FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Emerson, SU Huang, YK Nguyen, H Brockington, A Govindarajan, S St Claire, M Shapiro, M Purcell, RH AF Emerson, SU Huang, YK Nguyen, H Brockington, A Govindarajan, S St Claire, M Shapiro, M Purcell, RH TI Identification of VP1/2A and 2C as virulence genes of hepatitis A virus and demonstration of genetic instability of 2C SO JOURNAL OF VIROLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; NUCLEIC-ACID TRANSFECTION; A VIRUS; CELL-CULTURE; ADAPTATION; GROWTH; CDNA; PARTICLES; MUTATIONS; STRAINS AB Fourteen different chimeric virus genomes were constructed from two infectious cDNA clones encoding a virulent and an attenuated isolate, respectively, of the HM175 strain of hepatitis A virus. The ability of each recombinant virus to infect tamarins and to cause acute hepatitis was determined. Comparisons of the genotype and phenotype of each virus suggested that VP1/2A and 2C genes were responsible for virulence. The 2C gene derived from the attenuated parent virus was unstable, and one or more mutations arose in this gene during the first passage in tamarins. 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. Univ So Calif, Rancho Los Amigos Med Ctr, Liver Res Lab, Downey, CA 90242 USA. Bioqual Inc, Rockville, MD 20850 USA. RP Emerson, SU (reprint author), Bldg 50,Room 6537,50 South Dr,MSC-8009, Bethesda, MD 20892 USA. FU PHS HHS [1-A0-02733] NR 24 TC 21 Z9 24 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 SEP PY 2002 VL 76 IS 17 BP 8551 EP 8559 DI 10.1128/JVI.76.17.8551-8559.2002 PG 9 WC Virology SC Virology GA 582DR UT WOS:000177334900006 PM 12163575 ER PT J AU Green, KY Mory, A Fogg, MH Weisberg, A Belliot, G Wagner, M Mitra, T Ehrenfeld, E Cameron, CE Sosnovtsev, SV AF Green, KY Mory, A Fogg, MH Weisberg, A Belliot, G Wagner, M Mitra, T Ehrenfeld, E Cameron, CE Sosnovtsev, SV TI Isolation of enzymatically active replication complexes from feline calicivirus-infected cells SO JOURNAL OF VIROLOGY LA English DT Article ID DEPENDENT RNA-POLYMERASE; CAPSID PROTEIN GENE; ENDOPLASMIC-RETICULUM; NUCLEOTIDE-SEQUENCE; POLIOVIRUS INFECTION; PRECURSOR PROTEIN; VIRAL-PROTEINS; BREFELDIN-A; IN-VITRO; IDENTIFICATION AB A membranous fraction that could synthesize viral RNA in vitro in the presence of magnesium salt, ribonucleotides, and an ATP-regenerating system was isolated from feline calicivirus (FCV)-infected cells. The enzymatically active component of this fraction was designated FCV replication complexes (RCs), by analogy to other positive-strand RNA viruses. The newly synthesized RNA was characterized by Northern blot analysis, which demonstrated the production of both full-length (8.0-kb) and subgenomic-length (2.5-kb) RNA molecules similar to those synthesized in FCV-infected cells. The identity of the viral proteins associated with the fraction was investigated. The 60-kDa VP1 major capsid protein was the most abundant viral protein detected. VP2, a minor structural protein encoded by open reading frame 3 (ORF3), was also present. Nonstructural proteins associated with the fraction included the precursor polypeptides Pro-Pol (76 kDa) and p30-VPg (43 kDa), as well as the mature nonstructural proteins p32 (derived from the N-terminal region of the ORF1 polyprotein), p30 (the putative "3A-like" protein), and p39 (the putative nucleoside triphosphatase). The isolation of enzymatically active RCs containing both viral and cellular proteins should facilitate efforts to dissect the contributions of the virus and the host to FCV RNA replication. C1 NIH, Bethesda, MD 20892 USA. Penn State Univ, University Pk, PA 16802 USA. RP Green, KY (reprint author), NIH, Bldg 50,Room 6318,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 48 TC 47 Z9 47 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2002 VL 76 IS 17 BP 8582 EP 8595 DI 10.1128/JVI.76.17.8582-8585.2002 PG 14 WC Virology SC Virology GA 582DR UT WOS:000177334900009 PM 12163578 ER PT J AU Malaspina, A Moir, S Nickle, DC Donoghue, ET Ogwaro, KM Ehler, LA Liu, SY Mican, JAM Dybul, M Chun, TW Mullins, JI Fauci, AS AF Malaspina, A Moir, S Nickle, DC Donoghue, ET Ogwaro, KM Ehler, LA Liu, SY Mican, JAM Dybul, M Chun, TW Mullins, JI Fauci, AS TI Human immunodeficiency virus type 1 bound to B cells: Relationship to virus replicating in CD4(+) T cells and circulating in plasma SO JOURNAL OF VIROLOGY LA English DT Article ID FOLLICULAR DENDRITIC CELLS; ACTIVE ANTIRETROVIRAL THERAPY; HETERODUPLEX MOBILITY ASSAY; LYMPHOID-TISSUE; HIV-1; INFECTION; DYNAMICS; POPULATIONS; DISEASE; HAART AB Human immunodeficiency virus type 1 (HIV-1) virions bind to B cells in the peripheral blood and lymph nodes through interactions between CD21 on B cells and complement-complexed virions. B-cell-bound virions have been shown to be highly infectious, suggesting a unique mode of HIV-1 dissemination by B cells circulating between peripheral blood and lymphoid tissues. In order to investigate the relationship between B-cell-bound HIV-1 and viruses found in CD4(+) T cells and in plasma, we examined the genetic relationships of HIV-1 found in the blood and lymph nodes of chronically infected patients with heteroduplex mobility and tracking assays and DNA sequence analysis. In samples from 13 of 15 patients examined, HIV-1 variants in peripheral blood-derived B cells were closely related to virus in CD4(+) T cells and more divergent from virus in plasma. In samples from five chronically viremic patients for whom analyses were extended to include lymph node-derived HIV-1 isolates, B-cell-associated HIV-1 and CD4(+)-T-cell-associated HIV-1 in the lymph nodes were equivalent in their divergence from virus in peripheral blood-derived B cells and generally more distantly related to virus in peripheral blood-derived CD4(+) T cells. These results indicates virologic cross talk between B cells and CD4(+) T cells within the microenvironment of lymphoid tissues and, to a lesser extent, between cells in lymph nodes and the peripheral blood. These findings also indicate that most of the virus in plasma originates from cells other than CD4(+) T cells in the peripheral blood and lymph nodes. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,MSC-1576,Bldg 10,Room 6A02, Bethesda, MD 20892 USA. NR 31 TC 28 Z9 31 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 SEP PY 2002 VL 76 IS 17 BP 8855 EP 8863 DI 10.1128/JVI.76.17.8855-8863.2002 PG 9 WC Virology SC Virology GA 582DR UT WOS:000177334900036 PM 12163605 ER PT J AU Reuter, JD Vivas-Gonzalez, BE Gomez, D Wilson, JH Brandsma, JL Greenstone, HL Rose, JK Roberts, A AF Reuter, JD Vivas-Gonzalez, BE Gomez, D Wilson, JH Brandsma, JL Greenstone, HL Rose, JK Roberts, A TI Intranasal vaccination with a recombinant vesicular stomatitis virus expressing cottontail rabbit papillomavirus L1 protein provides complete protection against papillomavirus-induced disease SO JOURNAL OF VIROLOGY LA English DT Article ID CERVICAL-CANCER; IMMUNIZATION; PARTICLES; CHALLENGE; CRPV; DNA; INFECTION; VACCINES AB Immunizations with live recombinant vesicular stomatitis viruses (rVSV) expressing foreign viral proteins have successfully protected animals from challenges with several heterologous viruses. We developed an rVSV expressing the major capsid protein (L1) of cottontail rabbit papillomavirus (CRPV) and tested the efficacy of protection following CRPV challenge. An rVSV expressing L1 of CRPV (VSV-L1) was characterized for the protective ability afforded by intranasal, intradermal, or intramuscular vaccination in rabbits subsequently challenged with CRPV. Protein expression of L1 in VSV-L1 was confirmed by radioimmunoprecipitation assays. Nuclear localization of L1 was demonstrated by indirect immunofluorescence assays. Immunized rabbits elicited significant VSV neutralization and VLP-L1 enzyme-linked immunosorbent assay titers. VSV-L1 vaccination was not associated with weight loss or any other adverse clinical signs in the rabbit model. VSV shedding in nasal secretions occurred in some rabbits, peaking at 4 to 6 days after intranasal vaccination, with no further shedding after day 6. Specific Immoral immunity to the L1 protein was consistently seen after a single VSV-L1 vaccination when administered through an intradermal or intramuscular route or after a boost via the intranasal route. Rabbits were completely protected from CRPV-induced papillomas after VSV-L1 vaccination and boost given intranasally or intramuscularly. Vaccination with VSV-L1 is a novel approach to prevent papillomavirus-induced disease and demonstrates a potential strategy for developing a human papillomavirus vaccine that can be given without injection. C1 Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Cellular Biol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Reuter, JD (reprint author), Yale Univ, Sch Med, Comparat Med Sect, POB 208016, New Haven, CT 06520 USA. FU NIAID NIH HHS [R01AI24345] NR 41 TC 62 Z9 63 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 SEP PY 2002 VL 76 IS 17 BP 8900 EP 8909 DI 10.1128/JVI.76.17.8900-8909.2002 PG 10 WC Virology SC Virology GA 582DR UT WOS:000177334900040 PM 12163609 ER PT J AU Yang, YP McKerlie, C Borenstein, SH Lu, Z Schito, M Chamberlain, JW Buchwald, M AF Yang, YP McKerlie, C Borenstein, SH Lu, Z Schito, M Chamberlain, JW Buchwald, M TI Transgenic expression in mouse lung reveals distinct biological roles for the adenovirus type 5 E1A 243-and 289-amino-acid proteins SO JOURNAL OF VIROLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; NATURAL-KILLER CELLS; TATA-BINDING PROTEIN; TRANSCRIPTION FACTOR; EPITHELIAL-CELLS; DNA-SYNTHESIS; P53-DEPENDENT APOPTOSIS; ACTIVATED MACROPHAGES; ONCOGENE INDUCTION; PROMOTER AB Little is known about the biological significance of human adenovirus type 5 (Ad5) E1A in vivo. However, Ads E1A is well defined in vitro and can be detected frequently in the lungs of patients with pulmonary disease. Transgenic expression of the Ads E1A gene targeted to the mouse lung reveals distinct biological effects caused by two Ads E1A products. Either of two Ads E1A proteins was preferentially expressed in vivo in the transgenic lungs. The preferential expression of the Ads E1A 243-amino-acid (aa) protein at a moderate level was associated with cellular hyperplasia, nodular lesions of proliferating lymphocyte-like cells, and a low level of p53-dependent apoptosis in the lungs of transgenic mice. In contrast, the preferential expression of the Ads E1A 289-aa protein at a moderate level resulted in a proapoptotic injury and an acute pulmonary proinflammation in the lungs of transgenic mice, mediated by multiple apoptotic pathways, as well as an enhancement of the host immune cell response. Expression of the Ads E1A 243-aa protein resulted in proliferation-stimulated p53 upregulation, while expression of the Ads E1A 289-aa protein led to DNA damage-induced p53 activation. These data suggest that the Ads E1A 243- and 289-aa proteins lead to distinct biological roles in vivo. C1 Univ Toronto, Hosp Sick Children, Res Inst, Program Genet & Genom Biol, Toronto, ON M5G 1X8, Canada. Univ Toronto, Hosp Sick Children, Res Inst, Program Immun Infect Injury & Repair, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON, Canada. Univ Toronto, Dept Immunol, Toronto, ON, Canada. Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. Sunnybrook & Womens Coll Hlth Sci Ctr, Mol & Cellular Biol Res Program, Toronto, ON, Canada. RP Yang, YP (reprint author), NCI, Mouse Canc Genet Program, Canc Res Ctr, Bldg 560,Room 32-16,POB B, Frederick, MD 21702 USA. NR 63 TC 7 Z9 8 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 SEP PY 2002 VL 76 IS 17 BP 8910 EP 8919 DI 10.1128/JVI.76.17.8910-8919.2002 PG 10 WC Virology SC Virology GA 582DR UT WOS:000177334900041 PM 12163610 ER PT J AU Johansson, S Niklasson, B Maizel, J Gorbalenya, AE Lindberg, AM AF Johansson, S Niklasson, B Maizel, J Gorbalenya, AE Lindberg, AM TI Molecular analysis of three Ljungan virus isolates reveals a new, close-to-root lineage of the Picornaviridae with a cluster of two unrelated 2A proteins SO JOURNAL OF VIROLOGY LA English DT Article ID MOUTH-DISEASE VIRUS; MULTIPLE SEQUENCE ALIGNMENT; HUMAN PARECHOVIRUS 1; ENCEPHALOMYOCARDITIS VIRUS; ENCODED PROTEINASES; CLEAVAGE ACTIVITIES; DISTINCT SEROTYPES; RNA-POLYMERASE; SITE; NUCLEOTIDE AB Ljungan virus (LV) is a suspected human pathogen recently isolated from bank voles (Clethrionomys glareolus). In the present study, it is revealed through comparative sequence analysis that three newly determined Swedish LV genomes are closely related and possess a deviant picornavirus-like organization: 5' untranslated region-VP0-VP3-VP1-2A1-2A2-2B-2C-3A-3B-3C-3D-3' untranslated region. The LV genomes and the polyproteins encoded by them exhibit several exceptional features, such as the absence of a predicted maturation cleavage of VP0, a conserved sequence determinant in VP0 that is typically found in VP1 of other picornaviruses, and a cluster of two unrelated 2A proteins. The 2A1 protein is related to the 2A protein of cardio-, erbo-, tescho-, and aphthoviruses, and the 2A2 protein is related to the 2A protein of parechoviruses, kobuviruses, and avian encephalomyelitis virus. The unprecedented association of two structurally different 2A proteins is a feature never previously observed among picornaviruses and implies that their functions are not mutually exclusive. Secondary polyprotein processing of the LV polyprotein is mediated by proteinase 3C (3C(pro)) possessing canonical affinity to Glu and Gln at the P1 position and small amino acid residues at the P1' position. In addition, LV 3C(pro) appears to have unique substrate specificity to Asn, Gln, and Asp and to bulky hydrophobic residues at the P2 and P4 positions, respectively. Phylogenetic analysis suggests that LVs form a separate division, which, together with the Parechovirus genus, has branched off the picornavirus tree most closely to its root. The presence of two 2A proteins indicates that some contemporary picornaviruses with a single 2A may have evolved from the ancestral multi-2A picornavirus. C1 Univ Kalmar, Dept Chem & Biomed Sci, S-39182 Kalmar, Sweden. Nya Apodemus, S-11453 Stockholm, Sweden. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Gorbalenya, AE (reprint author), Univ Kalmar, Dept Chem & Biomed Sci, S-39182 Kalmar, Sweden. EM a.e.gorbalenya@lumc.nl; michael.lindberg@hik.se RI Lindberg, Michael/B-8465-2013; Gorbalenya, Alexander/J-4818-2012 OI Lindberg, Michael/0000-0003-3841-4826; Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-12400, N01-CO-56000, N01CO12400] NR 67 TC 63 Z9 64 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 SEP PY 2002 VL 76 IS 17 BP 8920 EP 8930 DI 10.1128/JVI.76.17.8920-8930.2002 PG 11 WC Virology SC Virology GA 582DR UT WOS:000177334900042 PM 12163611 ER PT J AU Khan, MA Akari, H Kao, S Aberham, C Davis, D Buckler-White, A Strebel, K AF Khan, MA Akari, H Kao, S Aberham, C Davis, D Buckler-White, A Strebel, K TI Intravirion processing of the human immunodeficiency virus type 1 Vif protein by the viral protease may be correlated with Vif function SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-DEPENDENT REQUIREMENT; BLOOD MONONUCLEAR-CELLS; HIV-1 PROTEASE; VIRION INCORPORATION; REVERSE TRANSCRIPTION; MUTATIONAL ANALYSIS; RESTRICTIVE CELLS; CO-ENCAPSIDATION; INFECTED-CELLS; GENE-PRODUCT AB The human immunodeficiency virus type 1 (HIV-1) Vif protein is specifically packaged into virus particles through an interaction with viral genomic RNA in which it associates with the viral nucleoprotein complex. We now demonstrate for the first time that virus-associated Vif is subject to proteolytic processing by the viral protease (Pr). Pr-dependent processing of Vif was observed both in vivo and in vitro. In vivo processing of Vif was cell type independent and evident by the appearance of a 7-kDa processing product, which was restricted to cell-free virus preparations. Processing of Vif required an active viral Pr and was sensitive to Pr inhibitors such as ritonavir. The processing site in Vif was characterized both in vivo and in vitro and mapped to Ala(150). Interestingly, the Vif processing site is located in a domain that is highly conserved among HIV-1, HIV-2, and simian immunodeficiency virus Vif isolates. Mutations at or near the processing site did not affect protein stability or packaging efficiency but had dramatic effects on Vif processing. In general, mutations that markedly increased or decreased the sensitivity of Vif to proteolytic processing severely impaired or completely abolished Vif function. In contrast, mutations at the same site that had little or no effect on processing efficiency also did not influence Vif function. None of the mutants affected the ability of the virus to replicate in permissive cell lines. Our data suggest that mutations in Vif that cause a profound change in the sensitivity to Pr-dependent processing also severely impaired Vif function, suggesting that intravirion processing of Vif is important for the production of infectious viruses. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. NCI, HIV Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, NIH, 4-312,4 Ctr Dr Dr,MSC 0460, Bethesda, MD 20892 USA. NR 64 TC 26 Z9 28 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 SEP PY 2002 VL 76 IS 18 BP 9112 EP 9123 DI 10.1128/JVI.76.18.9112-9123.2002 PG 12 WC Virology SC Virology GA 587TF UT WOS:000177658500014 PM 12186895 ER PT J AU Boyer, PL Sarafianos, SG Arnold, E Hughes, SH AF Boyer, PL Sarafianos, SG Arnold, E Hughes, SH TI Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision SO JOURNAL OF VIROLOGY LA English DT Article ID STERIC HINDRANCE; 3TC RESISTANCE; AZT RESISTANCE; AMINO-ACIDS; MECHANISM; MUTATIONS; INHIBITORS; UNBLOCKING; CODON-69; THERAPY AB Although anti-human immunodeficiency virus type 1 (HIV-1) therapy has prolonged the lives of patients, drug resistance is a significant problem. Of particular concern are mutations that cause cross-resistance to a particular class of drugs. Among the mutations that cause resistance to several nucleoside analogs are the insertion of amino acids in the fingers subdomain of HIV-1 reverse transcriptase (RT) at positions 69 and 70. These insertions are usually associated with changes in the flanking amino acids and with a change to F or Y at position 215. We have proposed that the T215F/Y mutation makes the binding of ATP to HIV-1 RT more effective, which increases the excision of 3-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) in vitro and increases zidovudine (AZT) resistance in vivo. Although the mechanism of AZT resistance involves enhanced excision, resistance to 3TC involves a block to incorporation of the analog. We measured the effects of fingers insertion mutations on the misincorporation and excision of several nucleoside analogs. RT variants with the amino acid insertions in the fingers and T215Y have a decreased level of misincorporation of ddATP and 3TCTP. These mutants also have the ability to excise AZTMP by ATP-dependent pyrophosphorylysis. However, unlike the classic AZT resistance mutations (M41L/D67N/K70R/T215Y or F/K219E or Q), the combination of the amino acid insertions in the fingers and the T215Y mutation allows efficient excision of ddTMP and d4TMP, even when relatively high levels of deoxynucleoside triphosphates are present in the reaction. Although the dideoxynucleoside analogs of other nucleosides were excised more slowly than AZTMP, ddTMP, and d4TMP, the mutants with the fingers insertion and T215Y excised all of the nucleoside analogs that were tested more efficiently than wild-type RT or a mutant RT carrying the classical AZT resistance mutations. In the ternary complex (RT/template-primer/dNTP), the presence of the bound dNTP prevents the end of the primer from gaining access to the nucleotide binding site(N site) where excision occurs. Gel shift analysis showed that the amino acid insertions in the fingers destabilized the ternary complex compared to wild-type HIV-1 RT. If the ternary complex is unstable, the end of the primer can gain access to the N site and excision can occur. This could explain the enhanced excision of the nucleoside analogs. C1 NCI, FCRDC, HIV Drug Resistance Program, Frederick, MD 21702 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, FCRDC, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [R37 AI027690, AI 27690]; NIGMS NIH HHS [GM 55609] NR 26 TC 73 Z9 76 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 SEP PY 2002 VL 76 IS 18 BP 9143 EP 9151 DI 10.1128/JVI.76.18.9143-9151.2002 PG 9 WC Virology SC Virology GA 587TF UT WOS:000177658500017 PM 12186898 ER PT J AU Triyatni, M Saunier, B Maruvada, P Davis, AR Ulianich, L Heller, T Patel, A Kohn, LD Liang, TJ AF Triyatni, M Saunier, B Maruvada, P Davis, AR Ulianich, L Heller, T Patel, A Kohn, LD Liang, TJ TI Interaction of hepatitis C virus-like particles and cells: a model system for studying viral binding and entry SO JOURNAL OF VIROLOGY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; GLYCOPROTEIN COMPLEXES; ENDOPLASMIC-RETICULUM; CANDIDATE RECEPTOR; ENVELOPE PROTEINS; INSECT CELLS; IN-VITRO; E2; CALCIUM; CD81 AB Hepatitis C virus-like particles (HCV-LPs) containing the structural proteins of HCV H77 strain (1a genotype) was used as a model for HCV virion to study virus-cell interaction. HCV-LPs showed a buoyant density of 1.17 to 1.22 g/cm(3) in a sucrose gradient and formed double-shelled particles 35 to 49 nm in diameter. Flow cytometry analysis by an indirect method (detection with anti-E2 antibody) and a direct method (use of dye-labeled HCV-LPs) showed that HCV-LPs binds to several human hepatic (primary hepatocytes, HepG2, HuH7, and NKNT-3) and T-cell (Molt-4) lines. HCV-LPs binding to cells occurred in a dose- and calcium-dependent manner and was not mediated by CD81. Scatchard plot analysis suggests the presence of two binding sites for HCV-LPs with high (K-d similar to1 mug/ml) and low (K-d similar to50 to 60 mug/ml) affinities of binding. Anti-E1 and -E2 antibodies inhibited HCV-LPs binding to cells. While preincubation of HCV-LPs with very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), or high-density lipoprotein (HDL) blocked its binding to cells, preincubation of cells with VLDL, LDL, HDL, or anti-LDL-R antibody did not. Confocal microscopy analysis showed that, after binding to cells, dye-labeled HCV-LPs were internalized into the cytoplasm. This process could be inhibited with anti-E1 or anti-E2 antibodies, suggesting that E1 and E2 proteins mediate HCV-LPs binding and, subsequently, their entry into cells. Altogether, our results indicate that HCV-LPs can be used to further characterize the mechanisms involved in the early steps of HCV infection. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Cell Regulat Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. MRC, Inst Virol, Glasgow, Lanark, Scotland. Ohio Univ, Edison Biotechnol Inst, Athens, OH 45701 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Sect, NIH, Bldg 10,Rm 9B06,10 Ctr Dr, Bethesda, MD 20892 USA. NR 55 TC 87 Z9 94 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2002 VL 76 IS 18 BP 9335 EP 9344 DI 10.1128/JVI.76.18.9335-9344.2002 PG 10 WC Virology SC Virology GA 587TF UT WOS:000177658500035 PM 12186916 ER PT J AU Ruff, CT Ray, SC Kwon, P Zinn, R Pendleton, A Hutton, N Ashworth, R Gange, S Quinn, TC Siliciano, RF Persaud, D AF Ruff, CT Ray, SC Kwon, P Zinn, R Pendleton, A Hutton, N Ashworth, R Gange, S Quinn, TC Siliciano, RF Persaud, D TI Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTED PATIENTS; CD4(+) T-CELLS; COMBINATION THERAPY; REVERSE-TRANSCRIPTASE; PLASMA VIREMIA; VIRAL LOAD; LYMPHOCYTES; RESISTANCE; ZIDOVUDINE; REPLICATION AB Although highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection can reduce levels of HIV-1 RNA in plasma to below the limit of detection, replication-competent forms of the virus persist in all infected individuals. One form of persistence involves a stable reservoir of latent but potentially infectious virus that resides in resting memory CD4(+) T cells. The mechanisms involved in maintaining this latent reservoir are incompletely understood. In the present study, we examined the dynamic characteristics of this reservoir in a cohort of children who developed drug-resistant HIV-1 as a result of extensive exposure to inadequately suppressive one- or two-drug regimens prior to the advent of HAART. We have previously shown that drug-resistant viruses selected by nonsuppressive pre-HAART regimens can enter and persist in this reservoir. We have extended these findings here by demonstrating that archival wild-type HIV-1 persists in this reservoir despite the fact that in these patients drug-resistant mutants have been favored by the selective conditions for many years. Phylogenetic analysis of replication-competent viruses persisting in resting CD4(+) T cells revealed a striking lack of temporal structure in the sense that isolates obtained at later time points did not show greater sequence divergence than isolates from earlier time points. The persistence of drug-sensitive virus and the lack of temporal structure in the latent reservoir provide genetic evidence for the idea that HIV-1 can persist in a latent form free of selective pressure from antiretroviral drugs in long-lived resting memory CD4(+) T cells. Although there may be other mechanisms for viral persistence, this stable pool of latently infected cells is of significant concern because of its potential to serve as a lasting source of replication-competent viruses, including the infecting wild-type form and all drug-resistant variants that have arisen subsequently. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1049 Ross Bldg,720 Putland Ave, Baltimore, MD 21205 USA. RI Ray, Stuart/B-7527-2008; OI Ray, Stuart/0000-0002-1051-7260; Gange, Stephen/0000-0001-7842-512X FU NIAID NIH HHS [AI43222, R01 AI043222] NR 40 TC 100 Z9 101 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2002 VL 76 IS 18 BP 9481 EP 9492 DI 10.1128/JVI.76.18.9481-9492.2002 PG 12 WC Virology SC Virology GA 587TF UT WOS:000177658500049 PM 12186930 ER PT J AU Schisterman, EF Gallagher, AM Merz, CNB Whitcomb, BW Faraggi, D Moysich, KB Lewin, H AF Schisterman, EF Gallagher, AM Merz, CNB Whitcomb, BW Faraggi, D Moysich, KB Lewin, H TI The association of hormone replacement therapy and coronary calcium as determined by electron beam tomography SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID POSTMENOPAUSAL WOMEN; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ESTROGEN REPLACEMENT; COMPUTED-TOMOGRAPHY; ARTERY DISEASE; HEART-DISEASE; FOLLOW-UP; CALCIFICATION; OBESITY AB Background: Observational studies have shown that hormone replacement therapy (HRT) is associated with lower coronary heart disease (CHD), and animal studies demonstrate potent antiatherosclerotic estrogen effects. Paradoxically, recent clinical trials have not demonstrated a protective effect. This paradox may be explained by a healthy woman effect bias. Women using HRT have improved health outcomes unrelated to underlying atherosclerotic burden. Examination of the association between coronary calcium (CC), a marker of atherosclerotic plaque burden, and the use of HRT in postmenopausal women may help address this paradox. Methods: The study population comprised 641 asymptomatic postmenopausal women, 425 (66%) of whom were taking HRT. Data obtained from a self-administered questionnaire and blood samples were analyzed. Electron beam tomography (EBT) for CC was performed on each subject. Analysis of variance (ANOVA) was used to evaluate adjusted means. Results: Independent t tests found that age, low-density lipoproteins (LDL), high-density lipoproteins (HDL), body mass index (BMI), vitamin use, coronary calcium score (CCS), coronary calcified volume (CCV), and the number of coronary calcium lesions (CCL) were significantly different between the HRT group and the non-HRT group. However, after controlling for potential confounders, no significant differences were observed in CCS, CCV, or the number of CCL between the HRT and non-HRT groups. Stratifying by BMI shows that obese/overweight women taking HRT have lower adjusted CCS and fewer CCL than the obese/overweight women not taking HRT. Conclusions: These findings demonstrate no association between HRT use and CCS, CCV, and CCL after adjusting for measurable confounders in postmenopausal women. Our failure to demonstrate an independent association between HRT use and a marker of atherosclerotic plaque burden suggests that a healthy woman effect may explain the beneficial association between HRT use and CHD in observational studies. C1 Univ Calif Los Angeles, Dept Imaging, Div Nucl Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Burns & Allen Res Inst, Cedars Sinai Med Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. Roswell Pk Canc Inst, Dept Epidemiol Biostat & Canc Prevent, Buffalo, NY USA. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent, NIH, Bldg 6100,Suite 7B03,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Schisterman, Enrique/0000-0003-3757-641X NR 41 TC 13 Z9 13 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD SEP PY 2002 VL 11 IS 7 BP 631 EP 638 DI 10.1089/152460902760360577 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 602NQ UT WOS:000178511700005 PM 12396895 ER PT J AU Butler, RN Fossel, M Harman, SM Heward, CB Olshansky, SJ Perls, TT Rothman, DJ Rothman, SM Warner, HR West, MD Wright, WE AF Butler, RN Fossel, M Harman, SM Heward, CB Olshansky, SJ Perls, TT Rothman, DJ Rothman, SM Warner, HR West, MD Wright, WE TI Is there an antiaging medicine? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review ID HORMONE-REPLACEMENT THERAPY; HUMAN GROWTH-HORMONE; LIFE-SPAN EXTENSION; CAENORHABDITIS-ELEGANS; CALORIC RESTRICTION; HUMAN LONGEVITY; STEM-CELLS; SACCHAROMYCES-CEREVISIAE; ANTIOXIDANT VITAMINS; POSTMENOPAUSAL WOMEN AB In spite of considerable hype to the contrary. there is no convincing evidence that currently existing so-called "antiaging" remedies promoted by a variety of companies and other organizations can slow aging or increase longevity in humans. Nevertheless, a variety of experiments with laboratory animals indicate that aging rates and life expectancy can be altered. Research going back to the 1930s has shown that caloric restriction (also called dietary restriction) extends life expectancy by 30-40% in experimental animals, presumably at least partially by delaying the occurrence of age-dependent diseases. Mutations that decrease production of insulin growth factor I in laboratory mammals, and those that decrease insulin-like signaling in nematodes and fruit flies, have increased life expectancy as well. Other general strategies that appear promising include interventions that reduce oxidative stress and/or increase resistance to stress; hormone and cell replacement therapies may also have value in dealing with specific age-related pathologies. This article reports the findings of a consensus workshop that discussed what is known about existing and future interventions to slow, stop, or reverse aging in animals, and how these might be applied to humans through future research. C1 Int Longev Ctr USA, New York, NY 10028 USA. Kronos Longev Res Inst, Phoenix, AZ USA. Univ Illinois, Sch Publ Hlth, Chicago, IL 60680 USA. Boston Med Ctr, Dept Geriatr, Boston, MA USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10027 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. Adv Cell Technol, Worcester, MA USA. Univ Texas, SW Med Ctr, Dallas, TX USA. RP Butler, RN (reprint author), Int Longev Ctr USA, 60 E 86th St, New York, NY 10028 USA. NR 110 TC 41 Z9 42 U1 4 U2 10 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 SEP PY 2002 VL 57 IS 9 BP B333 EP B338 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 590BJ UT WOS:000177797100001 PM 12196485 ER PT J AU Salerno, JA Nagy, C AF Salerno, JA Nagy, C TI Guest editorial - Terrorism and aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER; IMPAIRMENT; WAR C1 NIA, Bethesda, MD 20892 USA. RP Salerno, JA (reprint author), NIA, Bldg 31,Room 5C35,31 Ctr Dr,MSC 2292, Bethesda, MD 20892 USA. NR 20 TC 7 Z9 7 U1 2 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2002 VL 57 IS 9 BP M552 EP M554 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 590BJ UT WOS:000177797100004 PM 12196488 ER PT J AU Parascandola, M Hawkins, J Danis, M AF Parascandola, M Hawkins, J Danis, M TI Patient autonomy and the challenge of clinical uncertainty SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID DECISION-MAKING; BREAST-CANCER; INFORMED CONSENT; PROSTATE-CANCER; WOMEN; PHYSICIANS; RISK; EXPRESSIONS; INFORMATION; CERTAINTY AB Bioethicists have articulated an ideal of shared decision making between physician and patient, but in doing so the role of clinical uncertainty has not been adequately confronted. In the face of uncertainty about the patient's prognosis and the best course of treatment, many physicians revert to a model of nondisclosure and nondiscussion, thus closing off opportunities for shared decision making. Empirical studies suggest that physicians find it more difficult to adhere to norms of disclosure in situations where there is substantial uncertainty. They may be concerned that acknowledging their own uncertainty will undermine patient trust and create additional confusion and anxiety for the patient. We argue, in contrast, that effective disclosure will protect patient trust in the long run and that patients can manage information about uncertainty. In situations where there is substantial uncertainty, extra vigilance is required to ensure that patients are given the tools and information they need to participate in cooperative decision making about their care. C1 Univ Toronto, Scarborough, ON M1C 1A4, Canada. NCI, Sect Eth & Hlth Pol, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 57 TC 48 Z9 49 U1 5 U2 12 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD SEP PY 2002 VL 12 IS 3 BP 245 EP 264 DI 10.1353/ken.2002.0018 PG 20 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 596MT UT WOS:000178169200002 PM 12472078 ER PT J AU Shlipak, MG Fried, LF Crump, C Bleyer, AJ Manolio, TA Tracy, RP Furberg, CD Psaty, BM AF Shlipak, MG Fried, LF Crump, C Bleyer, AJ Manolio, TA Tracy, RP Furberg, CD Psaty, BM TI Cardiovascular disease risk status in elderly persons with renal insufficiency SO KIDNEY INTERNATIONAL LA English DT Article DE coronary heart disease; stroke; age and cardiovascular disease; risk predictors; serum creatinine; subclinical heart disease; kidney insufficiency; chronic renal disease ID NUTRITION EXAMINATION SURVEY; BLOOD-PRESSURE INDEX; 3RD NATIONAL-HEALTH; SERUM CREATININE; KIDNEY-DISEASE; OLDER ADULTS; MORTALITY; HYPERTENSION; DYSFUNCTION; PREDICTION AB Background. Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency. Methods. This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level greater than or equal to1.3 mg/dL in women and greater than or equal to1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors. Results. Among the 5808 participants with creatinine levels measured at entry, 15.9% of men (N = 394), and 7.6% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64% in persons with renal insufficiency compared with 43% in those without it [odds ratio (OR) 2.34; 95 % confidence interval (95 % CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95% CI, 1.18,1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk >20% by the Framingham equations, 78% of men and 61% of women with renal insufficiency had elevated cardiovascular risk status. Conclusions. Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults. C1 Vet Affairs Med Ctr, Med Serv, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. RP Shlipak, MG (reprint author), Vet Affairs Med Ctr, Med Serv, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. FU NHLBI NIH HHS [N01 HC 85079, N01 HC 85086, R03 HL 68099-01, N01 HC 15103, N01 HC 35129] NR 30 TC 119 Z9 125 U1 0 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2002 VL 62 IS 3 BP 997 EP 1004 DI 10.1046/j.1523-1755.2002.00522.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 584WR UT WOS:000177492200030 PM 12164883 ER PT J AU Alderson, C Garnett, NL AF Alderson, C Garnett, NL TI Disaster Recovery: "Who ya gonna call?" SO LAB ANIMAL LA English DT Article AB When dealing with recovery from a disaster, NIH-funded animal research institutions have certain responsibilities to OLAW and OPERA. The authors outline these responsibilities and identify areas in which these offices can aid the affected institution in the recovery effort. C1 NIH, OLAW, Off Extramural Res, Bethesda, MD 20892 USA. NIH, Off Policy Extramural Res Adm, Off Extramural Res, Bethesda, MD 20892 USA. RP Garnett, NL (reprint author), NIH, OLAW, Off Extramural Res, RKL1,Suite 360,MSC 7982,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 8 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 SEP PY 2002 VL 31 IS 8 BP 27 EP 30 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 589TR UT WOS:000177776900008 PM 12200583 ER PT J AU Westergaard, GC Suomi, SJ Higley, JD AF Westergaard, GC Suomi, SJ Higley, JD TI Handedness is associated with immune functioning and behavioural reactivity in rhesus macaques SO LATERALITY LA English DT Article ID CEREBRAL LATERALIZATION; BIOLOGICAL MECHANISMS; BRAIN ASYMMETRY; HAND PREFERENCE; MACACA-MULATTA; MONKEYS; MICE; MODULATION; HYPOTHESIS; NEOCORTEX AB In the present study we examined the relationship among handedness, immune functioning, and behavioural reactivity in rhesus macaques. We used the absolute number of CD4+ (T-helper) and CD8+ (T-suppressor) cells as dependent measures of immune functioning. We derived reactivity profiles from behavioural responses to a threat, and hand preference profiles from a quadrupedal food-reaching test. The results indicate positive correlations between the frequency of right versus left hand reaches and the absolute number of CD4+ cells, and between the frequency of right versus left hand reaches and the degree of human-directed aggression in response to an invasive threat. Immune measures were not associated with the strength of hand preference. These results are consistent with and extend previous findings obtained with rodents to nonhuman primates and provide further support for the view that behavioural lateralisation is associated with immune functioning and behavioural reactivity. C1 LABS Virginia Inc, Div Res, Yemassee, SC 29945 USA. NICHHD, Bethesda, MD 20892 USA. NIAAA, Rockville, MD 20852 USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. NR 31 TC 9 Z9 9 U1 2 U2 5 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1357-650X J9 LATERALITY JI Laterality PD SEP PY 2002 VL 7 IS 4 BP 359 EP 369 DI 10.1080/13576500143000230 PG 11 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA 592TY UT WOS:000177954000007 PM 15513210 ER PT J AU Lumkul, R Gorin, NC Malehorn, MT Hoehn, GT Zheng, R Baldwin, B Small, D Gore, S Smith, D Meltzer, PS Civin, CI AF Lumkul, R Gorin, NC Malehorn, MT Hoehn, GT Zheng, R Baldwin, B Small, D Gore, S Smith, D Meltzer, PS Civin, CI TI Human AML cells in NOD/SCID mice: engraftment potential and gene expression SO LEUKEMIA LA English DT Article DE acute myeloid leukemia; NOD/SCID mice; flow cytometry; cDNA microarrays; gene expression ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; FLT3 GENE; STEM-CELLS; SCID MICE; CONSTITUTIVE ACTIVATION; BONE-MARROW; HEMATOPOIESIS; REPOPULATION AB Most cases of human acute myelold leukemia (AML) engraft in irradiated non-obese diabetic/severe combined immuno-deficient (NOD/SCID) mice. Intravenous transfer of as few as 105 human AML cells resulted in engraftment. Cases with poor prognosis clinical features, including FLT3 mutations, tended to engraft efficiently. Nevertheless, AML cells obtained from patients at relapse did not engraft more efficiently than cells obtained from the same patients at initial diagnosis. One passage of human AML cells in NOD/SCID mice did not appear to select for increased virulence, as measured by serial transplantation efficiency. Finally, cDNA microarray analyses indicated that similar to95% of genes were expressed at similar levels in human AML cells immunopurified after growth in mice, as compared to cells assessed directly from patients. Thus, the growth of human AML cells in NOD/SCID mice could yield large numbers of human AML cells for direct experimental use and could also function as a renewable, potentially unlimited source of leukemia cells, via serial transplantation. C1 Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. Hosp St Antoine, Dept Hematol, Paris, France. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Civin, CI (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Bunting Blaustein Canc Res Bldg 2M44,1650 Orleans, Baltimore, MD 21231 USA. FU NCI NIH HHS [P01CA70970] NR 33 TC 41 Z9 43 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2002 VL 16 IS 9 BP 1818 EP 1826 DI 10.1038/sj.leu.2402632 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 593XF UT WOS:000178019200033 PM 12200698 ER PT J AU Kone, J Arroyo, J Savinelli, T Lin, S Boyd, K Wu, Y Nimmakayalu, M Copeland, NG Jenkins, NA Qumsiyeh, M Hu, P Prescott, A Wu, H Yang, L Roe, B Perkins, AS AF Kone, J Arroyo, J Savinelli, T Lin, S Boyd, K Wu, Y Nimmakayalu, M Copeland, NG Jenkins, NA Qumsiyeh, M Hu, P Prescott, A Wu, H Yang, L Roe, B Perkins, AS TI F-MuLV acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4 SO LEUKEMIA LA English DT Article DE leukemia; retrovirus; chromosome 7q ID MURINE LEUKEMIA-VIRUS; CHROMOSOME-7 LONG ARM; B-CELL LEUKEMIAS; MYELOID DISORDERS; FRIEND-VIRUS; GENE; ERYTHROLEUKEMIA; EXPRESSION; SEQUENCE; REGIONS AB We describe here the development of a murine system for the identification of genes involved in myelomonocytic neoplasms. Transgenic C57BL/6J mice expressing SV40 early region under a myelomonocytic promoter develop histiocytic sarcomas with a latency of 167 days. We used retroviral proviral tagging to accelerate tumorigenesis and to uncover genetic changes that contribute to tumor development. Infection of transgenic mice with Friend murine leukemia virus (F-MuLV) shortened the latency of morbidity to 103 days (P < 0.001); this was associated with clonal proviral integrations in tumor DNA. As expected for F-MuLV, proviral insertions occurred at Fli1 in both transgenic and nontransgenic tumors. Four insertions were found at a novel locus, termed Fim4, on chromosome 6. This region is syntenic to human 7q32, a region that is commonly deleted in human myelodysplastic syndrome and acute myeloid leukemia. A murine BAC containing Fim4 was sequenced and analyzed, and while there was significant human-mouse homology in the area of the insertions, no candidate gene has been identified. Thus we have established a system to identify genes involved in myelomonocytic tumors, and have used it to identify Fim4, a new common site of proviral insertion. Study of this locus may provide insight into genes involved in AML-associated 7q32 deletions in humans. C1 Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. Yale Univ, Dept Genet, New Haven, CT 06510 USA. Yale Univ, Dept Lab Med, New Haven, CT 06510 USA. NCI, Mammalian Genet Lab, Frederick, MD 21701 USA. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. RP Perkins, AS (reprint author), Yale Univ, Sch Med, Dept Pathol, 310 Cedar St,POB 208023, New Haven, CT 06520 USA. OI Qumsiyeh, Mazin/0000-0003-2002-3026 NR 51 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2002 VL 16 IS 9 BP 1827 EP 1834 DI 10.1038/sj.leu.2402598 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 593XF UT WOS:000178019200034 PM 12200699 ER PT J AU Xiao, X Phogat, SK Sidorov, IA Yang, J Horikawa, I Prieto, D Adelesberger, J Lempicki, R Barrett, JC Dimitrov, DS AF Xiao, X Phogat, SK Sidorov, IA Yang, J Horikawa, I Prieto, D Adelesberger, J Lempicki, R Barrett, JC Dimitrov, DS TI Identification and characterization of rapidly dividing U937 clones with differential telomerase activity and gene expression profiles: role of c-Myc/Mad1 and Id/Ets proteins SO LEUKEMIA LA English DT Letter ID TARGET GENES; CELLS; ETS C1 NCI, LECB, NIH, Frederick, MD 21702 USA. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. RP Dimitrov, DS (reprint author), NCI, LECB, NIH, Bldg 469,Rm 246,POB B,Miller Dr, Frederick, MD 21702 USA. RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Sidorov, Igor/0000-0001-6519-4983 NR 7 TC 16 Z9 16 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2002 VL 16 IS 9 BP 1877 EP 1880 DI 10.1038/sj.leu.2402607 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 593XF UT WOS:000178019200048 PM 12200713 ER PT J AU Ishibe, N Prieto, DR Hosack, DA Lempicki, RA Goldin, LR Raffeld, M Marti, GE Caporaso, NE AF Ishibe, N Prieto, DR Hosack, DA Lempicki, RA Goldin, LR Raffeld, M Marti, GE Caporaso, NE TI Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia SO LEUKEMIA RESEARCH LA English DT Article DE familial CLL; telomere length; V-H mutation ID V-H GENES; B-CLL; EXPRESSION AB We examined whether telomere lengths of peripheral blood mononuclear cells are associated with immunoglobulin gene usage in 21 familial chronic lymphocytic leukemia (CLL) patients. Subjects with unmutated V genes tended to have shorter telomeres than those with somatic mutations, especially after adjusting for age. Unlike V-H mutation status, telomere length was not predictive for survival. Our results suggest that telomere length is associated with V-H gene mutation status and provides further evidence that the biological basis of familial B-CLL is similar to that of sporadic patients. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. NIH, Clin Serv Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Res & Evaluat, Div Cell & Gene Therapies, Flow & Image Cytometry Sect, Bethesda, MD 20852 USA. RP Ishibe, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,MSC 7236, Rockville, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 9 TC 16 Z9 16 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2002 VL 26 IS 9 BP 791 EP 794 AR PII S0145-2126(02)00010-3 DI 10.1016/S0145-2126(02)00010-3 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 591TJ UT WOS:000177896100004 PM 12127552 ER PT J AU Hwang, SG Lee, HC Trepel, JB Jeon, BH AF Hwang, SG Lee, HC Trepel, JB Jeon, BH TI Anticancer drugs-induced apoptotic cell death in leukemia cells is associated with proteolysis of beta-catenin SO LEUKEMIA RESEARCH LA English DT Article DE apoptosis inducer; catenin; cleavage; cell death; transcription; leukemia cells ID TUMOR-SUPPRESSOR PROTEIN; ENZYME-LIKE PROTEASE; REGULATES EXPRESSION; MONOCLONAL-ANTIBODY; COLON-CARCINOMA; CLEAVAGE; PATHWAY; FAS; DEGRADATION; RECEPTOR AB beta-Catenin is a known regulator of cell-cell adhesion and transcriptional regulation. However, the role of beta-catenin and its regulation in non-adherent cells has not been examined. Therefore, we examined the role and fate of beta-catenin during hematopoietic cell apoptosis using Jurkat T-acute lymphoblastic and U937 acute myeloblastic leukemia cells. The results presented here demonstrate that the treatment of Jurkat cells with the apoptosis inducers anti-Fas, TRAIL, staurosporin, and etoposide induces proteolytic fragments of beta-catenin, as did TRAIL and staurosporin in U937 cells. In Jurkat cells, beta-catenin was cleaved at both the N- and C-terminal after anti-Fas addition. Cleavage of intact beta-catenin was completely inhibited by caspase selective protease inhibitors. There was a clear accumulation of the large proteolytic fragment in Jurkat cells treated with lactacystin or N-acetyl-leucyl leucyl-methioninal (ALLM). These results suggest that both the proteasome and calpain may recognize the large beta-catenin fragment as a substrate for further degradation. Densitometric analysis demonstrated that the loss of intact beta-catenin was more rapid in the cell nucleus (beta-catenin T-1/2 of similar to1.5 h in cytoplasm and 0.5 h in nucleus). Down-regulation of beta-catenin-associated transcription was an early event in response to anti-Fas. These results suggest that P-catenin plays a role in promoting Jurkat survival. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Wonkwang Univ, Coll Oriental Med, Dept Pathol, Chonbuk 570749, South Korea. NCI, Div Clin Sci, Med Branch, NIH, Bethesda, MD 20892 USA. RP Jeon, BH (reprint author), Wonkwang Univ, Coll Oriental Med, Dept Pathol, Iksan, Chonbuk 570749, South Korea. NR 48 TC 11 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2002 VL 26 IS 9 BP 863 EP 871 AR PII S0145-2126(02)00018-8 DI 10.1016/S0145-2126(02)00018-8 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 591TJ UT WOS:000177896100015 PM 12127563 ER PT J AU Jeffrey, BG Mitchell, DC Hibbeln, JR Gibson, RA Chedester, AL Salem, N AF Jeffrey, BG Mitchell, DC Hibbeln, JR Gibson, RA Chedester, AL Salem, N TI Visual acuity and retinal function in infant monkeys fed long-chain PUFA SO LIPIDS LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; DOCOSAHEXAENOIC ACID; TERM INFANTS; A-WAVE; PRETERM INFANTS; HUMAN ELECTRORETINOGRAM; RETINITIS-PIGMENTOSA; ARACHIDONIC-ACID; CONTROLLED TRIAL; RAT RETINA AB Previous randomized clinical trials suggest that supplementation of the human infant diet with up to 0.35% DHA may benefit visual development. The aim of the current study was to assess the impact of including arachidonic acid (AA) and a higher level of DHA in the postnatal monkey diet on visual development. Infant rhesus monkeys were fed either a control diet (2.0% alpha-linolenic acid as the sole n-3 FA) or a supplemented diet (1.0% DHA and 1.0% AA) from birth. Visual evoked potential acuity was measured at 3 mon of age. Rod and cone function were assessed in terms of parameters describing phototransduction. Electroretinogram (ERG) amplitudes and implicit times were recorded over a wide intensity range (-2.2 to 4.0 log scot td-sec) and assessed in terms of intensity response functions. Plasma DHA and AA were significantly increased (P < 0.001) in the diet-supplemented monkeys compared with the control monkeys. There was an approximately equal effect of diet for the rod phototranscluction parameters, sensitivity, and capacitance but in the opposite directions. Diet-supplemented-monkeys had significantly shorter b-wave implicit times at low retinal illuminances (<-0.6 log scot td-sec). There were no significant effects of diet for visual acuity or the other 23 ERG parameters measured. The results suggest that supplementation of the infant monkey diet with 1.0% DHA and 1.0% AA neither harms nor provides substantial benefit to the development of visual acuity or retinal function in the first four postnatal months. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Flinders Univ S Australia, Flinders Med Ctr, Dept Paediat & Child Hlth, Bedford Pk, SA 5042, Australia. Child Hlth Res Inst, Child Nutr Res Ctr, Adelaide, SA 5000, Australia. NIAAA, Unit Lab Anim Sci, NIH, Rockville, MD 20852 USA. RP Salem, N (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Rm 1-14, Rockville, MD 20852 USA. RI Gibson, Robert/E-7546-2012 OI Gibson, Robert/0000-0002-8750-525X NR 67 TC 14 Z9 14 U1 0 U2 2 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD SEP PY 2002 VL 37 IS 9 BP 839 EP 848 DI 10.1007/s11745-002-0969-0 PG 10 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 615UP UT WOS:000179265500001 PM 12458618 ER PT J AU Hood, MN Ho, VB Foo, TKF Marcos, HB Hess, SL Choyke, PL AF Hood, MN Ho, VB Foo, TKF Marcos, HB Hess, SL Choyke, PL TI High-resolution gadolinium-enhanced 3D MRA of the infrapopliteal arteries: Lessons for improving bolus-chase peripheral MRA SO MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance angiography; magnetic resonance imaging; peripheral arteries; contrast media; gadolinium ID MAGNETIC-RESONANCE ANGIOGRAPHY; LOWER-EXTREMITIES; SUBTRACTION; INJECTION; VESSELS; DISEASE; AORTA; VIEW AB Peripheral magnetic resonance angiography (MRA) is growing in use. However, methods of performing peripheral MRA vary widely and continue to be optimized, especially for improvement in illustration of infrapopliteal arteries. The main purpose of this project was to identify imaging factors that can improve arterial visualization in the lower leg using bolus chase peripheral MRA. Eighteen healthy adults were imaged on a 1.5T MR scanner. The calf was imaged using conventional three-station bolus chase three-dimensional (3D) MRA, two dimensional (2D) time-of-flight (TOF) MRA and single-station Gadolinium (Gd)-enhanced 3D MRA. Observer comparisons of vessel visualization, signal to noise ratios (SNR), contrast to noise ratios (CNR) and spatial resolution comparisons were performed. Arterial SNR and CNR were similar for all three techniques. However, arterial visualization was dramatically improved on dedicated, arterial-phase Gd-enhanced 3D MRA compared with the multi-station bolus chase MRA and 2D TOF MRA. This improvement was related to optimization of Gd-enhanced 3D MRA parameters (fast injection rate of 2 mL/sec, high spatial resolution imaging, the use of dedicated phased array coils, elliptical centric k-space sampling and accurate arterial phase timing for image acquisition). The visualization of the infrapopliteal arteries can be substantially improved in bolus chase peripheral MRA if voxel size, contrast delivery, and central k-space data acquisition for arterial enhancement are optimized. Improvements in peripheral MRA should be directed at these parameters. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. GE Co, Med Syst, Appl Sci Lab, Milwaukee, WI 53201 USA. RP Hood, MN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. NR 18 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD SEP PY 2002 VL 20 IS 7 BP 543 EP 549 AR PII S0730-725X(02)00531-3 DI 10.1016/S0730-725X(02)00531-3 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 613GJ UT WOS:000179124300005 PM 12413600 ER PT J AU Latour, LL Warach, S AF Latour, LL Warach, S TI Cerebral spinal fluid contamination of the measurement of the apparent diffusion coefficient of water in acute stroke SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion; stroke; ischemia; DWI; ADC ID TRANSIENT ISCHEMIC ATTACKS; APPEARING WHITE-MATTER; HUMAN BRAIN; TISSUE VIABILITY; GRAY-MATTER; TIME-COURSE; MRI; PERFUSION; VOLUME; EVOLUTION AB xThe measurement of the apparent diffusion coefficient (ADC) of water in brains of stroke patients is used in models developed to help distinguish reversible from irreversible ischemic injury. The ADC by conventional methods may be overestimated by the presence of cerebral spinal fluid (CSF) in sulci and perivascular spaces. In this study the hypothesis that DWI with CSF suppression (FLAIR-DWI) would result in different ADC values than those obtained with the conventional DWI technique was investigated. Thirty-one patients with stroke onset of less than 6 hr and an acute lesion on conventional DWI were studied. Both conventional isotropic DWI and FLAIR-DWI were performed using a single-shot echo-planar technique. In all 31 patients, CSF-suppressed ADC was lower than conventional ADC. The mean (SD) of the 31 patients' lesion ADC was 0.64 (0.08) X 10(-3) mm(2) s(-1) with FLAIR-DWI and 0.72 (0.09) x 10(-3) mm(2) s(-1) with conventional DWI (P < 0.001). The overestimation of ADC in conventional DWI corresponded to the percentage of the voxel that contained CSF. Suppression of CSF leads to lesion ADC values that are more homogeneous and more than 15% lower than those obtained with conventional DWI techniques. This suggests that FLAIR-DWI ADC measurements are more accurate than conventional ADC maps. Published 2002 Wiley-Liss, Inc.(dagger) C1 NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bethesda, MD 20878 USA. RP Latour, LL (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bldg 36,Room 4A03, Bethesda, MD 20878 USA. NR 38 TC 36 Z9 43 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2002 VL 48 IS 3 BP 478 EP 486 DI 10.1002/mrm.10238 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 588UX UT WOS:000177721000009 PM 12210912 ER PT J AU Murugesan, R English, S Reijnders, K Yamada, K Cook, JA Mitchell, JB Subramanian, S Krishna, MC AF Murugesan, R English, S Reijnders, K Yamada, K Cook, JA Mitchell, JB Subramanian, S Krishna, MC TI Fluorine electron double resonance imaging for F-19 MRI in low magnetic fields SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE overhauser effect; dynamic nuclear polarization; free radicals; imaging ID IN-VIVO; NMR-SPECTROSCOPY; GD-DTPA; TUMOR; INVIVO; RAT; POLARIZATION; ENHANCEMENT; TOMOGRAPHY; METABOLISM AB This work demonstrates the feasibility of generating fluorine NMR images at a very low magnetic field of 0.015 T by making use of the Overhauser enhancement of F-19 NMR signal brought about by a stable, water-soluble, narrow-line paramagnetic contrast agent. The enhancement in the F-19 NMR images depends on the concentration of the single electron contrast agent, the PO2, and the electron paramagnetic resonance (EPR) irradiation power. The applicability of this technique for F-19 NMR imaging is demonstrated with phantom samples, where a time resolution of 4-10 min is achieved. Proton electron double resonance imaging (PEDRI) and fluorine electron double resonance imaging (FEDRI) images were also obtained from rat kidneys ex vivo, perfused with 10 mM Oxo63 and 10 M trifluoroacetic acid. The spatial and temporal resolutions of these images are comparable to those obtained at magnetic fields 2-3 orders of magnitude larger. Constant NMR frequency (628 kHz) operation permits both FEDRI and PEDRI of identical slices without removing the object under investigation. This feasibility of coregistration of proton-based anatomical PEDRI image with physiological FEDRI image offers good potential for studying fluorine-containing tracers. Published 2002 Wiley-Liss, lnc.(dagger) C1 NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bldg 10,Room B3 B69,MSC 1002, Bethesda, MD 20892 USA. RI Yamada, Ken-ichi/E-6318-2012 NR 40 TC 16 Z9 16 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2002 VL 48 IS 3 BP 523 EP 529 DI 10.1002/mrm.10221 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 588UX UT WOS:000177721000015 PM 12210918 ER PT J AU Pamplona, R Portero-Otin, M Requena, J Gredilla, R Barja, G AF Pamplona, R Portero-Otin, M Requena, J Gredilla, R Barja, G TI Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE aging; free radicals; protein carbonyls; malondialdehyde; protein damage; carbonyl stress; fatty acids ID FATTY-ACID UNSATURATION; GLYCATION END-PRODUCT; FOOD RESTRICTION; DIETARY RESTRICTION; LIPID-PEROXIDATION; SKELETAL-MUSCLE; SKIN COLLAGEN; MOUSE; LIFE; ACCUMULATION AB In this investigation the effect of 4 months of 40% restriction of calories on defined markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins was studied. The protein markers assessed were N-epsilon-(carboxyethyl)lysine (CEL), N-epsilon(carboxymethyl)lysine (CML), N-epsilon-(malondialdehyde)lysine (MDA-lys), and the recently described (PNAS 98:69-74, 2001) main constituents of protein carbonyls glutamic and aminoadipic semialdehydes. All these markers were measured by gas chromatography/mass spectrometry. The results showed that glutamic semialdehyde was present in rat heart mitochondria at levels 20-fold higher than aminoadipic semialdehyde. After 4 months of caloric restriction, the levels of CEL, CML, MDA-lys and glutamic semialdehyde were significantly lower in the mitochondria from caloric restricted animals than in the controls. These decreases were not due to a lower degree of oxidative attack to mitochondrial proteins, since the rate of mitochondrial oxygen radical generation was not modified by 4 months of caloric restriction. The decreases in MDA-lys and CML were not due either to changes in the sensitivity of mitochondrial lipids to peroxidation since measurements of the fatty acid composition showed that the total number of fatty acid double bonds and the peroxidizability index were not changed by caloric restriction. The results globally indicate that caloric restriction during 4 months decreases oxidative stress-derived damage to heart mitochondrial proteins. They also suggest that these decreases are due to an increase in the capacity of the restricted mitochondria to decompose oxidatively modified proteins. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Complutense, Fac Biol, Dept Anim Biol Anim Physiol 2, E-28040 Madrid, Spain. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Lleida Univ, Fac Med, Dept Basic Med Sci, Metab Physiopathol Res Grp, Lleida 25198, Spain. RP Barja, G (reprint author), Univ Complutense, Fac Biol, Dept Anim Biol Anim Physiol 2, E-28040 Madrid, Spain. RI Portero-Otin, Manuel/B-7122-2009; Gustavo, Barja/B-5591-2012; Pamplona, Reinald/A-7359-2010 OI Portero-Otin, Manuel/0000-0002-1823-0299; Pamplona, Reinald/0000-0003-4337-6107 NR 37 TC 88 Z9 91 U1 0 U2 12 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 PY 2002 VL 123 IS 11 BP 1437 EP 1446 AR PII S0047-6374(02)00076-3 DI 10.1016/S0047-6374(02)00076-3 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 618JN UT WOS:000179415100002 PM 12425950 ER PT J AU Smith, GH Boulanger, CA AF Smith, GH Boulanger, CA TI Mammary stem cell repertoire: new insights in aging epithelial populations SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE aging; stem cell; transplantation; epithelium; mammary gland; cell lineage; development ID IN-VIVO; EXPRESSION; TUMORIGENESIS; MICE; CANCER; BREAST; DIFFERENTIATION; SENESCENCE; TGF-BETA-1; PHENOTYPE AB The proliferative lifespan of mammary stem cells was examined in serially transplanted clonal-dominant epithelial populations. Five successive transplant generations were done. The epithelial cell number in each outgrowth expands similar to500-fold in nulliparous hosts and similar to10000-fold in impregnated hosts. Despite this, all resulting mammary outgrowths showed lineal identity with the original. Growth senescence was observed in some implants beginning at the third generation in impregnated recipients. The ability of an individual implant to support ductal morphogenesis and also secretory lobule development decayed at independent rates. Individual implants from a single clonal-dominant outgrowth occasionally gave rise to markedly different ductal development within the same host indicating an epithelial cell autonomous mechanism in ductal patterning. Both premalignant and malignant populations appeared focally within the aging transplants. These populations were also lineally related to the original outgrowth supporting the conclusion that the primary growth was derived clonally from one or a few lineally related antecedents. The premalignant and malignant descendant populations no longer exhibit growth senescence suggesting that they are supported by a perpetually self-renewing progenitor. Our evidence indicates that a single mammary cell may have the capacity to self-renew through five transplant generations. Even some sixth generation implants show vigorous growth. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Basic Res Lab, Mammary Biol Grp, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NIH, Bldg 10,Room 8B07,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 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 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD SEP PY 2002 VL 123 IS 11 BP 1505 EP 1519 AR PII S0047-6374(02)00114-8 DI 10.1016/S0047-6374(02)00114-8 PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 618JN UT WOS:000179415100009 PM 12425957 ER PT J AU Anisimov, SV Tarasov, KV Riordan, D Wobus, AM Boheler, KR AF Anisimov, SV Tarasov, KV Riordan, D Wobus, AM Boheler, KR TI SAGE identification of differentiation responsive genes in P19 embryonic cells induced to form cardiomyocytes in vitro SO MECHANISMS OF DEVELOPMENT LA English DT Article DE serial analysis of g epsilon expression; p19 embryonic carcinoma cells; in vitro differentiation; development; transcriptome; heart; delta-like 1 homolog; insulin-like growth factor binding protein 5; high mobility group AT-hook 2; podocalyxin; pleiotrophin ID EARLY HEART DEVELOPMENT; CARCINOMA-CELLS; STEM-CELLS; TRANSCRIPTION FACTORS; MOUSE EMBRYOGENESIS; CARDIAC DEVELOPMENT; MUSCLE DEVELOPMENT; SERIAL ANALYSIS; GROWTH-HORMONE; IN-VITRO AB Transcriptome profiling facilitates the identification of developmentally regulated genes. To quantify the functionally active genome of P19 embryonic carcinoma (EC) cells induced to form cardiomyocytes, we employed serial analysis of gene expression (SAGE) to sequence and compare a total of 171,735 SAGE tags from three libraries (undifferentiated P19 EC cells, differentiation days 3 + 0.5 and 3 + 3.0). After in vitro differentiation, only 3.1% of the gene products demonstrated significant (P < 0.05) changes in expression. The most highly significant changes (P < 0.01) involved altered expression of 410 genes encoding predominantly transcription factors, differentiation factors and growth regulators. Quantitative polymerase chain reaction analysis and in situ hybridization revealed five growth regulators (Dlk1, Igfbp5, Hmga2, Podx1 and Ptn) and two unknown ESTs with expression profiles similar to known cardiac transcription factors, implicating these growth regulators in cardiac differentiation. These SAGE libraries thus serve as a reference resource for understanding the role of differentiation-dependent genes in embryonic stem cell models induced to form cardiomyocytes in vitro. Published by Elsevier Science Ireland Ltd. C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Inst Pflanzengenet & Kulturpflanzenforsch, Gatersleben, Germany. RP Boheler, KR (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 58 TC 38 Z9 40 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2002 VL 117 IS 1-2 BP 25 EP 74 AR PII S0925-4773(02)00177-6 DI 10.1016/S0925-4773(02)00177-6 PG 50 WC Developmental Biology SC Developmental Biology GA 598GT UT WOS:000178268200003 PM 12204248 ER PT J AU Badenhorst, P Finch, JT Travers, AA AF Badenhorst, P Finch, JT Travers, AA TI Tramtrack co-operates to prevent inappropriate neural development in Drosophila SO MECHANISMS OF DEVELOPMENT LA English DT Article DE tramtrack; BTB domain; Drosophila; neurogenesis; peripheral nervous system; Achaete-Scute complex ID TRANSCRIPTIONAL REPRESSOR TRAMTRACK; ASYMMETRIC CELL-DIVISION; PRONEURAL GENE ACTIVITY; ACHAETE-SCUTE COMPLEX; LOOP-HELIX REPRESSOR; DNA-BINDING; BTB/POZ DOMAIN; POZ DOMAIN; FATE DETERMINATION; ORGAN DEVELOPMENT AB Each sensory organ of the Drosophila peripheral nervous system is derived from a single sensory organ precursor cell (SOP). These originate in territories defined by expression of the proneural genes of the Achaete-Scute complex (AS-C). Formation of ectopic sensilla outside these regions is prevented by transcriptional repression of proneural genes. We demonstrate that the BTB/POZ-domain transcriptional repressor Tramtrack (Ttk) co-operates in this repression. Ttk is expressed ubiquitously, except in proneural clusters and SOPs. Ttk over-expression represses proneural genes and sensilla formation. Loss of Ttk enhances bristle-promoting mutants. Using neural repression as an assay, we dissected functional domains of Ttk, confirming the importance of the bric-a-brac-tramtrack-broad complex (BTB) motif. We show that the Ttk BTB domain is a protein-protein interaction motif mediating tetramer formation. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Badenhorst, P (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 6066, Bethesda, MD 20892 USA. NR 64 TC 33 Z9 34 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 SEP PY 2002 VL 117 IS 1-2 BP 87 EP 101 AR PII S0925-4773(02)00183-1 DI 10.1016/S0925-4773(02)00183-1 PG 15 WC Developmental Biology SC Developmental Biology GA 598GT UT WOS:000178268200005 PM 12204250 ER PT J AU McNeil, DE Cote, TR Clegg, L Rorke, LB AF McNeil, DE Cote, TR Clegg, L Rorke, LB TI Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: A SEER update SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE medulloblastoma; primitive neuroectodermal tumor; epidemiology; SEER ID CENTRAL-NERVOUS-SYSTEM AB Background. it has been suggested that cerebellar medulloblastoma (M) and primitive neuroectodermal tumors (PNET) arising elsewhere in the nervous system, represent a single entity (M/PNET), although this concept is controversial, Cancer registries permit population-based description of cases reported as medulloblastoma, those reported as PNET and description of the aggregate, M/PNET. Procedure, We reviewed the 768 cases of M/PNET (633 diagnosed medulloblasoma and 135 diagnosed PNET) among persons under 20 years of age in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. Results. The incidence of M/PNET rose 23%, from 4 per 10(6) person-years in 1973-77, to 4.9 per 10(6) person-years in 1993-98. Cases reported as PNET were more likely than those reported as medulloblastoma to be supratentorial (30.4% vs. 1.9%, P<0.001) and to be female (42.2% vs. 35.4%, P=0.13). The difference in 5-year survival between the 600 children with infratentorial medulloblastoma vs. the 49 children with infratentoral PNET not statistically significant (55% vs. 43%), Regardless of reporting diagnosis, survival was poorer among children age 0-3 years and those with supratentorial tumors. Children diagnosed in the more recent period from 1985-1998 had a longer median survival than children diagnosed in 1973-84 (4.9 year vs. 10 year, P = 0.05), Rates were 42% higher among Whites compared to Black (4.5/10(6) person-year vs. 3.1/10(6) person-year, P = 0.01), Conclusions. We found M/PNET is increasing in incidence and more frequent among Whites. Given that medulloblastoma and PNET are histologically identical and have similar epidemiologic profiles, future studies should provide analyses that combine these entities. Published 2002 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Rockville, MD USA. NCI, Div Canc Control & Populat Sci, Canc Stat Branch, Rockville, MD USA. Childrens Hosp Philadelphia, Dept Pathol Neuropathol, Philadelphia, PA 19104 USA. RP McNeil, DE (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,EPS, Room 7125,6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. NR 18 TC 93 Z9 99 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 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD SEP PY 2002 VL 39 IS 3 BP 190 EP 194 DI 10.1002/mpo.10121 PG 5 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 579TA UT WOS:000177192900008 PM 12210449 ER PT J AU Chen, DT Miller, FG Rosenstein, DL AF Chen, DT Miller, FG Rosenstein, DL TI Enrolling decisionally impaired adults in clinical research SO MEDICAL CARE LA English DT Article; Proceedings Paper CT Conference on Making Informed Consent Meaningful CY MAR 07-09, 2001 CL WASHINGTON, D.C. SP Dept Vet Affairs, Off Res & Dev DE research ethics; capacity assessment; competence; surrogate decision making; monitoring ID INFORMED CONSENT; COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; EMERGENCY RESEARCH; CHILDREN; RISK; SCHIZOPHRENIA; COMPETENCY; CAPACITY; MEDICINE AB Progress in diagnosing, treating, and preventing medical conditions that impair decision-making abilities depends on clinical research involving individuals who may be either unable to or have diminished ability to give informed consent. Such research, however, raises ethical concern and controversy about the potential exploitation of these vulnerable individuals. This article addresses a range of ethical and practical issues concerning the enrollment of adults who are decisionally impaired, and those at risk of becoming so, in clinical research. These include (1) the relationship of decision-making capacity to competence, and the framework for determining competence in adults receiving clinical care and making treatment decisions for those who lack competence; (2) the differences between clinical practice and clinical research that influence the criteria for permissible research involving incompetent adults and the applicability of the framework guiding treatment decisions to clinical research decisions; and (3) the regulatory framework developed to guide the ethical participation of children in research and its applicability to determining the scope and limits of research with incompetent adults. C1 NIMH, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Bioeth, Bethesda, MD USA. RP Chen, DT (reprint author), NIMH, NIH, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. NR 60 TC 17 Z9 17 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2002 VL 40 IS 9 SU S BP 20 EP 29 DI 10.1097/01.MLR.0000023952.15394.88 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 591HU UT WOS:000177874300004 ER PT J AU Reuben, DB Keeler, E Seeman, TE Sewall, A Hirsch, SH Guralnik, JM AF Reuben, DB Keeler, E Seeman, TE Sewall, A Hirsch, SH Guralnik, JM TI Development of a method to identify seniors at high risk for high hospital utilization SO MEDICAL CARE LA English DT Article DE health care costs; managed care; case-management ID RANDOMIZED CLINICAL-TRIAL; CASE-MANAGEMENT; SERUM-ALBUMIN; OLDER PERSONS; SELF-REPORT; MORTALITY; MEDICARE; CARE; PERFORMANCE; ASSOCIATION AB BACKGROUND. A small percentage of older persons account for most Medicare costs. If persons at high risk for high health care utilization can be identified, resources can be directed to improve their health care and reduce utilization. OBJECTIVE. To develop an efficient and economical approach to identifying older persons at risk for high future health care utilization. DESIGN. Validation cohort. SETTING. Three communities. SUBJECTS. Five thousand one hundred thirty-eight community-dwelling persons aged 71 years or older. MAIN OUTCOME MEASURES. High utilization (defined as greater than or equal to11 hospital days during 3 years) and overall Part A Medicare hospital costs during 3 years. RESULTS. Predictive multivariable models were created that relied on prior hospitalization only, self-report only, and combined self-report and physical examination/lab data. Ten self-report items (hospitalizations in prior year and year before that, male gender, fair/poor health, not working, infrequent religious participation, needing help bathing, unable to walk 1/2 mile, diabetes, and taking loop diuretics) and two lab tests (low serum albumin and iron) remained as independent predictors of high utilization. Based upon these variables, approximately 1/4 of the population was identified as being at high risk (greater than or equal to0.28 probability) for high health care utilization and those identified accounted for approximately half of all Medicare Part A costs for the entire population. Finally, a two-phase strategy was developed in which tests are only administered to individuals whose risk cannot be adequately determined by self-report variables (approximately 1/4 of subjects). CONCLUSIONS. Simple questions and laboratory tests can accurately and efficiently identify seniors at high risk for high health care utilization. C1 Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, Sch Med, Los Angeles, CA 90095 USA. RAND Corp, Santa Monica, CA 90406 USA. Sewell Inc, Bethesda, MD USA. NIA, Bethesda, MD 20892 USA. RP Reuben, DB (reprint author), Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, Sch Med, 10945 Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. FU NIA NIH HHS [AG16677] NR 40 TC 28 Z9 28 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2002 VL 40 IS 9 BP 782 EP 793 DI 10.1097/01.MLR.0000024611.65466.AE PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 589ZD UT WOS:000177790900008 PM 12218769 ER PT J AU Newman, AH Kulkarni, S AF Newman, AH Kulkarni, S TI Probesfor the dopamine transporter: New leads toward a cocaine-abuse therapeutic - A focus on analogues of benztropine and rimcazole SO MEDICINAL RESEARCH REVIEWS LA English DT Review DE cocaine; dopamine transporter; benztropine; rimcazole; cocaine-abuse therapeutic; monoamine uptake inhibitor ID N-SUBSTITUTED 3-ALPHA-TROPANE; CONDITIONED PLACE PREFERENCE; SIGMA-RECEPTOR LIGANDS; ACID METHYL-ESTERS; MONOAMINE TRANSPORTERS; UPTAKE INHIBITORS; RHESUS-MONKEYS; HIGH-AFFINITY; 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; SEROTONIN TRANSPORTERS AB In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems. in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related,to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics. (C) 2002 Wiley Periodicals, Inc. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 160 TC 66 Z9 68 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0198-6325 J9 MED RES REV JI Med. Res. Rev. PD SEP PY 2002 VL 22 IS 5 BP 429 EP 464 DI 10.1002/med.10014 PG 36 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 584UB UT WOS:000177486200001 PM 12210554 ER PT J AU Hull, KM Drewe, E Aksentijevich, I Singh, HK Wong, K McDermott, EM Dean, J Powell, RJ Kastner, DL AF Hull, KM Drewe, E Aksentijevich, I Singh, HK Wong, K McDermott, EM Dean, J Powell, RJ Kastner, DL TI The TNF receptor-associate periodic syndrome (TRAPS) - Emerging concepts of an autoinflammatory disorder SO MEDICINE LA English DT Article ID FAMILIAL MEDITERRANEAN FEVER; NECROSIS-FACTOR RECEPTOR; ENCODING MEVALONATE KINASE; HYPERIMMUNOGLOBULINEMIA-D; GENE; MUTATIONS; TNFRSF1A; AMYLOIDOSIS; PHENOTYPE; GENOTYPE AB The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases. C1 NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. NIAMSD, Genet & Genomics Branch, NIH, Bethesda, MD 20892 USA. Univ Rochester, Med Ctr, Dept Internal Med & Pediat, Rochester, NY USA. Armed Forces Inst Pathol, Dept Neuropathol & Ophthalm Pathol, Div Neuromuscular Pathol, Washington, DC 20306 USA. Queens Med Ctr, Clin Immunol Unit, Nottingham NG7 2UH, England. RP Hull, KM (reprint author), NIAMS, NIH, Bldg 10-9S205, Bethesda, MD 20892 USA. NR 46 TC 244 Z9 257 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD SEP PY 2002 VL 81 IS 5 BP 349 EP 368 DI 10.1097/01.md.0000031361.64336.03 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 595WH UT WOS:000178131200002 PM 12352631 ER PT J AU Suzuki, H Conwit, RA Stashuk, D Santarsiero, L Metter, EJ AF Suzuki, H Conwit, RA Stashuk, D Santarsiero, L Metter, EJ TI Relationships between surface-detected EMG signals and motor unit activation SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE surface EMG; motor unit physiology; muscle force; submaximal contraction ID ISOMETRIC CONTRACTIONS; FIRING RATE; ACTION-POTENTIALS; HUMAN MUSCLES; DECOMPOSITION; RECRUITMENT; FATIGUE; FORCE; FREQUENCY; SPECTRUM AB Introduction: Surface-detected electromyographic (S-EMG) signals are used in exercise science to assess the extent of muscle activation, muscle fatigue, and neural activity during muscle contraction. However, the relationship has not been studied between S-EMG signal amplitude and motor unit activation at different muscle force levels. Methods: S-EMG signals were measured from 76 healthy subjects during target force levels of 5, 10, 20, 30, and 50% of maximal voluntary contraction (MVC) of the knee extensors over 20-30 s. Mean absolute S-EMG amplitude, surface-detected motor unit action potential amplitude (S-MUAP), motor unit mean firing rate (mFR), and motor unit mean voltage, which is the product of S-MUAP amplitude and mFR, were assessed in the vastus medialis by using EMG signal-decomposition and spike-triggered averaging techniques. Results: Motor unit mean voltage increased to the same degree as mean absolute S-EMG amplitude with increasing force, implying that motor unit size and firing rate explain the increase in mean absolute S-EMG amplitude with increasing force generation. In addition, mean absolute S-EMG amplitude increased linearly during the course of each 20-30 s contraction, with the slope being greater at higher force levels. A small change was observed in the shape of needle-detected motor unit action potentials during the contraction, but this change was not sufficient to explain the large change in mean absolute S-EMG amplitude during the contraction. Conclusion: Mean absolute S-EMG amplitude at different force levels and its changes during the course of a submaximal contraction are dependent on the number of motor units active, their size, and firing rates. C1 Dokkyo Univ, Sch Med, Dept Rehabil Med, Mibu, Tochigi 32102, Japan. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. Univ Waterloo, Dept Syst Design Engn, Waterloo, ON N2L 3G1, Canada. Colgate Univ, Hamilton, NY 13346 USA. RP Suzuki, H (reprint author), Dokkyo Univ, Sch Med, Dept Rehabil Med, 880 Shimotuga, Mibu, Tochigi 32102, Japan. NR 29 TC 33 Z9 37 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD SEP PY 2002 VL 34 IS 9 BP 1509 EP 1517 DI 10.1249/01.MSS.0000027711.31651.AF PG 9 WC Sport Sciences SC Sport Sciences GA 593MR UT WOS:000177995700018 PM 12218747 ER PT J AU Kolenbrander, PE Andersen, RN Blehert, DS Egland, PG Foster, JS Palmer, RJ AF Kolenbrander, PE Andersen, RN Blehert, DS Egland, PG Foster, JS Palmer, RJ TI Communication among oral bacteria SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID SURFACE PROTEIN ANTIGEN; STREPTOCOCCUS-GORDONII DL1; PROLINE-RICH PROTEINS; CELL-WALL POLYSACCHARIDES; HUMAN PERIODONTAL POCKETS; IN-SITU HYBRIDIZATION; PORPHYROMONAS-GINGIVALIS; FUSOBACTERIUM-NUCLEATUM; DENTAL PLAQUE; SALMONELLA-TYPHIMURIUM AB Human oral bacteria interact with their environment by attaching to surfaces and establishing mixed-species communities. As each bacterial cell attaches, it forms a new surface to which other cells can adhere. Adherence and community development are spatiotemporal; such order requires communication. The discovery of soluble signals, such as autoinducer-2, that may be exchanged within multispecies communities to convey information between organisms has emerged as a new research direction. Direct-contact signals, such as adhesins and receptors, that elicit changes in gene expression after cell-cell contact and biofilm growth are also an active research area. Considering that the majority of oral bacteria are organized in dense three-dimensional biofilms on teeth, confocal microscopy and fluorescently, labeled probes provide valuable approaches for investigating the architecture of these organized communities in situ. Oral biofilms are readily accessible to microbiologists and are excellent model systems for studies of microbial communication. One attractive model system is a saliva-coated flowcell with oral bacterial biofilms growing on saliva as the sole nutrient source; an intergeneric mutualism is discussed. Several oral bacterial species are amenable to genetic manipulation for molecular characterization of communication both among bacteria and between bacteria and the host. A successful search for genes critical for mixed-species community, organization will be accomplished only, when it is conducted with mixed-species communities. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Kolenbrander, PE (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, 30 Convent Dr MSC4350,Bldg 30,Rm 310, Bethesda, MD 20892 USA. NR 157 TC 411 Z9 436 U1 4 U2 71 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD SEP PY 2002 VL 66 IS 3 BP 486 EP + DI 10.1128/MMBR.66.3.486-505.2002 PG 21 WC Microbiology SC Microbiology GA 591AL UT WOS:000177857300007 PM 12209001 ER PT J AU Hotta, Y Nagatsu, A Liu, W Muto, T Narumiya, C Lu, XL Yajima, M Ishikawa, N Miyazeki, K Kawai, N Mizukami, H Sakakibara, J AF Hotta, Y Nagatsu, A Liu, W Muto, T Narumiya, C Lu, XL Yajima, M Ishikawa, N Miyazeki, K Kawai, N Mizukami, H Sakakibara, J TI Protective effects of antioxidative serotonin derivatives isolated from safflower against postischemic myocardial dysfunction SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE N-(p-Coumaroyl)serotonin; N-feruroylserotonin; EPR (Electron paramagnetic resonance) spectormetry; fluorometry; Guinea-pig hearts; ischemia-reperfusion injury; NO-selective electrode ID ISCHEMIA-REPERFUSION INJURY; NITRIC-OXIDE SYNTHASE; OXYGEN-FREE-RADICALS; NUCLEAR-MAGNETIC-RESONANCE; H+ EXCHANGE INHIBITOR; GUINEA-PIG HEART; L. OIL CAKE; SARCOPLASMIC-RETICULUM; PEROXYNITRITE; SUPEROXIDE AB N-(p-Coumaroyl)serotonin (C) and N-feruroylserotonin (F) with antioxidative activity are present in safflower oil. The protective effects of C and F were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Changes in cellular levels of high phosphorous energy, NO and Ca2+ in the heart together with simultaneous recordings of left ventricular developed pressure (LVDP) were monitored by an nitric oxide (NO) electrode, fluorometry and P-31-NMR. The rate of recovery of LVDP from ischemia by reperfusion was 30.8% in the control, while in the presence of C or F a gradual increase to 63.2 or 61.0% was observed. Changes of transient NO signals (T-NO) released from heart tissue in one contraction (LVDP) were observed to be upside-down with respect to transient fura-2-Ca2+ signals (T-Ca) and transient O-2 signals detected with a pO(2) electrode. At the final stage of ischemia, the intracellular concentration of Ca2+ ([Ca2+](i)) and the release of NO increased with no twitching and remained at a high steady level. The addition of C increased the NO level at the end of ischemia compared with the control, but [Ca2+](i) during ischemia decreased. On reperfusion, the increased diastolic level of T-Ca and T-NO returned rapidly to the control level with the recovery of LVDP. By in vitro EPR, C and F were found to directly quench the activity of active radicals. Therefore, it is concluded that the antioxidant effects of two derivatives isolated from safflower play an important role in ischemia-reperfusion hearts in close relation with NO. C1 Aichi Med Univ, Sch Med, Dept Pharmacol, Aichi 4801195, Japan. Aichi Med Univ, Sch Med, Dept Cardiovasc Surg, Aichi 4801195, Japan. Aichi Med Univ, Sch Med, Dept Anat, Aichi 4801195, Japan. Nagoya City Univ, Fac Pharmaceut Sci, Nagoya, Aichi 467, Japan. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD USA. RP Hotta, Y (reprint author), Aichi Med Univ, Sch Med, Dept Pharmacol, 21 Yazakoaza Karimata Nagakute, Aichi 4801195, Japan. NR 43 TC 35 Z9 38 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD SEP PY 2002 VL 238 IS 1-2 BP 151 EP 162 DI 10.1023/A:1019992124986 PG 12 WC Cell Biology SC Cell Biology GA 588JE UT WOS:000177697700017 PM 12349903 ER PT J AU Xu, ZP Wawrousek, EF Piatigorsky, J AF Xu, ZP Wawrousek, EF Piatigorsky, J TI Transketolase haploinsufficiency reduces adipose tissue and female fertility in mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DIPHOSPHATE-DEPENDENT ENZYME; MOUSE; METABOLISM; CLONING; CORNEA; GENE; FAT; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; DEFICIENCY; PROTEINS AB Transketolase (TKT) is a ubiquitous enzyme used in multiple metabolic pathways. We show here by gene targeting that TKT-null mouse embryos are not viable and that disruption of one TKT allele can cause growth retardation (approximate to35%) and preferential reduction of adipose tissue (approximate to77%). Other TKT+/- tissues had moderate (approximate to33%; liver, gonads) or relatively little (approximate to7 to 18%; eye, kidney, heart, brain) reductions in mass. These mice expressed a normal level of growth hormone and reduced leptin levels. No phenotype was observed in the TKT+/- cornea, where TKT is especially abundant in wild-type mice. The small female TKT+/- mice mated infrequently and had few progeny (with a male/female ratio of 1.4:1) when pregnant. Thus, TKT in normal mice appears to be carefully balanced at a threshold level for well-being. Our data suggest that TKT deficiency may have clinical significance in humans and raise the possibility that obesity may be treated by partial inhibition of TKT in adipose tissue. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, 6 Ctr Dr,Bldg 6,Room 201, Bethesda, MD 20892 USA. RI Wawrousek, Eric/A-4547-2008 NR 31 TC 36 Z9 36 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2002 VL 22 IS 17 BP 6142 EP 6147 DI 10.1128/MCB.22.17.6142-6147.2002 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 584UZ UT WOS:000177488300012 PM 12167708 ER PT J AU Vinson, C Myakishev, M Acharya, A Mir, AA Moll, JR Bonovich, M AF Vinson, C Myakishev, M Acharya, A Mir, AA Moll, JR Bonovich, M TI Classification of human B-ZIP proteins based on dimerization properties SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID GCN4 LEUCINE-ZIPPER; DNA-BINDING DOMAIN; INTERHELICAL ELECTROSTATIC INTERACTIONS; LIVER NUCLEAR-PROTEIN; HELICAL COILED COILS; FOS-JUN INTERACTION; SMALL MAF PROTEINS; TRANSCRIPTION FACTOR; AMINO-ACID; RESPONSE ELEMENT C1 NCI, Lab Metab, NCI, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NCI, Bldg 37,Room 2D24, Bethesda, MD 20892 USA. EM Vinsonc@dc37a.nci.nih.gov NR 105 TC 261 Z9 263 U1 3 U2 16 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 SEP PY 2002 VL 22 IS 18 BP 6321 EP 6335 DI 10.1128/MCB.22.18.6321-6335.2002 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 587LR UT WOS:000177642900001 PM 12192032 ER PT J AU Shen, CH Leblanc, BP Neal, C Akhavan, R Clark, DJ AF Shen, CH Leblanc, BP Neal, C Akhavan, R Clark, DJ TI Targeted histone acetylation at the yeast CUP1 promoter requires the transcriptional activator, TATA boxes, and the putative histone acetylase encoded by SPT10 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID METALLOTHIONEIN GENE-TRANSCRIPTION; DNA-BINDING PROTEIN; SACCHAROMYCES-CEREVISIAE; IN-VIVO; GEL-ELECTROPHORESIS; NUCLEOSOMAL DNA; SPT21 GENES; CHROMATIN; EXPRESSION; COPPER AB The relationship between chromatin remodeling and histone acetylation at the yeast CUP1 gene was addressed. CUP1 encodes a metallothionein required for cell growth at high copper concentrations. Induction of CUP1 with copper resulted in targeted acetylation of both H3 and H4 at the CUP1 promoter. Nucleosomes containing upstream activating sequences and sequences farther upstream were the targets for H3 acetylation. Targeted acetylation of H3 and H4 required the transcriptional activator (Acelp) and the TATA boxes, suggesting that targeted acetylation occurs when TATA-binding protein binds to the TATA box or at a later stage in initiation. We have shown previously that induction results in nueleosome repositioning over the entire CUP1 gene, which requires Acelp but not the TATA boxes. Therefore, the movement of nucleosomes occurring on CUP1 induction is independent of targeted acetylation. Targeted acetylation of both H3 and H4 also required the product of the SPT10 gene, which encodes a putative histone acetylase implicated in regulation at core promoters. Disruption of SPT10 was lethal at high copper concentrations and correlated with slower induction and reduced maximum levels of CUP1 mRNA. These observations constitute evidence for a novel mechanism of chromatin activation at CUP1, with a major role for the TATA box. 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 3148,50 S Dr, Bethesda, MD 20892 USA. NR 56 TC 22 Z9 22 U1 1 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 SEP PY 2002 VL 22 IS 18 BP 6406 EP 6416 DI 10.1128/MCB.22.18.6406-6416.2002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 587LR UT WOS:000177642900009 PM 12192040 ER PT J AU Liu, H Kang, H Liu, R Chen, X Zhao, K AF Liu, H Kang, H Liu, R Chen, X Zhao, K TI Maximal induction of a subset of interferon target genes requires the chromatin-remodeling activity of the BAF complex SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL-CYCLE ARREST; TRANSCRIPTIONAL ACTIVATION; MUSCLE DIFFERENTIATION; ORDERED RECRUITMENT; SWI/SNF COMPLEX; PROMOTER; PROTEINS; ALPHA; BINDING; FAMILY AB The mammalian SWI/SNF-like chromatin-remodeling BAF complex plays several important roles in controlling cell proliferation and differentiation. Interferons (IFNs) are key mediators of cellular antiviral and antiproliferative activities. In this report, we demonstrate that the BAF complex is required for the maximal induction of a subset of IFN target genes by alpha IFN (IFN-alpha). The BAF complex is constitutively associated with the IFITM3 promoter in vivo and facilitates the chromatin remodeling of the promoter upon IFN-a induction. Furthermore, we show that the ubiquitous transcription activator Sp1 interacts with the BAF complex in vivo and augments the BAF-mediated activation of the IFITM3 promoter. Sp1 binds constitutively to the IFITM3 promoter in the absence of the BAF complex, suggesting that it may recruit and/or stabilize the BAF complex binding to the IFITM3 promoter. Our results bring new mechanistic insights into the antiproliferative effects of the chromatin-remodeling BAF complex. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. RP Zhao, K (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N252,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 52 TC 78 Z9 78 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 SEP PY 2002 VL 22 IS 18 BP 6471 EP 6479 DI 10.1128/MCB.22.18.6471-6479.2002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 587LR UT WOS:000177642900014 PM 12192045 ER PT J AU Maruyama, T Farina, A Dey, A Cheong, J Bermudez, VP Tamura, T Sciortino, S Shuman, J Hurwitz, J Ozato, K AF Maruyama, T Farina, A Dey, A Cheong, J Bermudez, VP Tamura, T Sciortino, S Shuman, J Hurwitz, J Ozato, K TI A mammalian bromodomain protein, Brd4, interacts with replication factor C and inhibits progression to S phase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL NUCLEAR ANTIGEN; EFFECT HOMEOTIC GENE; DNA-REPLICATION; LARGE SUBUNIT; COMPLEX-FORMATION; EUKARYOTIC CELLS; ATPASE ACTIVITY; DROSOPHILA-FSH; RING3 GENE; IDENTIFICATION AB Brd4 belongs to the BET family of nuclear proteins that carry two bromodomains implicated in the interaction with chromatin. Expression of Brd4 correlates with cell growth and is induced during early G, upon mitogenic stimuli. In the present study, we investigated the role of Brd4 in cell growth regulation. We found that ectopic expression of Brd4 in NIH 3T3 and HeLa cells inhibits cell cycle progression from G, to S. Coimmunoprecipitation experiments showed that endogenous and transfected Brd4 interacts with replication factor C (RFC), the conserved five-subunit complex essential for DNA replication. In vitro analysis showed that Brd4 binds directly to the largest subunit, RFC-140, thereby interacting with the entire RFC. In line with the inhibitory activity seen in vivo, recombinant Brd4 inhibited RFC-dependent DNA elongation reactions in vitro. Analysis of Brd4 deletion mutants indicated that both the interaction with RFC-140 and the inhibition of entry into S phase are dependent on the second bromodomain of Brd4. Lastly, supporting the functional importance of this interaction, it was found that cotransfection with RFC-140 reduced the growth-inhibitory effect of Brd4. Taken as a whole, the present study suggests that Brd4 regulates cell cycle progression in part by interacting with RFC. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Mem Sloan Kettering Canc Ctr, Dept Mol Biol & Virol, New York, NY 10021 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A01, Bethesda, MD 20892 USA. OI Shuman, Jon/0000-0001-8412-9087 NR 47 TC 93 Z9 98 U1 1 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 SEP PY 2002 VL 22 IS 18 BP 6509 EP 6520 DI 10.1128/MCB.22.18.6509-6520.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 587LR UT WOS:000177642900018 PM 12192049 ER PT J AU Blagosklonny, MV Robey, R Sackett, DL Du, L Traganos, F Darzynkiewicz, Z Fojo, T Bates, SE AF Blagosklonny, MV Robey, R Sackett, DL Du, L Traganos, F Darzynkiewicz, Z Fojo, T Bates, SE TI Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; SODIUM-BUTYRATE; UP-REGULATION; CANCER CELLS; SP1 SITES; APOPTOSIS; P21(WAF1/CIP1); PROMOTER; FR901228; P53 AB By preventing deacetylation of histones, histone deacetylase inhibitors (HDIs) transcriptionally induce p21. Here we show that the HDIs sodium butyrate (Bu), trichostatin A (TSA) and depsipeptide (FR901228) all induced p21, but only TSA and FR901228 caused mitotic arrest (in addition to arrest in G(1) and G(2)). The ability to cause mitotic arrest correlated with the higher cytotoxicity of these compounds. Although causing mitotic arrest, TSA and FR901228 (unlike paclitaxel) did not affect tubulin polymerization. Unlike FR9012208, TSA caused acetylation of tubulin at lysine 40; both soluble tubulin and microtubules were acetylated. Whereas the induction of p21 reached a maximum by 8 h, tubulin was maximally acetylated after only 1 h of TSA treatment. Tubulin acetylation was detectable after treatment with 12-25 ng/ml TSA although acetylation plateaued at 50 ng/ml TSA, coinciding with G(2)-M arrest, appearance of cells with a sub-2N DNA content, poly(ADP-ribose) polymerase cleavage, and rapid cell death. We conclude that HDIs have differential effects on non-histone deacetylases and that rapid acetylation of tubulin caused by TSA is a marker of nontranscriptional effects of TSA. C1 New York Med Coll, Brander Canc Res Inst, Valhalla, NY 10595 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), Brander Canc Res Inst, 19 Bradhurst Ave, Hawthorne, NY 10532 USA. RI Traganos, Frank/B-8021-2012; OI Darzynkiewicz, Zbigniew/0000-0002-2040-7081 FU NCI NIH HHS [R01 CA028704, R01 CA028704-25] NR 25 TC 172 Z9 184 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2002 VL 1 IS 11 BP 937 EP 941 PG 5 WC Oncology SC Oncology GA 607BP UT WOS:000178770800007 PM 12481415 ER PT J AU Friedman, HS Keir, S Pegg, AE Houghton, PJ Colvin, OM Moschel, RC Bigner, DD Dolan, ME AF Friedman, HS Keir, S Pegg, AE Houghton, PJ Colvin, OM Moschel, RC Bigner, DD Dolan, ME TI O-6-benzylguanine-mediated enhancement of chemotherapy SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MAMMALIAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; CARMUSTINE PLUS O-6-BENZYLGUANINE; PROGRESSIVE MALIGNANT GLIOMA; SYSTEM TUMOR XENOGRAFTS; INTERSTRAND CROSS-LINK; ATHYMIC NUDE-MICE; PHASE-I TRIAL; ALKYLATING-AGENTS; O(6)-ALKYLGUANINE-DNA ALKYLTRANSFERASE; NITROGEN-MUSTARD AB We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990) that O-6-benzylguanine (O-6-BG) enhances nitrosourea, temozolomide, and cyclophosphamide activity in malignant glioma xenografts growing in athymic nude mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the combination of temozolomide plus irinotecan (CPT-11) displays a schedule-dependent enhancement of antitumor activity secondary to trapping of topoisomerase I by O-6-methylguanine residues in DNA. These studies suggested that there might be favorable therapeutic interactions between O-6-BG and combinations of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus cyclophosphamide or temozolomide plus CPT-11, respectively. Our present results indicate that the combination of cyclophosphamide plus BCNU plus O-6-BG produces growth delays modestly-to-markedlysuperior to combinations of cyclophosphamide with BCNU. Although the combination of temozolomide and CPT-11 reveals a marked increase in activity compared with either agent used alone, the addition of O-6-BG to this combination dramatically increased the growth delay of the O-6-alkylguanine-DNA alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest that a Phase I trial of CPT-11 plus temozolomide plus O-6-BG in AGT-positive tumors may be an important intervention to maximize the therapeutic benefits of the combination of CPT-11 and temozolomide. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38101 USA. Milton S Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Friedman, HS (reprint author), Duke Univ, Med Ctr, Dept Surg, Room 047,Baker House,Trent Dr, Durham, NC 27710 USA. FU NCI NIH HHS [CA81485, CA57725]; NINDS NIH HHS [NS20023, NS30245] NR 42 TC 66 Z9 68 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2002 VL 1 IS 11 BP 943 EP 948 PG 6 WC Oncology SC Oncology GA 607BP UT WOS:000178770800008 PM 12481416 ER PT J AU Martinez-Cruz, B David, VA Godoy, JA Negro, JJ O'Brien, SJ Johnson, WE AF Martinez-Cruz, B David, VA Godoy, JA Negro, JJ O'Brien, SJ Johnson, WE TI Eighteen polymorphic microsatellite markers for the highly endangered Spanish imperial eagle (Aquila adalberti) and related species SO MOLECULAR ECOLOGY NOTES LA English DT Article DE Aquila adalberti; individual identification; microsatellites; paternity assessment; population genetics; Spanish imperial eagle ID NATURAL-POPULATIONS; FALCO-PEREGRINUS; DNA MARKERS AB Here we describe the development of 18 polymorphic microsatellite markers for the endangered Spanish imperial eagle (Aquila adalberti). Microsatellites were tested in five other raptor species. These markers were revealed as good molecular tools for genetic population studies, individual identification and parentage assessment in Spanish imperial eagle and closely related species. C1 CSIC, Estac Biol Donana, Seville 41013, Spain. NCI, FCRDC, Lab Genom Divers, Frederick, MD 21702 USA. RP Martinez-Cruz, B (reprint author), CSIC, Estac Biol Donana, Avda Maria Luisa S-N, Seville 41013, Spain. RI Godoy, Jose A./B-9288-2008; Negro, Juan/I-2653-2015; Johnson, Warren/D-4149-2016; CSIC, EBD Donana/C-4157-2011 OI Godoy, Jose A./0000-0001-7502-9471; Negro, Juan/0000-0002-8697-5647; Johnson, Warren/0000-0002-5954-186X; CSIC, EBD Donana/0000-0003-4318-6602 NR 17 TC 85 Z9 85 U1 1 U2 14 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1471-8278 J9 MOL ECOL NOTES JI Mol. Ecol. Notes PD SEP PY 2002 VL 2 IS 3 BP 323 EP 326 DI 10.1046/j.1471-8278.2002.00231.x PG 4 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 592YK UT WOS:000177964300043 ER PT J AU Zhang, XY Kaneshige, M Kamiya, Y Kaneshige, K McPhie, P Cheng, SY AF Zhang, XY Kaneshige, M Kamiya, Y Kaneshige, K McPhie, P Cheng, SY TI Differential expression of thyroid hormone receptor isoforms dictates the dominant negative activity of mutant beta receptor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVITY; GENERALIZED RESISTANCE; POLYCLONAL ANTIBODIES; BINDING DOMAIN; LIGAND-BINDING; C-ERBA; GENE; MICE; LIVER AB Mutations in the thyroid hormone receptor beta gene (TRbeta) cause resistance to thyroid hormone (RTH). Genetic analyses indicate that phenotypic manifestation of RTH is due to the dominant negative action of mutant TRbeta. However, the molecular mechanisms underlying the dominant negative action of mutants and how the same mutation results in marked variability of resistance in different tissues in vivo are not clear. Here we used a knock-in mouse (TRbetaPV mouse) that faithfully reproduces human RTH to address these questions. We demonstrated directly that TRbeta1 protein was approximately 3-fold higher than TRalpha1 in the liver of TRbeta(+/+) mice but was not detectable in the heart of wild-type and TRbetaPV mice. The abundance of PV in the liver of TRbeta(PV/PV) was more than TRbeta(PV/+) mice but not detectable in the heart. TRalpha1 in the liver was approximately 6-fold higher than that in the heart of wild-type and TRbetaPV mice. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed not only with TR isoforms for binding to thyroid hormone response elements (TRE) but also competed with TR for the retinoid X receptors in binding to TRE. These competitions led to the inhibition of the thyroid hormone (T-3)-positive regulated genes in the liver. In the heart, however, PV was significantly lower and thus could not effectively compete with TRalpha1 for binding to TRE, resulting in activation of the T-3-target genes by higher levels of circulating thyroid hormones. These results indicate that in vivo, differential expression of TR isoforms in tissues dictates the dominant negative activity of mutant beta receptor, thereby resulting in variable phenotypic expression in RTH. C1 NCI, Gene Regulat Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, NIH, Bldg 37,Room 5128A,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. NR 29 TC 42 Z9 43 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2002 VL 16 IS 9 BP 2077 EP 2092 DI 10.1210/me.2002-0080 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 590KF UT WOS:000177821500008 PM 12198244 ER PT J AU Garman, SC Garboczi, DN AF Garman, SC Garboczi, DN TI Structural basis of Fabry disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE EC 3.2.1.22; Fabry disease; alpha-galactosidase; lysosomal storage disease; human mutation; homology model; EC3.2.1.49; glycosidase ID HUMAN ALPHA-GALACTOSIDASE; HUMAN-LIVER; N-ACETYLGALACTOSAMINIDASE; REPLACEMENT THERAPY; GENE; PURIFICATION; SEQUENCE; DATABASE AB Fabry disease is a lysosomal storage disease caused by deficiency in the enzyme alpha-galactosidase (alpha-GAL). To understand the molecular defects responsible for Fabry disease, we have collected more than 190 reported point and stop mutations and mapped them onto a model of human alpha-GAL based on the X-ray structure of the closely related enzyme alpha-N-acetylgalactosaminidase (alpha-NAGAL). The locations of the human alpha-GAL point mutations reveal two major classes of Fabry disease protein defects: active site mutations and folding mutations. Active site mutations reduce enzymatic activity by perturbing the active site without necessarily affecting the overall alpha-GAL structure. Folding mutations reduce the stability of alpha-GAL by disrupting its hydrophobic core. Examining the frequency of mutation around each alpha-GAL residue identifies the active site as a hotspot for mutations leading to Fabry disease. This study furthers our understanding of the structural basis for mutations leading to Fabry disease, from which new avenues for the treatment of lysosomal storage diseases may be developed. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIAID, Immunogenet Lab, Struct Biol Sect, NIH, Rockville, MD 20852 USA. RP Garman, SC (reprint author), NIAID, Immunogenet Lab, Struct Biol Sect, NIH, Twinbrook 11,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 25 TC 32 Z9 33 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2002 VL 77 IS 1-2 BP 3 EP 11 AR PII S1096-7192(02)00151-8 DI 10.1016/S1096-7192(02)00151-8 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 612KQ UT WOS:000179074500002 PM 12359124 ER PT J AU Introne, WJ Phornphutkul, C Bernardini, I McLaughlin, K Fitzpatrick, D Gahl, WA AF Introne, WJ Phornphutkul, C Bernardini, I McLaughlin, K Fitzpatrick, D Gahl, WA TI Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE alkaptonuria; homogentisic acid; renal tubular secretion; kidney transplantation; ochronosis ID MUTATIONS; GENE; HGO; DIOXYGENASE AB In alkaptonuria, homogentisate 1,2-dioxygenase deficiency causes tissue accumulation of homogentisic acid (HGA), followed by signs and symptoms of ochronosis. These include massive urinary excretion of HGA, arthritis and joint destruction, pigmentation of cartilage and connective tissue, and cardiac valve deterioration. We describe a 46-year-old man with alkaptonuria and diabetic renal failure whose plasma HGA concentration was twice that of any other alkaptonuria patient, and whose ochronosis progressed much more rapidly than that of his two alkaptonuric siblings. After renal transplantation, the plasma HGA normalized, and the daily urinary excretion of HGA decreased by 2-3 g. This case illustrates the critical role of renal tubular secretion in eliminating HGA from the body, and suggests that renal transplantation in a uremic patient not only restores HGA excretion, but may also provide homogentisate 1,2-dioxygenase activity for the metabolism of HGA. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NHGRI, MGB, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Calgary, Fac Med, Calgary, AB, Canada. RP Gahl, WA (reprint author), NHGRI, MGB, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 15 TC 31 Z9 31 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2002 VL 77 IS 1-2 BP 136 EP 142 AR PII S1096-7192(02)00121-X DI 10.1016/S1096-7192(02)00121-X PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 612KQ UT WOS:000179074500019 PM 12359141 ER PT J AU Farook, VS Bogardus, C Prochazka, M AF Farook, VS Bogardus, C Prochazka, M TI Analysis of MGEA5 on 10q24.1-q24.3 encoding the beta-O-linked N-acetylglucosaminidase as a candidate gene for type 2 diabetes mellitus in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE MGEA5; O-GlcNAcase; O-GlcNAc; type 2 diabetes mellitus; candidate gene; single nucleotide polymorphism; chromosome 10q24; Pima Indians ID AUTOSOMAL GENOMIC SCAN; INDEPENDENT REPLICATION; SUSCEPTIBILITY LOCUS; INSULIN-RESISTANCE; SKELETAL-MUSCLE; IN-VIVO; NUCLEAR; HYALURONIDASE; GLUCOSAMINE; PROTEINS AB Several diseases including type 2 diabetes mellitus (T2DM) are associated with abnormal O-glycosylation of proteins. beta-O-linked N-acetylglucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10g24.1-q24.3 removes N-acetylglucosamine (O-GlcNAc), and we investigated this locus in Pima Indians who have the world's highest prevalence of T2DM. We detected two variants but there was no association with parameters of insulin resistance or diabetes in similar to1300 Pimas. We conclude that mutations in MGEA5 are unlikely to contribute to T2DM in this population. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Farook, VS (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 22 TC 20 Z9 21 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2002 VL 77 IS 1-2 BP 189 EP 193 AR PII S1096-7192(02)00127-0 DI 10.1016/S1096-7192(02)00127-0 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 612KQ UT WOS:000179074500024 PM 12359146 ER PT J AU Rivera, J AF Rivera, J TI Special issue: Proceedings of the Fourth International Workshop on Signal Transduction in the Activation and development of Mast Cells and Basophils - Preface SO MOLECULAR IMMUNOLOGY LA English DT Editorial Material C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, NIH, Bldg 10,Rm 9N228, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1171 EP 1171 AR PII S0161-5890(02)00057-3 DI 10.1016/S0161-5890(02)00057-3 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900001 ER PT J AU Metzger, H Eglite, S Haleem-Smith, H Reischl, I Torigoe, C AF Metzger, H Eglite, S Haleem-Smith, H Reischl, I Torigoe, C TI Quantitative aspects of signal transduction by the receptor with high affinity for IgE SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE aggregation; signal transduction; kinetic proofreading; gene activation; MCP-1 ID FC-EPSILON-RI; BASOPHILIC LEUKEMIA-CELLS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; MAST-CELLS; IMMUNOGLOBULIN-E; LYN KINASE; AGGREGATION; MECHANISM; COMPLEXES; ALPHA AB Identification of the major components, how these interact with each other, and the modifications that follow in the sequence of events triggered by the receptor with high affinity for IgE, is progressing rapidly. A new challenge is to understand these interactions quantitatively. We present the fundamentals of the mechanistic model we are testing through mathematical modeling. The object is to see if the predictions of the model fit with the experimental results. (C) 2002 Published by Elsevier Science Ltd. C1 NIAMS, Sect Chem Immunol, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Metzger, H (reprint author), NIAMS, Sect Chem Immunol, Arthrit & Rheumatism Branch, NIH, Rm 9N-228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 46 TC 9 Z9 9 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1207 EP 1211 AR PII S0161-5890(02)00065-2 DI 10.1016/S0161-5890(02)00065-2 PG 5 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900008 PM 12217385 ER PT J AU Siraganian, RP Zhang, J Suzuki, K Sada, K AF Siraganian, RP Zhang, J Suzuki, K Sada, K TI Protein tyrosine kinase Syk in mast cell signaling SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE mast cells; protein tyrosine kinase Syk; signal transduction; Fe epsilon RI; histamine release ID AFFINITY IGE RECEPTOR; FC-EPSILON-RI; BASOPHILIC LEUKEMIA-CELLS; ACTIVATION LOOP TYROSINES; PHOSPHORYLATION; P72(SYK); TRANSDUCTION; AGGREGATION; COMPONENT; PEPTIDES AB The tyrosine kinase Syk is essential for signaling from FcepsilonRI in mast cells. The Src homology domain mediated binding of Syk to the phosphorylated immunoreceptor tyrosine-based motif (ITAM) of the receptor subunits results in a conformational change and activation. Studies in Syk deficient mast cells have defined the pathways that are activated upstream and downstream of Syk and have demonstrated the functional importance of the linker region of Syk in signaling in mast cells. Published by Elsevier Science Ltd. C1 NIDCR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), NIDCR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bldg 10,Room 1N106, Bethesda, MD 20892 USA. RI Sada, Kiyonao/H-7373-2015 OI Sada, Kiyonao/0000-0001-6124-3100 NR 32 TC 96 Z9 97 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1229 EP 1233 AR PII S0161-5890(02)00068-8 DI 10.1016/S0161-5890(02)00068-8 PG 5 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900011 PM 12217388 ER PT J AU Jolly, PS Rosenfeldt, HM Milstien, S Spiegel, S AF Jolly, PS Rosenfeldt, HM Milstien, S Spiegel, S TI The roles of sphingosine-1-phosphate in asthma SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE asthma; mast cells; airway smooth muscle cells; sphingosine; sphingosine-1-phosphate; sphingosine kinase ID AIRWAY SMOOTH-MUSCLE; FC-EPSILON-RI; SPHINGOSINE 1-PHOSPHATE; PROTEIN-KINASE; RECEPTOR EDG-1; CELL-MIGRATION; CALCIUM MOBILIZATION; SIGNALING PATHWAYS; GROWTH-FACTORS; PROLIFERATION AB Asthma is a complex condition in which exposure to environmental antigens induces inflammatory reactions in the airway characterized by activation of mast cells and eosinophils. Mast cells are known to be the main effector cells in eliciting IgE-mediated allergic response. These cells secrete various substances that perpetuate inflammation and provoke airway smooth muscle (ASM) contraction. A newly recognized addition to the repertoire of FcepsilonRI-mediated signaling events is the activation of sphingosine kinase leading to the generation of the potent sphingolipid mediator, sphingosine-1-phosphate (S1P) from sphingosine. S1P secretion by the lung significantly increases after challenge with an allergen, adding this sphingolipid metabolite to the variety of mediators that are released during an allergic reaction [FASEB J. 15 (2001) 1212]. Indeed, similar to previous reports, we found that FcepsilonRI cross-linking not only increased cellular levels of S1P, it also markedly enhanced its secretion from rat basophilic leukemia RBL-2H3 cells. Moreover, S1P induced degranulation of RBL and bone marrow derived mast cells (BMMCs) cells as determined by hexosaminidase release. Treatment of BMMCs with the sphingosine kinase inhibitors, DL-threo-dihydrosphingosine and dimethylsphingosine, reduced IgE/Ag stimulated histamine release. RT-PCR analysis demonstrated that these mast cells express S1P receptors EDG-1 and EDG-5 but not EDG-3, EDG-6 or EDG-8 transcripts. Further studies are needed to determine whether IgE triggering results in transactivation of EDG-1 or EDG-5 present on mast cells and whether this is a critical event for mast cell activation. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Richmond, VA 23298 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Campus, Richmond, VA 23298 USA. FU NIAID NIH HHS [AIS0094] NR 42 TC 70 Z9 73 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1239 EP 1245 AR PII S0161-5890(02)00070-6 DI 10.1016/S0161-5890(02)00070-6 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900013 PM 12217390 ER PT J AU Rivera, J Cordero, JR Furumoto, Y Luciano-Montalvo, C Gonzalez-Espinosa, C Kovarova, M Odom, S Parravicini, V AF Rivera, J Cordero, JR Furumoto, Y Luciano-Montalvo, C Gonzalez-Espinosa, C Kovarova, M Odom, S Parravicini, V TI Macromolecular protein signaling complexes and mast cell responses: a view of the organization of IgE-dependent mast cell signaling SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE Fc epsilon RI; Gab2; LAT; Vav1; macromolecular signaling complex ID FC-EPSILON-RI; HIGH-AFFINITY; T-CELL; IMMUNOGLOBULIN-E; BETA-SUBUNIT; ACTIVATION; RECEPTOR; LAT; AMPLIFIER; MEMBRANE AB The generation of signals following engagement of cell surface receptors is an ordered process that requires tight regulation as spurious signals could result in unwanted, and possibly deleterious, cellular responses. Like other cell surface receptors, stimulation of a mast cell via the high affinity IgE receptor (FcepsilonRI) causes multiple biochemical events that ultimately result in cell activation and effector responses. Recently, our knowledge of how these events are ordered has increased. We now have identified some of the molecules involved, how they are organized into macromolecular complexes by FcepsilonRI stimulation, and the role of some of the constituents of these macromolecular signaling complexes in mast cell effector responses. In brief, we review the knowledge on macromolecular signaling complexes used by FcepsilonRI in mast cell activation and provide our view on the regulation of signal generation and its effect on mast cell activation. Published by Elsevier Science Ltd. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Acad Sci Czech Republ, Inst Mol Genet, Prague, Czech Republic. RP Rivera, J (reprint author), NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. NR 22 TC 22 Z9 23 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1253 EP 1258 AR PII S0161-5890(02)00072-X DI 10.1016/S0161-5890(02)00072-X PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900015 PM 12217392 ER PT J AU Chahdi, A Choi, WS Kim, YM Fraundorfer, PF Beaven, MA AF Chahdi, A Choi, WS Kim, YM Fraundorfer, PF Beaven, MA TI Serine/threonine protein kinases synergistically regulate phospholipase D1 and 2 and secretion in RBL-2H3 mast cells SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE phospholipase D1 and 2; protein kinases; mast cells; secretion ID PLASMA-MEMBRANE; PHOSPHORYLATION; ACTIVATION; RECEPTOR; EXOCYTOSIS; ANTIGEN; STIMULATION; MECHANISM; CALCIUM; MYOSIN AB The role of phospholipase (PL) D in secretion was examined in RBL-2H3 mast cells which contain both PLD1 and 2. The effects of pharmacologic stimulants and inhibitors of Ca2+/calmodulin-dependent kinase II, protein kinase C, and protein kinase A suggested that all three kinases synergistically stimulate PLD and, when associated with a calcium signal, secretion as well to indicate a possible linkage between these two events. Overexpression of either PLD1 or 2 markedly enhanced the activation of PLD by pharmacologic stimulants as well as antigen and both isoforms thus appear co-ordinately regulated. As the expressed PLD1 was associated with secretory granules and PLD2 with the plasma membrane, the two isoforms may serve distinct but complementary functions in secretion. Published by Elsevier Science Ltd. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 13 Z9 13 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1269 EP 1276 AR PII S0161-5890(02)00074-3 DI 10.1016/S0161-5890(02)00074-3 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900017 PM 12217394 ER PT J AU Tkaczyk, C Okayama, Y Woolhiser, MR Hagaman, DD Gilfillan, AM Metcalfe, DD AF Tkaczyk, C Okayama, Y Woolhiser, MR Hagaman, DD Gilfillan, AM Metcalfe, DD TI Activation of human mast cells through the high affinity IgG receptor SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE IgG receptor; human mast cells; GM-CSF ID FC-GAMMA-RI; IFN-GAMMA; ARACHIDONIC-ACID; UP-REGULATION; EXPRESSION; AGGREGATION; ALPHA AB Mast cells are known to participate in the induction of inflammation through interaction of antigen with specific IgE bound to the high affinity receptor for IgE (FcepsilonRI). Human mast cells, derived from CD34(+) hematopoietic precursors, not only express FcepsilonRI but also express high affinity receptors for IgG (FcgammaRI), the latter only after IFN-gamma exposure. Human mast cells that express FcgammaRI are activated following FcgammaRI aggregation, either using antibodies directed to the receptor or through IgG bound to the receptor. This activation results in degranulation, with the release of granule-associated mediators, and the generation of metabolites of arachidonic acid and secretion of chemokines and cytokines. These observations provide evidence that human mast cells may also be recruited into inflammation through IgG-dependent mechanisms. Published by Elsevier Science Ltd. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. NR 21 TC 34 Z9 41 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1289 EP 1293 AR PII S0161-5890(02)00077-9 DI 10.1016/S0161-5890(02)00077-9 PG 5 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900020 PM 12217397 ER PT J AU Blank, U Cyprien, B Martin-Verdeaux, S Paumet, F Pombo, I Rivera, J Roa, M Varin-Blank, N AF Blank, U Cyprien, B Martin-Verdeaux, S Paumet, F Pombo, I Rivera, J Roa, M Varin-Blank, N TI SNAREs and associated regulators in the control of exocytosis in the RBL-2H3 mast cell line SO MOLECULAR IMMUNOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Signal Transduction in the Activation and Development of Mast Cells and Basophils CY NOV 26-30, 2001 CL NATL INST HLTH, BETHESDA, MARYLAND SP UCB Res Ubc HO NATL INST HLTH DE mast cell; exocytosis; SNARE proteins; Rab3D ID FC-EPSILON-RI; MEMBRANE-FUSION; SECRETORY GRANULES; DEGRANULATION; RAB3; SYNAPTOTAGMIN; COMPARTMENT; LYSOSOMES; PROTEINS; RELEASE AB Mast cells participate in inflammation and allergies by releasing biologically active mediators stored in numerous cytoplasmic granules. Degranulation is tightly controlled and requires activation of cell surface receptors, such as the high affinity IgE receptor (FcepsilonRI). Here, we discuss some of the key components of the molecular machinery that regulates the final steps of fusion between the granular and plasma membrane based on results obtained with the rat mast cell line RBL-2H3. We emphasize the role of soluble N-ethylmaleimide attachment protein receptors (SNAREs) proteins such as syntaxin 4 that can promote membrane fusion through formation of a stable complex with SNAP-23. We also highlight the role of a Ser/Thr kinase found to be associated with Rab3D, a negative regulator of degranulation. Associated kinase activity, which diminishes after stimulation as a consequence of intracellular calcium increases, specifically phosphorylates syntaxin 4 thereby affecting its capacity to bind to its t-SNARE partner SNAP-23. Our results suggest a new way of how Rab3 GTPases may intersect with the function of SNAREs thought to be universal mediators of membrane fusion. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Inst Pasteur, Unite Immunoallergie, F-75724 Paris 15, France. Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA. NIAMSD, Mol Inflammat Sect, NIH, Bethesda, MD 20892 USA. Hop Cochin, ICGM, INSERM, U363,Unite Oncol Cellulaire & Mol, F-75014 Paris, France. RP Blank, U (reprint author), Inst Pasteur, Unite Immunoallergie, 28 Rue Dr Roux, F-75724 Paris 15, France. NR 29 TC 37 Z9 38 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2002 VL 38 IS 16-18 BP 1341 EP 1345 AR PII S0161-5890(02)00085-8 DI 10.1016/S0161-5890(02)00085-8 PG 5 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 598GP UT WOS:000178267900028 PM 12217405 ER PT J AU Ferguson, SS Lecluyse, EL Negishi, M Goldstein, JA AF Ferguson, SS Lecluyse, EL Negishi, M Goldstein, JA TI Regulation of human CYP2C9 by the constitutive androstane receptor: Discovery of a new distal binding site SO MOLECULAR PHARMACOLOGY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; HUMAN HEPATOCYTES; CYTOCHROME-P450 GENES; MOLECULAR-BIOLOGY; DRUG-INTERACTIONS; S-MEPHENYTOIN; INDUCTION; CAR; ENZYMES; PXR AB The CYP2C subfamily metabolizes many clinically important drugs. These genes respond to prototypical inducers such as phenobarbital and rifampicin, yet little has been reported on the mechanisms of induction. This report examines the regulation of CYP2C9 with respect to two specific receptors thought to be involved in phenobarbital (PB) induction, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Transfection of either mouse CAR (mCAR) or human CAR (hCAR) into HepG2 cells results in increased CYP2C9 mRNA content. Inducers further increased this response in CAR transfected cells. mCAR but not hCAR conferred drug inducibility to the proximal -2145 bp of the CYP2C9 promoter in luciferase assays. Further examination of a -2925-bp promoter construct revealed that hCAR cotransfection increased activity 20-fold. Gel shift assays confirmed the presence of a distal PB-responsive enhancer module-like enhancer module, CAR-responsive enhancer (CAR-RE), between -2900 and -2841 bp consisting of two DR-5 nuclear receptor binding motifs capable of binding hCAR, mCAR, and, to a lesser extent, human PXR. The majority of binding and hCAR activation is derived from the NR1 portion of the CAR-RE. PB treatment did not further increase the hCAR activation in any of the constructs. In summary, a new CAR/PXR binding site was identified in the CYP2C9 promoter, and this site seems to constitutively regulate transcription via a CAR-dependent mechanism; however, it could not be shown to account for PB inducibility of the gene. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. RP Goldstein, JA (reprint author), NIEHS, Lab Pharmacol & Chem, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RI Goldstein, Joyce/A-6681-2012; OI LeCluyse, Edward/0000-0002-2149-8990 NR 31 TC 110 Z9 113 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2002 VL 62 IS 3 BP 737 EP 746 AR UNSP 1696/1008152 DI 10.1124/mol.62.3.737 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 583YG UT WOS:000177438900036 PM 12181452 ER PT J AU Muller, J Seppi, K Stefanova, N Poewe, W Litvan, I Wenning, GK AF Muller, J Seppi, K Stefanova, N Poewe, W Litvan, I Wenning, GK TI Freezing of gait in postmortem-confirmed atypical parkinsonism SO MOVEMENT DISORDERS LA English DT Article DE freezing; gait; corticobasal degeneration; dementia with Lewy bodies; multiple system atrophy; progressive supranuclear palsy ID PROGRESSIVE SUPRANUCLEAR PALSY; STEELE-RICHARDSON-OLSZEWSKI; LEWY BODY DISEASE; INTERNATIONAL WORKSHOP; PURE AKINESIA; CORTICOBASAL DEGENERATION; CLINICAL-CRITERIA; IGNITION FAILURE; DIAGNOSIS; DEMENTIA AB The frequency and pathophysiology of freezing of gait (FoG) in atypical parkinsonism is unknown. We analysed the frequency of FoG in postmortem-confirmed atypical parkinsonian disorders (APD) comprising corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Sixty-six patients with pathologically confirmed APD (CBD, n = 13; DLB, n = 14; MSA, n = 15; PSP, n = 24) formed the basis for a multicenter clinicopathological study. Clinical features at first and last clinical visit were abstracted from patient records on standardized forms following strict instructions. At the first visit (median 36 months after symptom onset), 24% of APD had FoG (CBD, 8%; DLB, 21%; PSP, 25%; MSA, 40%). Logistic regression analysis showed a significant association of FoG and urinary incontinence (P = 0.04) at first visit. At last visit, 47% of APD had FoG (CBD, 25%; PSP, 53%; DLB, 54%; MSA, 54%). Clinicopathological correlation based on routine postmortem examination failed to identify a consistent neuropathological substrate of FoG. This study demonstrates that (1) FoG is common in APD, and (2) urinary incontinence is significantly associated with FoG in these disorders. Whether FoG and urinary incontinence share similar neuropathological substrates remains to be determined by future studies. 