cycle into depression. Patients were given extensive assessments at baseline and 6-, 12-, and 24-month follow-ups. Comparisons between the two groups were made on demographic variables, clinical ratings, and outcome variables. Results: Approximately 16% of the patients with a first episode of mania cycled into major depression. Patients who cycled into depression were more likely to have higher depressive scores at admission and tended to have the mixed subtype of bipolar disorder. Conclusions: Patients with first-episode mania who score high for depression at admission may be at greater risk of cycling into a major depressive episode. C1 NIMH, Mood & Anziety Disorders Program, Bethesda, MD 20892 USA. Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02178 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. Univ Massachusetts, Med Ctr, Behav Sci Res Core, Worcester, MA 01655 USA. RP Zarate, CA (reprint author), NIMH, Mood & Anziety Disorders Program, 9000 Rockville Pike,Bldg 10,Unit 3 W,Rm 3S250, Bethesda, MD 20892 USA. NR 10 TC 10 Z9 10 U1 1 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2001 VL 158 IS 9 BP 1524 EP 1526 DI 10.1176/appi.ajp.158.9.1524 PG 3 WC Psychiatry SC Psychiatry GA 468QP UT WOS:000170769900030 PM 11532746 ER PT J AU Parascandola, M AF Parascandola, M TI Cigarettes and the surgeon general's report - Response SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 NCI, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, Off Prevent Oncol, Div Canc Prevent, Execut Plaza S,Suite T-41, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2001 VL 91 IS 9 BP 1345 EP 1345 DI 10.2105/AJPH.91.9.1345-a PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 466MY UT WOS:000170650400002 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI Night shift in a glass factory SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Nonbook Collect, Hist Med Div, Bethesda, MD 20894 USA. RP Theerman, P (reprint author), Natl Lib Med, Nonbook Collect, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2001 VL 91 IS 9 BP 1370 EP 1370 DI 10.2105/AJPH.91.9.1370 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 466MY UT WOS:000170650400015 PM 11527759 ER PT J AU Davis, MS Freed, AN AF Davis, MS Freed, AN TI Repeated hyperventilation causes peripheral airways inflammation, hyperreactivity, and impaired bronchodilation in dogs SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE asthma; beta-agonist; bronchoconstriction; hyperreactivity; airway resistance ID CANINE LUNG PERIPHERY; CROSS-COUNTRY SKIERS; HIGH PREVALENCE; ASTHMA; RESPONSIVENESS; CONSTRICTION; EPITHELIUM; CYTOKINES; RESPONSES AB Winter athletes have an increased incidence of asthma, suggesting that repetitive hyperventilation with cold air may predispose individuals to airways disease. We used a canine model of exercise induced hyperpnea to examine the effects of repeated hyperventilation with cool, dry air (i.e., dry air challenge [DAC]) on peripheral airway resistance (Rp), reactivity, and inflammation. Specific bronchi were exposed to a single DAC on five consecutive days. Rp and Delta Rp to aerosolized histamine, intravenous histamine, or hypocapnia were measured daily. Bronchoalveolar lavage fluid (BALF) was obtained on the fifth day. Rp increased from 0.70 +/- 0.08 to 1.13 +/- 0.22 cm H2O/ml/s (n = 25) 24 h after the first DAC, rose to 1.49 +/- 0.24 cm H2O/ml/s by Day 3, and remained elevated throughout the remainder of the protocol, Repeated DAC increased reactivity to hypocapnia and intravenous histamine. Intravenous salbutamol failed to reduce Rp as effectively in challenged airways (111% of Day 1 baseline) as in naive airways (54% of baseline). Repeated DAC caused increased BALF neutrophils, eosinophils, and sulfidopeptide leukotrienes. We conclude that repeated DAC causes peripheral airways inflammation, obstruction, hyperreactivity, and impaired beta -agonist-induced relaxation. This suggests that other mechanisms in addition to increased smooth muscle tone may contribute to the development of repetitive hyperventilation-induced bronchial obstruction and hyperreactivity. C1 Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Div Physiol, Baltimore, MD USA. RP Freed, AN (reprint author), NHLBI, Div Extramural Affairs, Rockledge Ctr 2, Review Branch, Suite 7190,6701 Rockledge Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL09594, HL63186, HL07543-13] NR 25 TC 50 Z9 54 U1 1 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2001 VL 164 IS 5 BP 785 EP 789 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 472QQ UT WOS:000170996800014 PM 11549533 ER PT J AU Samet, JM Hatch, GE Horstman, D Steck-Scott, S Arab, L Bromberg, PA Levine, M McDonnell, WF Devlin, RB AF Samet, JM Hatch, GE Horstman, D Steck-Scott, S Arab, L Bromberg, PA Levine, M McDonnell, WF Devlin, RB TI Effect of antioxidant supplementation on ozone-induced lung injury in human subjects SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE antioxidants; ozone; human; inflammation ID DEFICIENT GUINEA-PIGS; NUTRITION-EXAMINATION-SURVEY; VITAMIN-C; PULMONARY-FUNCTION; NATIONAL-HEALTH; INFLAMMATION; EXPOSURE; CAROTENOIDS; MECHANISMS; ASCORBATE AB To determine whether antioxidants can influence human susceptibility to ozone (O-3)-induced changes in lung function and airway inflammation, we placed 31 healthy nonsmoking adults (18 to 35 yr old) on a diet low in ascorbate for 3 wk. At 1 wk, subjects were exposed to filtered air for 2 h while exercising (20 L/min/m(2)), and then underwent bronchoalveolar lavage (BAL) and were randomly assigned to receive either a placebo or 250 mg of vitamin C, 50 IU of alpha -tocopherol, and 12 oz of vegetable cocktail daily for 2 wk. Subjects were then exposed to 0.4 PPM O-3 for 2 h and underwent a second BAL. On the day of the O-3 exposure, supplemented subjects were found to have significantly increased levels of plasma ascorbate, tocopherols, and carotenoids as compared with those of the placebo group. Pulmonary function testing showed that O-3-induced reductions in FEV1 and FVC were 30% and 24% smaller, respectively, in the supplemented cohort. In contrast, the inflammatory response to O-3 inhalation, as represented by the percent neutrophils and the concentration of interleukin-6 recovered in the BAL fluid at 1 h after O-3 exposure was not different for the two groups. These data suggest that dietary antioxidants protect against O-3-induced pulmonary function decrements in humans. C1 Natl Hlth & Environm Effects Res Lab, Human Studies Div, Res Triangle Pk, NC USA. Natl Hlth & Environm Effects Res Lab, Expt Toxicol Div, Res Triangle Pk, NC USA. Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. Univ N Carolina, Ctr Environm Med & Lung Biol, Chapel Hill, NC USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Samet, JM (reprint author), EPA Human Studies Facil, CB 7315,104 Mason Farm Rd, Chapel Hill, NC 27599 USA. RI Steck, Susan/G-5736-2013 NR 53 TC 96 Z9 97 U1 0 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2001 VL 164 IS 5 BP 819 EP 825 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 472QQ UT WOS:000170996800020 PM 11549539 ER PT J AU Beaty, MW Toro, J Sorbara, L Stern, JB Pittaluga, S Raffeld, M Wilson, WH Jaffe, ES AF Beaty, MW Toro, J Sorbara, L Stern, JB Pittaluga, S Raffeld, M Wilson, WH Jaffe, ES TI Cutaneous lymphomatoid granulomatosis - Correlation of clinical and biologic features SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE lymphomatoid granulomatosis; cutaneous; histopathology; dermatologic features; molecular analysis; Epstein-Barr virus ID EPSTEIN-BARR-VIRUS; INTERFERON-INDUCIBLE PROTEIN-10; NECROSIS IN-VIVO; T-CELL LYMPHOMA; LYMPHOPROLIFERATIVE DISORDERS; B-LYMPHOCYTES; LESIONS; TUMOR; PROLIFERATION; PATHOLOGY AB Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus-associated B-cell lymphoproliferative disorder (EBV-BLPD), varying widely from an indolent process to an aggressive large cell lymphoma. The skin is the extrapulmonary organ most commonly involved in LYG. We studied 32 skin lesions from 20 patients with known pulmonary LYG, using immunohistochemistry, in situ hybridization for EBV, and polymerase chain reaction for the presence of antigen receptor gene rearrangements (IgH and TCR) to better define both the clinicopathologic spectrum and pathogenesis of the cutaneous lesions. We describe two distinct patterns of cutaneous involvement. Multiple erythematous dermal papules and/or subcutaneous nodules, with or without ulceration, were present in 17 patients (85%). These lesions demonstrate a marked angiocentric lymphohistiocytic infiltrate, composed predominantly of CD4-positive T-cells, with a high propensity for involving the subcutaneous tissues, and exhibiting angiodestruction, necrosis, and cytologic atypia. EBV-positive B-cells were detected in the nodules from five patients', clonal immunoglobulin heavy chain gene (IgH) rearrangements were detected by polymerase chain reaction in two patients. Multiple indurated, erythematous to white plaques were present in three patients (15%). The plaque lesions were negative for EBV and clonal IgH gene rearrangements in all cases studied. The clinical course of overall disease was variable, ranging from spontaneous regression without treatment (1 of 13; 7%), resolution with chemo/immunomodulatory therapy (8 of 13, 62%), and progression (4 of 13; 31%). The clinical and histopathologic features of cutaneous LYG are extremely diverse. However, the majority (85%) of the cutaneous lesions mirrors to some extent LYG in the lung, although EBV+ cells are less frequently identified. This subset of cases shows the histopathologic triad of angiodestruction with associated necrosis, panniculitis, and in some cases atypical lymphoid cells. The commonality of the histologic features in this group suggests a common pathophysiologic basis, possibly mediated by cytokines and chemokines induced by EBV. A small percentage of the lesions (15%) presented as indurated and atrophic plaques, and EBV was not identified in the small number of cases studied. The relationship of the plaque-like lesions to LYG remains uncertain. Whereas some cases of LYG regress spontaneously, most require therapy. C1 NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10 Room 2N202,10 Ctr dr MSC-1500, Bethesda, MD 20892 USA. NR 43 TC 50 Z9 55 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2001 VL 25 IS 9 BP 1111 EP 1120 DI 10.1097/00000478-200109000-00001 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 466NX UT WOS:000170652600001 PM 11688570 ER PT J AU Ferraris, JD Garcia-Perez, A AF Ferraris, JD Garcia-Perez, A TI Osmotically responsive genes: The mammalian osmotic response element (ORE) SO AMERICAN ZOOLOGIST LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY JAN 04-08, 2000 CL ATLANTA, GEORGIA SP Soc Integrat & Comparat Biol ID ALDOSE REDUCTASE GENE; RENAL MEDULLARY CELLS; GENOMIC ORGANIZATION; EXTRACELLULAR NACL; WATER-STRESS; PROTEIN; IDENTIFICATION; TRANSCRIPTION; PROMOTER; PURIFICATION AB Evolutionarily, adaptation to hyperosmotic stress through accumulation of osmotically active organic solutes (organic osmolytes) is a highly conserved mechanism. Hyperosmotic accumulation of organic osmolytes is transcriptionally regulated: e.g., betaine in bacteria (e.g., Escherichia coli), glycerol in yeast (e.g., Saccharomyces cerevisiae), betaine in plants (e.g., Spinacea oleracea L.) and sorbitol, betaine, and inositol in cells of the mammalian renal medulla. Renal medullary cells, among mammalian cells, are uniquely exposed to hyperosmotic stress; in these cells, hyperosmotic stress results in accumulation of sorbitol as one of the predominant osmolytes. Sorbitol accumulates due to a rise in the synthesis rate of aldose reductase (AR), which catalyzes the conversion of glucose to sorbitol. Hyperosmotic stress increases transcription of the AR gene which leads to a rise in AR mRNA levels. In cloning and characterizing the rabbit AR gene, the first evidence of a eukaryotic osmotic response element (ORE) was found. Since then, several mammalian OREs (also called TonE) have been discovered. Sequence containing an ORE was identified for the canine Na+- and Cl -coupled betaine transporter gene as well as the Na+/myo-inositol cotransporter gene. Because it is possible to find homology between the OREs of the AR genes and those of the betaine and inositol genes, a consensus for the mammalian OBE; was derived by functional assessment. Most recent studies have resulted in the discovery of other cis-elements that potentiate the ORE response and a trans-activating factor that binds to the ORE. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Ferraris, JD (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. NR 33 TC 9 Z9 9 U1 0 U2 0 PU SOC INTEGRATIVE COMPARATIVE BIOLOGY PI MCLEAN PA 1313 DOLLEY MADISON BLVD, NO 402, MCLEAN, VA 22101 USA SN 0003-1569 J9 AM ZOOL JI Am. Zool. PD SEP PY 2001 VL 41 IS 4 BP 734 EP 742 DI 10.1668/0003-1569(2001)041[0734:ORGTMO]2.0.CO;2 PG 9 WC Zoology SC Zoology GA 513WG UT WOS:000173403000005 ER PT J AU Soltis, J Thomsen, R Takenaka, O AF Soltis, J Thomsen, R Takenaka, O TI The interaction of male and female reproductive strategies and paternity in wild Japanese macaques, Macaca fuscata SO ANIMAL BEHAVIOUR LA English DT Article ID SANTIAGO RHESUS MACAQUES; DOMINANCE RANK; MALE PRIMATES; MATE CHOICE; SEXUAL SELECTION; YAKUSHIMA ISLAND; MALE COMPETITION; GENETIC-MARKERS; MATING STRATEGY; VERVET MONKEYS AB Japanese macaques reside in large, mixed-sex social groups in which various reproductive strategies of both sexes operate simultaneously. This report represents the first study combining behavioural and genetic data to examine the interaction of male and female reproductive strategies in primates (N=15 adult males, N=15 adult females, Yakushima Island, Japan). During one mating season, socially dominant males monopolized most female matings. Furthermore, the six offspring sired by troop males were more likely sired by higher-ranking males than lower-ranking males. Nontroop males sired three additional offspring in the troop. Lower-ranking troop males avoided direct competition with higher-ranking males by engaging in sneak copulations with females outside of the presence of other males. Also, females expressed mate choice behaviour towards multiple males of various dominance ranks. Thus, the female strategy of attempting to mate with multiple males conflicted with the mate-guarding strategy of high-ranking males. Despite some female mate choice for mid- and low-ranking males and alternative male mating tactics by subordinate males, high-ranking males were able to monopolize most, but not all, within-troop mating and paternity. This result was due in part to the low number of females mating at the same time. The mean number of females displaying mating behaviour per day was 2.42 (range 1-5), and higher-ranking males more successfully monopolized females on days when fewer females were mating. The number of females mating simultaneously influences the outcome of reproductive conflicts between the sexes. (C) 2001 The Association for the study of Animal Behaviour. C1 LM Univ Munich, Dept Zool, D-80333 Munich, Germany. Kyoto Univ, Primate Res Inst, Dept Cellular & Mol Biol, Inuyama, Aichi 484, Japan. Kyoto Univ, Primate Res Inst, Dept Ecol & Social Behav, Kyoto, Japan. RP Soltis, J (reprint author), NIH, Comparat Ethol Lab, Anim Ctr, Box 529, Poolesville, MD 20837 USA. NR 78 TC 65 Z9 67 U1 5 U2 34 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0003-3472 J9 ANIM BEHAV JI Anim. Behav. PD SEP PY 2001 VL 62 BP 485 EP 494 DI 10.1006/anbe.2001.1774 PN 3 PG 10 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA 484ZW UT WOS:000171727900010 ER PT J AU Smith, MS AF Smith, MS TI Applying information technology to the problem of acute myocardial infarction access to care, diagnosis, and evaluation: Report of a symposium SO ANNALS OF EMERGENCY MEDICINE LA English DT Article C1 Washington Hosp Ctr, Dept Emergency Med, Washington, DC 20010 USA. George Washington Univ, Sch Med & Hlth Sci, Dept Emergency Med, Washington, DC 20052 USA. RP Smith, MS (reprint author), NHLBI, Off Prevent Educ & Control, 7550 Wisconsin Ave,Room 708, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2001 VL 38 IS 3 BP 286 EP 292 DI 10.1067/mem.2001.117946 PG 7 WC Emergency Medicine SC Emergency Medicine GA 468RK UT WOS:000170771800013 PM 11524649 ER PT J AU Wandinger, KP Sturzebecher, CS Bielekova, B Detore, G Rosenwald, A Staudt, LM McFarland, HF Martin, R AF Wandinger, KP Sturzebecher, CS Bielekova, B Detore, G Rosenwald, A Staudt, LM McFarland, HF Martin, R TI Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes SO ANNALS OF NEUROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; FACTOR-ALPHA; CHEMOKINE RECEPTORS; DISEASE-ACTIVITY; I INTERFERONS; BRAIN-LESIONS; MESSENGER-RNA AB Multiple sclerosis (MS) is considered an autoimmune disease that is mediated by proinflammatory T helper-1 lymphocytes. The putative mechanism of interferon-beta (IFN-beta), an approved treatment for MS, includes the inhibition of T-cell proliferation, blocking of blood-brain-barrier opening and T-cell transmigration into the brain via interference with cell adhesion, and the upregulation of anti-inflammatory cytokines. In the present study, a gene expression analysis of IFN-beta -treated peripheral blood mononuclear cells by cDNA microarray documents the broad effects of IFN-beta that are not purely anti-inflammatory. Specifically, we addressed the effect of IFN-beta on T helper-1 differentiation- or lineage markers such as the IL-12 receptor beta (2) chain and the chemokine receptor CCR5 that have been implicated in the pathogenesis of MS. Both markers were significantly upregulated in vitro and in vivo under IFN-beta therapy, supporting that this cytokine exerts complex effects on the immune system. The combination of cDNA microarray and quantitative PCR will expand our knowledge of the immunological effects of such pleiotropic agents as IFN-beta, may provide a key to why certain patients fail to respond, and eventually may influence our view of the disease pathogenesis. C1 NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, Bldg 10,Room 5B-16,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. NR 53 TC 145 Z9 148 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2001 VL 50 IS 3 BP 349 EP 357 DI 10.1002/ana.1096 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 469FD UT WOS:000170803200010 PM 11558791 ER PT J AU Alfaro, CL McClure, RK Vertrees, JE Benavides, R AF Alfaro, CL McClure, RK Vertrees, JE Benavides, R TI Unanticipated plasma concentrations in two clozapine-treated patients SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE clozapine; cytochrome P450; therapeutic drug monitoring ID REFRACTORY SCHIZOPHRENIC-PATIENTS; CLINICAL-RESPONSE; SERUM; NORCLOZAPINE; METABOLITES; MEDICATION; RESISTANT; TIME AB OBJECTIVE: To report two cases of lower than anticipated clozapine plasma concentrations despite near maximum recommended doses of clozapine 800-900 mg/d in two medication-compliant schizophrenic inpatients. CASE SUMMARIES: Clozapine therapy was initiated in two male schizophrenic inpatients for treatment of psychotic symptoms refractory to other typical and atypical antipsychotics. Despite receiving adequate doses of clozapine for at least two months, these patients remained symptomatic. Therapeutic drug monitoring was used to target a clozapine plasma concentration of greater than or equal to 250 ng/mL, the minimum value reported in the literature to be associated with increased clinical response. Clozapine plasma concentrations remained at 200 ng/mL in one patient despite dosage increases from 600 to 800 mg/d. In the second patient, administration of the maximum recommended dose resulted in concentrations between 200 and 250 ng/mL. Increasing the clozapine dosage to 1000 mg/d did not increase the clozapine plasma concentration. Evaluation of the ratio of clozapine plasma concentration clozapine to dose yielded lower than expected values compared with those reported in the literature. DISCUSSION: These two patients exhibited lower than anticipated clozapine plasma concentrations despite receiving high doses of clozapine. Several studies evaluating clozapine serum concentrations and clinical response have suggested threshold concentrations of greater than or equal to 350 ng/mL, greater than or equal to 370 ng/mL, or greater than or equal to 420 ng/mL. The only study that randomized patients to three concentration ranges found that patients who achieved a clozapine serum concentration in a medium range (mean 251 ng/mL) responded better than patients in a low range (mean 91 ng/mL) and similar to patients in a high range (mean 396 ng/mL). However, attaining plasma concentrations in this range for these patients proved difficult. Reasons for the low concentrations are unclear and may be related to increased metabolic activity at several cytochrome P450 isoenzymes involved in the metabolism of clozapine. CONCLUSIONS: These cases illustrate lower than anticipated clozapine plasma concentrations despite high-dose clozapine therapy. Strategies to increase clozapine plasma concentrations in such patients might include adding a drug to partially inhibit the metabolism of clozapine. If those strategies are unacceptable based on risk assessment, patient compliance, or other reasons, clinicians may consider addition of a low-dose typical or other atypical antipsychotic drug to augment clozapine response. C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. San Antonio State Hosp, Clin Res Unit, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Adv Psychopharmacol Evaluat Lab, San Antonio, TX USA. RP Alfaro, CL (reprint author), NIH, Ctr Clin, Dept Pharm, 10 Ctr Dr,Bldg 10,Room 1N257, Bethesda, MD 20892 USA. NR 21 TC 5 Z9 5 U1 2 U2 3 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD SEP PY 2001 VL 35 IS 9 BP 1028 EP 1031 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 473KV UT WOS:000171043800009 PM 11573850 ER PT J AU Fitch, JT AF Fitch, JT TI Are condoms effective in reducing the risk of sexually transmitted disease? SO ANNALS OF PHARMACOTHERAPY LA English DT Editorial Material ID TRANSMISSION C1 NIAID, NIH, Dept Hlth & Human Serv, Washington, DC USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, San Antonio, TX 78284 USA. RP Fitch, JT (reprint author), 7959 Broadway,Ste 604, San Antonio, TX 78209 USA. NR 8 TC 2 Z9 2 U1 0 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD SEP PY 2001 VL 35 IS 9 BP 1136 EP 1138 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 473KV UT WOS:000171043800027 PM 11573868 ER PT J AU Aloia, TA Harpole, DH Reed, CE Allegra, C Moore, MBH Herndon, JE D'Amico, TA AF Aloia, TA Harpole, DH Reed, CE Allegra, C Moore, MBH Herndon, JE D'Amico, TA TI Tumor marker expression is predictive of survival in patients with esophageal cancer SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 47th Annual Meeting of the Southern-Thoracic-Surgical-Association CY NOV 09-11, 2000 CL MARCO ISL, FLORIDA SP SO Thorac Surg Assoc ID EPIDERMAL GROWTH-FACTOR; PROGNOSTIC-SIGNIFICANCE; FACTOR-ALPHA; CARCINOMA; SURGERY; P53 AB Background. This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with node-negative esophageal cancer treated with complete resection alone. Methods. Resection specimens were collected from 61 patients with node-negative T1 (n = 31), T2 (n = 14), and T3 (n = 16) esophageal cancer. A panel of 10 tumor markers was chosen for immunohistochemical analysis, based on associations with differing oncologic mechanisms: apoptosis (p53), growth regulation (transforming growth factor-alpha, epidermal growth factor receptor, and Her2-neu), angiogenesis (factor VIII), metastatic potential (CD44), platinum resistance (p-glycoprotein and metallothionein), 5-fluorouracil resistance (thymidylate synthetase), and carcinogenic detoxification (glutathione S-transferase-pi). Results. Complete resection was performed in all patients (44 adenocarcinoma, 17 squamous cell carcinoma), with no operative deaths. Multivariable analysis demonstrated a significant relationship between cancer-specific death and the following variables: low-level P-gp expression (p = 0.004), high-level expression of p53 (p = 0.04), and low-level expression of transforming growth factor-alpha (P = 0.03). In addition, the number of involved tumor markers present was strongly predictive of negative outcome (p = 0.0001). Conclusions. This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of P-gp, p53, and transforming growth factor-alpha, in patients with esophageal carcinoma treated with complete resection alone. (C) 2001 by The Society of Thoracic Surgeons. C1 Duke Univ, Med Ctr, Div Cardiothorac Surg, Durham, NC 27710 USA. Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. NCI, Bethesda, MD 20892 USA. RP D'Amico, TA (reprint author), Duke Univ, Med Ctr, Div Cardiothorac Surg, Box 3496, Durham, NC 27710 USA. NR 18 TC 43 Z9 46 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2001 VL 72 IS 3 BP 859 EP 866 DI 10.1016/S0003-4975(01)02838-7 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 469LV UT WOS:000170817900050 PM 11565671 ER PT J AU D'Ambrosio, SM Gibson-D'Ambrosio, RE Wani, G Casto, B Milo, GE Kelloff, GJ Steele, VE AF D'Ambrosio, SM Gibson-D'Ambrosio, RE Wani, G Casto, B Milo, GE Kelloff, GJ Steele, VE TI Modulation of Ki67, p53 and RAR beta expression in normal, premalignant and malignant human oral epithelial cells by chemopreventive agents SO ANTICANCER RESEARCH LA English DT Article DE chemoprevention; oral cancer; retinoids; non-retinoids; biomarkers; p53; Ki67 retinoic acid receptors ID ACID RECEPTOR-BETA; CYCLE CONTROL; CANCER CHEMOPREVENTION; SQUAMOUS CARCINOMA; PROGNOSTIC-SIGNIFICANCE; GROWTH-INHIBITION; RETINOIDS; PREVENTION; MECHANISMS; HEAD AB Background: Aberrant expression of Ki67, p53 and RARbeta are characteristic of many tumor types including those of the oral cavity. Chemopreventive agents may act by modulating their expression to more normal levels. Materials and Methods: The effects of 21 chemopreventive agents on the expression of Ki67, p53 and RARbeta were determined using a human in vitro model of normal, premalignant and malignant oral epithelial cell lines. Results: Ki67 and mutant p53 (mtp53) were overexpressed in both the premalignant and malignant cell lines, whereas expression of RARbeta was high in the normal, low in the premalignant and not detectable in the malignant cell lines. Most of the agents selectively inhibited the expression of Ki67 in the premalignant and malignant cell lines. Eight of the 21 agents increased, while four agents decreased, the levels of mtp53 protein in the premalignant cell line. In the malignant cell line, five of the agents increased, while ten agents decreased mtp53 protein levels. The agents increased RARbeta expression to near normal levels in the premalignant cell line. Conclusion: The data suggest that the suppression of Ki67 and mtp53 are good indicators of the effectiveness of agents in premalignant and malignant oral cells, whereas the enhancement of RARbeta is a measure of effectiveness in premalignant oral cells. C1 Ohio State Univ, Sch Med & Publ Hlth, Columbus, OH 43210 USA. Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA. NCI, Rockville, MD 20852 USA. RP D'Ambrosio, SM (reprint author), 400 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [N01-CN-85144]; NIDCR NIH HHS [P0I-DE12704] NR 55 TC 5 Z9 5 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 2001 VL 21 IS 5 BP 3229 EP 3235 PG 7 WC Oncology SC Oncology GA 519RZ UT WOS:000173740400013 PM 11848477 ER PT J AU Suarez-Alvarez, B Suarez, MDMG Arguelles, ME Sampedro, A Marcos, CA Mira, E Van Den Brule, FA Liu, FT Chowdhury, PS Toyos, JRDL AF Suarez-Alvarez, B Suarez, MDMG Arguelles, ME Sampedro, A Marcos, CA Mira, E Van Den Brule, FA Liu, FT Chowdhury, PS Toyos, JRDL TI Circulating IgG response to stromelysin-3, collagenase-3, galectin-3 and mesothelin in patients with pharynx/larynx squamous cell carcinoma SO ANTICANCER RESEARCH LA English DT Article DE cancer antigens; humoral immune response ID ANTI-P53 ANTIBODY-RESPONSE; P53 SERUM ANTIBODIES; CANCER-PATIENTS; BINDING-PROTEIN; MATRIX METALLOPROTEINASE-13; RHEUMATOID-ARTHRITIS; TISSUE INHIBITORS; IMMUNE-RESPONSE; NECK-CANCER; EXPRESSION AB With the aim of identifying tumor-associated antigens that could be potential markers and/or targets of diagnostic and/or therapeutic approaches, we studied the occurrence of circulating IgG antibodies to human stromelysin-3, collagenase-3, galectin-3 and mesothelin, by Western blot against their purified recombinant forms, in the sera of 50 patients with pharynx/larynx squamous cell carcinoma (PLSCC), as well as in the sera of 50 healthy blood donors. Overall, antibodies to collagenase-3 were detected in 50% of all the cancer patients and 16% of the blood donors examined; this percentage difference was statistically significant (p = 0.00066). With respect to anti-galectin-3 antibodies, the percentages were 32% and 18%, respectively, but they were not statistically different (p = 0.16). Low levels of antibodies to stromelysin-3 and to mesothelin were detected in sera from only two cancer patients. No significant correlations were found in the present study between the presence of antibodies to these proteins and tumor site, clinical and T stages, lymph node involvement, DNA ploidy and histological grade of differentiation of the primary tumors. To our knowledge, this is the first report on the detection of circulating IgG to collagenase-3 in cancer patients. Some of the percentages found here in certain groups of patients are among the highest reported of circulating antibodies to any tumor component studied so far. The monitoring and the use of human antibodies to collagenase-3 could be of diagnostic and therapeutic interest. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. La Jolla Inst Allergy & Immunol, Div Allergy, San Diego, CA 92121 USA. Metastasis Res Lab, B-4000 Liege, Belgium. Univ Autonoma Madrid, CSIC, Ctr Nacl Biotecnol, Dept Inmunol & Oncol, E-28049 Madrid, Spain. Hosp Valle del Nalon, Dept Otorrinolaringol, Oviedo 33920, Spain. Univ Oviedo, Inst Univ Oncol, Serv Cient Tecn Citometria & Inmunotecnol, E-33006 Oviedo, Spain. RP Toyos, JRDL (reprint author), Univ Oviedo, Hosp Cent Asturias, Serv Cient Tecn Citometria & Immunotecnol, Bloque Polivalente A,Planta 1A,C Julian Claveria, Oviedo 33006, Spain. RI MIRA, EMILIA/K-2456-2014; de los Toyos, Juan/M-1681-2014 OI MIRA, EMILIA/0000-0002-4226-1829; de los Toyos, Juan/0000-0002-3880-6339 NR 45 TC 10 Z9 10 U1 0 U2 4 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 2001 VL 21 IS 5 BP 3677 EP 3684 PG 8 WC Oncology SC Oncology GA 519RZ UT WOS:000173740400078 PM 11848542 ER PT J AU Vandegraaff, N Kumar, R Hocking, H Burke, TR Mills, J Rhodes, D Burrell, CJ Li, P AF Vandegraaff, N Kumar, R Hocking, H Burke, TR Mills, J Rhodes, D Burrell, CJ Li, P TI Specific inhibition of human immunodeficiency virus type 1 (HIV-1) integration in cell culture: Putative inhibitors of HIV-1 integrase SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RETROVIRAL DNA INTEGRATION; PREINTEGRATION COMPLEXES; STRAND TRANSFER; CENTRIFUGAL ENHANCEMENT; REVERSE TRANSCRIPTION; PRODUCTIVE INFECTION; CDNA INTEGRATION; GENE-EXPRESSION; REPLICATION; PROTEIN AB To study the effect of potential human immunodeficiency virus type 1 (HIV-1) integrase inhibitors during virus replication in cell culture, we used a modified nested Alu-PCR assay to quantify integrated HIV DNA in combination with the quantitative analysis of extrachromosomal HIV DNA. The two diketo acid integrase inhibitors (L-708,906 and L-731,988) blocked the accumulation of integrated HIV-1 DNA in T cells following infection but did not alter levels of newly synthesized extrachromosomal HIV DNA. In contrast, we demonstrated that L17 (a member of the bisaroyl hydrazine family of integrase inhibitors) and AR177 (an oligonucleotide inhibitor) blocked the HIV replication cycle at, or prior to, reverse transcription, although both drug's inhibited integrase activity in cell-free assays. Quercetin dihydrate (a flavone) was shown to not have any antiviral activity in our system despite reported anti-integration properties in cell-free assays. This refined Alu-PCR assay for HIV provirus is a useful tool for screening anti-integration compounds identified in biochemical assays for their ability to inhibit the accumulation of integrated HIV DNA in cell culture, and it may be useful for studying the effects of these inhibitors in clinical trials. C1 Inst Med & Vet Sci, Infect Dis Labs, Natl Ctr HIV Virol Res, Adelaide, SA 5000, Australia. Univ Adelaide, Dept Mol Biosci, Adelaide, SA 5000, Australia. NCI, Med Chem Lab, Div Basic Sci, Bethesda, MD 20892 USA. Macfarlene Burnet Ctr Med Res, Natl Ctr HIV Virol Res, Fairfield, Vic 3141, Australia. Amrad Operat, Richmond, Vic 3121, Australia. RP Vandegraaff, N (reprint author), Inst Med & Vet Sci, Infect Dis Labs, Natl Ctr HIV Virol Res, Frome Rd, Adelaide, SA 5000, Australia. RI Burke, Terrence/N-2601-2014 NR 51 TC 36 Z9 38 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2001 VL 45 IS 9 BP 2510 EP 2516 DI 10.1128/AAC.45.9.2510-2516.2001 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 465KQ UT WOS:000170588500017 PM 11502522 ER PT J AU Lamb, ME Fauchier, A AF Lamb, ME Fauchier, A TI The effects of question type on self-contradictions by children in the course of forensic interviews SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID SEXUAL ABUSE VICTIMS; INVESTIGATIVE UTTERANCE TYPES; PRESCHOOLERS; EVENTS; STATEMENTS; STRESSFUL; WITNESSES; VALIDITY; MEMORY; DOLLS AB Twenty-four forensic interviews of seven alleged victims of child sexual abuse were examined to elucidate the circumstances in which the children contradicted forensically relevant details they had provided earlier, Suggestive questions by the interviewers elicited a disproportionate number of contradictions, whereas open-ended invitations never elicited contradictions. Because contradictions necessarily imply that details were stated inaccurately at least once, these close analyses of forensic interviews demonstrate that, as in analogue contexts, open-ended prompts yield more accurate information than do focused questions, particularly option-posing and suggestive prompts. Published in 2001 by John Wiley & Sons. Ltd. C1 NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Suite 804B,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 41 TC 64 Z9 64 U1 0 U2 5 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD SEP PY 2001 VL 15 IS 5 BP 483 EP 491 DI 10.1002/acp.726 PG 9 WC Psychology, Experimental SC Psychology GA 480CB UT WOS:000171443000002 ER PT J AU Foster, JD Wiedemann, JM Pang, CJ Chou, JY Nordlie, RC AF Foster, JD Wiedemann, JM Pang, CJ Chou, JY Nordlie, RC TI Discriminant responses of the catalytic unit and glucose 6-phosphate transporter components of the hepatic glucose-6-phosphatase system in Ehrlich ascites-tumor-bearing mice SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE glucose-6-phosphatase; Ehrlich ascites tumor; glucose 6-phosphate transporter ID N-BROMOACETYLETHANOLAMINE PHOSPHATE; RAT-LIVER GLUCOSE-6-PHOSPHATASE; STORAGE-DISEASE TYPE-1A; GENE-EXPRESSION; ENDOPLASMIC-RETICULUM; IN-VIVO; TRANSLOCASE; SEQUENCE; PROTEINS; SUBUNIT AB The effect of Ehrlich ascites tumor cells, in vivo, on the hepatic glucose-6-phosphatase (G6Pase) system was examined. The V-max for glucose 6-phosphate hydrolysis by G6Pase was reduced by 40% and a greater than 15-fold decrease in mRNA encoding the catalytic unit of the G6Pase system was observed 8 days after injection with tumor cells. Blood glucose concentration was decreased from 169 +/- 17 to 105 +/- 9 mg/dl in tumor-bearing mice. There was no change in the G6P transporter (G6PT) mRNA level. However, there was a significant decrease in G6P accumulation into hepatic microsomal vesicles derived from tumor-bearing mice. Decreased G6P accumulation was also associated with a decrease in G6Pase hydrolytic activity in the presence of vanadate, a potent catalytic-unit inhibitor. In addition, G6P accumulation was nearly abolished in microsomes treated with N-bromoacetylethanolamine phosphate, an irreversible inhibitor of the G6PT. These results demonstrate that the catalytic unit and G6PT components of the G6Pase system can be discriminantly regulated, and that microsomal glucose 6-phosphate uptake is dependent on catalytic unit activity as well as G6PT action. (C) 2001 Academic Press. C1 Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58203 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Foster, JD (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, 501 N Columbia Rd, Grand Forks, ND 58203 USA. FU NIDDK NIH HHS [DK07141] NR 30 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD SEP 1 PY 2001 VL 393 IS 1 BP 117 EP 122 DI 10.1006/abbi.2001.2481 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 470LD UT WOS:000170872700013 PM 11516168 ER PT J AU Michalek, JE Akhtar, FZ Longnecker, MP Burton, JE AF Michalek, JE Akhtar, FZ Longnecker, MP Burton, JE TI Relation of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) level to hematological examination results in veterans of Operation Ranch Hand SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article DE Agent Orange; dioxin; hematology; TCDD ID HEALTH-STATUS; DIOXIN; VIETNAM; HERBICIDES; MORTALITY; "2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; THROMBOCYTOSIS; CHEMICALS; EXPOSURE; TOXICITY AB The authors studied indices of hematologic function and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam War veterans of Operation Ranch Hand- the Air Force unit responsible for the aerial spraying of Agent Orange and other herbicides in Vietnam. The herbicides were contaminated with TCDD. The authors measured TCDD serum levels in 1987 or later and extrapolated the result to the time of service in Vietnam. The authors studied serum TCDD level in relation to red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, white blood cell count, platelet count, and erythrocyte sedimentation rate at each of 4 physical examinations. Compared with veterans not involved in Operation Ranch Hand, those with the highest TCDD levels in Operation Ranch Hand had mean corpuscular volumes that were about 1% higher and platelet counts that were about 4% higher. These small increases were unlikely to be of clinical significance and may not have been caused by TCDD. C1 USAF, Res Lab, Brooks AFB, TX 78235 USA. SpecPro, San Antonio, TX USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. RP Michalek, JE (reprint author), 2602 Doolittle Rd, Brooks AFB, TX 78235 USA. OI Longnecker, Matthew/0000-0001-6073-5322 NR 44 TC 6 Z9 6 U1 0 U2 0 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0003-9896 J9 ARCH ENVIRON HEALTH JI Arch. Environ. Health PD SEP-OCT PY 2001 VL 56 IS 5 BP 396 EP 405 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 505KP UT WOS:000172912200002 PM 11777020 ER PT J AU Holmes, JM Beck, RW Repka, MX Leske, DA Kraker, RT Blair, RC Moke, PS Birch, EE Saunders, RA Hertle, RW Quinn, GE Simons, KA Miller, JM AF Holmes, JM Beck, RW Repka, MX Leske, DA Kraker, RT Blair, RC Moke, PS Birch, EE Saunders, RA Hertle, RW Quinn, GE Simons, KA Miller, JM CA Pediat Eye Dis Invest Grp TI The amblyopia treatment study visual acuity testing protocol SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CARD PROCEDURE; YOUNG-CHILDREN; INTEROBSERVER AGREEMENT; GRATING ACUITY; RELIABILITY AB Objective: To evaluate the reliability of a new visual acuity testing protocol for children using isolated surrounded HOTV optotypes. Methods: After initial pilot testing and modification, the protocol was evaluated using the Baylor-Video Acuity Tester (BVAT) to present isolated surrounded HOTV optotypes. At 6 sites, the protocol was evaluated for testability in 178 children aged 2 to 7 years and for reliability in a subset of 88 children. Twenty-eight percent of the 178 children were, classified as having amblyopia. Results: Using the modified protocol, testability ranged from 24% in 2-year-olds to 96% in 5- to 7-year-olds. Test-retest reliability was high (r=0.82), with 93% of retest scores within 0.1 logMAR unit of the initial test score. The 95% confidence interval for an acuity score was calculated to be the score +/-0.125 logMAR unit. For a change between 2 acuity scores, the 95% confidence interval was the difference +/-0.18 logMAR unit. Conclusions: The visual acuity protocol had a high level of testability in 3- to 7-year-olds and excellent test-retest reliability. The protocol has been incorporated into the multicenter Amblyopia Treatment Study and has wide potential application for standardizing visual acuity testing in children. C1 PEDIG Data Coordinating Ctr, Jaeb Ctr Hlth Res, Tampa, FL 33613 USA. Mayo Clin, Dept Ophthalmol, Rochester, MN USA. Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. Retina Fdn SW, Dallas, TX USA. Med Univ S Carolina, Dept Ophthalmol, Storm Eye Inst, Charleston, SC 29425 USA. NEI, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Div Pediat Ophthalmol, Philadelphia, PA 19104 USA. Univ Arizona, Dept Ophthalmol, Tucson, AZ USA. RP Holmes, JM (reprint author), PEDIG Data Coordinating Ctr, Jaeb Ctr Hlth Res, 3010 E 138th Ave,Suite 9, Tampa, FL 33613 USA. FU NEI NIH HHS [EY11751] NR 29 TC 168 Z9 170 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2001 VL 119 IS 9 BP 1345 EP 1353 PG 9 WC Ophthalmology SC Ophthalmology GA 471DM UT WOS:000170912400013 PM 11545641 ER PT J AU Szymko-Bennett, YM Mastroianni, MA Shotland, LI Davis, J Ondrey, FG Balog, JZ Rudy, SF McCullagh, L Levy, HP Liberfarb, RM Francomano, CA Griffith, AJ AF Szymko-Bennett, YM Mastroianni, MA Shotland, LI Davis, J Ondrey, FG Balog, JZ Rudy, SF McCullagh, L Levy, HP Liberfarb, RM Francomano, CA Griffith, AJ TI Auditory dysfunction in Stickler syndrome SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article; Proceedings Paper CT 23rd Meeting of the Association-for-Research-in-Otolaryngology CY FEB 21-23, 2000 CL ST PETERSBURG, FLORIDA SP Assoc Res Otolaryngol ID HEARING-LOSS; MARSHALL-SYNDROME; OTOACOUSTIC EMISSIONS; IMPEDANCE AUDIOMETRY; AUTOSOMAL-DOMINANT; COL11A2 GENE; COLLAGEN; MUTATIONS; PHENOTYPE; FAMILIES AB Objectives: To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthroophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders. Design: Multifamily study. Setting: Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md. Subjects: Forty-six affected individuals from 29 different families segregating Stickler syndrome. Interventions: Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants. Results: The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals. Conclusions: The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders. C1 Natl Inst Deafness & Other Commun Disorders, Hearing Sect, Neurootol Branch, Lab Mol Genet,NIH, Bethesda, MD USA. Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Mol Genet Lab, NIH, Bethesda, MD USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Ct,Room 2A-02, Rockville, MD 20850 USA. FU NIDCD NIH HHS [Z01 DC 00054-01, Z01 DC 00055-01] NR 37 TC 23 Z9 24 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD SEP PY 2001 VL 127 IS 9 BP 1061 EP 1068 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 471XK UT WOS:000170953800005 PM 11556853 ER PT J AU Cheng, L Bostwick, DG Li, G Zhang, SB Vortmeyer, AO Zhuang, ZP AF Cheng, L Bostwick, DG Li, G Zhang, SB Vortmeyer, AO Zhuang, ZP TI Conserved genetic findings in metastatic bladder cancer - A possible utility of allelic loss of chromosomes 9p21 and 17p13 in diagnosis SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID PROSTATE CARCINOMA; P53 GENE; DELETION; ACCUMULATION; PROGRESSION; MUTATIONS; ORIGIN; P16 AB Context.-Molecular analysis of microsatellite alterations of biologically distinct tumor cell subpopulations from the same patient may aid in the determination of tumor origin and further our understanding of the genetic basis of cancer progression. Design.-The authors examined the pattern of allelic loss with polymorphic microsatellite markers on chromosome 9p21 (D9S161, D9S171, IFNA), regions of putative tumor suppressor gene p16, and on chromosome 17p13 (TP53), the p53 locus, in matched primary and metastatic bladder cancers from 9 patients. All patients underwent cystectomy for bladder cancer and had regional lymph node metastases at the time of surgery. Genomic DNA was prepared from primary cancers and matched synchronous lymph node metastases using a microdissection method. Results.-The overall frequency of allelic loss was 78% in primary cancer and 89% in paired metastatic cancer. The frequency of allelic loss in the primary cancer was 86% with D9S161, 67% with D9S171, 71% with IFNA, and 80% with TP53. The frequency of allelic loss in matched metastatic cancer was 100% with D9S161, 62% with D9S171, 71% with IFNA, and 80% with TP53. An identical pattern of allelic imbalance (allelic loss or retention) at multiple DNA loci was observed in matched primary and metastatic carcinoma in 8 (88%) cases. One case showed allelic loss in the metastasis, but not in the primary cancer. Conclusions.-The pattern of allelic loss at chromosome 9p21 (p16) and 17p13 (p53) was generally maintained during cancer progression to metastasis, and identical allelic loss in primary cancer was conserved in paired metastatic carcinoma. These data suggest that these genetic changes may be useful in establishing a diagnosis and determining tumor origins in difficult cases. C1 Indiana Univ, Sch Med, Dept Pathol, Indianapolis, IN 46202 USA. Bostwick Labs, Richmond, VA USA. NCI, Mol Pathogenesis Unit, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Cheng, L (reprint author), Indiana Univ, Sch Med, Dept Pathol, UH 3465,550 N Univ Blvd, Indianapolis, IN 46202 USA. NR 16 TC 12 Z9 14 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD SEP PY 2001 VL 125 IS 9 BP 1197 EP 1199 PG 3 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 472EQ UT WOS:000170970900011 PM 11520271 ER PT J AU Teive, HAG Raskin, S Iwamoto, FM Germiniani, FMB Baran, MHH Werneck, LC Allan, N Quagliato, E Leroy, E Ide, SE Polymeropoulos, MH AF Teive, HAG Raskin, S Iwamoto, FM Germiniani, FMB Baran, MHH Werneck, LC Allan, N Quagliato, E Leroy, E Ide, SE Polymeropoulos, MH TI The G209A mutation in the alpha-synuclein gene in brazilian families with Parkinson's disease SO ARQUIVOS DE NEURO-PSIQUIATRIA LA English DT Article DE Parkinson's disease; alpha-synuclein; genetics ID ASSOCIATION AB A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp451. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families. C1 Univ Fed Parana, Hosp Clin, Neurol Serv, Movement Disorders Unit, BR-80069900 Curitiba, Parana, Brazil. Ctr Aconselhamento & Lab Genet, Genetika, Curitiba, Parana, Brazil. Hosp Base, Neurol Serv, Brasilia, DF, Brazil. UNICAMP, Dept Neurol, Campinas, SP, Brazil. NHGRI, Bethesda, MD USA. NR 21 TC 5 Z9 7 U1 0 U2 1 PU ASSOC ARQUIVOS DE NEURO- PSIQUIATRIA PI SAO PAULO SP PA PR AMADEU AMARAL 47/33, 01327-010 SAO PAULO SP, BRAZIL SN 0004-282X J9 ARQ NEURO-PSIQUIAT JI Arq. Neuro-Psiquiatr. PD SEP PY 2001 VL 59 IS 3B BP 722 EP 724 DI 10.1590/S0004-282X2001000500013 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 482BP UT WOS:000171555200013 PM 11593272 ER PT J AU Phillips, SJ AF Phillips, SJ TI Thrombogenic influence of biomaterials in patients with the Omni series heart valve: Pyrolytic carbon versus titanium SO ASAIO JOURNAL LA English DT Review ID CLINICAL-EXPERIENCE; IN-VITRO; OMNICARBON; REPLACEMENT; PROSTHESIS; DESIGN AB An opportunity to assess the thromboembolic rates caused by the construction materials on valve replacements is possible with the Omni series of mechanical heart valves. The Omnicarbon and Omniscience valves are identical in form but differ in that the Omnicarbon valve is constructed entirely of pyrolytic carbon, whereas the Omniscience valve uses titanium for its housing, the rest of its structure being pyrolytic carbon. The literature was reviewed and a comparison in similar groups of patients was made between these two model valves for their thromboembolic rates in the mitral and aortic positions. A total of 569 aortic Omnicarbon valves (4,146 patient years [pt yrs.]) had a thromboembolic events (T/E rate) of 0.5% compared with 1.7% for 468 aortic Omniscience (1,552 pt yrs); p < 0.0001. A total of 298 mitral Omnicarbon valves (3,333 pt yrs) had a T/E rate of 1.6% compared with 2.6% for 716 mitral Omniscience valves (2,134 pt yrs), p < 0.001. There was no difference in the anticoagulation management between the two model valves although the Omniscience valve required higher prothrombin or International Normalized Rate maintenance levels, which resulted in higher bleeding rates among patients with Omniscience valves. C1 Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Phillips, SJ (reprint author), Natl Lib Med, NIH, Bldg 38,Room 2E17,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 34 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1058-2916 J9 ASAIO J JI Asaio J. PD SEP-OCT PY 2001 VL 47 IS 5 BP 429 EP 431 DI 10.1097/00002480-200109000-00002 PG 3 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 472QV UT WOS:000170997200002 PM 11575807 ER PT J AU Russo, GT Meigs, JB Cupples, LA Demissie, S Otvos, JD Wilson, PWF Lahoz, C Cucinotta, D Couture, P Mallory, T Schaefer, EJ Ordovas, JM AF Russo, GT Meigs, JB Cupples, LA Demissie, S Otvos, JD Wilson, PWF Lahoz, C Cucinotta, D Couture, P Mallory, T Schaefer, EJ Ordovas, JM TI Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study SO ATHEROSCLEROSIS LA English DT Article DE apoC3; triglycerides; polymorphisms; lipoprotein particle size; insulin resistance ID APOLIPOPROTEIN-C-III; HIGH-DENSITY-LIPOPROTEIN; FAMILIAL COMBINED HYPERLIPIDEMIA; INSULIN-RESPONSE ELEMENT; CIII GENE; A-I; DNA POLYMORPHISMS; ARTERY DISEASE; PLASMA-LIPOPROTEINS; JAPANESE POPULATION AB Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P < 0.04) and HDL2-C (P < 0.02) and a significant increase in apoCIII non-HDL (P < 0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P = 0.30). Conversely, in women, the S2 allele was associated with increased TC (P < 0.03), low-density lipoprotein cholesterol (LDL-C; P < 0.03), and ApoB levels (P < 0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P < 0.04). In women, there was a significant increase in intermediate LDL particles (P < 0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P < 0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population. ((C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Lipid Metab Lab, Boston, MA 02111 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. N Carolina State Univ, Boston Univ, Sch Publ Hlth, Raleigh, NC 27695 USA. N Carolina State Univ, Dept Biochem, Raleigh, NC 27695 USA. NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. Univ Messina, Dept Internal Med, Messina, Italy. Wako Diagnost, Richmond, VA USA. RP Ordovas, JM (reprint author), Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Lipid Metab Lab, 711 Washington St, Boston, MA 02111 USA. RI cucinotta, domenico/F-4832-2014; OI Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [HL54776, HL35243, N01 HL38038] NR 67 TC 86 Z9 90 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD SEP PY 2001 VL 158 IS 1 BP 173 EP 181 DI 10.1016/S0021-9150(01)00409-9 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 466YK UT WOS:000170673600022 PM 11500189 ER PT J AU Gomez-Serrano, M Tonelli, L Listwak, S Sternberg, E Riley, AL AF Gomez-Serrano, M Tonelli, L Listwak, S Sternberg, E Riley, AL TI Effects of cross fostering on open-field behavior, acoustic startle, lipopolysaccharide-induced corticosterone release, and body weight in lewis and Fischer rats SO BEHAVIOR GENETICS LA English DT Article DE HPA axis postnatal development; inbred rats; stress; gender differences ID PITUITARY-ADRENAL AXIS; F344/N RATS; ADRENOCORTICAL-RESPONSE; STRESS RESPONSES; LEW/N RATS; FACTOR CRF; HORMONE; SUSCEPTIBILITY; ARTHRITIS; STRAINS AB Lewis (LEW/N) and Fischer (F344/N) rats differ on a myriad of behavioral and physiological endpoints, some of which have been reported to be affected by maternal experience in outbred rats and other strains. To assess whether epigenetic factors contribute to the differential behavioral responses to stress and pro-inflammatory challenges in these strains, the effects of cross fostering on open-field, acoustic startle, and glucocorticoid reactivity to lipopolysaccharide (LPS) were examined in the present experiment. In the open-field test, although in-fostered female LEWIN and F344/N strains did not differ, female LEWIN rats displayed significantly greater activity than female F344/N rats in the cross-fostered condition. Differences between males of the two strains were increased by cross fostering, with the LEWIN strain displaying greater total activity. In acoustic startle, there was little strain difference between in-fostered or cross-fostered female rats. On the other hand, in-fostered male LEWIN rats had a significantly greater startle response than in-fostered male F344/N rats, an effect that was dramatically reduced by cross fostering. In-fostered female LEWIN rats displayed a blunted corticosterone response relative to in-fostered female F344/N rats, an effect that was reduced by cross fostering. Conversely, although there was nos train difference between male in-fostered rats, cross-fostered male F344/N rats displayed a significantly greater corticosterone response to LPS than cross-fostered male LEWIN rats. Finally, body weight differences between in-fostered LEWIN and F344/N rats were reduced by cross fostering. Together, these data illustrate that maternal factors play a role in the behavioral and physiological responses to stress between the two strains. C1 American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. NIMH, Sect Neuroendocrine Immunol & Behav, Clin Neuroendocrine Branch, Bethesda, MD 20892 USA. RP Gomez-Serrano, M (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. NR 43 TC 53 Z9 53 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 2001 VL 31 IS 5 BP 427 EP 436 DI 10.1023/A:1012742405141 PG 10 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 505YV UT WOS:000172943900004 PM 11777171 ER PT J AU Anderson, DE AF Anderson, DE TI Respiratory psychophysiology in hypertension research SO BEHAVIOR MODIFICATION LA English DT Article ID END-TIDAL CO2; BLOOD-PRESSURE; CAROTID ATHEROSCLEROSIS; NATURAL-ENVIRONMENT; METABOLIC-RATE; WOMEN; SODIUM; STRESS; ANXIETY; ADULTS AB The pathogenesis of hypertension results from an interaction of genetic and environmental factors. Behavioral factors might participate in sodium sensitive forms of hypertension via a cascade of physiological responses triggered by conditioned inhibition of breathing. When an individual decreases ventilation sufficient to increase PCO2 but not sufficient to activate chemoreceptor reflexes, plasma pH decreases transiently to stimulate a renal mechanism that can expand plasma volume via sodium retention. The combination of high resting PCO2 and high sodium intake elevates resting blood pressure in laboratory animals and healthy human participants. In the natural environment, this mechanism seems to be more important for the development of hypertension in women than in men, perhaps due to differential expression of anger and aggression. Studies are needed to clarify the role of breathing pattern in individual differences in resting PCO2 and the effects of breathing interventions on salt sensitivity and sodium sensitive forms of hypertension. C1 NIA, Behav Hypertens Sect, Cardiovasc Sci Lab, Bethesda, MD 20892 USA. RP Anderson, DE (reprint author), NIA, Behav Hypertens Sect, Cardiovasc Sci Lab, Bethesda, MD 20892 USA. NR 37 TC 4 Z9 4 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD SEP PY 2001 VL 25 IS 4 BP 606 EP 620 DI 10.1177/0145445501254007 PG 15 WC Psychology, Clinical SC Psychology GA 464CC UT WOS:000170514300007 PM 11530718 ER PT J AU Clark, WA Jian, XY Chen, L Northup, JK AF Clark, WA Jian, XY Chen, L Northup, JK TI Independent and synergistic interaction of retinal G-protein subunits with bovine rhodopsin measured by surface plasmon resonance SO BIOCHEMICAL JOURNAL LA English DT Article DE affinity; synergy; transducin ID BETA-GAMMA-SUBUNITS; ROD OUTER SEGMENTS; A(1) ADENOSINE RECEPTORS; TRANSDUCIN-ALPHA-SUBUNIT; GTP-BINDING PROTEIN; ADENYLATE-CYCLASE; SIGNAL TRANSFER; CELL-MEMBRANES; RECONSTITUTION; PURIFICATION AB We have used surface plasmon resonance (SPR) measurements for the kinetic analysis of G-protein-receptor interaction monitored in real time. Functionally active rhodopsin was immobilized on an SPR surface, with full retention of biochemical specific activity for catalysis of nucleotide exchange on the retinal G-protein alpha subunit, via binding to immobilized concanavalin A. The binding interactions of bovine retinal alpha (t) and beta (1)gamma (1) subunits with rhodopsin measured by SPR were profoundly synergistic. Synergistic binding of the retinal G-protein subunits to rhodopsin was not observed for guanosine 5'-[gamma -thio]triphosphate-bound G alpha (t), nor was binding observed with squid retinal G alpha (q), which is not activated by bovine rhodopsin. The binding affinity (336 +/- 171 nM; mean value+/-S.D.) of retinal beta gamma for rhodopsin in the presence of retinal alpha subunit measured by SPR confirmed the apparent affinity of 254 nM determined previously by nucleotide exchange assays. Binding of beta (1)gamma (1), beta (1)gamma (2), and beta (1)gamma (8-olf) dimers to rhodopsin, independently of the alpha subunit, was readily observable by SPR. Further, these dimers, differing only in their gamma subunit compositions, displayed markedly distinct binding affinities and kinetics. The beta (1)gamma (2) dimer bound with a kinetically determined K-d of 13 +/- 3 nM, a value nearly identical with the biochemically determined K-1/2 of 10 nM. The physiologically appropriate beta (1)gamma (1) displayed rapid association and dissociation kinetics, whereas the other beta (1)gamma dimers dissociated at a rate less than 1/100 as fast. Thus rhodopsin interaction with its native signalling partners is both rapid and transient, whereas the interaction of rhodopsin with heterologous G beta gamma dimers is markedly, prolonged. These results suggest that the duration of a G-protein-coupled receptor signalling event is an intrinsic property of the G-protein coupling partners; in particular, the beta gamma dimer. C1 Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Rockville, MD 20850 USA. RP Northup, JK (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Room 2A-11,5 Res Court, Rockville, MD 20850 USA. NR 42 TC 23 Z9 23 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD SEP 1 PY 2001 VL 358 BP 389 EP 397 DI 10.1042/0264-6021:3580389 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 470NK UT WOS:000170877900013 PM 11513737 ER PT J AU Lisinski, I Schurmann, A Joost, HG Cushman, SW Al-Hasani, H AF Lisinski, I Schurmann, A Joost, HG Cushman, SW Al-Hasani, H TI Targeting of GLUT6 (formerly GLUT9) and GLUT8 in rat adipose cells SO BIOCHEMICAL JOURNAL LA English DT Article DE glucose transporter; GLUT4; insulin ID GLUCOSE-TRANSPORTER GLUT4; SKELETAL-MUSCLE; INSULIN; TRANSLOCATION; ENDOCYTOSIS; ADIPOCYTES; PATHWAYS; DYNAMIN; MEMBER; FAMILY AB The subcellular targeting of the two recently cloned novel mammalian glucose transporters, GLUT6 {previously referred to as GLUT9 [Doege, Bocianski, Joost and Schurmann (2000) Biochem. J. 350, 771-776]} and GLUTS, was analysed by expression of haemagglutinin (HA)-epitope-tagged GLUTs in transiently transfected primary rat adipose cells. Similar to HA-GLUT4, both transporters, HA-GLUT6 and HA-GLUT8, were retained in intracellular compartments in non-stimulated cells. In contrast, mutation of the N-terminal dileucine motifs in both constructs led to constitutive expression of the proteins on the plasma membrane. Likewise, when endocytosis was blocked by co-expression of a dominant-negative mutant of the dynamin GTPase, wild-type HA-GLUT6 and HA-GLUT8 accumulated on the cell surface. However, in contrast with HA-GLUT4, no translocation of HA-GLUT6 and HA-GLUT8 to the plasma membrane was observed when the cells were stimulated with insulin, phorbol ester or hyperosmolarity. Thus GLUT6 and GLUTS appear to recycle in a dynamin-dependent manner between internal membranes and the plasma membrane in rat adipose cells, but are unresponsive to stimuli that induce translocation of GLUT4. C1 Univ Cologne, Inst Biochem, Ctr Mol Med, D-50674 Cologne, Germany. Rhein Westfal TH Aachen, Inst Pharmacol & Toxicol, Aachen, Germany. NIDDK, Diabet Branch, NIH, Bethesda, MD USA. RP Al-Hasani, H (reprint author), Univ Cologne, Inst Biochem, Ctr Mol Med, Otto Fischer Str 12-14, D-50674 Cologne, Germany. RI Joost, Hans-Georg/J-4462-2013 OI Joost, Hans-Georg/0000-0002-5860-606X NR 19 TC 62 Z9 63 U1 1 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD SEP 1 PY 2001 VL 358 BP 517 EP 522 DI 10.1042/0264-6021:3580517 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 470NK UT WOS:000170877900029 PM 11513753 ER PT J AU Searle, F Gac-Breton, S Keane, R Dimitrijevic, S Brocchini, S Sausville, EA Duncan, R AF Searle, F Gac-Breton, S Keane, R Dimitrijevic, S Brocchini, S Sausville, EA Duncan, R TI N-(2-hydroxypropyl)methacrylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates. Synthesis, in vitro, and preliminary in vivo evaluation SO BIOCONJUGATE CHEMISTRY LA English DT Article ID ANTITUMOR-ACTIVITY; IN-VITRO; ELLIPTICINE; CELLS; DNA; INVITRO; AGENTS; CYTOFLUORESCENCE; PHARMACOKINETICS; CYTOTOXICITY AB Ellipticine derivatives have potential as anticancer drugs. Their clinical use has been limited, however, by poor solubility and host toxicity. As N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-anticancer conjugates are showing promise in early clinical trials, a series of novel HPMA copolymer conjugates have been prepared containing the 6-(3-aminopropyl)-ellipticine derivative (APE, NSC176328). Drug was linked to the polymer via GFLG or GG peptide side chains. To optimize biological behavior, HPMA copolymer-GFLG-APE conjugates with different drug loading (total APE: 2.3-7% w/w; free APE: <0.1% w/w) were synthesized. Conjugation of APE to HPMA copolymers considerably increased its aqueous solubility (> 10-fold). HPMA copolymer-GG-APE did not liberate drug in the presence of isolated lysosomal enzymes (tritosomes), but HPMA copolymer-GFLG-APE released APE to a maximum of 60% after 5 h. The rate of drug release was influenced by drug loading; lower loading led to greater release. Whereas free APE (35 mug/mL) caused significant hemolysis (50% after 1 h), HPMA copolymer-APE conjugates were not hemolytic up to 300 mug/mL (APE-equiv). As would be expected from its cellular pharmacokinetics, HPMA copolymer-GFLG-APE was > 75 times less cytotoxic than free drug (IC50 similar to 0.4 mug/mL) against B16F10 melanoma in vitro. However, in vivo when tested in mice bearing s.c. B16F10 melanoma, HPMA copolymer-GFLG-APE (1-10 mg/kg single dose, APE-equiv) given i.p. was somewhat more active (highest TIC value of 143%) than free APE (1 mg/kg) (T/C = 127%). HPMA copolymer-APE conjugates warrant further evaluation as potential anticancer agents. C1 Univ London, Sch Pharm, Ctr Polymer Therapeut, London WC1N 1AX, England. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Duncan, R (reprint author), Cardiff Univ, Welsh Sch Pharm, Ctr Polymer Therapeut, Redwood Bldg, Cardiff CF10 3XF, S Glam, Wales. NR 38 TC 30 Z9 30 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD SEP-OCT PY 2001 VL 12 IS 5 BP 711 EP 718 DI 10.1021/bc0001544 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 476AZ UT WOS:000171205200007 PM 11562189 ER PT J AU Makalowska, I Ryan, JF Baxevanis, AD AF Makalowska, I Ryan, JF Baxevanis, AD TI GeneMachine: gene prediction and sequence annotation SO BIOINFORMATICS LA English DT Article ID PROTEIN AB Motivation: A number of free-standing programs have been developed in order to help researchers find potential coding regions and deduce gene structure for long stretches of what is essentially 'anonymous DNA'. As these programs apply inherently different criteria to the question of what is and is not a coding region, multiple algorithms should be used in the course of positional cloning and positional candidate projects to assure that all potential coding regions within a previously-identified critical region are identified. Results: We have developed a gene identification tool called GeneMachine which allows users to query multiple exon and gene prediction programs in an automated fashion. BLAST searches are also performed in order to see whether a previously-characterized coding region corresponds to a region in the query sequence. A suite of Perl programs and modules are used to run MZEF, GENSCAN, GRAIL 2, FGENES, RepeatMasker, Sputnik, and BLAST The results of these runs are then parsed and written into ASN.1 format. Output files can be opened using NCBI Sequin, in essence using Sequin as both a workbench and as a graphical viewer. The main feature of GeneMachine is that the process is fully automated; the user is only required to launch GeneMachine and then open the resulting file with Sequin. Annotations can then be made to these results prior to submission to GenBank, thereby increasing the intrinsic value of these data. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, NIH, Bldg 49,Room 4A-22, Bethesda, MD 20892 USA. NR 7 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP PY 2001 VL 17 IS 9 BP 843 EP 844 DI 10.1093/bioinformatics/17.9.843 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 482FW UT WOS:000171566400010 PM 11590102 ER PT J AU Wassermann, EM Greenberg, BD Nguyen, MB Murphy, DL AF Wassermann, EM Greenberg, BD Nguyen, MB Murphy, DL TI Motor cortex excitability correlates with an anxiety-related personality trait SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Neurological-Association CY OCT 15-18, 2000 CL BOSTON, MASSACHUSETTS SP Amer Neurol Assoc DE transcranial magnetic stimulation; motor cortex; obsessive-compulsive disorder; anxiety disorders; GABA; sex differences ID OBSESSIVE-COMPULSIVE DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; CORTICAL EXCITABILITY; RECEPTOR; INHIBITION; POLYMORPHISM; FACILITATION; ASSOCIATION; GABA(A); HUMANS AB Background: In an earlier study comparing obsessive-compulsive disorder (OCD) patients to psychiatrically screened normals, we found lowered motor evoked potential (MEP) threshold to transcranial magnetic stimulation (THS) and decreased intracortical inhibition in OCD. We sought to determine whether this pattern was specific to OCD. Methods: We measured the threshold and amplitude of MEPs to single and paired (subthreshold-suprathreshold; 3, 4, 10, 15 msec intervals) TMS in 46 healthy volunteers (23 women, 23 men) who were given the NEO-PI-R personality inventory. Nineteen of the men also received cognitive and motor tests. Results: The paired-pulse conditioned/unconditioned MEP amplitude ratios correlated with Neuroticism (N), a stable measure of trait-level anxiety and other negative emotions, in the whole sample (r = 0.48; p = 0.0006), and in the men (r = 0.63; p = 0.0009). There were no other significant correlations. Conclusions: This relationship reflects a factor that contributes to both personality and cortical regulation. It was not statistically significant in women, probably because of confounding hormonal influences on excitability. Decreased intracortical inhibition may be related more to trait anxiety and depression, which are high in OCD, than to OCD itself. However, the MEP threshold (significantly lowered in OCD) was unrelated to N. Biol Psychiatry 2001;50:377-382 (C) 2001 Society, of Biological Psychiatry. C1 NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), NINDS, Brain Stimulat Unit, NIH, Bldg 10,Room 5N226, Bethesda, MD 20892 USA. NR 33 TC 69 Z9 76 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2001 VL 50 IS 5 BP 377 EP 382 DI 10.1016/S0006-3223(01)01210-0 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 467YQ UT WOS:000170731700010 PM 11543742 ER PT J AU Sette, A Livingston, B McKinney, D Appella, E Fikes, J Sidney, J Newman, M Chesnut, R AF Sette, A Livingston, B McKinney, D Appella, E Fikes, J Sidney, J Newman, M Chesnut, R TI The development of multi-epitope vaccines: Epitope identification, vaccine design and clinical evaluation SO BIOLOGICALS LA English DT Article; Proceedings Paper CT International Symposius on Immunological Applications of Synthetic Peptides CY MAY 09-11, 2001 CL LYON, FRANCE SP Merieux Fdn, Int Assoc Biol DE epitope; vaccines; HLA; CTL; HTL; population coverage; HIV; cancer ID T-CELL EPITOPES; HLA-A; SUPERMOTIFS; POLYMORPHISM; SUPERTYPES; PEPTIDES; ANTIGENS; CTL AB We have developed efficient methods for epitope identification and vaccine design. Our process for epitope selection based on the combined use of motif analyses, binding assays and immunogenicity evaluations is described. We also describe how the projected population coverage and vaccine design can be optimized. Finally, it is discussed how vaccine potency is evaluated by immunogenicity and antigenicity assays. (C) 2001 The International Association for Biologicals. C1 Epimmune Inc, San Diego, CA 92121 USA. NCI, Div Chem, Bethesda, MD 20892 USA. RP Sette, A (reprint author), Epimmune Inc, 5820 Nancy Ridge Dr, San Diego, CA 92121 USA. FU NIAID NIH HHS [N01 AI 95362, P01 AI 48238] NR 16 TC 62 Z9 67 U1 0 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD SEP-DEC PY 2001 VL 29 IS 3-4 BP 271 EP 276 DI 10.1006/biol.2001.0297 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 512ZA UT WOS:000173352400019 PM 11851327 ER PT J AU Strickland, PT Qian, Z Friesen, MD Rothman, N Sinha, R AF Strickland, PT Qian, Z Friesen, MD Rothman, N Sinha, R TI Measurement of 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) in acid-hydrolyzed urine by high-performance liquid chromatography with fluorescence detection SO BIOMARKERS LA English DT Article DE urine metabolites; PhIP; HPLC; biomarker; heterocyclic amines; dietary carcinogens ID HETEROCYCLIC AROMATIC-AMINES; FOOD MUTAGEN 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; CYTOCHROME P4501A2; COLORECTAL-CANCER; BORNE CARCINOGEN; COLON-CANCER; COOKED FOOD; DNA ADDUCTS; FRIED MEAT; HUMANS AB Heterocyclic aromatic amines are carcinogenic combustion products formed during the cooking of meat at moderate to high temperatures. The authors have developed a simplified method to measure the commonly formed heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo( 4,5-b) pyridine (PhIP), in acid-hydrolyzed human urine by HPLC with fluorescence detection after immuno-affinity chromatography. The method was compared with a previously validated method using gas chromatography/mass spectrometry after chemical derivatization. The comparison was performed using 100 urine samples from a study of 10 subjects before, during and after ingesting identical amounts of charbroiled (grilled) meat on 5 consecutive days. The overall correlation between the two assays was r = 0.87 (p < 0.0001). The HPLC method was then used to measure PhIP in acid-hydrolyzed urine collected from 66 subjects participating in a study of fried meat ingestion. Fried meat cooked at high temperature was fed to subjects based on body weight; urines were collected before feeding and 0-12 and 12-24 h after feeding. In a subset of six subjects, urinary PhIP concentration was 3-13-fold higher in the 0-12-h urine than in the 12-24-h urine. In the total study population, a significant correlation (r = 0.61, p < 0.0001) between the amount of fried meat ingested and urinary PhIP was observed. These results indicate that measurement of urinary PhIP by HPLC after immuno-affinity chromatography is a useful alternative to mass spectrometry methods for assessing recent exposure in subjects ingesting moderate to high levels of PhIP. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. Int Agcy Res Canc, Div Gene Environm Interact, F-69372 Lyon, France. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Strickland, PT (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RI Friesen, Marlin/D-7328-2012; Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 33 TC 15 Z9 15 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD SEP PY 2001 VL 6 IS 5 BP 313 EP 325 PG 13 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 459DF UT WOS:000170235200002 ER PT J AU Roth, MJ Qiao, YL Rothman, N Tangrea, JA Dawsey, SM Wang, GQ Cho, SH Kang, D Taylor, PR Strickland, PT AF Roth, MJ Qiao, YL Rothman, N Tangrea, JA Dawsey, SM Wang, GQ Cho, SH Kang, D Taylor, PR Strickland, PT TI High urine 1-hydroxypyrene glucuronide concentrations in Linxian, China, an area of high risk for squamous oesophageal cancer SO BIOMARKERS LA English DT Article DE 1-hydroxypyrene-glucuronide; squamous oesophageal cancer; polycyclic aromatic hydrocarbons; China; biomarker ID POLYCYCLIC AROMATIC-HYDROCARBONS; ENVIRONMENTAL EXPOSURE; OCCUPATIONAL EXPOSURE; BENZOPYRENE; BIOMARKER; METABOLITES; ESOPHAGEAL; EXCRETION; AMBIENT; WORKERS AB Most squamous cell carcinomas of the oesophagus in low-risk populations are attributable to alcohol and tobacco consumption, but the aetiologic agents in many highrisk populations have yet to be definitively identified. Linxian, China has some of the highest oesophageal cancer rates in the world. Recent studies suggest that an association exists between high-level exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo[a] pyrene (B[a] P), and the development of oesophageal cancer. The inhabitants of this high-risk region extensively use coal and wood for cooking and heating in unvented stoves, and thus may be exposed to PAHs produced during the incomplete combustion of these fuel sources. High levels of B[ a] P were recently detected in staple food samples from Linxian and histopathologic changes that may be associated with PAH exposure have also been identified in oesophagectomy specimens from the region. In an effort to determine whether this high-risk population is exposed to high levels of PAHs, voided urines from non-smokers. n = 22) without occupational exposure were collected and analysed using immunoaffinity chromatography and synchronous fluorescence spectroscopy for 1-hydroxypyrene glucuronide, a PAH metabolite and index biomarker for mixed PAH exposure. The median urine 1-hydroxypyrene glucuronide concentration (2.06 pmol ml(1)) was equivalent to concentrations detected in current smokers. To the authors' knowledge, this represents the first report of elevated urine 1-hydroxpyrene glucuronide concentrations in Linxian, and the first biologic confirmation that the inhabitants of this rural, non-industrial, high oesophageal cancer risk region are exposed to carcinogenic PAHs. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. Chinese Acad Med Sci, Inst Canc, Dept Endoscopy, Beijing 100021, Peoples R China. Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RP Roth, MJ (reprint author), Suite 321,6006 Execut Blvd,MSC 7058, Bethesda, MD 20892 USA. RI Kang, Dae Hee/E-8631-2012; Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 35 TC 35 Z9 36 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD SEP PY 2001 VL 6 IS 5 BP 381 EP 386 PG 6 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 459DF UT WOS:000170235200008 ER PT J AU Schafer, DW Lubin, JH Ron, E Stovall, M Carroll, RJ AF Schafer, DW Lubin, JH Ron, E Stovall, M Carroll, RJ TI Thyroid cancer following scalp irradiation: A reanalysis accounting for uncertainty in dosimetry SO BIOMETRICS LA English DT Article DE Berkson measurement error; dose uncertainty; dosimetry; errors-in-variables; likelihood; measurement error; missing data; person-year tables; Poisson regression; regression calibration; survival analysis ID COVARIATE MEASUREMENT ERRORS; PROPORTIONAL HAZARDS MODEL; BOMB SURVIVOR DATA; RADIATION; REGRESSION; EXPOSURE; VARIABLES; COHORT; TIME AB In the 1940s and 1950s, over 20,000 children in Israel were treated for tinea capitis (scalp ringworm) by irradiation to induce epilation. Follow-up studies showed that the radiation exposure was associated with the development of malignant thyroid neoplasms. Despite this clear evidence of an effect, the magnitude of the dose-response relationship is much less clear because of probable errors in individual estimates of dose to the thyroid gland. Such errors have the potential to bias dose-response estimation, a potential that was not widely appreciated at the time of the original analyses. We revisit this issue, describing in detail how errors in dosimetry might occur, and we develop a new dose-response model that takes the uncertainties of the dosimetry into account. Our model for the uncertainty in dosimetry is a complex and new variant of the classical multiplicative Berkson error model, having components of classical multiplicative measurement error as well as missing data. Analysis of the tinea capitis data suggests that measurement error in the dosimetry has only a negligible effect on dose-response estimation and inference as well as on the modifying effect of age at exposure. C1 Oregon State Univ, Dept Stat, Corvallis, OR 97331 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Schafer, DW (reprint author), Oregon State Univ, Dept Stat, Corvallis, OR 97331 USA. FU NCI NIH HHS [CA57030, N01-CP-91024]; NIEHS NIH HHS [P30-ES09106] NR 20 TC 27 Z9 27 U1 1 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2001 VL 57 IS 3 BP 689 EP 697 DI 10.1111/j.0006-341X.2001.00689.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 467YY UT WOS:000170732400004 PM 11550916 ER PT J AU Chatterjee, N Shih, J AF Chatterjee, N Shih, J TI A bivariate cure-mixture approach for modeling familial association in diseases SO BIOMETRICS LA English DT Article DE copula models; correlated failure times; cure models; mixture models; semiparametric models ID BREAST-CANCER; SEGREGATION ANALYSIS; SURVIVAL-DATA; TIME; DISTRIBUTIONS; REGRESSION; RISK; AIDS AB For modeling correlation in familial diseases with variable ages at onset, we propose a bivariate model that incorporates two types of pairwise association, one between the lifetime risk or the overall susceptibility of two individuals and one between the ages at onset between two susceptible individuals. For estimation, we consider a two-stage estimation procedure similar to that of Shih (1998, Biometrics 54, 1115-1128). We evaluate the properties of the estimators through simulations and compare the performance with that from a bivariate survival model that allows correlation between ages at onset only. We apply the methodology to breast cancer using the kinship data from the Washington Ashkenazi Study. We also discuss potential applications of the proposed method in the area of cure modeling. C1 NCI, Stat Res & Applicat Sect, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Biometr Res Branch, Rockville, MD 20852 USA. RP Chatterjee, N (reprint author), NCI, Stat Res & Applicat Sect, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8038, Rockville, MD 20852 USA. NR 26 TC 27 Z9 27 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2001 VL 57 IS 3 BP 779 EP 786 DI 10.1111/j.0006-341X.2001.00779.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 467YY UT WOS:000170732400016 PM 11550928 ER PT J AU Frangakis, CE AF Frangakis, CE TI Compliance subsampling designs for comparative research: Estimation and optimal planning SO BIOMETRICS LA English DT Article DE causal inference; compliance subsampling; double sampling; noncompliance; optimal design; principal stratification ID ADVANCE DIRECTIVES; CLINICAL-TRIALS; NONCOMPLIANCE; REGRESSION; RANDOMIZATION; EQUIVALENCE; INFERENCE AB For studies with treatment noncompliance, analyses have been developed recently to better estimate treatment efficacy. However, the advantage and cost of measuring compliance data have implications on the study design that have not been as systematically explored. In order to estimate better treatment efficacy with lower cost, we propose a new class of compliance subsampling (CSS) designs where, after subjects are assigned treatment, compliance behavior is measured for only subgroups of subjects. The sizes of the subsamples are allowed to relate to the treatment assignment, the assignment probability, the total sample size, the anticipated distributions of outcome and compliance, and the cost parameters of the study. The CSS design methods relate to prior work (i) on two-phase designs in which a covariate is subsampled and (ii) on causal inference because the subsampled postrandomization compliance behavior is not the true covariate of interest. For each CSS design, we develop efficient estimation of treatment efficacy under binary outcome and all-or-none observed compliance. Then we derive a minimal cost CSS design that achieves a required precision for estimating treatment efficacy. We compare the properties of the CSS design to those of conventional protocols in a study of patient choices for medical care at the end of life. C1 Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Frangakis, CE (reprint author), Johns Hopkins Univ, Dept Biostat, 615 N Wolfe St,E2006, Baltimore, MD 21205 USA. FU NICHD NIH HHS [R01 HD38209]; NIDA NIH HHS [R01 DA10184] NR 34 TC 10 Z9 10 U1 0 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2001 VL 57 IS 3 BP 899 EP 908 DI 10.1111/j.0006-341X.2001.00899.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 467YY UT WOS:000170732400031 PM 11550943 ER PT J AU Shaffer, KM Lin, HJ Maric, D Pancrazio, JJ Stenger, DA Barker, JL Ma, W AF Shaffer, KM Lin, HJ Maric, D Pancrazio, JJ Stenger, DA Barker, JL Ma, W TI The use of GABA(A) receptors expressed in neural precursor cells for cell-based assays SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE basic fibroblast growth factor; biosensor; Ca2+ imaging; GABA(A) receptors; high-throughput screening; neural stem cells; neurotoxicity; RT-PCR ID IN-VITRO; HIPPOCAMPAL-NEURONS; GAMMA-1 SUBUNITS; MESSENGER-RNAS; CHLORIDE; SUBTYPES; CALCIUM; CHANNELS; ALPHA-4; BETA-1 AB GABA(A) receptors are known targets for certain classes of environmental neurotoxins and pharmaceutical compounds. Since few neural cell lines express functional GABA(A) receptors, the capacity to rapidly screen for compounds that affect GABA(A) receptor function is presently limited. Previous work has demonstrated that rat neural precursor cells express functional GABA(A) receptors that can be monitored via Call imaging. This study examined GABA(A) receptor subunit expression to determine whether GABA(A) receptor function and its interactions with neurotoxins is preserved after passaging. Neural precursor cells isolated from embryonic day 13 rat brain were expanded in serum-free medium containing basic fibroblast growth factor and passaged three times. Reverse transcription-polymerase chain reaction analysis demonstrated early expression of abundant mRNAs encoding various GABA(A) receptor subunits. Ca2+ imaging showed that the highly proliferating precursor cells in passaged cultures maintained expression of functional GABA(A) receptors. In addition, we showed that trimethylolpropane phosphate, a neurotoxin generated during partial pyrolysis of a synthetic ester turbine engine lubricant, potently inhibited muscimol (GABA(A) receptor agonist) but not depolarization-induced cytosolic Call increase. The findings of this study suggest that neural precursor cells may be well suited for the evaluation of certain environmental neurotoxins with convulsant activity. The potential use of neural precursor cells in high-throughput screens for compounds acting on GABA(A) receptors is discussed. (C) 2001 Elsevier Science B.V. All rights reserved. C1 USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. NINCDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Ma, W (reprint author), USN, Res Lab, Ctr Biomol Sci & Engn, Code 6900, Washington, DC 20375 USA. RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 NR 36 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD SEP PY 2001 VL 16 IS 7-8 BP 481 EP 489 DI 10.1016/S0956-5663(01)00162-2 PG 9 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 476ZD UT WOS:000171257900008 PM 11544042 ER PT J AU Derby, E Reddy, V Baseler, M Malyguine, A AF Derby, E Reddy, V Baseler, M Malyguine, A TI Flow cytometric assay for the simultaneous analysis of cell-mediated cytotoxicity and effector cell phenotype SO BIOTECHNIQUES LA English DT Article C1 NCI, SAIC Frederick, Clin Serv Program, Lab Cell Mediated Immun, Frederick, MD 21702 USA. RP Malyguine, A (reprint author), NCI, SAIC Frederick, Clin Serv Program, Lab Cell Mediated Immun, POB B, Frederick, MD 21702 USA. NR 8 TC 9 Z9 10 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2001 VL 31 IS 3 BP 660 EP + PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 471EZ UT WOS:000170916500032 PM 11570508 ER PT J AU Chian, RJ Young, S Danilkovitch-Miagkova, A Ronnstrand, L Leonard, E Ferrao, P Ashman, L Linnekin, D AF Chian, RJ Young, S Danilkovitch-Miagkova, A Ronnstrand, L Leonard, E Ferrao, P Ashman, L Linnekin, D TI Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant SO BLOOD LA English DT Article ID RECEPTOR TYROSINE KINASE; COLONY-STIMULATING FACTOR; LIGAND-INDEPENDENT ACTIVATION; SURVIVAL SIGNALING PATHWAY; GROWTH-FACTOR RECEPTOR; SRC FAMILY KINASES; N-TERMINAL KINASE; STEEL FACTOR; MAST-CELLS; POINT MUTATION AB Stem cell factor (SCF) binds the receptor tyrosine kinase c-Kit and Is critical for normal hematopoiesis. Substitution of valine for aspartic acid 816 (D816V) constitutively actives human c-Kit, and this mutation is found in patients with mastocytosis, leukemia, and germ cell tumors. Immortalized murine progenitor cells (MIHCs) transduced with wild-type c-Kit proliferate in response to SCF, whereas cells expressing D816V c-Kit (MIHC-D816V) are factor-independent and tumorigenic. However, the mechanisms mediating transformation by D816V c-Kit are unknown. The objective of this study was to identify signaling components that contribute to D816V c-Kit-mediated transformation. SCIF stimulates association of p85(PI3K) with phosphorylated tyrosine 721 of wild-type c-Kit. Phosphatidylinositol 3 kinase (PI3K) subsequently contributes to the activation at Akt and Jnks. In contrast, these studies demonstrated that the D816V c-Kit mutant was constitutively associated with phosphorylated p85(PI3K), and, downstream of PI3K, Jnk 1 and Jnk 2 were activated but Akt was not. Interestingly, Erks 1 and 2 were not constitutively activated by D816V c-Kit. Thus, D816V c-Kit maintains the activity of PI3K but not of all signaling pathways activated by wild-type c-Kit. Further, all pathways downstream at PI3K are not constitutively active in MIHC-D816V cells. Studies with a PI3K inhibitor and D816V/Y721F c-Kit, a mutant incapable of recruiting PI3K, indicate that constitutive activation of PI3K through direct recruitment by D816V c-Kit plays a role in factor-independent growth at MIHC and is critical for tumorigenicity. (C) 2001 by The American Society of Hematology. C1 NCI, Div Basic Sci, Basic Res Lab, Ft Detrick, MD 21702 USA. NCI, Div Basic Sci, Immunobiol Lab, Ft Detrick, MD 21702 USA. Univ Adelaide, Hanson Ctr Canc Res, Inst Med & Vet Sci, Adelaide, SA, Australia. Univ Adelaide, Dept Med, Adelaide, SA, Australia. Ludwig Inst Canc Res, S-75124 Uppsala, Sweden. RP Linnekin, D (reprint author), NCI, Div Basic Sci, Basic Res Lab, Bldg 567,Rm 226, Ft Detrick, MD 21702 USA. RI Ronnstrand, Lars/A-2429-2011; ASHMAN, LEONIE/G-7631-2013 OI ASHMAN, LEONIE/0000-0003-3559-3611 NR 70 TC 99 Z9 100 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2001 VL 98 IS 5 BP 1365 EP 1373 DI 10.1182/blood.V98.5.1365 PG 9 WC Hematology SC Hematology GA 467DH UT WOS:000170685000016 PM 11520784 ER PT J AU Sakai, JA Nagai, M Brennan, MB Mora, CA Jacobson, S AF Sakai, JA Nagai, M Brennan, MB Mora, CA Jacobson, S TI In vitro spontaneous lymphoproliferation in patients with human T-cell lymphotropic virus type I-associated neurologic disease: predominant expansion of CD8+ T cells SO BLOOD LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; CYTOTOXIC LYMPHOCYTES-T; HTLV-I; LEUKEMIA-VIRUS; CEREBROSPINAL-FLUID; PERIPHERAL-BLOOD; INTERFERON-ALPHA; HAM/TSP PATIENTS; MYELOPATHY HAM; PROVIRAL LOAD AB Peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) proliferate spontaneously in vitro. This spontaneous lymphoproliferation (SP) is one of the immunologic hallmarks of HAM/TSP and Is considered to be an important factor related to the pathogenesis of HAM/TSP. However, the cell populations involved in this phenomenon have not yet been definitively Identified. To address this issue, the study directly evaluated proliferating cell subsets in SP with a flow cytometric method using bromodeoxyuridine and Ki-67. Although both CD4(+) and CD8(+) T cells proliferated spontaneously, the percentage of proliferating CW T cells was 2 to 5 times higher than that of CD4(+) T cells. In addition, more than 40% of HTLV-I Tax-11-19-specific CD8(+) T cells as detected by an HLA-a*0201/Tax11-19 tetramer proliferated in culture. In spite of this expansion of HTLV-I-specific CD8(+) T cells, HTLV-I proviral load did not decrease. This finding will help elucidate the dynamics of in vivo virus-host Immunologic interactions that permit the coexistence of high HTLV-I-specific, CD8+ cytotoxic T-lymphocyte responses and high HTLV-1 proviral load in HAM/TSP. (C) 2001 by The American Society of Hematology. C1 NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 35 TC 37 Z9 37 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2001 VL 98 IS 5 BP 1506 EP 1511 DI 10.1182/blood.V98.5.1506 PG 6 WC Hematology SC Hematology GA 467DH UT WOS:000170685000033 PM 11520801 ER PT J AU Mir, SS Richter, BWM Duckett, CS AF Mir, SS Richter, BWM Duckett, CS TI Response: Strength of CD30 signal determines sensitivity to apoptosis SO BLOOD LA English DT Letter ID LARGE-CELL LYMPHOMA C1 NCI, Div Clin Sci, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Duckett, CS (reprint author), NCI, Div Clin Sci, Metab Branch, NIH, 10 Ctr Dr,Rm 6B-05, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2001 VL 98 IS 5 BP 1631 EP 1632 PG 2 WC Hematology SC Hematology GA 467DH UT WOS:000170685000056 ER PT J AU De Luca, LM Ozato, K AF De Luca, LM Ozato, K TI Response: Vitamin A deficiency and myeloid cell growth SO BLOOD LA English DT Letter C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NR 8 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 SEP 1 PY 2001 VL 98 IS 5 BP 1636 EP 1637 PG 2 WC Hematology SC Hematology GA 467DH UT WOS:000170685000062 ER PT J AU Savage, WJ Bleesing, JJH Douek, D Brown, MR Linton, GM Malech, HL Horwitz, ME AF Savage, WJ Bleesing, JJH Douek, D Brown, MR Linton, GM Malech, HL Horwitz, ME TI Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism SO BONE MARROW TRANSPLANTATION LA English DT Article DE non-myeloablative; immune reconstitution; vaccine; chronic granulomatous disease; TREC; engraftment ID BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; IMMUNE RECONSTITUTION; UNMANIPULATED GRAFTS; CONDITIONING REGIMEN; IGG SUBCLASS; RECIPIENTS; CHILDREN; REGENERATION; CHEMOTHERAPY AB The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using How cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until I year in adults. Early quantitative B cell recovery was not accompanied by an early humoral immune response to tetanus toxoid (TT). Emergence of TT-specific T cell responses coincided with naive T cell reconstitution, as measured by CD4/CD45RA T cell recovery and TREC quantification. These data suggest that immune reconstitution occurs faster in pediatric patients who have prolonged mixed hematopoietic chimerism compared to adults, who have rapid donor stem cell engraftment. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Dept Lab Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NCI, Dept Expt Transplantat & Immunol Med, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, New York, NY USA. RP Savage, WJ (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 34 TC 33 Z9 37 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD SEP PY 2001 VL 28 IS 5 BP 463 EP 471 DI 10.1038/sj.bmt.1703176 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 473VT UT WOS:000171069900006 PM 11593319 ER PT J AU Arora, NK Gustafson, DH Hawkins, RP McTavish, F Cella, DF Pingree, S Mendenhall, JH Mahvi, DM AF Arora, NK Gustafson, DH Hawkins, RP McTavish, F Cella, DF Pingree, S Mendenhall, JH Mahvi, DM TI Impact of surgery and chemotherapy on the quality of life of younger women with breast carcinoma - A prospective study SO CANCER LA English DT Article; Proceedings Paper CT 2nd Annual Wisconsin Health Services Research Conference CY NOV 04-05, 1999 CL MADISON, WISCONSIN DE breast carcinoma; quality of life; chemotherapy; surgery; early stage ID TERM FOLLOW-UP; OF-LIFE; FUNCTIONAL ASSESSMENT; CANCER-THERAPY; ADJUVANT CHEMOTHERAPY; PSYCHOSOCIAL ADJUSTMENT; SOCIAL SUPPORT; BODY-IMAGE; MASTECTOMY; CONSERVATION AB BACKGROUND. Studies that prospectively and simultaneously evaluate, within the first year of diagnosis, the impact of surgery and chemotherapy on quality of life (QOL) of younger women (60 years or younger) with early stage breast carcinoma are limited. METHODS. Quality of life of 103 women who had surgery (lumpectomy, 49; mastectomy, 54) approximately 1 month before the start of the study was evaluated at baseline and again after 5 months. Thirty-two women received chemotherapy during the study. RESULTS. Over time, subjects reported improvement in body image and physical, emotional, and functional well-being (P < 0.001). They were less bothered by swollen/tender arms and worried less about risk of cancer to family members (P < 0.001). However, satisfaction with sex life, social support, and social/family well-being declined (P < 0.001). In the period closer to surgery, women with mastectomy reported poorer body image (P = 0.001) and worse functional (P = 0.08) and physical well-being (P = 0.10). Women with lumpectomy worried more about the effects of stress on their illness (P < 0.01) and had lower emotional well-being (P = 0.06). By 6 months after surgery, the two groups reported similar QOL scores. Chemotherapy had a negative impact on women's sexual functioning (P = 0.01) and their physical well-being (P = 0.09). Women who received chemotherapy also reported more shortness of breath (P = 0.07). Post hoc analysis showed that women with breast reconstruction had higher emotional well-being at baseline than those with lumpectomy (P = 0.001) and mastectomy alone (P < 0.01). CONCLUSIONS. Younger women with breast carcinoma could experience a range of adjustment problems at various points in the treatment cycle. Interventions that would help reduce the negative impact of treatment on QOL need to be designed and integrated into routine clinical practice. (C) 2001 American Cancer Society. C1 Univ Wisconsin, Ctr Hlth Syst Res & Anal, Madison, WI USA. Evanston Northwestern Healthcare, Ctr Outcomes Res & Educ, Evanston, IL USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL USA. Univ Wisconsin, Sch Med, Div Gen Surg, Madison, WI USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, ARP, DCCPS, 6130 Execut Blvd,MSC 7344,EPN Room 4005, Bethesda, MD 20892 USA. FU NICHD NIH HHS [5R01HD323922] NR 56 TC 119 Z9 125 U1 1 U2 6 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 1 PY 2001 VL 92 IS 5 BP 1288 EP 1298 DI 10.1002/1097-0142(20010901)92:5<1288::AID-CNCR1450>3.0.CO;2-E PG 11 WC Oncology SC Oncology GA 472FC UT WOS:000170972000030 PM 11571745 ER PT J AU Hoque, A Albanes, D Lippman, SM Spitz, MR Taylor, PR Klein, EA Thompson, IM Goodman, P Stanford, JL Crowley, JJ Coltman, CA Santella, RM AF Hoque, A Albanes, D Lippman, SM Spitz, MR Taylor, PR Klein, EA Thompson, IM Goodman, P Stanford, JL Crowley, JJ Coltman, CA Santella, RM TI Molecular epidemiologic studies within the selenium and vitamin e cancer prevention trial (SELECT) SO CANCER CAUSES & CONTROL LA English DT Article DE molecular epidemiology; primary prevention; prostate cancer; selenium; vitamin E ID GROWTH-FACTOR-I; DNA ADDUCT LEVELS; BENIGN PROSTATIC HYPERPLASIA; BINDING PROTEIN-3; IGF-I; AROMATIC-HYDROCARBONS; GENETIC POLYMORPHISMS; BODY-COMPOSITION; FAT DISTRIBUTION; CELL CARCINOMA AB Objective: To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions. Methods: The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components. Results: Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5 alpha -reductase type II, CYP17, and beta -hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin. Conclusion: SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY 10032 USA. Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. SW Oncol Grp, Ctr Stat, Seattle, WA 98109 USA. SW Oncol Grp, San Antonio, TX 78245 USA. Cleveland Clin Fdn, Dept Urol, Cleveland, OH 44195 USA. Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78284 USA. RP Santella, RM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, 701 168th St Room 505, New York, NY 10032 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [1 U 10 CA 37429] NR 48 TC 61 Z9 63 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2001 VL 12 IS 7 BP 627 EP 633 DI 10.1023/A:1011277600059 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 457WT UT WOS:000170160400006 PM 11552710 ER PT J AU Koch, CJ Hahn, SM Rockwell, K Covey, JM McKenna, WG Evans, SM AF Koch, CJ Hahn, SM Rockwell, K Covey, JM McKenna, WG Evans, SM TI Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitrolmidazoles SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE predictive assays; hypoxia detection; radiation sensitizers; plasma half-life; renal clearance ID METABOLISM-INDUCED BINDING; PHASE-I TRIAL; SR-2508 ETANIDAZOLE; MAMMALIAN-CELLS; RADIOSENSITIZER; MISONIDAZOLE; TUMORS; THERAPY; 2-NITROIMIDAZOLES; NITROIMIDAZOLES AB Objectives: Pharmacokinetic studies were performed on the first 28 patients enrolled in a phase I trial to determine the ability of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] to detect hypoxia in human tumors in the absence of patient toxicity. Methods: EF5 was made in purified form and formulated for intravenous injection by the National Cancer Institute. After obtaining consent from the patients, EF5 was administered and blood samples were drawn at various times over approximately 48 h. For most patients it was possible to collect total urine at approximately 8-h intervals. EF5 in plasma and urine was analyzed by high-performance liquid chromatography. Results: EF5's plasma concentration followed a simple exponential decay following infusion. The plasma half-life was 11.7 +/- 2.6 h ( SD) and was not affected by drug dose (9 to 28 mg/kg), fractional urine recovery, patient weight or gender. Absolute plasma values suggested even biodistribution of the drug throughout the soft tissue with a volume of distribution equal to 0.56 l/kg. Despite the relatively high lipid partition coefficient (logP = 0.6), EF5 was excreted primarily (up to 70%) via kidney clearance. No drug metabolites (e.g. retaining the 2-nitroimidazole chromophore) were detected in either plasma or urine. No toxicity was found at drug doses adequate to detect tumor hypoxia. Conclusions: Currently held paradigms of 2-nitroimidazole metabolism (e.g. clearance rate and toxicity as affected by octanol/water partition coefficient) are discussed. The results reported herein suggest that EF5 is biologically stable with predictable pharmacokinetics. EF5's consistent half-life and clearance properties will allow quantitative analysis of EF5 binding relative to tissue oxygen levels. C1 Univ Penn, Sch Med, Invest Drug Serv, Philadelphia, PA 19104 USA. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Koch, CJ (reprint author), Univ Penn, Sch Med, Invest Drug Serv, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA75285] NR 59 TC 54 Z9 54 U1 1 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2001 VL 48 IS 3 BP 177 EP 187 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XZ UT WOS:000171255200001 PM 11592338 ER PT J AU Supko, JG Garcia-Carbonero, R Puchalski, TA Malspeis, L AF Supko, JG Garcia-Carbonero, R Puchalski, TA Malspeis, L TI Plasma pharmacokinetics and bioavailability of 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea after intravenous and oral administration to mice and dogs SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE antineoplastic agents; nitrosoureas; pharmacokinetics; preclinical studies ID AMINO-ACID AMIDES; GLIOMA CELL-LINE; TRANSPORT; SK-MG-1; BCNU; CHLOROETHYLNITROSOUREA; SARCOSINAMIDE; CONGENERS; SYSTEM; ASSAY AB Purpose: Chloroethylnitrosoureas are among the most widely used chemotherapeutic agents for the treatment of brain tumors. SarCNU (1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea) is an investigational nitrosourea analogue that has shown greater antitumor activity and a more favorable toxicity profile than 1,3-bis(2-chloroethyl)-1-nitrosourea in preclinical studies. The purpose of the present study was to characterize the plasma pharmacokinetics and oral bioavailability of SarCNU in mice and dogs treated by intravenous infusion and gastric intubation. Methods: SarCNU was administered to mice by i.v. injection or orally at doses ranging from 10 to 100 mg/kg. Plasma samples were obtained from groups of five animals at each time-point at intervals ranging from 3 min to 2.5 h after dosing. A group of three male beagle dogs were treated with Sar CNU 10 mg/kg given both by i.v. infusion and orally in a crossover design. The concentration of SarCNU in plasma was measured by high-performance liquid chromatography. Results: During the initial 90 min after i.v. injection to mice, SarCNU was eliminated from plasma in a monoexponential manner with a mean half-life of 9.8 +/- 0.8 min. The total plasma clearance was 47.3 +/- 8.7 ml/min per kg and the apparent volume of distribution was 0.7 +/- 0.11/kg. SarCNU exhibited linear pharmacokinetic behavior following both i.v. and oral administration of doses ranging from approximately 10 to 100 mg/kg. Peak plasma levels provided by it dose of 100 mg/kg given by the i.v. and oral routes were 142.4 mug/ml (0.5 min) and 27.8 mug/ml (9.8 min), respectively. The mean oral bioavailability of the drug was 57.3 +/- 12.6% in mice. In comparison, the disposition of SarCNU in dogs after rapid i.v. injection was biexponential, with half-lives of 5.4 +/- 8.4 min and 40.8 +/- 9.0 min for the initial and terminal disposition phases. respectively. Mean values of the total plasma clearance and apparent volume of distribution were 17.8 +/- 1.8 ml/min per kg and 1.1 +/- 0.3 l/kg, respectively. The C-max was 18.5 +/- 6.5 mug/ml after i.v. injection and 8.5 +/- 0.4 mug/ml after oral administration of it 10 mg/kg dose. Oral bioavailability or the drug in dogs (71.7 +/- 21.2%) was greater than that observed in mice. Conclusions: SarCNU exhibited linear and consistent pharmacokinetics in mice and dogs with very good oral bioavailability in both species. These findings support the rationale for evaluating SarCNU given by the oral route of administration in phase I clinical trials. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02114 USA. NCI, Lab Pharmaceut Chem, Dev Therapeut Program, Div Canc Treatment,NIH, Bethesda, MD 20892 USA. RP Supko, JG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol Oncol, 55 Fruit St, Boston, MA 02114 USA. NR 26 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2001 VL 48 IS 3 BP 202 EP 208 DI 10.1007/s002800100326 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XZ UT WOS:000171255200004 PM 11592341 ER PT J AU Thomas, RR Dahut, W Harold, N Grem, JL Monahan, BP Liang, M Band, RA Cottrell, J Llorens, V Smith, JA Corse, W Arbuck, SG Wright, J Chen, AP Hamilton, JM Allegra, CJ Takimoto, CH AF Thomas, RR Dahut, W Harold, N Grem, JL Monahan, BP Liang, M Band, RA Cottrell, J Llorens, V Smith, JA Corse, W Arbuck, SG Wright, J Chen, AP Hamilton, JM Allegra, CJ Takimoto, CH TI A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE camptothecin; topoisomerase I poison; chemotherapy ID DNA TOPOISOMERASE-I; TOPOTECAN INFUSION; 72-HOUR INFUSION; CELLS-INVITRO; CAMPTOTHECIN; MICE; INHIBITORS; XENOGRAFTS; TRIAL; PHARMACOKINETICS AB Purpose: To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion. Methods: 9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m(2) per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule. Results: Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at greater than or equal to0.6 mg/m(2) per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m(2) per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Ena, pharmacodynamic model. Conclusion: The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m(2) per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m(2) per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer. C1 Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD 20889 USA. NCI, Invest Drug Branch, Canc Treatment Evaluat Program, Div Cancer Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Dept, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI, Med Branch, Natl Naval Med Ctr, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20892 USA. EM gremj@mail.nih.gov NR 27 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2001 VL 48 IS 3 BP 215 EP 222 DI 10.1007/s002800100329 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XZ UT WOS:000171255200006 PM 11592343 ER PT J AU Salzer, W Widemann, B McCully, C Adamson, PC Balis, FM AF Salzer, W Widemann, B McCully, C Adamson, PC Balis, FM TI Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE methotrexate; cerebrospinal fluid; intrathecal; probenecid; nonhuman primate model; pharmacokinetics ID CENTRAL-NERVOUS-SYSTEM; CHEMOTHERAPY; INHIBITION; RESERVOIR; TRANSPORT; LEUKEMIA AB Purpose: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmaco kinetics of MTX after intralumbar and intraventricular administration. Methods: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure. Results: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX. Conclusion: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Salzer, W (reprint author), Keesler AFB, 81st MDOS SGOC 301 Fisher St,Room 1A132, Biloxi, MS 39534 USA. NR 20 TC 7 Z9 8 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2001 VL 48 IS 3 BP 235 EP 240 DI 10.1007/s002800100328 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 476XZ UT WOS:000171255200009 PM 11592346 ER PT J AU Wang, WW Spurdle, AB Kolachana, P Bove, B Modan, B Ebbers, SM Suthers, G Tucker, MA Kaufman, DJ Doody, MM Tarone, RE Daly, M Levavi, H Pierce, H Chetrit, A Yechezkel, GH Chenevix-Trench, G Offit, K Godwin, AK Struewing, JP AF Wang, WW Spurdle, AB Kolachana, P Bove, B Modan, B Ebbers, SM Suthers, G Tucker, MA Kaufman, DJ Doody, MM Tarone, RE Daly, M Levavi, H Pierce, H Chetrit, A Yechezkel, GH Chenevix-Trench, G Offit, K Godwin, AK Struewing, JP TI A single nucleotide polymorphism in the 5 ' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; GENETIC-HETEROGENEITY; FAMILIES; PROTEIN; SEQUENCE; REPAIR; REPEAT AB RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. Queensland Inst Med Res, Brisbane, Qld 4029, Australia. S Australian Clin Genet Serv, Adelaide, SA 5005, Australia. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Chaim Sheba Med Ctr, IL-52641 Tel Hashomer, Israel. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, NIH, Bldg 41-D702,41 Lib Dr, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Spurdle, Amanda/A-4978-2011; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Spurdle, Amanda/0000-0003-1337-7897; Struewing, Jeffery/0000-0002-4848-3334 NR 26 TC 128 Z9 136 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 SEP PY 2001 VL 10 IS 9 BP 955 EP 960 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 470YA UT WOS:000170899000007 PM 11535547 ER PT J AU Ojeifo, JO Lee, HR Rezza, P Su, N Zwiebel, JA AF Ojeifo, JO Lee, HR Rezza, P Su, N Zwiebel, JA TI Endothelial cell-based systemic gene therapy of metastatic melanoma SO CANCER GENE THERAPY LA English DT Article DE interleukin 2; endothelial cells; gene therapy; murine melanoma ID BREAST-CANCER; BONE-MARROW; TUMOR ANGIOGENESIS; PROGENITOR CELLS; IN-VITRO; SIGNAL-TRANSDUCTION; RETROVIRAL VECTORS; DRUG-DELIVERY; LYMPHOCYTES-T; MURINE TUMORS AB Cancer metastasis accounts for a significant proportion of morbidity and mortality in patients. Effective means of treating disseminated disease remains elusive. The purpose of this study was to determine whether genetically modified endothelial cells (GMEC) can selectively target and deliver recombinant therapeutic molecules to sites of tumor metastases. Following the establishment of lung metastases of 4T1 mammary tumor in mice, intravenously (i.v.) administered, lacZ transgene-expressing endothelial cells (lacZ-GMEC) accumulated at the tumor sites. An average of 32% and 90% of the pulmonary metastases were X-gal stained following one and three tail vein injections of 10(5) lacZ-GMEC, respectively. The linear pattern of X-gal staining seen within the tumor sites and the histological appearance of the tumor vasculature were consistent with the incorporation of lacZ-GMEC into blood vessels. In C57B1/6 mice harboring lung metastases of melanoma, the administration of three sequential i.v. injections of 105 endothelial cells expressing a human interleukin 2 transgene abrogated the tumor metastases and prolonged survival of the animals. These results demonstrate that i.v.-administered GMEC can selectively accumulate, survive, and stably express exogenous genes at multiple tumor sites. These findings support a role for i.v.-administered GMEC as a potential therapeutic strategy for the systemic treatment of cancer metastases. C1 Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NCI, NIH, Div Canc Treatment & Diag,Biol Evaluat Sect, Canc Therapy Evaluat Program,Invest Drug Branch, Rockville, MD 20852 USA. RP Zwiebel, JA (reprint author), EPN 7114,6130 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [P30 CA-51008, 5P50-CA58185, CA 53922] NR 64 TC 19 Z9 19 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD SEP PY 2001 VL 8 IS 9 BP 636 EP 648 DI 10.1038/sj.cgt.7700356 PG 13 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 475QM UT WOS:000171175600003 PM 11593332 ER PT J AU Cao, Q Abeysinghe, H Chow, O Xu, J Kaung, HL Fong, CT Keng, P Insel, RA Lee, WCM Barrett, JC Wang, N AF Cao, Q Abeysinghe, H Chow, O Xu, J Kaung, HL Fong, CT Keng, P Insel, RA Lee, WCM Barrett, JC Wang, N TI Suppression of tumorigenicity in human ovarian carcinoma cell line SKOV-3 by microcell-mediated transfer of chromosome 11 SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID BREAST-CANCER CELLS; FREQUENT LOSS; TUMOR; HETEROZYGOSITY; ADENOCARCINOMA; EXPRESSION; REGION; GENES; 17Q; 3P AB To determine the pathogenic role of chromosomes 11 and 17 in the carcinogenesis of human ovarian cancers, neo(R)-tagged chromosome 11 or 17 was transferred from cell lines A9H11 or A9H17 respectively, into the ovarian carcinoma cell line SKOV-3 using microcell-mediated chromosome transfer. The chromosome transfer was verified by polymerase chain reaction detection of the neo(R) gene, fluorescence in situ hybridization detection of an extra chromosome 11, and microsatellite polymorphism detection of an exogeneous chromosome It. Five SKOV-3/A9H11 hybrids and five SKOV-3/A9H17 hybrid clones were generated. For the chromosome 11 transfer. complete suppression of tumorigenicity was observed in four clones. (11)9-8 and 11(H)7-2. 11(H)8-3 and 11(H)7-2. 100 days post implantation. For the chromosome 17 transfer, no complete suppression of tumorigenicity was observed. However. an increased latency period ranging from 25 to 49 days in contrast to 7 days for the SKOV-3 parental line, and a significant reduction in tumor size was observed. There was no correlation between the in vitro growth rate and the tumorigenicity or length of latency period. Our results demonstrate functionally that chromosome 11 may carry a tumor suppressor gene(s) while chromosome 17 may carry a tumor growth-inhibitor gene(s) for the ovarian carcinoma cell line. SKOV-3. (C) 2001 Elsevier Science Inc. All rig-hts reserved. C1 Dept Pathol & Lab Med, Rochester, NY USA. Dept Pediat, Rochester, NY USA. Univ Rochester, Sch Med & Dent, Dept Radiat Oncol, Rochester, NY USA. Case Western Reserve Univ, Dept Anat, Cleveland, OH 44106 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wang, N (reprint author), Dept Pathol & Lab Med, Rochester, NY USA. FU NCI NIH HHS [CA52761] NR 27 TC 21 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD SEP PY 2001 VL 129 IS 2 BP 131 EP 137 DI 10.1016/S0165-4608(01)00442-3 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 474KK UT WOS:000171105500007 PM 11566343 ER PT J AU Patt, J Morrison, S AF Patt, J Morrison, S TI National Cancer Institute resources for patients and their caregivers SO CANCER PRACTICE LA English DT Article C1 NCI, Canc Informat Serv Branch, Bethesda, MD 20892 USA. Aspen Syst Corp, Rockville, MD USA. RP Patt, J (reprint author), NCI, Canc Informat Serv Branch, Bethesda, MD 20892 USA. NR 9 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD SEP-OCT PY 2001 VL 9 IS 5 BP 257 EP 261 DI 10.1046/j.1523-5394.2001.009005257.x PG 5 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 473CM UT WOS:000171022100008 PM 11879323 ER PT J AU Seftor, REB Seftor, EA Koshikawa, N Meltzer, PS Gardner, LMG Bilban, M Stetler-Stevenson, WG Quaranta, V Hendrix, MJC AF Seftor, REB Seftor, EA Koshikawa, N Meltzer, PS Gardner, LMG Bilban, M Stetler-Stevenson, WG Quaranta, V Hendrix, MJC TI Cooperative interactions of laminin 5 gamma 2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma SO CANCER RESEARCH LA English DT Article ID TISSUE INHIBITOR; CELL-MIGRATION; ANGIOGENESIS; EXPRESSION; MT1-MMP AB Vasculogenic mimicry describes a process where aggressive tumor cells in three-dimensional matrices mimic embryonic vasculogenesis by forming extracellular matrix (ECM)-rich, patterned tubular networks. Microarray gene chip analyses revealed significant increases in the expression of laminin 5 (Ln-5, gamma2 chain) and matrix metalloproteinases (MMP)-1, -2, -9, and MT1-MMP (MMP-14) in aggressive compared with poorly aggressive melanoma cells. These components colocalized with developing patterned networks and antisense oligonucleotides to the Ln-5 gamma2 chain (but not sense oligonucleotides), and antibodies to MMP-2 or MT1-MMP (but not MMP-9) inhibited the formation of these networks. Cultures which did not receive antibodies to either MMPs-2 or -14 contained the Ln-5 gamma2 chain promigratory cleavage fragments. Poorly aggressive melanoma cells seeded on collagen I matrices preconditioned by the aggressive cells formed tubular networks along the Ln-5 gamma2 chain-enriched tracks deposited by the aggressive cells. These results suggest that increased expression of MMP-2 and MT1-MMP, along with matrix deposition of the Ln-5 gamma2 chain and/or its cleavage fragments, are required for vasculogenic mimicry by aggressive melanoma cells. Furthermore, the apparent recapitulation of laminin-rich, patterned networks observed in aggressive melanoma patients' tissue sections by aggressive melanoma tumor cells in three-dimensional culture may also serve as a model to help identify specific molecular targets which could function as templates for the coordinated migration of aggressive tumor cells and their proteolytic remodeling of the ECM and may have profound implications for the development of novel therapies directed at the ECM to alter tumor progression. C1 Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Hendrix, MJC (reprint author), Univ Iowa, Dept Anat & Cell Biol, 51 Newton Rd,1-100 BSB, Iowa City, IA 52242 USA. RI Stetler-Stevenson, William/H-6956-2012; Quaranta, Vito/G-6512-2016 OI Stetler-Stevenson, William/0000-0002-5500-5808; Quaranta, Vito/0000-0001-7491-8672 FU NCI NIH HHS [CA88043-2S, CA47858, CA47858-13S, CA59702, CA80318, CA83137]; NIGMS NIH HHS [GM46902] NR 20 TC 231 Z9 255 U1 1 U2 16 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2001 VL 61 IS 17 BP 6322 EP 6327 PG 6 WC Oncology SC Oncology GA 466GU UT WOS:000170637700003 PM 11522618 ER PT J AU Kitazono, M Goldsmith, ME Aikou, T Bates, S Fojo, T AF Kitazono, M Goldsmith, ME Aikou, T Bates, S Fojo, T TI Enhanced adenovirus transgene expression in malignant cells treated with the histone deacetylase inhibitor FR901228 SO CANCER RESEARCH LA English DT Article ID RECEPTOR; GENE; POTENT AB The presence of coxsackie and adenovirus receptor (CAR) and alpha (v) integrin on cell surfaces is required for efficient adenovirus infection. Treatment of cells with the histone deacetylase inhibitor FR901228 (depsipeptide) increased CAR and alpha (v) integrin RNA levels in six cancer cell lines. Sodium butyrate and trichostatin A, other histone deacetylase inhibitors, caused similar increases. Cells treated with FR901228 prior to infection had a 4-10-fold increase in transgene expression from a beta -galactosidase-expressing adenoviral vector. These studies suggest that FR901228 increases the efficiency of adenoviral transgene expression and may be useful in cancer gene therapy. C1 NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Kagoshima Univ, Fac Med, Dept Surg 1, Kagoshima 8908520, Japan. RP Fojo, T (reprint author), NCI, Canc Res Ctr, NIH, Bldg 10,Room 12C103,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 76 Z9 78 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2001 VL 61 IS 17 BP 6328 EP 6330 PG 3 WC Oncology SC Oncology GA 466GU UT WOS:000170637700004 PM 11522619 ER PT J AU Hussain, SP Amstad, P Raja, K Sawyer, M Hofseth, L Shields, PG Hewer, A Phillips, DH Ryberg, D Haugen, A Harriss, CC AF Hussain, SP Amstad, P Raja, K Sawyer, M Hofseth, L Shields, PG Hewer, A Phillips, DH Ryberg, D Haugen, A Harriss, CC TI Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; HUMAN CANCER; MOLECULAR EPIDEMIOLOGY; CYTOSINE METHYLATION; HUMAN HEPATOCYTES; BENZOPYRENE; TRANSVERSION; MUTAGENESIS; CARCINOMA; SPECTRUM AB p53 mutations are common in lung cancer. In smoking-associated lung cancer, the occurrence of G:C to TA transversions at hotspot codons, e.g., 157, 248, 249, and 273, has been linked to the presence of carcinogenic chemicals in tobacco smoke including polycyclic aromatic hydrocarbons such as benzo(a)pyrene (BP). In the present study, we have used a highly sensitive mutation assay to determine the p53 mutation load in nontumorous human lung and to study the mutability of p53 codons 157, 248, 249, and 250 to benzo(a)pyrene-diol-epoxide (BPDE), an active metabolite of BP in human bronchial epithelial BEAS-2B cells. We determined the p53 mutational load at codons 157, 248, 249, and 250 in nontumorous peripheral lung tissue either from lung cancer cases among smokers or noncancer controls among smokers and nonsmokers. A 5-25-fold higher frequency of GTC(val) to TTCphe transversions at codon 157 was found in nontumorous samples (57%) from cancer cases (n = 14) when compared with noncancer controls (n = 8; P < 0.01). Fifty percent (7/14) of the nontumorous samples from lung cancer cases showed a high frequency of codon 249 AGG(arg) to AGT(ser) mutations (P < 0.02). Four of these seven samples with AGT(ser) mutations also showed a high frequency of codon 249 AGG(arg) to ATG(met) mutations, whereas only one sample showed a codon 250 CCC to ACC transversion. Tumor tissue from these lung cancer cases (38%) contained p53 mutations but were different from the above mutations found in the nontumorous pair. Noncancer control samples from smokers or nonsmokers did not contain any detectable mutations at codons 248, 249, or 250. BEAS-2B bronchial epithelial cells exposed to doses of 0.125, 0.5, and 1.0 muM BPDE, showed G:C to T:A transversions at codon 157 at a frequency of 3.5 x 10(-7), 4.4 x 10(-7), and 8.9 x 10(-7), respectively. No mutations at codon 157 were found in the DMSO-treated controls. These doses of BPDE induced higher frequencies, ranging from 4-12-fold, of G:C to TA transversions at codon 248, G:C to T:A transversions and G:C to A:T transitions at codon 249, and C;G to TA transitions at codon 250 when compared with the DMSO-treated controls. These data are consistent with the hypothesis that chemical carcinogens such as BP in cigarette smoke cause G:C to T:A transversions at p53 codons 157, 248, and 249 and that nontumorous lung tissues from smokers with lung cancer carry a high p53 mutational load at these codons. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harriss, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 2C05, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 NR 34 TC 99 Z9 105 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2001 VL 61 IS 17 BP 6350 EP 6355 PG 6 WC Oncology SC Oncology GA 466GU UT WOS:000170637700009 PM 11522624 ER PT J AU Goldman, R Enewold, L Pellizzari, E Beach, JB Bowman, ED Krishnan, SS Shields, PG AF Goldman, R Enewold, L Pellizzari, E Beach, JB Bowman, ED Krishnan, SS Shields, PG TI Smoking increases carcinogenic polycyclic aromatic hydrocarbons in human lung tissue SO CANCER RESEARCH LA English DT Article ID DNA-ADDUCTS; CANCER; BENZOPYRENE; INDUCTION AB Tobacco smoke is a major source of human exposure to polycyclic aromatic hydrocarbons (PAHs). The concentration of PAHs in lung tissue would reflect an individual's dose, and its variation could perhaps reflect cancer risk. Eleven PAHs were measured in 70 lung tissue samples from cancer-free autopsy donors by gas chromatography-mass spectrometry. There were 37 smokers and 33 nonsmokers as estimated by serum cotinine concentration. The sum of PAH concentrations was higher in smokers (P = 0.01), and there was a dose-response relationship for greater smoking (P < 0.01). Smoking increased the concentration of five PAHs including benzo(a)pyrene, which increased 2-fold. The risk for increasing carcinogenic PAHs (odds ratio, 8.20; 95% confidence interval, 2.39-28.09) was 3-fold compared with noncarcinogenic PAHs (odds ratio, 2.61; 95% confidence interval, 0.75-9.12). A higher concentration of PAHs was detected in the lung tissue of males, although the estimated smoking was similar in males and females. Race was not associated with PAH concentrations overall, but PAH concentrations appeared to be higher in African-American males than in any other group. Age was weakly correlated with an increase in fluoranthene and pyrene. The measurement of PAHs in human lung tissue can be used to estimate the actual dose to the target organ. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Canc Genet & Epidemiol Program, Washington, DC 20007 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Shields, PG (reprint author), Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Canc Genet & Epidemiol Program, Res Bldg W315,3970 Reservoir Rd NW, Washington, DC 20007 USA. RI Shields, Peter/I-1644-2012 NR 24 TC 66 Z9 76 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2001 VL 61 IS 17 BP 6367 EP 6371 PG 5 WC Oncology SC Oncology GA 466GU UT WOS:000170637700012 PM 11522627 ER PT J AU Chervinsky, DS Lam, DH Melman, MP Gross, KW Aplan, PD AF Chervinsky, DS Lam, DH Melman, MP Gross, KW Aplan, PD TI scid thymocytes with TCR beta gene rearrangements are targets for the oncogenic effect of SCL and LMO1 transgenes SO CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; COMBINED IMMUNE-DEFICIENCY; T-CELL MALIGNANCIES; V(D)J RECOMBINATION; RECEPTOR GENES; MICE; TAL-1; EXPRESSION; LYMPHOMA; MURINE AB SCL and LMO1 were both discovered by virtue of their activation by chromosomal translocation in patients with T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of SCL and LMO1 in the thymus of transgenic mice leads to T-ALL at a young age. scid (severe combined immunodeficient) mice are unable to efficiently recombine antigen receptor genes and consequently display a developmental block at the CD4-CD8- to CD4+CD8+ transition. To test the hypothesis that this developmental block would protect SCL/LMO1 transgenic mice from developing T-ALL, we crossed the SCL and LVO1 transgenes onto a scid background. The age of onset for T-ALL in the SCL/LMO1/scid mice was significantly delayed (P < 0.001) compared with SCL/LMO1/wild-type mice. Intriguingly, all of the SCL/LMO1/scid malignancies displayed clonal, in-frame TCR gene rearrangements. Taken together, these findings suggest that the "leaky" scid thymocyte that undergoes a productive TCR beta gene rearrangement is susceptible to the oncogenic action of SCL and LMO1 and additionally suggests that TCR beta gene rearrangements may be required for the oncogenic action of SCL and LMO1. C1 NCI, Dept Genet, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. RP Aplan, PD (reprint author), NCI, Div Clin Sci, Ctr Adv Technol, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. RI Aplan, Peter/K-9064-2016 NR 27 TC 15 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2001 VL 61 IS 17 BP 6382 EP 6387 PG 6 WC Oncology SC Oncology GA 466GU UT WOS:000170637700015 PM 11522630 ER PT J AU Martin, KR Trempus, C Saulnier, M Kari, FW Barrett, JC French, JE AF Martin, KR Trempus, C Saulnier, M Kari, FW Barrett, JC French, JE TI Dietary N-acetyl-L-cysteine modulates benzo[alpha]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice SO CARCINOGENESIS LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; TRANSGENIC MOUSE MODELS; MALIGNANT CONVERSION; EXPRESSION; GROWTH; KERATOACANTHOMAS; BENZOPYRENE; PROGRESSION; PAPILLOMAS; PROMOTION AB Epidemiologic studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence from clinical trials and laboratory data suggest that in some cases individual antioxidant supplements may actually exacerbate carcinogenesis. Our goal was to explore these paradoxical activities in a rodent model that possesses genotypic characteristics of human cancers. We selected the p53 haploinsufficient Tg.AC (v-Ha-ras) mouse as a model, because it contains an activated, carcinogen-inducible ras oncogene and an inactivated p53 tumor suppressor gene, which are frequent genetic alterations in human cancers. These mice develop chemically induced benign and malignant skin tumors rapidly which can easily be quantified. Mice were fed basal diets with or without 3% N-acetyl-L-cysteine (NAC), a well-recognized antioxidant, prior to, during and after topical application of the carcinogen benzo[alpha ]pyrene (64 mug/mouse) applied twice per week for 7 weeks. Tumor incidence exceeded 90% for both groups, and NAC did not reduce tumor latency. Mice fed NAC displayed a 43% reduction (P<0.05) in tumor multiplicity and delayed the appearance of lesions (P<0.05). Dietary NAC also significantly (P<0.05) improved group survival by 5 weeks. Total tumor yields were reduced in both dietary groups but malignant spindle cell tumors (SCT) increased by 25% in NAC-fed mice. The v-Ha-ras oncogene and p53 protein products were clearly co-expressed in both benign and malignant lesions from both dietary groups. In summary, dietary supplementation with NAC was chemopreventive, but the marginal increase in SCT suggests a paradoxical effect. C1 NIEHS, Transgen Carcinogenesis Unit, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP French, JE (reprint author), NIEHS, Transgen Carcinogenesis Unit, Lab Environm Carcinogenesis & Mutagenesis, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 45 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2001 VL 22 IS 9 BP 1373 EP 1378 DI 10.1093/carcin/22.9.1373 PG 6 WC Oncology SC Oncology GA 473CC UT WOS:000171021100006 PM 11532857 ER PT J AU Yagi, E Barrett, JC Tsutsui, T AF Yagi, E Barrett, JC Tsutsui, T TI The ability of four catechol estrogens of 17 beta-estradiol and estrone to induce DNA adducts in Syrian hamster embryo fibroblasts SO CARCINOGENESIS LA English DT Article ID VITAMIN-C; INDUCED CARCINOGENESIS; METABOLIC-ACTIVATION; MAMMALIAN-CELLS; TRANSFORMATION; MECHANISM; CANCER; INHIBITION; INITIATION; HORMONES AB Catechol estrogens are considered critical intermediates in estrogen-induced carcinogenesis. We demonstrated previously that 17 beta -estradiol (E-2), estrone (E-1) and four of their catechol estrogens, 2- and 4-hydroxyestradiols (2- and 4-OHE2,), and 2- and 4-hydroxyestrones (2- and 4-OHE1) induce morphological transformation in Syrian hamster embryo (SHE) fibroblasts, and the transforming abilities vary as follows: 4-OHE1 > 2-OHE1 > 4-OHE2 > 2-OHE2 greater than or equal to E-2, E-1. To examine the involvement of catechol estrogens in the initiation of hormonal carcinogenesis, we studied the ability of E-2, E-1 and their catechol estrogens to induce DNA adducts in SHE cells by using a P-32-post- labeling assay. DNA adducts were detected in cells treated with each of all the catechol estrogens at concentrations of 10 mug/ml for 1 h and more. 2- or 4-OHE2 formed a single DNA adduct, which was chromatographically distinct from each other. In contrast, 2- or 4-OHE2 produced one major and one minor adduct, and the two adducts formed by each catechol estrogen exhibited identical mobilities on the chromatograms. Neither E-2 nor E-1 at concentrations up to 30 mug/ml induced DNA adducts. The abilities of the estrogens to induce DNA adducts were ranked as follows: 4-OHE1, > 2-OHE1 > 4-OHE2 > 2-OHE2 >> E-2, E-1, which corresponds well to the transforming and carcinogenic abilities of the estrogens. In addition, the level of DNA adducts induced by the catechol estrogens was markedly decreased by co-treatment of cells with the antioxidant L-ascorbic acid. The results indicate the possible involvement of oxidative metabolites of catechol estrogens of E-2 and E-1 in the initiation of endogenous estrogen-induced carcinogenesis. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Nippon Dent Univ, Sch Dent, Dept Pharmacol, Tokyo 1028159, Japan. NCI, Bethesda, MD 20892 USA. RP Barrett, JC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 20 Z9 20 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2001 VL 22 IS 9 BP 1505 EP 1510 DI 10.1093/carcin/22.9.1505 PG 6 WC Oncology SC Oncology GA 473CC UT WOS:000171021100022 PM 11532873 ER PT J AU Devanesan, P Santen, RJ Bocchinfuso, WP Korach, KS Rogan, EG Cavalieri, E AF Devanesan, P Santen, RJ Bocchinfuso, WP Korach, KS Rogan, EG Cavalieri, E TI Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-alpha knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors SO CARCINOGENESIS LA English DT Article ID CHROMOSOMAL LOCALIZATION; GLAND HYPERPLASIA; EXPRESSION; BETA; GENE; CARCINOGENESIS; GLUTATHIONE; CLONING; INT-1 AB A novel model of breast cancer was established by crossing mice carrying the Wnt-1 transgene (100% of adult females develop spontaneous mammary tumors) with the ERKO mouse line, in which mammary tumors develop despite a lack of functional estrogen receptor-alpha. To begin investigating whether metabolite-mediated genotoxicity of estrogens may play an important role in the initiation of mammary tumors, the pattern of estrogen metabolites and conjugates was examined in ERKO/Wnt-1 mice. Extracts of hyperplastic mammary tissue and mammary tumors were analyzed by HPLC with identification and quantification of compounds by multichannel electrochemical detection. Picomole amounts of the 4-catechol estrogens (CE) were detected, but their methoxy conjugates, as well as the 2-CE and their methoxy conjugates, were not. 4-CE conjugates with glutathione or its hydrolytic products (cysteine and N-acetylcysteine) were detected in picomole amounts in both tumors and hyperplastic mammary tissue, demonstrating the formation of CE-3,4-quinones. These preliminary findings show that the estrogen metabolite profile in the mammary tissue is unbalanced, in that the normally minor 4-CE metabolites were detected in the mammary tissue and not the normally predominant 2-CE. These results are consistent with the hypothesis that the mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones, which may react with DNA to induce oncogenic mutations. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Univ Virginia, Hlth Sci Ctr, Div Hematol Oncol & Endocrinol, Charlottesville, VA 22908 USA. NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cavalieri, E (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NCI NIH HHS [P01 CA49210, P30 CA36727] NR 29 TC 71 Z9 71 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2001 VL 22 IS 9 BP 1573 EP 1576 DI 10.1093/carcin/22.9.1573 PG 4 WC Oncology SC Oncology GA 473CC UT WOS:000171021100031 PM 11532882 ER PT J AU Smaili, SS Hsu, YT Sanders, KM Russel, JT Youle, RJ AF Smaili, SS Hsu, YT Sanders, KM Russel, JT Youle, RJ TI Bax translocation to mitochondria subsequent to a rapid loss of mitochondrial membrane potential SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE mitochondria; Bax; mitochondrial membrane potential; mitochondrial inhibitors ID CYTOCHROME-C RELEASE; PERMEABILITY TRANSITION PORE; PROGRAMMED CELL-DEATH; BCL-X-L; INDUCED CASPASE ACTIVATION; PROAPOPTOTIC PROTEIN BAX; CHANNEL-FORMING ACTIVITY; IN-VIVO; MAMMALIAN-CELLS; DEFICIENT MICE AB Bax, a pro-apoptotic member of the Bcl-2 family, is a cytosolic protein that inserts into mitochondrial membranes upon induction of cell death. Using the green fluorescent protein fused to Bax (GFP-Bax) to quantitate mitochondrial binding in living cells we have investigated the cause of Bax association with mitochondria and the time course relative to endogenous and induced changes in mitochondrial membrane potential (Delta Psi (m)). We have found that staurosporine (STS) induces a loss in Delta Psi (m) before GFP-Bax translocation can be measured. The onset of the Delta Psi (m) loss is followed by a rapid and complete collapse of Delta Psi (m) which is followed by Bax association with mitochondria. The mitochondria uncoupler FCCP, in the presence of the F-1-F-0 ATPase inhibitor oligomycin, can trigger Bax translocation to mitochondria suggesting that when ATP levels are maintained a collapse of Delta Psi (m) induces Bax translocation. Neither FCCP nor oligomycin alone alters Bax location. Bax association with mitochondria is also triggered by inhibitors of the electron transport chain, antimycin and rotenone, compounds that collapse Delta Psi (m) without inducing rapid ATP hydrolysis that typically occurs with uncouplers such as FCCP. Taken together, our results suggest that alterations in mitochondrial energization associated with apoptosis can initiate Bax docking to mitochondria. C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo, Brazil. NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 67 TC 117 Z9 121 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 2001 VL 8 IS 9 BP 909 EP 920 DI 10.1038/sj.cdd.4400889 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 463JA UT WOS:000170472300005 PM 11526446 ER PT J AU McNairy, SA AF McNairy, SA TI Message from the director SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Editorial Material C1 Natl Ctr Res Resources, Div Res Infrastruct, NIH, Bethesda, MD 20892 USA. RP McNairy, SA (reprint author), Natl Ctr Res Resources, Div Res Infrastruct, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD SEP PY 2001 VL 47 IS 6 BP 973 EP 975 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 506QL UT WOS:000172983200002 ER PT J AU Ruszczynski, PS Kish, LB Bezrukov, SM AF Ruszczynski, PS Kish, LB Bezrukov, SM TI Noise-assisted traffic of spikes through neuronal junctions SO CHAOS LA English DT Article ID STOCHASTIC RESONANCE; COLORED NOISE; 1/F NOISE; ENHANCEMENT; SYSTEMS; FLOW; FLUCTUATION; WAVES; JAMS; CAR AB The presence of noise, i.e., random fluctuations, in the nervous system raises at least two different questions. First, is there a constructive role noise can play for signal transmission in a neuron channel? Second, what is the advantage of the power spectra observed for the neuron activity to be shaped like 1/f(k)? To address these questions a simple stochastic model for a junction in neural spike traffic channels is presented. Side channel traffic enters main channel traffic depending on the spike rate of the latter one. The main channel traffic itself is triggered by various noise processes such as Poissonian noise or the zero crossings of Gaussian 1/f(k) noise whereas the variation of the exponent k gives rise to a maximum of the overall traffic efficiency. It is shown that the colored noise is superior to the Poissonian and, in certain cases, to deterministic, periodically ordered traffic. Further, if this periodicity itself is modulated by Gaussian noise with different spectral exponents k, then such modulation can lead to noise-assisted traffic as well. The model presented can also be used to consider car traffic at a junction between a main and a side road and to show how randomness can enhance the traffic efficiency in a network. (C) 2001 American Institute of Physics. C1 Uppsala Univ, Angstrom Lab, SE-75212 Uppsala, Sweden. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Ruszczynski, PS (reprint author), Uppsala Univ, Angstrom Lab, POB 534, SE-75212 Uppsala, Sweden. NR 35 TC 2 Z9 2 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 1054-1500 J9 CHAOS JI Chaos PD SEP PY 2001 VL 11 IS 3 BP 581 EP 586 DI 10.1063/1.1379308 PG 6 WC Mathematics, Applied; Physics, Mathematical SC Mathematics; Physics GA 469EC UT WOS:000170800800016 ER PT J AU Mylonas, M Malandrinos, G Plakatouras, J Hadjiliadis, N Kasprzak, KS Krezel, A Bal, W AF Mylonas, M Malandrinos, G Plakatouras, J Hadjiliadis, N Kasprzak, KS Krezel, A Bal, W TI Stray Cu(II) may cause oxidative damage when coordinated to the -TESHHK- sequence derived from the C-terminal tail of histone H2A SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID COPPER(II) COMPLEXES; REDUCTION POTENTIALS; OXYGEN ACTIVATION; PULSE-RADIOLYSIS; 3RD RESIDUE; NICKEL(II); BINDING; STABILITY; DNA; PEPTIDES AB CH3CO-Thr-Glu-Ser-His-His-Lys-NH2, a hexapeptide representing the 120-125 sequence of histone H2A, coordinates Cu(II) ions efficiently. Monomeric complexes are formed. In the major complex at physiological pH, CuH-1L, Cu(II) is coordinated equatorially through the imidazole nitrogen of the His-4 residue and the amide nitrogens of the Ser-3 and His-4 residues, and axially through the imidazole nitrogen of the His-5 residue. This complex reacts with H2O2 and the resulting reactive oxygen intermediate efficiently oxidizes 2 ' -deoxyguanosine. The underlying mechanism involves the formation of Cu(III) and a metal-bound hydroxyl radical species. C1 Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland. Univ Ioannina, Dept Chem, GR-45110 Ioannina, Greece. Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Polish Acad Sci, Inst Biochem & Biophys, Warsaw, Poland. RP Bal, W (reprint author), Univ Wroclaw, Fac Chem, PL-50383 Wroclaw, Poland. RI Krezel, Artur/E-7047-2011 NR 47 TC 26 Z9 26 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2001 VL 14 IS 9 BP 1177 EP 1183 DI 10.1021/tx010031n PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 475GJ UT WOS:000171153800004 PM 11559031 ER PT J AU Ju, C Pohl, LR AF Ju, C Pohl, LR TI Immunohistochemical detection of protein adducts of 2,4-dinitrochlorobenzene in antigen presenting cells and lymphocytes after oral administration to mice: Lack of a role of Kupffer cells in oral tolerance SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID SINUSOIDAL ENDOTHELIAL-CELLS; PORTAL VENOUS TOLERANCE; CD4(+) T-CELLS; IDIOSYNCRATIC DRUG-REACTIONS; ACTIVATION IN-VITRO; IMMUNE-RESPONSES; DENDRITIC CELLS; INDUCTION; LIVER; RAT AB Although current studies suggest that most drug-induced allergic reactions (DIARS) are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins, it is not clear why these reactions are relatively rare. One possible pathway that may explain the low incidence of DIARS in many cases is oral tolerance, an antigen-specific immunological hyporesponsiveness induced by oral administration of antigens. The mechanism of oral tolerance, however, is not clearly understood and is difficult to study directly with drugs, because animal models of DIARS have been elusive. We chose 2,4-dinitrochlorobenzene (DNCB) as a model compound to circumvent this problem because animal models of allergic reactions have been established for this compound. DNCB forms immunogenic 2,4-dinitrophenylated (DNP) protein conjugates that can induce immune reactions and it causes oral tolerance when it is fed to animals prior to sensitization. We hypothesized that DNP-protein conjugates may have a role in oral tolerance. To test this idea, we have begun to identify cells bearing these conjugates after the oral administration of DNCB. Female C57BL/6J mice were fed DNCB and tissues were examined after 6 and 24 h. Immunohistochemical analysis indicated the presence of DNP-protein conjugates in enterocytes of the small intestine, in macrophages and lymphocytes of the mesenteric lymph nodes, in dendritic cells and lymphocytes of the spleen, and in Kupffer cells and other sinusoidal cells of the liver. It was found that Kupffer cell depletion did not affect oral tolerance to DNCB. The findings suggest that the cells bearing DNP-protein conjugates, other than Kupffer cells, in the liver and other tissues may be important in the induction of oral tolerance against DNCB. Protein adducts of drugs administered orally may also be present in these cells, and they may have a role in the downregulation of DIARS in many individuals. C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ju, C (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 55 TC 13 Z9 13 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2001 VL 14 IS 9 BP 1209 EP 1217 DI 10.1021/tx0100587 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 475GJ UT WOS:000171153800008 PM 11559035 ER PT J AU Ilankumaran, P Pannell, LK Gebreselassie, P Pilcher, AS Yagi, H Sayer, JM Jerina, DM AF Ilankumaran, P Pannell, LK Gebreselassie, P Pilcher, AS Yagi, H Sayer, JM Jerina, DM TI Patterns of resistance to exonuclease digestion of oligonucleotides containing polycyclic aromatic hydrocarbon diol epoxide adducts at N-6 of deoxyadenosine SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID SNAKE-VENOM PHOSPHODIESTERASE; DNA-ADDUCTS; OPPOSITE DT; 9,10-EPOXIDE-DEOXYADENOSINE ADDUCTS; SOLUTION CONFORMATION; N-6-AMINO GROUP; BENZOPHENANTHRENE; DUPLEX; SITE; CIS AB The effect of adduct stereochemistry on the susceptibility to hydrolysis by snake venom (VPD) and bovine spleen (SPD) phosphodiesterases was investigated with short deoxyoligonucleotides containing defined adducts derived from alkylation of the exocyclic 6-amino group of dA by polycyclic aromatic hydrocarbon diol epoxides (DEs). In accordance with several earlier reports, we have found that adducts with R configuration at the site of attachment of dA to the DE moiety derived from either benzo[alpha ]pyrene (BaP) or benzo[c]phenanthrene (BcPh) are generally more resistant to hydrolysis by VPD than are their (S)-diastereomers. The reaction with VPD initially yields a fragment containing the adducted dA residue at its 3 ' -end, which slowly hydrolyzes to a dimer (pXpA*) with an intact 5 ' -phosphodiester bond to the adducted dA. With several of the adducts studied, this dimer underwent cleavage to release eventually the monomeric adduct p(dA*). Adducts derived from cis opening of the epoxide ring of both BaP and BcPh DEs were considerably more resistant to VPD than the corresponding trans-opened adducts. Although several previous investigations had suggested that oligonucleotides containing adducts which have S configuration at the site of attachment of the hydrocarbon to adenine are more resistant to cleavage by SPD than are their (R)-diastereomers, the present results with a more extensive set of oligonucleotides indicate that SPD, in contrast to VPD, exhibits little discrimination between adducts with R and S configuration at the site of attachment to the base. Notably, for both enzymes, the most resistant internucleotide linkage (the bond 3 ' -sugar to phosphate for VPD and 5 ' -sugar to phosphate for SPD) is between the modified base and the base immediately 5 ' to it, regardless of the configuration of the adduct. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 32 TC 10 Z9 10 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2001 VL 14 IS 9 BP 1330 EP 1338 DI 10.1021/tx010092l PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 475GJ UT WOS:000171153800023 PM 11559050 ER PT J AU Appelbaum, M Batten, DA Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, A Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Vandell, DL Weinraub, M AF Appelbaum, M Batten, DA Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, A Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Vandell, DL Weinraub, M CA NICHD Early Child Res Network TI Child care and children's peer interaction at 24 and 36 months: The NICHD study of early child care SO CHILD DEVELOPMENT LA English DT Review ID INFANT DAY-CARE; SOCIAL COMPETENCE; DEVELOPMENTAL PERSPECTIVE; 2ND YEAR; QUALITY; AGGRESSION; CONFLICT; PRESCHOOLERS; AGE; ADJUSTMENT AB Data from the National Institute of Child Health and Human Development Study of Early Child Care were examined to determine how children's experiences in child care were related to peer competence at 24 and 36 months of age, after controlling for the effects of family and child characteristics. Peer competence was assessed using mother and caregiver ratings as well as observations of children with their peers in child care, and at 36 months from observations of dyadic play with a familiar peer. Consistent, albeit modest, relations were found between child-care experiences in the first 3 years of life and children's peer competencies. Positive, responsive caregiver behavior was the feature of child care most consistently associated with positive, skilled peer interaction in child care. Children with more experience in child-care settings with other children present were observed to be more positive and skilled in their peer play in child care, although their caregivers rated them as more negative with playmates. Children who spent more hours in child care were rated by their caregivers as more negative in peer play, but their observed peer play was not related to the quantity of care. Child-care experiences were not associated with peer competence as rated by mothers or as observed in dyadic play with a friend. Maternal sensitivity and children's cognitive and language competence predicted peer competence across all settings and informants, suggesting that family and child-care contexts may play different, but complementary roles in the development of early emerging individual differences in peer interaction. C1 NICHHD, Early Child Care Res Network, CRMC, Rockville, MD 20852 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ London Birkbeck Coll, London WC1E 7HX, England. Univ Washington, Seattle, WA 98195 USA. Univ Arkansas, Little Rock, AR 72204 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ N Carolina, Chapel Hill, NC USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NICHHD, Rockville, MD USA. Temple Univ, Philadelphia, PA 19122 USA. Univ Texas, Austin, TX 78712 USA. Wellesley Coll, Wellesley, MA 02181 USA. Harvard Univ, Cambridge, MA 02138 USA. Univ Kansas, Lawrence, KS 66045 USA. Univ Texas, Dallas, TX 75230 USA. Georgetown Univ, Washington, DC USA. Univ Virginia, Charlottesville, VA USA. Univ Washington, Seattle, WA 98195 USA. Univ Wisconsin, Madison, WI 53706 USA. Temple Univ, Philadelphia, PA 19122 USA. RP Appelbaum, M (reprint author), NICHHD, Early Child Care Res Network, CRMC, 6100 Execut Blvd,4B05, Rockville, MD 20852 USA. RI Marshall, Nancy/C-3428-2012 NR 116 TC 100 Z9 101 U1 8 U2 25 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD SEP-OCT PY 2001 VL 72 IS 5 BP 1478 EP 1500 PG 23 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 484AW UT WOS:000171668900014 ER PT J AU Hooks, JJ Tso, MOM Detrick, B AF Hooks, JJ Tso, MOM Detrick, B TI Retinopathies associated with antiretinal antibodies SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID CANCER-ASSOCIATED RETINOPATHY; MELANOMA-ASSOCIATED RETINOPATHY; PIGMENT EPITHELIAL-CELLS; IMMUNOLOGICAL CROSS-REACTIVITY; PARANEOPLASTIC RETINOPATHY; RETINITIS-PIGMENTOSA; ONCHOCERCA-VOLVULUS; PHOTORECEPTOR DEGENERATION; OCULAR ONCHOCERCIASIS; BIPOLAR CELLS C1 NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Wilmer Eye Inst, 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 60 TC 23 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD SEP PY 2001 VL 8 IS 5 BP 853 EP 858 DI 10.1128/CDLI.8.5.853-858.2001 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 471ZR UT WOS:000170959000001 PM 11527791 ER PT J AU Blazevic, V Jankelevich, S Steinberg, SM Jacobsen, F Yarchoan, R Shearer, GM AF Blazevic, V Jankelevich, S Steinberg, SM Jacobsen, F Yarchoan, R Shearer, GM TI Highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: Analysis of cellular immune responses SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID HIV-INFECTED PATIENTS; T-CELLS; INTERLEUKIN-12 PRODUCTION; INDIVIDUALS; DISEASE; LYMPHOCYTES; REPLICATION; EXPRESSION; RITONAVIR; INHIBITOR AB The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4(+) T-cell counts, plasma HIV RNA levels, and the delayed-ty-pe hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4(+) T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4(+) T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Blazevic, V (reprint author), Univ Tampere, Inst Med Technol, Lenkkeilijankatu 6, FIN-33101 Tampere, Finland. NR 36 TC 15 Z9 16 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD SEP PY 2001 VL 8 IS 5 BP 943 EP 948 DI 10.1128/CDLI.8.5.943-948.2001 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 471ZR UT WOS:000170959000018 PM 11527808 ER PT J AU Trollfors, B Lagergard, T Taranger, J Bergfors, E Schneerson, R Robbins, JB AF Trollfors, B Lagergard, T Taranger, J Bergfors, E Schneerson, R Robbins, JB TI Serum immunoglobulin G antibody responses to Bordetella pertussis lipooligosaccharide and B. parapertussis lipopolysaccharide in children with pertussis and parapertussis SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID WHOOPING-COUGH; BRONCHISEPTICA; DIAGNOSIS; VACCINE; TRIAL AB Serum immunoglobulin G (IgG) antibodies against the lipooligosaccharide (LOS) of Bordetella pertussis and the lipopolysaccharide (LPS) of Bordetella parapertussis were measured by enzyme-linked immunosorbent assay in paired sera from 40 children with pertussis and 14 with parapertussis. Wide differences in the individual responses were noted. Both anti-LOS and -LPS IgG levels increased significantly in the children with pertussis, as did anti-LPS but not anti-LOS in those with parapertussis. C1 Goteborg Primary Hlth Care Syst, Goteborg Pertussis Vaccine Study, Gothenburg, Sweden. Univ Gothenburg, Dept Med Microbiol & Immunol, Gothenburg, Sweden. NICHHD, NIH, Bethesda, MD 20892 USA. RP Trollfors, B (reprint author), Sahlgrenska Univ Hosp E, Dept Pediat, S-41685 Gothenburg, Sweden. NR 21 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD SEP PY 2001 VL 8 IS 5 BP 1015 EP 1017 DI 10.1128/CDLI.8.5.1015-1017.2001 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 471ZR UT WOS:000170959000030 PM 11527820 ER PT J AU Nicoletti, MI Valoti, G Giannakakou, P Zhan, ZR Kim, JH Lucchini, V Landoni, F Mayo, JG Giavazzi, R Fojo, T AF Nicoletti, MI Valoti, G Giannakakou, P Zhan, ZR Kim, JH Lucchini, V Landoni, F Mayo, JG Giavazzi, R Fojo, T TI Expression of beta-tubulin isotypes in human ovarian carcinoma xenografts and in a sub-panel of human cancer cell lines from the NCI-anticancer drug screen: Correlation with sensitivity to microtubule active agents SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC BREAST-CANCER; ANTITUMOR-ACTIVITY; PACLITAXEL RESISTANCE; ALTERED EXPRESSION; NUDE-MICE; TAXOL; QUANTITATION; SEQUENCES; DYNAMICS; THERAPY AB Paclitaxel resistance has been associated with overexpression of P-glycoprotein and alterations involving tubulin. To investigate the clinical relevance of these in vitro resistance mechanisms, we established 12 human ovarian carcinoma xenografts, using samples from patients before the start of therapy or after paclitaxel treatment. These xenografts showed a wide range of sensitivity to paclitaxel, and in 4 of them, very low levels of multidrug resistance-1 expression were detected. Using quantitative PCR and human specific primers, the expression of five beta -tubulin isotypes was determined. HM40 was the predominant, accounting for 84.7-98.7% of all tubulin; expression of the other four isotypes (H beta9, H beta4, H%beta, and H beta2) was also detected but at lower levels. No correlation could be demonstrated between isotype expression and paclitaxel sensitivity in these 12 xenografts. A similar pattern of beta -tubulin isotype expression was observed in a subset of cell lines from the National Cancer Institute-Anticancer Drug Screen. In these cell lines, however, a significant correlation between increased expression of H beta4 isotype and resistance to paclitaxel was found. Taken together, these results suggest that altered expression of specific R-tubulin isotypes may not play a significant role in paclitaxel sensitivity in vivo and argue against a possible significance in a clinical setting. C1 Mario Negri Inst Pharmacol Res, Dept Oncol, I-24125 Bergamo, Italy. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Ulsan, Asan Med Ctr, Dept Obstet & Gynecol, Seoul, South Korea. San Gerardo Hosp, Dept Pathol, I-20052 Monza, Italy. San Gerardo Hosp, Dept Gynecol Oncol, I-20052 Monza, Italy. NCI, Frederick Canc Res & Dev Ctr, Biol Testing Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Nicoletti, MI (reprint author), Mario Negri Inst Pharmacol Res, Dept Oncol, Via Gavazzeni 11, I-24125 Bergamo, Italy. NR 33 TC 70 Z9 77 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 2001 VL 7 IS 9 BP 2912 EP 2922 PG 11 WC Oncology SC Oncology GA 473GD UT WOS:000171031400043 PM 11555610 ER PT J AU Uzel, G Frucht, DM Fleisher, TA Holland, SM AF Uzel, G Frucht, DM Fleisher, TA Holland, SM TI Detection of intracellular phosphorylated STAT-4 by flow cytometry SO CLINICAL IMMUNOLOGY LA English DT Article ID INTERLEUKIN-12 RECEPTOR; TYROSINE PHOSPHORYLATION; IFN-GAMMA; T-CELL; IL-12; IMMUNITY; CYTOKINE; SALMONELLA; PATHWAYS; MYCOBACTERIAL AB The convergence of innate and adaptive immunity is critical for host defense, allowing for early protection and the generation of specific responses. STAT-4 is at that point of convergence, unifying the IFN alpha and IL-12 pathways. Activation of STAT-4 is crucial to T cell polarization, B cell and NK cell activation, and the control of intracellular pathogens. However, techniques to detect phosphorylated STAT-4 are cumbersome and require many cells. We have developed a flow cytometric detection technique to investigate IL-12 signaling in human peripheral blood mononuclear cells. Using different polyclonal antibodies that recognize either total STAT-4 protein or tyrosine-phosphorylated STAT-4, we can easily detect IL-12 and IFN alpha signaling in PHA/IL-2 blasts derived from peripheral blood lymphocytes. This technique not only allows us to evaluate IL-12 signaling, but it is also less time consuming and labor intensive than alternative methods. Using this flow cytometry-based method, we should be able to detect patients with defects in IL-12 receptor signal transduction, who typically present with disseminated nontuberculous mycobacterial infections. C1 NIAMS, Serv Immunol, Dept Lab Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NIAMS, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Uzel, G (reprint author), NIAMS, Serv Immunol, Dept Lab Med, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NR 24 TC 57 Z9 57 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD SEP PY 2001 VL 100 IS 3 BP 270 EP 276 DI 10.1006/clim.2001.5078 PG 7 WC Immunology SC Immunology GA 470MM UT WOS:000170875800003 PM 11513540 ER PT J AU Bleesing, JJH Brown, MR Dale, JK Straus, SE Lenardo, MJ Puck, JM Atkinson, TP Fleisher, TA AF Bleesing, JJH Brown, MR Dale, JK Straus, SE Lenardo, MJ Puck, JM Atkinson, TP Fleisher, TA TI TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis SO CLINICAL IMMUNOLOGY LA English DT Article DE human; T lymphocytes; apoptosis; autoimmunity; cell surface molecules; CD45; CD43; sialic acid; O-glycan; neuraminidase; N acetylglucosaminyltransferase ID FAS GENE-MUTATIONS; LYMPHOCYTE APOPTOSIS; LPR/LPR MICE; SUGAR CHAINS; SIALIC ACIDS; ACTIVATION; DISEASE; SUBSET; ABNORMALITIES; GALECTIN-1 AB Autoimmune lymphoproliferative syndrome (ALPS), caused by inherited defects in apoptosis secondary to mutations in genes encoding Fas/CD95/APO-1 and Fas ligand (Fas1)/CD95L, is characterized by nonmalignant lymphadenopathy and splenomegaly, increased T cell receptor alpha/beta (+) CD4(-)CD8(-) T cells (alpha/beta (+) double-negative T cells [alpha/beta (+)-DNT cells]), autoimmunity, hypergammaglobulinemia, and cytokine abnormalities. The alpha/beta (+)-DNT cells are immunophenotypically and functionally similar to alpha/beta (+)-DNT cells that accumulate in lpr and gld mice, which bear genetic mutations in Fas and FasL. In these mice, alpha/beta (+)-DNT cells express the B-cell-specific CD45R isoform B220. We show that alpha/beta (+)-DNT cells of ALPS patients, with either Fas or FasL mutations, also express B220. In addition, also similar to LPR/gLD mice, they have an unusual population of B220-positive CD4(+) T cells. B220 expression, together with our finding of characteristic lectin binding profiles, demonstrates that cell surface O-linked glycoproteins have undergone specific modifications, which may have consequences for lymphocyte trafficking, cell-cell interactions, and access to alternative apoptosis pathways. (C) 2001 Academic Press. C1 NIAID, Serv Immunol, Dept Lab Med, Warren G Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Pediat, Div Allergy Immunol, Birmingham, AL 35294 USA. RP Bleesing, JJH (reprint author), NIAID, Serv Immunol, Dept Lab Med, Warren G Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NR 51 TC 39 Z9 39 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD SEP PY 2001 VL 100 IS 3 BP 314 EP 324 DI 10.1006/clim.2001.5069 PG 11 WC Immunology SC Immunology GA 470MM UT WOS:000170875800008 PM 11513545 ER PT J AU Jain, VK Cheson, BD AF Jain, VK Cheson, BD TI Editorial SO CLINICAL LYMPHOMA LA English DT Editorial Material C1 Baylor Sammons Canc Ctr, Lymphoma Biol Sect, Dallas, TX USA. NCI, Clin Invest Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Jain, VK (reprint author), Baylor Sammons Canc Ctr, Lymphoma Biol Sect, Dallas, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CANCER INFORMATION GROUP, LP PI DALLAS PA 3535 WORTH ST, SAMMONS TOWER, STE 4802, DALLAS, TX 75246 USA SN 1526-9655 J9 CLIN LYMPHOMA JI Clin. Lymphoma PD SEP PY 2001 VL 2 IS 2 BP 73 EP 73 DI 10.3816/CLM.2001.n.013 PG 1 WC Oncology SC Oncology GA 480RX UT WOS:000171477200001 ER PT J AU Sander, CA Flaig, MJ Jaffe, ES AF Sander, CA Flaig, MJ Jaffe, ES TI Cutaneous manifestations of lymphoma: Clinical guide based on the WHO classification SO CLINICAL LYMPHOMA LA English DT Review DE cutaneous follicle center lymphoma; diffuse large B-cell lymphoma; lymphomatoid papulosis; mycosis fungoides; cutaneous anaplastic large-cell lymphoma ID T-CELL LYMPHOMA; EUROPEAN-AMERICAN CLASSIFICATION; ANGIOTROPIC INTRAVASCULAR LYMPHOMA; FUNGOIDES SEZARY-SYNDROME; POLYMERASE CHAIN-REACTION; BCL-2 PROTEIN EXPRESSION; GRANULOMATOUS SLACK SKIN; NON-HODGKINS-LYMPHOMAS; MANTLE ZONE LYMPHOMA; EPSTEIN-BARR-VIRUS AB Cutaneous lymphomas are a heterogeneous group of lymphomas that show variations in histology, immunophenotype, and prognosis. At the time of presentation, cutaneous lymphomas may be primary or may involve the skin as a secondary site of involvement. Primary cutaneous lymphomas, in many instances, are distinct from morphologically similar lymphomas arising in lymph nodes. Their natural history is often more indolent than nodal lymphomas, and for that reason, they often require different therapeutic approaches. A classification scheme should recognize those lymphomas that are unique to the skin, as well as those arising in other sites. The mode of presentation of a lymphoma is often an indication of underlying biological distinctions. However, organ-specific classification systems undermine communication among medical specialists. The World Health Organization classification of hematopoietic and lymphoid malignancies offers a comprehensive approach and proposes that lymphomas should be viewed as a list of individual diseases and that each disease can be defined by a constellation of morphological, biological, and clinical features. The current review will focus on the spectrum of primary and secondary cutaneous lymphomas, emphasizing those features of importance to the clinical oncologist. C1 NCI, Hematopathol Sect, Pathol Lab, Dept Pathol,NIH, Bethesda, MD 20892 USA. Univ Munich, Dept Dermatol, D-8000 Munich, Germany. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Dept Pathol,NIH, Bldg 10,Room 2N202,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. NR 140 TC 23 Z9 24 U1 0 U2 0 PU CANCER INFORMATION GROUP, LP PI DALLAS PA 3535 WORTH ST, SAMMONS TOWER, STE 4802, DALLAS, TX 75246 USA SN 1526-9655 J9 CLIN LYMPHOMA JI Clin. Lymphoma PD SEP PY 2001 VL 2 IS 2 BP 86 EP 100 DI 10.3816/CLM.2001.n.014 PG 15 WC Oncology SC Oncology GA 480RX UT WOS:000171477200004 PM 11707848 ER PT J AU Abbott, KC Agodoa, LY AF Abbott, KC Agodoa, LY TI Multiple myeloma and light chain-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival SO CLINICAL NEPHROLOGY LA English DT Article DE multiple myeloma; light chain nephropathy; male; Caucasian; dialysis; USRDS; survival ID SOCIOECONOMIC-STATUS; PRESENTING FEATURES; FAILURE; DIALYSIS AB Aims: The patient characteristics and clinical course of nephropathy associated with multiple myeloma/light chain disease (MMN) has not been described for a national sample of end-stage renal disease patients. Methods: 375,152 patients in the United States Renal Data System were initiated on ESRD therapy between January 1, 1992 and June 30, 1997, and were analyzed in a retrospective registry study of MMN (PDIS = 2030A, 2030B, 2030Z, and 203Z). Results: Of the study population, 3298 (0.88%) had MMN. Patients with MMN were disproportionately male (59.5% vs. 53.2%) and Caucasian (76.2% vs. 64.1%, p < 0.01 by Chi-square for both comparisons) and older (68.00 +/- 11.78 vs. 60.69 +/- 16.55 years, p < 0.01 by Student's t-test). In logistic regression analysis, patients with MMN were more likely male and Caucasian, were older, had lower serum hemoglobin, higher creatinine, and more likely to have been started on hemodialysis than peritoneal dialysis. The two-year all-cause mortality of patients with MMN during the study period was 58% vs. 31% in all other patients (p < 0.01 by log rank test). In Cox regression, MMN was independently associated with decreased all-cause patient survival (p < 0.01, hazard ratio for mortality = 2.52, 95% CI 2.38 - 2.67). Conclusions: MMN was associated with Caucasian race, male gender, and older age, compared with other ESRD patients. Patients with MMN had evidence of poorer medical condition on initiation of dialysis compared to other patients. MMN was associated with decreased patient survival after initiation of dialysis, although better than in some previous reports, and patients with MMN may be initiated on dialysis at a lower level of renal function than other patients with ESRD. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. NIDDK, NIH, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 11 TC 41 Z9 48 U1 1 U2 2 PU DUSTRI-VERLAG DR KARL FEISTLE PI OBERHACHING PA BAJUWARENRING 4, D-82041 OBERHACHING, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD SEP PY 2001 VL 56 IS 3 BP 207 EP 210 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 487QZ UT WOS:000171887900004 PM 11597035 ER PT J AU James, LP Farrar, HC Darville, TL Sullivan, JE Givens, TG Kearns, GL Wasserman, GS Simpson, PM Hinson, JA AF James, LP Farrar, HC Darville, TL Sullivan, JE Givens, TG Kearns, GL Wasserman, GS Simpson, PM Hinson, JA CA Nat Inst Child Hlth Human Dev TI Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents SO CLINICAL PHARMACOLOGY & THERAPEUTICS 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 ID FULMINANT HEPATIC-FAILURE; HEPATOTOXICITY; LIVER; MACROPHAGES; PROTEIN; ALPHA; MICE AB Background: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. Methods: Serum levels of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peals cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. Results: Five patients had aspartate aminotransferase or alanine aminotransferase levels > 1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels greater than or equal to 100 IU/L and less than or equal to 1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1 beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P < .001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at > 15 hours, as compared with other patients (Mann-Whitney U test, P < .01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity In addition, interleukin 8 concentrations of > 20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P < .015). Conclusions: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults. C1 Arkansas Childrens Hosp, Sect Clin Pharmacol & Toxicol, Little Rock, AR 72202 USA. Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. Univ Louisville, Dept Pediat, Louisville, KY 40292 USA. Univ Louisville, Dept Pharmacol, Louisville, KY 40292 USA. Univ Louisville, Dept Toxicol, Louisville, KY 40292 USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp, Div Pediat Clin Pharmacol & Toxicol, Kansas City, MO 64108 USA. NICHHD, Bethesda, MD 20892 USA. RP James, LP (reprint author), Arkansas Childrens Hosp, Sect Clin Pharmacol & Toxicol, 800 Marshall St, Little Rock, AR 72202 USA. FU NICHD NIH HHS [1 U10 HD31324-06, 1 U01 HD31313-06]; NIGMS NIH HHS [GM-58884] NR 22 TC 18 Z9 18 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2001 VL 70 IS 3 BP 280 EP 286 DI 10.1067/mcp.2001.118243 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 475XW UT WOS:000171196100011 PM 11557916 ER PT J AU Burgess, TH Steele, KE Schoneboom, BA Grieder, FB AF Burgess, TH Steele, KE Schoneboom, BA Grieder, FB TI Clinicopathologic features of viral agents of potential use by bioterrorists SO CLINICS IN LABORATORY MEDICINE LA English DT Review ID VENEZUELAN EQUINE ENCEPHALITIS; WEST-NILE-VIRUS; ARGENTINE HEMORRHAGIC-FEVER; INFECTIOUS RNA TRANSCRIPTS; NECROSIS-FACTOR-ALPHA; PROTECT GUINEA-PIGS; EBOLA-VIRUS; NONHUMAN-PRIMATES; RHESUS-MONKEYS; MOLECULAR CHARACTERIZATION AB Concerns regarding the possible use of viral agents as weapons of mass destruction have heightened our need to recognize disease syndromes caused by these pathogens and to increase our understanding of potential countermeasures. This article reviews the clinical and pathologic features of various viruses that are generally thought to be potential biowarfare threat, and other related agents of topical interest. The epidemiologic and clinical aspect of recent natural outbreaks of disease caused by exotic viral agents are briefly described. Viral tissue target, immune responses to these agents, relevant animal models, and diagnostic and potential therapeutic modalities also are discussed. C1 Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Med, Bethesda, MD 20814 USA. USN, Viral Dis Dept, Med Res Ctr, Silver Spring, MD USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. USA, Grad Program Anesthesia Nursing, Tripler Army Med Ctr, Honolulu, HI USA. NIH, Lab Anim Sci Program, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Burgess, TH (reprint author), USN, Viral & Rickettsial Dis Dept, Med Res Ctr, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. NR 107 TC 7 Z9 7 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD SEP PY 2001 VL 21 IS 3 BP 475 EP + PG 20 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 474NL UT WOS:000171113300007 PM 11572138 ER PT J AU Halcox, JPJ Quyyumi, AA AF Halcox, JPJ Quyyumi, AA TI Coronary vascular endothelial function and myocardial ischemia: why should we worry about endothelial dysfunction? SO CORONARY ARTERY DISEASE LA English DT Review DE endothelium; myocardial ischemia; myocardial infarction; atherosclerosis; nitric oxide; thrombosis; endothelial function; inflammation; coronary disease ID CONVERTING ENZYME-INHIBITION; C-REACTIVE PROTEIN; NITRIC-OXIDE ACTIVITY; POSITRON-EMISSION-TOMOGRAPHY; RENIN-ANGIOTENSIN SYSTEM; STABLE ANGINA-PECTORIS; VENTRICULAR ENLARGEMENT TRIAL; PLASMA FIBRINOLYTIC BALANCE; TYPE-1 RECEPTOR ANTAGONISM; AVERAGE CHOLESTEROL LEVELS C1 NHLBI, NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, NIH, Cardiol Branch, Bldg 10,Room 7B15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. OI Halcox, Julian/0000-0001-6926-2947 NR 154 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD SEP PY 2001 VL 12 IS 6 BP 475 EP 484 DI 10.1097/00019501-200109000-00006 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 481FT UT WOS:000171509800006 PM 11696686 ER PT J AU Wong, P Ulyanova, T Organisciak, DT Bennett, S Lakins, J Arnold, JM Kutty, RK Tenniswood, M vanVeen, T Darrow, RM Chader, G AF Wong, P Ulyanova, T Organisciak, DT Bennett, S Lakins, J Arnold, JM Kutty, RK Tenniswood, M vanVeen, T Darrow, RM Chader, G TI Expression of multiple forms of clusterin during light-induced retinal degeneration SO CURRENT EYE RESEARCH LA English DT Article DE retinal degeneration; light damage; oxidative damage; clusterin; apoptosis ID RAT VENTRAL PROSTATE; BINDING PROTEIN IRBP; APOLIPOPROTEIN-J; MESSENGER-RNA; HUMAN-SERUM; RETINITIS-PIGMENTOSA; PHOTORECEPTOR CELLS; CHROMAFFIN GRANULES; DAMAGE; APOPTOSIS AB Purpose. Clusterin has been associated with active cell death in several different model systems, including animal models of retinal degeneration. Clusterin is also expressed in normal tissues, a finding that leads to the question of how it could then play a cell death-specific role during tissue regression. To address this paradox, we have examined clusterin expression during light-induced retinal damage in rats. Methods, Normal albino rats were reared in darkness and then exposed to intense visible light to induce retinal degeneration. Clusterin expression was then examined at various times after light treatment. Standard molecular techniques including Northern analysis, immunohistochemistry, and Western analysis were employed. Results. Northern analysis established that the largest increase in clusterin expression occurs after a decrease in interphotoreceptor retinoid binding protein, IRBP, expression (an indication of a photoreceptor cell dysfunction) and after an increase in heme oxygenase 1, HO-1, expression (an oxidative stress inducible gene), suggesting that induction of clusterin expression is an oxidative stress response. Immunohistochemical analysis with two different clusterin-specific antibodies, anti(SGP-2) and anti(301), localized distinct forms of clusterin to Muller cells and degenerating photoreceptor cells. Western analysis demonstrated degeneration associated isoforms of clusterin in light treated retina that are not present in normal retina. Conclusion. Clusterin over-expression is characteristic of a retinal degeneration phenotype and we propose that clusterin action may be defined by the nature in which it is modified. We hypothesize that alternate processing leads to retinal degeneration-specific forms of the protein (6 5, 6 1, and 50 kDa) that are not present in normal retina. C1 Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. Washington Univ, Dept Pathol, St Louis, MO 63130 USA. Wright State Univ, Dept Biochem & Mol Biol, Petticrew Res Lab, Dayton, OH 45435 USA. Wright State Univ, Dept Ophthalmol, Petticrew Res Lab, Dayton, OH 45435 USA. Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada. Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. Natl Res Council Canada, Steacie Inst Mol Sci, Ottawa, ON, Canada. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Lund Hosp, Dept Ophthalmol, S-22185 Lund, Sweden. Natl Retinitis Pigmentosa Inc, Hunt Valley, MD USA. RP Wong, P (reprint author), Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. FU NEI NIH HHS [EY-01959] NR 46 TC 29 Z9 29 U1 0 U2 1 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 SEP PY 2001 VL 23 IS 3 BP 157 EP 165 DI 10.1076/ceyr.23.3.157.5463 PG 9 WC Ophthalmology SC Ophthalmology GA 509FL UT WOS:000173135600001 PM 11803476 ER PT J AU Knepper, MA Brooks, HL AF Knepper, MA Brooks, HL TI Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review ID DISTAL CONVOLUTED TUBULE; EXCHANGER ISOFORM NHE3; NA-CL COTRANSPORTER; RENAL BRUSH-BORDER; RAT-KIDNEY; NA+/H+ EXCHANGER; TARGETED PROTEOMICS; PARATHYROID-HORMONE; MEDIATED REGULATION; PROXIMAL TUBULES AB The regulation of sodium transport in the kidney is important for maintenance of extracellular fluid volume and arterial blood-pressure regulation. The major sodium transporters and channels in individual renal tubule segments have been identified via physiological techniques, and complementary DNAs for all of the key sodium transporters and channels expressed along the renal tubule have been cloned. Complementary DNA probes and antibodies are now being used to investigate the molecular basis of renal tubule sodium-transport regulation. This review summarizes some of the major observations made in the past year that are relevant to the regulation of the major sodium transporters in the proximal tubule (the type 3 sodium-hydrogen exchanger, NHE3), the thick ascending limb of Henle (the bumetanide-sensitive sodium-potassium-chloride cotransporter, NKCC2), and the distal convoluted tubule (the thiazide-sensitive sodium-chloride cotransporter, NCC). Curr Opin Nephrol Hypertens 10:655-659,,(C) 2001 Lippincott Williams & Wilkins. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr DR MSC-1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 38 TC 33 Z9 34 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD SEP PY 2001 VL 10 IS 5 BP 655 EP 659 DI 10.1097/00041552-200109000-00017 PG 5 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 467QA UT WOS:000170714200017 PM 11496061 ER PT J AU Siebert, R Rosenwald, A Staudt, LM Morris, SW AF Siebert, R Rosenwald, A Staudt, LM Morris, SW TI Molecular features of B-cell lymphoma SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID NF-KAPPA-B; CASPASE RECRUITMENT DOMAIN; POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMA; REED-STERNBERG CELLS; MALT-LYMPHOMA; CONTAINING PROTEIN; BCL10 GENE; T(1/14)(Q21,Q32) TRANSLOCATION; HEMATOLOGICAL MALIGNANCIES AB Malignant transformation of B cells can occur at various steps of lymphocyte development, starting from early B-cell progenitors up to mature B cells, which reflects the heterogeneity of B-cell malignancies with regard to their biologic and clinical behavior. The genetic characterization of B-cell neoplasms during the past two decades has elucidated the mechanisms underlying B-cell lymphomagenesis and led to a more precise definition of lymphoma subgroups. This progress is reflected in the upcoming World Health Organization classification for hematologic neoplasms, which stresses the diagnostic importance of recurrent genetic alterations in leukemias and lymphomas. In the recent past, several genes deregulated by such recurrent chromosomal aberrations have been identified. In addition, the recent introduction of microarray technology has now allowed a more global assessment of gene dysregulation in B-cell oncogenesis and provided a new means for more exactly defining the molecular hallmarks of distinct lymphoma subtypes. This review will focus on recently described molecular features of B-cell lymphomas discovered by the application of new molecular cytogenetic techniques, advanced breakpoint cloning strategies, and microarray approaches. Curr Opin Oncol 2001, 13:316-324 (C) 2001 Lippincott Williams & Wilkins, Inc. C1 St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. Univ Kiel, Univ Hosp Kiel, Inst Human Genet, Kiel, Germany. NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. Univ Tennessee, Coll Med, Dept Pediat, Memphis, TN USA. RP Morris, SW (reprint author), St Jude Childrens Res Hosp, Dept Pathol, Thomas Tower,Room 5024,332 N Lauderdale St, Memphis, TN 38105 USA. EM steve.morris@stjude.org RI Siebert, Reiner/A-8049-2010 FU NCI NIH HHS [CA21765, CA69129, CA87064] NR 82 TC 43 Z9 44 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD SEP PY 2001 VL 13 IS 5 BP 316 EP 324 DI 10.1097/00001622-200109000-00002 PG 9 WC Oncology SC Oncology GA 466UK UT WOS:000170664400002 PM 11555707 ER PT J AU Ceciliani, F Pergami, P AF Ceciliani, F Pergami, P TI Infective proteins: The prion puzzle SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; FATAL FAMILIAL INSOMNIA; GERSTMANN-STRAUSSLER SYNDROME; AMYLOID PRECURSOR GENE; SPONGIFORM ENCEPHALOPATHIES; NEUROFIBRILLARY TANGLES; SCHEINKER-DISEASE; TRANSGENIC MICE; NMR STRUCTURE; PHENOTYPIC VARIABILITY AB According to the Koch postulates an infectious organism is the one that can be isolated from an host suffering from a disorder, can be propagated in laboratory, can cause the same disease when introduced in another host, and finally, can be re-isolated from the host itself. If we change the word "organism" with the word "protein" we have a quite exact description of prions. Prion related disorders are a very unique category of infectious diseases. The ethiology of the so-called prionoses is related to the conversion of a normal protein (PrPC, the cellular isoform of the prion protein) into a pathological form (the scrapie isoform of the prion protein, PrPSc) which is able to propagate. The striking difference between the two forms seems to consist in a conformational modification of a mainly alpha -helix structured PrPC into a mainly beta -sheet PrPSc. The latter forms amyloid-like fibrils which precipitate into insoluble aggregates leading to the neurodegenerative changes specific of Spongiform Encephalopathies. This review will focus on the structure of the prion proteins and on PrPC cellular cycle, and it will discuss some hypothesis about the protein biochemical function. Finally, the various molecular mechanisms proposed for the development of conformational modifications will be reviewed, i.e. how a protein can become infectious by simply changing its structure. C1 Univ Milan, Dipartimento Patol Anim Igiene & Sanita Pubbl Vet, I-20133 Milan, Italy. NINCDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20814 USA. RP Ceciliani, F (reprint author), Univ Milan, Dipartimento Patol Anim Igiene & Sanita Pubbl Vet, Via Celoria 10, I-20133 Milan, Italy. NR 131 TC 2 Z9 2 U1 1 U2 2 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD SEP PY 2001 VL 2 IS 3 BP 191 EP 204 DI 10.2174/1389203013381099 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 485RE UT WOS:000171770200001 PM 12369932 ER PT J AU Giacoia, GP AF Giacoia, GP TI Adverse drug events and adverse drug reactions in pediatric patients: Overview SO CURRENT THERAPEUTIC RESEARCH-CLINICAL AND EXPERIMENTAL LA English DT Editorial Material C1 NICHHD, Dev Pediat Pharmacol Program, NIH, Rockville, MD 20852 USA. RP Giacoia, GP (reprint author), NICHHD, Dev Pediat Pharmacol Program, NIH, 6100 Execut Blvd,Room 4B-11, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0011-393X J9 CURR THER RES CLIN E JI Curr. Ther. Res.-Clin. Exp. PD SEP PY 2001 VL 62 IS 9 BP 625 EP 626 DI 10.1016/S0011-393X(01)80068-0 PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 486DZ UT WOS:000171804300002 ER PT J AU Roederer, M Treister, A Moore, W Herzenberg, LA AF Roederer, M Treister, A Moore, W Herzenberg, LA TI Probability binning comparison: A metric for quantitating univariate distribution differences SO CYTOMETRY LA English DT Article DE flow cytometry; data analysis; K-S statistics; histogram comparisons ID POSITIVE CELLS; FLOW; NUMBER AB Background: Comparing distributions of data is an important goal in many applications. For example, determining whether two samples (e.g., a control and test sample) are statistically significantly different is useful to detect a response, or to provide feedback regarding instrument stability by detecting when collected data varies significantly over time. Methods: We apply a variant of the chi-squared statistic to comparing univariate distributions. In this variant, a control distribution is divided such that an equal number of events fall into each of the divisions, or bins. This approach is thereby a mini-max algorithm, in that it minimizes the maximum expected variance for the control distribution. The control-derived bins are then applied to test sample distributions, and a normalized chi-squared value is computed. We term this algorithm Probability Binning. Results: Using a Monte-Carlo simulation, we determined the distribution of chi-squared values obtained by comparing sets of events derived from the same distribution. Based on this distribution, we derive a conversion of any given chi-squared value into a metric that is analogous to a t-score, i.e., it can be used to estimate the probability that a test distribution is different from a control distribution. We demonstrate that this metric scales with the difference between two distributions, and can be used to rank samples according to similarity to a control. Finally, we demonstrate the applicability of this metric to ranking immunophenotyping distributions to suggest that it indeed can be used to objectively determine the relative distance of distributions compared to a single control. Conclusion: Probability Binning, as shown here, provides a useful metric for determining the probability that two or more flow cytometric data distributions are different. This metric can also be used to rank distributions to identify which are most similar or dissimilar. In addition, the algorithm can be used to quantitate contamination of even highly-overlapping populations. Finally, as demonstrated in an accompanying paper, Probability Binning can be used to gate on events that represent significantly different subsets from a control sample. Cytometry 45: 37-46, 2001. Published 2001 Wiley-Liss, Inc.dagger C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Tree Star Inc, San Carlos, CA USA. Stanford Univ, Dept Genet, Stanford, CA 94305 USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 15 TC 77 Z9 78 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOMETRY JI Cytometry PD SEP 1 PY 2001 VL 45 IS 1 BP 37 EP 46 DI 10.1002/1097-0320(20010901)45:1<37::AID-CYTO1142>3.0.CO;2-E PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 472ZN UT WOS:000171015000005 PM 11598945 ER PT J AU Roederer, M Moore, W Treister, A Hardy, RR Herzenberg, LA AF Roederer, M Moore, W Treister, A Hardy, RR Herzenberg, LA TI Probability binning comparison: A metric for quantitating multivariate distribution differences SO CYTOMETRY LA English DT Article DE flow cytometry; data analysis; K-S statistics; histogram comparisons ID POSITIVE CELLS; NUMBER AB Background: While several algorithms for the comparison of univariate distributions arising from flow cytometric analyses have been developed and studied for many years, algorithms for comparing multivariate distributions remain elusive. Such algorithms could be useful for comparing differences between samples based on several independent measurements, rather than differences based on any single measurement. It is conceivable that distributions could be completely distinct in multivariate space, but unresolvable in any combination of univariate histograms. Multivariate comparisons could also be useful for providing feedback about instrument stability, when only subtle changes in measurements are occurring. Methods: We apply a variant of Probability Binning, described in the accompanying article, to multidimensional data. In this approach, hyper-rectangles of n dimensions (where n is the number of measurements being compared) comprise the bins used for the chi-squared statistic. These hyper-dimensional bins are constructed such that the control sample has the same number of events in each bin; the bins are then applied to the test samples for chi-squared calculations. Results: Using a Monte-Carlo simulation, we determined the distribution of chi-squared values obtained by comparing sets of events from the same distribution; this distribution of chi-squared values was identical as for the univariate algorithm. Hence, the same formulae can be used to construct a metric, analogous to a t-score, that estimates the probability with which distributions are distinct. As for univariate comparisons, this metric scales with the difference between two distributions, and can be used to rank samples according to similarity to a control. We apply the algorithm to multivariate immunophenotyping data, and demonstrate that it can be used to discriminate distinct samples and to rank samples according to a biologically-meaningful difference. Conclusion: Probability binning, as shown here, provides a useful metric for determining the probability with which two or more multivariate distributions represent distinct sets of data. The metric can be used to identify the similarity or dissimilarity of samples. Finally, as demonstrated in the accompanying paper, the algorithm can be used to gate on events in one sample that are different from a control sample, even if those events cannot be distinguished on the basis of any combination of univariate or bivariate displays. Cytometry 45:47-55, 2001. Published 2001 Wiley-Liss, Inc.dagger. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Stanford Univ, Dept Genet, Stanford, CA 94305 USA. Tree Star Inc, San Carlos, CA USA. Fox Chase Canc Ctr, Fox Chase, PA USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 9 TC 69 Z9 73 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 0196-4763 J9 CYTOMETRY JI Cytometry PD SEP 1 PY 2001 VL 45 IS 1 BP 47 EP 55 DI 10.1002/1097-0320(20010901)45:1<47::AID-CYTO1143>3.0.CO;2-A PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 472ZN UT WOS:000171015000006 PM 11598946 ER PT J AU Roederer, M Hardy, RR AF Roederer, M Hardy, RR TI Frequency difference gating: A multivariate method for identifying subsets that differ between samples SO CYTOMETRY LA English DT Article DE flow cytometry; data analysis; probability binning comparison; Frequency Difference Gating; multivariate data analysis ID FLOW-CYTOMETRY AB Background: In multivariate distributions (for example, in 3- or more color flow cytometric datasets), it can become difficult or impossible to identify populations that differ between samples based only on a combination of univariate or bivariate displays. Indeed, it is possible that such differences can only be identified in "n"-dimensional space, where "n" is the number of parameters measured. Therefore, computer assisted identification of such differences is necessary. Such a method could be used to identify responses (i.e., by comparing cell samples before and after stimulation) in exquisite detail by allowing complete analysis of the collected data on only those events which have responded. Methods: Multivariate Probability Binning can be used to compare different datasets to identify the distance and statistical significance of a difference between the distributions. An intermediate step in the algorithm provides access to the actual locations within the n-dimensional comparison which are most different between the distributions. Gates based on collections of hyper-rectangular bins can then be applied to datasets, thereby selecting those events (or clusters of events) that are different between samples. We term. this process Frequency Difference Gating. Results. Frequency Difference Gating was used in several test scenarios to evaluate its utility. First, we compared PBMC subsets identified by solely by immunofluorescence staining: based on this training data set, the algorithm automatically generated an accurate forward and side-scatter gate to identify lymphocytes. Second, we applied the algorithm to identify subtle differences between CD4 memory subsets based on 8-color immunophenotyping data. The resulting 3-dimensional gate could resolve cells subsets much more frequent in one subset compared to the other; no combination of two-dimensional gates could accomplish this resolution. Finally, we used the algorithm to compare B cell populations derived from mice of different ages or strains, and found that the algorithm could find very subtle differences between the populations. Conclusion. Frequency Difference Gating is a powerful tool that automates the process of identifying events comprising underlying differences between samples. It is not a clustering tool; it is not meant to identify subsets in multidimensional space. Importantly, this method may reveal subtle changes in small populations of cells, changes that only occur simultaneously in multiple dimensions in such a way that identification by univariate or bivariate analyses is impossible. Finally, the method may significantly aid in the analysis of high-order multivariate data (i.e., 6-12 color flow cytometric analyses), where identification of differences between datasets becomes so time-consuming as to be impractical. Cytometry 45:,56-64, 2001. Published 2001 Wiley-Liss, Inc.dagger. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Fox Chase, PA USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 8 TC 54 Z9 57 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 0196-4763 J9 CYTOMETRY JI Cytometry PD SEP 1 PY 2001 VL 45 IS 1 BP 56 EP 64 DI 10.1002/1097-0320(20010901)45:1<56::AID-CYTO1144>3.0.CO;2-9 PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 472ZN UT WOS:000171015000007 PM 11598947 ER PT J AU Birve, A Sengupta, AK Beuchle, D Larsson, J Kennison, JA Rasmuson-Lestander, A Muller, J AF Birve, A Sengupta, AK Beuchle, D Larsson, J Kennison, JA Rasmuson-Lestander, A Muller, J TI Su(z)12, a novel Drosophila Polycomb group gene that is conserved in vertebrates and plants SO DEVELOPMENT LA English DT Article DE Su(z)12; Polycomb group; Drosophila melanogaster ID POSITION-EFFECT VARIEGATION; HOMEOTIC GENE; BITHORAX COMPLEX; SEX-COMBS; CAENORHABDITIS-ELEGANS; PROTEIN COMPLEX; ULTRABITHORAX PROTEINS; BMI-1 PROTOONCOGENE; MATERNAL CONTROL; EMF GENES AB In both Drosophila and vertebrates, spatially restricted expression of HOX genes is controlled by the Polycomb group (PcG) repressors. Here we characterize a novel Drosophila PcG gene, Suppressor of zeste 12 (Su(z)12). Su(z)12 mutants exhibit very strong homeotic transformations and Su(z)12 function is required throughout development to maintain the repressed state of HOX genes. Unlike most other PcG mutations, Su(z)12 mutations are strong suppressors of position-effect variegation (PEV), suggesting that Su(z)12 also functions in heterochromatin-mediated repression. Furthermore, Su(z)12 function is required for germ cell development. The Su(z)12 protein is highly conserved in vertebrates and is related to the Arabidopsis proteins EMF2, FIS2 and VRN2. Notably, EMF2 is a repressor of floral homeotic genes. These results suggest that at least some of the regulatory machinery that controls homeotic gene expression is conserved between animals and plants. C1 Max Planck Inst Dev Biol, D-72076 Tubingen, Germany. Umea Univ, Dept Genet, S-90187 Umea, Sweden. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Muller, J (reprint author), Max Planck Inst Dev Biol, Spemannstr 35-3, D-72076 Tubingen, Germany. NR 59 TC 140 Z9 146 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP PY 2001 VL 128 IS 17 BP 3371 EP 3379 PG 9 WC Developmental Biology SC Developmental Biology GA 480TJ UT WOS:000171478600015 PM 11546753 ER PT J AU Mukhopadhyay, M Shtrom, S Rodriguez-Esteban, C Chen, L Tsukui, T Gomer, L Dorward, DW Glinka, A Grinberg, A Huang, SP Niehrs, C Belmonte, JCI Westphal, H AF Mukhopadhyay, M Shtrom, S Rodriguez-Esteban, C Chen, L Tsukui, T Gomer, L Dorward, DW Glinka, A Grinberg, A Huang, SP Niehrs, C Belmonte, JCI Westphal, H TI Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse SO DEVELOPMENTAL CELL LA English DT Article ID ANTERIOR NEURAL PLATE; SPEMANN ORGANIZER; PRECHORDAL PLATE; GENE-EXPRESSION; VERTEBRATE DEVELOPMENT; RESTRICTED EXPRESSION; SECRETED PROTEINS; VISCERAL ENDODERM; NEGATIVE SIGNALS; EYE DEVELOPMENT AB Dickkopf1 (Dkk1) is a secreted protein that acts as a Wnt inhibitor and, together with BMP inhibitors, is able to induce the formation of ectopic heads in Xenopus. Here, we show that Dkk1 null mutant embryos lack head structures anterior of the midbrain. Analysis of chimeric embryos implicates the requirement of Dkk1 in anterior axial mesendoderm but not in anterior visceral endoderm for head induction. In addition, mutant embryos show duplications and fusions of limb digits. Characterization of the limb phenotype strongly suggests a role for Dkk1 both in cell proliferation and in programmed cell death. Our data provide direct genetic evidence for the requirement of secreted Wnt antagonists during embryonic patterning and implicate Dkk1 as an essential inducer during anterior specification as well as a regulator during distal limb patterning. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Deutsch Krebsforschungszentrum, Div Mol Embryol, D-69120 Heidelberg, Germany. RP Mukhopadhyay, M (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 86 TC 410 Z9 423 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD SEP PY 2001 VL 1 IS 3 BP 423 EP 434 DI 10.1016/S1534-5807(01)00041-7 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546XJ UT WOS:000175301400014 PM 11702953 ER PT J AU Osei-Hyiaman, D Hou, LF Ren, ZY Zhang, ZM Yu, HQ Amankwah, AA Harada, S AF Osei-Hyiaman, D Hou, LF Ren, ZY Zhang, ZM Yu, HQ Amankwah, AA Harada, S TI Association of a novel point mutation (C159G) of the CTLA4 gene with type 1 diabetes in West Africans but not in Chinese SO DIABETES LA English DT Article ID SUSCEPTIBILITY; POLYMORPHISM; MELLITUS; LINKAGE; ASSAY AB Here, we report on the detection of a novel point mutation of the CTLA4 gene at nucleotide position 159 (C -->G) leading to amino acid substitution at position 53 (I -->M), as well as its association with type 1 diabetes in two ethnically distinct populations. Subjects included 182 unrelated type 1 diabetes children and 201 control subjects from Ghana, West Africa. The Chinese study population consisted of 350 type 1 diabetic children and 420 healthy control subjects from central China. Polymerase chain reaction-single-strand conformation polymorphism and sequence analysis were used to screen for polymorphisms in the CTLA4 gene. CTLA4 49 (A-G) mutation conferred a risk of type 1 diabetes in the Chinese children (odds ratio 1.78, 95% CI 1.58-2.0), but not in the West African children (1.17, 0.84-1.64). On the other hand, the novel CTLA4 159 (C -->G) mutation conferred a risk of type I diabetes in the West African children (2.1, 1.54-2.86), but not in the Chinese type 1 diabetic children. The novel CTLA4 gene polymorphism at nucleotide position 159 significantly associated with type I diabetes in West Africans, but not in Chinese. On the other hand, the CTLA4 gene polymorphism at nucleotide position 49 significantly associated with type I diabetes in Chinese, but not in West Africans. C1 Univ Tsukuba, Grad Sch Med, Inst Community Med, Tsukuba, Ibaraki 305, Japan. Safo Adu Hosp, Div Endocrinol, Dept Med, Kumasi, Ghana. Taiyuan City Hosp, Dept Internal Med, Shanxi, Peoples R China. Shanxi Med Univ, Dept Epidemiol, Shanxi, Peoples R China. Beicheng Cent Hosp, Dept Internal Med, Taiyuan, Shanxi, Peoples R China. Univ Sci & Technol, Sch Med Sci, Kumasi, Ghana. RP Osei-Hyiaman, D (reprint author), NIAAA, DICBR, LPS, NIH, 12420 Parklawn Dr,MSC-8115, Bethesda, MD USA. NR 17 TC 33 Z9 35 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2001 VL 50 IS 9 BP 2169 EP 2171 DI 10.2337/diabetes.50.9.2169 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466QU UT WOS:000170656900028 PM 11522687 ER PT J AU Bennett, PH Lee, ET Lu, M Keen, H Fuller, JH AF Bennett, PH Lee, ET Lu, M Keen, H Fuller, JH CA WHO Multinatl Study Grp TI Increased urinary albumin excretion and its associations in the WHO Multinational Study of Vascular Disease in Diabetes SO DIABETOLOGIA LA English DT Article DE albuminuria; prevalence; vascular complications; risk factors; multinational study ID BLOOD-PRESSURE; RENAL-DISEASE; PIMA-INDIANS; OVERT NEPHROPATHY; MICROALBUMINURIA; MELLITUS; PROTEINURIA; MORTALITY; SUSCEPTIBILITY; HYPERTENSION AB Aim/hypothesis. We aimed to determine variations in the prevalence of increased urinary albumin excretion, associated risk factors and complications in patients with diabetes participating in the WHO Multinational Study of Vascular Disease in Diabetes follow-up. Methods. Urinary albumin to urinary creatinine ratios were measured centrally in 2033 of the 2550 (79.7%) re-examined patients from eight centres in seven countries and the frequency of microalbuminuria and macroalbuminuria and their associations with risk factors and complications were examined. Results. Macroalbuminuria prevalence (overall 15.6%) varied tenfold (3-37%) among centres, was higher in American Indian and Asian centres and not clearly related to type of diabetes. Microalbuminuria (overall 19.7%) varied less (12-31%). Increased albumin excretion was related overall to baseline fasting plasma glucose in the pooled group in whom it was measured and to increased arterial pressure, insulin use, coronary heart disease, lower extremity amputation, retinopathy and stroke in most centres. Conclusion/interpretation. Centres varied widely in the prevalence of increased albumin excretion but associations with risk factors and vascular complications were generally similar in most centres and in both major types of diabetes with ethnic and genetic differences probably contributing. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. Guys Hosp, Metab Med Unit, London SE1 9RT, England. UCL, Dept Epidemiol & Publ Hlth, EURODIAB, London, England. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. RI Nelson, Robert/B-1470-2012 NR 36 TC 21 Z9 22 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S37 EP S45 DI 10.1007/PL00002938 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100006 PM 11587049 ER PT J AU Chi, ZS Lee, ET Lu, M Keen, H Bennett, PH AF Chi, ZS Lee, ET Lu, M Keen, H Bennett, PH CA WHO Multinatl Study Grp TI Vascular disease prevalence in diabetic patients in China: standardised comparison with the 14 centres in the WHO multinational study of vascular disease in diabetes SO DIABETOLOGIA LA English DT Article DE macrovascular disease; microvascular disease; diabetes; China; multinational study; arterial pressure; plasma cholesterol; risk factors ID CORONARY HEART-DISEASE AB Aims/hypothesis. Rates of vascular complications of diabetes in a cohort of mainland Chinese patients with diabetes, ascertained and examined by similar methodology, are compared with those of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Methods. The standardised procedures carried out in the WHO MSVDD were followed in assembling and examining a Chinese cohort of 447 diabetic patients recruited in Beijing and Tianjin [2]. Results. Compared with the WHO MSVDD centres, the Chinese cohort was slightly older, had a shorter duration of known diabetes and had fewer insulin-treated patients. Arterial pressure, total blood cholesterol and body mass index were substantially lower. Large vessel disease rate for age, sex and duration adjusted data (17.9%) was about half that of the combined WHO MSVDD centres (33.5% p < 0.001). However, retinopathy (47.4% vs 35.8% p < 0.001) and proteinuria (57.1 vs 24.9% p < 0.001) rates were significantly higher. Conclusion/interpretation. Relatively low arterial pressures and blood cholesterol are likely contributors to the notably low arterial disease rates in this Chinese diabetic cohort; they reflect low rates in the Chinese mainland general population and resemble the Tokyo and Hong Kong centres of the WHO MSVDD. The high rates of retinopathy and proteinuria could relate to later diagnosis, degree of hyperglycaemia and/or increased susceptibiltiy to microangiopathy. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. Capital Hosp, Dept Endocrinol, Beijing, Peoples R China. Guys Hosp, Metab Med Unit, London SE1 9RT, England. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. RI Nelson, Robert/B-1470-2012 NR 12 TC 33 Z9 33 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S82 EP S86 DI 10.1007/PL00002944 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100012 PM 11587055 ER PT J AU Colhoun, HM Lee, ET Bennett, PH Lu, M Keen, H Wang, SL Stevens, LK Fuller, JH AF Colhoun, HM Lee, ET Bennett, PH Lu, M Keen, H Wang, SL Stevens, LK Fuller, JH CA WHO Multinatl Study Grp TI Risk factors for renal failure: The WHO multinational study of vascular disease in diabetes SO DIABETOLOGIA LA English DT Article DE renal failure; nephropathy; Type I (insulin-dependent) diabetes mellitus; Type II (non-insulin-dependent) diabetes mellitus; triglycerides; systolic blood pressure; plasma glucose; smoking; cholesterol; retinopathy; ECG ID URINARY ALBUMIN EXCRETION; EURODIAB IDDM COMPLICATIONS; INSULIN-DEPENDENT DIABETICS; BLOOD-PRESSURE; MICROVASCULAR COMPLICATIONS; PIMA-INDIANS; NEPHROPATHY; MELLITUS; MICROALBUMINURIA; SMOKING AB Aims/hypothesis. We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. Methods. Risk factors for renal failure were examined in 3558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Results. In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2559 with Type II (noninsulin-dependent) diabetes mellitus, the average follow-up was 8.4 years (+/-2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG ab normalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. Conclusion/interpretation. We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type If diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure. C1 UCL, Dept Epidemiol & Publ Hlth, EURODIAB, London WC1E 6BT, England. Guys Hosp, Metab Med Unit, London SE1 9RT, England. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. RP Colhoun, HM (reprint author), UCL, Dept Epidemiol & Publ Hlth, EURODIAB, 1-19 Torrington Pl, London WC1E 6BT, England. RI Nelson, Robert/B-1470-2012; Wang, Shu-Li/C-1367-2010 NR 44 TC 53 Z9 53 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S46 EP S53 DI 10.1007/PL00002939 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100007 PM 11587050 ER PT J AU Keen, H Lee, ET Russell, D Miki, E Bennett, PH Lu, M AF Keen, H Lee, ET Russell, D Miki, E Bennett, PH Lu, M CA WHO Multinatl Study Grp TI The appearance of retinopathy and progression to proliferative retinopathy: the WHO multinational study of vascular disease in diabetes SO DIABETOLOGIA LA English DT Article DE diabetic retinopathy; proliferative diabetic retinopathy; incidence; multinational study; risk factors; ethnic; arterial pressure; plasma glucose; plasma lipids; smoking ID PIMA-INDIANS; INTERNATIONAL VARIATIONS; 4-YEAR INCIDENCE; BLOOD-PRESSURE; RISK-FACTORS; DIAGNOSIS; NIDDM; AGE; COMPLICATIONS; POPULATION AB Aims/hypothesis. We aimed to estimate incidences of any retinopathy and proliferative diabetic retinopathy (PDR) by direct ophthalmoscopy and relate them to baseline risk factors in re-examined diabetic survivors from 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes. Methods. After a mean follow-up of 8.4 years (11.7 years in Oklahoma), 2877 (71.6%) survivors were resubmitted to standardised direct ophthalmoscopy as at baseline. The presence of any retinopathy and PDR were recorded at each centre and their incidence estimated in those without retinopathy and PDR at baseline. The independent associations of these incidences with baseline risk factors are expressed as odds ratios derived from multiple logistic regression analyses, within individual centres (which included fasting plasma glucose in 8 and triglyceride in 5) and in pooled data. Results. Of the 4662 original patients, 465 (10.4%) of those without and 77 (43.0%) of those with baseline PDR had died (p < 0.001). Any retinopathy was newly reported at follow-up in 47.7% and PDR in 9.7% of those free of them at baseline, with reported incidences varying substantially among centres. Incident retinopathy appeared earlier in the known course of diabetes but incidence rates rose more slowly with duration in patients with Type IT (non-insulin-dependent) diabetes mellitus than in those with Type I (insulin-dependent) diabetes mellitus. In pooled data and in some individual centres, any retinopathy incidence gave significantly positive odds ratios with age, diabetes duration, systolic pressure, plasma cholesterol, BMI, insulin treatment and proteinuria, and with fasting plasma glucose in the centres where it was measured. Positive odds ratios for PDR were similarly obtained for age, duration, insulin treatment, cholesterol, proteinuria and fasting glycaemia. Smoking status odds ratios were negative for both outcomes. Conclusion/interpretation. Incidence of ophthalmoscopically ascertained any retinopathy varied about twofold and of PDR about threefold among centres. Although, in part attributable to differences between observers, variation in incidence in all centres and in some cases within centres was associated with a number of baseline risk factors. Such associations are not likely due to observer variation or selection biases and emerged despite the imprecision of clinical ophthalmoscopy. Improved detection and control of these risk factors should reduce the impact of diabetic retinopathy and its consequences. C1 Guys Hosp, Metab Med Unit, London SE1 9RT, England. Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, Oklahoma City, OK 73104 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Coll Publ Hlth, Oklahoma City, OK 73104 USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Keen, H (reprint author), Guys Hosp, Metab Med Unit, Campus KCL,St Thomas St, London SE1 9RT, England. RI Nelson, Robert/B-1470-2012 NR 50 TC 29 Z9 32 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S22 EP S30 DI 10.1007/PL00002935 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100004 PM 11587046 ER PT J AU Lee, ET Lu, M Bennett, PH Keen, H AF Lee, ET Lu, M Bennett, PH Keen, H CA WHO Multinatl Study Grp TI Vascular disease in younger-onset diabetes: comparison of European, Asian and American Indian cohorts of the WHO multinational study of vascular disease in diabetes SO DIABETOLOGIA LA English DT Article DE type I (insulin-dependent) diabetes mellitus; type II (non-insulin-dependent) diabetes mellitus; ethnic differences; cardiovascular disease; amputation; retinopathy; nephropathy ID RENAL-DISEASE; PIMA-INDIANS; RISK-FACTORS; FOLLOW-UP; MELLITUS; MORTALITY AB Aims/hypothesis. This study compared the incidence of vascular disease in subjects with younger-onset diabetes from different ethnic groups. Methods. The incidence of vascular disease endpoints has been studied in a sub-group (n = 994) of participants of the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) who had younger-onset diabetes (diagnosed before the age of 30 years). The study participants have been divided into European (n = 631), Asian (n = 84) and American Indian (n = 91) cohorts. Results. For Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus, American Indian men had a higher incidence of lower-extremity amputation and renal failure than the other cohorts, whereas European women had a higher incidence of angina than other cohorts. American Indians also had a higher incidence of any retinopathy, clinical proteinuria and albuminuria than the European and Asian cohorts. Conclusion/interpretation. This study confirms the high burden of large and small-vessel disease complications manifest in American Indian people with younger-onset diabetes. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. Guys Hosp, Metab Med Unit, London SE1 9RT, England. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. RI Nelson, Robert/B-1470-2012 NR 13 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S78 EP S81 DI 10.1007/PL00002943 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100011 PM 11587054 ER PT J AU Lee, ET Keen, H Bennett, PH Fuller, JH Lu, M AF Lee, ET Keen, H Bennett, PH Fuller, JH Lu, M CA WHO Multinatl Study Grp TI Follow-up of the WHO multinational study of vascular disease in diabetes: general description and morbidity SO DIABETOLOGIA LA English DT Article DE diabetes mellitus; retinopathy; nephropathy; amputation; atherosclerosis; hypertension; incidence; epidemiology; ethnicity; multinational study ID PIMA-INDIANS; RISK-FACTORS; MORTALITY; OKLAHOMA; NIDDM; DETERMINANTS; PROTEINURIA; RETINOPATHY AB Aims. The incidence of retinal, renal and cardiovascular complications and their relation to baseline risk factors was documented in this follow-up study of 10 of the 14 original centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Methods. The incidence of specified items of vascular disease and some associated risk factors was ascertained after 7 to 9 years (11-12 years in Oklahoma, USA) follow-up, re-using baseline examination methodology in 3165 patients (66.9%) and, through secondary information in 717 (15.2%) of the 4729 original patients, of whom 540 (11.4%) had died and 307 (6.5%) were untraceable. Results. During follow-up, approximately one third of the patients developed hypertension and one third started insulin. Coronary heart disease incidence varied 10 to 20-fold among centres as did limb amputation rates. Inter-centre differences in incident retinopathy and severe visual impairment were smaller but incident clinical proteinuria and renal failure varied markedly. Vascular disease incidence of all categories was high in Native Americans though coronary heart disease incidence was relatively low in Pima Indians and absolutely low in Hong Kong and Tokyo patients. Specific vascular events and their relation with baseline risk factors are analysed in accompanying papers, summarised in the Epilogue. Conclusion/interpretation. These 10 centres reported very different incidence rates of vascular complications. Observer variation, selection biases and competing causes of mortality contributed to these differences but their validity is supported by the more objective outcome indicators. The following papers also suggest that baseline factors such as raised arterial pressure, cholesterol and fasting glucose (in the centres where it was measured) were important and potentially reversible predictors of risk. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. Guys Hosp, Metab Med Unit, London SE1 9RT, England. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. UCL, Dept Epidemiol & Publ Hlth, EURODIAB, London, England. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. RI Nelson, Robert/B-1470-2012 FU NIDDK NIH HHS [N01-DK-8-2232] NR 22 TC 65 Z9 66 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S3 EP S13 DI 10.1007/PL00002936 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100002 PM 11587047 ER PT J AU Miki, E Lu, M Lee, ET Keen, H Bennett, PH Russell, D AF Miki, E Lu, M Lee, ET Keen, H Bennett, PH Russell, D CA WHO Multinatl Study Grp TI The incidence of visual impairment and its determinants in the WHO multinational study of vascular disease in diabetes SO DIABETOLOGIA LA English DT Article DE visual impairment; incidence; diabetes mellitus; prevalence; diabetic retinopathy; risk factors; multinational study ID PROLIFERATIVE RETINOPATHY; EPIDEMIOLOGICAL COHORT; BLOOD-PRESSURE; PIMA-INDIANS; BLINDNESS; NIDDM; POPULATION; OKLAHOMA; MELLITUS; FALSTER AB Aims/hypothesis. Incidence of severe visual impairment and the ultimate prevalence of all grades of impairment were estimated in the 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participating in the followup. Methods. Visual function was ascertained at followup in 2994 (77.9%) of the 3845 eligible participating survivors of the 4709 originally recruited for the WHO MSVDD using the same baseline enquiry method. The associations between incident severe visual impairment, follow-up prevalence of all grades of impairment and baseline risk factors were examined by univariate and stepwise multiple logistic regression analysis. Results. Overall, 8.4 year incidence of severe visual impairment was 1.94% and showed statistically significant univariate correlations with age at diagnosis, diabetes duration, systolic blood pressure, fasting blood glucose and cholesterol, insulin treatment and strongly with baseline retinopathy. Baseline retinopathy, systolic pressure and cholesterol were statistically significant in multivariable analysis. Differences between centres (0.3% to 3.45%) were not significant. Ultimate prevalence of all grades of impairment differed between centres and within almost all of them was correlated in multivariable analysis with baseline retinopathy and proteinuria. Conclusion/interpretation. Comparisons of incident severe visual impairment between centres are restricted by selective mortality, low incidence rates and relatively small numbers in each centre but before retinopathy, baseline systolic pressure and cholesterol predicted severe visual impairment. Followup prevalence of all degrees of impairment varied among centres and were associated with prior retinopathy and renal disease at baseline. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. Guys Hosp, Metab Med Unit, London SE1 9RT, England. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26901, Oklahoma City, OK 73190 USA. RI Nelson, Robert/B-1470-2012 NR 41 TC 12 Z9 13 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2001 VL 44 SU 2 BP S31 EP S36 DI 10.1007/PL00002937 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 475ZY UT WOS:000171201100005 PM 11587048 ER PT J AU Fetsch, PA Simsir, A Abati, A AF Fetsch, PA Simsir, A Abati, A TI Comparison of antibodies to HBME-1 and calretinin for the detection of mesothelial cells in effusion cytology SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article DE calretinin; HBME-1; immunocytochemistry; mesothelial cells ID DIFFERENTIAL-DIAGNOSIS; MALIGNANT MESOTHELIOMA; PLEURAL MESOTHELIOMA; E-CADHERIN; ADENOCARCINOMA; MARKERS; UTILITY; THROMBOMODULIN; TUMORS AB The distinction of mesothelial cells in cytologic samples is often a diagnostic challenge. This is particularly true in potentially, malignant effusions in which reactive mesothelial cells may simulate adenocarcinoma (ACA) cells, and in the differentiation of ACA vs. mesothelioma. We sought to determine the superior antibody for the positive identification of mesothelial cells in these circumstances. Cell block sections of 25 reactive and 8 malignant mesothelioma effusions were immunostained with an avidin-biotin procedure, using antibodies to HBME-1 and calretinin. No Pretreatment Of samples was necessary for the HBME-1-stained slides; microwave antigen retrieval was performed on all slides stained for calretinin. A negative control was performed on each sample. The staining intensity of tumor cells was scored on a scale of 0-3+, with the proportion of immunoreactive cells categorized as < 25%, 25-50%, 50-75%, and > 75%. The predominant staining pattern for HBME-1 was surface, with rare samples also exhibiting cytoplasmic staining as well. The calretinin-staining pattern was cytoplasmic, with peripheral condensation/prominence and accompanying nuclear staining. All samples were immunoreactive with both antibodies. Fifty-five percent (18/33) of samples showed significantly stronger immunoreactivity with calretinin than with HBME-1; 45% (15/33) of samples showed equivalent staining with the two markers. None of the samples in this study showed stronger immunoreactivity with HBME-1 than with calretinin. Sixty-one percent (20/33) of samples stained with HBME-1 at a moderate (2+) intensity. Fifty-five percent (18/33) of samples stained with calretinin at a strong (3+) intensify. While only 12% of samples showed > 75% immunoreactivity for HBME-1, 58% of samples showed > 75% of cells immunoreactive for calretinin. Calretinin is the preferred marker in identifying mesothelial cells in cytologic samples, showing the highest sensitivity for mesothelial cells, as evidenced by a more intense staining reaction in a higher percentage of cells than with HBME-1. Published 2001 Wiley-Liss, Inc.(dagger). C1 NCI, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Cytopathol Sect, NIH, Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 22 TC 28 Z9 28 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 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD SEP PY 2001 VL 25 IS 3 BP 158 EP 161 DI 10.1002/dc.2028 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 467HB UT WOS:000170695400003 PM 11536437 ER PT J AU Tang, J Cao, Y Rose, RL Brimfield, AA Dai, D Goldstein, JA Hodgson, E AF Tang, J Cao, Y Rose, RL Brimfield, AA Dai, D Goldstein, JA Hodgson, E TI Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse, and rat liver microsomes SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PARATHION; ACTIVATION; TOXICITY; BIOTRANSFORMATION; IDENTIFICATION; OXIDATION AB One of the factors determining the toxicity of chlorpyrifos (CPS), an organophosphorus (OP) insecticide, is its biotransformation. CPS can be activated by cytochrome P450 (CYP) through a desulfuration reaction to form chlorpyrifos-oxon (CPO), a potent anticholinesterase. CPS can also be detoxified by CYP through a dearylation reaction. Using pooled human liver microsomes (HLM), a K-mapp of 30.2 muM and V-maxapp of 0.4 nmol/min/mg of protein was obtained for desulfuration, and a K-mapp of 14.2 muM and a V-maxapp of 0.7 nmol/min/mg of protein was obtained for dearylation. These activities are lower than those obtained from rat liver microsomes. Gender differences in humans were also observed with female HLM possessing greater activity than male HLM. Use of human CYP isoforms expressed in human lymphoblastoma cells demonstrated that CYP1A2, 2B6, 2C9*1, 2C19, and 3A4 are involved in CPS metabolism. CYP2B6 has the highest desulfuration activity, whereas dearylation activity is highest for 2C19. CYP3A4 has high activity for both dearylation and desulfuration. The use of phenotyped individual HLM demonstrated that predictions of metabolic activation and/or detoxication could be made based on relative amounts of CYP2B6, 2C19, and 3A4 in the microsomes. Thus, individuals with high CYP2C19 but low 3A4 and 2B6 are more active in dearylation than in desulfuration. Similarly, individuals possessing high levels of CYP2B6 and 3A4 have the greatest potential to form the activation product. These differences between individuals suggest that differential sensitivities to CPS may exist in the human population. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. USA, Med Res Inst Chem Def, Aberdeen Proving Ground, MD 21010 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Hodgson, E (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Box 7633, Raleigh, NC 27695 USA. RI Goldstein, Joyce/A-6681-2012 NR 20 TC 152 Z9 158 U1 3 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD SEP PY 2001 VL 29 IS 9 BP 1201 EP 1204 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 465MV UT WOS:000170593500006 PM 11502728 ER PT J AU Cherstniakova, SA Bi, DQ Fuller, DR Mojsiak, JZ Collins, JM Cantilena, LR AF Cherstniakova, SA Bi, DQ Fuller, DR Mojsiak, JZ Collins, JM Cantilena, LR TI Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine, by human cytochrome P450 enzymes SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID COCAINE-MEDIATED HEPATOTOXICITY; DOPAMINE REUPTAKE INHIBITOR; GBR-12909; GBR12909; RAT; BEHAVIOR; HISTORY AB Vanoxerine (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; GBR12909) is a promising agent for the treatment of cocaine dependence. Knowledge of the major pathway for GBR12909 metabolism is important for prediction of the likelihood of drug-drug interactions, which may affect the therapeutic clinical outcome, when this agent is used in cocaine-dependent individuals receiving multiple drug therapy. We studied biotransformation of GBR12909 in human liver microsomes (n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. A high-pressure liquid chromatography assay was used to measure parent GBR12909 and its primary metabolite. GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes; by 92 +/- 2 and 92.4 +/- 0.4%, respectively. Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 +/- 22% inhibition in human liver microsomes and 54 +/- 35% in hepatocytes. Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 +/- 18.5% in primary human hepatocytes. Ciprofloxacin (CYP1A2), sulfaphenazole (CYP2C9), quinidine (CYP2D6), chlorzoxazone (CYP2E1), and mephenytoin (CYP2C19) did not demonstrate statistically significant inhibition (p > 0.05) of GBR12909 biotransformation in liver microsomes. cDNA-expressed P450 3A4 metabolized GBR12909 to a greater extent than 2C8 and 2E1. These data suggest the possibility that multiple P450 isoforms may be involved in human GBR12909 metabolism but that CYP3A appears to be the major enzyme responsible for human GBR12909 biotransformation. C1 Uniformed Serv Univ Hlth Sci, Div Clin Pharmacol & Med Toxicol, Bethesda, MD 20814 USA. NIDA, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Drug Evaluat, Lab Clin Pharmacol, Rockville, MD 20857 USA. RP Cantilena, LR (reprint author), Uniformed Serv Univ Hlth Sci, Div Clin Pharmacol & Med Toxicol, 4301 Jones Bridge Rd,Room B2020, Bethesda, MD 20814 USA. FU NIDA NIH HHS [Y1 DA-9094-02] NR 29 TC 5 Z9 6 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD SEP PY 2001 VL 29 IS 9 BP 1216 EP 1220 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 465MV UT WOS:000170593500009 PM 11502731 ER PT J AU Davy, A Bello, P Thierry-Mieg, N Vaglio, P Hitti, J Doucette-Stamm, L Thierry-Mieg, D Reboul, J Boulton, S Walhout, AJM Coux, O Vidal, M AF Davy, A Bello, P Thierry-Mieg, N Vaglio, P Hitti, J Doucette-Stamm, L Thierry-Mieg, D Reboul, J Boulton, S Walhout, AJM Coux, O Vidal, M TI A protein-protein interaction map of the Caenorhabditis elegans 26S proteasome SO EMBO REPORTS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; PROTEOLYSIS; COMPLEX; LINK AB The ubiquitin-proteasome proteolytic pathway is pivotal in most biological processes. Despite a great level of information available for the eukaryotic 26S proteasome-the protease responsible for the degradation of ubiquitylated proteins-several structural and functional questions remain unanswered. To gain more insight into the assembly and function of the metazoan 26S proteasome, a two-hybrid-based protein interaction map was generated using 30 Caenorhabditis elegans proteasome subunits. The results recapitulate interactions reported for other organisms and reveal new potential interactions both within the 19S regulatory complex and between the 19S and 20S subcomplexes. Moreover, novel potential proteasome interactors were identified, including an E3 ubiquitin ligase, transcription factors, chaperone proteins and other proteins not yet functionally annotated. By providing a wealth of novel biological hypotheses, this interaction map constitutes a framework for further analysis of the ubiquitin-proteasome pathway in a multicellular organism amenable to both classical genetics and functional genomics. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. CRBM, CNRS UPR 1086, IFR 24, F-34293 Montpellier, France. IMAG, Lab LSR, F-38041 Grenoble, France. Genome Therapeut Corp, Waltham, MA 02453 USA. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Coux, Olivier/B-3406-2010; Thierry-Mieg, Nicolas/M-6007-2014; Reboul, Jerome/P-9103-2016; OI Coux, Olivier/0000-0001-8455-3849; Reboul, Jerome/0000-0002-5513-4546; Vaglio, Philippe/0000-0003-2900-5596; Walhout, Marian/0000-0001-5587-3608 FU NCI NIH HHS [7R33 CA81658-02, P01 CA080111, P01CA80111-02]; NHGRI NIH HHS [R01 HG001715, 5R01HG01715-02]; PHS HHS [232] NR 30 TC 128 Z9 138 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD SEP PY 2001 VL 2 IS 9 BP 821 EP 828 DI 10.1093/embo-reports/kve184 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 477MM UT WOS:000171287400018 PM 11559592 ER PT J AU O'Connor, S Taylor, C Campbell, LA Epstein, S Libby, P AF O'Connor, S Taylor, C Campbell, LA Epstein, S Libby, P TI Potential infectious etiologies of atherosclerosis: A multifactorial perspective SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CHLAMYDIA-PNEUMONIAE INFECTION; CORONARY HEART-DISEASE; HERPES-SIMPLEX VIRUS; PRIOR CYTOMEGALOVIRUS-INFECTION; CARDIAC ALLOGRAFT VASCULOPATHY; FUTURE MYOCARDIAL-INFARCTION; SECONDARY PREVENTION TRIAL; BLOOD MONONUCLEAR-CELLS; SMOOTH-MUSCLE CELLS; ARTERY DISEASE AB Coronary heart disease (CHD) contributes substantially to illness and death worldwide. Experimental studies demonstrate that infection can stimulate atherogenic processes. This review presents a spectrum of data regarding the link between CHD and infection. In addition, the need for improved diagnostic tools, the significance of multiple pathogens, and potential intervention strategies are discussed. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Washington Hosp Ctr, MedStar Res Inst, Washington, DC 20010 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP O'Connor, S (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop C-12, Atlanta, GA 30333 USA. NR 97 TC 65 Z9 69 U1 0 U2 2 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP-OCT PY 2001 VL 7 IS 5 BP 780 EP 788 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 489EQ UT WOS:000171979400003 PM 11747688 ER PT J AU Richards, RG Klotz, DM Bush, MR Walmer, DK DiAugustine, RP AF Richards, RG Klotz, DM Bush, MR Walmer, DK DiAugustine, RP TI E2-induced degradation of uterine insulin receptor substrate-2: Requirement for an IGF-I-stimulated, proteasome-dependent pathway SO ENDOCRINOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; MOUSE UTERUS; TYROSINE PHOSPHORYLATION; PHOSPHOTYROSINE PROTEIN; 3T3-L1 ADIPOCYTES; ADAPTER PROTEIN; FACTOR-ALPHA; SH2 DOMAIN; KAPPA-B; C-CBL AB The insulin receptor substrates are docking proteins that bind various receptor tyrosine kinases and signaling proteins. Previous studies have shown that E2 or progesterone can regulate the relative abundance of insulin receptor substrate-1 and -2 in cells and tissues. For instance, uterine insulin receptor substrate-2 was decreased markedly at 24 h after E2 treatment of mice. In the present study we used various in vivo experimental approaches to examine the mechanism by which E2 influences uterine insulin receptor substrate-2 expression. Uterine insulin receptor substrate-2 mRNA levels were diminished after E2 treatment, but this diminution did not account for the total reduction in insulin receptor substrate-2 protein, suggesting that the E2-induced decrease in insulin receptor substrate-2 is not regulated solely at the mRNA level. Cotreatment with progesterone prevented the E2-stimulated reduction in insulin receptor substrate-2 protein at 24 h after hormone exposure. In addition, MG-132 and epoxomicin, inhibitors of proteasomal protease activity, inhibited the E2-induced decrease in uterine insulin receptor substrate-2 protein levels, and this correlated to an increase in uterine protein ubiquitination. Insulin receptor substrate-2 protein was diminished in uteri of E2-treated insulin receptor substrate-l-null mutant mice, but not in E2-treated IGF-I-null mutant mice. Furthermore, E2-induced diminution of uterine insulin receptor substrate-2 protein was only partially inhibited in the presence of wortmannin, a PI3K inhibitor. Collectively, these data suggest that the E2-induced decrease in uterine insulin receptor substrate-2 requires IGF-I signaling, is not dependent solely on insulin receptor substrate-1 and PI3K, and is blocked by progesterone as well as by pharmacological inhibition of proteasomal protease activity. We speculate that the IGF-I-activated IGF-I receptor, in response to E2, directly or indirectly modifies insulin receptor substrate-2, probably through phosphorylation, leading to ubiquitination and subsequent degradation of this docking protein by the proteasome. This degradation could be a regulatory step to inhibit insulin receptor substrate-2-dependent signaling in the uterus. C1 NIEHS, Hormones & Canc Grp, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Durham, NC 27710 USA. RP DiAugustine, RP (reprint author), NIEHS, Hormones & Canc Grp, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr,MD D4-04, Res Triangle Pk, NC 27709 USA. NR 56 TC 10 Z9 11 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2001 VL 142 IS 9 BP 3842 EP 3849 DI 10.1210/en.142.9.3842 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467EM UT WOS:000170689500015 PM 11517161 ER PT J AU Armando, I Carranza, A Nishimura, Y Hoe, KL Barontini, M Terron, JA Falcon-Neri, A Ito, T Juorio, AV Saavedra, JM AF Armando, I Carranza, A Nishimura, Y Hoe, KL Barontini, M Terron, JA Falcon-Neri, A Ito, T Juorio, AV Saavedra, JM TI Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation stress SO ENDOCRINOLOGY LA English DT Article ID MESSENGER-RNA EXPRESSION; BLOOD-BRAIN-BARRIER; PARAVENTRICULAR NUCLEUS; RAT-BRAIN; PHOSPHOINOSITIDE HYDROLYSIS; SUBFORNICAL ORGAN; GENE-EXPRESSION; TYPE-1 RECEPTOR; SUBTYPES; AT(2) AB Angiotensin II, which stimulates AT, receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT, receptor antagonist candesartan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type binding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiography and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) mRNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan blocked AT(1) binding in paraventricular nucleus and adrenal gland; prevented the isolation-induced alterations in pituitary ACTH and AVP and in adrenal corticosterone, aldosterone, and catecholamines; abolished the increase in AT(2) binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT(1) receptor antagonist blocks brain and peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders. C1 NIMH, Pharmacol Sect, NIH, Bethesda, MD 20814 USA. Consejo Nacl Invest Cient & Tecn, Ctr Invest Endocrinol, RA-1013 Buenos Aires, DF, Argentina. RP Armando, I (reprint author), NIMH, Pharmacol Sect, NIH, Bethesda, MD 20814 USA. RI chen, xuanlan/H-4158-2011 NR 50 TC 90 Z9 94 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2001 VL 142 IS 9 BP 3880 EP 3889 DI 10.1210/en.142.9.3880 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467EM UT WOS:000170689500020 PM 11517166 ER PT J AU Grattan, DR Xu, JJ McLachlan, MJ Kokay, IC Bunn, SJ Hovey, RC Davey, HW AF Grattan, DR Xu, JJ McLachlan, MJ Kokay, IC Bunn, SJ Hovey, RC Davey, HW TI Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b SO ENDOCRINOLOGY LA English DT Article ID TYROSINE-HYDROXYLASE GENE; TUBEROINFUNDIBULAR DOPAMINERGIC-NEURONS; PROLACTIN RECEPTOR IMMUNOREACTIVITY; MESSENGER-RNA; OVARIECTOMIZED RATS; MATERNAL-BEHAVIOR; RESPONSE ELEMENT; ARCUATE NUCLEUS; DEFICIENT MICE; KNOCKOUT MICE AB PRL secretion from the anterior pituitary gland is inhibited by dopamine produced in the tuberoinfundibular dopamine neurons of the hypothalamus. The activity of tuberoinfundibular dopamine neurons is stimulated by PRL; thus, PRL regulates its own secretion by a negative feedback mechanism. PRL receptors are expressed on tuberoinfundibular dopamine neurons, but the intracellular signaling pathway is not known. We have observed that mice with a disrupted signal transducer and activator of transcription 5b gene have grossly elevated serum PRL concentrations. Despite this hyperprolactinemia, mRNA levels and immunoreactivity of tyrosine hydroxylase, the key enzyme in dopamine synthesis, were significantly lower in the tuberoinfundibular dopamine neurons of these signal transducer and activator of transcription 5b-deficient mice. Concentrations of the dopamine metabolite dihydroxyphenylacetic acid in the median eminence were also significantly lower in signal transducer and activator of transcription 5b-deficient mice than in wild-type mice. No changes were observed in nonhypothalamic dopaminergic neuronal populations, indicating that the effects were selective to tuberoinfundibular dopamine neurons. These data indicate that in the absence of signal transducer and activator of transcription 5b, PRL signal transduction in tuberoinfundibular dopamine neurons is impaired, and they demonstrate that this transcription factor plays an obligatory and nonredundant role in mediating the negative feedback action of PRL on tuberoinfundibular dopamine neurons. C1 Univ Otago, Dept Anat & Struct Biol, Dunedin, New Zealand. AgResearch, Ruakura Res Ctr, Hamilton, New Zealand. NCI, Ctr Canc Res, Mol & Cellular Endocrinol Sect, NIH, Bethesda, MD 20892 USA. RP Grattan, DR (reprint author), Univ Otago, Dept Anat & Struct Biol, POB 913, Dunedin, New Zealand. EM dave.grattan@anatomy.otago.ac.nz OI Grattan, Dave/0000-0001-5606-2559 NR 54 TC 52 Z9 52 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2001 VL 142 IS 9 BP 3935 EP 3940 DI 10.1210/en.142.9.3935 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467EM UT WOS:000170689500026 PM 11517172 ER PT J AU Habib, KE Gold, PW Chrousos, GP AF Habib, KE Gold, PW Chrousos, GP TI Neuroendocrinology of stress SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; RECEPTOR MESSENGER-RNA; PITUITARY-ADRENAL AXIS; POTENTIAL CLINICAL IMPLICATIONS; IRRITABLE-BOWEL-SYNDROME; CENTRAL-NERVOUS-SYSTEM; NEUROPEPTIDE-Y; RAT-BRAIN; LOCUS-COERULEUS; HORMONE CRH AB Stimuli that are interpreted by the brain as extreme or threatening, regardless of their modality, elicit an immediate stereotypic response characterized by enhanced cognition, affective immobility, vigilance, autonomic arousal, and a global catabolic state. The brain's ability to mobilize this so-called stress response is paralleled by activation of corticotropin-releasing hormone (CRH) in several nuclei, including the hypothalamus, amygdala and locus ceruleus, and stimulation of the locus ceruleus norepinephrine (LC/NE) system in the brain stem. These systems perpetuate one another, interact with several other transmitter systems in the brain and directly activate the hypothalamic-pituitary-adrenal (HPA) axis and the three components of the autonomic nervous system, namely the sympatho-adrenal, the cranio-sacral parasympathetic, and the enteric nervous systems. The widespread body system responses to stress are discussed, and the implications of aberrant stress system activity on physical and mental health are outlined. Moreover, the promise of nonpeptide CRH type-1 receptor antagonists to directly target the stress system in the brain is highlighted. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Habib, KE (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Bldg 10,Room 2D-46, Bethesda, MD 20892 USA. NR 122 TC 196 Z9 203 U1 1 U2 16 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD SEP PY 2001 VL 30 IS 3 BP 695 EP + DI 10.1016/S0889-8529(05)70208-5 PG 36 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 472YW UT WOS:000171013400010 PM 11571937 ER PT J AU Lobenhofer, EK Bushel, PR Afshari, CA Hamadeh, HK AF Lobenhofer, EK Bushel, PR Afshari, CA Hamadeh, HK TI Progress in the application of DNA microarrays SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE DNA chips; gene expression profiling; microarray; toxicogenomics ID GENE-EXPRESSION PATTERNS; COMPARATIVE GENOMIC HYBRIDIZATION; CANCER CELL-LINES; LASER CAPTURE MICRODISSECTION; MESSENGER-RNA EXPRESSION; PROTEIN-KINASE-C; BREAST-CANCER; CDNA MICROARRAY; COMPLEMENTARY-DNA; GROWTH-FACTOR AB Microarray technology has been applied to a variety of different fields to address fundamental research questions. The use of microarrays, or DNA chips, to study the gene expression profiles of biologic samples began in 1995. Since that time, the fundamental concepts behind the chip, the technology required for making and using these chips, and the multitude of statistical tools for analyzing the data have been extensively reviewed. For this reason, the focus of this review will be not on the technology itself but on the application of microarrays as a research tool and the future challenges of the Field. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Afshari, CA (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM afshari@niehs.nih.gov NR 190 TC 30 Z9 31 U1 4 U2 11 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 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2001 VL 109 IS 9 BP 881 EP 891 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 481PT UT WOS:000171529100018 PM 11673116 ER PT J AU Catallo, WJ Kennedy, CH Henk, W Barker, SA Grace, SC Penn, A AF Catallo, WJ Kennedy, CH Henk, W Barker, SA Grace, SC Penn, A TI Combustion products of 1,3-butadiene are cytotoxic and genotoxic to human bronchial epithelial cells SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE blebbing; BSDE; butadiene soot; fluorescence; free radicals; human bronchial epithelial cells; PAHs ID DIESEL EXHAUST PARTICLES; POLYCYCLIC AROMATIC-HYDROCARBONS; CYTOKINE PRODUCTION; ACTIVATION; INDUCTION AB Adverse health effects of airborne toxicants, especially small respirable particles and their associated adsorbed chemicals, are of growing concern to health professionals, governmental agencies, and the general public. Areas rich in petrochemical processing facilities (e.g., eastern Texas and southern California) chronically have poor air quality. Atmospheric releases of products of incomplete combustion (e.g., soot) from these facilities are not subject to rigorous regulatory enforcement. Although soot can include respirable particles and carcinogens, the toxicologic and epidemiologic consequences of exposure to environmentally relevant complex soots have not been well investigated. Here we continue our physico-chemical analysis of butadiene soot and report effects of exposure to this soot on putative targets, normal human bronchial epithelial (NHBE) cells. We examined organic extracts of butadiene soot by gas chromatography-mass spectrometry (GC-MS), probe distillation MS, and liquid chromatography (LC)-MS-MS. Hundreds of aromatic hydrocarbons and polycyclic aromatic hydrocarbons with molecular mass as high as 1,000 atomic mass units were detected, including known and suspected human carcinogens (e.g., benzo(a)pyrene). Butadiene soot particles also had strong, solid-state free-radical character in electron spin resonance analysis. Spin-trapping studies indicated that fresh butadiene soot in a buffered aqueous solution containing dimethylsulfoxide (DMSO) oxidized the DMSO, leading to CH3. radical formation. Butadiene soot DMSO extract (BSDE)-exposed NHBE cells displayed extranuclear fluorescence within 4 hr of exposure. BSDE was cytotoxic to > 20% of the cells at 72 hr. Morphologic alterations, including cell swelling and membrane blebbing, were apparent within 24 hr of exposure. These alterations are characteristic of oncosis, an ischemia-induced form of cell death. BSDE treatment also produced significant genotoxicity, as indicated by binucleated cell formation. The combination of moderate cytotoxicity and genotoxicity, as occurred here, can be pro-carcinogenic. C1 Louisiana State Univ, Sch Vet Med, Dept Comparat Biomed Sci, Baton Rouge, LA 70803 USA. Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. Louisiana State Univ, Inst Biodynam, Baton Rouge, LA 70803 USA. Univ Arkansas, Dept Biol, Little Rock, AR 72204 USA. RP Penn, A (reprint author), Louisiana State Univ, Sch Vet Med, Dept Comparat Biomed Sci, Skip Bertman Dr, Baton Rouge, LA 70803 USA. NR 28 TC 17 Z9 18 U1 1 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2001 VL 109 IS 9 BP 965 EP 971 DI 10.2307/3455000 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 481PT UT WOS:000171529100030 PM 11673128 ER PT J AU London, SJ Gauderman, WJ Avol, E Rappaport, EB Peters, JM AF London, SJ Gauderman, WJ Avol, E Rappaport, EB Peters, JM TI Family history and the risk of early-onset persistent, early-onset transient, and late-onset asthma SO EPIDEMIOLOGY LA English DT Article DE asthma; wheeze; genetic susceptibility; parental history; smoking; pregnancy; in utero; sibling ID MATERNAL SMOKING; LUNG-FUNCTION; PARENTAL SMOKING; RESPIRATORY-FUNCTION; CHILDHOOD ASTHMA; AIR-POLLUTION; PREGNANCY; CHILDREN; EXPOSURE; INFANTS AB Family history of asthma and allergies strongly influences asthma risk in children, but the association may differ for early-onset persistent, early-onset transient, and late-onset asthma. We analyzed the relation between family history and these types of asthma using cross-sectional data from a school-based study of 5,046 Southern California children. Parental and/or sibling history of asthma and allergy were generally more strongly associated with early-onset persistent asthma compared with early-onset transient or late-onset asthma. For children with two asthmatic parents relative to those with none, the prevalence ratio for early-onset persistent asthma was 12.1 [95% confidence interval (CI) = 7.91-18.7] compared with 7.51 (95% CI = 2.62-21.5) for early,onset transient asthma and 5.38 (95% CI = 3.40-8.50) for late-onset asthma. Maternal smoking in pregnancy was predominantly related to the risk of early-onset persistent asthma in the presence of parental history of allergy and asthma, and the joint effects were more than additive (interaction contrast ratio = 3.10, 95% CI = 1.45-4.75). Our results confirm earlier data that parental history of asthma and allergy is most strongly associated with early-onset persistent asthma and suggest that among genetically predisposed children, an early-life environmental exposure, maternal smoking during pregnancy, favors the development of early-onset asthma that persists into later early childhood. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. RP London, SJ (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI London, Stephanie/0000-0003-4911-5290 FU NHLBI NIH HHS [R01 HL/ES 61768-01]; NIEHS NIH HHS [R01 ES10421, 1PO1 ES0939581-05, 5P30 ES07048-02, P30 ES007048, R01 ES010421, Z01 ES049019] NR 28 TC 51 Z9 53 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2001 VL 12 IS 5 BP 577 EP 583 DI 10.1097/00001648-200109000-00019 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 465GJ UT WOS:000170581000020 PM 11505179 ER EF