0 2002 Movement Disorder Society. C1 Univ Innsbruck Hosp, Dept Neurol, A-6020 Innsbruck, Austria. Neuropharmacol Unit, Defense & Vet Head Injury Program, Henry M Jackson Fdn, Bethesda, MD USA. Natl Inst Neurol Disorders & Stroke, Med Neurol Branch, NIH, Bethesda, MD USA. RP Wenning, GK (reprint author), Univ Innsbruck Hosp, Dept Neurol, Anichstr 35, A-6020 Innsbruck, Austria. OI Litvan, Irene/0000-0002-3485-3445 NR 38 TC 31 Z9 33 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 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2002 VL 17 IS 5 BP 1041 EP 1045 DI 10.1002/mds.10234 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 600HK UT WOS:000178384400023 PM 12360556 ER PT J AU Subramony, SH Hernandez, D Adam, A Smith-Jefferson, S Hussey, J Gwinn-Hardy, K Lynch, T McDaniel, O Hardy, J Farrer, M Singleton, A AF Subramony, SH Hernandez, D Adam, A Smith-Jefferson, S Hussey, J Gwinn-Hardy, K Lynch, T McDaniel, O Hardy, J Farrer, M Singleton, A TI Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians SO MOVEMENT DISORDERS LA English DT Article DE SCA3; Machado-Joseph disease; Parkinson's disease; ataxia; epidemiology; genetics ID SPINOCEREBELLAR ATAXIA TYPE-3; FAMILY; GENE AB We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities. (C) 2002 Movement Disorder Society. C1 Mayo Clin, Dept Neurosci, Neurogenet Lab, Jacksonville, FL 32224 USA. Univ Mississippi, Ctr Med, Dept Neurol, Jackson, MS USA. NIA, Neurogenet Lab, NIH, Bethesda, MD USA. NINDS, Lab Neurogenet, NINDS, Bethesda, MD USA. Univ Mississippi, Ctr Med, Dept Prevent Med, Div Med Genet, Jackson, MS USA. Columbia Univ, Dept Neurol, New York, NY USA. Mater Misericordiae Univ Hosp, Dept Neurol, Dublin, Ireland. Univ Mississippi, Ctr Med, Dept Surg, Jackson, MS USA. Royal Free & UCL, Sch Med, Reta Lila Weston Inst Neurol Studies, Dept Neurol, London, England. RP Hardy, J (reprint author), Mayo Clin, Dept Neurosci, Neurogenet Lab, Jacksonville, FL 32224 USA. EM hardy@mayo.edu RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 9 TC 41 Z9 42 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2002 VL 17 IS 5 BP 1068 EP 1071 DI 10.1002/mds.10241 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 600HK UT WOS:000178384400028 PM 12360561 ER PT J AU Fahn, S Hallett, M DeLong, M AF Fahn, S Hallett, M DeLong, M TI Fourth International Dystonia Symposium - Introduction - Report on the Fourth International Dystonia Symposium SO MOVEMENT DISORDERS LA English DT Editorial Material C1 Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10027 USA. Presbyterian Hosp, Neurol Inst New York, New York, NY 10027 USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Emory Univ, Atlanta, GA 30322 USA. RP Fahn, S (reprint author), Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2002 VL 17 IS 5 BP 1115 EP 1116 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 600HK UT WOS:000178384400040 ER PT J AU Baxevanis, AD Collins, FS AF Baxevanis, AD Collins, FS TI Power to the people SO NATURE GENETICS LA English DT Editorial Material C1 NHGRI, Bethesda, MD 20892 USA. RP Baxevanis, AD (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2002 VL 32 SU S BP 2 EP 2 DI 10.1038/ng962 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 591HK UT WOS:000177873500002 ER PT J AU Wolfsberg, TG Wetterstrand, KA Guyer, MS Collins, FS Baxevanis, AD AF Wolfsberg, TG Wetterstrand, KA Guyer, MS Collins, FS Baxevanis, AD TI A user's guide to the human genome SO NATURE GENETICS LA English DT Editorial Material ID PROTEIN FAMILIES; HUMAN GENES; DATABASE; SEQUENCE; ANNOTATION; RESOURCE; PROJECT; MOUSE; BLAST AB The primary aim of A User's Guide to the Human Genome is to provide the reader with an elementary hands-on guide for browsing and analyzing data produced by the International Human Genome Sequencing Consortium and other systematic sequencing efforts. The majority of this supplement is devoted to a series of worked examples, providing an overview of the types of data available, details on how these data can be browsed, and step-by-step instructions for using many of the most commonly-used tools for sequence-based discovery. The major web portals featured throughout include the National Center for Biotechnology Information Map Viewer, the University of California, Santa Cruz Genome Browser, and the European Bioinformatics Institute's Ensembl system, along with many others that are discussed in the individual examples. it is hoped that readers will become more familiar with these resources, allowing them to apply the strategies used in the examples to advance their own research programs. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Wolfsberg, TG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM andy@nhgri.nih.gov NR 39 TC 5 Z9 5 U1 0 U2 2 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 SEP PY 2002 VL 32 SU S BP 4 EP 79 DI 10.1038/ng964 PG 76 WC Genetics & Heredity SC Genetics & Heredity GA 591HK UT WOS:000177873500004 ER PT J AU Suzuki, T Shen, HF Akagi, K Morse, HC Malley, JD Naiman, DQ Jenkins, NA Copeland, NG AF Suzuki, T Shen, HF Akagi, K Morse, HC Malley, JD Naiman, DQ Jenkins, NA Copeland, NG TI New genes involved in cancer identified by retroviral tagging SO NATURE GENETICS LA English DT Article ID RECOMBINANT INBRED MICE; BREAST-CARCINOMA; MOUSE; TRANSPOSITION; LYMPHOMAS; MAP; PROTOONCOGENE; EXPRESSION; ACTIVATION; INSERTION AB Retroviral insertional mutagenesis in BXH2 and AKXD mice induces a high incidence of myeloid leukemia and B- and T-cell lymphoma, respectively. The retroviral integration sites (RISs) in these tumors thus provide powerful genetic tags for the discovery of genes involved in cancer(1,2). Here we report the first large-scale use of retroviral tagging for cancer gene discovery in the post-genome era. Using high throughput inverse PCR1, we cloned and analyzed the sequences of 884 RISs from a tumor panel composed primarily of B- cell lymphomas. We then compared these sequences, and another 415 RIS sequences previously cloned from BXH2 myeloid leukemias and from a few AKXD lymphomas, against the recently assembled mouse genome sequence. These studies identified 152 loci that are targets of retroviral integration in more than one tumor (common retroviral integration sites, CISs) and therefore likely to encode a cancer gene. Thirty-six CISs encode genes that are known or predicted to be genes involved in human cancer or their homologs, whereas others encode candidate genes that have not yet been examined for a role in human cancer. Our studies demonstrate the power of retroviral tagging for cancer gene discovery in the post-genome era and indicate a largely unrecognized complexity in mouse and presumably human cancer. C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NIAID, Immunopathol Lab, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Math Sci, Baltimore, MD 21218 USA. RP Copeland, NG (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RI Naiman, Daniel/A-3304-2010; OI Naiman, Daniel/0000-0001-6504-9081; Morse, Herbert/0000-0002-9331-3705 NR 27 TC 309 Z9 314 U1 4 U2 6 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 SEP PY 2002 VL 32 IS 1 BP 166 EP 174 DI 10.1038/ng949 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 588RR UT WOS:000177714900017 PM 12185365 ER PT J AU Rosenberg, MJ Agarwala, R Bouffard, G Davis, J Fiermonte, G Hilliard, MS Koch, T Kalikin, LM Makalowska, I Morton, DH Petty, EM Weber, JL Palmieri, F Kelley, RI Schaffer, AA Biesecker, LG AF Rosenberg, MJ Agarwala, R Bouffard, G Davis, J Fiermonte, G Hilliard, MS Koch, T Kalikin, LM Makalowska, I Morton, DH Petty, EM Weber, JL Palmieri, F Kelley, RI Schaffer, AA Biesecker, LG TI Mutant deoxynucleotide carrier is associated with congenital microcephaly SO NATURE GENETICS LA English DT Article ID LINKAGE ANALYSIS; GENE; RECONSTITUTION; TRANSPORT; PROTEINS; MARKERS; AMISH; MAP AB The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death(1). The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC)(2), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. NIH, Intramural Sequencing Ctr, Gaithersburg, MD USA. Univ Bari, Dept Pharmacobiol, Biochem & Mol Biol Lab, Bari, Italy. Logicon ROW Sci Corp, Rockville, MD USA. Konrad Zuse Zentrum Informat Tech, Berlin, Germany. Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. Clin Special Children, Strasburg, PA USA. Marshfield Med Res Fdn, Marshfield, WI 54449 USA. Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA. Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. RP Rosenberg, MJ (reprint author), NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM marjr@nhgri.nih.gov RI Schaffer, Alejandro/F-2902-2012 FU Telethon [E.0958] NR 26 TC 80 Z9 82 U1 0 U2 1 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 SEP PY 2002 VL 32 IS 1 BP 175 EP 179 DI 10.1038/ng948 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 588RR UT WOS:000177714900018 PM 12185364 ER PT J AU Valujskikh, A Lantz, O Celli, S Matzinger, P Heeger, PS AF Valujskikh, A Lantz, O Celli, S Matzinger, P Heeger, PS TI Cross-primed CD8(+) T cells mediate graft rejection via a distinct effector pathway SO NATURE IMMUNOLOGY LA English DT Article ID MURINE CARDIAC ALLOGRAFTS; CLASS-I EXPRESSION; MINOR H-ANTIGENS; ENDOTHELIAL-CELLS; TRANSPLANTATION ANTIGEN; VASCULAR ENDOTHELIUM; EXOGENOUS ANTIGEN; SKIN-GRAFTS; IFN-GAMMA; MHC AB To prevent bystander destruction of healthy host tissues, cytotoxic CD8(+) T lymphocytes are fitted with specific receptors that direct their destructive forces specifically against chosen targets. We show here, however, that anti-H-Y monospecific, H-2(b)-restricted MataHari CD8(+) T cells reject H-2(k) male skin grafts, with which they cannot directly interact. Such rejection is interferon-gamma-dependent and only occurs if the recipient endothelium expresses H-2(b). The findings suggest an alternate indirect effector pathway that requires processing and presentation of the donor H-Y antigen by recipient endothelium and have implications for both transplantation and autoimmune disease. C1 Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, Cleveland, OH 44195 USA. Case Western Reserve Univ, Sch Med, Inst Pathol, Cleveland, OH 44106 USA. Inst Curie, Immunol Lab, F-75005 Paris, France. Inst Curie, Unite 520, INSERM, F-75005 Paris, France. NIAID, Ghost Lab, LCMI, NIH, Bethesda, MD 20892 USA. RP Heeger, PS (reprint author), Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. RI Lantz, Olivier/J-4960-2012; Celli, Susanna/M-7138-2014 OI Lantz, Olivier/0000-0003-3161-7719; FU NIAID NIH HHS [AI-43578-01] NR 55 TC 126 Z9 127 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 SEP PY 2002 VL 3 IS 9 BP 844 EP 851 DI 10.1038/ni831 PG 8 WC Immunology SC Immunology GA 588GZ UT WOS:000177694900013 PM 12172545 ER PT J AU Wu, CY Kirman, JR Rotte, MJ Davey, DF Perfetto, SP Rhee, EG Freidag, BL Hill, BJ Douek, DC Seder, RA AF Wu, CY Kirman, JR Rotte, MJ Davey, DF Perfetto, SP Rhee, EG Freidag, BL Hill, BJ Douek, DC Seder, RA TI Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo SO NATURE IMMUNOLOGY LA English DT Article ID CD4 T-CELLS; IN-VIVO; CYTOKINE EXPRESSION; TRANSCRIPTION FACTOR; GAMMA PRODUCTION; TH1; LYMPHOCYTES; IL-12; ANTIGEN; INTERLEUKIN-12 AB We studied here the long-term maintenance of distinct populations of T helper type 1 (THI)-lineage cells in vivo and found that effector THI cells, defined by their secretion of interferon-gamma (IFN-gamma), are short-lived and do not efficiently develop into long-term memory THI cells. In contrast, a population of activated THI-lineage cells that did not secrete IFN-gamma after primary antigenic stimulation persisted for several months in vivo and developed the capacity to secrete IFN-gamma upon subsequent stimulation. These data suggest that a linear differentiation pathway, as defined by the transition from IFN-gamma-producing to resting memory cells, is relatively limited in vivo and support a revised model for THI memory differentiation. C1 NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. OI Rotte, Masashi/0000-0001-6088-4248 NR 50 TC 219 Z9 234 U1 0 U2 3 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 SEP PY 2002 VL 3 IS 9 BP 852 EP 858 DI 10.1038/ni832 PG 7 WC Immunology SC Immunology GA 588GZ UT WOS:000177694900014 PM 12172546 ER PT J AU Muraro, PA AF Muraro, PA TI An international solution to recruiting physician-scientists? SO NATURE MEDICINE LA English DT Letter C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Muraro, PA (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 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 SEP PY 2002 VL 8 IS 9 BP 902 EP 903 DI 10.1038/nm0902-902 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 589KQ UT WOS:000177757900003 PM 12205433 ER PT J AU Petricoin, EF Zoon, KC Kohn, EC Barrett, JC Liotta, LA AF Petricoin, EF Zoon, KC Kohn, EC Barrett, JC Liotta, LA TI Clinical proteomics: Translating benchside promise into bedside reality SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID TYROSINE KINASE INHIBITOR; IMMOBILIZED PH GRADIENTS; OVARIAN-CANCER; 2-DIMENSIONAL ELECTROPHORESIS; PROTEIN MICROARRAYS; MASS-SPECTROMETER; MYELOID-LEUKEMIA; BREAST-CANCER; END-POINTS; THERAPY AB The ultimate goal of proteomics is to characterize the information flow through protein networks. This information can be a cause, or a consequence, of disease processes. Clinical proteomics is an exciting new subdiscipline of proteomics that involves the application of proteomic technologies at the bedside, and cancer, in particular, is a model disease for studying such applications. Here, we describe proteomic technologies that are being developed to detect cancer earlier, to discover the next generation of targets and imaging biomarkers, and finally to tailor the therapy to the patient. C1 US FDA, FDA NCI Clin Proteom Program, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Off Director, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, FDA NCI Clin Proteom Program,Lab Pathol, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, FDA NCI Clin Proteom Program, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NR 82 TC 366 Z9 391 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2002 VL 1 IS 9 BP 683 EP 695 DI 10.1038/nrd891 PG 13 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 607EK UT WOS:000178778500013 PM 12209149 ER PT J AU Lawson, ND Weinstein, BM AF Lawson, ND Weinstein, BM TI Arteries and veins: Making a difference with zebrafish SO NATURE REVIEWS GENETICS LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; SONIC HEDGEHOG; DANIO-RERIO; CARDIOVASCULAR DEVELOPMENT; VASCULAR MORPHOGENESIS; VENOUS DIFFERENTIATION; ANGIOGENIC GROWTH; GENE-EXPRESSION; SMOOTH-MUSCLE; CHICK-EMBRYO AB Arteries and veins are structurally different and have long been functionally defined by the direction of blood flow that they carry. However, a growing body of evidence indicates that the identity of the endothelial cells that line these vessels is determined in the developing embryo, before circulation begins. Recent work on the zebrafish has led to the identification of signals that are responsible for arterial and venous differentiation of endothelial cells, and highlights the unique benefits of this model organism in the study of vascular development. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHHD, Genet Mol Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 68 TC 150 Z9 154 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD SEP PY 2002 VL 3 IS 9 BP 674 EP 682 DI 10.1038/nrg888 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 589WZ UT WOS:000177785700014 PM 12209142 ER PT J AU Hodes, RJ Hathcock, KS Weng, NP AF Hodes, RJ Hathcock, KS Weng, NP TI Telomeres in T and B cells SO NATURE REVIEWS IMMUNOLOGY LA English DT Editorial Material ID HEMATOPOIETIC STEM-CELLS; GERMINAL CENTER REACTION; REPLICATIVE SENESCENCE; REVERSE-TRANSCRIPTASE; LENGTH REGULATION; DYSKERATOSIS-CONGENITA; LYMPHOCYTE DEVELOPMENT; SHORTENED TELOMERES; HUMAN FIBROBLASTS; MOUSE TELOMERASE C1 NIA, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIA, NIH, Bldg 31,Room 5C35, Bethesda, MD 20892 USA. NR 67 TC 152 Z9 156 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2002 VL 2 IS 9 BP 699 EP 706 DI 10.1038/nri890 PG 8 WC Immunology SC Immunology GA 636DL UT WOS:000180439200027 PM 12209138 ER PT J AU Fortini, ME AF Fortini, ME TI gamma-secretase-mediated proteolysis in cell-surface-receptor signalling SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID AMYLOID PRECURSOR PROTEIN; CAENORHABDITIS-ELEGANS; INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; SUBCELLULAR-LOCALIZATION; DROSOPHILA-MELANOGASTER; NUCLEAR TRANSLOCATION; SEL-12 PRESENILIN; AXONAL-TRANSPORT; ASPARTATE MUTANT AB Many cell-surface receptors transmit signals to the nucleus through complex protein cascades. By contrast, the Notch signalling pathway uses a relatively direct mechanism, in which the intracellular domain of the receptor is liberated by intramembrane cleavage and translocates to the nucleus. This critical cleavage is mediated by the gamma-secretase complex, and new findings reveal that this mechanism is used by various receptors, although many questions remain about the biochemical details. C1 NCI, Div Basic Sci, Frederick, MD 21702 USA. RP Fortini, ME (reprint author), NCI, Div Basic Sci, Bldg 560,Room 22-12,Ft Detrick, Frederick, MD 21702 USA. NR 146 TC 279 Z9 292 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD SEP PY 2002 VL 3 IS 9 BP 673 EP 684 DI 10.1038/nrm910 PG 12 WC Cell Biology SC Cell Biology GA 589XR UT WOS:000177787300016 PM 12209127 ER PT J AU Owens, DF Kriegstein, AR AF Owens, DF Kriegstein, AR TI Is there more to GABA than synaptic inhibition? SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID GAMMA-AMINOBUTYRIC-ACID; SUBUNIT MESSENGER-RNAS; EARLY NEOCORTICAL DEVELOPMENT; DEVELOPING HYPOTHALAMIC NEURONS; CULTURED HIPPOCAMPAL-NEURONS; RECEPTOR-MEDIATED RESPONSES; EARLY POSTNATAL-DEVELOPMENT; CORTICAL PROGENITOR CELLS; CEREBELLAR GRANULE CELLS; RAT SOMATOSENSORY CORTEX AB In the mature brain, GABA (gamma-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal. C1 NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. RP Kriegstein, AR (reprint author), NINDS, Mol Biol Lab, Bldg 36,Room 3C09,36 Convent Dr, Bethesda, MD 20892 USA. NR 179 TC 624 Z9 648 U1 5 U2 46 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 SEP PY 2002 VL 3 IS 9 BP 715 EP 727 DI 10.1038/nrn919 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 589XN UT WOS:000177787000015 PM 12209120 ER PT J AU Lukasik, SM Zhang, LN Corpora, T Tomanicek, S Li, YH Kundu, M Hartman, K Liu, PP Laue, TM Biltonen, RL Speck, NA Bushweller, JH AF Lukasik, SM Zhang, LN Corpora, T Tomanicek, S Li, YH Kundu, M Hartman, K Liu, PP Laue, TM Biltonen, RL Speck, NA Bushweller, JH TI Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYOSIN HEAVY-CHAIN; DEFINITIVE HEMATOPOIESIS; TRANSCRIPTION FACTORS; GENE CBFB-MYH11; FUSION GENE; AML1; DNA; DOMAIN; EXPRESSION AB Chromosomal translocations involving the human CBFB gene, which codes for the non-DNA binding subunit of CBF (CBF), are associated with a large percentage of human leukemias. The translocation inv(16) that disrupts the CBFB gene produces a chimeric protein composed of the heterodimerization domain of CBF fused to the C-terminal coiled-coil domain from smooth muscle myosin heavy chain (CBFbeta-SMMHC). Isothermal titration calorimetry results show that this fusion protein binds the Runt domain from Runx1 (CBF) with higher affinity than the native CBF protein. NMR studies identify interactions in the CBF portion of the molecule, as well as the SMMHC coiled-coil domain. This higher affinity provides an explanation for the dominant negative phenotype associated with a knock-in of the CBFB-MYH11 gene and also helps to provide a rationale for the leukemia-associated dysregulation of hematopoietic development that this protein causes. C1 Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. Dartmouth Coll Sch Med, Dept Biochem, Hanover, NH 03755 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ New Hampshire, Dept Biochem & Mol Biol, Durham, NH 03824 USA. Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. RP Bushweller, JH (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 30 TC 34 Z9 35 U1 0 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD SEP PY 2002 VL 9 IS 9 BP 674 EP 679 DI 10.1038/nsb831 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 587RK UT WOS:000177656200012 PM 12172539 ER PT J AU Betanzos, M Chiang, CS Guy, HR Sukharev, S AF Betanzos, M Chiang, CS Guy, HR Sukharev, S TI A large iris-like expansion of a mechanosensitive channel protein induced by membrane tension SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID ESCHERICHIA-COLI; GATING MECHANISM; SINGLE RESIDUE; ION-CHANNEL; MSCL; MODELS AB MscL, a bacterial mechanosensitive channel of large conductance, is the first structurally characterized mechanosensor protein. Molecular models of its gating mechanisms are tested here. Disulfide crosslinking shows that M1 transmembrane alpha-helices in MscL of resting Escherichia coli are arranged similarly to those in the crystal structure of MscL from Mycobacterium tuberculosis. An expanded conformation was trapped in osmotically shocked cells by the specific bridging between Cys 20 and Cys 36 of adjacent M1 helices. These bridges stabilized the open channel. Disulfide bonds engineered between the M1 and M2 helices of adjacent subunits (Cys 32-Cys 81) do not prevent channel gating. These findings support gating models in which interactions between M1 and M2 of adjacent subunits remain unaltered while their tilts simultaneously increase. The MscL barrel, therefore, undergoes a large concerted iris-like expansion and flattening when perturbed by membrane tension. C1 Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Sukharev, S (reprint author), Univ Maryland, Dept Biol, College Pk, MD 20742 USA. OI Sukharev, Sergei/0000-0002-4807-9665 NR 18 TC 112 Z9 119 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD SEP PY 2002 VL 9 IS 9 BP 704 EP 710 DI 10.1038/nsb828 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 587RK UT WOS:000177656200017 PM 12172538 ER PT J AU Wan, XL Helman, LJ AF Wan, XL Helman, LJ TI Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 s6 kinase pathway SO NEOPLASIA LA English DT Article DE IGF-II; p70 S6K; cisplatin; apoptosis; survival ID MESSENGER-RNA; BINDING-PROTEINS; IGF-II; PHOSPHORYLATION; TRANSLATION; INHIBITION; REGULATORS; P70(S6K); 4E-BP1; CANCER AB Insulin-like growth factor (IGF-II) is overexpressed in a variety of human tumors and has both mitogenic and antiapoptotic activity. Although the mechanisms of IGF-II-induced proliferation have been well studied, the mechanisms underlying its survival signaling have been less well characterized. In this report, we investigated the role of IGF-II on cisplatin-induced apoptosis. We found that IGF-11 overexpression was associated with an increase in p70 ribosomal protein S6 kinase (p70 S6K). Cisplatin treatment of C2C12 mouse myoblasts led to cell death associated with an inhibition of p70 S6K activity. Endogenous or exogenous IGF-11 addition to C2C12 cells caused protection to cisplatin-induced apoptosis. This protection was associated in both cases with an increase in p70 S6K basal activity as well as resistance to cisplatin -induced decreased activity. Blockade of p70 S6K activation by rapamycin abrogated the IGF-II-mediated protection of cells to cisplatin-induced apoptosis. Furthermore, treatment of IGF-II-overexpressing Rh30 and CTR rhabdomyosarcoma cells with rapamycin restored sensitivity to cisplatininduced apoptosis. These data together suggest that IGF-II-associatedprotection to cisplatin-induced apoptosis is mediated through an activation of the p70 S6K pathway. Thus, inhibition of the p70 S6 pathway may enhance chemotherapy-induced apoptosis in the treatment of IGF-II-overexpressing tumors. C1 NCI, Mol Oncol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Helman, LJ (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. NR 42 TC 44 Z9 47 U1 1 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP-OCT PY 2002 VL 4 IS 5 BP 400 EP 408 DI 10.1038/sj.neo.7900242 PG 9 WC Oncology SC Oncology GA 589GB UT WOS:000177749500004 PM 12192598 ER PT J AU Abbott, KC Agodoa, LY AF Abbott, KC Agodoa, LY TI Hospitalizations for valvular heart disease in chronic dialysis patients in the United States SO NEPHRON LA English DT Article DE valvular heart disease; aortic; mitral; hospitalization; complications; dialysis; USRDS; age; African-American; erythropoietin; heart failure ID STAGE RENAL-DISEASE; SECONDARY HYPERPARATHYROIDISM; AORTIC-STENOSIS; HEMODIALYSIS-PATIENTS; PARATHYROID-HORMONE; VALVE REPLACEMENT; CALCIFICATION; MORTALITY; RISK; FAILURE AB Background. Valvular heart disease has not been studied in a national population of end stage renal disease patients. Methods: 327,993 dialysis patients in the United States Renal Data System initiated from 1 January 1992 to 30 June 1997 were analyzed in a historical cohort study of patients hospitalized for valvular heart disease (ICD9 Code 424.x, excluding endocarditis, and 394.x-397.x). Results: 2,778 dialysis patients were hospitalized for VHD (incidence rate, 3.57 per 1,000 person years), and dialysis patients had an age-adjusted incidence ratio for valvular heart disease of 5.06 (95% confidence interval, 4.00-6.42) compared to the general population in 1996. In Cox regression analysis, time to hospitalization for valvular heart disease was associated with earlier year of first dialysis, increased age, congestive heart failure and use of erythropoietin prior to dialysis, while African-American race (AHR 0.62, 0.52-0.74) was associated with decreased risk of hospitalization for valvular heart disease. Patients hospitalized for valvular heart disease had increased mortality compared to all other dialysis patients (adjusted hazard ratio by Cox regression 1.35, 95% Cl, 1.25-1.46). Conclusions: Dialysis patients were at increased risk for hospitalizations for valvular heart disease compared to the general population, which substantially decreased patient survival. The reasons for the decreased risk of African-Americans on chronic dialysis for this complication should be the subject of future trials. Copyright (C) 2002 S. Karger AG, Basel. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDKD, NIH, Bethesda, MD 20892 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 39 TC 10 Z9 10 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-2766 J9 NEPHRON JI Nephron PD SEP PY 2002 VL 92 IS 1 BP 43 EP 50 DI 10.1159/000064476 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 589YE UT WOS:000177788500006 PM 12187083 ER PT J AU Mattson, MP Duan, WZ Chan, SL Cheng, AW Haughey, N Gary, DS Guo, ZH Lee, JW Furukawa, K AF Mattson, MP Duan, WZ Chan, SL Cheng, AW Haughey, N Gary, DS Guo, ZH Lee, JW Furukawa, K TI Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior SO NEUROBIOLOGY OF AGING LA English DT Article; Proceedings Paper CT Meeting on Brain Aging - Identifying Accelerators and Brakes CY NOV, 2001 CL SAN DIEGO, CALIFORNIA DE Alzheimer's disease; apolipoprotein; apoptosis; BDNF; caloric restriction; chaperone; folic acid; Parkinson's disease; telomerase ID AMYLOID BETA-PEPTIDE; PROTECTS HIPPOCAMPAL-NEURONS; CENTRAL-NERVOUS-SYSTEM; ALPHA-SYNUCLEIN GENE; NF-KAPPA-B; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LIPID-PEROXIDATION; PRECURSOR PROTEIN; DENTATE GYRUS AB Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIA, Gerontol Res Ctr 4F01, 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 4F01, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 NR 126 TC 73 Z9 80 U1 2 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP-OCT PY 2002 VL 23 IS 5 BP 695 EP 705 AR PII S0197-4580(02)00025-8 DI 10.1016/S0197-4580(02)00025-8 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 615EA UT WOS:000179231800012 PM 12392775 ER PT J AU Temple, MD Kosik, KS Steward, O AF Temple, MD Kosik, KS Steward, O TI Spatial learning and memory is preserved in rats after early development in a microgravity environment SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE spatial mapping; development; hippocampus; microgravity; rat ID HIPPOCAMPAL; COMPLEXITY; EXPOSURE AB This study evaluated the cognitive mapping abilities of rats that spent part of their early development in a microgravity environment. Litters of male and female Sprague-Dawley rat pups were launched into space aboard the National Aeronautics and Space Administration space shuttle Columbia on postnatal day 8 or 14 and remained in space for 16 days. These animals were designated as FLT groups. Two age-matched control groups remained on Earth: those in standard vivarium housing (VIV) and those in housing identical to that aboard the shuttle (AGC). On return to Earth, animals were tested in three different tasks that measure spatial learning ability, the Morris water maze (MWM), and a modified version of the radial arm maze (RAM). Animals were also tested in an open field apparatus to measure general activity and exploratory activity. Performance and search strategies were evaluated in each of these tasks using an automated tracking system. Despite the dramatic differences in early experience, there were remarkably few differences between the FLT groups and their Earth-bound controls in these tasks. FLT animals learned the MWM and RAM as quickly as did controls. Evaluation of search patterns suggested subtle differences in patterns of exploration and in the strategies used to solve the tasks during the first few days of testing, but these differences normalized rapidly. Together, these data suggest that development in an environment without gravity has minimal long-term impact on spatial learning and memory abilities. Any differences due to development in microgravity are quickly reversed after return to earth normal gravity. (C) 2002 Elsevier Science (USA). C1 Univ Calif Irvine, Coll Med, Reeve Irvine Res Ctr, Dept Anat & Neurobiol, Irvine, CA 92697 USA. NINDS, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Univ Calif Irvine, Coll Med, Reeve Irvine Res Ctr, Dept Neurobiol & Behav, Irvine, CA 92697 USA. Univ Calif Irvine, Coll Med, Reeve Irvine Res Ctr, Irvine, CA 92697 USA. RP Steward, O (reprint author), Univ Calif Irvine, Coll Med, Reeve Irvine Res Ctr, Dept Anat & Neurobiol, 1105 Gillespie Neurosci Res Facil, Irvine, CA 92697 USA. OI Steward, Oswald/0000-0001-7069-8756 NR 13 TC 12 Z9 13 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD SEP PY 2002 VL 78 IS 2 BP 199 EP 216 DI 10.1006/nlme.2001.4049 PG 18 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 598BQ UT WOS:000178255600002 PM 12431413 ER PT J AU Markowska, AL Savonenko, AV AF Markowska, AL Savonenko, AV TI Protective effect of practice on cognition during aging: Implications for predictive characteristics of performance and efficacy of practice SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE longitudinal; previous experience; spatial learning; memory; aging; rats; swim speed ID LONG-TERM POTENTIATION; AGE-RELATED-CHANGES; SPATIAL MEMORY; WATER MAZE; FISCHER-344 RATS; WORKING-MEMORY; SPINE DENSITY; HIPPOCAMPAL; PLASTICITY; DEFICITS AB In the present study, the effect of previous experience on spatial memory, which required the retention of information either over long intervals or within a single session, was longitudinally tested in the water maze in male F-344 rats that were from 6 to 24 months of age. Performance in these tasks was found to be age-dependent (Markowska, 1999). Other behavioral tasks in the Straight alley and with a visible platform in the water maze controlled the noncognitive components of performance. For all tasks, performance was significantly correlated between 12-month-old and 18-month-old rats, indicating that cognitive performance at the early, but not advanced, stage of aging could be predicted from performance at a younger age if the novelty of the first exposure to the task was eliminated. The protective effect of experience was more robust in the reference memory task as compared to the working memory task and was modified by age when training was initiated. Behavior during the probe trials was more sensitive to the effect of aging and more resistant to the beneficial effect of practice as compared to the performance in the platform trials. The speed of swimming of experienced rats progressively decreased with age only when tested in the cognitive tasks but not in the straight alley. This indicates that speed of swimming during cognitive tasks does not exclusively reflect the ability to swim, but might be also affected by the cognitive demands of the task. Protective effect of experience on cognition was Dot modified by restriction in diet. (C) 2002 Elsevier Science (USA). C1 Johns Hopkins Univ, Dept Psychol, Neuromnemon Lab, Baltimore, MD 21218 USA. RP Markowska, AL (reprint author), NIA, Sci Review Off, NIH, Gateway Bldg,Room 2C-212,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG07735, AG15947] NR 46 TC 25 Z9 26 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD SEP PY 2002 VL 78 IS 2 BP 294 EP 320 DI 10.1006/nlme.2002.4064 PG 27 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 598BQ UT WOS:000178255600008 PM 12431419 ER PT J AU Armando, I Terron, JA Falcon-Neri, A Takeshi, I Hauser, W Inagami, T Saavedra, JM AF Armando, I Terron, JA Falcon-Neri, A Takeshi, I Hauser, W Inagami, T Saavedra, JM TI Increased angiotensin II AT(1) receptor expression in paraventricular nucleus and hypothalamic-pituitary-adrenal axis stimulation in AT(2) receptor gene disrupted mice SO NEUROENDOCRINOLOGY LA English DT Article DE renin-angiotensin system; angiotensin receptors; stress; adrenal gland; paraventricular nucleus; corticotropin; adrenal steroids; catecholamines ID TYPE-2 RECEPTOR; QUANTITATIVE AUTORADIOGRAPHY; MESSENGER-RNA; AT1 RECEPTOR; BRAIN; STRESS; SUBTYPES; ANTAGONIST; GLAND; ALDOSTERONE AB Angiotensin II AT(2) receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT(1) receptors. We studied hypothalamic AT(1) receptor binding and mRNA by receptor autoradiography and in situ hybridization, adrenal catecholamines by HPLC, adrenal tyrosine hydroxylase mRNA by in situ hybridization and pituitary and adrenal hormones by RIA in AT(2) receptor-gene disrupted mice and wildtype controls. To confirm the role of adrenal AT(1) receptors, we treated wild-type C57 BL/6J mice with the AT(1) antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT(2) receptor transcription, we found increased AT(1) receptor binding in brain areas involved in the regulation of the hypothalamic-pituitary-adrenal axis, the hypothalamic paraventricular nucleus and the median eminence, and increased adrenal catecholamine synthesis as shown by higher adrenomedullary tyrosine hydroxylase mRNA and higher adrenal dopamine, norepinephrine and epinephrine levels when compared to wild-type mice. In addition, in AT(2) receptor gene-disrupted mice there were higher plasma adrenocorticotropin (ACTH) and corticosterone levels and lower adrenal aldosterone content when compared to wildtype controls. Conversely, AT(1) receptor inhibition in CB57 BL/6J mice reduced adrenal tyrosine hydroxylase mRNA and catecholamine content and increased adrenal aldosterone content. These results can help to explain the enhanced response of AT(2) receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT(1) and AT(2) receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT(1) receptor expression, and suggest that expression of AT(1) receptors can be dependent on AT(2) receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model. Copyright (C) 2002 S. KargerAG, Basel. C1 NIMH, Pharmacol Sect, DIRP, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA. RP Armando, I (reprint author), NIMH, Pharmacol Sect, DIRP, 10 Ctr Dr MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Armandoi@intra.nimb.nih.gov NR 47 TC 26 Z9 26 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD SEP PY 2002 VL 76 IS 3 BP 137 EP 147 DI 10.1159/000064525 PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 596PY UT WOS:000178174300001 PM 12218346 ER PT J AU Pacak, K Tjurmina, O Palkovits, M Goldstein, DS Koch, CA Hoff, T Chrousos, GP AF Pacak, K Tjurmina, O Palkovits, M Goldstein, DS Koch, CA Hoff, T Chrousos, GP TI Chronic hypercortisolemia inhibits dopamine synthesis and turnover in the nucleus accumbens: An in vivo microdialysis study SO NEUROENDOCRINOLOGY LA English DT Article DE prefrontal cortex; catecholamines; nucleus accumbens; adrenal steroids; dihydroxyphenylalanine; dihydroxyphenylacetic acid; homovanillic acid; amino acid decarboxylase ID MEDIAL PREFRONTAL CORTEX; IN-VIVO; CUSHINGS-SYNDROME; FRONTAL-CORTEX; PARAVENTRICULAR NUCLEUS; EXTRACELLULAR DOPAMINE; DEPRESSED-PATIENTS; SUBSTANTIA-NIGRA; MOOD DISORDERS; BRAIN DOPAMINE AB Over 60% of patients with Cushing's syndrome suffer from major depression, which frequently abates after correction of the hypercortisolism. The mesolimbic, and mesocortical dopaminergic (DAergic) systems are thought to participate in psychiatric disorders. In this study, we investigated whether hypercortisolemia affects indices of DAergic activity in the nucleus accumbens (NAG) and the prefrontal cortex (PFC) of freely moving rats. Cortisol (CORT, 25 mg/kg/day) was infused subcutaneously for 7 days via an osmotic minipump. Microdialysate collection (30-min periods, 2 mul/min) began 24 h after probe placement. Concentrations of dihydroxyphenylalanine (DOPA) in interstitial fluid in the nucleus accumbens (NAG) and perifrontal cortex (PFC) were measured before and after local perfusion with NSD-1015, an irreversible inhibitor of L-aromatic amino acid decarboxylase, to assess local dopamine (DA) biosynthesis. The sum of microdialysate DA, dihydroxyphenylacetic acid, and homovanillic acid was used as an index of local DA turnover. DOPA accumulation after NSD-1015 was markedly attenuated in CORT-treated compared with saline-treated animals (5,703 1,849 vs. 10,902 +/- 2,454 pg/ml; p < 0.01). In contrast, the two groups did not differ in DOPA accumulation in the PFC. Values for the turnover index of DA were also significantly lower in CORT-treated animals in the NAG but not in the PFC. The results indicate that CORT inhibits DA synthesis and turnover in the NAG but not in the PFC. Region-specific CORT-induced inhibition of DAergic activity may help to explain depressive symptoms in patients with chronic hypercortisolemia and normalization after medical or surgical correction of hypercortiscilism. Copyright (C) 2002 S. Karger AG, Basel. C1 NICHD, PREB, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Humboldt Univ, Dept Physiol, Berlin, Germany. Semmelweis Univ, Neuromorphol Lab, Budapest, Hungary. RP Pacak, K (reprint author), NICHD, PREB, NIH, Bldg 10,Room 10N236,10 Ctr Dr MSC-1583, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; Palkovits, Miklos/F-2707-2013; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242; Palkovits, Miklos/0000-0003-0578-0387 NR 79 TC 26 Z9 27 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD SEP PY 2002 VL 76 IS 3 BP 148 EP 157 DI 10.1159/000064522 PG 10 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 596PY UT WOS:000178174300002 PM 12218347 ER PT J AU Catani, M Howard, RJ Pajevic, S Jones, DK AF Catani, M Howard, RJ Pajevic, S Jones, DK TI Virtual in vivo interactive dissection of white matter fasciculi in the human brain SO NEUROIMAGE LA English DT Article DE white matter; fasciculi; tractography; diffusion tensor; MRI; VIVID ID DIFFUSION-TENSOR MRI; MAGNETIC-RESONANCE; FIBER ORIENTATION; TRACKING; ANISOTROPY; PATHWAYS; ARCHITECTURE; TISSUES; SCHEMES; IMAGES AB This work reports the use of diffusion tensor magnetic resonance tractography to visualize the three-dimensional (3D) structure of the major white matter fasciculi within living human brain. Specifically, we applied this technique to visualize in vivo (i) the superior longitudinal (arcuate) fasciculus, (ii) the inferior longitudinal fasciculus, (iii) the superior fronto-occipital (subcallosal) fasciculus, (iv) the inferior fronto-occipital fasciculus, (v) the uncinate fasciculus, (vi) the cingulum, (vii) the anterior commissure, (viii) the corpus callosum, (ix) the internal capsule, and (x) the fornix. These fasciculi were first isolated and were then interactively displayed as a 3D-rendered object. The virtual tract maps obtained in vivo using this approach were faithful to the classical descriptions of white matter anatomy that have previously been documented in postmortem studies. Since we have been able to interactively delineate and visualize white matter fasciculi over their entire length in vivo, in a manner that has only previously been possible by histological means, "virtual in vivo interactive dissection" (VIVID) adds a new dimension to anatomical descriptions of the living human brain. (C) 2002 Elsevier Science (USA). C1 Inst Psychiat, Old Age Psychiat Sect, London SE5 8AF, England. Univ Perugia, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Leicester Royal Infirm, Div Med Phys, Leicester LE1 5WW, Leics, England. RP Catani, M (reprint author), Inst Psychiat, Old Age Psychiat Sect, De Crespigny Pk, London SE5 8AF, England. RI Jones, Derek/D-1460-2009; Howard, Robert/E-4890-2010; Catani, Marco/H-7801-2012; OI Catani, Marco/0000-0002-5488-6463; Jones, Derek/0000-0003-4409-8049 NR 63 TC 771 Z9 780 U1 3 U2 40 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 77 EP 94 DI 10.1006/nimg.2002.1136 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000006 PM 12482069 ER PT J AU Dreher, JC Koechlin, E Ali, SO Grafman, J AF Dreher, JC Koechlin, E Ali, SO Grafman, J TI The roles of timing and task order during task switching SO NEUROIMAGE LA English DT Article DE fMRI; task switching; prefrontal cortex ID POSITRON-EMISSION-TOMOGRAPHY; ANTERIOR PREFRONTAL CORTEX; EVENT-RELATED FMRI; WORKING-MEMORY; EXECUTIVE CONTROL; FRONTAL-CORTEX; FUNCTIONAL NEUROANATOMY; TRANSIENT ACTIVATION; HUMAN COGNITION; NEURAL SYSTEMS AB The neural bases of the different processes involved in task switching remain poorly identified. Whether distinct brain regions are involved according to the overall structure of the task sequence and the predictability of task timing during task switching is unknown. To address this question, we used functional magnetic resonance imaging and a 2 x 2 factorial design varying timing (fixed/random) and task order (predictable/unpredictable). We hypothesized that predictable task order should activate brain regions involved in long-term memory retrieval because retrieving which task has to be performed constitutes the essential part of what subjects can do to prepare before stimulus presentation. When examining the "pure" main effects of task order/timing predictability/unpredictability, we found that anticipating task order activated the right hippocampus, the anterior medial prefrontal cortex, and the posterior cingulate cortex, while anticipating task onset timing activated the left middle and superior frontal gyrus. Furthermore, task order unpredictability activated the intraparietal. cortex bilaterally while random relative to fixed timing activated the right cerebellum. Interactions between task order and timing were found in a network, which included the left frontopolar cortex and the lateral prefrontal cortex bilaterally. Specifically, the left frontopolar cortex was more activated when both timing and task order were predictable, while the lateral prefrontal. cortices were more activated when both task order and timing were unpredictable. These results indicate a hierarchic organization of the prefrontal cortex along a posterioanterior axis as the task becomes more endogenously guided. Finally, we found no evidence for specific brain regions involved in task switching because a bilateral prefronto-parietal network, which was activated in task switching relative to performing each task separately, was no longer activated relative to a control condition, which required subjects to maintain two tasks in memory without switching between them. (C) 2002 Elsevier Science (USA). C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Univ Paris 06, INSERM, U483, F-75005 Paris, France. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Dreher, JC (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RI Koechlin, Etienne/E-5061-2016; OI Grafman, Jordan H./0000-0001-8645-4457; Ali, Syed/0000-0003-3131-3299 NR 66 TC 112 Z9 112 U1 5 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 95 EP 109 DI 10.1006/nimg.2002.1169 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000007 PM 12482070 ER PT J AU Gallinat, J Mulert, C Bajbouj, M Herrmann, WM Schunter, J Senkowski, D Moukhtieva, R Kronfeldt, D Winterer, G AF Gallinat, J Mulert, C Bajbouj, M Herrmann, WM Schunter, J Senkowski, D Moukhtieva, R Kronfeldt, D Winterer, G TI Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia SO NEUROIMAGE LA English DT Article DE schizophrenia; attention deficit; anterior cingulate cortex; auditory cortex; event-related potentials; minimum-norm analysis; LORETA; multiple dipole analysis; BESA ID ANTERIOR CINGULATE CORTEX; CEREBRAL-BLOOD-FLOW; TO-NOISE RATIO; EVOKED-POTENTIALS; SELECTIVE ATTENTION; FUNCTIONAL-ANATOMY; MAGNETIC-FIELDS; MIDDLE-LATENCY; RHESUS-MONKEY; HUMAN-BRAIN AB Attention deficits have been consistently described in schizophrenia. Functional neuroimaging and electrophysiological studies have focused on anterior cingulate cortex (ACC) dysfunction as a possible mediator. However, recent basic research has suggested that the effect of attention is also observed as a relative amplification of activity in modality-associated cortical areas. In the present study, the question was addressed whether an amplification deficit is seen in the auditory cortex of schizophrenic patients during an attention-requiring choice reaction task. Twenty-one drug-free schizophrenic patients and 21 age- and sex-matched healthy controls were studied (32-channel EEG). The underlying generators of the event-related N1 component were separated in neuroanatomic space using a minimum-norm (LORETA) and a multiple dipole (BESA) approach. Both methods revealed activation in the primary auditory cortex (peak latency approximate to 100 ms) and in the area of the ACC (peak latency approximate to 130 ms). In addition, the adapted multiple dipole model also showed a temporal-radial source activation in nonprimary auditory areas (peak latency approximate to 140 ms). In schizophrenic patients, significant activation deficits were found in the ACC as well as in the left nonprimary auditory areas that differentially correlated with negative and positive symptoms. The results suggest that (1) the source in the nonprimary auditory cortex is detected only with a multiple dipole approach and (2) that the N1 generators in the ACC and in the nonprimary auditory cortex are dysfunctional in schizophrenia. This would be in line with the notion that attention deficits in schizophrenia involve an extended cortical network. (C) 2002 Elsevier Science (USA). C1 Free Univ Berlin, Dept Psychiat, D-14050 Berlin, Germany. Max Planck Inst Cognit Neurosci, Leipzig, Germany. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Gallinat, J (reprint author), Free Univ Berlin, Dept Psychiat, Eschenallee 3, D-14050 Berlin, Germany. EM juergen.gallinat@medizin-fu-berlin.de RI Mulert, Christoph/F-2576-2012; Senkowski, Daniel/G-6100-2012; Bajbouj, Malek/B-3579-2012 NR 94 TC 97 Z9 97 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 110 EP 127 DI 10.1006/nimg.2002.1213 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000008 PM 12482071 ER PT J AU Toma, K Matsuoka, T Immisch, I Mima, T Waldvogel, D Koshy, B Hanakawa, T Shill, H Hallett, M AF Toma, K Matsuoka, T Immisch, I Mima, T Waldvogel, D Koshy, B Hanakawa, T Shill, H Hallett, M TI Generators of movement-related cortical potentials: fMRI-constrained EEG dipole source analysis SO NEUROIMAGE LA English DT Article ID SUPPLEMENTARY MOTOR AREA; EVENT-RELATED FMRI; FINGER MOVEMENTS; MAGNETIC-FIELDS; HAND MOVEMENTS; VOLUNTARY MOVEMENTS; CINGULATE CORTEX; INVERSE PROBLEM; FUNCTIONAL MRI; MEDIAL WALL AB To clarify the precise location and timing of the motor cortical activation in voluntary movement, dipole source analysis integrating multiple constraints was conducted for the movement-related cortical potential (AMCP). Six healthy subjects performed single self-paced extensions of the right index finger at about 15-s intervals during EEG and event-related fMRI acquisitions. EEG was recorded from 58 scalp electrodes, and fMRI of the entire brain was obtained every 2.6 s. Coordinates of the two methods were coregistered using anatomical landmarks. During dipole source modeling, a realistic three-layer head model was used as a volume conductor. To identify the number of uncorrelated sources in the MRCP, principal component (PC) analysis was performed, which was consistent with the existence of six sources in the left (Lt SM1) and right (Rt SM1) sensorimotor and medial frontocentral (WC) areas. After dipoles were seeded at the activated spots revealed by fMRI, dipole orientations were fixed based on the interpretation of the topography of distribution of the PC. The strength of the six dipoles (three dipoles in Lt SM1, two in Rt SM1, and one in MFC) was then computed over time. Within the bilateral SM1, activation of the precentral gyrus occurs bilaterally with similar strength from -1.2 s, followed by that of the precentral bank from -0.5 s with contralateral preponderance. Subsequently, the postcentral bank becomes active only on the contralateral side at 0.1 s after movement. Activation of the MFC shows timing similar to that of the bilateral precentral gyri. These deduced patterns of activation are consistent with previous studies of electrocorticography in humans. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Toma, K (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. OI Mima, Tatsuya/0000-0001-7787-4855 NR 57 TC 52 Z9 53 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 161 EP 173 DI 10.1006/nimg.2002.1165 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000011 PM 12482074 ER PT J AU Wright, IC Sham, P Murray, RM Weinberger, DR Bullmore, ET AF Wright, IC Sham, P Murray, RM Weinberger, DR Bullmore, ET TI Genetic contributions to regional variability in human brain structure: Methods and preliminary results SO NEUROIMAGE LA English DT Article DE brain anatomy; twins; genetic correlation; matrix; heritability; asymmetry; MRI; path analysis; structural equation modeling ID SULCAL VARIABILITY; MONOZYGOTIC TWINS; PATH-ANALYSIS; SCHIZOPHRENIA; MORPHOLOGY; SIZE; HERITABILITY; SUBDIVISIONS; COVARIANCE; DISCORDANT AB Twin studies provide one approach for investigating and partitioning genetic and environmental contributions to phenotypic variability in human brain structure. Previous twin studies have found that cerebral volume, hemispheric volume, ventricular volume, and cortical gyral pattern variability were heritable. We investigated the contributions of genetic and environmental factors to both global (brain volume and lateral ventricular volume) and regional (parcellated gray matter) variability in brain structure. We examined MR images from 10 pairs of healthy monozygotic and 10 pairs of same-sex dizygotic twins. Regional gray matter volume was estimated by automated image segmentation, transformation to standard space, and parcellation using a digital atlas. Heritability was estimated by path analysis. Estimated heritability for brain volume variability was high (0.66; 95% confidence interval 0.17, 1.0) but the major effects on lateral ventricular volume variability were common and unique environmental factors. We constructed a map of regional brain heritability and found large genetic effects shared in common between several bilateral brain regions, particularly paralimbic structures and temporal-parietal neocortex. We tested three specific hypotheses with regard to the genetic control of brain variability: (i) that the strength of the genetic effect is related to gyral ontogenesis, (ii) that there is greater genetic control of left than of right hemisphere variability, and (iii) that random or fluctuating asymmetry in bilateral structures is not heritable. We found no evidence in support of the first two hypotheses, but our results were consistent with the third hypothesis. Finally, we used principal component (PC) analysis of the genetic correlation matrix, to identify systems of anatomically distributed gray matter regions which shared major genetic effects in common. Frontal and parietal neocortical areas loaded positively on the first PC; some paralimbic and limbic areas loaded negatively. Bilateral insula, some frontal regions, and temporal neocortical regions functionally specialized for audition and language loaded strongly on the second PC. We conclude that large samples are required for powerful investigation of genetic effects in imaging data from twins. However, these preliminary results suggest that genetic effects on structure of the human brain are regionally variable and predominantly symmetric in paralimbic structures and lateral temporal cortex. (C) 2002 Elsevier Science (USA). C1 Kings Coll London, Inst Psychiat, London WC2R 2LS, England. NIMH, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Psychiat, Cambridge, England. RP Wright, IC (reprint author), Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RI Murray, Robin/F-8658-2012; Bullmore, Edward/C-1706-2012 OI Murray, Robin/0000-0003-0829-0519; Bullmore, Edward/0000-0002-8955-8283 NR 56 TC 138 Z9 139 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 256 EP 271 DI 10.1006/nimg.2002.1163 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000019 PM 12482082 ER PT J AU Hariri, AR Tessitore, A Mattay, VS Fera, F Weinberger, DR AF Hariri, AR Tessitore, A Mattay, VS Fera, F Weinberger, DR TI The amygdala response to emotional stimuli: A comparison of faces and scenes SO NEUROIMAGE LA English DT Article ID FACIAL EXPRESSIONS; FEAR; RECOGNITION; ACTIVATION; HIPPOCAMPUS; PERCEPTION; UNPLEASANT; PLEASANT; VALENCE; CROWD AB As a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Hariri, AR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RI Hariri, Ahmad/D-5761-2011 NR 28 TC 393 Z9 405 U1 6 U2 56 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2002 VL 17 IS 1 BP 317 EP 323 DI 10.1006/nimg.2002.1179 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 595HD UT WOS:000178102000023 PM 12482086 ER PT J AU Witkin, JM Gasior, M Schad, C Zapata, A Shippenberg, T Hartman, T Slusher, BS AF Witkin, JM Gasior, M Schad, C Zapata, A Shippenberg, T Hartman, T Slusher, BS TI NAALADase (GCP II) inhibition prevents cocaine-kindled seizures SO NEUROPHARMACOLOGY LA English DT Article DE NAALADase inhibition; NAAG; cocaine; seizure kindling; mice ID METABOTROPIC GLUTAMATE RECEPTORS; RAT-BRAIN; SENSITIZATION; ANTAGONISTS; MICE; NAAG; NEUROPROTECTION; EPILEPSY; RELEASE; CORTEX AB The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutaillate, would produce antiepileptogenic effects against cocaine was tested. Cocame kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg. cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA)produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant Stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDA, Addict Res Ctr, Drug Dev Grp, NIH, Baltimore, MD 21224 USA. NIDA, Addict Res Ctr, Integrat Neurosci Sect, NIH, Baltimore, MD 21224 USA. Guilford Pharmaceut Inc, Baltimore, MD USA. RP Witkin, JM (reprint author), NIDA, Addict Res Ctr, Drug Dev Grp, NIH, POB 5180, Baltimore, MD 21224 USA. NR 38 TC 23 Z9 23 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2002 VL 43 IS 3 BP 348 EP 356 AR PII S0028-3908(02)00124-7 DI 10.1016/S0028-3908(02)00124-7 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 608CE UT WOS:000178826900004 PM 12243764 ER PT J AU Chang, CF Morales, M Chou, J Chen, HL Hoffer, B Wang, Y AF Chang, CF Morales, M Chou, J Chen, HL Hoffer, B Wang, Y TI Bone morphogenetic proteins are involved in fetal kidney tissue transplantation-induced neuroprotection in stroke rats SO NEUROPHARMACOLOGY LA English DT Article DE ischemia; trophic factors; BMP; kidney; noggin ID MIDDLE CEREBRAL-ARTERY; NEUROTROPHIC FACTOR PROTECTS; MICE LACKING GDNF; BRAIN INJURY; ADULT-RATS; OSTEOGENIC PROTEIN-1; TOPICAL APPLICATION; FAMILY MEMBERS; MESSENGER-RNA; ISCHEMIA AB Both bone morphogenetic proteins (BMPs) and glial cell line-derived neurotrophic factor (GDNF) reduce ischemia-induced cerebral injury in rats. Intracerebral transplantation of fetal kidney tissue, which normally expresses BMPs and GDNF during development, reduces ischemic injury in cerebral cortex. In this study, we tested the hypothesis that BMP is involved in this neuroprotective response. Fetal kidney tissue was Cut into small pieces and transplanted into cortical areas acjacent to the right middle cerebral artery (MCA) in adult rats. In situ hybridization of brain indicated that these fetal kidney transplants contained high levels of BMP-7 mRNA three days after grafting. Immunohistochemical analysis of grafted brain showed co-localization of BMP-7 and PAX-2 immunoreactivity in the graft, suggesting that these transplants contained BMP protein. Some animals were grafted with fetal kidney tissue after intraventricular administration (ICV) of the BMP antagonist noggin (1 mug) or after vehicle, followed by MCA ligation for 60 min. Animals receiving fetal kidney tissue transplantation developed significantly less body asymmetry, as compared to stroke animals that either did not receive transplantation or received fetal kidney grafts and noggin pretreatment. Analysis of these brains after triphenyltetrazolium chloride staining showed that fetal kidney tissue transplantation reduced the volume of infarction in the cerebral cortex. Noggin pretreatment reduced the protection induced by fetal kidney grafting, although noggin itself did not cause increase in cerebral infarction. Eight hours after ischemia, brain homogenates were obtained from grafted and control animals to assay caspase-3 enzymatic activity. This analysis demonstrated that fetal kidney grafts significantly reduced ischemia-induced pretreatment. In conclusion, our data suggest caspase-3 activity. Reduction of caspase-3 activity could also be antagonized by noggin that fetal kidney transplantation reduces ischemia/reperfusion-induced cortical infarction and behavioral deficits in adult rats, which are, at least partially, mediated through the effect of BMPs from the transplants. Published by Elsevier Science Ltd. C1 Tri Serv Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. NIDA, IRP, Baltimore, MD 21224 USA. RP Chang, CF (reprint author), Tri Serv Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. NR 36 TC 33 Z9 34 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2002 VL 43 IS 3 BP 418 EP 426 AR PII S0028-3908(02)00092-8 DI 10.1016/S0028-3908(02)00092-8 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 608CE UT WOS:000178826900011 PM 12243771 ER PT J AU Katz, MM Halbreich, UM Bowden, CL Frazer, A Pinder, RM Rush, AJ Wheatley, DP Lebowitz, BD AF Katz, MM Halbreich, UM Bowden, CL Frazer, A Pinder, RM Rush, AJ Wheatley, DP Lebowitz, BD TI Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE antidepressant; clinical trial; antidepressant drug development; clinical methodology; componential behavioral approach; onset of drug action ID DEPRESSIVE SYMPTOMATOLOGY IDS; SELF-REPORT; PLACEBO; IMIPRAMINE; AMITRIPTYLINE; SCALE; PSYCHOPATHOLOGY; METHODOLOGY; OUTPATIENTS; IMPROVEMENT AB Concern about disappointing results from recent multicenter trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) and Food and Drug Administration (FDA) participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Univ Texas, Hlth Sci Ctr, Dept Psychiat, Bethesda, MD 20816 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, Bethesda, MD 20816 USA. SUNY Buffalo, Dept Psychiat, Buffalo, NY 14260 USA. Univ Texas, SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75235 USA. NIMH, Bethesda, MD USA. RP Katz, MM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Psychiat, 6305 Walhonding Rd, Bethesda, MD 20816 USA. EM mkbsk@Worldnet.ATT.net OI Rush, Augustus/0000-0003-2004-2382 NR 49 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2002 VL 27 IS 3 BP 319 EP 328 AR PII S0893-133X(02)00329-9 DI 10.1016/S0893-133X(02)00329-9 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 584UK UT WOS:000177487000001 PM 12225690 ER PT J AU Weinrich, M McCall, D Boser, KI Virata, T AF Weinrich, M McCall, D Boser, KI Virata, T TI Narrative and procedural discourse production by severely aphasic patients SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE apbasia; rebabilitation; computer; augmentative and alternative communication ID SENTENCE PRODUCTION; LANGUAGE PRODUCTION; VERB RETRIEVAL; COMPREHENSION; INFORMATIVENESS; COMMUNICATION; EFFICIENCY; MORPHOLOGY; SYSTEM; ADULTS AB Five chronically aphasic subjects were trained on a computerized iconographic communication system (C-VIC). Their performance in producing single sentences, scripts, and narratives was assessed using both spoken English and C-VIC. The requisite vocabulary necessary and the narrative complexity of the target productions were controlled. Subject performance using C-VIC indicates that the ability to construct discourse at the macrostructural level is largely intact. Despite significant improvements in spoken production after C-VIC training, especially at the single sentence level, the subjects' spoken discourse remains severely impaired by their failures at the microlinguistic level. These results point to the limits of currently available approaches to the remediation of aphasia and suggest avenues for future research. C1 NCMRR, Rockville, MD 20852 USA. NICHHD, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Neurol & Rehabil, Baltimore, MD USA. Johns Hopkins Sch Med, Baltimore, MD USA. Good Samaritan Hosp, Baltimore, MD USA. RP Weinrich, M (reprint author), NCMRR, 6100 Execut Blvd,Room 2A-03, Rockville, MD 20852 USA. EM mw287k@nih.gov FU NIDCD NIH HHS [DCD00856] NR 50 TC 11 Z9 13 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD SEP PY 2002 VL 16 IS 3 BP 249 EP 274 DI 10.1177/154596802401105199 PG 26 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 845II UT WOS:000223235300004 PM 12234088 ER PT J AU Wan, WS DePetrillo, PB AF Wan, WS DePetrillo, PB TI Ritonavir protects hippocampal neurons against oxidative stress-induced apoptosis SO NEUROTOXICOLOGY LA English DT Article DE 4-hydroxynonenal; oxidative stress; inhibitor; ritonavir; hippocampal neuron ID DEATH AB Oxidative stress plays an important role in many neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. 4-Hydroxynonenal (HNE), a lipid-soluble aldehydic product of membrane peroxidation, has been known to decrease neuronal survival by impairing Na+, K+, and -ATPase activity. HNE also increases neuronal vulnerability to excitotoxic injury and disrupts homeostasis by activating proteases which mediate the destruction of cellular protein and structure. The present study demonstrated that the hydrophobic HIV protease inhibitor ritonavir inhibited HNE-mediated apoptosis in hippocampal primary neurons. In neurons exposed to oxidative stress induced by HNE (1 muM), ritonavir at 100 pM increased cell survival and completely abolished the apoptotic effects of HNE (P < 0.01). Ritonavir and its analogues might have useful cytoprotective effects for use in limiting the natural course of tissue injury after conditions where oxidative stress plays a role. Published by Elsevier Science Inc. C1 NIAAA, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Div Intramural Clin & Biochem Res,NIH, Bethesda, MD 20892 USA. RP DePetrillo, PB (reprint author), NIAAA, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Div Intramural Clin & Biochem Res,NIH, 10-3C103,10 Ctr Dr MSC 1256, Bethesda, MD 20892 USA. NR 6 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD SEP PY 2002 VL 23 IS 3 BP 301 EP 306 AR PII S0161-813X(02)00057-8 DI 10.1016/S0161-813X(02)00057-8 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 602UH UT WOS:000178522500004 PM 12387358 ER PT J AU Arnold, EV Citro, ML Saavedra, EA Davies, KM Keefer, LK Hrabie, JA AF Arnold, EV Citro, ML Saavedra, EA Davies, KM Keefer, LK Hrabie, JA TI Mechanistic insight into exclusive nitric oxide recovery from a carbon-bound diazeniumdiolate SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE nitric oxide; diazeniumdiolate; kinetics ID GENERATION AB We report that NaON=N(O)-X-N(O)=NONa (1), where X is para-disubstituted benzene, hydrolyzes to 2 mol of nitric oxide (NO) with concurrent production of 1 mol of p-benzoquinone dioxime at physiological pH. The reaction is acid catalyzed, with a rate that slows as the substrate concentration is increased. The results demonstrate that a carbon-bound diazeniumdiolate can be quantitatively hydrolyzed to produce NO as the only gaseous nitrogen-containing product. The data also suggest that N-N bond cleavage is the rate-determining step in NO release, since C-N cleavage followed by dissociation of O=N-N=O to two NO molecules cannot be operative in this case. The finding that this oxime can absorb NO in organic media and regenerate it quantitatively at physiological pHs extends the potential pharmacological implications of the carbon-bound diazeniumdiolates. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. RP Hrabie, JA (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU PHS HHS [N01-C0-12400] NR 22 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD SEP PY 2002 VL 7 IS 2 BP 103 EP 108 AR PII S1089-8603(02)00101-5 DI 10.1016/S1089-8603(02)00101-5 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 601JW UT WOS:000178430000004 PM 12223179 ER PT J AU Dunbar-Jacob, J Schron, E AF Dunbar-Jacob, J Schron, E TI Ancillary studies in clinical trials SO NURSING RESEARCH LA English DT Article DE ancillary studies; controlled clinical trials AB Background: Randomized clinical trials offer unique opportunities for testing questions of relevance to nursing through the mechanism of ancillary studies. Approach: A review of the strategies to prepare and negotiate an ancillary study through a randomized clinical trial structure is offered. Results: Several steps are required that are unique to the ancillary studies arena. These steps involve (a) accessing the main trial; (b) obtaining approval; (c) funding; and (d) publication. There are hurdles and strategies to address them. Discussion: Collaboration and compromise are the keys to success in the conduct of an ancillary study of scientific merit. The cost-effectiveness, excellent collaboration, and the opportunity to further develop one's research skills and research program in a highly scientific interdisciplinary environment are well worth the effort. C1 Univ Pittsburgh, Sch Nursing, Ctr Res Chron Disorders, Pittsburgh, PA 15261 USA. NHLBI, Clin Trials Sci Grp, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Dunbar-Jacob, J (reprint author), Univ Pittsburgh, Sch Nursing, Ctr Res Chron Disorders, 3500 Victoria Bldg,Room 350, Pittsburgh, PA 15261 USA. FU NINR NIH HHS [5 P30 NR03924] NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 J9 NURS RES JI Nurs. Res. PD SEP-OCT PY 2002 VL 51 IS 5 BP 336 EP 338 DI 10.1097/00006199-200209000-00011 PG 3 WC Nursing SC Nursing GA 597BL UT WOS:000178202100011 PM 12352783 ER PT J AU Teschke, K Olshan, AF Daniels, JL De Roos, AJ Parks, CG Schulz, M Vaughan, TL AF Teschke, K Olshan, AF Daniels, JL De Roos, AJ Parks, CG Schulz, M Vaughan, TL TI Occupational exposure assessment in case-control studies: opportunities for improvement SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Review ID POLYCYCLIC AROMATIC-HYDROCARBONS; REPORTED WORK HISTORY; RETROSPECTIVE ASSESSMENT; INTERRATER AGREEMENT; INDUSTRIAL-HYGIENE; ASBESTOS EXPOSURE; LUNG-CANCER; SUBJECTIVE ASSESSMENT; GENERAL-POPULATION; RESPIRATORY HEALTH AB Community based case-control studies are an efficient means to study disease aetiologies, and may be the only practical means to investigate rare diseases. However, exposure assessment remains problematic. We review the literature on the validity and reliability of common case-control exposure assessment methods: occupational histories, job-exposure matrices (JEMs), self reported exposures, and expert assessments. Given the variable quality of current exposure assessment techniques, we suggest methods to improve assessments, including the incorporation of hygiene measurements: using data from administrative exposure databases; using results of studies identifying determinants of exposure to develop questionnaires and where reasonable given latency and biological half life considerations, directly measuring exposures of study subjects. C1 Univ British Columbia, Dept Hlth Care & Epidemiol, Vancouver, BC V6T 1Z3, Canada. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NCI, Occupat Eidemiol Branch, Rockville, MD USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Teschke, K (reprint author), Univ British Columbia, Dept Hlth Care & Epidemiol, 2222 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada. EM teschke@interchange.ubc.ca NR 129 TC 194 Z9 196 U1 3 U2 15 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2002 VL 59 IS 9 BP 575 EP 593 DI 10.1136/oem.59.9.575 PG 19 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 592VH UT WOS:000177957200002 PM 12205230 ER PT J AU Klein, HG AF Klein, HG TI Blood substitutes: How close to a solution? SO ONCOLOGY-NEW YORK LA English DT Article; Proceedings Paper CT 5th Quality of Life Symposium CY MAR 09-10, 2002 CL PASADENA, CALIFORNIA SP St Mary Med Ctr ID BOVINE HEMOGLOBIN; TRANSFUSIONS; OXYGENATION; EMULSION; EFFICACY; SURGERY; ANEMIA; TRIAL; MODEL AB The term "blood substitute" is commonly misused when "red cell substitute" is meant. The ideal red cell substitute should deliver oxygen (02), require no compatibility testing, cause few side effects, have prolonged storage qualities, persist in the circulation, and be available at reasonable cost. While no drug with all of these qualities is on the near horizon, several early generation red cell substitutes are approaching submission for licensure, at least for limited indications. Hemoglobin-derived red cell substitutes from human bovine and recombinant sources, as well as perfluorochemicals that dissolve O-2, are in different stages of development. While each formulation has its own physical characteristics, biologic activities, and adverse reaction profile, all share one characteristic: The physiologic consequences of delivering O-2 with small molecules is poorly understood, both accounting for problems seen in the clinical trials and providing therapeutic opportunities for the cancer patient. All the red cell substitutes in phase III trials have a life measured in hours and are unlikely to replace transfusions or drugs that stimulate erythropoiesis for chronic anemia, but they may play a role in cancer surgery, or even in radiation therapy, or in the management of cancer-related vascular occlusive syndromes. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Klein, HG (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C-711, Bethesda, MD 20892 USA. NR 20 TC 8 Z9 8 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 SEP PY 2002 VL 16 IS 9 SU 10 BP 147 EP 151 PG 5 WC Oncology SC Oncology GA 603ZL UT WOS:000178591100016 PM 12380965 ER PT J AU Levy-Clarke, GA Buggage, RR Shen, DF Vaughn, LO Chan, CC Davis, JL AF Levy-Clarke, GA Buggage, RR Shen, DF Vaughn, LO Chan, CC Davis, JL TI Human T-cell lymphotropic virus type-1 associated T-cell leukemia/lymphoma masquerading as necrotizing retinal vasculitis SO OPHTHALMOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PRIMARY INTRAOCULAR LYMPHOMA; OCULAR MANIFESTATIONS; HTLV-I; LEUKEMIA; INFECTION; TISSUES; AMERICA; UVEITIS AB Objective. To report a case of adult T-cell leukemia/lymphoma (ATL) presenting as a bilateral retinal vasculitis and diagnosed by molecular detection of a rearrangement in the T-cell receptor (TCR) and the presence of the human T-cell lymphotropic virus type 1 (HTLV-1) pol gene in the malignant lymphoid cells. Design: Case report. Methods: Routine histologic and immunohistochemical analyses were performed on the retinal biopsy specimen before referral to the National Eye Institute. Lymphoid cells associated with granulomatous inflammation infiltrating the retina and surrounding retinal blood vessels were microdissected from the paraffin sections of the retinal biopsy specimen. The polymerase chain reaction (PCR) was performed using primers for the TCR gene and HTLV-1 pol and gag genes. Results: Microscopic examination showed a necrotizing granulomatous retinal vasculitis with a predominant T-cell infiltrate detected by immunohistochemistry. Molecular analysis demonstrated a clonal rearrangement of the TCR and the presence of the HTLV-1 pol gene in the microdissected lymphoid cells diagnostic of ATL. Conclusions: Necrotizing retinitis and retinal vasculitis are rare manifestations of ATL. Human T-cell lymphotropic virus type 1 infection should be considered in the differential diagnosis of patients from endemic areas who have retinal vasculitis at presentation. This case further demonstrates the usefulness of microdissection and PCR for the diagnosis of ocular disease, including HTLV-1 infection. C1 NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. RP Chan, CC (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 22 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD SEP PY 2002 VL 109 IS 9 BP 1717 EP 1722 AR PII S0161-6420(02)01132-6 DI 10.1016/S0161-6420(02)01132-6 PG 6 WC Ophthalmology SC Ophthalmology GA 592CT UT WOS:000177919700033 PM 12208722 ER PT J AU Canto, MT Devesa, SS AF Canto, MT Devesa, SS TI Oral cavity and pharynx cancer incidence rates in the United States, 1975-1998 SO ORAL ONCOLOGY LA English DT Article DE oral; pharynx; cancer; SEER; incidence ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; HEAD; NECK; BLACKS; RISK AB To identify subgroups of oral cavity and pharynx (OCP) cancers that may be etiologically distinct, we evaluated age-adjusted incidence rates by histologic type, anatomical site, race, and sex using cases diagnosed during 1975-1998 in nine US Surveillance, Epidemiology, and End Results (SEER) program registries. Male/female rate ratios were about one for adenocarcinoma (AC), three or more for squamous cell carcinoma (SCC), and undetermined for Kaposi's sarcoma (KS). Among males, black/white rate ratios exceeded two for cancers of the palate, tonsil, oropharynx, and pyriform sinus, and were less than one only for lip and salivery gland cancers. Among females, rates by race were similar for all oral sites except lip, but rates for each of the pharynx subsites were higher among blacks, Findings suggest that OCP cancers may be separated into SCC of the lip, SCC of the oral cavity, SCC of the pharynx, AC and KS. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, DER, Bethesda, MD 20892 USA. Natl Canc Inst, Descript Studies Sect,Biostat Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Canto, MT (reprint author), Natl Inst Dent & Craniofacial Res, DER, 45 Ctr Dr,Bldg 45,Room 4AN24K, Bethesda, MD 20892 USA. NR 35 TC 118 Z9 121 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2002 VL 38 IS 6 BP 610 EP 617 AR PII S1368-8375(01)00109-9 DI 10.1016/S1368-8375(01)00109-9 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 590NV UT WOS:000177829700013 PM 12167440 ER PT J AU Jamison, RN Gracely, RH Raymond, SA Levine, JG Marino, B Herrmann, TJ Daly, M Fram, D Katz, NP AF Jamison, RN Gracely, RH Raymond, SA Levine, JG Marino, B Herrmann, TJ Daly, M Fram, D Katz, NP TI Comparative study of electronic vs. paper VAS ratings: a randomized, crossover trial using healthy volunteers SO PAIN LA English DT Article DE visual analogue scales; palmtop computers; electronic data; verbal rating scale; pain ID VISUAL ANALOG SCALES; PAIN ASSESSMENT; RELIABILITY; VALIDATION; ARTHRITIS; DIARIES; ASTHMA AB The visual analogue scale (VAS) is an established, validated, self-report measure usually consisting of a 10 cm line on paper with verbal anchors labeling the ends. Palmtop computers (PTCs also known as personal digital appliances) have incorporated VAS entry by use of a touch screen. However, the validity and psychophysical properties of the electronic VAS have never been formally compared with the conventional paper VAS. The aim of this Study is to determine the agreement between the electronic (eVAS) and paper (pVAS) modes. Twenty-four healthy volunteers were recruited for this study. Each study participant provided input using both measurement methods by marking the eVAS and pVAS in response to two kinds of stimuli, cognitive and sensory. A verbal rating scale of seven descriptors of intensity represented the cognitive stimuli. Participants were asked to mark the location that best corresponded to the pain intensity described by each word on scales from 'no pain' to 'worst possible pain'. The sensory stimuli used were a set of test weights consisting of plastic containers ranging from 7 to 129 g. The VAS for sensory stimuli ranged from 0 (no weight) to 'reference weight' (the heaviest weight outside the range of test weights). There were two types of input stimuli and two modes for recording responses for a total of four experimental conditions. Two evaluators independently measured and recorded all the pVAS forms to the nearest millimeter. A total of 2016 stimuli were rated. The overall correlation for ratings of both sensory and cognitive stimuli on eVAS and pVAS was r = 0.91. For paired verbal stimuli the correlation was r = 0.97. For paired sensory stimuli the correlation was r = 0.86. The correlation between group eVAS and pVAS ratings to common verbal stimuli was r = 0.99. For common sensory stimuli the group correlation was r = 0.99. The median of correlations comparing eVAS and pVAS ratings was 0.99 for verbal stimuli and 0.98 for sensory stimuli. Multivariate analyses showed equivalent stimuli to be rated much the same whether entered on paper VAS or PTC touch screen VAS (P < 0.0001). Support was found for the validity of the computer version of the VAS scale. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp,Pain Management Ctr, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. PHT Corp, Boston, MA 02129 USA. Lincoln Technol Inc, Belmont, MA 02478 USA. RP Jamison, RN (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Pain Management Ctr, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. OI Jamison, Robert/0000-0003-1768-0906 NR 23 TC 89 Z9 92 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD SEP PY 2002 VL 99 IS 1-2 BP 341 EP 347 AR PII s0304-0959(02)00178-1 DI 10.1016/S0304-3959(02)00178-1 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 601HE UT WOS:000178439800036 PM 12237213 ER PT J AU Ferreira, CAS Barbosa, MC Silveira, TCL Valenzuela, JG Vaz, ID Masuda, A AF Ferreira, CAS Barbosa, MC Silveira, TCL Valenzuela, JG Vaz, ID Masuda, A TI cDNA cloning, expression and characterization of a Boophilus microplus paramyosin SO PARASITOLOGY LA English DT Article DE paramyosin; Boophilus microplus; IgG binding protein; collagen binding protein; tick ID CHINESE SCHISTOSOMA-JAPONICUM; BM86 ANTIGEN PREPARATION; PROTECTIVE IMMUNITY; BINDING-PROTEINS; CAENORHABDITIS-ELEGANS; AMBLYOMMA-AMERICANUM; VACCINE DEVELOPMENT; TICK HEMOLYMPH; FC-RECEPTORS; SEQUENCE AB The tick Boophilus microphis is a I-host tick that causes important losses to bovine herds, and protective antigens are being investigated in order to develop vaccines that avoid the use of acaricides. Paramyosins are multi-functional invertebrate muscle proteins, whose roles may include host immunomodulation, and seem to be a prominent candidate in a schistosomiasis vaccine. We report here the cloning, expression and characterization of a B. nacroplus paramyosin (BmPRM). Sequence analysis of the full length coding sequence cDNA shows high identity to other arthropod paramyosin sequences, and the predicted molecular weight, pI and secondary structure are consistent with a typical paramyosin. Western-blot expression analysis indicates the presence of BmPRM in all tissues and developmental stages tested, but not in saliva. The recombinant protein (rBmPRM) was shown to bind both IgG and collagen. Possible implications of these activities with host evasion mechanisms are discussed. C1 UFRGS, Ctr Biotecnol Estado Rio Grande Sul, BR-91501970 Porto Alegre, RS, Brazil. UFRGS, Dept Biol Mol & Biotecnol, BR-91501970 Porto Alegre, RS, Brazil. UFRGS, Fac Vet, BR-91501970 Porto Alegre, RS, Brazil. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. PUC RS, Dept Ciencias Microbiol, BR-90619900 Porto Alegre, RS, Brazil. UNISINOS, Ctr Ciencias Saude, BR-93022000 Sao Leopoldo, RS, Brazil. RP Masuda, A (reprint author), UFRGS, Ctr Biotecnol Estado Rio Grande Sul, Campus Vale,Caixa Postal 15005,Av Bento Goncalves, BR-91501970 Porto Alegre, RS, Brazil. RI da Silva Vaz Jr, Itabajara/A-5943-2009; Ferreira, Carlos /J-3672-2015 OI da Silva Vaz Jr, Itabajara/0000-0003-0309-9328; Ferreira, Carlos /0000-0002-3727-5097 NR 50 TC 14 Z9 16 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD SEP PY 2002 VL 125 BP 265 EP 274 DI 10.1017/S0031182002002019 PN 3 PG 10 WC Parasitology SC Parasitology GA 600ZC UT WOS:000178420800007 PM 12358423 ER PT J AU Lacbawan, FL Muenke, M AF Lacbawan, FL Muenke, M TI Central nervous system embryogenesis and its failures SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Review DE central nervous system embryogenesis; central nervous system malformations; molecular embryology; holoprosencenphaly ID LEMLI-OPITZ-SYNDROME; DROSOPHILA PATCHED GENE; ONE-EYED PINHEAD; DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; HEDGEHOG PROTEIN BIOGENESIS; CELL-CELL COMMUNICATION; SONIC-HEDGEHOG; FLOOR PLATE; CORTICAL DEVELOPMENT; NEURAL INDUCTION AB The well-orchestrated development of the central nervous system (CNS) requires highly integrated regulatory processes to ensure its precise spatial organization that provides the foundation for proper function. As emphasized in this review, the type, timing, and location of regulatory molecules influence the different stages of development from neuronal induction, regional specification, neuronal specification, and neuronal migration to axonal growth and guidance, neuronal survival, and synapse formation. The known molecular mechanisms are summarized from studies of invertebrates and lower vertebrates, in which we have learned more about the different ligands, receptors, transcription factors, and the intracellular signaling pathways that play specific roles in the different stages of development. Despite known molecular mechanisms of some disturbances, most of the clinical entities that arise from failures of CNS embryogenesis remain unexplained. As more novel genes and their functions are discovered, existing mechanisms will be refined and tenable explanations will be made. With these limitations, two specific clinical entities that have been relatively well studied, holoprosencephaly and neuronal migration defects, are discussed in more detail to illustrate the complexity of regulators, mechanisms that govern well-defined stages of CNS development. C1 NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20010 USA. RP Muenke, M (reprint author), NHGRI, NIH, Med Genet Branch, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 183 TC 7 Z9 7 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD SEP-OCT PY 2002 VL 5 IS 5 BP 425 EP 447 DI 10.1007/s10024-002-0003-3 PG 23 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 602MB UT WOS:000178508100003 PM 12202995 ER PT J AU Mirochnick, M Dorenbaum, A Holland, D Cunningham-Schrader, B Cunningham, C Gelber, R Mofenson, L Culnane, M Connor, J Sullivan, JL AF Mirochnick, M Dorenbaum, A Holland, D Cunningham-Schrader, B Cunningham, C Gelber, R Mofenson, L Culnane, M Connor, J Sullivan, JL TI Concentrations of protease inhibitors in cord blood after in utero exposure SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE human immunodeficiency virus; pregnancy; protease inhibitors; placental transfer ID IMMUNODEFICIENCY-VIRUS TYPE-1; PERINATAL TRANSMISSION; PREGNANT-WOMEN; HUMAN PLASMA; ZIDOVUDINE; NEVIRAPINE; HIV-1; RISK; RNA AB Objective. To determine the concentrations of protease inhibitors in cord blood after prenatal protease inhibitor use by pregnant women. Design. Retrospective analysis of samples collected in a clinical trial. Methods. Protease inhibitor concentrations were measured in cord blood samples collected from women enrolling in the PACTG 316 study who were receiving prenatal protease inhibitor antiretroviral therapy. Results. In cord blood samples from 68 women treated with protease inhibitors during pregnancy, the concentration of these drugs was below the assay lower limit of detection in most samples, including all samples from women receiving indinavir (n = 21) and saquinavir (n = 8), 5 of 6 samples (83%) from women receiving ritonavir and 24 of 38 samples (63%) from women receiving nelfinavir. Conclusions. Low protease inhibitor concentrations in the fetus decrease the likelihood of teratogenic and toxic effects of these drugs but could fail to provide protection from transplacental or intrapartum transmission of HIV-1. C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Chiron Corp, Emeryville, CA 94608 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. SUNY Upstate Med Univ, Syracuse, NY USA. NICHHD, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Worcester, MA USA. RP Mirochnick, M (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 21 TC 51 Z9 54 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 SEP PY 2002 VL 21 IS 9 BP 835 EP 838 DI 10.1097/01.inf.0000027591.04920.c7 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 595DK UT WOS:000178091400007 PM 12352805 ER PT J AU Ment, LR Bada, HS Barnes, P Grant, PE Hirtz, D Papile, LA Pinto-Martin, J Rivkin, M Slovis, TL AF Ment, LR Bada, HS Barnes, P Grant, PE Hirtz, D Papile, LA Pinto-Martin, J Rivkin, M Slovis, TL TI Practice parameter: neuroimaging of the neonate - Report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society SO PEDIATRIC RADIOLOGY LA English DT Article C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY USA. Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. NINDS, Clin Trials Sect, Bethesda, MD 20892 USA. Univ New Mexico, Dept Pediat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI USA. RP Ment, LR (reprint author), Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD SEP PY 2002 VL 32 IS 9 BP 620 EP 620 PG 1 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 594GY UT WOS:000178042400002 ER PT J AU Offit, PA Gerber, MA Hackett, C Marcuse, E Gellin, B AF Offit, PA Gerber, MA Hackett, C Marcuse, E Gellin, B TI Too many vaccinations? Reply SO PEDIATRICS LA English DT Letter ID MULTIPLE-SCLEROSIS; RISK C1 Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Hosp, Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Childrens Hosp, Med Ctr,Sect Infect Dis, Seattle, WA USA. Vanderbilt Univ, Med Ctr, Dept Prevent Med, Nashville, TN USA. RP Offit, PA (reprint author), Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NR 4 TC 0 Z9 0 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 SEP PY 2002 VL 110 IS 3 BP 649 EP 649 PG 1 WC Pediatrics SC Pediatrics GA 589MN UT WOS:000177762900046 ER PT J AU Woodard, GE Zhao, J Rosado, JA Brown, J AF Woodard, GE Zhao, J Rosado, JA Brown, J TI A-type natriuretic peptide receptor in the spontaneously hypertensive rat kidney SO PEPTIDES LA English DT Article DE ANP; NPR-A; hypertension; kidney ID COLLECTING DUCT; GUANYLATE-CYCLASE; BINDING-SITES; CROSS-LINKING; ATRIAL; CELLS; EXPRESSION; SODIUM; IDENTIFICATION; LOCALIZATION AB Renal NPR-A binding characteristics was examined in SHR. Renal ANP binding sites of NPR-A showed a lower maximal binding capacity and higher affinity in SHR than in WKY at all intrarenal sites. Despite the lower B-max in SHR, both ANP(1-28) and ANP(5-25) stimulate similar or greater cGMP production in isolated glomeruli. Studies on guanylate cyclase from glomerular and papillary membranes have reported an increased basal and stimulated guanylate cyclase activity in SHR. The present study provides further evidences for altered NPR-A receptors in SHR kidney, which might act as a negative feedback in response to hypertension. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Cambridge, Physiol Lab, Cambridge CB2 3EG, England. RP Woodard, GE (reprint author), NIDDKD, NIH, Bldg 10,Room 8C-208,10 Ctr Dr,MSC 174, Bethesda, MD 20824 USA. RI Woodard, Geoffrey/A-8608-2009; rosado, juan/H-3488-2015 OI rosado, juan/0000-0002-9749-2325 NR 28 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD SEP PY 2002 VL 23 IS 9 BP 1637 EP 1647 AR PII S0196-9781(02)00106-7 DI 10.1016/S0196-9781(02)00106-7 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 599MR UT WOS:000178339300014 PM 12217425 ER PT J AU Lauritzen, HPMM Reynet, C Schjerling, P Ralston, E Thomas, S Galbo, H Ploug, T AF Lauritzen, HPMM Reynet, C Schjerling, P Ralston, E Thomas, S Galbo, H Ploug, T TI Gene gun bombardment-mediated expression and translocation of EGFP-tagged GLUT4 in skeletal muscle fibres in vivo SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE in vivo transfection; muscle contraction; exercise; insulin stimulation; protein trafficking; GFP ID GREEN-FLUORESCENT PROTEIN; PLASMID DNA; GLUCOSE-TRANSPORT; RAT MUSCLE; REAL-TIME; INSULIN; FIBERS; INJECTION; THERAPY; MICE AB Cellular protein trafficking has been studied to date only in vitro or with techniques that are invasive and have a low time resolution. To establish a gentle method for analysis of glucose transporter-4 (GLUT4) trafficking in vivo in fully differentiated rat skeletal muscle fibres we combined the enhanced green fluorescent protein (EGFP) labelling technique with physical transfection methods in vivo: intramuscular plasmid injection or gene gun bombardment. During optimisation experiments with plasmid coding for the EGFP reporter alone EGFP-positive muscle fibres were counted after collagenase treatment of in vivo transfected flexor digitorum brevis (FDB) muscles. In contrast to gene gun bombardment, intramuscular injection produced EGFP expression in only a few fibres. Regardless of the transfection technique, EGFP expression was higher in muscles from 2-week-old rats than in those from 6-week-old rats and peaked around 1 week after transfection. The gene gun was used subsequently with a plasmid coding for EGFP linked to the C-terminus of GLUT4 (GLUT4-EGFP). Rats were anaesthetised 5 days after transfection and insulin given i.v. with or without accompanying electrical hindleg muscle stimulation. After stimulation, the hindlegs were fixed by perfusion. GLUT4-EGFP-positive FDB fibres were isolated and analysed by confocal microscopy. The intracellular distribution of GLUT4-EGFP under basal conditions as well as after translocation to the plasma membrane in response to insulin, contractions, or both, was in accordance with previous studies of endogenous GLUT4. Finally, GLUT4-EGFP trafficking in quadriceps muscle in vivo was studied using time-lapse microscopy analysis in anaesthetised mice and the first detailed timelapse recordings of GLUT4-EGFP translocation in fully differentiated skeletal muscle in vivo were obtained. C1 Univ Copenhagen, Copenhagen Muscle Res Ctr, Panum Inst, Dept Med Physiol 12 4, DK-2200 Copenhagen N, Denmark. Novo Nordisk AS, DK-2880 Bagsvaerd, Denmark. Rigshosp, Copenhagen Muscle Res Ctr, Dept Mol Muscle Biol, Sect 9312, DK-2100 Copenhagen, Denmark. NIAMS, Light Imaging Sect, NIH, Bethesda, MD 20892 USA. Carlsberg Lab, Dept Physiol, DK-2500 Valby, Denmark. RP Lauritzen, HPMM (reprint author), Univ Copenhagen, Copenhagen Muscle Res Ctr, Panum Inst, Dept Med Physiol 12 4, Blegdamsvej 3C, DK-2200 Copenhagen N, Denmark. OI Schjerling, Peter/0000-0001-7138-3211 NR 47 TC 19 Z9 21 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD SEP PY 2002 VL 444 IS 6 BP 710 EP 721 DI 10.1007/s00424-002-0862-5 PG 12 WC Physiology SC Physiology GA 606UK UT WOS:000178752200004 PM 12355170 ER PT J AU Lebeau, C Hanaoka, K Moore-Hoon, ML Guggino, WB Beauwens, R Devuyst, O AF Lebeau, C Hanaoka, K Moore-Hoon, ML Guggino, WB Beauwens, R Devuyst, O TI Basolateral chloride transporters in autosomal dominant polycystic kidney disease SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE ADPKD; anion exchanger; CFTR; chloride channel; renal cyst; sodium-potassium-chloride cotransporter ID TRANSMEMBRANE CONDUCTANCE REGULATOR; K-CL COTRANSPORTER; MEDULLARY COLLECTING DUCT; CYSTIC-FIBROSIS; MOLECULAR-CLONING; NA+-K+-2CL(-) COTRANSPORTER; NA-K-2CL COTRANSPORTER; ION-TRANSPORT; CELLS; EXPRESSION AB Transepithelial Cl- secretion mediated by apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels plays a key role in cyst fluid accumulation in autosomal dominant polycystic kidney disease (ADPKD). The molecular identity of the basolateral transporter(s) responsible for Cl- entry in ADPKD cells is unknown, although pharmacological studies suggest that a bumetanide-sensitive Na+-K+-2Cl(-) cotransporter (NKCC/BSC) is involved. We investigated the expression of NKCC1, CFTR and anion exchanger type I (AE1) in ADPKD kidneys and cultured ADPKD cells. Immunoblotting and immunoprecipitation detected NKCC1 at similar to170 kDa in ADPKD cells and kidney extracts. Immunostaining located NKCC1 in one-third of ADPKD cysts, with a pattern of basolateral reactivity. Staining of serial sections showed that cysts positive for NKCC1 also stained for CFTR. Additional studies demonstrated that AE1 is expressed in ADPKD kidneys, and is located at the basolateral pole of CFTR-positive ADPKD cysts that do not express NKCC1. RT-PCR and sequence analyses confirmed the selective expression of NKCC1 or AEI in cultured ADPKD cells that also express CFTR. The fact that most CFTR-positive ADPKD cysts also express NKCC1 suggests that transepithelial Cl- secretion in ADPKD involves molecular mechanisms similar to secretory epithelia. AE1 might be an alternative basolateral pathway for Cl- in a minority of cysts. C1 Univ Catholique Louvain, Div Nephrol, B-1200 Brussels, Belgium. Free Univ Brussels, Dept Phytopathol, Brussels, Belgium. Johns Hopkins Univ, Sch Med, Dept Physiol, Bethesda, MD USA. NIDCD, NIH, Bethesda, MD USA. RP Devuyst, O (reprint author), Univ Catholique Louvain, Div Nephrol, 10 Ave Hippocrate, B-1200 Brussels, Belgium. FU NICHD NIH HHS [N01 HD 73263]; NIDDK NIH HHS [DK 32793] NR 40 TC 17 Z9 18 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD SEP PY 2002 VL 444 IS 6 BP 722 EP 731 DI 10.1007/s00424-002-0880-3 PG 10 WC Physiology SC Physiology GA 606UK UT WOS:000178752200005 PM 12355171 ER PT J AU Liang, S Van Derveer, D Qian, SY Sturgeon, B Bu, XR AF Liang, S Van Derveer, D Qian, SY Sturgeon, B Bu, XR TI A chiral salen vanadyl complex with two significantly different configurations in solid state: synthesis, characterization, and molecular structure SO POLYHEDRON LA English DT Article DE vanadyl complexes; Schiff bases; chiral complexes; EPR; X-ray structures ID ASYMMETRIC OXIDATION; HALOPEROXIDASES; LIGANDS; CRYSTAL AB A chiral vanadyl complex prepared from a chiral Salen ligand possessing branched bulky groups at 3- and 5-positions showed two independent molecules in solid state in which the core conformations are significantly different. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Clark Atlanta Univ, Dept Chem, Atlanta, GA 30314 USA. Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA. NIEHS, Free Rad Metabolite Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Bu, XR (reprint author), Clark Atlanta Univ, Dept Chem, Atlanta, GA 30314 USA. NR 18 TC 18 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-5387 J9 POLYHEDRON JI Polyhedron PD SEP 1 PY 2002 VL 21 IS 20 BP 2021 EP 2025 AR PII S0277-5387(02)01134-8 DI 10.1016/S0277-5387(02)01134-8 PG 5 WC Chemistry, Inorganic & Nuclear; Crystallography SC Chemistry; Crystallography GA 598GZ UT WOS:000178269000008 ER PT J AU Lebowitz, J Lewis, MS Schuck, P AF Lebowitz, J Lewis, MS Schuck, P TI Modern analytical ultracentrifugation in protein science: A tutorial review SO PROTEIN SCIENCE LA English DT Review DE sedimentation velocity; sedimentation equilibrium; protein interactions; reversible association; hydrodynamic shape; membrane proteins ID SEDIMENTATION-VELOCITY DATA; MEMBRANE-PROTEINS; MOLECULAR-WEIGHT; SELF-ASSOCIATION; LAMM EQUATION; COEFFICIENT DISTRIBUTION; MACROMOLECULAR SYSTEMS; REVERSE-TRANSCRIPTASE; BOUNDARY ANALYSIS; DNA INTERACTIONS AB Analytical ultracentrifugation (AU) is reemerging as a versatile tool for the study of proteins. Monitoring the sedimentation of macromolecules in the centrifugal field allows their hydrodynamic and thermodynamic characterization in solution, without interaction with any matrix or surface. The combination of new instrumentation and powerful computational software for data analysis has led to major advances in the characterization of proteins and protein complexes. The pace of new advancements makes it difficult for protein scientists to gain sufficient expertise to apply modern AU to their research problems. To address this problem, this review builds from the basic concepts to advanced approaches for the characterization of protein systems, and key computational and internet resources are provided. We will first explore the characterization of proteins by sedimentation velocity (SV). Determination of sedimentation coefficients allows for the modeling of the hydrodynamic shape of proteins and protein complexes. The computational treatment of SV data to resolve sedimenting components has been achieved. Hence, SV can be very useful in the identification of the oligomeric state and the stoichiometry of heterogeneous interactions. The second major part of the review covers sedimentation equilibrium (SE) of proteins, including membrane proteins and glycoproteins. This is the method of choice for molar mass determinations and the study of self-association and heterogeneous interactions, such as protein-protein, protein-nucleic acid, and protein-small molecule binding. C1 NIH, Mol Interact Resource, Div Bioengn & Phys Sci, ORS,OD, Bethesda, MD 20892 USA. RP Lebowitz, J (reprint author), NIH, Mol Interact Resource, Div Bioengn & Phys Sci, ORS,OD, 13 South Dr,Bldg 13,Rm 3N17, Bethesda, MD 20892 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 80 TC 449 Z9 460 U1 10 U2 82 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2002 VL 11 IS 9 BP 2067 EP 2079 DI 10.1110/ps.0207702 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585ZX UT WOS:000177558400001 PM 12192063 ER PT J AU Rocha, BA Mead, AN Kosofsky, BE AF Rocha, BA Mead, AN Kosofsky, BE TI Increased vulnerability to self-administer cocaine in mice prenatally exposed to cocaine SO PSYCHOPHARMACOLOGY LA English DT Article DE prenatal cocaine; mice; cocaine; self-administration ID SOCIAL STRESS; ADULT-RATS; REINFORCING PROPERTIES; ACCUMBENS DOPAMINE; NMDA RECEPTORS; IN-UTERO; ACQUISITION; NEURONS; BRAIN; AMPHETAMINE AB Rationale: At least 40,000 infants born each year in the U.S. are estimated to have been exposed to crack cocaine and, therefore, may be at risk for increased vulnerability to cocaine addiction. Objectives: The present study tested the hypothesis that prenatal exposure to cocaine significantly increased subsequent cocaine-taking behavior in mice. Methods: Swiss Webster male mice that had been exposed to cocaine in utero were tested at 5 months of age in the cocaine self-administration paradigm. They were the offspring of dams that received one of the following treatments during gestation days 817: cocaine (40 mg/kg or 20 mg/kg per day; COC40 and COC20 mice, respectively), saline with access to food ad libitum (SAL mice), or saline with access to food restricted to that of the COC40 dams (i.e., pair-fed; SPF40 mice). Mice were initially trained to lever press for a condensed-in ilk solution, were implanted with an indwelling, intravenous (i.v.) catheter and, subsequently, allowed to self-administer cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg per injection) under a fixed ratio (FR) 1 schedule of reinforcement. Results: Latency for acquisition of food-reinforced responding appeared to be independent of prenatal treatment, as was acquisition of cocaine self-administration, which was found to be dose dependent. Both COC40 and SAL mice reached cocaine self-administration criteria at 1.0 mg/kg or 2.0 mg/kg per injection doses, while neither group did so at lower doses. It was also observed that, at each of the doses tested, a higher number of COC40 mice reached criteria for acquisition. A logistic regression analysis confirmed that the likelihood for acquiring cocaine self-administration was positively correlated to prenatal exposure to cocaine and the dose of cocaine tested. Conclusions: These data provide evidence, for the first time, that prenatal exposure to higher doses of cocaine increase the probability of acquiring cocaine self-administration at moderate doses during adulthood and modulate vulnerability to cocaine-taking behavior in mice. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. Univ Maryland, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. MGH E, Lab Mol & Dev Neurosci, Charlestown, MA 02129 USA. Univ Sussex, Sch Biol Sci, Expt Psychol Lab, Brighton BN1 9QG, E Sussex, England. RP Rocha, BA (reprint author), Merck Res Labs, Dept Pharmacol, R80Y-140,POB 2000, Rahway, NJ 07065 USA. FU NIDA NIH HHS [DA-00354, DA-08648, DA-11652] NR 57 TC 37 Z9 38 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2002 VL 163 IS 2 BP 221 EP 229 DI 10.1007/s00213-002-1140-0 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 598EP UT WOS:000178262700011 PM 12202969 ER PT J AU Gilliss, B Malanga, CJ Pieper, JO Carlezon, WA AF Gilliss, B Malanga, CJ Pieper, JO Carlezon, WA TI Cocaine and SKF-82958 potentiate brain stimulation reward in Swiss-Webster mice SO PSYCHOPHARMACOLOGY LA English DT Article DE brain stimulation reward; intracranial self-stimulation; cocaine; D-1 agonist; addiction; mice ID DOPAMINE-RECEPTOR AGONISTS; VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; SEEKING BEHAVIOR; SELF-STIMULATION; CHRONIC AMPHETAMINE; SQUIRREL-MONKEYS; RHESUS-MONKEYS; WITHDRAWAL; RATS AB Rationale: The dopamine D-1-like receptor agonist SKF-82958 reportedly blocks reinstatement of cocaine-seeking behavior in rats and non-human primates. It is not known if SKF-82958 reduces drug-seeking behaviors in animals exposed previously to cocaine by causing reward-like effects or withdrawal-like aversive effects. Objectives: Intracranial self-stimulation (ICSS) studies were conducted to determine if SKF-82958 has reward-like or withdrawal-like effects in mice exposed previously to cocaine, or under the influence of cocaine at the time of testing. Methods: Swiss-Webster mice with lateral hypothalamic stimulating electrodes were trained to self-administer rewarding brain stimulation. The mice were tested in a "curve-shift" variant of the ICSS procedure after intraperitoneal administration of cocaine alone (2.5-20 mg/kg), SKF-82958 alone (0.03-0.3 mg/ kg), or a mixture of both drugs (SKF 0.03 mg/kg+2.5 or 5.0 mg/kg cocaine). Each treatment was given twice. Results: Cocaine and SKF-82958 each caused dose-dependent decreases in brain stimulation reward thresholds that were largest immediately after administration. A dose of SKF-82958 with no reward-related effects of its own potentiated the reward-related effects of low doses of cocaine. Repeated administration did not cause progressive changes in the ability of any treatment to decrease thresholds. Conclusions: Cocaine and SKF-82958 each potentiate the rewarding effects of lateral hypothalamic brain stimulation in Swiss-Webster mice, implying that these drugs have rewarding effects of their own. The reward-facilitating effects of low doses of cocaine and SKF-82958 are additive (or synergistic). These data suggest that SKF-82958 may decrease cocaine-seeking behavior by mechanisms related to reward rather than aversion. C1 Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. McLean Hosp, Belmont, MA 02478 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Carlezon, WA (reprint author), Harvard Univ, Sch Med, Dept Psychiat, MRC 217,115 Mill St, Belmont, MA 02478 USA. OI Malanga, C.J./0000-0003-4808-3995 FU NIDA NIH HHS [DA14789]; NIMH NIH HHS [MH63266] NR 55 TC 30 Z9 30 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2002 VL 163 IS 2 BP 238 EP 248 DI 10.1007/s00213-002-1153-8 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 598EP UT WOS:000178262700013 PM 12202971 ER PT J AU Keil, A Bradley, MM Hauk, O Rockstroh, B Elbert, T Lang, PJ AF Keil, A Bradley, MM Hauk, O Rockstroh, B Elbert, T Lang, PJ TI Large-scale neural correlates of affective picture processing SO PSYCHOPHYSIOLOGY LA English DT Article ID EVENT-RELATED POTENTIALS; BRAIN POTENTIALS; ELECTROMAGNETIC TOMOGRAPHY; BIOELECTRICAL ECHOES; ELECTRICAL-ACTIVITY; EMOTIONAL STIMULI; STARTLE REFLEX; HEART-RATE; AROUSAL; DISCRIMINATION AB Hemodynamic and electrophysiological studies indicate differential brain response to emotionally arousing, compared to neutral, pictures. The time course and source distribution of electrocortical potentials in response to emotional stimuli, using a high-density electrode (129-sensor) array were examined here. Event-related potentials (ERPs) were recorded while participants viewed pleasant, neutral, and unpleasant pictures. ERP voltages were examined in six time intervals, roughly corresponding to P1, N1, early P3, late P3 and a slow wave window. Differential activity was found for emotional, compared to neutral, pictures at both of the P3 intervals, as well as enhancement of later posterior positivity. Source space projection was performed using a minimum norm procedure that estimates the source currents generating the extracranially measured electrical gradient. Sources of slow wave modulation were located in occipital and posterior parietal cortex, with a right-hemi spheric dominance. C1 Univ Konstanz, Dept Psychol, D-78457 Constance, Germany. Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL USA. MRC, Cognit & Brain Sci Unit, Cambridge, England. RP Keil, A (reprint author), Univ Konstanz, Dept Psychol, POB D25, D-78457 Constance, Germany. RI Elbert, Thomas/C-8556-2009; Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 NR 45 TC 345 Z9 354 U1 4 U2 37 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2002 VL 39 IS 5 BP 641 EP 649 DI 10.1017/S0048577202394162 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 592LN UT WOS:000177939300012 PM 12236331 ER PT J AU Ho, VB Allen, SF Hood, MN Choyke, PL AF Ho, VB Allen, SF Hood, MN Choyke, PL TI Renal masses: Quantitative assessment of enhancement with dynamic MR imaging SO RADIOLOGY LA English DT Article DE kidney, cysts; kidney, MR; kidney neoplasms; magnetic resonance (MR), contrast enhancement ID LESION CHARACTERIZATION; CT; ECHO AB Purpose: To establish a quantitative magnetic resonance (MR) imaging contrast enhancement criterion for distinguishing cysts from solid renal lesions. Materials and methods: Regions of interest were measured in 74 patients with renal lesions evaluated by means of dynamic contrast material-enhanced MR imaging with serial breath-hold spoiled gradient-echo acquisitions. Sensitivity for, renal tumors and specificity for renal cysts were established by using percentage of enhancement thresholds that varied between 5% and 35%. Results: The mean percentage of enhancement at MR imaging for the 50. renal cysts was less than 5%; for the 50 renal tumors, it was 97% or higher. With use of a threshold percentage of enhancement of 15% and results obtained between 2 and 4 minutes after administration of contrast material, all malignancies (sensitivity for tumor, 100%) were diagnosed, and there were 6% or fewer false-positive tumor diagnoses. Lower thresholds resulted in unacceptably high false-positive rates (ie, cysts that appeared to enhance-pseudoenhancement), whereas higher threshold values (>20%) resulted in an unacceptably lower sensitivity for tumors. Conclusion: The optimal percentage of enhancement threshold for distinguishing cysts from malignancies with the imaging technique prescribed was 15%, and the optimal timing for measurement was 2-4 minutes after administration of contrast material. C1 Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, MR Res Div, Bethesda, MD 20814 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Ho, VB (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, MR Res Div, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 15 TC 100 Z9 103 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2002 VL 224 IS 3 BP 695 EP 700 DI 10.1148/radiol.2243011048 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 587BY UT WOS:000177621700011 PM 12202701 ER PT J AU Shelby, MD AF Shelby, MD TI Introduction NTP center for the evaluation of risks to human reproduction phthalates expert panel reports SO REPRODUCTIVE TOXICOLOGY LA English DT Editorial Material C1 NIEHS, EC 32, CERHR, Res Triangle Pk, NC 27709 USA. RP Shelby, MD (reprint author), NIEHS, EC 32, CERHR, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [ES-85425] NR 0 TC 3 Z9 4 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 451 EP 451 AR PII S0890-6238(02)00045-X DI 10.1016/S0890-6238(02)00045-X PG 1 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200001 PM 12406491 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of butyl benzyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE butyl benzyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID ESTROGEN-RECEPTOR; IN-VITRO; RECOMBINANT YEAST; RATS; ESTERS; SPERM; EMBRYOLETHALITY; ABSORPTION; CHEMICALS; DIESTERS C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [R29 ES007981-05, ES-85425] NR 65 TC 61 Z9 69 U1 3 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 453 EP 487 AR PII S0890-6238(02)00029-1 DI 10.1016/S0890-6238(02)00029-1 PG 35 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200002 PM 12406492 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-butyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE di-n-butyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID DI(N-BUTYL) PHTHALATE; ESTROGEN-RECEPTOR; IN-VITRO; MONO(2-ETHYLHEXYL) PHTHALATE; DI(2-ETHYLHEXYL) PHTHALATE; ENVIRONMENTAL CHEMICALS; QUANTITATIVE-EVALUATION; ALTERNATIVE MECHANISMS; RECOMBINANT YEAST; LATE-GESTATION C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Calif Environm Prot Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES-85425, R29 ES007981-05] NR 75 TC 88 Z9 112 U1 2 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 489 EP 527 AR PII S0890-6238(02)00033-3 DI 10.1016/S0890-6238(02)00033-3 PG 39 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200003 PM 12406493 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE di(2-ethylhexyl) phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID POLYVINYL-CHLORIDE BAGS; HEPATIC PEROXISOME PROLIFERATION; DIFFERENTIAL PRENATAL TOXICITY; RAT EMBRYONIC-DEVELOPMENT; ACTIVATED RECEPTOR-ALPHA; SUBCHRONIC ORAL TOXICITY; CELL FUNCTION-INVITRO; FISCHER 344 RATS; DI-(2-ETHYLHEXYL) PHTHALATE; DI-2-ETHYLHEXYL PHTHALATE C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. FU NIEHS NIH HHS [ES-85425, R29 ES007981-05] NR 248 TC 191 Z9 208 U1 6 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 529 EP 653 AR PII S0890-6238(02)00032-1 DI 10.1016/S0890-6238(02)00032-1 PG 125 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200004 PM 12406494 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Fuastman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Fuastman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-isodecyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE di-isodecyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID ESTROGEN-RECEPTOR; IN-VITRO; RECOMBINANT YEAST; ESTERS; CHEMICALS; ABSORPTION; RATS; PLASTICIZERS; XENOBIOTICS; DIESTERS C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES-85425] NR 43 TC 22 Z9 24 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 655 EP 678 AR PII S0890-6238(02)00068-0 DI 10.1016/S0890-6238(02)00068-0 PG 24 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200005 PM 12406495 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-isononyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE di-isononyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID DIFFERENTIAL PRENATAL TOXICITY; ESTROGEN-RECEPTOR; IN-VITRO; RECOMBINANT YEAST; RATS; ESTERS; PLASTICIZERS; ABSORPTION; CHEMICALS; RODENTS C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES-85425] NR 50 TC 50 Z9 53 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 679 EP 708 AR PII S0890-6238(02)00034-5 DI 10.1016/S0890-6238(02)00034-5 PG 30 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200006 PM 12406496 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-hexyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE di-n-hexyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID ESTROGEN-RECEPTOR; IN-VITRO; ACID ESTERS; CHEMICALS; ABSORPTION; MICE; RATS; DI(2-ETHYLHEXYL)PHTHALATE; DIESTERS; MOUSE C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES-85425] NR 32 TC 25 Z9 28 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 709 EP 719 AR PII S0890-6238(02)00030-8 DI 10.1016/S0890-6238(02)00030-8 PG 11 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200007 PM 12406497 ER PT J AU Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T AF Kavlock, R Boekelheide, K Chapin, R Cunningham, M Faustman, E Foster, P Golub, M Henderson, R Hinberg, I Little, R Seed, J Shea, K Tabacova, S Tyl, R Williams, P Zacharewski, T TI NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-octyl phthalate SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE di-n-octyl phthalate; reproductive toxicity; developmental toxicity; review; exposure; systemic toxicity; toxicokinetics; risk evaluation ID ESTROGEN-RECEPTOR; IN-VITRO; DI(2-ETHYLHEXYL) PHTHALATE; RECOMBINANT YEAST; ACID ESTERS; RAT; CHEMICALS; HYDROLYSIS; DIESTERS; CULTURES C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Brown Univ, Providence, RI 02912 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC USA. Calif Environm Protect Agcy, Sacramento, CA USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. US EPA, Off Tox Subst, Washington, DC 20460 USA. Duke Univ, Durham, NC USA. US FDA, Rockville, MD 20857 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Harvard Univ, Boston, MA 02115 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Kavlock, R (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. OI Chapin, Robert/0000-0002-5997-1261 FU NIEHS NIH HHS [ES-85425] NR 36 TC 49 Z9 54 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP-OCT PY 2002 VL 16 IS 5 BP 721 EP 734 AR PII S0890-6238(02)00031-X DI 10.1016/S0890-6238(02)00031-X PG 14 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 615UL UT WOS:000179265200008 PM 12406498 ER PT J AU Takeda, H Spatz, M Ruetzler, C McCarron, R Becker, K Hallenbeck, J AF Takeda, H Spatz, M Ruetzler, C McCarron, R Becker, K Hallenbeck, J TI Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats SO STROKE LA English DT Article DE E selectin; endothelium; immune tolerance; risk factors; rats ID ANTIENDOTHELIAL CELL ANTIBODIES; LEUKOCYTE ADHESION MOLECULE-1; ACUTE CORONARY SYNDROMES; FOCAL CEREBRAL-ISCHEMIA; GROWTH-FACTOR-BETA; ENDOTHELIAL-CELL; ORAL TOLERANCE; AUTOIMMUNE-DISEASES; T-CELLS; ACTIVATION AB Background and Purpose-Inflammatory and immune mechanisms can precipitate cerebrovascular thrombosis and hemorrhage Immunologic tolerance can be induced to a specific antigen by intranasal instillation of that antigen Lymphocytes tolerized in this way provide local immunosuppression on restimulation with the same antigen This study tests whether tolerization of lymphocytes to E selectin can suppress local vessel activation and prevent stroke Methods-Spontaneously hypertensive genetically stroke prone rats (n = 113) were distributed among the following studies comparison of ischemic infarcts/intraparenchymal hemorrhages after single or repetitive tolerization schedules with ovalbumin E selectin or PBS comparison of E selectin tolerization- and PBS tolerization-induced suppression of delayed type hypersensitivity in animals subsequently sensitized to E selectin and comparison of PBS- ovalbumin- and E selectin-tolerized groups (after intravenous lipopolysaccharide to activate vessels) regarding transforming growth factor beta1-positive splenocyte counts plasma interferon gamma levels anti human E selectin antibodies endothelial intercellular adhesion molecule 1 and anti-endothelial cell antibodies Results-Nasal instillation of E selectin which is specifically expressed on activated endothelium potently inhibited the development of ischemic and hemorrhagic strokes in spontaneously hypertensive stroke prone rats with untreated hypertension Repeated schedules of tolerization were required to maintain the resistance to stroke Suppression of delayed type hypersensitivity to E selectin and increased numbers of transforming growth factor beta1-positive splenocytes showed that intranasal exposure to E selectin induced immunologic tolerance E selectin tolerization also reduced endothelial activation and immune responses after intravenous lipopolysaccharide as shown by marked suppression of intercellular adhesion molecule 1 expression anti-endothelial cell antibodies on luminal endothelium and plasma interferon gamma levels compared with the control condition Conclusions-The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. USN, Resuscitat Med Dept, Med Res Ctr, Silver Spring, MD USA. Univ Washington, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. RP Hallenbeck, J (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Room 4A03,36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 39 TC 60 Z9 64 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2002 VL 33 IS 9 BP 2156 EP 2163 DI 10.1161/01.STR.0000029821.82531.8B PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 592JK UT WOS:000177934400019 PM 12215580 ER PT J AU Ito, T Yamakawa, H Bregonzio, C Terron, JA Neri, AF Saavedra, JM AF Ito, T Yamakawa, H Bregonzio, C Terron, JA Neri, AF Saavedra, JM TI Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT(1) antagonist SO STROKE LA English DT Article DE cerebral blood flow; hypertension; peptides; receptors; stroke ID ANTIHYPERTENSIVE TREATMENT; BRAIN; INFARCTION; AUTOREGULATION; HYPERTROPHY; EXPRESSION; DILATATION; MECHANISM; BLOCKER AB Background and Purpose-Pretreatment with angiotensin II AT(1) receptor antagonists protects against cerebral ischemia We studied whether modulation of cerebral blood flow (CBF) and morphometric changes in brain arteries participated in this protective mechanism Methods-We pretreated adult spontaneously hypertensive rats with equally antihypertensive doses of candesartan (0 1 or 0 3 mg/kg per day) nicardipine (0 1 mg/kg per day) or captopril (3 0 mg/kg per day) for 3 or 28 days via subcutaneous osmotic minipumps followed by permanent left middle cerebral artery (MCA) occlusion distal to the origin of the lenticulostriate arteries We measured CBF by autoradiography with 4 iodo [N methyl C-14]antipyrine 3 hours after operation and the areas of infarct and tissue swelling 24 hours after operation Morphometric changes in the MCA were studied after anti hypertensive treatment Results-Twenty eight days of candesartan Pretreatment decreased the infarct area by 31% reduced the CBF decrease at the peripheral area of ischemia and the cortical volume of severe ischemic lesion where CBF was <0 50 mL/g per minute increased the MCA external diameter by 16% and reduced the media thickness of the MCA by 23% Captopril pretreatment for 28 days decreased the infarct area by 25% Pretreatment with candesartan for 3 days or nicardipine for 28 days was ineffective Conclusions-Angiotensin II system inhibition protects against neuronal injury more effectively than calcium channel blockade Protection after AT(1) receptor blockade is not directly correlated with blood pressure reduction but with normalization of MCA media thickness leading to increased arterial compliance and reduced CBF decrease during ischemia at the periphery of the lesion. C1 NIMH, Pharmacol Sect, Intramural Res Program, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Intramural Res Program, 10 Ctr Dr,Bldg 10,Room 2D 57, Bethesda, MD 20892 USA. NR 31 TC 141 Z9 148 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2002 VL 33 IS 9 BP 2297 EP 2303 DI 10.1161/01.STR.0000027274.03779.F3 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 592JK UT WOS:000177934400044 PM 12215602 ER PT J AU Ialongo, N McCreary, BK Pearson, JL Koenig, AL Wagner, BM Schmidt, NB Poduska, J Kellam, SG AF Ialongo, N McCreary, BK Pearson, JL Koenig, AL Wagner, BM Schmidt, NB Poduska, J Kellam, SG TI Suicidal behavior among urban, African American young adults SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL-COMORBIDITY-SURVEY; RISK-FACTORS; TELEPHONE INTERVIEW; MENTAL-DISORDERS; UNITED-STATES; SUBSTANCE USE; PREVALENCE; IDEATION; RELIABILITY AB The objectives of the present study were four-fold. First, to determine the lifetime, last year, and 6-month prevalence and demographic correlates of suicidal behavior in a defined population of urban, African American young adults. Second, to determine the degree of mental health service utilization among attempters. Third, to study the comorbidity between mental disorders and suicidal behavior, along with the variation in the numbers and types of psychiatric disorders associated with attempts versus ideation only. Fourth, to examine gender differences in the psychiatric diagnoses associated with attempts and ideation. Data relevant to each of these objectives were gathered through structured interviews of 1,157 economically disadvantaged, African American young adults. Lifetime, last year, and 6-month prevalence rates for attempts were 5.3%, 1.2%, and 0.4%, respectively, whereas the lifetime and 6-month prevalence of ideation were 14% and 1.9%, respectively. Approximately two thirds of those who reported lifetime ideation, and a similar proportion of those who reported lifetime attempts, had a history of at least one lifetime psychiatric disorder. There were no gender differences in terms of the degree of risk for suicidal behavior (ideation or attempts) associated with any of the comorbid psychiatric diagnoses assessed. Despite the severity of most attempts, few attempters received mental health services in their lifetime or at the time of their most recent attempt. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. NIMH, Bethesda, MD USA. Ohio State Univ, Columbus, OH 43210 USA. RP Ialongo, N (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hyg, 624 N Broadway, Baltimore, MD 21205 USA. FU NIMH NIH HHS [R01 MH42968, T32 MH 18834, P50 MH38725] NR 45 TC 32 Z9 32 U1 4 U2 4 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0363-0234 J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD FAL PY 2002 VL 32 IS 3 BP 256 EP 271 DI 10.1521/suli.32.3.256.22176 PG 16 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 600EV UT WOS:000178378400004 PM 12374472 ER PT J AU Collins, SL Kunko, PM Ladenheim, B Cadet, JL Carroll, FI Izenwasser, S AF Collins, SL Kunko, PM Ladenheim, B Cadet, JL Carroll, FI Izenwasser, S TI Chronic cocaine increases kappa-opioid receptor density: Lack of effect by selective dopamine uptake inhibitors SO SYNAPSE LA English DT Article DE cocaine; GBR 12909; opiate; autoradiography; kappa-opioid ID PRODYNORPHIN GENE-EXPRESSION; MESSENGER-RNA; NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; RAT-BRAIN; BEHAVIORAL SENSITIZATION; CAUDATE-PUTAMEN; TIME-COURSE; TRANSPORTER; AGONIST AB Continuous infusion of cocaine or the selective dopamine uptake inhibitors GBR 12909 or RTI-117 increases locomotor stimulation, to which partial tolerance occurs. In addition, all three drugs produce significant decreases in tyrosine hydroxylase immunoreactivity in caudate putamen and nucleus accumbens core, suggesting a decreased dopaminergic tone. An interaction between cocaine and opioids has long been documented. Chronic cocaine significantly increases mu- and kappa-opioid receptors and treatment with a kappa-opioid agonist markedly reduces the behavioral effects of cocaine. In addition, chronic cocaine, but not GBR 12909, increases prodynorphin gene expression in caudate putamen. To further understand the interaction between cocaine and the kappa-opioid system, the effects of a chronic continuous infusion for 14 days of cocaine or one of the selective dopamine uptake inhibitors GBR 12909 or RTI-117 via osmotic minipump were examined on kappa-opioid receptors using the selective kappa-opioid ligand [H-3] U-69593. [H-3] U-69593 binding density was significantly increased in caudate putamen, nucleus accumbens shell, claustrum, and endopiriform nucleus after cocaine, while neither GBR 12909 nor RTI-117 had any effect. The increased kappa-opioid receptor densities observed following cocaine are likely not related to dopamine uptake inhibition, since they were not produced by selective dopamine uptake inhibitors. These findings suggest that regulation Of kappa-opioid receptors by cocaine may be via inhibition of serotonin or norepinephrine uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition. C1 Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. NIDA, Div Intramural Res, Baltimore, MD USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Izenwasser, S (reprint author), Univ Miami, Sch Med, Dept Psychiat & Behav Sci, 1695 NW 9th Ave,Room 3302 D-21, Miami, FL 33136 USA. RI Izenwasser, Sari/G-9193-2012 FU NIDA NIH HHS [DA 11960] NR 36 TC 21 Z9 21 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 0887-4476 J9 SYNAPSE JI Synapse PD SEP 1 PY 2002 VL 45 IS 3 BP 153 EP 158 DI 10.1002/syn.10091 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 580CB UT WOS:000177215800001 PM 12112394 ER PT J AU Horne, MK McCloskey, DJ Cullinane, AM Merryman, PK Rick, ME Hortin, GL Waclawiw, MA Cannon, RO AF Horne, MK McCloskey, DJ Cullinane, AM Merryman, PK Rick, ME Hortin, GL Waclawiw, MA Cannon, RO TI Parameters of coagulant and fibrinolytic capacity and activity in postmenopausal women: within-subject variability SO THROMBOSIS RESEARCH LA English DT Article DE postmenopause; thrombophilia; hyperhomocysteinemia; statistics ID HORMONE-REPLACEMENT THERAPY; VENOUS THROMBOEMBOLISM; INTRAINDIVIDUAL VARIABILITY; HEMOSTATIC FACTORS; BLOOD-COAGULATION; LONG-TERM; RISK; DISEASE; COMPONENTS; FIBRINOGEN AB We have analyzed the within-subject variability of a battery of parameters of coagulant and fibrinolytic capacity and activity in postmenopausal women. We observed large differences in within-subject variability among the tests and have demonstrated how such data can be used to estimate the number of times a parameter must be measured to produce a statistically adequate sample. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NHLBI, Dept Lab Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NHLBI, Dept Lab Med, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Rm C306, Bethesda, MD 20892 USA. NR 29 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 SEP 1 PY 2002 VL 107 IS 5 BP 229 EP 233 AR PII S0049-3848(02)00332-8 DI 10.1016/S0049-3848(02)00332-8 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 637ZH UT WOS:000180543200007 PM 12479883 ER PT J AU Gomez-Angelats, M Cidlowski, JA AF Gomez-Angelats, M Cidlowski, JA TI Cell volume control and signal transduction in apoptosis SO TOXICOLOGIC PATHOLOGY LA English DT Review DE apoptosis; volume decrease; ions; signaling ID FAS-MEDIATED APOPTOSIS; TUMOR-NECROSIS-FACTOR; CYTOCHROME-C RELEASE; T-LYMPHOCYTES; NEURONAL APOPTOSIS; TYROSINE KINASES; PLASMA-MEMBRANE; K+ CHANNELS; CD95-INDUCED APOPTOSIS; CPP32-LIKE PROTEASES AB Apoptosis is a physiological form of death in which cells turn-on an intrinsic genetic program that eventually leads to their destruction in a highly regulated manner. This process renders elimination of "unwanted cells" in the body, and accounts for cellular turnover and homeostasis of tissues in multicellular organisms. Consequently, an imbalance in the apoptotic rate in a particular tissue can lead to profound effects in the whole organism. Exposure of cells to apoptotic stimuli induces a rapid loss of cell volume (apoptotic volume decrease) that plays a pivotal role in the decision of a cell to undergo apoptosis. Interestingly, the apoptotic volume decrease is driven by changes in ionic fluxes across the plasma membrane that promote a decrease in the intracellular ions that ultimately also leads to a reduction in intracellular ionic strength. Despite an intensive research effort however, the cellular and molecular mechanisms that trigger changes in cell volume during apoptosis remain poorly understood. Nevertheless, this apoptotic volume decrease has been shown to be a necessary component of the apoptotic cascade and an important point of modulation for the entire cell death process. In this review, we will focus on the importance of the apoptotic volume decrease in the context of signaling and modulation of programmed cell death. C1 NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 97 TC 23 Z9 24 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2002 VL 30 IS 5 BP 541 EP 551 DI 10.1080/01926230290105820 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YH UT WOS:000178193700001 PM 12371662 ER PT J AU Wormser, U Sintov, A Brodsky, B Amitai, Y Nyska, A AF Wormser, U Sintov, A Brodsky, B Amitai, Y Nyska, A TI Protective effect of topical iodine preparations upon heat-induced and hydrofluoric acid-induced skin lesions SO TOXICOLOGIC PATHOLOGY LA English DT Article DE chemical exposure; dermal toxicity ID HUMAN EPIDERMAL-KERATINOCYTES; GUINEA-PIG SKIN; SULFUR MUSTARD; PROTEASE ACTIVITY; INDUCED APOPTOSIS; CELLS; OINTMENT; BURNS; MANAGEMENT; ACTIVATION AB In this study, the protective prophylactic and post-exposure effects of novel topical iodine preparations were demonstrated upon heat- and hydrofluoric acid-induced skin lesions in the haired guinea pig. Prophylactic treatment of thermal burns with a liquid iodine preparation resulted in statistically significant reductions of 39% and 30%, respectively, in acute inflammation and hemorrhage-microscopic dermal parameters indicative of acute tissue damage. A clear trend of iodine-induced reduction in dermal necrosis occurred, and the epidermal healing markers, acanthosis and hyperkeratosis, were increased. Postexposure treatment of thermal burns with an iodine ointment preparation immediately after occurrence also conferred significant therapeutic reduction in parameters of tissue damage such as epidermal ulceration (87%), acute inflammation (58%), and hemorrhage (30%). Gross pathological evaluation showed that prophylactic and postexposure treatments with the liquid iodine preparation significantly reduced the heat-induced ulceration area by 97% and 65%, respectively. In addition, immediate treatment with an ointment iodine formulation significantly decreased the ulceration area by 98%; its tetraglycol vehicle also had a beneficial effect. Postexposure treatment with the iodine ointment proved efficacious upon hydrofluoric acid-induced skin burns. We observed statistically significant reductions of 76% and 68% in ulceration areas at intervals of 5 and 10 minutes between exposure and treatment, whereas a weaker effect was observed at a longer time interval of 15 minutes. Our findings suggest the therapeutic usage of these newly developed iodine preparations for thermally induced and hydrofluoric acid-induced skin burns. C1 Hebrew Univ Jerusalem, Fac Sci, IL-91904 Jerusalem, Israel. Ben Gurion Univ Negev, Inst Appl Res, Beer Sheva, Israel. Minist Hlth, Mother Child & Adolescent Hlth Dept, Jerusalem, Israel. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Hebrew Univ Jerusalem, Ctr Pharm, IL-91905 Jerusalem, Israel. RP Wormser, U (reprint author), Hebrew Univ Jerusalem, Fac Sci, Berman Bldg,Edmond Safra Campus, IL-91904 Jerusalem, Israel. NR 33 TC 11 Z9 11 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2002 VL 30 IS 5 BP 552 EP 558 DI 10.1080/01926230290105767 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YH UT WOS:000178193700002 PM 12371663 ER PT J AU Turusov, VS Torii, M Sills, RC Willson, GA Herbert, RA Hailey, JR Haseman, JK Boorman, GA AF Turusov, VS Torii, M Sills, RC Willson, GA Herbert, RA Hailey, JR Haseman, JK Boorman, GA TI Hepatoblastomas in mice in the US National Toxicology Program (NTP) studies SO TOXICOLOGIC PATHOLOGY LA English DT Article DE hepatocellular tumors; adenoma; rodent studies; cancer; B6C3F1 mice; cancer rates; bioassays; 2-year studies; embryonal tumors ID B6C3F(1) MICE; HELICOBACTER-HEPATICUS; N-NITROSODIETHYLAMINE; BODY-WEIGHT; F344/N RATS; CARCINOGENICITY; NEOPLASMS; PROMOTION; OXAZEPAM; SURVIVAL AB Over the last 8 years, a 5-fold increase in the incidence of mice with spontaneous hepatoblastomas and a moderate increase in the incidence of chemically induced hepatoblastomas in B6C3F1 mice occurred in 2-year NTP studies compared to the previous 7 years. There was a positive association between an increased incidence of mice with hepatoblastoma and an increased incidence of mice with hepatocellular tumors in the treated mice. The rate of pulmonary metastases for hepatoblastoma was similar to that of pulmonary metastasis for hepatocellular carcinomas. Although a variety of chemicals caused an increased incidence of mice with hepatoblastoma, there was no apparent association between a specific chemical structure or a biological class of compounds and their capacity to induce hepatoblastomas. Hepatoblastomas frequently arose within hepatocellular carcinomas or adenomas and were induced by the same compounds that induced hepatocellular neoplasms. Therefore, it seems reasonable to combine the incidence of mice with hepatoblastomas and the incidence of mice with hepatocellular carcinomas in hazard identification studies. C1 NN Blokhin Canc Res Ctr, Moscow 115446, Russia. Shionogi & Co Ltd, Drug Safety Evaluat Dev Res Labs, Osaka 5610825, Japan. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Expt Pathol Labs, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Dis & Med Program, Res Triangle Pk, NC 27709 USA. RP Boorman, GA (reprint author), NIEHS, Expt Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 46 TC 13 Z9 13 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2002 VL 30 IS 5 BP 580 EP 591 DI 10.1080/01926230290105802 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YH UT WOS:000178193700006 PM 12371667 ER PT J AU Takahashi, K Dinse, GE Foley, JF Hardisty, JF Maronpot, RR AF Takahashi, K Dinse, GE Foley, JF Hardisty, JF Maronpot, RR TI Comparative prevalence, multiplicity, and progression of spontaneous and vinyl carbamate-induced liver lesions in five strains of male mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE hepatocarcinogenesis; tumor progression; neonatal mouse model ID MOUSE-LIVER; RAS PROTOONCOGENE; ETHYL CARBAMATE; B6C3F1 MOUSE; HA-RAS; ACTIVATED ONCOGENES; INFANT MOUSE; HEPATOCARCINOGENESIS; TUMORS; DIETHYLNITROSAMINE AB The overall and age-specific prevalences and multiplicities of spontaneous and chemically induced hepatocellular neoplasia were compared among male B6D2F1, B6C3F1, C3H (C3H/HeNCrl MTV-), B6CF1, and C57BL/6 (C57BL/6NCrl) mice following a single intraperitoneal injection of 0.03 muM vinyl carbamate (VC)/g body weight or vehicle alone at 15 days of age. Additional groups of B6C3F1, C3H, and C57BL/6 males received 0.15 muM VC/g body weight at 15 days of age. For male B6D2F1, B6C3F1, C3H, B6CF1, and C57BL/6 mice, the estimated overall prevalences (and multiplicities) of hepatocellular adenomas or carcinomas in vehicle controls were 14.1% (0.19), 12.3% (0.15), 8.2% (0.10), 7.2% (0.09), and 2.4% (0.02), respectively. The analogous estimates in the low-dose group were 59.2% (1.19), 72.9% (4.07), 48.6% (1.99), 22.8% (0.29), and 43.9% (0.82). Analogous estimates for B6C3F1, C3H, and C57BL/6 mice in the high-dose group were 45.3% (4.29), 59.7% (6.63), and 46.8% (1.74), respectively. Age-specific multiplicity estimates suggested a progression from altered hepatocellular foci (AHF) to hepatocellular neoplasms. Further evidence of progression was provided by the temporal occurrence of hepatocellular adenomas before carcinomas, and the apparent origination of carcinomas within adenomas. Pulmonary metastases were observed in many of the mice with hepatocellular carcinomas. These findings confirm previous observations of strain differences in liver neoplasm response, suggest a progressive development from AHF to adenomas, and ultimately to carcinomas, and show sensitivity to VC-induced hepatocarcinogenesis in all 5 strains. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Nippon Vet & Anim Sci Univ, Tokyo, Japan. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Expt Pathol Labs Inc, Res Triangle Pk, NC USA. RP Maronpot, RR (reprint author), NIEHS, Lab Expt Pathol, NIH, POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 42 TC 8 Z9 8 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2002 VL 30 IS 5 BP 599 EP 605 DI 10.1080/01926230290105776 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YH UT WOS:000178193700008 ER PT J AU Newbold, RR Moore, AB Dixon, D AF Newbold, RR Moore, AB Dixon, D TI Characterization of uterine leiomyomas in CD-1 mice following developmental exposure to diethylstilbestrol (DES) SO TOXICOLOGIC PATHOLOGY LA English DT Article DE diethylstilbestrol; DES; leiomyomas; uterus; mice; growth factors ID GROWTH-FACTOR-ALPHA; PRENATAL EXPOSURE; ESTROGENS; ADENOCARCINOMA; TRANSFORMATION; CHEMICALS; MODEL; CELLS AB Experimental animal and clinical studies have well established the association of prenatal exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities, including poor reproductive outcome and neoplasia. Overwhelmingly, the focus has been on DES-induced epithelial lesions, particularly vaginal adenosis and adenocarcinoma; however, uterine smooth muscle cells are also recognized as cellular targets of DES. This descriptive report characterizes uterine leiomyomas that occur in outbred CD-1 mice following exposure to DES prenatally on days 9 to 16 of gestation or on neonatal days 1 to 5. These DES-induced uterine leiomyomas have typical histomorphologic, and some immunohistochemical characteristics of spontaneously occurring uterine smooth muscle tumors of B6C3F1 mice previously described in our laboratory, and they are also similar to uterine leiomyomas (fibroids) commonly observed in premenopausal women. C1 NIEHS, Comparat Pathobiol Grp, Lab Expt Pathol, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), NIEHS, Comparat Pathobiol Grp, Lab Expt Pathol, Environm Toxicol Program, POB 12233,MDC2-09, Res Triangle Pk, NC 27709 USA. NR 29 TC 48 Z9 48 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2002 VL 30 IS 5 BP 611 EP 616 DI 10.1080/01926230290105839 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 596YH UT WOS:000178193700010 PM 12371671 ER PT J AU O'Brien, ML Cunningham, ML Spear, BT Glauert, HP AF O'Brien, ML Cunningham, ML Spear, BT Glauert, HP TI Peroxisome proliferators do not activate the transcription factors AP-1, early growth response-1, or heat shock factors 1 and 2 in rats or hamsters SO TOXICOLOGICAL SCIENCES LA English DT Article DE peroxisome proliferators; hamsters; rats; Egr-1; HSF; AP-1 ID NF-KAPPA-B; LIVER-CELL PROLIFERATION; DNA-BINDING ACTIVITY; LONG-TERM EXPOSURE; LIPID-PEROXIDATION; PERFLUORODECANOIC ACID; NUCLEAR EXTRACTS; HEPATIC DNA; INDUCED HEPATOCARCINOGENESIS; DIFFERENTIAL ACTIVATION AB Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice, whereas hamsters are less responsive to these compounds. PPs increase peroxisomal beta-oxidation and P4504A subfamily activity, which have been hypothesized to result in oxidative stress. Work in our laboratory indicated that differential modulation of the redox-sensitive transcription factor NF-kappaB may contribute to the resulting difference in species susceptibility following PP administration. Therefore, we hypothesized that other redox-sensitive transcription factors such as AP-1, early growth response gene 1 (Egr-1), and heat-shock factors 1 and 2 (HSF1/2) may also be alternatively activated in differentially susceptible species. Accordingly, we measured the activation of these transcription factors using gel mobility shift assays, with hepatic nuclear extracts derived from rats and Syrian hamsters fed two doses of three peroxisome proliferators (dibutyl-phthalate [DBP], gemfibrozil and Wy-14,643) for 6, 34, or 90 days. Although changes were observed at various time points, no consistent, dose-responsive changes were observed in the DNA binding activities of these transcription factors following PP treatment. The lack of increased binding of AP-1, Egr-1, and HSFs suggests that these factors are not involved in increased cell proliferation following PP administration, although we cannot rule out that these factors are activated at earlier time points than those examined in this study. C1 Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40506 USA. Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40506 USA. Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40506 USA. Univ Kentucky, Dept Pathol & Lab Med, Lexington, KY 40506 USA. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Glauert, HP (reprint author), Univ Kentucky, Grad Ctr Nutr Sci, 204 Funkhouser Bldg, Lexington, KY 40506 USA. OI Spear, Brett/0000-0002-4343-9393 FU NIEHS NIH HHS [ES07266, ES09771] NR 75 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2002 VL 69 IS 1 BP 139 EP 148 DI 10.1093/toxsci/69.1.139 PG 10 WC Toxicology SC Toxicology GA 593NC UT WOS:000177996800015 PM 12215668 ER PT J AU George, JD Price, CJ Marr, MC Myers, CB Jahnke, GD AF George, JD Price, CJ Marr, MC Myers, CB Jahnke, GD TI Evaluation of the developmental toxicity of formamide in New Zealand White rabbits SO TOXICOLOGICAL SCIENCES LA English DT Article DE formamide; developmental toxicity; teratogenicity; rabbits; morphological development ID N-METHYLFORMAMIDE; CD-RATS; N,N-DIMETHYLFORMAMIDE; DIMETHYLFORMAMIDE; WORKERS; MICE; METABOLITES AB Naturally mated female New Zealand White (NZW) rabbits (24/group) received formamide (35, 70, or 140 mg/kg/day) or vehicle (1 ml/kg deionized/distilled water) by gavage on gestational days (GD) 6 through 29. The study was conducted using a 2-replicate design. Maternal food consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. One and four maternal deaths occurred at the low and high doses, respectively. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140-mg/kg/day dose groups, respectively. Other clinical signs associated with formamide exposure were minimal: primarily reduced or absent fecal output at the high dose (2-13 animals/day). Also at the high dose, maternal body weight was significantly depressed on GD 21, 24, and 27 (87-90% of the control value); maternal body weight gain was significantly reduced for GD 12 to 15, 18 to 21, and 21 to 24 (treated animals gained less than 1 g, or lost up to 100 g). In addition, maternal body weight gain was reduced at the middle dose for GD 18 to 21. Maternal body weight gain, corrected for gravid uterine weight, was unaffected. Relative maternal food consumption in the high-dose group was 34-59% of control intake from GD 12 through GD 24, but was comparable to controls thereafter. At termination (GD 30), confirmed-pregnant females (9-20 per group) were evaluated for clinical status, liver weights, and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal liver weight (absolute or relative to body weight) was unaffected by treatment, but gravid uterine weight at the high dose was 71% of the control value. A significantly increasing trend was noted for the percent non-live implants per litter. In addition, although not statistically significant from the control group, the values for the percent late fetal deaths per litter and percent non-live implants per litter in the 140-mg/kg/day group were higher than maximum historical values, suggesting an increase in late gestational deaths in the surviving high-dose animals. Formamide decreased the mean number of live fetuses per litter at the high dose to 66% of the control value. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose; mean female fetal body weight was also decreased, although the difference did not reach statistical significance. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations in animals surviving to scheduled necropsy. In summary, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 70 mg/kg/day and the lowest-observed-adverse-effect level (LOAEL) was 140 mg/kg/day under the conditions of this study. Similarly, the NOAEL for developmental toxicity was 70 mg/kg/day and the LOAEL was 140 mg/kg/day. C1 Res Triangle Inst, Ctr Life Sci & Toxicol, Res Triangle Pk, NC 27709 USA. NIEHS, Dev & Reprod Toxicol Grp, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP George, JD (reprint author), Res Triangle Inst, Ctr Life Sci & Toxicol, Herman Lab Bldg,POB 12194, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES-65405] NR 59 TC 7 Z9 7 U1 1 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 SEP PY 2002 VL 69 IS 1 BP 165 EP 174 DI 10.1093/toxsci/69.1.165 PG 10 WC Toxicology SC Toxicology GA 593NC UT WOS:000177996800018 PM 12215671 ER PT J AU Hejtmancik, MR Trela, BA Kurtz, PJ Persing, RL Ryan, MJ Yarrington, JT Chhabra, RS AF Hejtmancik, MR Trela, BA Kurtz, PJ Persing, RL Ryan, MJ Yarrington, JT Chhabra, RS TI Comparative gavage subchronic toxicity studies of o-chloroaniline and m-chloroaniline in f344 rats and B6C3F1 mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE o-chloroaniline; p-chloroaniline; methemoglobin; Heinz body formation; hematopoiesis; splenomegaly; F344 rats; B6C3F1 mice ID ZERO DOSE CONTROL; ANILINE; CARCINOGENICITY AB ortho-Chloroaniline (o-CA) andmeta-chloroaniline (m-CA) are chemical intermediates for pigment production in the textile industry. Comparative subchronic gavage studies were conducted to determine the effect of structure on toxicity.o-CA orm-CA was administered to 10 animals/sex/species in deionized water at dosages of 0, 10, 20, 40, 80, and 160 mg/kg for 13 weeks. Blood samples for clinical pathology were collected after 3 and 23 days in rats and at study termination (Day 93) in rats and mice. No mortalities occurred that could be directly attributed to treatment. Transient clinical signs of toxicity observed after dosing included cyanosis in rats and ataxia and tremors in mice. Methemoglobin formation was directly related to dosage (rats and mice) and duration of treatment (rats). At study termination, Heinz body formation in erythrocytes in association with decreased hemoglobin, hematocrit, and red blood cell count was a prominent treatment-related effect. Enlarged spleens (gross necropsy observation) and increased spleen weight were treatment effects of each chemical in both species. Microscopic lesions typical of increased red blood cell production were found in hematopoietic tissues (bone marrow, spleen, and liver), while lesions due to increased red cell destruction were found in these tissues and also the kidneys (rats). Microscopic changes were more frequently seen and severe, and involved more body organs, in rats than mice, and in m-CA-treated animals thano-CA-treated animals. Sex differences in lesion incidence/severity were not evident. C1 Battelle Mem Inst, Columbus, OH 43201 USA. NIEHS, Div Toxicol Res, Res Triangle Pk, NC 27709 USA. NIEHS, Testing Program, Res Triangle Pk, NC 27709 USA. RP Hejtmancik, MR (reprint author), Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. FU NIEHS NIH HHS [N01-ES-15320] NR 33 TC 15 Z9 15 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2002 VL 69 IS 1 BP 234 EP 243 DI 10.1093/toxsci/69.1.234 PG 10 WC Toxicology SC Toxicology GA 593NC UT WOS:000177996800026 PM 12215679 ER PT J AU Brambila, EM Achanzar, WE Qu, W Webber, MM Waalkes, MP AF Brambila, EM Achanzar, WE Qu, W Webber, MM Waalkes, MP TI Chronic arsenic-exposed human prostate epithelial cells exhibit stable arsenic tolerance: Mechanistic implications of altered cellular glutathione and glutathione S-transferase SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic resistance; human; prostate ID HAMSTER OVARY CELLS; INDUCED MALIGNANT TRANSFORMATION; ACUTE PROMYELOCYTIC LEUKEMIA; BILIARY-EXCRETION; WELL WATER; RESISTANCE; TOXICITY; MORTALITY; PROTEINS; TRIOXIDE AB Acquisition of stable arsenic tolerance in human cells following chronic arsenic exposure has not been previously reported. In the present work, we describe acquisition of stable arsenic tolerance in the human prostate epithelial cell line RWPE-1 following chronic arsenic exposure in vitro. RWPE-1 cells continuously exposed to 5 muM sodium arsenite for greater than or equal to18 weeks exhibited dramatic resistance to acute arsenite toxicity. The LC50 for acute arsenite exposure in these chronic arsenic-exposed prostate epithelial (CAsE-PE) cells was 43.8 muM versus 17.6 muM in control cells. Similar results were obtained using the antineoplastic agent arsenic trioxide. This tolerance was stable, as CAsE-PE cells grown in arsenic-free medium for 5 weeks retained their resistant phenotype. Compared to control cells, CAsE-PE cells showed a 90% reduction in arsenic accumulation over 24 h coupled with a 2.6-fold increase in the rate of arsenic efflux. CAsE-PE cells had increased basal GSH levels (4.9-fold) and increased GST activity (2.4-fold) and both GSH depletion and inhibition of GST activity abolished arsenic tolerance. Arsenic tolerance was also abolished by treatment with inhibitors of the Mdr1 and Mrp1 transporters, although no increases in mdr1 or mrp1 gene expression were observed. Our results indicate that this tolerance in human cells involves increases in GSH levels and GST activity that allow for more efficient arsenic efflux by MRP1 and MDR1. This study represents the first report of stable acquired arsenic tolerance in human cells, which could have important implications for both the toxicology and the pharmacology of arsenic. (C) 2002 Elsevier Science (USA). C1 NCI, Inorgan Carcinogenesis Sect, NIEHS, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Michigan State Univ, Dept Med, E Lansing, MI 48823 USA. Michigan State Univ, Dept Zool, E Lansing, MI 48823 USA. RP Waalkes, MP (reprint author), NCI, Inorgan Carcinogenesis Sect, NIEHS, Comparat Carcinogenesis Lab, 111 Alexander Dr,Bldg 101,SC MD F0-09,RM F-095, Res Triangle Pk, NC 27709 USA. NR 44 TC 44 Z9 51 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2002 VL 183 IS 2 BP 99 EP 107 DI 10.1006/taap.2002.9468 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 595UK UT WOS:000178127000004 PM 12387749 ER PT J AU Moriyama, K Bonifacino, JS AF Moriyama, K Bonifacino, JS TI Pallidin is a component of a multi-protein complex involved in the biogenesis of lysosome-related organelles SO TRAFFIC LA English DT Article DE adaptors; BLOC-1; Hermansky-Pudlak syndrome; lysosomes; melanosomes; pigmentation ID HERMANSKY-PUDLAK-SYNDROME; STORAGE POOL DEFICIENCY; PALE EAR EP; AP-3 ADAPTER; INTRACELLULAR-TRANSPORT; MOUSE MODELS; GENE; MUTATION; SUBUNIT; TRAFFICKING AB The Hermansky-Pudlak syndrome defines a group of genetic disorders characterized by defective lysosome-related organelles such as melanosomes and platelet dense bodies. Hermansky-Pudlak syndrome can be caused by mutations of at least four genes in humans and 15 genes in mice. One of these genes is mutated in the pallid mouse strain and encodes a novel protein named pallidin (L. Huang, Y. M. Kuo and J. Gitschier, Nat Genet 1999; 23: 329-332). Pallidin has no homology to any other known protein and no recognizable functional motifs. We have conducted a biochemical characterization of human pallidin using a newly developed polyclonal antibody. We show that pallidin is a ubiquitously expressed similar to 25 kDa protein found both in the cytosol and peripherally associated to membranes. Sedimentation velocity analyses show that native pallidin has a sedimentation coefficient of similar to 5.1 S, much larger than expected from the molecular mass of the pallidin polypeptide. In line with this observation, cosedimentation and coprecipitation analyses reveal that pallidin is part of a hetero-oligomeric complex. One of the subunits of this complex is the product of another Hermansky-Pudlak syndrome gene, muted. Fibroblasts derived from the muted mouse strain exhibit reduced levels of pallidin, suggesting that the absence of the muted protein destabilizes pallidin. These observations indicate that pallidin is a subunit of a novel multi-protein complex involved in the biogenesis of lysosome-related organelles. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 41 TC 42 Z9 47 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD SEP PY 2002 VL 3 IS 9 BP 666 EP 677 DI 10.1034/j.1600-0854.2002.30908.x PG 12 WC Cell Biology SC Cell Biology GA 585VC UT WOS:000177544400008 PM 12191018 ER PT J AU Busch, MP Stramer, SL Dodd, RY Notari, EP Glynn, S Wright, DJ Kleinman, S AF Busch, MP Stramer, SL Dodd, RY Notari, EP Glynn, S Wright, DJ Kleinman, S TI New strategy for estimating residual risk and yield of NAT screening assays. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 Blood Ctr Pacific, San Francisco, CA USA. Amer Red Cross, Gaithersburg, MD USA. Amer Red Cross, Rockville, MD USA. Westat Corp, Rockville, MD USA. Westat Corp, San Luis Obispo, CA USA. Westat Corp, Victoria, BC, Canada. Westat Corp, NHLBI Retrovirus Epidemiol Donor Study, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 2S EP 3S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700008 ER PT J AU Sanchez, A Glynn, S Kessler, D Nass, C Hirschler, N Fridey, J Murphy, E Busch, M Schreiber, G AF Sanchez, A Glynn, S Kessler, D Nass, C Hirschler, N Fridey, J Murphy, E Busch, M Schreiber, G TI The impact of male-to-male sexual experience on risk profiles of blood donors. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FL SP Amer Assoc Blood Banks C1 Westat Corp, Rockville, MD USA. New York Blood Ctr, New York, NY 10021 USA. Amer Red Cross, Blood Serv, Baltimore, MD USA. Blood Ctr Pacific Irwin, San Francisco, CA USA. Blood Bank, San Bernardino, CA USA. Blood Ctr Pacific Irwin, San Francisco, CA USA. Westat Corp, NHLBI Retrovirus Epidemiol Donor Study, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 12S EP 12S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700044 ER PT J AU Damesyn, MA Glynn, S Schreiber, G Ownby, HE McMullen, QE Garratty, G AF Damesyn, MA Glynn, S Schreiber, G Ownby, HE McMullen, QE Garratty, G TI Prevalence of risk behaviors and viral markers in donors less than 25 years of age. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 Amer Red Cross, Evans, GA USA. Westat Corp, Rockville, MD USA. Amer Red Cross, Los Angeles, CA USA. NHLBI Retrovirus Epidemiol Donor Study, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 13S EP 13S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700046 ER PT J AU Glynn, S Busch, MP Schreiber, G Murphy, E Wright, DJ Tu, Y Kleinman, S AF Glynn, S Busch, MP Schreiber, G Murphy, E Wright, DJ Tu, Y Kleinman, S TI Characteristics and five month return rates of donors who gave for the first time following the 9-11-2001 terrorism attack. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 Blood Ctr Pacific, San Francisco, CA USA. WESTAT Corp, NHLBI Retrovirus Epidemiol Donor Study, Rockville, MD 20850 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 13S EP 14S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700048 ER PT J AU Wang, B Busch, MP Nass, C Orton, S Murphy, E Glynn, S AF Wang, B Busch, MP Nass, C Orton, S Murphy, E Glynn, S TI Are donors with a history of transfusion at an increased risk for transfusion-transmitted viral infections? SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FL SP Amer Assoc Blood Banks C1 Westat Corp, Rockville, MD USA. Blood Ctr Pacific, San Francisco, CA USA. Amer Red Cross, Blood Serv Chesapeake & Potomac Region, Baltimore, MD USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Blood Ctr Pacific, San Francisco, CA USA. NHLBI, Retrovirus Epidemiol Donor Study, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 13S EP 13S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700045 ER PT J AU Byrne, KM Stroncek, DF Leitman, S AF Byrne, KM Stroncek, DF Leitman, S TI Increasing oxygen tension prevents the occlusion of leukocyte reduction filters by sickle cell trait donor RBCs. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 15S EP 15S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700053 ER PT J AU Greer, SE Leitman, S Shih, JW Conry-Cantilena, C Melpolder, JJ Schechterly, C Nass, C Ness, PM Gibble, JW Alter, HJ AF Greer, SE Leitman, S Shih, JW Conry-Cantilena, C Melpolder, JJ Schechterly, C Nass, C Ness, PM Gibble, JW Alter, HJ TI A 17-year prospective evaluation of HIV outcomes in a cohort enrolled as asymptomatic blood donors. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. Greater Chesapeake & Potomac Area Amer Red Cross, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 23S EP 23S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700083 ER PT J AU Bolan, CD Yau, YY Carter, CS Cullis, H Leitman, S AF Bolan, CD Yau, YY Carter, CS Cullis, H Leitman, S TI Effect of device settings and whole blood flow rate (WBFR) on PBSC collection efficiency SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. Amer Fluoroseal Corp, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 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 SEP PY 2002 VL 42 IS 9 SU S BP 31S EP 31S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700110 ER PT J AU Haddad, S Winer, K Gupta, A Chakrabarti, S Noel, P Klein, HG AF Haddad, S Winer, K Gupta, A Chakrabarti, S Noel, P Klein, HG TI Munchausen syndrome diagnosed in a puzzling case of anemia. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 43S EP 43S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700155 ER PT J AU Lockwood, FL Csako, G Choyke, P Cannon, R Wesley, R Ruiz, M Giesel, F Fu, X Costello, R Leser, M Schenke, W Sink, B Pucino, F Leitman, S AF Lockwood, FL Csako, G Choyke, P Cannon, R Wesley, R Ruiz, M Giesel, F Fu, X Costello, R Leser, M Schenke, W Sink, B Pucino, F Leitman, S TI Frequent blood donation fails to improve markers of atherosclerosis. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 65S EP 66S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700241 ER PT J AU Schreiber, G Sharma, U Glynn, S Tu, Y Zuck, T Nass, C AF Schreiber, G Sharma, U Glynn, S Tu, Y Zuck, T Nass, C TI Where do first-time donors choose to return to donate? SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NHLBI, REDS, Westat, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 71S EP 71S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700262 ER PT J AU Smith, JW Sharma, U Glynn, S Schreiber, G Kleinman, S AF Smith, JW Sharma, U Glynn, S Schreiber, G Kleinman, S TI Autologous donations: Declining use and viral marker prevalence. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NHLBI, REDS, Westat, Rockville, MD 20850 USA. Oklahoma Blood Inst, Oklahoma City, OK USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 71S EP 71S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700261 ER PT J AU Sharma, U Stramer, SL Wright, DJ Glynn, S Hermansen, S Schreiber, G Kleinman, S Busch, MP AF Sharma, U Stramer, SL Wright, DJ Glynn, S Hermansen, S Schreiber, G Kleinman, S Busch, MP CA NHLBI Retrovirus Epidemiology Dona TI Impact of changes in viral marker screening assays. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 WESTAT Corp, NHLBI Retrovirus Epidemiol Donor Study, REDS, Rockville, MD 20850 USA. Amer Red Cross, Natl Confirmatory Testing Lab, Gaithersburg, MD USA. Blood Ctr Pacific, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 85S EP 86S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700316 ER PT J AU Wu, GG Su, YQ Yu, Q Jin, SZ Zhao, TM AF Wu, GG Su, YQ Yu, Q Jin, SZ Zhao, TM TI Development of a DNA based genotyping method for screening rare di(b-) blood donors. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 Shen Zhen Inst Transfus Med, Shen Zhen, Peoples R China. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 111S EP 112S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700411 ER PT J AU Browning, JN Sink, BS Leitman, S AF Browning, JN Sink, BS Leitman, S TI Simplifying the evaluation of donors who travel to foreign countries. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2002 VL 42 IS 9 SU S BP 118S EP 118S PG 1 WC Hematology SC Hematology GA 592MP UT WOS:000177941700431 ER PT J AU Leitman, S Oblitas, J Sparks, E Browning, JN AF Leitman, S Oblitas, J Sparks, E Browning, JN TI Commitment to blood donation by disaster appeal respondents. SO TRANSFUSION LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 26-29, 2002 CL ORLANDO, FLORIDA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 SEP PY 2002 VL 42 IS 9 SU S BP 123S EP 124S PG 2 WC Hematology SC Hematology GA 592MP UT WOS:000177941700450 ER PT J AU Parada, LA Misteli, T AF Parada, LA Misteli, T TI Chromosome positioning in the interphase, nucleus SO TRENDS IN CELL BIOLOGY LA English DT Review ID HUMAN-CELLS; SPATIAL-ORGANIZATION; CENTROMERIC HETEROCHROMATIN; DROSOPHILA-MELANOGASTER; TRANSCRIPTION SITES; CHROMATIN STRUCTURE; COILED BODIES; LIVING CELLS; TAIL DOMAIN; IN-VITRO AB Chromosomes occupy distinct territories in the interphase cell nucleus. These chromosome territories are non-randomly arranged within the nuclear space. We are only just uncovering how chromosome territories are organized, what determines their position and how their spatial organization affects the expression of genes and genomes. He re, we discuss emerging models of non-random nuclear chromosome organization and consider the functional implications of chromosome positioning for gene expression and genome stability. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Parada, LA (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 86 TC 199 Z9 207 U1 2 U2 23 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 SEP PY 2002 VL 12 IS 9 BP 425 EP 432 AR PII S0962-8924(02)02351-6 DI 10.1016/S0962-8924(02)02351-6 PG 8 WC Cell Biology SC Cell Biology GA 587NP UT WOS:000177648000012 PM 12220863 ER PT J AU Weinstein, BM AF Weinstein, BM TI Vascular cell biology in vivo: A new piscine paradigm? SO TRENDS IN CELL BIOLOGY LA English DT Review ID DOUBLE-STRANDED-RNA; GENE-EXPRESSION; TRANSGENIC ZEBRAFISH; ENDOTHELIAL-CELLS; DIFFERENTIATION; HETEROGENEITY; INJECTION; BEHAVIOR; EMBRYO; FATE AB Understanding how blood vessels form has become increasingly important in recent years yet remains difficult to Study. The architecture and context of blood vessels are difficult to reproduce! in vitro, and most developing blood vessels in vivo are relatively inaccessible to observation and experimental manipulation. Zebrafish, however, provide several advantages. They have small, accessible, transparent embryos and larvae, facilitating high-resolution imaging in vivo. In addition, genetic and experimental tools and methods are available for functional manipulation of the entire organism, vascular tissues or even single vascular- or non-vascular cells. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 32 TC 38 Z9 45 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD SEP PY 2002 VL 12 IS 9 BP 439 EP 445 AR PII S0962-8924(02)02358-9 DI 10.1016/S0962-8924(02)02358-9 PG 7 WC Cell Biology SC Cell Biology GA 587NP UT WOS:000177648000014 PM 12220865 ER PT J AU Sinal, CJ Gonzalez, FJ AF Sinal, CJ Gonzalez, FJ TI Guggulsterone: an old approach to a new problem SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID BILE-ACID; RECEPTOR AB The hepatic conversion of cholesterol to bile acids is an important mechanism for the elimination of excess dietary cholesterol. Bile acid biosynthesis and transport are regulated by the farnesoid X receptor (FXR), a member of the of nuclear hormone receptor gene superfamily. Thus, therapeutic strategies that target FXR represent a promising new approach for the treatment of hypercholesterolemia. Recent studies have provided new evidence in support of the potential for FXR ligands as antihypercholesterolemic agents. C1 Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Sinal, CJ (reprint author), Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. NR 7 TC 48 Z9 50 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD SEP PY 2002 VL 13 IS 7 BP 275 EP 276 AR PII S1043-2760(02)00640-9 DI 10.1016/S1043-2760(02)00640-9 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 584XN UT WOS:000177494200001 PM 12163224 ER PT J AU Wolf, YI Rogozin, IB Grishin, NV Koonin, EV AF Wolf, YI Rogozin, IB Grishin, NV Koonin, EV TI Genome trees and the Tree of Life SO TRENDS IN GENETICS LA English DT Review ID LATERAL GENE-TRANSFER; PHYLOGENETIC CLASSIFICATION; CHIMERIC ORIGIN; EVOLUTION; PROTEINS; ARCHAEA; CONTEXT; OPERONS; ORDER AB Genome comparisons indicate that horizontal gene transfer and differential gene loss are major evolutionary phenomena that, at least in prokaryotes, involve a large fraction, if not the majority, of genes. The extent of these events casts doubt on the feasibility of constructing a 'Tree of Life', because the trees for different genes often tell different stories. However, alternative approaches to tree construction that attempt to determine tree topology on the basis of comparisons of complete gene sets seem to reveal a phylogenetic signal that supports the three-domain evolutionary scenario and suggests the possibility of delineation of previously undetected major clades of prokaryotes. If the validity of these whole-genome approaches to tree building is confirmed by analyses of numerous new genomes, which are currently being sequenced at an increasing rate, it would seem that the concept of a universal 'species' tree is still appropriate. However, this tree should be reinterpreted as a prevailing trend in the evolution of genome-scale gene sets rather than as a complete picture of evolution. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RP Wolf, YI (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 52 TC 229 Z9 244 U1 0 U2 16 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD SEP PY 2002 VL 18 IS 9 BP 472 EP 479 DI 10.1016/S0168-9525(02)02744-0 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 587VH UT WOS:000177663800008 PM 12175808 ER PT J AU Cragg, GM Newman, DJ AF Cragg, GM Newman, DJ TI Chemical diversity: a function of biodiversity SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Letter C1 NCI, Fairview Ctr, Nat Prod Branch, Frederick, MD 21702 USA. RP Cragg, GM (reprint author), NCI, Fairview Ctr, Nat Prod Branch, Suite 206,POB B, Frederick, MD 21702 USA. NR 1 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD SEP PY 2002 VL 23 IS 9 BP 404 EP 405 DI 10.1016/S0165-6147(02)02099-0 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 592AX UT WOS:000177915500004 PM 12237150 ER PT J AU Hobbs, AJ Gladwin, MT Patel, RP Williams, DLH Butler, AR AF Hobbs, AJ Gladwin, MT Patel, RP Williams, DLH Butler, AR TI Haemoglobin: NO transporter, NO inactivator or NOne of the above? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID NITRIC-OXIDE PRODUCTION; SICKLE-CELL HEMOGLOBIN; REGIONAL BLOOD-FLOW; S-NITROSOHEMOGLOBIN; OXYGEN-BINDING; BIOCHEMICAL-CHARACTERIZATION; PHYSIOLOGICAL CONDITIONS; PLATELET-AGGREGATION; BIOLOGICAL-ACTIVITY; ENDOTHELIAL-CELLS AB The structural and functional characterization of haemoglobin (Hb) exceeds that of any other mammalian protein. Recently, the biological role attributed to Hb has been extended from the classical role in the transport and exchange of the respiratory gases O-2 and CO2 to include a third gaseous molecule, nitric oxide (NO). It is postulated that Hb might be involved in the systemic transport and delivery of NO to tissues and in the facilitation of O-2 release. However, definitive evidence for these putative activities is yet to be produced and many questions remain. Here we describe the present status of these hypotheses and their strengths and weaknesses. C1 UCL, Wolfson Inst Biomed Res, London WC1E 6AE, England. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Univ Alabama Birmingham, Dept Pathol, Ctr Free Rad Biol, Birmingham, AL 35294 USA. Univ Durham, Dept Chem, Durham DH1 3LE, England. Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland. Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9ST, Fife, Scotland. RP Hobbs, AJ (reprint author), UCL, Wolfson Inst Biomed Res, Cruciform Bldg,Gower St, London WC1E 6AE, England. EM a.hobbs@ucl.ac.uk OI Patel, Rakesh/0000-0002-1526-4303 NR 60 TC 59 Z9 65 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD SEP PY 2002 VL 23 IS 9 BP 406 EP 411 DI 10.1016/S0165-6147(02)02067-9 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 592AX UT WOS:000177915500006 PM 12237152 ER PT J AU Ogawa, R Kondo, T Honda, H Zhao, QL Fukuda, S Riesz, P AF Ogawa, R Kondo, T Honda, H Zhao, QL Fukuda, S Riesz, P TI Effects of dissolved gases and an echo contrast agent on ultrasound mediated in vitro gene transfection SO ULTRASONICS SONOCHEMISTRY LA English DT Article DE ultrasound; transfection; cavitation; gaseous effect; sonoporation; Levovist ID FREE-RADICAL FORMATION; GUIDED FOCUSED ULTRASOUND; MAMMALIAN-CELLS; PLASMID DNA; IN-VITRO; EXPRESSION; CAVITATION; THERAPY; CANCER AB The effects of acoustic cavitation on in vitro transfection by ultrasound were investigated. HeLa cells were exposed to 1.0 MHz continuous ultrasound in culture media containing the luciferase gene. Transfection efficiency was elevated when an echo contrast agent, Levovist was added or air was dissolved in the medium. When cells were sonicated in medium saturated with Ar, N-2 or N2O which have different gamma values (C-p/C-v), or were saturated with He, Ar or Ne with different thermal conductivities, the effectiveness for the dissolved gases in the ultrasound mediated transfection was Ar > N-2 > NCO or At > Ne > He, respectively. When free radical formation in water by ultrasound was monitored as a measure of inertial cavitation, it was similarly affected by dissolved gases. These results indicate that the efficiency of ultrasound mediated transfection was significantly affected either by occurrence of or by modification of inertial cavitation due to various gases. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Toyama Med & Pharmaceut Univ, Fac Med, Dept Radiol Sci, Toyama 9300194, Japan. Himi Municipal Hosp, Dept Obstet & Gynecol, Himi 9358531, Japan. Wakasa Wan Energy Res Ctr, Div Med, Tsuruga 9140192, Japan. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Kondo, T (reprint author), Toyama Med & Pharmaceut Univ, Fac Med, Dept Radiol Sci, 2630 Sugitani, Toyama 9300194, Japan. NR 25 TC 32 Z9 38 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD SEP PY 2002 VL 9 IS 4 BP 197 EP 203 AR PII S1350-4177(02)00075-5 DI 10.1016/S1350-4177(02)00075-5 PG 7 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 588GL UT WOS:000177693700003 PM 12219581 ER PT J AU Sawczuk, IS Pickens, CL Vasa, UR Ralph, DA Norris, KA Miller, MC Ng, AY Grossman, HB Veltri, RW AF Sawczuk, IS Pickens, CL Vasa, UR Ralph, DA Norris, KA Miller, MC Ng, AY Grossman, HB Veltri, RW TI DD23 biomarker - A prospective clinical assessment in routine urinary cytology specimens from patients being monitored for TCC SO UROLOGIC ONCOLOGY LA English DT Article DE bladder cancer; urine cytology; urine cellular biomarkers; diagnostic cytology; DD23 biomarker ID BLADDER-CANCER; CELL-CARCINOMA; SENSITIVITY; CYTOMETRY; NEOPLASMS; ANTIGEN AB Background: A prospective clinical study was conducted to assess the ability of the DD23 murine monoclonal antibody to enhance detection of bladder cancer in routine alcohol fixed urine cytology samples. Methods: Prospectively, 308 bladder cytology specimens were obtained from patients with a history of bladder cancer with a mean age of 71.4+/-11.9 (27% female, 73% male). Data included 121 biopsy-confirmed results and 187 cystoscopy results to assess presence or absence of cancer. Thirty-five normal cytology specimens were obtained from asymptomatic men and women between 55-85 years of age. Separate slides from the alcohol fixed cytology specimens were stained using the Papanicolaou (Pap) and Feulgen staining procedures. The DD23 assay was performed using an avidin-biotin alkaline phosphatase immunocytochemical procedure, with a single urothelial cell exhibiting intense immunostaining sufficient to make a positive call. RESULTS: Pap-Feulgen cytopathology for the 308 cases yielded an overall sensitivity of 65.5% and a specificity of 85.1%, and the DD23 biomarker alone yielded a sensitivity of 80.5% and a specificity of 59.7%. Analysis of the voided urines only (n = 164) yielded sensitivities of 61.0% and 73.2% and specificities of 86.2% and 67.5% for cytopathology and DD23 alone, respectively. Results in 49 bladder wash urine cytology cases produced a sensitivity of 70.2% and 100% and specificities of 92.3% and 61.5% for cytopathology and DD23 alone, respectively. In 133 patients that underwent biopsy or had positive cystoscopy results, cytopathology yielded a sensitivity of 65.5% and a specificity of 69.6% while DD23 yielded a sensitivity of 80.5% and a specificity of 58.7%. In 25 biopsy-confirmed low-grade cancers, DD23 improved cancer detection from 32% to 72% when compared to cytopathology. The DD23 biomarker had a specificity of 85.7% in 35 age-matched normal asymptomatic control specimens. Conclusions: The DD23 biomarker is an adjuvant test that provides improved detection of bladder cancer in cytology specimens and enhances the sensitivity of the cytopathology diagnosis, especially in low-grade cancers. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Columbia Univ, Dept Urol, New York, NY 10032 USA. UroCor Inc, Oklahoma City, OK 73104 USA. Belenus Biomed Inc, Edmond, OK 73034 USA. NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. RP Sawczuk, IS (reprint author), Hackensack Univ, Med Ctr, 20 Prospect Ave, Hackensack, NJ 07601 USA. NR 21 TC 17 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL JI Urol. Oncol. PD SEP-OCT PY 2002 VL 7 IS 5 BP 185 EP 190 AR PII S1078-1439(02)00188-6 DI 10.1016/S1078-1439(02)00188-6 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 603UN UT WOS:000178579100004 PM 12644214 ER PT J AU Garvey, TL Bertin, J Siegel, RM Lenardo, MJ Cohen, JI AF Garvey, TL Bertin, J Siegel, RM Lenardo, MJ Cohen, JI TI The death effector domains (DEDs) of the molluscum contagiosum virus MC159 v-FLIP protein are not functionally interchangeable with each other or with the DEDs of caspase-8 SO VIROLOGY LA English DT Article ID FACTOR RECEPTOR-1-INDUCED APOPTOSIS; NECROSIS-FACTOR RECEPTOR; TNF RECEPTOR; INHIBITORY PROTEIN; SIGNALING COMPLEX; DISTINCT; DEGRADATION; HOMOLOG; FAMILY AB The molluscum contagiosum virus (MCV) MC159 protein contains two death effector domains (DEDs) that bind to the DEDs of caspase-8 and FADD and inhibit apoptosis. We constructed MC159 truncation mutants and found that the amino-terminal region before the first DED and nearly all the carboxyl terminus after the second DED were dispensable for the antiapoptotic activity of MC159, We also engineered tandem repeats of two identical MC159 DEDs, MC159 DEDs in the reverse orientation, and MC159-caspase-8 chimeras in which a DED of MC159 was replaced with the corresponding DED of caspase-8. Each of these constructs bound to caspase-8, but was unable to bind to FADD or block apoptosis. In addition, we constructed mutants containing only a single DED of MC159. These mutants bound to both FADD and caspase-8, but could not block apoptosis or the formation of death effector filaments. Thus, the DEDs of MC159 are not functionally interchangeable with each other or with those of caspase-8. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Dev Immune Syst, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Room 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 32 TC 18 Z9 18 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2002 VL 300 IS 2 BP 217 EP 225 DI 10.1006/viro.2002.1518 PG 9 WC Virology SC Virology GA 598BC UT WOS:000178254400005 PM 12350352 ER PT J AU Senkevich, TG White, CL Weisberg, A Granek, JA Wolffe, EJ Koonin, EV Moss, B AF Senkevich, TG White, CL Weisberg, A Granek, JA Wolffe, EJ Koonin, EV Moss, B TI Expression of the vaccinia virus A2.5L redox protein is required for virion morphogenesis SO VIROLOGY LA English DT Article ID DISULFIDE BOND FORMATION; PSI-BLAST; GENOME; SEQUENCE; PATHWAY; GENE AB In this article we report the initial biochemical, genetic, and electron microscopic analysis of a previously uncharacterized, 8.9-kDa, predicted thiol-redox protein. The name A2.5L was assigned to the corresponding vaccinia virus gene, which is conserved in all sequenced poxviruses. Multiple alignment analysis and secondary structure prediction indicated that the A2.5L gene product is an all-a-helical protein with a conserved Cxx(x)C motif in the N-terminal alpha-helix. The DNA replication requirement and kinetics of A2.5L protein accumulation in virus-infected cells were typical of a late gene product, in agreement with the predicted promoter sequence. The A2.5L protein was a monomer under reducing conditions, but was mostly associated with the vaccinia virus E10R redox protein as a heterodimer under nonreducing conditions. The A2.5L protein was detected in virus particles at various stages of assembly, suggesting that it is an integral component of intracellular virions. An inducer-dependent A2.5L null mutant was constructed: in the absence of inducer, infectious virus formation was abolished and electron microscopy revealed an assembly block with an accumulation of crescent membranes and immature virions. This stage of assembly block was similar to that occurring when the E10R and G4L redox proteins were repressed, which is compatible with the involvement of E10R, A2.5L, and G4L in the same redox pathway. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MAC 0445, Bethesda, MD 20892 USA. OI Granek, Joshua/0000-0003-3908-5016 NR 18 TC 23 Z9 26 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2002 VL 300 IS 2 BP 296 EP 303 DI 10.1006/viro.2002.1608 PG 8 WC Virology SC Virology GA 598BC UT WOS:000178254400013 PM 12350360 ER PT J AU Johnson, JM Franchini, G AF Johnson, JM Franchini, G TI Retroviral proteins that target complex the major histocompatibility class I SO VIRUS RESEARCH LA English DT Review DE HTLV-1; human immunodeficiency virus; cytotoxic T-lymphocytes ID VIRUS TYPE-I; HIV-1 NEF PROTEIN; TROPICAL SPASTIC PARAPARESIS; CD4 DOWN-REGULATION; READING-FRAME-I; MHC CLASS-I; CYTOTOXIC T-LYMPHOCYTES; HAIRY-CELL LEUKEMIA; HTLV-I; P12(I) PROTEIN AB The human T-cell leukemia virus type 1 (HTLV- 1) and human immunodeficiency virus type 1 (HIV-1) retroviruses are two evolutionary distinct human pathogens. HTLV-1 is the etiologic agent of two diverse diseases: adult T-cell leukemia/lymphoma, as well as the neurologic disorder tropical spastic paraparesis/HTLV-1-associated myelopathy. HTLV-1 is the only retrovirus known to be the etiologic agent of human cancer. HTLV-2, the other known oncovirus, is not apparently associated with human cancer. While HTLV-1 transforms T-cells in vitro, HIV kills CD4+ T-cells and is the etiological agent of human acquired immunodeficiency syndrome, characterized by a progressive loss of CD4+ cells, weakening of the immune system, and susceptibility to opportunistic infections and cancer. HTLV-1 and HIV-1 both cause lifelong infections, which suggests that they have evolved mechanism(s) to evade detection by the host's immune response; particularly to evade cytotoxic T-lymphocytes, which play a major role in cellular immunity against viruses and will be the focus of this review. Published by Elsevier Science B.V. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, 41-D804, Bethesda, MD 20892 USA. NR 70 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD SEP PY 2002 VL 88 IS 1-2 BP 119 EP 127 AR PII S0168-1702(02)00124-7 DI 10.1016/S0168-1702(02)00124-7 PG 9 WC Virology SC Virology GA 605MT UT WOS:000178682200009 PM 12297331 ER PT J AU Robbins, JB Schneerson, R Trollfors, B AF Robbins, JB Schneerson, R Trollfors, B TI Pertussis in developed countries SO LANCET LA English DT Editorial Material ID BORDETELLA-PERTUSSIS; VACCINE C1 NICHHD, NIH, Bethesda, MD 20892 USA. Dept Paediat, Gothenburg, Sweden. RP Robbins, JB (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 16 TC 7 Z9 8 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 31 PY 2002 VL 360 IS 9334 BP 657 EP 658 DI 10.1016/S0140-6736(02)09882-3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 590AM UT WOS:000177795100005 PM 12241870 ER PT J AU Deng, XY Kim, M Vandier, D Jung, YJ Rikiyama, T Sgagias, MK Goldsmith, M Cowan, KH AF Deng, XY Kim, M Vandier, D Jung, YJ Rikiyama, T Sgagias, MK Goldsmith, M Cowan, KH TI Recombinant adenovirus-mediated p14(ARF) overexpression sensitizes human breast cancer cells to cisplatin SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE p14(ARF); recombinant adenovirus; gene therapy; breast cancer; apoptosis; cisplatin ID TUMOR SUPPRESSION; CYCLE ARREST; MESOTHELIOMA CELLS; INK4A LOCUS; P53; APOPTOSIS; P19(ARF); PRODUCT; MDM2; RB AB p14(ARF) the alternative product from the human INK4a/ARF locus, is one of the major targets for alterations in the development of human cancers. Overexpression of p14(ARF) results in cell cycle arrest and apoptosis. To examine the potential therapeutic role of re-expressing p14(ARF) gene product in human breast cancer, a recombinant adenovirus expressing the human p14(ARF) cDNA (Adp14(ARF)) was constructed and used to infect breast cancer cells. Five days after infection, Adp14(ARF) had considerable cytotoxicity on p53-wild-type MCF-7 cells. A time-course study showed that Adp14(ARF) infection of MCF-7 cells at 100pfu/cell increased the number of cells in G0/G1 phase and decreased that in S and G2/M phases. The presence of apoptotic cells was confirmed using the TUNEL assay. Adp14(ARF)-mediated expression of p14(ARF) also resulted in a considerable increase in the amounts of p53 and its target proteins, P21(WAF1) and MDM2. Furthermore, the combination treatment of MCF-7 cells with Adp14(ARF) and cisplatin resulted in a significantly greater cell death. Together, we conclude that p14(ARF) plays an important role in the induction of cell cycle arrest and apoptosis in breast cancer cells and recombinant adenovirus-mediated p14(ARF) expression greatly increases the sensitivity of these cells to cisplatin. These results demonstrate that the proper combination of Adp14(ARF) with conventional chemotherapeutic drug(s) could have potential benefits in treating breast cancer that carries wild-type p53 gene. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Cent S Univ, Xiangya Sch Med, Canc Res Inst, Changsha 410078, Hunan, Peoples R China. Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68918 USA. Nebraska Med Ctr, UNMC Eppley Canc Ctr, Eppley Inst, Omaha, NE 68918 USA. RP Cowan, KH (reprint author), NCI, Med Branch, NIH, Bldg 10,Rm 10N226, Bethesda, MD 20892 USA. NR 34 TC 26 Z9 31 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 30 PY 2002 VL 296 IS 4 BP 792 EP 798 AR PII S0006-291X(02)00948-8 DI 10.1016/S0006-291X(02)00948-8 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 643WY UT WOS:000180887000003 PM 12200117 ER PT J AU Riess, J Duguet, T Magyar, P Bicout, D AF Riess, J Duguet, T Magyar, P Bicout, D TI Increase of quantum Hall plateau widths due to electron-phonon interaction SO INTERNATIONAL JOURNAL OF MODERN PHYSICS B LA English DT Article; Proceedings Paper CT 4th Conference on Physical Phenomena at High Magnetic Filds CY OCT 19-25, 2001 CL SANTA FE, NEW MEXICO ID SYSTEM AB We calculate the conductivities for a model system of the integer quantum Hall effect including electron-phonon interactions, with a substrate potential chosen such that microscopic processes can be understood in detail. We find that in general the macroscopic Hall current is not only composed of velocities arising from the Schrodinger time evolution but also of velocities generated by electron-phonon interactions and that the latter can contribute to the formation of the quantized Hall plateaus. We show that for typical quantum Hall systems the phonon induced contributions lead to Hall plateaus which are somewhat larger than the plateaus of the dissipative conductivity. Experimentally this difference has been known for a long time, but it seemed unexplained so far. In the case where the substrate potential has no spatial fluctuations in the direction of the macroscopic electric field, all states are conducting and the dissipative conductivity vanishes only near integer filling factors. Nevertheless, the calculated Hall conductivity shows broad quantized plateaus, which here are entirely generated by velocities arising from phonon induced relaxation processes. These results show that absence of dissipation is not indispensable for the existence of quantized Hall plateaus. C1 CNRS, Ctr Rech Tres Basses Temp, F-38042 Grenoble 9, France. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Riess, J (reprint author), CNRS, Ctr Rech Tres Basses Temp, BP 166, F-38042 Grenoble 9, France. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA JOURNAL DEPT PO BOX 128 FARRER ROAD, SINGAPORE 912805, SINGAPORE SN 0217-9792 J9 INT J MOD PHYS B JI Int. J. Mod. Phys. B PD AUG 30 PY 2002 VL 16 IS 20-22 BP 2973 EP 2976 DI 10.1142/S0217979202013353 PG 4 WC Physics, Applied; Physics, Condensed Matter; Physics, Mathematical SC Physics GA 598WU UT WOS:000178300100017 ER PT J AU Kim, BC Kim, HT Mamura, M Ambudkar, IS Choi, KS Kim, SJ AF Kim, BC Kim, HT Mamura, M Ambudkar, IS Choi, KS Kim, SJ TI Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca2+ release from the endoplasmic reticulum and suppressing Bcl-2 expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; INTRACELLULAR CALCIUM; SIGNAL-TRANSDUCTION; FACTOR RECEPTOR; TNF RECEPTOR-2; DEATH DOMAIN; ACTIVATION; PROTEIN; CASPASE; MECHANISM AB Tumor necrosis factor (TNF) plays an import role in the control of apoptosis. The most well known apoptotic pathway regulated by TNF involves the TNFR1-associated death domain protein, Fas-associated death domain protein, and caspase-8. This study examines the mechanism of TNF-induced apoptosis in FaO rat hepatoma cells. TNF treatment significantly increased the percentage of apoptotic cells. TNF did not activate caspase-8 but activated caspase-3, -10, and -12. The effect of TNF on the expression of different members of the Bcl-2 family in these cells was studied. We observed no detectable changes in the steady-state levels of Bcl-X-L, Bax, and Bid, although TNF suppresses Bcl-2 expression. Dantrolene suppressed the inhibitory effect of TNF on Bcl-2 expression. TNF induced release of Ca2+ from the endoplasmic reticulum. (ER) that was blocked by dantrolene. Importantly, the expression of BcI-2 blocked TNF-induced apoptosis and decreased TNF-induced Ca2+ release. These results suggest that TNF induces apoptosis by a mechanism that involves increasing Ca2+ release from the ER and suppression of Bcl-2 expression. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Ajou Univ, Sch Med, Inst Med Sci, Med Genet Lab, Suwon 442749, South Korea. Ajou Univ, Sch Med, Lab Endocrinol, Paldal Gu, Suwon 442749, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Rm B1106, Bethesda, MD 20892 USA. NR 53 TC 45 Z9 46 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 31381 EP 31389 DI 10.1074/jbc.M203465200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700014 PM 12077131 ER PT J AU Plo, I Hernandez, H Kohlhagen, G Lautier, D Pommier, Y Laurent, G AF Plo, I Hernandez, H Kohlhagen, G Lautier, D Pommier, Y Laurent, G TI Overexpression of the atypical protein kinase C xi reduces topoisomerase II catalytic activity, cleavable complexes formation, and drug-induced cytotoxicity in monocytic U937 leukemia cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEDIATED DNA CLEAVAGE; NF-KAPPA-B; PKC-ZETA; SIGNAL-TRANSDUCTION; INDUCED APOPTOSIS; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOLIPASE-C; ATP HYDROLYSIS; GROWTH-FACTOR; PC12 CELLS AB In this study, we evaluated the influence of protein kinase Czeta (PKCzeta) on topoisomerase II inhibitor-induced cytotoxicity in monocytic U937 cells. In U937-zetaJ and U937-zetaB cells, enforced PKCzeta expression, conferred by stable transfection of PKCzeta cDNA, resulted in total inhibition of VP-16- and mitoxantrone-induced apoptosis and decreased drug-induced cytotoxicity, compared with U937-neo control cells. In PKCzeta-overexpressing cells, drug resistance correlated with decreased VP-16-induced DNA strand breaks and DNA protein cross-links measured by alkaline elution. Kinetoplast decatenation assay revealed that PKCzeta overexpression resulted in reduced global topoisomerase 11 activity. Moreover, in PKCzeta-overexpressing cells, we found that PKCzeta interacted with both alpha and beta isoforms of topoisomerase II, and these two enzymes were constitutively phosphorylated. However, when human recombinant PKCzeta (rH-PKCzeta) was incubated with purified topoisomerase II isofoms, rH-PKCzeta interacted with topoisomerase IIbeta but not with topoisomerase IIalpha. PKCzeta/topoisomerase IIbeta interaction resulted in phosphorylation of this enzyme and in decrease of its catalytic activity. Finally, this report shows for the first time that topoisonterase IIbeta is a substrate for PKCzeta, and that PKCzeta may significantly influence topoisomerase II inhibitor-induced cytotoxicity by altering topoisomerase IIbeta activity through its kinase function. C1 Inst Claudius Regaud, INSERM E9910, F-31052 Toulouse, France. CHU Purpan, Hematol Serv, F-31059 Toulouse, France. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Laurent, G (reprint author), Inst Claudius Regaud, INSERM E9910, 20 Rue Pont St Pierre, F-31052 Toulouse, France. NR 39 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 31407 EP 31415 DI 10.1074/jbc.M204654200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700017 PM 12105221 ER PT J AU Yang, Q Zhang, R Wang, XW Spillare, EA Linke, SP Subramanian, D Griffith, JD Li, JL Hickson, ID Shen, JC Loeb, LA Mazur, SJ Appella, E Brosh, RM Karmakar, P Bohr, VA Harris, CC AF Yang, Q Zhang, R Wang, XW Spillare, EA Linke, SP Subramanian, D Griffith, JD Li, JL Hickson, ID Shen, JC Loeb, LA Mazur, SJ Appella, E Brosh, RM Karmakar, P Bohr, VA Harris, CC TI The processing of Holliday junctions by BLM and WRN helicases is regulated by p53 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING FUNCTION; TUMOR-SUPPRESSOR PROTEIN; WERNERS-SYNDROME PROTEIN; BLOOMS-SYNDROME HELICASE; HOMOLOGOUS RECOMBINATION; POSTTRANSLATIONAL MODIFICATIONS; EXONUCLEASE ACTIVITY; CRYSTAL-STRUCTURE; BRANCH MIGRATION; POLYMERASE-DELTA AB BLM, WRN, and p53 are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reduces abilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses these abilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM and WRN helicase activities, but phosphorylation at Ser(376) or Ser(378) completely abolishes this inhibition. Following blockage of DNA replication, Ser(15) phospho-p53, BLM, and RAD51 colocalize in nuclear foci at sites likely to contain DNA replication intermediates in cells. Our results are consistent with a novel mechanism for p53-mediated regulation of DNA recombinational repair that involves p53 post-translational modifications and functional protein-protein interactions with BLM and WRN DNA helicases. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Canc Res UK, Oxford OX3 9DS, England. Univ Washington, Dept Pathol, Gottstein Mem Canc Res Lab, Seattle, WA 98195 USA. Univ Washington, Dept Biochem, Gottstein Mem Canc Res Lab, Seattle, WA 98195 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Rm 2C05,37 Convent Dr, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 FU NCI NIH HHS [CA70343]; NIGMS NIH HHS [GM31819] NR 58 TC 89 Z9 90 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 31980 EP 31987 DI 10.1074/jbc.M204111200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700085 PM 12080066 ER PT J AU Goerke, A Sakai, N Gutjahr, E Schlapkohl, WA Mushinski, JF Haller, H Kolch, W Saito, N Mischak, H AF Goerke, A Sakai, N Gutjahr, E Schlapkohl, WA Mushinski, JF Haller, H Kolch, W Saito, N Mischak, H TI Induction of apoptosis by protein kinase C delta is independent of its kinase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHORBOL ESTER; CYTOCHROME-C; PROTEOLYTIC ACTIVATION; NUCLEAR TRANSLOCATION; PKC-DELTA; CELLS; CASPASES; EPSILON; DIFFERENTIATION; PHOSPHORYLATION AB Protein kinase C, a multigene family of phospholipid-dependent and diacylglycerol-activated Ser/Thr protein kinases, is a key component in many signal transduction pathways. The kinase activity was thought to be essential for a plethora of biological processes attributed to these enzymes. Here we show that at least one protein kinase C function, the induction of apoptosis by protein kinase Cdelta, is independent of the kinase activity. Stimulation of green fluorescent protein-protein kinase Cdelta fusion protein with phorbol ester or diacylglycerol led to its redistribution within seconds after the stimulus. Membrane blebbing, an early hallmark of apoptosis, was visible as early as 20 min after stimulation, and nuclear condensation was visible after 3-5 h. Apoptosis could be inhibited by expression of Bcl-2 but not by specific protein kinase C inhibitors. In addition, a kinase-negative mutant of protein kinase CS also induced apoptosis to the same extent as the wild type enzyme. Apoptosis was confined to the protein kinase Cdelta-overexpressing cells. Stimulation of overexpressed protein kinase Cepsilon did not result in increased apoptosis. Our results indicate that distinct protein kinase C isozymes induce apoptosis in vascular smooth muscle cells. More importantly, they show that some protein kinase C effector functions are independent of the catalytic activity. C1 Hannover Med Sch, Dept Nephrol, D-30625 Hannover, Germany. Kobe Univ, Mol Pharmacol Lab, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. CRC, Beatson Labs, Glasgow G61 1BD, Lanark, Scotland. RP Mischak, H (reprint author), Hannover Med Sch, Dept Nephrol, Carl Neuberg Str 1, D-30625 Hannover, Germany. RI Mischak, Harald/E-8685-2011; OI Mischak, Harald/0000-0003-0323-0306 NR 47 TC 43 Z9 45 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32054 EP 32062 DI 10.1074/jbc.M203734200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700094 PM 12055197 ER PT J AU Bai, RL Covell, DG Liu, CF Ghosh, AK Hamel, E AF Bai, RL Covell, DG Liu, CF Ghosh, AK Hamel, E TI (-)-doliculide, a new macrocyclic depsipeptide enhancer of actin assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HARE DOLABELLA-AURICULARIA; POTENT CYTOTOXIC CYCLODEPSIPEPTIDE; ANTINEOPLASTIC AGENTS; F-ACTIN; NATURAL PRODUCT; POLYMERIZATION; PHALLOIDIN; DOLICULIDE; TUBULIN; BINDING AB The cytotoxic, cyclic depsipeptide (-)-doliculide was originally isolated by Ishiwata et al (Ishiwata, H., Nemoto, T., Ojika, M., and Yamada, K. (1994) J. Org. Chem. 59,4710-4711 and Ishiwata, H., Sone, H., Kigoshi, H., and Yamada, K. (1994) J. Org. Chem. 59, 4712-4713) from the sea hare Dolabella auricularia collected in Japanese waters, but the mechanism of action of the depsipeptide was not known. Using synthetic (-)-doliculide, we found that the compound arrests cells at the G(2)/M phase of the cell cycle by interfering with normal actin assembly. In cells, normal stress fibers disappeared and were replaced by multiple clumps of apparently aggregated F-actin. These effects of (-)-doliculide on cells were essentially identical to those obtained with jasplakinolide. Like jasplakinolide, (-)-doliculide caused the hyperassembly of purified actin into F-actin as measured both fluorometrically and by centrifugation. In addition, (-)-doliculide, like jasplakinolide, readily displaced a fluorescent phalloidin derivative from actin polymer. In these biochemical assays (-)doliculide and jasplakinolide were quantitatively virtually identical in their behaviors. Similar effects have also been reported with a series of depsipeptides known as chondramides. Using recently developed, computer-driven shape descriptor analysis (Mansfield, M. L., Covell, D. G., and Jernigan, R. L. (2002) J. Chem. Inf. Comput. Sci. 42, 259-273), we compared (-)-doliculide with jasplakinolide, phalloidin, and chondramide C to gain insight into a possible pharmacophore that would explain the apparent binding of this diverse group of molecules at the same site on F-actin. We found that the segment of (-)-doliculide that best overlapped the other molecules encompassed its phenyl and isopropyl side chains and the portion of the macrocycle between these substituents. C1 Univ Illinois, Dept Chem, Chicago, IL 60607 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnost,NIH, Bldg 469,Rm 104, Frederick, MD 21702 USA. NR 27 TC 42 Z9 43 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32165 EP 32171 DI 10.1074/jbc.M205076200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700108 PM 12077149 ER PT J AU Koblinski, JE Dosescu, J Sameni, M Moin, K Clark, K Sloane, BF AF Koblinski, JE Dosescu, J Sameni, M Moin, K Clark, K Sloane, BF TI Interaction of human breast fibroblasts with collagen I increases secretion of procathepsin B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-ASSOCIATED LAMININ; CATHEPSIN-B; EXTRACELLULAR-MATRIX; PLASMINOGEN-ACTIVATOR; CANCER CELLS; MALIGNANT-CELLS; GENE-EXPRESSION; PROTEIN-KINASE; CARCINOMA; DEGRADATION AB Interactions of stromal and tumor cells with the extracellular matrix may regulate expression of proteases including the lysosomal proteases cathepsins B and D. In the present study, we determined whether the expression of these two proteases in human breast fibroblasts was modulated by interactions with the extracellular matrix component, collagen I. Breast fibroblasts were isolated from non-malignant breast tissue as well as from tissue surrounding malignant human breast tumors. Growth of these fibroblasts on collagen I gels affected cell morphology, but not the intracellular localization of vesicles staining for cathepsin B or D. Cathepsins B and D levels (mRNA or intracellular protein) were not affected in fibroblasts growing on collagen I gels or plastic, nor was cathepsin D secreted from these cells. In contrast, protein expression and secretion of cathepsin B, primarily procathepsin B, was induced by growth on collagen I gels. The induced secretion appeared to be mediated by integrins binding to collagen I, as inhibitory antibodies against alpha(1), alpha(2), and beta(1) integrin subunits prevented procathepsin B secretion from fibroblasts grown on collagen. In addition, procathepsin B secretion was induced when cells were plated on beta(1) integrin antibodies. To our knowledge, this is the first examination of cathepsin B and D expression and localization in human breast fibroblasts and their regulation by a matrix protein. Secretion of the cysteine protease procathepsin B from breast fibroblasts may have physiological and pathological consequences, as proteases are required for normal development and for lactation of the mammary gland, yet can also initiate and accelerate the progression of breast cancer. C1 Wayne State Univ, Dept Pharmacol, Sch Med, Detroit, MI 48201 USA. Wayne State Univ, Barbara Ann Karmanos Ctr Inst, Sch Med, Detroit, MI 48201 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Sloane, BF (reprint author), Wayne State Univ, Dept Pharmacol, Sch Med, 540 E Canfield, Detroit, MI 48201 USA. RI Sloane, Bonnie/A-1050-2009 FU NCI NIH HHS [CA36481, CA56586, P30CA22453]; NIEHS NIH HHS [P30ES06639] NR 69 TC 51 Z9 55 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32220 EP 32227 DI 10.1074/jbc.M204708200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700115 PM 12072442 ER PT J AU Miura, S Gan, JW Brzostowski, J Parisi, MJ Schultz, CJ Londos, C Oliver, B Kimmel, AR AF Miura, S Gan, JW Brzostowski, J Parisi, MJ Schultz, CJ Londos, C Oliver, B Kimmel, AR TI Functional conservation for lipid storage droplet association among perilipin, ADRP, and TIP47 (PAT)-related proteins in mammals, Drosophila, and Dictyostelium SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIFFERENTIATION-RELATED PROTEIN; ADIPOCYTES; EXPRESSION; GENE; LIPOLYSIS; CELLS; MEMBRANE; CAVEOLIN; OBESITY; BODIES AB Intracellular neutral lipid storage droplets are essential organelles of eukaryotic cells, yet little is known about the proteins at their surfaces or about the amino acid sequences that target proteins to these storage droplets. The mammalian proteins Perilipin, ADRP, and TIP47 share extensive amino acid sequence similarity, suggesting a common function. However, while Perilipin and ADRP localize exclusively to neutral lipid storage droplets, an association of TIP47 with intracellular lipid droplets has been controversial. We now show that GFP-tagged TIP47 co-localizes with isolated intracellular lipid droplets. We have also detected a close juxtaposition of TIP47 with the surfaces of lipid storage droplets using antibodies that specifically recognize TIP47, further indicating that TIP47 associates with intracellular lipid storage droplets. Finally, we show that related proteins from species as diverse as Drosophila and Dictyostelium can also target mammalian or Drosophila lipid droplet surfaces in vivo. Thus, sequence and/or structural elements within this evolutionarily ancient protein family are necessary and sufficient to direct association to heterologous intracellular lipid droplet surfaces, strongly indicating that they have a common function for lipid deposition and/or mobilization. C1 NIDDK, Membrane Regulat Sect, NIH, Bethesda, MD 20992 USA. NIDDK, Dev Biochem Sect, NIH, Bethesda, MD 20992 USA. NIDDK, Mol Mechanisms Dev Sect, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20992 USA. RP Londos, C (reprint author), NIDDK, Membrane Regulat Sect, NIH, 50 S Dr,50-3140, Bethesda, MD 20992 USA. RI Miura, Shinji/K-6516-2013 NR 33 TC 242 Z9 251 U1 2 U2 25 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32253 EP 32257 DI 10.1074/jbc.M204410200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700119 PM 12077142 ER PT J AU Seong, YS Kamijo, K Lee, JS Fernandez, E Kuriyama, R Miki, T Lee, KS AF Seong, YS Kamijo, K Lee, JS Fernandez, E Kuriyama, R Miki, T Lee, KS TI A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of plk1 in u-2 OS cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; XENOPUS EGG EXTRACTS; MITOTIC CHECKPOINT; PROTEIN-KINASE; GAMMA-TUBULIN; MICROTUBULE FUNCTION; BUDDING YEAST; MICE LACKING; LOCALIZATION; MITOSIS AB Polo kinases play critical roles for proper M-phase progression. They are characterized by the presence of two regions of homology in the C-terminal non-catalytic domain, termed polo-box 1 (PB1) and polo-box 2 (PB2). Here we demonstrate that both PB1 and PB2 are required for targeting the catalytic activity of Plk1 to centrosomes, midbody, and kinetochores. Expression of either kinase-inactive PLK1/K82M or the C-terminal plk1DeltaN induced a pre-anaphase arrest with elevated Cdc2 and Plk1 activity. Prophase-arrested cells exhibited randomly oriented spindle structures, whereas metaphase cells exhibited aberrant bipolar spindles with Mad2 localization at kinetochores of misaligned chromosomes. Microtubule nucleation activity of centrosomes was not compromised. In vivo time-lapse studies revealed that expression of plk1DeltaN resulted irk repeated cycles of bipolar spindle formation and disruption, suggestive of a defect in spindle stability. A prolonged arrest frequently led to the generation of micronucleated cells in the absence of sisterchromatid separation and centrosome duplication, indicating that micronucleation is not a result of accumulated cytokinesis failures. Interestingly, bypass of the mitotic arrest by dominant-negative spindle checkpoint components led to a failure in completion of cytokinesis. We propose that, in mammalian cells, the polo-box-dependent Plk1 activity is required for proper metaphase/anaphase transition and for cytokinesis. C1 NCI, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Lee, KS (reprint author), NCI, Ctr Canc Res, Lab Metab, NIH, 9000 Rockville Pike,Bldg 37,Rm 3D25, Bethesda, MD 20892 USA. NR 42 TC 162 Z9 163 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32282 EP 32293 DI 10.1074/jbc.M202602200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700123 PM 12034729 ER PT J AU Yan, ZJ Kim, YS Jetten, AM AF Yan, ZJ Kim, YS Jetten, AM TI RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING PROPERTIES; ORPHAN RECEPTOR; HORMONE RECEPTORS; RESPONSE ELEMENT; XENOPUS-LAEVIS; CLONING; SUPERFAMILY; EXPRESSION; REPRESSOR; GENE AB In this study, we describe the characterization of a novel nuclear protein, referred to as RAP80. The RAP80 cDNA was cloned from a human testis cDNA library and encodes a 719-amino acid protein containing two potential CX2CX11HX3C-type zinc finger motifs at its carboxyl-terminal region. Analysis of its genomic structure revealed that the RAP80 gene covers more than 90 kb and consists of 15 exons and 14 introns. Fluorescence in situ hybridization mapped the RAP80 gene to human chromosome 5q35. RAP80 mRNA is expressed in many human tissues, but its expression is particularly high in testis. In situ hybridization showed that RAP80 is highly expressed in germ cells of mouse testis but is not differentially regulated during spermatogenesis. Confocal microscopy showed that RAP80 is localized to the nucleus, where it is distributed in a speckled pattern. Deletion analysis showed that a bipartite nuclear localization signal at the amino terminus is important in mediating nuclear transport of RAP80. Monohybrid analysis showed that RAP80 might function as an active repressor of transcription. Mammalian two-hybrid analysis demonstrated that RAP80 was able to interact with the retinoid-related testis-associated receptor (RTR), an orphan receptor that has been implicated in the control of embryonic development and spermatogenesis. Pull-down analysis showed that RAP80 and RTR physically interact in vitro. Deletion and point mutation analyses revealed that part of the hinge domain of RTR is required for this interaction. RAP80 is able to inhibit the interaction of RTR with the co-repressor N-CoR likely by competing with N-CoR for RTR binding. Our results suggest that RAP80 may be functioning as a modulator of RTR signaling. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 43 TC 37 Z9 43 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32379 EP 32388 DI 10.1074/jbc.M203475200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700134 PM 12080054 ER PT J AU Hartsough, MT Morrison, DK Salerno, M Palmieri, D Ouatas, T Mair, M Patrick, J Steeg, PS AF Hartsough, MT Morrison, DK Salerno, M Palmieri, D Ouatas, T Mair, M Patrick, J Steeg, PS TI Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of ras via a histidine protein kinase pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID NUCLEOSIDE-DIPHOSPHATE KINASE; BREAST-CARCINOMA CELLS; GTP-BINDING PROTEINS; MEDIATED SIGNAL-TRANSDUCTION; NERVE GROWTH-FACTOR; KSR-1 GENE ENCODES; TUMOR-METASTASIS; MAP KINASE; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; PHOSPHOTRANSFERASE ACTIVITY AB The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of Arabidopsis "two-component" histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein kinase (MAPK) cascade. Nm23-H1 co-immuno-precipitated KSR from lysates of transiently transfected 293T cells and at endogenous protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR in vitro. Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis. C1 NCI, Pathol Lab, Womens Canc Sect,Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Steeg, PS (reprint author), NCI, Pathol Lab, Womens Canc Sect,Ctr Canc Res, NIH, Bldg 10,Rm 2A33, Bethesda, MD 20892 USA. RI Palmieri, Diane/B-4258-2015 NR 117 TC 123 Z9 131 U1 4 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2002 VL 277 IS 35 BP 32389 EP 32399 DI 10.1074/jbc.M203115200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 588UB UT WOS:000177718700135 PM 12105213 ER PT J AU Baker, SG Tockman, MS AF Baker, SG Tockman, MS TI Evaluating serial observations of precancerous lesions for further study as a trigger for early intervention SO STATISTICS IN MEDICINE LA English DT Article DE biomarker; diagnostic testing; early detection; screening ID MARKERS; CANCER AB Many long-term studies of the early detection of cancer involve serial observations of precancerous lesions and information as to whether or not the subject was diagnosed with cancer during the study period. Often the purpose of these studies is to decide whether or not the precancerous lesion should be studied in a future trial as a trigger for early intervention. A general approach to the analysis of cancer biomarkers is to estimate false and true positive rates to determine if they fall in the target region of those false and true positives that indicate promise for further study. The challenge with analysing serial data on precancerous lesions is estimating false and true positive rates when the number of observations varies among subjects. To solve this problem, we propose a Markov chain model in reverse time. The methodology is illustrated using serial observations of precancerous lesions found on sputum cytology. Published in 2002 by John Wiley Sons, Ltd. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. H Lee Moffit Canc Ctr & Res Inst, Mol Screening Program, Tampa, FL 33612 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CN-45037, P50 CA58184] NR 8 TC 6 Z9 6 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2002 VL 21 IS 16 BP 2383 EP 2390 DI 10.1002/sim.1194 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 584GJ UT WOS:000177458600008 PM 12210622 ER PT J AU Yewdell, JW Tscharke, DC AF Yewdell, JW Tscharke, DC TI Immunology - Inside the professionals SO NATURE LA English DT Editorial Material C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Tscharke, David/C-9133-2009 OI Tscharke, David/0000-0001-6825-9172 NR 6 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 29 PY 2002 VL 418 IS 6901 BP 923 EP 924 DI 10.1038/418923a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 588AP UT WOS:000177677500024 PM 12198526 ER PT J AU Pessoa, L Gutierrez, E Bandettini, PA Ungerleider, LG AF Pessoa, L Gutierrez, E Bandettini, PA Ungerleider, LG TI Neural correlates of visual working memory: fMRl amplitude predicts task performance SO NEURON LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; DELAYED-RESPONSE PERFORMANCE; GO/NO-GO DISCRIMINATION; HUMAN FRONTAL-CORTEX; UNIT-ACTIVITY; ORIENTATION DISCRIMINATION; FUNCTIONAL MRI; BRAIN ACTIVITY; SUSTAINED ACTIVITY; SPATIAL ATTENTION AB We used fMRI to investigate how moment-to-moment neural activity contributes to success or failure on individual trials of a visual working memory (WM) task. We found that different nodes of a distributed cortical network were activated to a greater extent for correct compared to incorrect trials during stimulus encoding, memory maintenance during delays, and at test. A logistic regression analysis revealed that the fMRI signal amplitude during the delay interval in a network of frontoparietal regions predicted successful performance on a trial-by-trial basis. Differential delay activity occurred even for only those trials in which BOLD activity during encoding was strong, demonstrating that it was not a simple consequence of effective versus ineffective encoding. Our results indicate that accurate memory depends on strong sustained signals that span the delay interval of WM tasks. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Pessoa, L (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NR 68 TC 239 Z9 239 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 29 PY 2002 VL 35 IS 5 BP 975 EP 987 DI 10.1016/S0896-6273(02)00817-6 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 589UY UT WOS:000177779800018 PM 12372290 ER PT J AU Pradhan, AD Manson, JE Rossouw, JE Siscovick, DS Mouton, CP Rifai, N Wallace, RB Jackson, RD Pettinger, MB Ridker, PM AF Pradhan, AD Manson, JE Rossouw, JE Siscovick, DS Mouton, CP Rifai, N Wallace, RB Jackson, RD Pettinger, MB Ridker, PM TI Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease - Prospective analysis from the Women's Health Initiative observational study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PLASMA-CONCENTRATION; UNSTABLE ANGINA; INSULIN-RESISTANCE; ADIPOSE-TISSUE; RISK; INTERLEUKIN-6; OBESITY AB Context Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the,effect of HRT on CRP represents a clinical hazard is unknown. Objectives To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk. Design, Setting, and Participants Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years. Main Outcome Measure Incidence of first myocardial infarction or death from CHD. Results Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P < 001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P < .001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend = .002) and 3.3 for IL-6 (95% 10, 2.0-5.5; P for trend <.001), After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP. Conclusions These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6. C1 Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Prevent Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Cardiol, Boston, MA 02215 USA. Brigham & Womens Hosp, Leducq Ctr Mol & Genet Epidemiol Cardiovasc Disor, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Texas, Hlth Sci Ctr, Dept Family & Community Med, Div Community Geriatr, San Antonio, TX USA. Childrens Hosp, Med Ctr, Dept Pathol, Boston, MA 02115 USA. Univ Iowa, Coll Med, Dept Epidemiol, Iowa City, IA USA. Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98104 USA. RP Ridker, PM (reprint author), Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. FU NHLBI NIH HHS [HL 07575, HL 63293]; WHI NIH HHS [N01-WH-3-2109] NR 38 TC 433 Z9 443 U1 2 U2 8 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 AUG 28 PY 2002 VL 288 IS 8 BP 980 EP 987 DI 10.1001/jama.288.8.980 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 587RM UT WOS:000177656400023 PM 12190368 ER PT J AU Waters, NC Kopydlowski, KM Guszczynski, T Wei, L Sellers, P Ferlan, JT Lee, PJ Li, ZY Woodard, CL Shallom, S Gardner, MJ Prigge, ST AF Waters, NC Kopydlowski, KM Guszczynski, T Wei, L Sellers, P Ferlan, JT Lee, PJ Li, ZY Woodard, CL Shallom, S Gardner, MJ Prigge, ST TI Functional characterization of the acyl carrier protein (PfACP) and beta-ketoacyl ACP synthase III (PfKASIII) from Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE malaria; Plasmodium falciparum; fatty acid biosynthesis; acyl carrier protein; ACR; FabH; FabI; beta-ketoacyl-ACP synthase III; KASIII; ENR; enoyl-ACP reductase; acetyl-coenzyme A ID FATTY-ACID BIOSYNTHESIS; STREPTOMYCES-COELICOLOR A3(2); ESCHERICHIA-COLI; TOXOPLASMA-GONDII; PURIFICATION; EXPRESSION; MALARIA; APICOMPLEXAN; INHIBITION; REDUCTASE AB The genome of the malaria parasite, Plasmodium falciparum, appears to contain the proteins necessary for a Type II dissociated fatty acid biosynthetic system. Here we report the functional characterization of two proteins from this system. Purified recombinant acyl carrier protein (ACP) and beta-ketoacyl-ACP synthase III (KASIII) from P. falciparum are soluble and active in a truncated form. Malarial ACP is activated by the addition of a 4'-phosphopantetheine prosthetic group derived from coenzyme A, generating holo-PfACP. Holo-PfACP is an effective substrate for the transacylase activity of PfKASIII, but substitution of a key active site cysteine in PfKASIII to alanine or serine abolishes enzymatic activity. During the schizont stage of parasite development, there is a significant up-regulation of the mRNAs corresponding to these proteins, indicating an important metabolic requirement for fatty acids during this stage. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Inst Genomic Res, Rockville, MD 20850 USA. Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Malaria Res Inst, Baltimore, MD 21205 USA. RP Prigge, ST (reprint author), Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA. NR 39 TC 40 Z9 43 U1 1 U2 2 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 AUG 28 PY 2002 VL 123 IS 2 BP 85 EP 94 AR PII S0166-6851(02)00140-8 DI 10.1016/S0166-6851(02)00140-8 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 606LQ UT WOS:000178735800001 PM 12270624 ER PT J AU Lenfant, C AF Lenfant, C TI Report of the task force on research in pediatric cardiovascular disease SO CIRCULATION LA English DT Article DE cardiovascular diseases; heart diseases; pediatrics C1 NHLBI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NR 0 TC 15 Z9 15 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 27 PY 2002 VL 106 IS 9 BP 1037 EP 1042 DI 10.1161/01.CIR.0000031063.20871.B5 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 590AK UT WOS:000177794800011 PM 12196324 ER PT J AU Platt, J DiSesa, V Gail, D Massicot-Fisher, J AF Platt, J DiSesa, V Gail, D Massicot-Fisher, J TI Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Xenotransplantation Working Group SO CIRCULATION LA English DT Article DE heart failure; National Institutes of Health; pulmonary disease; transplantation; transplantation, heterologous AB The National Heart, Lung, and Blood Institute (NHLBI) recently convened the Heart and Lung Xenotransplantation Working Group to identify hurdles to the clinical application of xenotransplantation, defined as the use of animal organs or tissue for transplantation, and to recommend possible solutions to these problems. The group consisted of experts in xenotransplantation from academia, industry, and federal agencies, and the discussions focused on those areas within the mission of the NHLBI. The areas covered included immunologic and physiological barriers to xenotransplantation, the limitations of the current animal models, the need for collaboration among groups, the high costs of studies using nonhuman primates and genetic engineering of pigs, and the unique problems of lung xenotransplantation. This report is a summary of those discussions. C1 NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. NHLBI, Div Head & Vasc Dis, NIH, Bethesda, MD 20892 USA. Mayo Clin, Dept Surg, Rochester, MN USA. Mayo Clin, Dept Immunol, Rochester, MN USA. Mayo Clin, Dept Pediat, Rochester, MN USA. Chester Cty Hosp, Dept Surg, Sect Cardiac Surg, W Chester, PA USA. RP Massicot-Fisher, J (reprint author), NHLBI, Div Lung Dis, NIH, 6701 Rockledge Dr,MSC 7940, Bethesda, MD 20892 USA. NR 8 TC 19 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 27 PY 2002 VL 106 IS 9 BP 1043 EP 1047 DI 10.1161/01.CIR.0000031064.67525.28 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 590AK UT WOS:000177794800012 PM 12196325 ER PT J AU Lewis, DW Ashwal, S Dahl, G Dorbad, D Hirtz, D Prensky, A Jarjour, I AF Lewis, DW Ashwal, S Dahl, G Dorbad, D Hirtz, D Prensky, A Jarjour, I TI Practice parameter: Evaluation of children and adolescents with recurrent headaches - Report of the quality standards subcommittee of the American Academy of Neurology and the practice Committee of the Child Neurology Society SO NEUROLOGY LA English DT Article ID MIGRAINE; PREVALENCE; EPIDEMIOLOGY; SCHOOL; EEG AB Objective: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. For this parameter, the authors reviewed available evidence on the evaluation of the child with recurrent headaches and made recommendations based on this evidence. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. Results: There is inadequate documentation in the literature to support any recommendation as to the appropriateness of routine laboratory studies or performance of lumbar puncture. EEG is not recommended in the routine evaluation, as it is unlikely to define or determine an etiology or distinguish migraine from other types of headaches. In those children undergoing evaluation for recurrent headache found to have a paroxysmal EEG, the risk for future seizures is negligible; therefore, further investigation for epilepsy or treatments aimed at preventing future seizures is not indicated. Obtaining a neuroimaging study on a routine basis is not indicated in children with recurrent headaches and a normal neurologic examination. Neuroimaging should be considered in children with an abnormal neurologic examination or other physical findings that suggest CNS disease. Variables that predicted the presence of a space-occupying lesion included 1) headache of less than 1-month duration; 2) absence of family history of migraine; 3) abnormal neurologic findings on examination; 4) gait abnormalities; and 5) occurrence of seizures. Conclusions: Recurrent headaches occur commonly in children and are diagnosed on a clinical basis rather than by any testing. The routine use of any diagnostic studies is not indicated when the clinical history has no associated risk factors and the child's examination is normal. C1 Childrens Hosp Kings Daughters, Eastern Virginia Med Sch, Dept Pediat, Norfolk, VA USA. Loma Linda Univ, Sch Med, Dept Pediat, Loma Linda, CA USA. NINDS, Bethesda, MD 20892 USA. St Louis Childrens Hosp, Dept Pediat, St Louis, MO 63110 USA. Med Coll Penn & Hahnemann Univ, Sch Med, MCP, Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. RP Lewis, DW (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. NR 41 TC 150 Z9 153 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 AUG 27 PY 2002 VL 59 IS 4 BP 490 EP 498 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 586YJ UT WOS:000177613500006 PM 12196640 ER PT J AU Theodore, WH Hunter, K Chen, R Vega-Bermudez, F Boroojerdi, B Reeves-Tyer, P Werhahn, K Kelley, KR Cohen, L AF Theodore, WH Hunter, K Chen, R Vega-Bermudez, F Boroojerdi, B Reeves-Tyer, P Werhahn, K Kelley, KR Cohen, L TI Transcranial magnetic stimulation for the treatment of seizures SO NEUROLOGY LA English DT Article ID ELECTRICAL-STIMULATION; CORTEX EXCITABILITY; BRAIN-STIMULATION; RATS; SUSCEPTIBILITY; INDUCTION; AMYGDALA AB Objective: To perform a controlled trial of transcranial magnetic stimulation (TMS). Methods: Twenty-four patients with localization-related epilepsy were randomized to blinded active or placebo stimulation. Weekly seizure frequency was compared for 8 weeks before and after 1 week of 1-Hz TMS for 15 minutes twice daily. Results: When the 8-week baseline and post-stimulation periods were compared, active patients had a mean seizure frequency reduction of 0.045 +/- 0.13 and sham-stimulated control subjects -0.004 +/- 0.20. Over 2 weeks, actively treated patients had a mean reduction in weekly seizure frequency of 0.16 +/- 0.18 and sham-stimulated control subjects 0.01 +/- 0.24. Neither difference was significant. Conclusion: The effect of TMS on seizure frequency was mild and short lived. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,5N-250, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 23 TC 133 Z9 141 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 27 PY 2002 VL 59 IS 4 BP 560 EP 562 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 586YJ UT WOS:000177613500016 PM 12196649 ER PT J AU Hale, DA Gottschalk, R Umemura, A Maki, T Monaco, AP AF Hale, DA Gottschalk, R Umemura, A Maki, T Monaco, AP TI Immunologic mechanisms in tolerance produced in mice with nonradiation-based lymphoablation and donor-specific bone marrow SO TRANSPLANTATION LA English DT Article ID MIXED ALLOGENEIC CHIMERAS; SKIN ALLOGRAFTS; ANTILYMPHOCYTE-SERUM; INJECTED MICE; NONSPECIFIC SUPPRESSION; TRANSPLANT RECIPIENTS; CLONAL DELETION; SPLEEN-CELLS; T-CELLS; UNRESPONSIVENESS AB Background. These experiments evaluate the mechanisms associated with tolerance in mice treated with sirolimus, antilymphocyte serum (ALS), and donor-specific bone marrow (MM). Methods. Tolerance to fully MHC-incompatible skin allografts was induced as follows: C57B1/10 (H2(b)) recipients received 0.5 mL of rabbit anti-mouse polyclonal ALS on days -1, +2, and +5 relative to B10.A (H2(k)) donor skin grafting on day 0. Sirolimus was given in a single dose (24 mg/kg intraperitoneally) on day 6. Freshly harvested B10.A (H2(k)) donor-specific BM was administered at a dose of 25 x 10(6) (ALS/BM25/sirolimus) or 150 x 10(6) (ALS/BM150/sirolimus) cells intravenously on day 7. Skin allograft survival was correlated with the recipient's immunologic status. Recipients were assayed for suppressor cell activity (mixed lymphocyte coculture assays), clonal deletion (T-cell receptor Vbeta11 assay), peripheral and thymic chimerism (flow cytometry and reverse transcriptase polymerase chain reaction), and anergy (response to exogenous interleukin 2). Results. Mice treated with ALS/BM25/sirolimus showed specifically prolonged but not indefinite allograft survival (median survival time 116 days). Allograft survival correlated with donor-specific clonal. deletion and the presence of donor class II mRNA in the recipient's thymus. Mice given the ALS/BM150/sirolimus protocol showed indefinite donor-specific tolerance. Tolerance could not be broken with the administration of high doses of interleukin 2. Splenocytes taken from mice 14 days after tolerance induction inhibited donor-specific and third-party mixed lymphocyte culture proliferation in a dose-dependent fashion. This suppression could be ablated by depleting splenocytes of cells of donor origin before use in coculture. Clonal deletion was detectable 30 days after tolerance induction in mice treated with ALS/BM150/sirolimus and was maintained indefinitely. Conclusiom Induction of tolerance by ALS, BM, and sirolimus results in a state of donor-specific tolerance, and multilineage chimeirism evolves that is permanent and associated with clonal deletion of alloreactive T cells. C1 Beth Israel Deaconess Med Ctr, Div Organ Transplantat, Boston, MA 02215 USA. RP Hale, DA (reprint author), NIDDK, NNTAB, NIH, Bldg 10,Room 11S219,10 Ctr Dr, Bethesda, MD 20892 USA. NR 31 TC 19 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2002 VL 74 IS 4 BP 477 EP 484 DI 10.1097/00007890-200208270-00008 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 590FV UT WOS:000177808600008 PM 12352905 ER PT J AU Wang, XQ McLachlan, J Zamore, PD Hall, TMT AF Wang, XQ McLachlan, J Zamore, PD Hall, TMT TI Modular recognition of RNA by a human pumilio-homology domain SO CELL LA English DT Article ID HUNCHBACK MESSENGER-RNA; SPERM-OOCYTE SWITCH; CAENORHABDITIS-ELEGANS; MOLECULAR REPLACEMENT; DROSOPHILA EMBRYOS; BINDING PROTEIN; NANOS; REGULATOR; SEQUENCE; PROGRAM AB Puf proteins are developmental regulators that control mRNA stability and translation by binding sequences in the 3' untranslated regions of their target mRNAs. We have determined the structure of the RNA binding domain of the human Puf protein, Pumilio 1 , bound to a high-affinity RNA ligand. The RNA binds the concave surface of the molecule, where each of the protein's eight repeats makes contacts with a different RNA base via three amino acid side chains at conserved positions. We have mutated these three side chains in one repeat, thereby altering the sequence specificity of Pumilio 1. Thus, the high affinity and specificity of the PUM-HD for RNA is achieved using multiple copies of a simple repeated motif. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Biol, Worcester, MA 01655 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Zamore, Phillip/A-8941-2013 NR 35 TC 272 Z9 278 U1 9 U2 29 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 23 PY 2002 VL 110 IS 4 BP 501 EP 512 DI 10.1016/S0092-8674(02)00873-5 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 587QJ UT WOS:000177653200011 PM 12202039 ER PT J AU Vinogradova, TM Bogdanov, KY Lakatta, EG AF Vinogradova, TM Bogdanov, KY Lakatta, EG TI Novel perspectives on the beating rate of the heart SO CIRCULATION RESEARCH LA English DT Letter ID INTRACELLULAR CA2+ RELEASE; SINOATRIAL NODE; PACEMAKER CELLS C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Vinogradova, TM (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. NR 10 TC 11 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 23 PY 2002 VL 91 IS 4 BP E3 EP E3 DI 10.1161/01.RES.0000031164.28289.55 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 591UZ UT WOS:000177899800015 PM 12193471 ER PT J AU Chen, Y Derin, R Petralia, RS Li, M AF Chen, Y Derin, R Petralia, RS Li, M TI Actinfilin, a brain-specific actin-binding protein in postsynaptic density SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POTASSIUM CHANNEL; DENDRITIC SPINES; BTB DOMAIN; POZ-DOMAIN; KELCH; FAMILY; CELLS; MECHANISMS; COMPLEX; ENCODES AB The dynamic assembly and disassembly of actin-based cytoskeleton is closely linked to the changes in the postsynaptic density in both number and shape, which is thought to be important in forming long-term memory. Thus, regulation of actin filaments may play a critical role in contributing to the formation of long-term memory. Here, we report the cloning of actinfilin, a brain-specific Kelch protein, which interacts with F-actin. Actinfilin contains an amino-terminal POZ/BTB domain and carboxyl positioned six tandem Kelch repeats that presumably form six blades of beta-propeller structure of the Kelch domain. Co-immunoprecipitation analyses showed that the amino-terminal POZ domain mediated actinfilin-actinfilin interaction. The recombinant Kelch domain alone was sufficient to mediate binding to F-actin. Immunohistochemistry studies of rat brain sections suggested that actinfilin is broadly expressed in neurons of most regions of the brain. The subcellular localization of actinfilin was studied by biochemical fractionation and immunogold labeling. The results showed the postsynaptic density distribution of actinfilin. Together, these results indicate that actinfilin may be a key player in the actin-based neuronal function. C1 Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NIDCD, NIH, Bethesda, MD 20892 USA. RP Li, M (reprint author), Johns Hopkins Univ, Sch Med, Dept Physiol, WBSB 216,725 N Wolfe St, Baltimore, MD 21205 USA. NR 33 TC 25 Z9 26 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30495 EP 30501 DI 10.1074/jbc.M202076200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800014 PM 12063253 ER PT J AU Beamish, H Kedar, P Kaneko, H Chen, P Fukao, T Peng, C Beresten, S Gueven, N Purdie, D Lees-Miller, S Ellis, N Kondo, N Lavin, MF AF Beamish, H Kedar, P Kaneko, H Chen, P Fukao, T Peng, C Beresten, S Gueven, N Purdie, D Lees-Miller, S Ellis, N Kondo, N Lavin, MF TI Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NIJMEGEN BREAKAGE SYNDROME; DNA-DAMAGE RESPONSE; S-PHASE; SYNDROME CELLS; SYNDROME GENE; DEPENDENT PHOSPHORYLATION; IONIZING-RADIATION; CHECKPOINT PATHWAY; POSITIONAL CLONING; NUCLEAR-STRUCTURE AB Chromosome aberrations, genomic instability, and cancer predisposition are hallmarks of a number of syndromes in which the defective genes recognize and/or repair DNA damage or are involved in some aspect of DNA processing. We report here direct interaction between BLM, mutated in Bloom's Syndrome (BS), and ATM, mutated is ataxia-telangiectasia, and we have mapped the sites of interaction. Full-length BLM cDNA corrected sister chromatid exchange (SCE) and radiosensitivity in BS cells. Mitotic phosphorylation of BLM was partially dependent on ATM, and phosphorylation sites on BLM were identified. A phosphospecific antibody against one of these sites (Thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. Stable cell lines expressing phosphorylation site mutants failed to correct radiosensitivity in BS cells but corrected SCE. These mutants also sensitized normal control cells to radiation and increased radiation-induced chromosome aberrations but did not cause SCE numbers to increase. These data suggest that ATM and BLM function together in recognizing abnormal DNA structures by direct interaction and that these phosphorylation sites in BLM are important for radiosensitivity status but not for SCE frequency. C1 PO Royal Brisbane Hosp, Queensland Inst Med Res, Queensland Canc Fund Res Labs, Brisbane, Qld 4029, Australia. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Gifu Univ, Sch Med, Dept Pediat, Gifu 5008076, Japan. Mem Sloan Kettering Canc Ctr, Dept Human Genet, New York, NY 10021 USA. Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. Univ Queensland, Dept Surg, Brisbane, Qld 4029, Australia. Univ Queensland, Dept Pathol, Brisbane, Qld 4029, Australia. RP Lavin, MF (reprint author), PO Royal Brisbane Hosp, Queensland Inst Med Res, Queensland Canc Fund Res Labs, Brisbane, Qld 4029, Australia. RI Lavin, Martin/F-5961-2014; Peng, Cheng/G-4845-2010 OI Lavin, Martin/0000-0002-5940-4769; FU NCI NIH HHS [R01 CA085867, R01 CA085867-02] NR 49 TC 90 Z9 91 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30515 EP 30523 DI 10.1074/jbc.M203801200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800017 PM 12034743 ER PT J AU Garcia-Barrio, M Dong, JS Cherkasova, VA Zhang, XL Zhang, F Ufano, S Lai, R Qin, J Hinnebusch, AG AF Garcia-Barrio, M Dong, JS Cherkasova, VA Zhang, XL Zhang, F Ufano, S Lai, R Qin, J Hinnebusch, AG TI Serine 577 is phosphorylated and negatively affects the tRNA binding and eIF2 alpha kinase activities of GCN2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION FACTOR-II; TRANSFER-RNA-SYNTHETASES; ACID-STARVED CELLS; PROTEIN-KINASE; SACCHAROMYCES-CEREVISIAE; TRANSLATIONAL ACTIVATION; YEAST; DOMAIN; EXPRESSION; GENE AB Protein kinase GCN2 regulates translation initiation by phosphorylating eukaryotic initiation factor 2alpha (eIF2alpha), impeding general protein synthesis but specifically inducing translation of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. GCN2 activity is stimulated in amino acid-deprived cells through binding of uncharged tRNA to a domain related to histidyl tRNA synthetase. We show that GCN2 is phosphorylated by another kinase on serine 577, located N-terminal to the kinase domain. Mutation of Ser-577 to alanine produced partial activation of GCN2 in nonstarved cells, increasing the level of phosphorylated eIF2alpha, derepressing GCN4 expression, and elevating the cellular levels of tryptophan and histidine. The Ala-577 mutation also increased the tRNA binding affinity of purified GCN2, which can account for the elevated kinase activity of GCN2-S577A in nonstarved cells where uncharged tRNA levels are low. Whereas Ser-577 remains phosphorylated in amino acid-starved cells, its dephosphorylation could mediate GCN2 activation in other stress or starvation conditions by lowering the threshold of uncharged tRNA required to activate the protein. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 6A,Rm B1A13, Bethesda, MD 20892 USA. NR 45 TC 25 Z9 26 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30675 EP 30683 DI 10.1074/jbc.M203187200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800036 PM 12070158 ER PT J AU Tuo, JS Jaruga, P Rodriguez, H Dizdaroglu, M Bohr, VA AF Tuo, JS Jaruga, P Rodriguez, H Dizdaroglu, M Bohr, VA TI The Cockayne syndrome group B gene product is involved in cellular repair of 8-hydroxyadenine in DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVELY DAMAGED DNA; TANDEM MASS-SPECTROMETRY; BASE EXCISION-REPAIR; COLI FPG PROTEIN; SUBSTRATE-SPECIFICITY; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; GLYCOSYLASE ACTIVITY; IONIZING-RADIATION; PUTATIVE HELICASES AB Cockayne syndrome (CS) is a human disease characterized by sensitivity to sunlight, severe neurological abnormalities, and accelerated aging. CS has two complementation groups, CS-A and CS-B. The CSB gene encodes the CSB protein with 1493 amino acids. We previously reported that the CSB protein is involved in cellular repair of 8-hydroxyguanine, an abundant lesion in oxidatively damaged DNA and that the putative helicase motif V/VI of the CSB may play a role in this process. The present study investigated the role of the CSB protein in cellular repair of 8-hydroxyadenine (8-OH-Ade), another abundant lesion in oxidatively damaged DNA. Extracts of CS-B-null cells and mutant cells with site-directed mutation in the motif VI of the putative helicase domain incised 8-hydroxyadenine in vitro less efficiently than wild type cells. Furthermore, CS-B-null and motif VI mutant cells accumulated more 8-hydroxyadenine in their genomic DNA than wild type cells after exposure to gamma-radiation at doses of 2 or 5 Gy. These results suggest that the CSB protein contributes to cellular repair of 8-OH-Ade and that the motif VI of the putative helicase domain of CSB is required for this activity. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RI Jaruga, Pawel/M-4378-2015 NR 48 TC 60 Z9 62 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30832 EP 30837 DI 10.1074/jbc.M204814200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800056 PM 12060667 ER PT J AU Fischer, L Boland, G Tuan, RS AF Fischer, L Boland, G Tuan, RS TI Wnt-3A enhances bone morphogenetic protein-2-mediated chondrogenesis of murine C3H10T1/2 mesenchymal cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; INTEGRIN-LINKED-KINASE; TRANSCRIPTION FACTOR LEF-1; N-CADHERIN EXPRESSION; CHICK LIMB BUD; BETA-CATENIN; SIGNALING PATHWAYS; PROTEIN-KINASE; MICROMASS CULTURES; PATTERN-FORMATION AB We have recently reported the chondrogenic effect of bone morphogenetic protein-2 (BMP-2) in high density cultures of the mouse multipotent mesenchymal C3H10T1/2 cell line and have shown the functional requirement of the cell-cell adhesion molecule N-cadherin in BMP-2-induced chondrogenesis in vitro (Denker, A. E., Nicoll, S. B., and Tuan, R. S. (1995) Differentiation 59, 25-34; Haas, A. R., and Tuan, R. S. (1999) Differentiation 64, 77-89). Furthermore, BMP-2 treatment also results in an increased protein level of beta-catenin, a known N-cadherin-associated Wnt signal transducer (Fischer, L., Haas, A., and Tuan, R. S. (2001) Signal Transduction 2, 66-78), suggesting functional cross-talk between the BW-2 and Wnt signaling pathways. We have observed previously that BMP-2 treatment up-regulates expression of Wnt-3A in high density cultures of C3H10T1/2 cells. To assess the contribution of Wnt-3A to BMP-2-mediated chondrogenesis, we have generated C3H10T1/2 cell lines overexpressing Wnt-3A and various forms of glycogen synthase kinase-3beta (GSK-3beta), an immediate cytosolic component of the Wnt signaling pathway, and examined their response to BMP-2. We show that overexpression of either Wnt-3A or kinase-dead GSK-3beta enhances BMP-2-mediated chondrogenesis. Furthermore, Wnt-3A overexpression results in decreases in both N-cadherin and GSK-3beta protein levels, whereas Wnt-3A as well as kinase-dead GSK-3beta overexpression increase total and nuclear levels of both beta-catenin and LEF-1. Direct cross-talk between Wnts and BMP-2 was also indicated by the up-regulated interaction between beta-catenin and SMAD-4 in response to BMP-2. These results suggest that Wnt-3A acts in a manner opposite to that of other Wnts, such as Wnt-7A which were previously identified as inhibitory to chondrogenesis, and is the first BMP-2-regulated, chondrogenesis-enhancing member of the Writ family. C1 NIAMS, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthoped Surg, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Grad Programs Biochem & Mol Biol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Cell & Tissue Engn, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMS, Cartilage Biol & Orthoped Branch, NIH, Bldg 50,Rm 1503,50 S Dr,MSC 8022, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR 45181, AR 39740]; NIDCR NIH HHS [DE 12864]; NIEHS NIH HHS [ES 07005] NR 65 TC 99 Z9 103 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30870 EP 30878 DI 10.1074/jbc.M109330200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800061 PM 12077113 ER PT J AU Kim, YS Lewandoski, M Perantoni, AO Kurebayashi, S Nakanishi, G Jetten, AM AF Kim, YS Lewandoski, M Perantoni, AO Kurebayashi, S Nakanishi, G Jetten, AM TI Identification of Glis1, a novel Gli-related, Kruppel-like zinc finger protein containing transactivation and repressor functions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOUSE LIMB DEVELOPMENT; HEDGEHOG-PATCHED-GLI; ZIC GENE FAMILY; SONIC-HEDGEHOG; TRANSCRIPTIONAL REPRESSOR; CUBITUS-INTERRUPTUS; DROSOPHILA EMBRYO; KINASE-IV; EXPRESSION; ACTIVATION AB In this study, we describe the identification and characterization of a novel Kruppel-like protein named Gli-similar 1 (Glis1). The Glis1 gene encodes an 84.3-kDa proline-rich protein. Its five tandem zinc finger motifs exhibit highest homology with those of members of the Gli and Zic subfamilies of Kruppel-like proteins. Glis1 was mapped to mouse chromosome 4C6. Northern blot analysis showed that expression of the 3.3-kb Glisl mRNA is most abundant in placenta and adult kidney and expressed at lower levels in testis. Whole mount in situ hybridization on mouse embryos demonstrated that Glisl is expressed in a temporal and spatial manner during development; expression was most prominent in several defined structures of mesodermal lineage, including craniofacial regions, branchial arches, somites, vibrissal and hair follicles, limb buds, and myotomes. Confocal microscopic analysis showed that Glis1 is localized to the nucleus. The zinc finger region plays an important role in the nuclear localization of Glis1. Electrophoretic mobility shift assays demonstrated that Glis1 is able to bind oligonucleotides containing the Gli-binding site consensus sequence GACCACCCAC. Although monohybrid analysis showed that in several cell types Glis1 was unable to induce transcription of a reporter, deletion mutant analysis revealed the presence of a strong activation function at the carboxyl terminus of Glis1. The activation through this activation function was totally suppressed by a repressor domain at its amino terminus. Constitutively active Ca2+-dependent calmodulin kinase IV enhanced Glis1-mediated transcriptional activation about 4-fold and may be mediated by phosphorylation/activation of a co-activator. Our results suggest that Glis1 may play a critical role in the control of gene expression during specific stages of embryonic development. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 76 TC 31 Z9 34 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 30901 EP 30913 DI 10.1074/jbc.M203563200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800065 PM 12042312 ER PT J AU Iwanaga, Y Kasai, T Kibler, K Jeang, KT AF Iwanaga, Y Kasai, T Kibler, K Jeang, KT TI Characterization of regions in hsMAD1 needed for binding hsMAD2 - A polymorphic change in an hsMAD1 leucine zipper affects MAD1-MAD2 interaction and spindle checkpoint function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOTIC CHECKPOINT; PROMOTING COMPLEX; BUDDING YEAST; PROTEIN MAD2; LUNG-CANCER; CENP-E; GENES; KINETOCHORES; HBUB1; MITOSIS AB In eukaryotes, the mitotic spindle assembly checkpoint provides a monitor for the fidelity of chromosomal segregation. In this context, the mitotic arrest deficiency protein 2 (MAD2) censors chromosomal mis-segregation by monitoring microtubule attachment/tension, a role that requires its attachment to kinetochores. Studies in yeast have shown that binding of MAD1 to MAD2 is important for the checkpoint function of the latter. The interactions between human MAD1 (hsMAD1) and human MAD2 (hsMAD2) have, however, remained poorly characterized. Here we report that two leucine zipper domains (amino acids 501-522 and 557-571) in hsMAD1 are required for its contact with hsMAD2. Interestingly, in several cancer cell lines, we noted the frequent presence of a coding single nucleotide Arg to His polymorphism at codon 558 located within the second leucine zipper of hsMAD1. We found that hsMAD1H558 is less proficient than hsMAD1R558 in binding hsMAD2 and in enforcing mitotic arrest. We also document a first example of loss-of-heterozygosity for a spindle checkpoint gene (at the hsMAD1 558 locus) in a human breast cancer. Based on our findings, it is possible that hsMAD1H558 could be an at-risk polymorphism that contributes to attenuated spindle checkpoint function in human cells. C1 NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), Bldg 4,Rm 306,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 43 TC 41 Z9 42 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 31005 EP 31013 DI 10.1074/jbc.M110666200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800078 PM 12042300 ER PT J AU Kedar, PS Kim, SJ Robertson, A Hou, E Prasad, R Horton, JK Wilson, SH AF Kedar, PS Kim, SJ Robertson, A Hou, E Prasad, R Horton, JK Wilson, SH TI Direct interaction between mammalian DNA polymerase beta and proliferating cell nuclear antigen SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; PURIFIED HUMAN PROTEINS; NEGATIVE GROWTH-CONTROL; REPLICATION-FACTOR-C; LIGASE-I; POLY(ADP-RIBOSE) POLYMERASE-1; BOVINE TESTIS; FACTOR PCNA; BINDING; RECONSTITUTION AB Proliferating cell nuclear antigen (PCNA) plays an essential role in nucleic acid metabolism as a component of the DNA replication and DNA repair machinery. As such, PCNA interacts with many proteins that have a sequence motif termed the PCNA interacting motif (PIM) and also with proteins lacking a PIM. Three regions in human and rat DNA polymerases beta (beta-pol) that resemble the consensus PIM were identified, and we show here that beta-polymerase and PCNA can form a complex both in vitro and in vivo. Immunoprecipitation experiments, yeast two-hybrid analysis, and overlay binding assays were used to examine the interaction between the two proteins. Competition experiments with synthetic PIM-containing peptides suggested the importance of a PIM in the interaction, and studies of a beta-polymerase PIM mutant, H222A/F223A, demonstrated that this alteration blocked the interaction with PCNA. The results indicate that at least one of the PIM-like sequences in beta-polymerase appears to be a functional PIM and was required in the interaction between beta-polymerase and PCNA. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 63 TC 95 Z9 100 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2002 VL 277 IS 34 BP 31115 EP 31123 DI 10.1074/jbc.M201497200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 586JA UT WOS:000177579800091 PM 12063248 ER PT J AU Yoshimura, Y Moon, HR Choi, Y Marquez, VE AF Yoshimura, Y Moon, HR Choi, Y Marquez, VE TI Enantioselective synthesis of bicyclo[3.1.0]hexane carbocyclic nucleosides via a lipase-catalyzed asymmetric acetylation. Characterization of an unusual acetal byproduct SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ADENOSINE RECEPTOR AGONISTS; (CYTOSINE C5)-METHYLTRANSFERASE; BIOLOGICAL-ACTIVITY; NEPLANOCIN-C; SUGAR RING; ANALOGS; OLIGONUCLEOTIDES; DEAMINASE; NUCLEOTIDES; THYMIDINE AB The bicyclo [3.1.0] hexane scaffold can lock the conformation of a carbocyclic nucleoside into one of the two antipodal (north or south) conformations typical of conventional nucleosides that normally exist in a rapid, two-state equilibrium in solution. In a recent brief communication, we reported a practical method to access the requisite bicyclo[3.1.0]hexane pseudosugar for the north antipode via an intramolecular olefin-ketocarbene cycloaddition. The most attractive features of this synthesis was that a relatively complex synthon was obtained from simple and inexpensive starting materials and that the resulting racemic mixtures of purine nucleosides could be successfully resolved by adenosine deaminase (ADA) hydrolysis. In this work, we describe the development of a more general, lipase-catalyzed double-acetylation reaction, which could successfully resolve an earlier precursor, 4-(tert-butyldiphenylsilamethoxy)-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-oI [(+/-)71, into enantiomerically pure (+)-diacetate 8 and (-)-monoacetate 9. The former diacetate was converted to the conformationally locked (north)-carbocyclic guanosine (+)-17 identical to the one obtained previously by ADA resolution. The present method represents a more general and efficient process applicable to the synthesis of all classes of (north) bicyclo[3.1.0]hexane nucleosides, including pyrimidine analogues. During the lipase-catalyzed resolution, we were able to demonstrate the presence of an unusual acetal-forming reaction that consumed small amounts of the unreactive monoacetate (-)-9. This side reaction was also enzyme-catalyzed and was triggered by the byproduct acetaldehyde generated during the reaction. C1 NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), NCI, Ctr Canc Res, Med Chem Lab, 376 Boyles St, Frederick, MD 21702 USA. RI Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 31 TC 28 Z9 29 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 23 PY 2002 VL 67 IS 17 BP 5938 EP 5945 AR UNSP JO020249U DI 10.1021/jo020249u PG 8 WC Chemistry, Organic SC Chemistry GA 586AM UT WOS:000177559800012 PM 12182625 ER PT J AU Lehner, T Shearer, GM AF Lehner, T Shearer, GM TI Alternative HIV vaccine strategies SO SCIENCE LA English DT Letter ID ALLOIMMUNIZATION C1 Guys Kings & St Thomas Med Sch, Dept Immunobiol, London SE1 9RT, England. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Lehner, T (reprint author), Guys Kings & St Thomas Med Sch, Dept Immunobiol, London SE1 9RT, England. NR 13 TC 4 Z9 5 U1 0 U2 0 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 AUG 23 PY 2002 VL 297 IS 5585 BP 1276 EP 1277 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586FL UT WOS:000177573900019 PM 12194176 ER PT J AU Mehlmann, LM Jones, TLZ Jaffe, LA AF Mehlmann, LM Jones, TLZ Jaffe, LA TI Meiotic arrest in the mouse follicle maintained by a G(s) protein in the oocyte SO SCIENCE LA English DT Article ID BETA-GAMMA-SUBUNITS; PLATELET MEMBRANES; ADENYLYL-CYCLASE; MOLECULAR-BASIS; XENOPUS-LAEVIS; RELEASE; MATURATION; INHIBITION; INVITRO; FLUID AB The mammalian ovarian follicle consists of a multilayered complex of somatic cells that surround the oocyte. A signal from the follicle cells keeps the oocyte cell cycle arrested at prophase of meiosis I until luteinizing hormone from the pituitary acts on the follicle cells to release the arrest, causing meiosis to continue. Here we show that meiotic arrest can be released in mice by microinjecting the oocyte within the follicle with an antibody that inhibits the stimulatory heterotrimeric GTP-binding protein G(s). This indicates that G(s) activity in the oocyte is required to maintain meiotic arrest within the ovarian follicle and suggests that the follicle may keep the cell cycle arrested by activating G(s). C1 Univ Connecticut, Ctr Hlth, Dept Physiol, Farmington, CT 06032 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mehlmann, LM (reprint author), Univ Connecticut, Ctr Hlth, Dept Physiol, Farmington, CT 06032 USA. NR 28 TC 135 Z9 140 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 23 PY 2002 VL 297 IS 5585 BP 1343 EP 1345 DI 10.1126/science.1073978 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586FL UT WOS:000177573900046 PM 12193786 ER PT J AU Zhou, HX Zwanzig, R AF Zhou, HX Zwanzig, R TI Barrier crossing coupled to a small set of oscillators SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID DYNAMICS; APPROXIMATION; RELAXATION; MYOGLOBIN; KRAMERS AB This paper presents a study of the behavior of a one-dimensional system, with two potential minima separated by a barrier, coupled to a small set of harmonic oscillators. The time correlation function of equilibrium fluctuations in particle number (number correlation function) is found by computer simulation. An analogue of Kramers turnover in the barrier crossing rate is observed. The Grote-Hynes theory of non-Markovian rate processes provides a reasonable estimate for the rate constant at intermediate frictions. However, at high friction, the number correlation function becomes nonexponential, and the decay is much slower than expected from the Grote-Hynes theory. The model shows that close coupling to a small heat bath provides a mechanism for "internal friction". C1 Drexel Univ, Dept Phys, Philadelphia, PA 19104 USA. NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Zhou, HX (reprint author), Drexel Univ, Dept Phys, Philadelphia, PA 19104 USA. EM hxzhou@einstein.drexel.edu; zwanzig@sunder.niddk.nih.gov RI Zhou, Huan-Xiang/M-5170-2016 OI Zhou, Huan-Xiang/0000-0001-9020-0302 NR 9 TC 10 Z9 10 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD AUG 22 PY 2002 VL 106 IS 33 BP 7562 EP 7564 DI 10.1021/jp013707w PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 584NC UT WOS:000177472700010 ER PT J AU Oyler, NA Tycko, R AF Oyler, NA Tycko, R TI Multiple quantum C-13 NMR spectroscopy in solids under high-speed magic-angle spinning SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; STATE NMR; ROTATING SOLIDS; TORSIONAL ANGLE; TIME-REVERSAL; AMINO-ACIDS; SIDE-BAND; L-ALANINE; FAST-MAS; EXCITATION AB We demonstrate an approach to efficient excitation and detection of high-order multiple quantum (MQ) C-13 NMR signals in solids under high-speed magic angle spinning (MAS). This approach combines homonuclear dipolar recoupling by the finite-pulse radio-frequency-driven recoupling (fpRFDR) pulse sequence with multiple quantum excitation pulse sequences developed for static solids based on time reversal. MQ 13C NMR spectroscopy is demonstrated on the model compounds 1-C-13-L-alanine, C-13(epsilon)-L-methionine, and U-C-13, N-15-L-valine, at an MAS frequency of 20.0 kHz. MQ signals resulting from coherences of 8-10 spins are observed experimentally in the singly labeled model compounds. The fpRFDR-based MQ NMR technique is also applied to both singly labeled and multiply labeled peptides in the form of amyloid fibrils. Additionally, the competition between the dipolar recoupling mechanisms of fpRFDR and delta-pulse RFDR is explored by numerical effective Hamiltonian calculations. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. NR 48 TC 31 Z9 31 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 22 PY 2002 VL 106 IS 33 BP 8382 EP 8389 DI 10.1021/jp020906m PG 8 WC Chemistry, Physical SC Chemistry GA 584ND UT WOS:000177472800056 ER PT J AU Rosovitz, MJ Leppla, SH AF Rosovitz, MJ Leppla, SH TI Medicine: Virus deals anthrax a killer blow SO NATURE LA English DT Editorial Material C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Rosovitz, MJ (reprint author), Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 22 PY 2002 VL 418 IS 6900 BP 825 EP 826 DI 10.1038/418825a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 585YR UT WOS:000177555600019 PM 12192391 ER PT J AU Schneider, ME Belyantseva, IA Azevedo, RB Kachar, B AF Schneider, ME Belyantseva, IA Azevedo, RB Kachar, B TI Structural cell biology: Rapid renewal of auditory hair bundles - The recovery time after noise-induced hearing loss is in step with a molecular treadmill. SO NATURE LA English DT Article ID STEREOCILIA; RECEPTORS; COCHLEA C1 Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. RP Schneider, ME (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. RI Azevedo, Ricardo/D-6273-2012 NR 10 TC 128 Z9 135 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 22 PY 2002 VL 418 IS 6900 BP 837 EP 838 DI 10.1038/418837a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 585YR UT WOS:000177555600027 PM 12192399 ER PT J AU Fisher, B Jeong, JH Anderson, S Bryant, J Fisher, ER Wolmark, N AF Fisher, B Jeong, JH Anderson, S Bryant, J Fisher, ER Wolmark, N TI Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PRIMARY BREAST-CANCER; POSTOPERATIVE RADIOTHERAPY; ALTERNATIVE TREATMENTS; PREMENOPAUSAL WOMEN; CLINICAL-TRIAL; RISK; CHEMOTHERAPY; DISSECTION; RADIATION; CARCINOMA AB Background In women with breast cancer, the role of radical mastectomy, as compared with less extensive surgery, has been a matter of debate. We report 25-year findings of a randomized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy. Methods A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive. A total of 586 women with clinically positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation. Kaplan-Meier and cumulative-incidence estimates of outcome were obtained. Results No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival, relapse-free survival, distant-disease-free survival, or overall survival. Among women with negative nodes, the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 (95 percent confidence interval, 0.91 to 1.28; P = 0.38), and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 (95 percent confidence interval, 0.87 to 1.23; P = 0.72). Among women with positive nodes, the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 (95 percent confidence interval, 0.89 to 1.27; P = 0.49). Conclusions The findings validate earlier results showing no advantage from radical mastectomy. Although differences of a few percentage points cannot be excluded, the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy. C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Fisher, B (reprint author), Natl Surg Adjuvant Breast & Bowel Project, 4 Allegheny Ctr,Suite 602, Pittsburgh, PA 15212 USA. OI Jeong, Jong/0000-0003-0596-2201; Anderson, Stewart/0000-0001-8948-0650 FU NCI NIH HHS [U10-CA-12027, U10-CA-37377, U10-CA-69651, U10-CA-69974] NR 24 TC 597 Z9 630 U1 1 U2 9 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 22 PY 2002 VL 347 IS 8 BP 567 EP 575 DI 10.1056/NEJMoa020128 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 587ZR UT WOS:000177675400005 PM 12192016 ER PT J AU Inga, A Nahari, D Velasco-Miguel, S Friedberg, EC Resnick, MA AF Inga, A Nahari, D Velasco-Miguel, S Friedberg, EC Resnick, MA TI A novel p53 mutational hotspot in skin tumors from UV-irradiated Xpc mutant mice alters transactivation functions SO ONCOGENE LA English DT Article DE p53 gene; yeast functional assay; p53 expression; mutational hotspots; enhanced transactivation; Xpc mice ID NUCLEOTIDE EXCISION-REPAIR; WILD-TYPE P53; IN-VIVO; HUMAN CANCER; CELL-LINES; IONIZING-RADIATION; GENE-EXPRESSION; TERMINAL DOMAIN; DEFICIENT MICE; BAX PROMOTER AB A mutation in codon 122 of the mouse p53 gene resulting in a T to L amino acid substitution (T122-->L) is frequently associated with skin cancer in UV-irradiated mice that are both homozygous mutant for the nucleotide excision repair (NER) gene Xpc (Xpc-/-) and hemizygous mutant for the p53 gene. We investigated the functional consequences of the mouse T122-->L mutation when expressed either in mammalian cells or in the yeast Saccharomyces cerevisiae. Similar to a non-functional allele, high expression of the T122-->L allele in p53-/- mouse embryo fibroblasts and human Saos-2 cells failed to suppress growth. However, the T122-->L mutant p53 showed wild-type transactivation levels with Bax and MDM2 promoters when expressed in either cell type and retained transactivation of the p21 and the c-Fos promoters in one cell line. Using a recently developed rheostatable p53 induction system in yeast we assessed the T122-->L transactivation capacity at low levels of protein expression using 12 different p53 response elements (REs). Compared to wild-type p53 the T122-->L protein manifested an unusual transactivation pattern comprising reduced and enhanced activity with specific REs. The high incidence of the T122-->L mutant allele in the Xpc-/- background suggests that both genetic and epigenetic conditions may facilitate the emergence of particular functional p53 mutations. Furthermore, the approach that we have taken also provides for the dissection of functions that may be retained in many p53 tumor alleles. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Dept Pathol, Lab Mol Pathol, SW Med Ctr, Dallas, TX 75390 USA. RP Resnick, MA (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233,Mail Drop D3-01,TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 66 TC 11 Z9 12 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 22 PY 2002 VL 21 IS 37 BP 5704 EP 5715 DI 10.1038/sj.onc.1205779 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 584JL UT WOS:000177463400005 PM 12173040 ER PT J AU Yao, RS Wang, Y Lubet, RA You, M AF Yao, RS Wang, Y Lubet, RA You, M TI Differentially expressed genes associated with mouse lung tumor progression SO ONCOGENE LA English DT Article DE mouse; lung; adenoma; adenocarcinoma; lung tumor progression gene; gene expression ID CELL-CYCLE ARREST; CANCER-CELLS; RETINOBLASTOMA PROTEIN; PRENEOPLASTIC LESIONS; CDK INHIBITORS; BETA; ADENOCARCINOMA; ACTIVATION; NEOPLASIA; MUTATIONS AB To detect altered gene expression associated with mouse lung tumor progression, we compared the gene expression profile of lung adenocarcinomas with that of lung adenomas and normal lungs. Autoradiographic analysis showed that among the 588 genes surveyed, 152 genes were detected and the remaining 436 genes did not give any signals. A gene-specific semiquantitative reverse transcription polymerase chain reaction method was used to confirm the expression profile. A total of 29 genes was found to be differentially expressed in mouse lung tumors when compared to normal lungs. The pattern of expression, either underexpression or overexpression, was the same for 10 genes between adenocarcinomas and adenomas. Among them, seven genes were over-expressed, two genes were underexpressed and one gene was lost. Interestingly, 19 genes showed differential expression or increased incidence or difference in level of change between lung adenomas and adenocarcinomas, including Stat1, ADAP, IGFBP-6, PDGF-A, TGF-beta2, Int-3, VEGFR2, BAX, BAG-1, c-Jun, FasL, TRAIL, YB-1, CD31, Cdc42, B-raf, Rab-2, Abi-1, and ACE. These,genes can be designated as candidate 'lung tumor progression' (LTP) genes because their expression changes may specifically affect lung tumor progression in mice. Further analyses of these candidate LTP genes may provide new leads for elucidation of lung tumor progression in mice. C1 Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Sch Publ Hlth, Columbus, OH 43210 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Med Res Facil 514, 420 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CA58554, CN05113, CA78797] NR 38 TC 38 Z9 43 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 22 PY 2002 VL 21 IS 37 BP 5814 EP 5821 DI 10.1038/sj.onc.1205422 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 584JL UT WOS:000177463400018 PM 12173053 ER PT J AU Zend-Ajusch, E Hornung, U Burgtorf, C Lutjens, G Shan, ZH Schartl, M Haaf, T AF Zend-Ajusch, E Hornung, U Burgtorf, C Lutjens, G Shan, ZH Schartl, M Haaf, T TI Isolation and characterization of cold-shock domain protein genes, Oryzias latipes Y-box protein 2 (OlaYP2) and Fugu rubripes Y-box protein 1 (FruYP1), in medakafish and pufferfish SO GENE LA English DT Article DE evolution; nuclei acid binding domain; Y box ID MOLECULAR-CLONING; BINDING-PROTEIN; MESSENGER-RNA; DANIO-RERIO; IDENTIFICATION; ZEBRAFISH; GENOME; FISH AB The Y-box protein (YP) family shares a nucleic acid binding domain, called cold-shock domain, that has been evolutionarily highly conserved from bacteria to human. The different YPs identified so far in vertebrates are thought to function as transcriptional activators, transcriptional repressors and/or translational repressors. Medakafish and pufferfish are very suitable vertebrate models for the study of developmental genetics and comparative genomics, respectively. Here we report the isolation of two teleost YP genes, medakafish Oryzias latipes (Ola)YP2 and Fugu rubripes (FYu)YP1, which are expressed in multiple tissues. Phylogenetic analysis demonstrated that OlaYP2 and FruYP1 belong to different subclasses of the cold-shock domain protein genes. Future studies in suitable model systems, like the medaka for developmental biology and Fugu for evolutionary genomics, are expected to contribute to our understanding of YPs. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Mainz, Sch Med, Inst Human Genet, D-55131 Mainz, Germany. Australian Natl Univ, Res Sch Biol Sci, Canberra, ACT 2601, Australia. Univ Wurzburg, Dept Physiol Chem 1, Bioctr, D-97074 Wurzburg, Germany. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. NCI, NIH, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Haaf, T (reprint author), Univ Mainz, Sch Med, Inst Human Genet, Bldg 601,Langenbeckstr 1, D-55131 Mainz, Germany. OI Schartl, Manfred/0000-0001-9882-5948 NR 18 TC 1 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 21 PY 2002 VL 296 IS 1-2 BP 111 EP 119 AR PII S0378-1119(02)00838-7 DI 10.1016/S0378-1119(02)00838-7 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 607HD UT WOS:000178785300012 PM 12383508 ER PT J AU Schechter, AN Rettig, RA AF Schechter, AN Rettig, RA TI Funding priorities for medical research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RAND Corp, Arlington, VA USA. RP Schechter, AN (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 5 TC 5 Z9 6 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 21 PY 2002 VL 288 IS 7 BP 832 EP 832 DI 10.1001/jama.288.7.832 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 585FC UT WOS:000177513100023 PM 12186598 ER PT J AU Wu, ZR Bax, A AF Wu, ZR Bax, A TI Measurement of long-range H-1-H-1 dipolar couplings in weakly aligned proteins SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL-SHIFTS; NMR EXPERIMENTS; MACROMOLECULES; ALIGNMENT; HOMONUCLEAR; VALIDATION; REFINEMENT; RESOLUTION; PROTON; N-15 C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 28 Z9 29 U1 1 U2 4 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 AUG 21 PY 2002 VL 124 IS 33 BP 9672 EP 9673 DI 10.1021/ja026845n PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 584EV UT WOS:000177455000008 PM 12175202 ER PT J AU Campia, U Choucair, WK Bryant, MB Waclawiw, MA Cardillo, C Panza, JA AF Campia, U Choucair, WK Bryant, MB Waclawiw, MA Cardillo, C Panza, JA TI Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID NUTRITION EXAMINATION SURVEY; VASCULAR SMOOTH-MUSCLE; CORONARY HEART-DISEASE; NITRIC-OXIDE; RACIAL-DIFFERENCES; ESSENTIAL-HYPERTENSION; VASODILATOR RESPONSE; BLACK-AMERICANS; NATIONAL-HEALTH; UNITED-STATES AB OBJECTIVES The goal of this study was to determine whether racial differences exist in the functional behavior of conduit vessels. BACKGROUND Compared with Caucasians, African Americans have a higher prevalence of cardiovascular disease and its complications, which may be related to reduced nitric oxide (NO)-dependent and -independent vasodilation of the microvasculature. However, whether a similar impairment is also present at the level of the conductance arteries is unknown. METHODS To this end, we studied endothelium-dependent (posthyperemia flow-mediated dilation) and -independent (nitroglycerin) vascular responses of the brachial artery by high-resolution ultrasound imaging. There were 46 black subjects (23 men and 23 women; age 37 8 years and 38 9 years, respectively) and 46 white subjects (23 men and 23 women; age 38 +/- 11 years and 36 +/- 9 years, respectively) in this study. RESULTS Baseline diameter was similar in blacks and in whites (4.4 +/- 0.9 mm and 4.1 +/- 0.7 mm, respectively). Mean reactive hyperemia after cuff deflation was similar in the two groups (793 +/- 653% in black and 852 +/- 734% in white subjects, respectively; p = 0.5). Flow-mediated dilation was significantly lower in black compared with white individuals (4.79 +/- 3.5% vs. 8.87 +/- 4.5%, respectively; p < 0.0001). Nitroglycerin-mediated dilation was also significantly lower in black individuals compared with white individuals (10.99 +/- 4.6% vs. 14.98 +/- 5.4%, respectively; p = 0.0002). CONCLUSIONS African Americans show reduced responsiveness of conductance vessels to both endogenous and exogenous NO compared with Caucasian Americans. These findings expand our understanding of racial differences in vascular function and suggest a mechanistic explanation for the increased incidence and severity of cardiovascular disease observed in African Americans. (C) 2002 by the American College of Cardiology Foundation. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 31 TC 71 Z9 71 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 21 PY 2002 VL 40 IS 4 BP 754 EP 760 AR PII S0735-1097(02)02015-6 DI 10.1016/S0735-1097(02)02015-6 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 584NP UT WOS:000177474000021 PM 12204507 ER PT J AU Varricchio, CG Sloan, JA AF Varricchio, CG Sloan, JA TI The need for and characteristics of randomized, phase III trials to evaluate symptom management in patients with cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 NINR, NIH, Off Extramural Programs, Bethesda, MD 20892 USA. Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. RP Varricchio, CG (reprint author), NINR, NIH, Off Extramural Programs, 1 Democracy Plaza,6701 Democracy Blvd,Rm 710, Bethesda, MD 20892 USA. NR 8 TC 24 Z9 24 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 21 PY 2002 VL 94 IS 16 BP 1184 EP 1185 PG 2 WC Oncology SC Oncology GA 584NR UT WOS:000177474200001 PM 12189214 ER PT J AU Mansky, PJ Straus, SE AF Mansky, PJ Straus, SE TI St. John's wort: More implications for cancer patients SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HYPERICUM-PERFORATUM C1 NCCAM, NIH, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), NCCAM, NIH, Bldg 31,Rm 2B-11,31 Ctr Dr, Bethesda, MD 20892 USA. NR 16 TC 13 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 21 PY 2002 VL 94 IS 16 BP 1187 EP 1188 PG 2 WC Oncology SC Oncology GA 584NR UT WOS:000177474200003 PM 12189216 ER PT J AU Eltom, MA Jemal, A Mbulaiteye, SM Devesa, SS Biggar, RJ AF Eltom, MA Jemal, A Mbulaiteye, SM Devesa, SS Biggar, RJ TI Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; EPSTEIN-BARR-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HOMOSEXUAL MEN; RISK-FACTORS; AIDS; INFECTION; CANCER; HUMAN-HERPESVIRUS-8; POPULATION AB Background: The incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) in the general population has markedly increased since the onset of the AIDS epidemic in 1981. However, during the 1990s, the dynamics of the AIDS epidemic changed, as human immunodeficiency virus (HIV) infection rates slowed and effective antiretroviral therapies were introduced. We examined the impact of these changes on the general population incidence of KS and NHL. Methods: Age-standardized incidences for KS and NHL from 1973 through 1998 were obtained from nine population-based cancer registries that participate in the Surveillance, Epidemiology and End Results (SEER) program. Results: During the mid-1990s, KS incidence declined sharply in all nine registries. Decreases in KS incidence were most evident in San Francisco, where KS rates among white men had risen from 0.5 per 100 000 people per year in 1973 to between 31.1 and 33.3 from 1987 through 1991 and then declined to 2.8 in 1998. With background NHL incidence in the general population being much higher than that for KS, changes in incidence related to the AIDS epidemic were most evident in subgroups at high risk of AIDS. In San Francisco, NHL rates among white men rose from 10.7 in 1973 to a peak of 31.4 in 1995 and then declined to 21.6 in 1998. NHL types that were most highly AIDS-associated declined most steeply, whereas the incidence of NHL types not associated with AIDS was either stable or increasing. Conclusion: Changes in KS and NHL incidence since the mid 1990s may reflect declines in the number of individuals with AIDS and improved immune function in such individuals following the introduction of effective antiretroviral therapies in the 1990s. Notably, non-AIDS-associated NHL incidence has continued to increase steadily through 1998. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Amer Canc Soc, Atlanta, GA 30329 USA. RP Biggar, RJ (reprint author), 6120 Execut Blvd,EPS Rm 8015,MSC 7248, Rockville, MD 20852 USA. NR 40 TC 150 Z9 160 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 21 PY 2002 VL 94 IS 16 BP 1204 EP 1210 PG 7 WC Oncology SC Oncology GA 584NR UT WOS:000177474200009 PM 12189223 ER PT J AU Martinez, A Vos, M Guedez, L Kaur, G Chen, Z Garayoa, M Pio, R Moody, T Stetler-Stevenson, WG Kleinman, HK Cuttitta, F AF Martinez, A Vos, M Guedez, L Kaur, G Chen, Z Garayoa, M Pio, R Moody, T Stetler-Stevenson, WG Kleinman, HK Cuttitta, F TI The effects of adrenomedullin overexpression in breast tumor cells SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANGIOGENIC FACTOR ADRENOMEDULLIN; POSSIBLE PROMOTION MECHANISM; SMOOTH-MUSCLE CELLS; CIRCULATING ADRENOMEDULLIN; HYPOTENSIVE PEPTIDE; POTENTIAL ROLE; CANCER-CELLS; EXPRESSION; GROWTH; APOPTOSIS AB Background: Adrenomedullin is a secreted peptide hormone with multiple activities. Several reports have indicated that adrenomedullin may be involved in tumor survival, but this has not been directly shown. Here we evaluate the in vitro and in vivo effects of adrenomedullin overexpression in human breast cancer cells. Methods: The human breast cancer cell lines T47D and MCF7, both of which express low basal levels of adrenomedullin, were stably transfected with an expression construct that contained the coding region of the human adrenomedullin gene or with empty expression vector. Properties of the transfected cells were assessed by proliferation and apoptosis assays, in vitro and in vivo angiogenesis assays, cell migration experiments, and xenograft implants. The effect of synthetic adrenomedullin on human ovarian (ECV) cancer cell motility was also tested. Western blot analysis was used to compare expression levels of several genes whose products are associated with cell growth and regulation of apoptosis. Results: T47D and MCF7 cells transfected with the adrenomedullin construct both expressed high levels of adrenomedullin mRNA and protein. Compared with cells transfected with empty vector, cells that overexpressed adrenomedullin displayed a more pleiotropic morphology, an increased angiogenic potential both in vitro and in vivo, and less apoptosis after serum deprivation. T47D and MCF7 cells did not display measurable motility, but ECV ovarian cancer cells treated with synthetic adrenomedullin were more motile than saline-treated ECV cells. Adrenomedullin-overexpressing T47D cells had higher levels of proteins involved in oncogenic signal transduction pathways (such as Ras, Raf, PKC, and MAPKp49) and lower levels of pro-apoptotic proteins (such as Bax, Bid, and caspase 8) than T47D cells transfected with empty vector. In a preliminary in vivo experiment, three of 10 nude mice injected with adrenomedullin-overexpressing T47D cells developed xenograft tumors, whereas none of the 10 nude mice injected with cells carrying the empty plasmid developed tumors. Conclusions: These results further support the role of adrenomedullin as a survival factor for tumors. Development of physiologically efficient inhibitors of adrenomedullin may prove useful in the clinical management of cancer. C1 Natl Canc Inst, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Vasc Biol Fac, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Extracellular Matrix Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Blood Testing Branch, Dev Therapeut Sect, SAIC Frederick,Frederick Canc Res & Dev Ctr, Frederick, MD USA. Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Bio & Regenerat Branch, NIH, Bethesda, MD USA. RP Martinez, A (reprint author), Natl Canc Inst, Cell & Canc Biol Branch, NIH, Bldg 10,Rm 13N262, Bethesda, MD 20892 USA. RI Guedez, Liliana/H-4951-2012; Martinez, Alfredo/A-3077-2013; Stetler-Stevenson, William/H-6956-2012; Pio, Ruben/F-5353-2017 OI Martinez, Alfredo/0000-0003-4882-4044; Stetler-Stevenson, William/0000-0002-5500-5808; Pio, Ruben/0000-0002-6831-6111 NR 41 TC 94 Z9 97 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 21 PY 2002 VL 94 IS 16 BP 1226 EP 1237 PG 12 WC Oncology SC Oncology GA 584NR UT WOS:000177474200012 PM 12189226 ER PT J AU Kaplan, JE Masur, H Holmes, KK AF Kaplan, JE Masur, H Holmes, KK TI Discontinuing prophylaxis against recurrent opportunistic infections in HIV-infected persons: A victory in the era of HAART SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ACTIVE ANTIRETROVIRAL THERAPY; PNEUMOCYSTIS-CARINII PNEUMONIA; SECONDARY PROPHYLAXIS; VIRAL-LOAD; RISK; RETINITIS; DISEASE; ADULTS C1 Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98122 USA. RP Kaplan, JE (reprint author), Ctr Dis Control & Prevent, Div HIV AIDS Prevent, 1600 Clifton Rd, Atlanta, GA 30333 USA. NR 16 TC 6 Z9 6 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 20 PY 2002 VL 137 IS 4 BP 285 EP 287 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 585BB UT WOS:000177502300009 PM 12186519 ER PT J AU Gravitt, PE Kamath, AM Gaffikin, L Chirenje, ZM Womack, S Shah, KV AF Gravitt, PE Kamath, AM Gaffikin, L Chirenje, ZM Womack, S Shah, KV TI Human papillomavirus genotype prevalence in high-grade squamous intraepithelial lesions and colposcopically normal women from Zimbabwe SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID CERVICAL-CANCER; HIGH-RISK; INFECTION; HIV; POPULATION; WORLDWIDE; NEOPLASIA; DNA C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. JHPIEGO Corp, Baltimore, MD USA. Univ Zimbabwe, Dept Obstet & Gynecol, Harare, Zimbabwe. RP Gravitt, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 7059,6120 Execut Blvd, Rockville, MD 20852 USA. NR 19 TC 24 Z9 24 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 AUG 20 PY 2002 VL 100 IS 6 BP 729 EP 732 DI 10.1002/ijc.10538 PG 4 WC Oncology SC Oncology GA 580AM UT WOS:000177211900018 PM 12209615 ER PT J AU Meyer-Lindenberg, A Ziemann, U Hajak, G Cohen, L Berman, KF AF Meyer-Lindenberg, A Ziemann, U Hajak, G Cohen, L Berman, KF TI Transitions between dynamical states of differing stability in the human brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUPPLEMENTARY MOTOR AREA; TRANSCRANIAL MAGNETIC STIMULATION; BIMANUAL COORDINATION; PREMOTOR CORTEX; INTERLIMB COORDINATION; NEURAL SYSTEMS; MOVEMENTS; LESIONS; ACTIVATION; SEQUENCES AB What mechanisms underlie the flexible formation, adaptation, synchronization, and dissolution of large-scale neural assemblies from the 1010 densely interconnected, continuously active neurons of the human brain? Nonlinear dynamics provides a unifying perspective on self-organization. It shows that the emergence of patterns in open, nonequilibrium systems is governed by their stability in response to small disturbances and predicts macroscopic transitions between patterns of differing stability. Here, we directly demonstrate that such transitions can be elicited in the human brain by interference at the neural level. As a probe, we used a classic motor coordination paradigm exhibiting well described movement states of differing stability. Functional neuroimaging identified premotor (PMA) and supplementary motor (SMA) cortices as having neural activity linked to the degree of behavioral instability. These regions then were transiently disturbed with graded transcranial magnetic stimulation, which caused sustained and macroscopic behavioral transitions from the less stable out-of-phase to the stable in-phase movement, whereas the stable pattern could not be affected. Moreover, the strength of the disturbance needed (a measure of neural stability) was linked to the degree of behavioral stability, demonstrating the applicability of nonlinear system theory as a powerful predictor of the dynamical repertoire of the human brain. C1 NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Unit, NIH, Bethesda, MD 20892 USA. RP Meyer-Lindenberg, A (reprint author), NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 42 TC 124 Z9 125 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 AUG 20 PY 2002 VL 99 IS 17 BP 10948 EP 10953 DI 10.1073/pnas.162114799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900003 PM 12151599 ER PT J AU Bartberger, MD Liu, W Ford, E Miranda, KM Switzer, C Fukuto, JM Farmer, PJ Wink, DA Houk, KN AF Bartberger, MD Liu, W Ford, E Miranda, KM Switzer, C Fukuto, JM Farmer, PJ Wink, DA Houk, KN TI The reduction potential of nitric oxide (NO) and its importance to NO biochemistry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOCHROME-C-OXIDASE; NITROXYL ANION; AQUEOUS-SOLUTION; ELECTROCATALYTIC REDUCTION; SUPEROXIDE-DISMUTASE; METAL-ELECTRODES; REDOX COUPLE; GENERATION; HNO; CYTOTOXICITY AB A potential of about -0.8 (+/-0.2) V (at 1 M versus normal hydrogen electrode) for the reduction of nitric oxide (NO) to its one-electron reduced species, nitroxyl anion ((NO-)-N-3) has been determined by a combination of quantum mechanical calculations, cyclic voltammetry measurements, and chemical reduction experiments. This value is in accord with some, but not the most commonly accepted, previous electrochemical measurements involving NO. Reduction of NO to (NO-)-N-1 is highly unfavorable, with a predicted reduction potential of about -1.7 (+/-0.2) V at 1 M versus normal hydrogen electrode. These results represent a substantial revision of the derived and widely cited values of +039 V and -0.35 V for the NO/(NO-)-N-3 and NO/(NO-)-N-1 couples, respectively, and provide support for previous measurements obtained by electrochemical and photoelectrochemical means. With such highly negative reduction potentials, NO is inert to reduction compared with physiological events that reduce molecular oxygen to superoxide. From these reduction potentials, the pKa of (NO-)-N-3 has been reevaluated as 11.6 ( 3.4). Thus, nitroxyl exists almost exclusively in its protonated form, HNO, under physiological conditions. The singlet state of nitroxyl anion, (NO-)-N-1, is physiologically inaccessible. The significance of these potentials to physiological and pathophysiological processes involving NO and O-2 under reductive conditions is discussed. C1 Univ Calif Los Angeles, Ctr Hlth Sci, Dept Chem & Biochem, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. NCI, Tumor Biol Sect, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Houk, KN (reprint author), Univ Calif Los Angeles, Ctr Hlth Sci, Dept Chem & Biochem, Los Angeles, CA 90095 USA. RI Miranda, Katrina/B-7823-2009; Liu, Peng/D-1233-2013; Switzer, Christopher/D-9203-2013; OI Farmer, Patrick/0000-0001-9911-999X FU NCI NIH HHS [F32 CA076770, F32CA76770]; NIGMS NIH HHS [GM08496, GM59446, R01 GM059446, T32 GM008496] NR 52 TC 203 Z9 204 U1 2 U2 24 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 AUG 20 PY 2002 VL 99 IS 17 BP 10958 EP 10963 DI 10.1073/pnas.162095599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900005 PM 12177417 ER PT J AU Berry, JP Reece, KS Rein, KS Baden, DG Haas, LW Ribeiro, WL Shields, JD Snyder, RV Vogelbein, WK Gawley, RE AF Berry, JP Reece, KS Rein, KS Baden, DG Haas, LW Ribeiro, WL Shields, JD Snyder, RV Vogelbein, WK Gawley, RE TI Are Pfiesteria species toxicogenic? Evidence against production of ichthyotoxins by Pfiesteria shumwayae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TOXIC DINOFLAGELLATE PFIESTERIA; NONRIBOSOMAL PEPTIDE-SYNTHESIS; ESTUARY-ASSOCIATED SYNDROME; SENSITIVE SODIUM-CHANNELS; RAT PITUITARY-CELLS; HUMAN-HEALTH; PISCICIDA DINOPHYCEAE; ATLANTIC MENHADEN; BREVETOXIN-B; SKIN ULCERS AB The estuarine genus Pfiesteria has received considerable attention since it was first identified and proposed to be the causative agent of fish kills along the mid-Atlantic coast in 1992. The presumption has been that the mechanism of fish death is by release of one or more toxins by the dinoflagellate. In this report, we challenge the notion that Pfiesteria species produce ichthyotoxins. Specifically, we show that (i) simple centrifugation, with and without ultrasonication, is sufficient to "detoxify" water of actively fish-killing cultures of Pfiesteria shumwayae, (ii) organic extracts of lyophilized cultures are not toxic to fish, (fit) degenerate primers that amplify PKS genes from several polyketide-producing dinoflagellates failed to yield a product with A shumwayae DNA or cDNA, and (iv) degenerate primers for NRPS genes failed to amplify any NRPS genes but (unexpectedly) yielded a band (among several) that corresponded to known or putative PKSs and fatty acid synthases. We conclude that P. shumwayae is able to kill fish by means other than releasing a toxin into bulk water. Alternative explanations of the effects attributed to Pfiesteria are suggested. C1 Univ Miami, Marine & Freshwater Biomed Sci Ctr, Dept Chem, NIEHS, Coral Gables, FL 33124 USA. Coll William & Mary, Virginia Inst Marine Sci, Gloucester Point, VA 23062 USA. Florida Int Univ, Dept Chem, Miami, FL 33199 USA. Univ N Carolina, Ctr Marine Sci, Wilmington, NC 28409 USA. RP Univ Miami, Marine & Freshwater Biomed Sci Ctr, Dept Chem, NIEHS, POB 249118, Coral Gables, FL 33124 USA. EM rgawley@miami.edu FU NIEHS NIH HHS [P30 ES005705, T32 ES007320, S11 ES011181, P30-ES05705, P01 ES010594, T32-ES07320, P01-ES09563, P01 ES010594-02] NR 68 TC 32 Z9 35 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 AUG 20 PY 2002 VL 99 IS 17 BP 10970 EP 10975 DI 10.1073/pnas.172221699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900007 PM 12163648 ER PT J AU Hoskins, JR Yanagihara, K Mizuuchi, K Wickner, S AF Hoskins, JR Yanagihara, K Mizuuchi, K Wickner, S TI ClpAP and ClpXP degrade proteins with tags located in the interior of the primary sequence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE molecular chaperones; proteases; ClpA; ClpX; Hsp100 ID ATP-DEPENDENT PROTEASES; MU-TRANSPOSASE TETRAMER; N-END RULE; ESCHERICHIA-COLI; MOLECULAR CHAPERONE; TAGGING SYSTEM; TRANSLOCATION; PROTEOLYSIS; BINDING; RECOGNITION AB Clp/Hsp100 ATPases comprise a large family of ATP-dependent chaperones, some of which are regulatory components of two-component proteases. Substrate specificity resides in the Clp protein and the current thinking is that Clp proteins recognize motifs located near one or the other end of the substrate. We tested whether or not ClpA and ClpX can recognize tags when they are located in the interior of the primary sequence of the substrate. A protein with an NH2-terminal ClpA recognition tag, plasmid P1 RepA, was fused to the COOH terminus of green fluorescent protein (GFP). GFP is not recognized by ClpA or ClpX and is not degraded by ClpAP or ClpXP. We found that ClpA binds and unfolds the fusion protein and ClpAP degrades the protein. Both the GFP and RepA portions of the fusion protein are degraded. A protein with a COOH-terminal ClpX tag, MuA, was fused to the NH2 terminus of GFP. ClpXP degrades MuA-GFP, however, the rate is 10-fold slower than that of GFP-MuA. The MuA portion but not the GFP portion of MuA-GFP is degraded. Thus, a substrate with an internal ClpA recognition motif can be unfolded by ClpA and degraded by ClpAP. Similarly, although less efficiently, ClpXP degrades a substrate with an internal ClpX recognition motif. We also found that ClpA recognizes the NH2-terminal 15 aa RepA tag, when it is fused to the COOH terminus of GFP. Moreover, ClpA recognizes the RepA tag in either the authentic or inverse orientation. C1 NCI, Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, Bldg 37, Bethesda, MD 20892 USA. NR 41 TC 53 Z9 55 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 AUG 20 PY 2002 VL 99 IS 17 BP 11037 EP 11042 DI 10.1073/pnas.172378899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900019 PM 12177439 ER PT J AU Pham, P Seitz, EM Saveliev, S Shen, X Woodgate, R Cox, MM Goodman, MF AF Pham, P Seitz, EM Saveliev, S Shen, X Woodgate, R Cox, MM Goodman, MF TI Two distinct modes of RecA action are required for DNA polymerase V-catalyzed translesion synthesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SOS mutagenesis; error-prone DNA polymerase; DNA damage-induced mutation ID IRRADIATED ESCHERICHIA-COLI; HOMOLOGOUS RECOMBINATION; MUTAGENESIS PROTEIN; POL-II; NUCLEOPROTEIN FILAMENTS; STRAND EXCHANGE; SOS MUTAGENESIS; REPLICATION; MUTANT; GENE AB SOS mutagenesis in Escherichia coli requires DNA polymerase V (pol V) and RecA protein to copy damaged DNA templates. Here we show that two distinct biochemical modes for RecA protein are necessary for pol V-catalyzed translesion synthesis. One RecA mode is characterized by a strong stimulation in nucleotide incorporation either directly opposite a lesion or at undamaged template sites, but by the absence of lesion bypass. A separate RecA mode is necessary for translesion synthesis. The RecA1730 mutant protein, which was identified on the basis of its inability to promote pol V (UmuD'C-2)-dependent UV-mutagenesis, appears proficient for the first mode of RecA action but is deficient in the second mode. Data are presented suggesting that the two RecA modes are "nonfilamentous". That is, contrary to current models for SOS mutagenesis, formation of a RecA nucleoprotein filament may not be required for copying damaged DNA templates. Instead, SOS mutagenesis occurs when pol V interacts with two RecA molecules, first at a 3' primer end, upstream of a template lesion, where RecA mode 1 stimulates pol V activity, and subsequently at a site immediately downstream of the lesion, where RecA mode 2 cocatalyzes lesion bypass. We posit that in vivo assembly of a RecA nucleoprotein filament may be required principally to target pol V to a site of DNA damage and to stabilize the pol V-RecA interaction at the lesion. However, it is only a RecA molecule located at the 3' filament tip, proximal to a damaged template base, that is directly responsible for translesion synthesis. C1 Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. NICHHD, Sect DNA Replicat & Mutagenesis, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. FU NIA NIH HHS [AG00093, T32 AG000093]; NIGMS NIH HHS [GM21422, GM42554, R37 GM021422, R01 GM021422, R01 GM052725, GM52725] NR 53 TC 38 Z9 40 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 AUG 20 PY 2002 VL 99 IS 17 BP 11061 EP 11066 DI 10.1073/pnas.172197099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900023 PM 12177433 ER PT J AU Espey, MG Thomas, DD Miranda, KM Wink, DA AF Espey, MG Thomas, DD Miranda, KM Wink, DA TI Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID XANTHINE-OXIDASE; AQUEOUS-SOLUTION; PEROXYNITRITE FORMATION; TYROSINE NITRATION; PULSE-RADIOLYSIS; S-NITROSYLATION; CARBON-DIOXIDE; N-NITROSATION; CENTER-DOT; IN-VIVO AB The impact of nitric oxide (NO) synthesis on different biological cascades can rapidly change dependent on the rate of NO formation and composition of the surrounding milieu. With this perspective, we used diaminonaphthalene (DAN) and diaminofluorescein (DAF) to examine the nitrosative chemistry derived from NO and superoxide (O-2(-)) simultaneously generated at nanomolar to low micromolar per Minute rates by spermine/NO decomposition and xanthine oxidase-catalyzed oxidation of hypoxanthine, respectively. Fluorescent triazole product formation from DAN and DAF increased as the ratio of O-2(-) to NO approached equimolar, then decreased precipitously as O-2(-) exceeded NO. This pattern was also evident in DAF-loaded MCF-7 carcinoma cells and when stimulated macrophages were used as the NO source. Cyclic voltammetry analysis and inhibition studies by using the N2O3 scavenger azide indicated that DAN- and DAF-triazole could be derived from both oxidative nitrosylation (e.g., DAF radical + NO) and nitrosation (NO+ addition). The latter mechanism predominated with higher rates of NO formation relative to O-2(-). The effects of oxymyoglobin, superoxide dismutase, and carbon dioxide were examined as potential modulators of reactant availability for the O-2(-) NO pathway in vivo. The findings suggest that the outcome of NO biosynthesis in a scavenger milieu can be focused by O-2(-) toward formation of NO adducts on nucleophilic residues (e.g., amines, thiols, hydroxyl) through convergent mechanisms involving the intermediacy of nitrogen dioxide. These modifications may be favored in microenvironments where the rate of O-2(-) production is temporally and spatially contemporaneous with nitric oxide synthase activity, but not in excess of NO generation. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Espey, MG (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 72 TC 117 Z9 121 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2002 VL 99 IS 17 BP 11127 EP 11132 DI 10.1073/pnas.152157599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900034 PM 12177414 ER PT J AU Boon, K Osorio, EC Greenhut, SF Schaefer, CF Shoemaker, J Polyak, K Morin, PJ Buetow, KH Strausberg, RL de Souza, SJ Riggins, GJ AF Boon, K Osorio, EC Greenhut, SF Schaefer, CF Shoemaker, J Polyak, K Morin, PJ Buetow, KH Strausberg, RL de Souza, SJ Riggins, GJ TI An anatomy of normal and malignant gene expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SERIAL ANALYSIS; CANCER; PROJECT; GENOME AB A gene's expression pattern provides clues to its role in normal physiology and disease. To provide quantitative expression levels on a genome-wide scale, the Cancer Genome Anatomy Project (CGAP) uses serial analysis of gene expression (SAGE). Over 5 million transcript tags from more than 100 human cell types have been assembled. To enhance the utility of this data, the CGAP SAGE project created SAGE Genie, a web site for the analysis and presentation of SAGE data (http://cgap.nci.nih.gov/SAGE). SAGE Genie provides an automatic link between gene names and SAGE transcript levels, accounting for alternative transcription and many potential errors. These informatics advances provide a rapid and intuitive view of transcript expression in the human body or brain, displayed on the SAGE Anatomic Viewer. We report here an easily accessible view of nearly any gene's expression in a wide variety of malignant and normal tissues. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NIA, Biol Chem Lab, Baltimore, MD 21224 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Off Canc Genomics, Bethesda, MD 20892 USA. NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. Ludwig Inst Canc Res, BR-01509010 Sao Paulo, Brazil. RP Riggins, GJ (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. FU NCI NIH HHS [U01 CA088128, U01 CA88128] NR 16 TC 229 Z9 242 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2002 VL 99 IS 17 BP 11287 EP 11292 DI 10.1073/pnas.152324199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900062 PM 12119410 ER PT J AU Yanagihara, K Mizuuchi, K AF Yanagihara, K Mizuuchi, K TI Mismatch-targeted transposition of Mu: A new strategy to map genetic polymorphism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DNA FRAGMENTS; MUTATIONS; SEQUENCE; CLEAVAGE AB Phage Mu DNA transposes to duplex target DNA sites with limited sequence specificity. Here we demonstrate that Mu transposition exhibits a strong target site preference for all single-nucleotide mismatches. This finding has implications for the mechanism of transposition and provides a powerful tool for genomic research. A single mismatch could be detected as a preferred target of Mu transposition in the presence of 300,000-fold excess of non-mismatched sites. We demonstrate the detection of both heterozygous and homozygous mutations in the cystic fibrosis transmembrane conductance regulator gene and single nucleotide polymorphism in HLA region by Mu transposition mismatch analysis procedure. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mizuuchi, K (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 14 TC 33 Z9 34 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 AUG 20 PY 2002 VL 99 IS 17 BP 11317 EP 11321 DI 10.1073/pnas.132403399 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900067 PM 12177413 ER PT J AU Basile, AS Fedorova, I Zapata, A Liu, XG Shippenberg, T Duttaroy, A Yamada, M Wess, J AF Basile, AS Fedorova, I Zapata, A Liu, XG Shippenberg, T Duttaroy, A Yamada, M Wess, J TI Deletion of the M-5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VENTRAL TEGMENTAL AREA; MICE LACKING; RAT-BRAIN; CHOLINERGIC RECEPTORS; NUCLEUS-ACCUMBENS; DOPAMINE EFFLUX; KNOCKOUT MICE; STIMULATION; EXPRESSION; REWARD AB Little is known about the physiological roles of the M-5 muscarinic receptor, the last member of the muscarinic receptor family (M-1-M-5) to be cloned. In the brain, the M-5 receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area. Dopaminergic neurons located in the ventral tegmental area are known to play important roles in mediating both the rewarding effects of opiates and other drugs of abuse and the manifestations of opiate/drug withdrawal symptoms. We therefore speculated that acetylcholine-dependent activation of M-5 receptors might modulate the manifestations of opiate reward and withdrawal. This hypothesis was tested in a series of behavioral, biochemical, and neurochemical studies using M-5 receptor-deficient mice (M-5(-/-) mice) as novel experimental tools. We found that the rewarding effects of morphine, as measured in the conditioned place preference paradigm, were substantially reduced in M-5(-/-) mice. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M-5(-/-) mice. In contrast, the analgesic efficacy of morphine and the development of tolerance to the analgesic effects of morphine remained unaltered by the lack of M-5 receptors. The finding that M-5 receptor activity modulates both morphine reward and withdrawal processes suggests that M-5 receptors may represent a novel target for the treatment of opiate addiction. C1 NIDDKD, Neurosci Grp, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NIDDKD, Sect Mol Signaling, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Basile, AS (reprint author), Alkermes Inc, Life Sci R&D, 64 Sidney St, Cambridge, MA 02139 USA. NR 37 TC 105 Z9 123 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2002 VL 99 IS 17 BP 11452 EP 11457 DI 10.1073/pnas.162371899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900090 PM 12154229 ER PT J AU Pessoa, L McKenna, M Gutierrez, E Ungerleider, LG AF Pessoa, L McKenna, M Gutierrez, E Ungerleider, LG TI Neural processing of emotional faces requires attention SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN EXTRASTRIATE CORTEX; HUMAN AMYGDALA; FACIAL EXPRESSIONS; SELECTIVE ATTENTION; PERCEPTION; FMRI; TASK; LOAD AB Attention gates the processing of stimuli relatively early in visual cortex. Yet, existing data suggest that emotional stimuli activate brain regions automatically, largely immune from attentional control. To resolve this puzzle, we used functional magnetic resonance imaging to first measure activation in regions that responded differentially to faces with emotional expressions (fearful and happy) compared with neutral faces. We then measured the modulation of these responses by attention, using a competing task with a high attentional load. Contrary to the prevailing view, all brain regions responding differentially to emotional faces, including the amygdala, did so only when sufficient attentional resources were available to process the faces. Thus, the processing of facial expression appears to be under top-down control. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Pessoa, L (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. RI Frank, David/E-8213-2012 NR 30 TC 698 Z9 729 U1 7 U2 63 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 AUG 20 PY 2002 VL 99 IS 17 BP 11458 EP 11463 DI 10.1073/pnas.172403899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 586VM UT WOS:000177606900091 PM 12177449 ER PT J AU Pitcher, WH Keller, SL Huestis, WH AF Pitcher, WH Keller, SL Huestis, WH TI Interaction of nominally soluble proteins with phospholipid monolayers at the air-water interface SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE protein-lipid interaction; air-water interface; hemoglobin; glyceraldehyde-3-phosphate dehydrogenase; phospholipid monolayer ID KINETICS; ADSORPTION; EXCHANGE; SURFACE; MEMBRANES; CHOLESTEROL AB The interactions of carbonmonoxyhemoglobin (HbCO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and polyhistidine with phospholipid monolayers at the air-water interface were studied at physiological pH and ionic strength. HbCO and GAPDH both interact more strongly with monolayers containing negatively charged lipids. The interaction of HbCO and GAPDH with lipid monolayers decreases with increasing pH. Both the HbCO-monolayer and the GAPDH-monolayer interactions can be modeled as diffusion-limited processes, with kinetic data fit to a stretched exponential equation. The significance of these kinetics are discussed. Polyhistidine interacts only with monolayers containing lipids with negatively charged headgroups. In total, the results presented are consistent with an UbCO-lipid interaction with a large electrostatic component, a GAPDH-lipid interaction with comparable electrostatic and hydrophobic components, and a polyhistidine-lipid interaction that is solely electrostatic. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Washington, Dept Chem, Seattle, WA 98195 USA. Stanford Univ, Dept Chem, Stanford, CA 94305 USA. RP Pitcher, WH (reprint author), NIEHS, Struct Biol Lab, Box 12233,MR-03, Res Triangle Pk, NC 27709 USA. NR 31 TC 13 Z9 14 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD AUG 19 PY 2002 VL 1564 IS 1 BP 107 EP 113 AR PII S0005-2736(02)00405-4 DI 10.1016/S0005-2736(02)00405-4 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 574NP UT WOS:000176896700015 PM 12101002 ER PT J AU Zhao, FQ Adachi, K Oka, T AF Zhao, FQ Adachi, K Oka, T TI Involvement of Oct-1 in transcriptional regulation of beta-casein gene expression in mouse mammary gland SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE transcriptional regulation; DNA binding protein; Oct-1; promoter ID OCTAMER-BINDING-PROTEINS; HISTONE H2B GENE; DNA-BINDING; EPITHELIAL-CELLS; POU DOMAIN; HORMONAL INDUCTION; RNA PROMOTER; HOMEODOMAIN; OTF-1; SITE AB Mouse beta-casein gene promoter contains a region termed block C which is crucial for its gene transcription induced by lactogenic hormones. Nuclear extracts from mouse mammary glands contain at least two binding complexes (DS1 and DS2) which specifically bind to double-stranded block C region DNA. The binding sequence of these complexes was identified to be 5'-AAATTAGCATGT-3' which contains a sequence element related to the consensus octamer motif's complement ATTTGCAT. In the present study, we demonstrate that this sequence element indeed is the binding site for octamer-binding transcription factors (Octs) and Octs represent the double-stranded DNA binding proteins specifically binding to the block C region. Formation of the specific double-stranded binding complexes can be completely blocked by Oct binding motif oligonucleotides and anti-rOct-1 antiserum. We also show that Oct-1B represents at least partial, if not all, double-stranded binding protein, DS1, in mammary nuclear extract. Oct-1B may function as a transcriptional activator on casein gene promoter. The Oct binding activity to beta-casein gene promoter in the mammary gland is affected under influence of hormones both in vitro and in vivo. The DS1 binding activity can be induced by the combination of lactogenic hormones insulin, hydrocortisone and prolactin in organ culture of virgin mouse mammary gland. The binding activity in vivo can be induced by injection of progesterone or its combination with estradiol in virgin mice. Published by Elsevier Science B.V. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Oka, T (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NR 46 TC 29 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD AUG 19 PY 2002 VL 1577 IS 1 BP 27 EP 37 AR PII S0167-4781(02)00402-5 DI 10.1016/S0167-4781(02)00402-5 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 584TX UT WOS:000177485800004 PM 12151092 ER PT J AU Miyamoto, T Fiorenza, MT Zhao, YG Hasuike, S Westphal, H AF Miyamoto, T Fiorenza, MT Zhao, YG Hasuike, S Westphal, H TI Molecular cloning and expression analysis of MPP alpha-2, a novel mouse transcript detected in a differential screen of pituitary libraries SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE protein phosphatase; differential screening; Lhx3; pituitary ID HUMAN PROTEIN PHOSPHATASE; LIM; LHX3 AB We identified a novel isoform transcript, MPPalpha-2, of the mouse Mg2+-dependent protein phosphatase (MPP) alpha gene. The amino acid sequence encoded by MPPalpha-2 differs from the previously known MPPalpha-1 sequence only at the carboxyl terminal region. Northern and in situ hybridization analysis revealed differential expression patterns of these two transcripts in the embryo and in the adult organism, suggesting an elaborate regulation of the MPPalpha gene. Published by Elsevier Science B.V. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 18 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD AUG 19 PY 2002 VL 1577 IS 1 BP 109 EP 112 AR PII S0167-4781(02)00293-2 DI 10.1016/S0167-4781(02)00293-2 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 584TX UT WOS:000177485800013 PM 12151101 ER PT J AU Ananthan, S Saini, SK Khare, R Clayton, SD Dersch, CM Rothman, RB AF Ananthan, S Saini, SK Khare, R Clayton, SD Dersch, CM Rothman, RB TI Identification of a novel partial inhibitor of dopamine transporter among 4-substituted 2-phenylquinazolines SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID BIOGENIC-AMINE TRANSPORTERS; POTENTIAL COCAINE ANTAGONISTS; NON-NITROGEN INHIBITORS; MONOAMINE TRANSPORTERS; PHOTOAFFINITY LIGANDS; SELECTIVE LIGANDS; BINDING-SITE; I-125 RTI-55; ANALOGS; DOMAINS AB In an attempt to identify novel ligands for the dopamine transporter, a series of 4-substituted-2-phenylquinazolines were synthesized and evaluated. Among the compounds studied, 4-[(diphenylmethyl)amino]-2-phenylquinazoline (4g) was identified as a novel partial inhibitor of [I-125]RTI-55 binding to the dopamine transporter and a partial inhibitor of [H-3]dopamine uptake. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 So Res Inst, Organ Chem Dept, Birmingham, AL 35255 USA. NIDA, IRP, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. RP Ananthan, S (reprint author), So Res Inst, Organ Chem Dept, Birmingham, AL 35255 USA. NR 32 TC 2 Z9 2 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 19 PY 2002 VL 12 IS 16 BP 2225 EP 2228 AR PII S0960-894X(02)00348-7 DI 10.1016/S0960-894X(02)00348-7 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 580FX UT WOS:000177225500039 PM 12127543 ER PT J AU Difilippantonio, MJ Petersen, S Chen, HT Johnson, R Jasin, M Kanaar, R Ried, T Nussenzweig, A AF Difilippantonio, MJ Petersen, S Chen, HT Johnson, R Jasin, M Kanaar, R Ried, T Nussenzweig, A TI Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE nonreciprocal translocations; gene amplification; bridge-fusion breakage; nonhomologous end-joining; tumorigenesis ID ATM-DEFICIENT MICE; END-JOINING PATHWAY; WILD-TYPE P53; V(D)J RECOMBINATION; CHROMOSOME TRANSLOCATIONS; GENOMIC STABILITY; MULTIPLE-MYELOMA; TELOMERE CAPTURE; LIGASE-IV; C-MYC AB Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic breakage, and replication. Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion. Here we report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Subsequent DNA repair events juxtaposing IgH and c-myc are mediated by a break-induced replication pathway. Cycles of breakage-fusion-b ridge result in amplification of IgH/c-myc while chromosome stabilization occurs through telomere capture. Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis. C1 NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA. Erasmus Univ, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. RP Difilippantonio, MJ (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 53 TC 178 Z9 179 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 19 PY 2002 VL 196 IS 4 BP 469 EP 480 DI 10.1084/jem.20020851 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 587XK UT WOS:000177669300006 PM 12186839 ER PT J AU Balaji, KN Schaschke, N Machleidt, W Catalfamo, M Henkart, PA AF Balaji, KN Schaschke, N Machleidt, W Catalfamo, M Henkart, PA TI Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CTL; cytotoxicity; protease; granule; exocytosis ID LYSOSOMAL CYSTEINE PROTEASES; CELL-MEDIATED CYTOTOXICITY; CD8(+) T-LYMPHOCYTES; NATURAL-KILLER-CELLS; CYTOLYTIC LYMPHOCYTES; GRANZYME-B; GRANULE EXOCYTOSIS; COGNATE PEPTIDES; TARGET-CELLS; PERFORIN AB The granule exocytosis cytotoxicity pathway is the major molecular mechanism for cytotoxic T lymphocyte (CTL) and natural killer (NK) cytotoxicity, but the question of how these cytotoxic lymphocytes avoid self-destruction after secreting perforin has remained unresolved. We show that CTL and NK cells die within a few hours if they are triggered to degranulate in the presence of nontoxic thiol cathepsin protease inhibitors. The potent activity of the impermeant, highly cathepsin B-specific membrane inhibitors CA074 and NS-196 strongly implicates extracellular cathepsin B. CTL suicide in the presence of cathepsin inhibitors requires the granule exocytosis cytotoxicity pathway, as it is normal with CTLs from gld mice, but does not occur in CTLs from perforin knockout mice. Flow cytometry shows that CTLs express low to undetectable levels of cathepsin B on their surface before degranulation, with a substantial rapid increase after T cell receptor triggering. Surface cathepsin B eluted from live CTL after degranulation by calcium chelation is the single chain processed form of active cathepsin B. Degranulated CTLs are surface biotinylated by the cathepsin B-specific affinity reagent NS-196, which exclusively labels immuno reactive cathepsin B. These experiments support a model in which granule-derived surface cathepsin B provides self-protection for degranulating cytotoxic lymphocytes. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Max Planck Inst Biochem, D-82152 Martinsried, Germany. Univ Munich, Adolf Butenandt Inst Physiol Chem Phys Biochem &, D-80336 Munich, Germany. RP Henkart, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM ph8j@nih.gov NR 59 TC 130 Z9 132 U1 0 U2 5 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 AUG 19 PY 2002 VL 196 IS 4 BP 493 EP 503 DI 10.1084/jem.20011836 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 587XK UT WOS:000177669300008 PM 12186841 ER PT J AU Kullberg, MC Jankovic, D Gorelick, PL Caspar, P Letterio, JJ Cheever, AW Sher, A AF Kullberg, MC Jankovic, D Gorelick, PL Caspar, P Letterio, JJ Cheever, AW Sher, A TI Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE inflammatory bowel disease; regulatory T cells; intestinal flora; CD25; immunoregulation ID INFLAMMATORY BOWEL-DISEASE; INTESTINAL INFLAMMATION; INTERLEUKIN-10-DEFICIENT MICE; CYTOKINE PRODUCTION; EFFECTOR FUNCTION; WASTING DISEASE; SCID MICE; IN-VITRO; LYMPHOCYTES; RESPONSES AB We have previously demonstrated that interleukin (IL)-10-deficient (IL-10 knockout [KO]) but not wild-type (WT) mice develop colitis after infection with Helicobactor hepaticus. Here, we show that infected recombination activating gene (RAG) KO mice develop intestinal inflammation after reconstitution with CD4(+) T cells from IL-10 KO animals and that the cotransfer of CD4(+) T cells from H. hepaticus-infected but not uninfected WT mice prevents this colitis. The disease-protective WT CD4(+) cells are contained within the CD45RB(low) fraction and unexpectedly were found in both the CD25(+) and the CD25(-) subpopulations of these cells, their frequency being higher in the latter. The mechanism by which CD25(+) and CD25(-) CD45RB(low) CD4(+) cells block colitis involves IL-10 and not transforming growth factor (TGF)-beta, as treatment with anti-IL-IOR, but not anti-TGF-beta monoclonal antibody abrogated their protective effect. In vitro, CD45RB(low) CD4(+) cells from infected WT mice were shown to produce IL-10 and suppress interferon-gamma production by IL-10 KO CD4(+) cells in an H. hepaticus antigen-specific manner. Together, our data support the concept that H. hepaticus infection results in the induction in WT mice of regulatory T cells that prevent bacteria-induced colitis. The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease. C1 NIAID, Immunobiol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp, NCI Frederick, Lab Anim Sci Program, Anim Hlth Diagnost Lab, Ft Detrick, MD 21702 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Kullberg, MC (reprint author), NIAID, Immunobiol Sect, Lab Parasit Dis, NIH, Bldg 50,Rm 6146,50 S Dr, Bethesda, MD 20892 USA. NR 50 TC 224 Z9 231 U1 1 U2 5 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 AUG 19 PY 2002 VL 196 IS 4 BP 505 EP 515 DI 10.1084/jem.20020556 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 587XK UT WOS:000177669300009 PM 12186842 ER PT J AU Hel, Z Johnson, JM Tryniszewska, E Tsai, WP Harrod, R Fullen, J Tartaglia, J Franchini, G AF Hel, Z Johnson, JM Tryniszewska, E Tsai, WP Harrod, R Fullen, J Tartaglia, J Franchini, G TI A novel chimeric Rev, Tat, and Nef (Retanef) antigen as a component of an SIV/HIV vaccine SO VACCINE LA English DT Article DE HIV-1; DNS; Retanef ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; CELLULAR IMMUNE-RESPONSES; CTL ESCAPE VIRUS; HIV-I TAT; ANTIRETROVIRAL TREATMENT; CD8(+) LYMPHOCYTES; CYNOMOLGUS MONKEYS; RAPID SELECTION; DOWN-REGULATION AB The human immunodeficiency virus type 1 (HIV-1) regulatory proteins Rev, Tat, and Nef are expressed at early time post-infection and represent attractive targets to be included in a vaccine candidate for AIDS. However, the putative immunosuppressive activities of some of these proteins may limit their immunogenicity. To circumvent these issues, a novel chimeric polyprotein vaccine candidate (Retanef), comprising genetically modified and re-assorted rev, tat, and nef open reading frames of simian immunodeficiency virus (SIV), was constructed and optimized for its expression in mammalian cells. Retanef encodes a protein of approximately 55 kDa localized primarily in the cytoplasm of transfected cells. The Retanef gene expressed in context of an eucaryotic expression vector (DNA-SIV-Retanef) or cloned into a highly attenuated poxvirus-based NYVAC vector (NYVAC-SIV-Retanef) was used to immunize either naive rhesus macaques or macaques chronically infected with SIVmac251 undergoing anti-retroviral therapy (ART). Three immunizations of naive macaques with DNA-SIV-Retanef followed by a single NYVAC-SIV-Retanef boost induced a response to the Mamu-A*01-restricted Tat epitope (Tat_SL8, TTPESANL) demonstrated by staining with a specific tetramer and by direct cytolytic activity assays, as well as responses to Rev, Tat and Nef proteins demonstrated by ELISPOT assays using overlapping peptide pools encompassing the entire proteins. Immunization of infected macaques with either DNA-SIV-Retanef or NYVAC-SIV-Retanef expanded the frequency of Tat-specific tetramer-staining cells by two- to seven-fold. No adverse effects were observed in either naive or SIV-infected rhesus macaques. Thus, an analogous HIV-1-based chimeric vaccine may represent useful component of an HIV-1 vaccine. Published by Elsevier Science Ltd. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. Med Acad Bialystok, Dept Paediat 3, PL-15274 Bialystok, Poland. Aventis Pasteur, N York, ON M2R 3T4, Canada. RP Franchini, G (reprint author), NCI, Basic Res Lab, 41-D804, Bethesda, MD 20892 USA. OI Hel, Zdenek/0000-0002-4923-4794 NR 85 TC 34 Z9 38 U1 0 U2 0 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 AUG 19 PY 2002 VL 20 IS 25-26 BP 3171 EP 3186 AR PII S0264-410X(02)00258-X DI 10.1016/S0264-410X(02)00258-X PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 594XD UT WOS:000178076900016 PM 12163269 ER PT J AU Baleja, JD Liu, YQ Nicklaus, MC Voigt, JH Liu, ZGG Chen, JJ Androphy, E AF Baleja, JD Liu, YQ Nicklaus, MC Voigt, JH Liu, ZGG Chen, JJ Androphy, E TI Design of papillomavirus inhibitors based on 3-D structures of E6-interacting proteins. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. Univ Massachusetts, Sch Med, Dept Med, Amherst, MA 01003 USA. NCI, Med Chem Lab, Frederick Canc Res & Dev Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 020-MEDI BP U8 EP U8 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300021 ER PT J AU Bleckwenn, NA AF Bleckwenn, NA TI Protein expression using recombinant vaccinia virus infected hela cells: Parameters affecting EGFP expression. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Maryland, Biotechnol Unit, NIDDK, NIH,Dept Chem Engn, Bethesda, MD 20892 USA. Univ Maryland, Ctr Agr Biotechnol, Dept Chem Engn, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 052-BIOT BP U207 EP U207 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200916 ER PT J AU Cao, JJ Kulkarni, S Bowen, W Williams, W Kopajtic, T Katz, JL Newman, AH AF Cao, JJ Kulkarni, S Bowen, W Williams, W Kopajtic, T Katz, JL Newman, AH TI [3-cis-3,5-dimethyl-1-piperazinyl)alkyl]-bis-(4 '-fluorophenyl) amine analogs as dual probes for the dopamine transporter and sigmal receptors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDA, Med Chem Sect, IRP, Baltimore, MD 21224 USA. NIDA, Pscyhobiol Sect, IRP, Baltimore, MD 21224 USA. NIDDK, Med Chem Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 264-MEDI BP U52 EP U52 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300264 ER PT J AU Choi, Y George, C Boyer, PL Kim, HS Hughes, SH Jacobson, KA Marquez, VE AF Choi, Y George, C Boyer, PL Kim, HS Hughes, SH Jacobson, KA Marquez, VE TI Asymmetric synthesis of a con for matio nally locked analogue of 3 '-deoxy thymidine and its triphosphate. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NCI, FCRDC, NCI HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009; Choi, Yongseok/F-8375-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; Choi, Yongseok/0000-0002-3622-3439 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 113-ORGN BP U118 EP U118 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300625 ER PT J AU Chong, HS Bishwajit, G Broker, GA Rogers, RD Brechbiel, MW AF Chong, HS Bishwajit, G Broker, GA Rogers, RD Brechbiel, MW TI Stereoselective and regioselective synthesis of azepane and azepine derivatives via piperidine ring expansion. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Cent Salt & Marine Chem Res Inst, Bhavnagar, Gujarat, India. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. Univ Alabama, Ctr Green Mfg, Tuscaloosa, AL 35487 USA. NIH, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 508-ORGN BP U195 EP U195 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422301020 ER PT J AU Covell, DG Rabow, AA Wallqvist, A Shoemaker, RH AF Covell, DG Rabow, AA Wallqvist, A Shoemaker, RH TI Mining the NCI's tumor screening and genomic databases: Relating molecular targets to candidate ligands. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick Canc Res & Dev Ctr, DTP, DCTD, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 062-COMP BP U478 EP U478 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422202388 ER PT J AU Dimitriadis, EK Horkay, F Kachar, B Chadwick, RS AF Dimitriadis, EK Horkay, F Kachar, B Chadwick, RS TI Measurement of the elastic modulus of polymer gels using the atomic force microscope. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIDCD, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 133-COLL BP U417 EP U417 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422202081 ER PT J AU French, JE AF French, JE TI Genetically-altered mouse models: Short-term alternatives to two-year carcinogenicity testing. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 162-AGFD BP U89 EP U89 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200306 ER PT J AU Gonzalez, FJ AF Gonzalez, FJ TI Transgenic animal models in toxicology studies. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 023-TOXI BP U364 EP U364 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201780 ER PT J AU Greenwald, P AF Greenwald, P TI The importance of cancer chemoprevention and the relationship to nutrition. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 030-TOXI BP U366 EP U366 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201787 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Osmotic and small-angle neutron scattering measurements on polyelectrolyte hydrogels swollen in physiological salt solutions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, UMR 5588, Spectrometrie Phys Lab, F-38042 Grenoble, France. RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 307-POLY BP U401 EP U402 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422302182 ER PT J AU Hummer, G Kalra, A Garde, S Rasaiah, JC Noworyta, JP AF Hummer, G Kalra, A Garde, S Rasaiah, JC Noworyta, JP TI Carbon nanotubes as molecular channels. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Rensselaer Polytech Inst, Dept Chem Engn, Troy, NY USA. Univ Maine, Orono, ME 04469 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 103-COLL BP U412 EP U412 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422202051 ER PT J AU Hummer, G Yeh, IC AF Hummer, G Yeh, IC TI Peptide loop-closure kinetics from microsecond molecular dynamics simulations in explicit solvent. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 182-BIOT BP U229 EP U229 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201046 ER PT J AU Jacobson, KA Kim, SK Barak, D Lee, K Kim, SG Chen, A Gao, ZG AF Jacobson, KA Kim, SK Barak, D Lee, K Kim, SG Chen, A Gao, ZG TI Recent developments in ligand recognition and function of adenosine receptors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDKD, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 416-MEDI BP U79 EP U79 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300416 ER PT J AU Karki, R Tang, Y Nicklaus, MC AF Karki, R Tang, Y Nicklaus, MC TI Model of the HIV-1 integrase-viral DNA complex - A template for structure-based design of HIV in inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 027-MEDI BP U9 EP U10 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300028 ER PT J AU Kim, HO Park, JG Lim, MH Chun, MW Jacobson, KA Jeong, LS AF Kim, HO Park, JG Lim, MH Chun, MW Jacobson, KA Jeong, LS TI Design and synthesis of selective ligands of adenosine A3 receptor. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Seoul Natl Univ, Div Chem & Mol Engn, Kwanak Ku, Seoul 151742, South Korea. Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul, South Korea. Seoul Natl Univ, Coll Pharm, Seoul, South Korea. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 274-MEDI BP U54 EP U55 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300274 ER PT J AU Kim, HS Ravi, RG Maddileti, S Boyer, JL Harden, TK Marquez, VE Jacobson, KA AF Kim, HS Ravi, RG Maddileti, S Boyer, JL Harden, TK Marquez, VE Jacobson, KA TI Methanocarba modification of uracil and adenine nucleotides: High potency of northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. NCI, Lab Med Chem, NIH, Bethesda, MD 20892 USA. NIH, Mol Recognit Sect, Bethesda, MD USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 276-MEDI BP U55 EP U55 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300276 ER PT J AU Kim, SA Marshall, MA Melman, N Muller, CE Jacobson, KA AF Kim, SA Marshall, MA Melman, N Muller, CE Jacobson, KA TI Structure activity relationships at the human A2B adenosine receptor of xanthine derivatives substituted at 1-, 3-, 7- and 8-positions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, LBC, MRS, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Internal Med, Charlottesville, VA 22903 USA. Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Bonn, Inst Pharmazeut, D-5300 Bonn, Germany. Univ Virginia, Dept Med & Mol Physiol, Charlottesville, VA 22903 USA. NIH, Mol Recognit Sect, Bethesda, MD USA. RI Jacobson, Kenneth/A-1530-2009; Muller, Christa/C-7748-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; Muller, Christa/0000-0002-0013-6624 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 329-MEDI BP U64 EP U64 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300329 ER PT J AU Kim, SK Barak, D Jacobson, KA AF Kim, SK Barak, D Jacobson, KA TI GPCR modeling: Comparison of adenosine receptor agonist and antagonist binding domains. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009; Muller, Christa/C-7748-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; Muller, Christa/0000-0002-0013-6624 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 330-MEDI BP U64 EP U64 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300330 ER PT J AU Kosmeder, JW Hirschelman, WH Song, LS Park, EJ Tan, YM Yu, R Hawthorne, M Mehta, RG Grubbs, CJ Lubet, RA Moriarty, RM Pezzuto, JM AF Kosmeder, JW Hirschelman, WH Song, LS Park, EJ Tan, YM Yu, R Hawthorne, M Mehta, RG Grubbs, CJ Lubet, RA Moriarty, RM Pezzuto, JM TI Cancer chemopreventive activity of oxomate, a monoifunctional inducer of phase II detoxification enzymes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Coll Liberal Arts & Sci, Dept Chem, Chicago, IL 60612 USA. Univ Illinois, Coll Med, Dept Surg Oncol, Chicago, IL 60612 USA. Univ Alabama, Chemoprevent Ctr, Birmingham, AL USA. NCI, Chemoprevent Agent Dev Res Grp, DCP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 098-MEDI BP U23 EP U23 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300099 ER PT J AU Lai, CC Kelley, JA AF Lai, CC Kelley, JA TI Practical considerations for the use of sample stacking with capillary electrophoresis for the analysis of nucleotides in synthetic and biological mixtures. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick Canc Res & Dev Ctr, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 058-ANYL BP U121 EP U121 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200483 ER PT J AU Lee, K Zhang, MC Yang, DJ Burke, TR AF Lee, K Zhang, MC Yang, DJ Burke, TR TI Design and synthesis of a novel phosphatase-stable beta-amino acid pTyr mimetic and its utilization in the preparation of novel Grb2 SH2 domain ligands. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 106-MEDI BP U24 EP U24 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300107 ER PT J AU Lewi, P de Jonge, M Daeyaert, F Koymans, L Vinkers, M Heeres, J Janssen, PAJ Arnold, E Das, K Clark, AD Hughes, SH Boyer, PL de Bethune, MP Pauwels, R Andries, K AF Lewi, P de Jonge, M Daeyaert, F Koymans, L Vinkers, M Heeres, J Janssen, PAJ Arnold, E Das, K Clark, AD Hughes, SH Boyer, PL de Bethune, MP Pauwels, R Andries, K TI On the detection of multiple binding modes of ligands to proteins, from biological, structural, and modelling data. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Janssen Pharmacuet NV, Ctr Mol Design, B-2350 Vosselaar, Belgium. Rutgers State Univ, Ctr Adv Biotechnol & Med, Dept Chem & Biol Chem, Piscataway, NJ 08855 USA. NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. Tibotec Virco, Mechelen, Belgium. RI de Jonge, Marc/B-3391-2010 OI de Jonge, Marc/0000-0003-3225-8172 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 101-COMP BP U484 EP U484 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422202426 ER PT J AU Li, P Li, BH Zhang, MC Yang, DJ Roller, PP AF Li, P Li, BH Zhang, MC Yang, DJ Roller, PP TI Structure-based design and synthesis of thioether-bridged cyclic peptides as highly potent Grb2-SH2 domain inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 232-MEDI BP U47 EP U47 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300232 ER PT J AU Linden, J Figler, RA Wang, GQ Jones, DR Jacobson, KA LaNoue, KF AF Linden, J Figler, RA Wang, GQ Jones, DR Jacobson, KA LaNoue, KF TI A2B adenosine receptor antagonists for asthma and diabetes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Virginia, Dept Med & Mol Physiol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Surg, Charlottesville, VA 22903 USA. Penn State Univ, University Pk, PA 16802 USA. NIH, Mol Recognit Sect, Bethesda, MD 20892 USA. Penn State Univ, University Pk, PA 16802 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 418-MEDI BP U79 EP U79 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300418 ER PT J AU Mandler, R Kobayashi, H Hinson, ER Davis, MY Sausville, EA Newman, DJ Yang, DJ Roettinger, AJ Brechbiel, MW Waldmann, TA AF Mandler, R Kobayashi, H Hinson, ER Davis, MY Sausville, EA Newman, DJ Yang, DJ Roettinger, AJ Brechbiel, MW Waldmann, TA TI Strategies in conjugating geldanamycin derivatives to monoclonal antibodies that enhance Herceptin efficacy in mice bearing her2-overexpressing xenografts. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, CCR, Metab Branch, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Nat Prod Branch, Bethesda, MD 20892 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. NCI, CCR, Radioimmune & Inorgan Chem, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 064-BIOT BP U209 EP U209 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200928 ER PT J AU Mohan, S Kourentzi, KD Smith-Gill, S Willson, RC AF Mohan, S Kourentzi, KD Smith-Gill, S Willson, RC TI Multi-step association in antigen-antibody interactions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Houston, Dept Chem Engn, Houston, TX 77204 USA. NCI, Frederick Canc Res & Dev Ctr, Struct Immunol Grp, Div Basic Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 106-BIOT BP U216 EP U216 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200970 ER PT J AU Phillips, TM Smith, PD AF Phillips, TM Smith, PD TI Multiple analyte analysis using an immunoaffinity array. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 200-ANYL BP U143 EP U143 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200625 ER PT J AU Ruan, Q Skorvaga, M Zou, Y Van Houten, B Amin, S Geacintov, NE AF Ruan, Q Skorvaga, M Zou, Y Van Houten, B Amin, S Geacintov, NE TI Prokaryotic nucleotide excision repair of BPDE-modified DNA duplexes flanked by A : T or G : C base pairs depends on local structural disturbances caused by the lesions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NYU, Dept Chem, New York, NY 10003 USA. E Tennessee State Univ, Johnson City, TN 37614 USA. NIEHS, NIH, Res Triangle Pk, NC USA. Amer Hlth Fdn, New York, NY 10017 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 084-TOXI BP U375 EP U375 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201841 ER PT J AU Shears, S AF Shears, S TI Nudix hydrolases and non-canonical substrates: The significance of metabolic competition between diadenosine and diphosphoinositol polyphosphates. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIEHS, Inositol Signaling Grp, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 035-CARB BP U264 EP U264 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201235 ER PT J AU Sigano, DM Nacro, K Yan, SQ Lewin, NE Pearce, LL Blumberg, PM Marquez, VE AF Sigano, DM Nacro, K Yan, SQ Lewin, NE Pearce, LL Blumberg, PM Marquez, VE TI Ligand discrimination in the differential binding modes of diacylglycerol (DAG) analogs with protein kinase C (PKC). SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD USA. RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 113-MEDI BP U26 EP U26 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300114 ER PT J AU Tarasov, SG Nelson, C Cholody, WM Hariprakasha, H Kosakowska-Cholody, T Casas-Finet, JR Michejda, CJ AF Tarasov, SG Nelson, C Cholody, WM Hariprakasha, H Kosakowska-Cholody, T Casas-Finet, JR Michejda, CJ TI Physico-chemical study of DNA binding properties of the naphtylimido-imidazoacridone wmc79 and related compounds. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. NCI Frederick, Struct Biophys Lab, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. Medimmune Inc, Analyt Biochem Div, Gaithersburg, MD 20878 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 160-BIOL BP U180 EP U180 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200839 ER PT J AU Tarasova, NI Amadei, G Seth, R Hrycyna, CA Gottesman, MM Michejda, CJ AF Tarasova, NI Amadei, G Seth, R Hrycyna, CA Gottesman, MM Michejda, CJ TI Transmembrane inhibitors of polytopic membrane proteins. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick Canc Res & Dev Ctr, Struct Biophys Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 407-MEDI BP U77 EP U77 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300407 ER PT J AU Teetsov, JA Campbell, L Satterfield, M Smith, K Wells, C Wells, S Courtney, A AF Teetsov, JA Campbell, L Satterfield, M Smith, K Wells, C Wells, S Courtney, A TI Advantages of membership in Iota Sigma Pi. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Gen Elect Global Res & Dev, Combinatorial Chem & Characterizat Technol, Niskayuna, NY 12204 USA. NIH, Bethesda, MD 20892 USA. Natl Inst Sci & Technol, Gaithersburg, MD USA. IBM Corp, Armonk, NY 10504 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. USDA, Washington, DC 20250 USA. EM teetsov@crd.ge.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 020-HIST BP U596 EP U596 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422203059 ER PT J AU Wainer, IW Moaddel, R Jozwiak, K Beigi, F AF Wainer, IW Moaddel, R Jozwiak, K Beigi, F TI Synthesis and characterization of immobilized neuronal nicotinic receptors and the on-line screening of nicotinic binding affinities via LC-MS. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIA, LCI, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 199-ANYL BP U143 EP U143 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200624 ER PT J AU Walker, CL Hodges, L Cook, J Lobenhofer, E Li, LP Bennett, L Bushel, P Afshari, C AF Walker, CL Hodges, L Cook, J Lobenhofer, E Li, LP Bennett, L Bushel, P Afshari, C TI Identification of critical determinants of agonism and antagonism in the breast by transcriptional SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Texas, MD Anderson Canc Ctr, Sci Pk Res Div, Dept Carcinogenesis, Smithville, TX 78957 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 005-TOXI BP U361 EP U361 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422201762 ER PT J AU Waterhouse, DJ Saavedra, JE Citro, ML Xu, X Keefer, LK AF Waterhouse, DJ Saavedra, JE Citro, ML Xu, X Keefer, LK TI Profile of PROLI/NO as a potential treatment for cerebral vasospasm. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAIC Frederick, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD USA. NIH, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 295-MEDI BP U58 EP U58 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300295 ER PT J AU Woods, AS AF Woods, AS TI Types of interactions in the formation of non-covalent complexes in biomolecules. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDA IRP, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 240-ANYL BP U149 EP U149 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422200662 ER PT J AU Wu, XW Wang, SM Brooks, BR AF Wu, XW Wang, SM Brooks, BR TI Direct observation of the folding and unfolding of a b-hairpin in explicit water through computer simulation. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Internal Med & Med Chem, Ann Arbor, MI 48109 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 266-COMP BP U509 EP U509 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RL UT WOS:000177422202591 ER PT J AU Xu, B Stephens, A Kirschenheuter, G Greslin, A Cheng, XQ Sennelo, J Chen, AS Kim, SA Kim, HS Bischofberger, N Cook, G Jacobson, KA AF Xu, B Stephens, A Kirschenheuter, G Greslin, A Cheng, XQ Sennelo, J Chen, AS Kim, SA Kim, HS Bischofberger, N Cook, G Jacobson, KA TI Acyclic analogs of adenosine bisphosphates as P2Y receptor antagonists: Phosphate substitution leads to multiple pathways of inhibition of platelet aggregation. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Gilead Sci Inc, Boulder, CO 80301 USA. Gilead Sci Inc, Foster City, CA 94404 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 275-MEDI BP U55 EP U55 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300275 ER PT J AU Zou, MF Kopajtic, T Katz, JL Newman, AH AF Zou, MF Kopajtic, T Katz, JL Newman, AH TI SAR comparison of (S)-2-substituted-3-alpha-[bis(4 '-fluorophenyl)methoxy]tropanes and (R)-2-substituted-3-beta-(3,4-dichlorophenyl)tropanes at the DAT. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDA, Med Chem Sect, IRP, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, IRP, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 18 PY 2002 VL 224 MA 262-MEDI BP U52 EP U52 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 583RM UT WOS:000177422300262 ER PT J AU Ozaki, K Leonard, WJ AF Ozaki, K Leonard, WJ TI Cytokine and cytokine receptor pleiotropy and redundancy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; THYMIC STROMAL LYMPHOPOIETIN; COLONY-STIMULATING FACTOR; MOLECULAR-CLONING; INTERLEUKIN-4 RECEPTOR; DEFICIENT MICE; ALPHA-CHAIN; GAMMA-CHAIN; GM-CSF; IMMUNE-RESPONSES C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Rm 7N252, Bethesda, MD 20892 USA. NR 71 TC 149 Z9 155 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2002 VL 277 IS 33 BP 29355 EP 29358 DI 10.1074/jbc.R200003200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585DW UT WOS:000177509300002 PM 12072446 ER PT J AU Yan, B Raben, N Plotz, P AF Yan, B Raben, N Plotz, P TI The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HAIR CELL-DIFFERENTIATION; NEURONAL DIFFERENTIATION; MOLECULAR CHARACTERIZATION; TRANSCRIPTION FACTORS; NEGATIVE REGULATOR; DROSOPHILA-HAIRY; MAMMALIAN NOTCH; HUMAN HOMOLOG; LUNG-CANCER; EXPRESSION AB Acid a-glucosidase (GAA) is a lysosomal enzyme that degrades glycogen. A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II. Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells. Hes-1 is a well studied downstream target gene in the Notch signaling pathway. In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling. In cotransfection experiments, Hes-1, up-regulated by overexpressed NICD, enhanced the repressive effect of the DNA element with wild type Hes-1 binding sites but not with mutant Hes-1 binding sites. Conversely, depletion of Notch-1 with phosphorothioated antisense oligonucleotides, corresponding to the fourth ankyrin repeat within NICD, led to reduced Hes-1. Constitutively overexpressed Hes-1 and Notch-1 repressed GAA gene expression. Therefore, our data establish that the human GAA gene, encoding a lysosomal enzyme, is a downstream target of the Notch-1/Hes-1 signaling pathway. C1 NIAMS, Clin Ctr, NIH, Bethesda, MD 20892 USA. NIAMS, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Plotz, P (reprint author), NIAMS, Clin Ctr, NIH, 9000 Rockville Pike,Bldg 10,Rm 9N244, Bethesda, MD 20892 USA. NR 46 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2002 VL 277 IS 33 BP 29760 EP 29764 DI 10.1074/jbc.M204721200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585DW UT WOS:000177509300053 PM 12065598 ER PT J AU Chen, YR Deterding, LJ Sturgeon, BE Tomer, KB Mason, RP AF Chen, YR Deterding, LJ Sturgeon, BE Tomer, KB Mason, RP TI Protein oxidation of cytochrome c by reactive halogen species enhances its peroxidase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; HYPOCHLOROUS ACID; HYDROGEN-PEROXIDE; HUMAN-NEUTROPHILS; METHIONINE OXIDATION; OXIDIZED METHIONINE; ENDOTHELIAL-CELLS; HYPOHALOUS ACIDS; MYELOPEROXIDASE; GLUTATHIONE AB Reactive halogen species (RHS; X-2 and HOX, where X represents Cl, Br, or I) are metabolites mediated by neutrophil activation and its accompanying respiratory burst. We have investigated the interaction between RHS and mitochondrial cytochrome c (cyt c) by using electrospray mass spectrometry and electron spin resonance (ESR). When the purified cyt c was reacted with an excess amount of hypochlorous acid (HOC1) at pH 7.4, the peroxidase activity of cyt c was increased by 4.5-, 6.9-, and 8.6-fold at molar ratios (HOCl/cyt c) of 2, 4, and 8, respectively. In comparison with native cyt c, the mass spectra obtained from the HOCl-treated cyt c revealed that oxygen is covalently incorporated into the protein as indicated by molecular ions of m/z = 12,360 (cyt c), 12,376 (cyt c + O), and 12,392 (cyt c + 20). Using tandem mass spectrometry, a peptide (obtained from the tryptic digests of HOCl-treated cyt c) corresponding to the amino acid sequence MIFAGIK, which contains the methionine that binds to the heme, was identified to be involved in the oxygen incorporation. The location of the oxygen incorporation was unequivocally determined to be the methionine residue, suggesting that the oxidation of heme ligand (Met-80) by HOCl results in the enhancement of peroxidase activity of cyt c. ESR spectroscopy of HOCl-oxidized cyt c, when reacted with H2O2 in the presence of the nitroso spin trap 2-methyl-2-nitrosopropane (MNP), yielded more immobilized MNP/tyrosyl adduct than native cyt c. In the presence of H2O2, the peroxidase activity of HOCl-oxidized cyt c exhibited an increasing ability to oxidize tyrosine to tyrosyl radical as measured directly by fast flow ESR. Titration of both native cyt c and HOCl-oxidized cyt c with various amounts of H2O2 indicated that the latter has a decreased apparent K-m for H2O2, implicating that protein oxidation of cyt c increases its accessibility to H2O2. HOCl-oxidized cyt c also displayed an impaired ability to support oxygen consumption by the purified mitochondrial cytochrome c oxidase, suggesting that protein oxidation of cyt c may break the electron transport chain and inhibit energy transduction in mitochondria. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 59 TC 80 Z9 81 U1 1 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2002 VL 277 IS 33 BP 29781 EP 29791 DI 10.1074/jbc.M200709200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585DW UT WOS:000177509300056 PM 12050149 ER PT J AU Isaacs, JS Jung, YJ Mimnaugh, EG Martinez, A Cuttitta, F Neckers, LM AF Isaacs, JS Jung, YJ Mimnaugh, EG Martinez, A Cuttitta, F Neckers, LM TI Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; HEAT-SHOCK PROTEIN; TUMOR-SUPPRESSOR PROTEIN; HELIX-LOOP-HELIX; CELL GLUCOCORTICOID RECEPTOR; HUMAN ERYTHROPOIETIN GENE; PROLYL HYDROXYLATION; SIGNAL-TRANSDUCTION; DIOXIN RECEPTOR; FACTOR 1-ALPHA AB HIF-1alpha is a normally labile proangiogenic transcription factor that is stabilized and activated in hypoxia. Although the von Hippel Lindau (VHL) gene product, the ubiquitin ligase responsible for regulating HIF-1alpha protein levels, efficiently targets HIF-1alpha for rapid proteasome-dependent degradation under normoxia, HIF-1alpha is resistant to the destabilizing effects of VHL under hypoxia. HIF-1alpha also associates with the molecular chaperone Hsp90. To examine the role of Hsp90 in HIF-1alpha function, we used renal carcinoma cell (RCC) lines that lack functional VHL and express stable HIF-1alpha protein under normoxia. Geldanamycin (GA), an Hsp90 antagonist, promoted efficient ubiquitination and proteasome-mediated degradation of HIF-1alpha in RCC in both normoxia and hypoxia. Furthermore, HIF-1alpha point mutations that block VHL association did not protect HIF-1alpha from GA-induced destabilization. Hsp90 antagonists also inhibited HIF-1alpha transcriptional activity and dramatically reduced both hypoxia-induced accumulation of VEGF mRNA and hypoxia-dependent angiogenic activity. These findings demonstrate that disruption of Hsp90 function 1) promotes HIF-1alpha degradation via a novel, oxygen-independent E3 ubiquitin ligase and 2) diminishes HIF-1alpha transcriptional activity. Existence of an Hsp90-dependent pathway for elimination of HIF-1alpha predicts that Hsp90 antagonists may be hypoxic cell sensitizers and possess antiangiogenic activity in vivo, thus extending the utility of these drugs as therapeutic anticancer agents. C1 NCI, Ctr Canc Res, Cell & Canc Biol Branch, NIH, Rockville, MD 20850 USA. RP Neckers, LM (reprint author), NCI, Ctr Canc Res, Cell & Canc Biol Branch, NIH, 9610 Med Ctr Dr,Ste 300, Rockville, MD 20850 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 80 TC 442 Z9 460 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2002 VL 277 IS 33 BP 29936 EP 29944 DI 10.1074/jbc.M204733200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585DW UT WOS:000177509300074 PM 12052835 ER PT J AU Zhao, P Iezzi, S Carver, E Dressman, D Girdley, T Sartorelli, V Hoffman, EP AF Zhao, P Iezzi, S Carver, E Dressman, D Girdley, T Sartorelli, V Hoffman, EP TI Slug is a novel downstream target of MyoD - Temporal profiling in muscle regeneration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SKELETAL-MUSCLE; DNA-BINDING; DROSOPHILA-MELANOGASTER; TRANSCRIPTION FACTORS; SATELLITE CELLS; GENE; EXPRESSION; MYOGENESIS; DIFFERENTIATION; ACTIVATION AB Temporal expression profiling was utilized to define transcriptional regulatory pathways in vivo in a mouse muscle regeneration model. Potential downstream targets of MyoD were identified by temporal expression, promoter data base mining, and gel shift assays; Slug and calpain 6 were identified as novel MyoD targets. Slug, a member of the snail/slug family of zinc finger transcriptional repressors critical for mesoderm/ectoderm development, was further shown to be a downstream target by using promoter/reporter constructs and demonstration of defective muscle regeneration in Slug null mice. C1 Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. George Washington Univ, Genet Program, Washington, DC 20010 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NIAMS, Muscle Gene Express Grp, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hoffman, EP (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NHLBI NIH HHS [1-U01-HL66614]; NICHD NIH HHS [R01-HD34883] NR 53 TC 78 Z9 81 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2002 VL 277 IS 33 BP 30091 EP 30101 DI 10.1074/jbc.M202668200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585DW UT WOS:000177509300092 PM 12023284 ER PT J AU Yang, LJ Beard, WA Wilson, SH Roux, B Broyde, S Schlick, T AF Yang, LJ Beard, WA Wilson, SH Roux, B Broyde, S Schlick, T TI Local deformations revealed by dynamics simulations of DNA polymerase beta with DNA mismatches at the primer terminus SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE dynamics simulations; DNA polymerase beta; opening; DNA mispairs; DNA extension ID TARGETED MOLECULAR-DYNAMICS; HIV-1 REVERSE-TRANSCRIPTASE; I KLENOW FRAGMENT; REPLICATION FIDELITY; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURES; KINETIC MECHANISM; NUCLEOTIDE INCORPORATION; BIOMOLECULAR DYNAMICS; CATALYTIC MECHANISM AB Nanosecond dynamics simulations for DNA polymerase beta (pol beta)/DNA complexes with three mismatched base-pairs, namely GG, CA, or CC (primer/template) at the DNA polymerase active site, are performed to investigate the mechanism of polymerase opening and how the mispairs may affect the DNA extension step; these trajectories are compared to the behavior of a pol beta/DNA complex with the correct GC base-pair, and assessed with the aid of targeted molecular dynamics (TMD) simulations of all systems from the closed to the open enzyme state. DNA polymerase conformational changes (subdomain closing and opening) have been suggested to play a critical role in DNA synthesis fidelity, since these changes are associated with the formation of the substrate-binding pocket for the nascent base-pair. Here we observe different large C-terminal subdomain (thumb) opening motions in the simulations of pol beta with GC versus GG base-pairs. Whereas the conformation of pol beta in the former approaches the observed open state in the crystal structures, the enzyme in the latter does not. Analyses of the motions of active-site protein/ DNA residues help explain these differences. Interestingly, rotation of Arg258 toward Asp192, which coordinates both active-site metal ions in the closed "active" complex, occurs rapidly in the GG simulation. We have previously suggested that this rotation is a key slow step in the closed to open transition. TMD simulations also point to a unique pathway for Arg258 rotation in the GG mispair complex. Simulations of the mismatched systems also reveal distorted geometries in the active site of all the mispair complexes examined. The hierarchy of the distortions (GG > CC > CA) parallels the experimentally deduced inability of pol beta to extend these mispairs. Such local distortions would be expected to cause inefficient DNA extension and polymerase dissociation and thereby might lead to proofreading by an extrinsic exonuclease. Thus, our studies on the dynamics of pol beta opening in mismatch systems provide structural and dynamic insights to explain experimental results regarding inefficient DNA extension following misincorporation; these details shed light on how proofreading may be invoked by the abnormal active-site geometry. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NYU, Dept Chem, New York, NY 10012 USA. NYU, Courant Inst Math Sci, New York, NY 10012 USA. Howard Hughes Med Inst, New York, NY 10012 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Cornell Univ, Dept Biochem, Weill Med Coll, New York, NY 10021 USA. NYU, Dept Biol, New York, NY 10003 USA. RP Schlick, T (reprint author), NYU, Dept Chem, 251 Mercer St, New York, NY 10012 USA. FU NCI NIH HHS [CA28038, CA75449]; NIGMS NIH HHS [R01 GM55164] NR 76 TC 46 Z9 47 U1 1 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 16 PY 2002 VL 321 IS 3 BP 459 EP 478 DI 10.1016/S0022-2836(02)00617-4 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 589MC UT WOS:000177761300007 PM 12162959 ER PT J AU Takeuchi, K Park, EJ Lee, CW Jae, KI Takahashi, H Swartz, KJ Shimada, I AF Takeuchi, K Park, EJ Lee, CW Jae, KI Takahashi, H Swartz, KJ Shimada, I TI Solution structure of omega-grammotoxin SIA, a gating modifier of P/Q and N-type Ca2+ channel SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE calcium channel; gating modifier; grammotoxin; nuclear magnetic resonance; potassium channel ID SENSITIVE CALCIUM-CHANNEL; NUCLEAR-MAGNETIC-RESONANCE; RELAXATION MATRIX ANALYSIS; DEPENDENT K+ CHANNELS; FUNNEL-WEB SPIDER; 3-DIMENSIONAL STRUCTURE; NMR-SPECTROSCOPY; PROTEIN STRUCTURES; CONOTOXIN GVIA; MOLECULAR DETERMINANTS AB omega-Grammotoxin SIA (GrTx) is a 36 amino acid residue protein toxin from spider venom that inhibits P/Q and N-type voltage-gated Ca2+ channels by modifying voltage-dependent gating. We determined the three-dimensional structure of GrTx using NMR spectroscopy. The toxin adopts an "inhibitor cystine knot" motif composed of two beta-strands (Leu19-Cys21 and Cys30-Trp32) and a beta-bulge (Trp6, Gly7-Cys30) with a +2x, - 1 topology, which are connected by four chain reversals. Although GrTx was originally identified as an inhibitor of voltage-gated Ca2+ channel, it also binds to K+ channels with lower affinity. A similar cross-reaction was observed for Hanatoxin1 (HaTx), which binds to the voltage-sensing domains of K+ and Ca2+ channels with different affinities. A detailed comparison of the GrTx and HaTx structures identifies a conserved face containing a large hydrophobic patch surrounded by positively charged residues. The slight differences in the surface shape, which result from the orientation of the surface aromatic residues and/or the distribution of the charged residues, may explain the differences in the binding affinity of these gating modifiers with different voltage-gated ion channels. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 1130033, Japan. Kwangju Inst Sci & Technol, Kwangju 500712, South Korea. Natl Inst Adv Ind Sci & Technol, Biol Informat Res Ctr, Koto Ku, Tokyo 1350064, Japan. NINDS, Mol Physiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Shimada, I (reprint author), Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 1130033, Japan. EM shimada@iw-nmr.f.u-tokyo.ac.jp RI Takeuchi, Koh/B-4971-2010 NR 63 TC 32 Z9 33 U1 3 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 16 PY 2002 VL 321 IS 3 BP 517 EP 526 DI 10.1016/S0022-2836(02)00595-8 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 589MC UT WOS:000177761300011 PM 12162963 ER PT J AU Little, J Bradley, L Bray, MS Clyne, M Dorman, J Ellsworth, DL Hanson, J Khoury, M Lau, J O'Brien, TR Rothman, N Stroup, D Taioli, E Thomas, D Vainio, H Wacholder, S Weinberg, C AF Little, J Bradley, L Bray, MS Clyne, M Dorman, J Ellsworth, DL Hanson, J Khoury, M Lau, J O'Brien, TR Rothman, N Stroup, D Taioli, E Thomas, D Vainio, H Wacholder, S Weinberg, C TI Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE case-control studies; causality; cohort studies; epidemlologic methods; gene frequency; genetic techniques; meta-analysis ID SINGLE NUCLEOTIDE POLYMORPHISMS; COMPLEX HUMAN-DISEASES; HUMAN GENOME; COLORECTAL-CANCER; POPULATION STRATIFICATION; LINKAGE DISEQUILIBRIUM; DIABETES-MELLITUS; POOLED ANALYSES; BLOOD SPOTS; METAANALYSIS AB The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis. C1 Ctr Dis Control & Prevent, Off Genom & Dis Prevent, Atlanta, GA 30341 USA. Univ Aberdeen, Epidemiol Grp, Dept Med & Therapeut, Aberdeen, Scotland. Sunrise Med Lab, Hauppauge, NY USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Tufts Univ New England Med Ctr, Div Clin Care Res, Boston, MA 02111 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. Univ So Calif, Biostat Div, Dept Prevent Med, Milan, Italy. Int Agcy Res Canc, F-69372 Lyon, France. NIEHS, Res Triangle Pk, NC 27709 USA. NHLBI, Bethesda, MD 20892 USA. IRCCS, Osped Policlin, Milan, Italy. RP Khoury, M (reprint author), Ctr Dis Control & Prevent, Off Genom & Dis Prevent, Atlanta, GA 30341 USA. NR 101 TC 294 Z9 304 U1 0 U2 4 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 AUG 15 PY 2002 VL 156 IS 4 BP 300 EP 310 DI 10.1093/aje/kwf054 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 584WX UT WOS:000177492700003 PM 12181099 ER PT J AU Burke, W Atkins, D Gwinn, M Guttmacher, A Haddow, J Lau, J Palomaki, G Press, N Richards, CS Wideroff, L Wiesner, GL AF Burke, W Atkins, D Gwinn, M Guttmacher, A Haddow, J Lau, J Palomaki, G Press, N Richards, CS Wideroff, L Wiesner, GL TI Genetic test evaluation: Information needs of clinicians, policy makers, and the public SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE factor V; genetic markers; genetic predisposition to disease; genetic screening; genetics; phenylketonurias ID FACTOR-V-LEIDEN; DEEP-VEIN THROMBOSIS; FOLLOW-UP CARE; VENOUS THROMBOEMBOLISM; BREAST-CANCER; INHERITED PREDISPOSITION; COLORECTAL-CANCER; FAMILY MEMBERS; RISK; BRCA2 AB Growing knowledge about gene-disease associations will lead to new opportunities for genetic testing. Many experts predict that genetic testing will become increasingly important as a guide to prevention, clinical management, and drug treatment based on genetic susceptibilities. As part of a Human Genetic Epidemiology workshop convened by the Centers for Disease Control and Prevention, a group of experts evaluated the evidence needed when considering the appropriate use of new genetic tests. Because new tests are likely to vary in their predictive value, their potential to direct prevention or treatment efforts, and their personal and social consequences, the task of determining appropriate use will require careful consideration of a variety of factors, including the analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications of the test. Standardized formats are needed to summarize what is known and not known about new genetic tests with respect to each of these features. Following criteria for the objective assessment of test properties, reports should be structured to enable policy makers, clinicians, and the public to identify the available evidence, so that uncertainties can be taken into account when considering test use and planning future research. C1 Ctr Dis Control & Prevent, Off Genet & Dis Prevent, Atlanta, GA 30341 USA. Univ Washington, Seattle, WA 98195 USA. Agcy Healthcare Res & Qual, Bethesda, MD USA. NHGRI, Bethesda, MD 20892 USA. Fdn Blood Res, Scarborough, ME 04074 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Baylor Coll Med, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Burke, W (reprint author), Ctr Dis Control & Prevent, Off Genet & Dis Prevent, 4770 Buford Highway NE,MS-K28, Atlanta, GA 30341 USA. RI Hernandez, Jessica/G-6527-2011 NR 39 TC 95 Z9 98 U1 3 U2 9 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 AUG 15 PY 2002 VL 156 IS 4 BP 311 EP 318 DI 10.1093/aje/kwf055 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 584WX UT WOS:000177492700004 PM 12181100 ER PT J AU Mink, PJ Shahar, E Rosamond, WD Alberg, AJ Folsom, AR AF Mink, PJ Shahar, E Rosamond, WD Alberg, AJ Folsom, AR TI Serum insulin and glucose levels and breast cancer incidence - The Atherosclerosis Risk in Communities Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; glucose; insulin ID MEDICAL CONDITIONS; C-PEPTIDE; HORMONES; RESISTANCE; HISTORY; OBESITY; WOMEN AB The authors examined the association of breast cancer incidence with serum levels of insulin and glucose in a cohort of 7,894 women aged 45-64 years from four US communities. Anthropometric factors and fasting levels of insulin and glucose were measured at baseline (1987-1989). Over an average follow-up period of 7.1 years (1987-1995), 187 breast cancer cases were ascertained. Breast cancer was associated positively with body mass index but not with waist:hip ratio or serum insulin level. After adjustment for age, race, and study site, the incidence of breast cancer was 60% higher among diabetic women than among women with fasting glucose levels under 100 mg/dl, but this association was attenuated after further adjustment for body mass index and other covariates (adjusted rate ratio = 1.39, 95% confidence interval: 0.86, 2.23). Circulating insulin levels were not predictive of future breast cancer incidence, but there may be a weak association with type 2 diabetes, perhaps modulated via increased adiposity. C1 NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Mink, PJ (reprint author), NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. FU NCI NIH HHS [T32CA09607, R03-CA65473]; NHLBI NIH HHS [N01-HC-55019, N01-HC-55018, N01-HC-55016, N01-HC-55021, N01-HC-55020, N01-HC-55015, N01-HC-55022] NR 19 TC 86 Z9 87 U1 1 U2 2 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 AUG 15 PY 2002 VL 156 IS 4 BP 349 EP 352 DI 10.1093/aje/kwf050 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 584WX UT WOS:000177492700009 PM 12181105 ER PT J AU Brenner, AV Lubin, JH Calista, D Landi, MT AF Brenner, AV Lubin, JH Calista, D Landi, MT TI Instrumental measurements of skin color and skin ultraviolet light sensitivity and risk of cutaneous malignant melanoma: A case-control study in an Italian population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; colorimetry; epidemiologic methods; melanoma; risk factors; skin pigmentation; spectrophotometry; ultraviolet; ultraviolet rays ID RADIATION-INDUCED ERYTHEMA; UV-INDUCED ERYTHEMA; SUN EXPOSURE; PIGMENTARY TRAITS; MEDITERRANEAN POPULATION; MELANOCYTIC NEVI; UNITED-STATES; DOSE-RESPONSE; HAIR COLOR; REFLECTANCE AB The authors evaluated objective measurements of constitutive skin color and ultraviolet light sensitivity in relation to risk of cutaneous malignant melanoma (CMM), Incident CMM cases (n = 183) were diagnosed between December 1994 and January 1999 at the Maurizio Bufalini Hospital in Cesena, Italy. Controls (n = 179) were mostly spouses/partners of cases and were frequency-matched by age and sex. In addition to interviews, constitutive skin color and skin ultraviolet light sensitivity were assessed by colorimetry and minimal erythema dose (MED), respectively, Odds ratios were estimated using unconditional logistic regression. The odds of CMM increased by a factor of 1.20 (95 percent confidence interval: 1.12, 1.30) for each unit of skin brightness and by a factor of 1.24 (95 percent confidence interval: 1.07, 1.43) per 10 mJ/cm(2) Of MED. These associations were largely independent of phenotypic or sun-related characteristics and were modified by sun exposure. Increased risk of CMM was observed only among subjects with the highest levels of sun exposure. Epidemiologic studies of CMM may benefit from the inclusion of colorimetric and MED measurements along with traditional risk factors to obtain more accurate, quantitative, and objective information. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Bufallini Hosp, Dept Dermatol, Cesena, Italy. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Landi, MT (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7362, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA 65558-01A2] NR 68 TC 7 Z9 8 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 AUG 15 PY 2002 VL 156 IS 4 BP 353 EP 362 DI 10.1093/aje/kwf045 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 584WX UT WOS:000177492700010 PM 12181106 ER PT J AU Schlessinger, D Herrera, L Crisponi, L Mumm, S Percesepe, A Pellegrini, M Pilia, G Forabosco, A AF Schlessinger, D Herrera, L Crisponi, L Mumm, S Percesepe, A Pellegrini, M Pilia, G Forabosco, A TI Genes and translocations involved in POF SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE menopause; gonadal dysgenesis; follicles; atresia; forkhead transcription factor ID PREMATURE OVARIAN FAILURE; HUMAN X-CHROMOSOME; TURNER SYNDROME; TRANSCRIPTION FACTOR; OOCYTE APOPTOSIS; SEX-CHROMOSOME; HUMAN HOMOLOG; REGION; MAP; CHOROIDEREMIA AB Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Fox12 and interacting proteins, or with defined changes in the X chromosome. Published 2002 Wiley-Liss, Inc. C1 NIA, TRIAD Ctr, Genet Lab, Baltimore, MD 21224 USA. CNR, Ist Ric Talassemie & Anemie Mediterranee, Cagliari, Italy. Washington Univ, Sch Med, Div Bone & Mineral Dis, St Louis, MO USA. Univ Modena & Reggio Emilia, Dept Morphol & Legal Med Sci, Modena, Italy. RP Schlessinger, D (reprint author), NIA, TRIAD Ctr, Genet Lab, Suite 4000,333 Cassell Dr, Baltimore, MD 21224 USA. RI Percesepe, Antonio/A-6076-2012; Pellegrini, Massimo/P-6359-2016 OI Percesepe, Antonio/0000-0002-3268-6786; Pellegrini, Massimo/0000-0002-0091-0077 FU Telethon [GP0049Y01] NR 60 TC 92 Z9 100 U1 3 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 AUG 15 PY 2002 VL 111 IS 3 BP 328 EP 333 DI 10.1002/ajmg.10565 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 579PE UT WOS:000177186400016 PM 12210333 ER PT J AU Oz, M Zhang, L Spivak, CE AF Oz, M Zhang, L Spivak, CE TI Direct noncompetitive inhibition of 5-HT3 receptor-mediated responses by forskolin and steroids SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE forskolin; steroids; 5-HT3 receptor; cyclicAMP; Xenopus oocyte ID NICOTINIC ACETYLCHOLINE-RECEPTORS; OOCYTE ADENYLATE-CYCLASE; MOUSE HIPPOCAMPAL; GABA(A) RECEPTORS; GANGLION NEURONS; TYPE-3 RECEPTOR; CELL-LINE; RAT-BRAIN; DESENSITIZATION; PROGESTERONE AB 5-HT3 receptors cloned from NCB-20 cells were expressed in Xenopus oocytes, and the effects of forskolin and steroids on the function of the receptors were investigated using the two-electrode voltage-clamp technique. Forskolin, 17-beta-estradiol, and progesterone inhibited the currents activated by 1 muM 5-HT in a reversible and concentration-dependent manner, with IC50 values of 12, 33, and 89 muM, respectively. The inhibitory effects of forskolin and 17-beta-estradiol were independent of the membrane potential. Forskolin and 17-beta-estradiol significantly reduced the maximal amplitude of the 5-HT concentration-response curve (E-max) without significantly affecting the EC50, indicating that these compounds act as noncompetitive inhibitors of the 5-HT3 receptor. The cAMP analogue, 8-Br-cAMP (0.2 mM), and the protein kinase A activator, Sp-cAMP (0.1 mM), did not affect the amplitude of 5-HT3 receptor-mediated currents. The membrane-permeable protein kinase A inhibitor Rp-cAMP (0.1 mM) and the estrogen-receptor antagonist tamoxifen (1 muM) did not affect the inhibition of 5-HT-activated current. In addition, 5-HT3 receptor-mediated currents were inhibited by both 1,9-dideoxy forskolin (30 muM), which does not activate adenylyl cyclase, and wForskolin (30 muM), a charged hydrophilic analogue of forskolin that is membrane impermeable. These results indicate that both forskolin and 17-beta-estradiol inhibit the function of the 5-HT3 receptor in a noncompetitive manner and that this inhibition is independent of cAMP levels. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIDA, Cellular Neurobiol Sect, Baltimore, MD 21224 USA. NIAAA, Cellular & Mol Neurobiol Lab, NIH, Rockville, MD 20852 USA. RP Oz, M (reprint author), NIDA, Cellular Neurobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Oz, Murat/E-2148-2012 NR 36 TC 23 Z9 25 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD AUG 15 PY 2002 VL 404 IS 2 BP 293 EP 301 AR PII S0003-9861(02)00279-5 DI 10.1016/S0003-9861(02)00279-5 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 585FU UT WOS:000177515400014 PM 12147268 ER PT J AU Anuchapreeda, S Leechanachai, P Smith, MM Ambudkar, SV Limtrakul, P AF Anuchapreeda, S Leechanachai, P Smith, MM Ambudkar, SV Limtrakul, P TI Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE curcumin; ATP hydrolysis; KB-V1 cells; chemosensitizers; multidrug resistance; P-glycoprotein ID POLYMERASE CHAIN-REACTION; NF-KAPPA-B; GENE-EXPRESSION; ATPASE ACTIVITY; DIETARY CURCUMIN; HUMAN TUMORS; MDR1 GENE; LINES; AP-1; CARCINOGENESIS AB Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in the tumor cells of a patient, resulting from enhanced drug efflux. It is often related to the overexpression of P-glycoprotein (Pgp) on the surface of tumor cells, thereby reducing drug cytotoxicity. In this study, curcumin was tested for its potential ability to modulate the expression and function of Pgp in the multidrug-resistant human cervical carcinoma cell line KB-V1. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) showed that treatment with 1, 5, and 10 muM curcumin for up to 72 hr was able to significantly lower Pgp expression in KB-V1 cells. Curcumin (1-10 muM) decreased Pgp expression in a concentration-dependent manner and was also found to have the same effect on MDR1 mRNA levels. The effect of curcumin on Pgp function was demonstrated by rhodamine 123 (Rh123) accumulation and efflux in Pgp-expressing KB-V1 cells. Curcumin increased Rh123 accumulation in a concentration-dependent manner (1-55 muM) and inhibited the efflux of Rh123 from these cells, but did not affect the efflux of Rh123 from the wild-type drug-sensitive KB-3-1 cells. Treatment of drug-resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with an increased intracellular accumulation of Rh123. In addition, curcumin inhibited verapamil-stimulated ATPase activity and the photoaffinity labeling of Pgp with the prazosin analog [I-125]iodoarylazidoprazosin in a concentration-dependent manner, demonstrating that curcumin interacts directly with the transporter. Thus, curcumin seems to be able to modulate the in vitro expression and function of Pgp in multidrug-resistant human KB-V1 cells. In summary, this study describes the duel modulation of MDR1 expression and Pgp function by the phytochemical curcumin, which may be an attractive new agent for the chemosensitization of cancer cells. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Chiang Mai Univ, Dept Biochem, Fac Med, Chiang Mai 50200, Thailand. Chiang Mai Univ, Dept Microbiol, Fac Associated Med Sci, Chiang Mai 50200, Thailand. NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Limtrakul, P (reprint author), Chiang Mai Univ, Dept Biochem, Fac Med, Chiang Mai 50200, Thailand. RI Ambudkar, Suresh/B-5964-2008 NR 43 TC 176 Z9 192 U1 0 U2 18 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 AUG 15 PY 2002 VL 64 IS 4 BP 573 EP 582 AR PII S0006-2952(02)01224-8 DI 10.1016/S0006-2952(02)01224-8 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 589UD UT WOS:000177778000003 PM 12167476 ER PT J AU Biragyn, A Belyakov, IM Chow, YH Dimitrov, DS Berzofsky, JA Kwak, LW AF Biragyn, A Belyakov, IM Chow, YH Dimitrov, DS Berzofsky, JA Kwak, LW TI DNA vaccines encoding human immunodeficiency virus-1 glycoprotein 120 fusions with proinflammatory chemoattractants induce systemic and mucosal immune responses SO BLOOD LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; MACROPHAGE-DERIVED CHEMOKINE; ANTITUMOR IMMUNITY; RHESUS-MONKEYS; SIV INFECTION; HIV-1; ANTIBODY; PROTEIN; IMMUNIZATION; VACCINATION AB DNA Immunizations with glycoprotein 120 (gp126) of human immunodeficiency virus-1 (HIV-1) usually require boosting with protein or viral vaccines to achieve optimal efficacy. Here, we demonstrate for the first time that mice Immunized with DNA encoding gp120 fused with proinflammatory chemoattractants of immature dendritic cells, such as beta-defensin 2, monocyte chemoattractant protein-3 (MCP-3/CCL7) or macrophage-derived chemokine (MDC/CCL22), elicited anti-gp120 antibodies with high titers of virus-neutralizing activity. The immunogenicity was further augmented with the use of chemokine fusion constructs with gp140, gp120 linked to the extracellular domain of gp41 via a 14-amino acid spacer peptide sequence. This construct elicited antibodies with more effective neutralizing activity than corresponding constructs expressing gp120. Responses were dependent on physical linkage with chemokine moiety, as no Immunity was detected following immunization of mice with DNA encoding a free mixture of chemokine and gp120. Although the route of immunization was inoculation Into skin, both systemic and mucosal CD8(+) cytolytic immune responses were elicited in mice immunized with DNA expressing MCP-3 or beta-defensin 2 fusion constructs. In contrast, no cytotoxic T lymphocyte activity (CTL) was detected in mice immunized with DNA encoding gp120 either alone or as fusion with MDC. Therefore, the potential for broad application of this approach lies in the induction of mucosal CTL and neutralizing antibodies to HIV-1 envelope, both key requirements for prevention of viral transmission and clearance of pathogenic HIV from mucosal reservoirs. (C) 2002 by The American Society of Hematology. C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Metab Branch, Mol Immunogenet & Vaccine Res Sect, Bethesda, MD 20892 USA. RP Biragyn, A (reprint author), NCI, Lab Expt & Computat Biol, Bldg 567,Room 207, Frederick, MD 21702 USA. RI Chow, Yen-Hung /E-3863-2010 NR 37 TC 106 Z9 124 U1 2 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2002 VL 100 IS 4 BP 1153 EP 1159 DI 10.1182/blood-2002-01-0086 PG 7 WC Hematology SC Hematology GA 582RG UT WOS:000177364500006 PM 12149191 ER PT J AU Sloand, E Kim, S Maciejewski, JP Tisdale, J Follmann, D Young, NS AF Sloand, E Kim, S Maciejewski, JP Tisdale, J Follmann, D Young, NS TI Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia SO BLOOD LA English DT Article ID BLOOD MONONUCLEAR-CELLS; SAA WORKING PARTY; BONE-MARROW; CLINICAL-RESPONSE; ANTILYMPHOCYTE GLOBULIN; ANTITHYMOCYTE GLOBULIN; INVITRO TESTS; TRANSPLANTATION; CYCLOSPORINE; COMPARTMENT AB Immunosuppressive therapy leads to meaningful hematologic improvement in most patients with aplastic anemia (AA). Failure to respond and a later relapse could be due to deficient numbers of hematopoietic stem cells, inadequate treatment of the immune process, or a nonimmunologic etiology. Interferon-gamma (IFN-gamma) has been implicated in the pathophysiology of hematopoletic failure in AA. On the basis of previous findings showing overexpression of IFN-gamma in bone marrow (BM) and peripheral blood (PB) in this disease, we hypothesized that quantitation of IFN-gamma might be applied to predict and monitor responses to Immunosuppressive therapy. We measured expression of IFN-gamma in lymphocytes obtained from 123 AA patients, using intracellular 2-color fluorescent staining and flow cytometry. Of 70 patients with severe AA, 36 (51%) demonstrated increased IFN-gamma in circulating T cells. IFN-gamma was detected in only 4 of 53 patients who had recovered from AA. IFN-gamma was not found in PB lymphocytes of patients with other hematologic diseases and heavy transfusion burdens or in healthy volunteers. Among 62 AA patients who were assessed before first treatment with immunosuppressive drugs, 27 of 28 (96%) with circulating IFN-gamma-containing T cells subsequently responded to therapy; in contrast, only 11 of 34 (32%) patients whose PB lacked IFN-gamma lymphocytes improved to transfusion independence. IFN-gamma-containing lymphocytes declined following treatment in all cases. Of 17 patients assessed during relapse, IFN-gamma was present in T cells prior to the blood count decline in 13, and 12 responded to reinstitution of immunosuppressive drugs. Of 30 BMs tested prior to first treatment, 20, all in responding patients, were positive for IFN-gamma, whereas the negative tests were obtained in 10 nonresponding patients. IFN-gamma is increased in the PB lymphocytes of many patients with AA, and these cells decline with therapy. The presence of intracellular IFN-gamma may predict response to immunosuppressive treatment and also the onset of relapse. (C) 2002 by The American Society of Hematology. C1 NHLBI, Haematol Branch, NIH, Bethesda, MD 20892 USA. RP Sloand, E (reprint author), NHLBI, Haematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 105 Z9 132 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2002 VL 100 IS 4 BP 1185 EP 1191 DI 10.1182/blood-2002-01-0035 PG 7 WC Hematology SC Hematology GA 582RG UT WOS:000177364500011 PM 12149196 ER PT J AU Yamaguchi, K Ariga, T Yamada, M Nelson, DL Kobayashi, R Kobayashi, C Noguchi, Y Ito, Y Katamura, K Nagatoshi, Y Kondo, S Katoh, H Sakiyama, Y AF Yamaguchi, K Ariga, T Yamada, M Nelson, DL Kobayashi, R Kobayashi, C Noguchi, Y Ito, Y Katamura, K Nagatoshi, Y Kondo, S Katoh, H Sakiyama, Y TI Mixed chimera status of 12 patients with Wiskott-Alchich syndrome (WAS) after hematopoietic stem cell transplantation: evaluation by flow cytometric analysis of intracellular WAS protein expression SO BLOOD LA English DT Article ID ALDRICH-SYNDROME PROTEIN; BONE-MARROW TRANSPLANTATION; IN-VIVO REVERSION; T-CELLS; PERIPHERAL-BLOOD; CARRIER STATUS; LYMPHOCYTES; POLYMERIZATION; APOPTOSIS; MUTATION AB Wiskott-Aldrich syndrome (WAS) is caused by defects in the WAS protein (WASP) gene on the X chromosome. We previously reported that flow cytometric analysis of intracellular WASP expression (FCM-WASP) was useful in the diagnosis of WAS in patients and carriers. In this study, we applied FCM-WASP to evaluate the mixed chimera (MC) status of 12 WAS patients who underwent hematopoietic stem cell transplantation (HST). After HST, donor- and recipient-derived peripheral blood mononuclear cells (PBMCs) could be distinguished easily with this method, since the donor cells were WASP(bright), whereas the defective recipient cells were WASP(dim). Furthermore, with use of 2-color FCM-WASP, the MC status could be characterized by cell lineage. Six of the 12 patients with WAS were found to have MC status after HST whereas others had complete chimera status. MC status was observed in every cell lineage examined. However, among PBMCs, recipient cells were most commonly observed in the monocyte population. Finally, to investigate the naive/memory status of donor and recipient T cells in these patients, 3-color FCM-WASP using anti-CD45RA or CD45RO was performed. We found that, in contrast to WASP(blight) T cells, most WASP(dim) T cells remained naive (CD45RA(+)/RO-) more than a year after HST. No imbalance in the ratio of naive to memory T cells was observed in WAS patients before HST. We conclude that FCM-WASP is a potentially useful method for clinical follow-up of WAS patients who have undergone HST. Our findings may also have important implications for the role of WASP during hematopoietic development. (C) 2002 by The American Society of Hematology. C1 Hokkaido Univ, Res Grp Human Gene Therapy, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. Hokkaido Univ, Div Canc Med, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. Hokkaido Univ, Dept Surg Oncol, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. Hokkaido Univ, Dept Pediat, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. NCI, NIH, Metab Branch, Bethesda, MD USA. Ibaraki Childrens Hosp, Dept Pediat, Mito, Ibaraki, Japan. Chiba Univ, Dept Pediat, Grad Sch Med, Chiba, Japan. Nagoya City Univ, Dept Pediat, Sch Med, Nagoya, Aichi, Japan. Kyoto Univ, Dept Pediat, Grad Sch Med, Kyoto, Japan. Kyushu Natl Canc Ctr, Paediat Sect, Fukuoka, Japan. RP Ariga, T (reprint author), Hokkaido Univ, Res Grp Human Gene Therapy, Grad Sch Med, Kita Ku, N-14,W-7, Sapporo, Hokkaido 0608638, Japan. RI Kondo, Satoshi/B-1114-2008; Ariga, Tadashi/A-4252-2012 NR 25 TC 27 Z9 28 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 AUG 15 PY 2002 VL 100 IS 4 BP 1208 EP 1214 DI 10.1182/blood-2002-01-0211 PG 7 WC Hematology SC Hematology GA 582RG UT WOS:000177364500014 PM 12149199 ER PT J AU Jurcic, JG Larson, SM Sgouros, G McDevitt, MR Finn, RD Divgi, CR Ballangrud, AM Hamacher, KA Ma, DS Humm, JL Brechbiel, MW Molinet, R Scheinberg, DA AF Jurcic, JG Larson, SM Sgouros, G McDevitt, MR Finn, RD Divgi, CR Ballangrud, AM Hamacher, KA Ma, DS Humm, JL Brechbiel, MW Molinet, R Scheinberg, DA TI Targeted at particle immunotherapy for myeloid leukemia SO BLOOD LA English DT Article ID MONOCLONAL-ANTIBODY M195; ACUTE MYELOGENOUS LEUKEMIA; FOLLOW-UP; PHASE-I; RADIOIMMUNOTHERAPY; ANTI-CD33; CELLS; DOSIMETRY; LYMPHOMA; ANTIGEN AB Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters I-131 and Y-90, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses.' To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting iso-tope Bi-213 was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg Bi-213-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the Bi-213-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of Bi-213-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans. (C) 2002 by The American Society of Hematology. C1 Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Phys Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Therapeut Program, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, New York, NY USA. NCI, NIH, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. European Commiss, Joint Res Ctr, Inst Transuranium Elements, Karlsruhe, Germany. RP Jurcic, JG (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Box 458,1275 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [P01 CA33049]; ODCDC CDC HHS [R01 CCA55349] NR 45 TC 239 Z9 250 U1 0 U2 14 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2002 VL 100 IS 4 BP 1233 EP 1239 PG 7 WC Hematology SC Hematology GA 582RG UT WOS:000177364500018 PM 12149203 ER PT J AU Otsu, M Steinberg, M Ferrand, C Merida, P Rebouissou, C Tiberghien, P Taylor, N Candotti, F Noraz, N AF Otsu, M Steinberg, M Ferrand, C Merida, P Rebouissou, C Tiberghien, P Taylor, N Candotti, F Noraz, N TI Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into bone marrow cells SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; RECEPTOR-GAMMA CHAIN; GREEN FLUORESCENT PROTEIN; T-CELLS; IN-VIVO; NEGATIVE SELECTION; TYROSINE KINASES; ANTIGEN RECEPTOR; ZAP-70; THERAPY AB Mutations In the ZAP-70 protein tyrosine kinase gene result in a severe combined Immunodeficiency (SCID) characterized by a selective inability to produce CD8(+) T cells and a signal transduction defect in peripheral CD4(+) cells. Transplantation of genetically modified hematopoietic progenitor cells that express the wild-type ZAP-70 gene may provide significant benefit to some of these infants. The feasibility of stem cell gene correction for human ZAP-70 deficiency was assessed using a ZAP-70 knock-out model. ZAP-70-deficient murine bone marrow progenitor cells were transduced with a retroviral vector expressing the human ZAP-70 gene. Engraftment of these cells in irradiated ZAP-70-deficient animals resulted in the development of mature CD4+ and CD8+ T cells. In marked contrast, both populations were absent in ZAP-70(-/-) mice undergoing transplantation with bone marrow progenitor cells transduced with a control vector. Importantly, ZAP-70-reconstituted T cells proliferated in response to T-cell receptor stimulation. Moreover, these ZAP-70-expressing T cells demonstrated a diverse T-cell receptor repertoire as monitored by the relative usage of each T-cell receptor 0 chain hypervariable region subfamily. The presence of ZAP-70 in B cells did not affect either lipopolysaccharide- or lipopolysaccharide/interleukin-4-mediated immunoglobulin isotype switching. Altogether, these data indicate that retroviral-mediated gene transfer of the ZAP-70 gene may prove to have a therapeutic benefit for patients with ZAP-70-SCID. (C) 2002 by The American Society of Hematology. C1 Inst Genet Mol Montpellier, UMR 5535 IFR24, F-34293 Montpellier 5, France. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD USA. INSERM EP10119, Etablissement Francasi Sang Bourgogne, Franche Comte, UPRES EA 2284, Besancon, France. RP Taylor, N (reprint author), Inst Genet Mol Montpellier, UMR 5535 IFR24, 1919 Route Mende, F-34293 Montpellier 5, France. RI Taylor, Naomi/H-4016-2014; OI Otsu, Makoto/0000-0002-9769-0217 NR 34 TC 16 Z9 16 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 AUG 15 PY 2002 VL 100 IS 4 BP 1248 EP 1256 DI 10.1182/blood-2002-01-0247 PG 9 WC Hematology SC Hematology GA 582RG UT WOS:000177364500020 PM 12149205 ER PT J AU Friedl, J Puhlmann, M Bartlett, DL Libutti, SK Turner, EN Gnant, MFX Alexander, HR AF Friedl, J Puhlmann, M Bartlett, DL Libutti, SK Turner, EN Gnant, MFX Alexander, HR TI Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF SO BLOOD LA English DT Article ID ISOLATED LIMB PERFUSION; ISOLATED HEPATIC PERFUSION; FACTOR-ALPHA; INTERFERON-GAMMA; FACTOR CACHECTIN; MALIGNANT-MELANOMA; RTNF-ALPHA; MELPHALAN; SARCOMA; COMBINATION AB Tumor necrosis factor (TNF) has marked effects on permeability and procoagulant activity on tumor-associated neovasculature when used In Isolation perfusion, the latter effect primarily mediated via Induction of cell surface expression of tissue factor (TF) on endothelial tissue. However, the cellular events that result In rapid alterations in endothelial cell (EC) permeability after intravascular TNF administration in isolation perfusion are not well characterized. We demonstrate that short exposure intervals to TNF induces TF expression on ECs but has no effect on permeability as assessed by flux of Evans blue-bound albumin across confluent EC monolayers using a 2-compartment model under basal culture conditions. However, a rapid and significant increase In EC permeability occurred with TNF In the presence of factor VIII-deficient plasma. Permeability was Induced only with luminal versus abluminal TNF exposure and was blocked by antithrombin 111, TF pathway inhibitor, or anti-TF antibody cotreatment. These data indicate that EC surface expression of TF and extrinsic clotting factors are critical in augmenting capillary leak following Intravascular TNF administration. Alterations in permeability were associated with intercellular gap formation at sites of down-regulation of vascular endothelial (VE)-cadherin expression, the primary endothelial intercellular adhesion molecule, and intracellular contraction and alignment of F-actin cytoskeletal elements. Rapid induction of TF by TNF may be the primary EC response that results in alterations in permeability and procoagulant activity observed following intravascular TNF administration in isolation perfusion. (C) 2002 by The American Society of Hematology. C1 NCI, Surg Metab Sect, Div Clin Sci, Surg Branch,Ctr Canc Res, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Div Clin Sci, Surg Branch,Ctr Canc Res, Bldg 10,Room 2B07, Bethesda, MD 20892 USA. OI Gnant, Michael/0000-0003-1002-2118 NR 34 TC 104 Z9 111 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 AUG 15 PY 2002 VL 100 IS 4 BP 1334 EP 1339 PG 6 WC Hematology SC Hematology GA 582RG UT WOS:000177364500030 PM 12149215 ER PT J AU Fisher, ER Wang, JP Bryant, J Fisher, B Mamounas, E Wolmark, N AF Fisher, ER Wang, JP Bryant, J Fisher, B Mamounas, E Wolmark, N TI Pathobiology of preoperative chemotherapy - Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-18 SO CANCER LA English DT Article DE breast carcinoma; neoadjuvant chemotherapy; pathobiology; doxorubicin; cyclophosphamide; National Surgical Adjuvant Breast Project (NSABP) protocol B-18 ID PATHOLOGIC FINDINGS; TUMOR-REGRESSION; SEQUENTIAL CYTOPUNCTURES; INDUCTION CHEMOTHERAPY; NODE MICROMETASTASES; CANCER; CARCINOMA; METASTASES; PROGNOSIS; EXTENSION AB BACKGROUND. Examination was performed on pathologic material from patients enrolled in the National Surgical Adjuvant Breast Project (NSABP) protocol B-18, in which the clinical effects of preoperative (preop) and postoperative (postop) doxorubicin and cyclophosphamide (AC) were compared. METHODS. Of the total number of 1523 patients, 12:34 patients (81%) were in the pathologically evaluable cohort. Six hundred twenty-six patients had been randomized prospectively to receive AC postop and 608 had been randomized to receive AC preop. Preentry diagnosis was made by fine-needle aspiration (FNA) and/or Tru-cut biopsy (TC). AC-induced and other pathologic changes were identified, and their relation to pathologic response and overall survival (OS) and disease-free survival (DFS) was determined. Frequencies of the number of lymph node metastases, their size, stromal reaction, and extracapsular extension (ECE) were compared in the two treatment groups, as was their correlation with OS and DFS. Survival estimates were based on 9 years of follow-up. RESULTS. Approximately 13% of primary breast carcinoma cases exhibited both a clinical complete response (cCR) and a pathologic complete response (absence of invasive tumor [pCR]) to preop AC. An additional 7% of patients exhibited a pCR in the absence of a cCR. A pCR occurred in 38% of those patients determined to have achieved a cCR. Poor nuclear grade of the tumor cells in the pre-entry FNA and/or TC specimens significantly predicted a pCR. Patients with the latter exhibited a better OS and DFS compared with those with a pathologic partial response (presence of sparse invasive tumor [pPRJ] or no pathologic response (pNR). Epithelial alterations considered to be induced in tumors by preop AC were comprised of types I and 2 giant cells with meganuclei, apocrine, metaplasia, and cytoplasmic vacuolation. They had a high degree of specificity (range, 86-99%) but a low sensitivity (range, 7-38%). All were predictive of a pPR and were found to be related adversely to OS and DFS. A fibrous stromal reaction noted in tumors or their putative sites in the preop group was found to have only modest degrees of specificity (63%) and sensitivity (74%). Moderate/marked sclerosis of basement membranes of the ductal and ductular elements of the terminal ductolobular unit (TDLU) was significantly more frequent in nontumor-bearing areas of breasts from patients in the preop treatment group compared with those in the postop treatment group (67% vs. 48%; P < 0.0001). The degrees of change in the TDLU in patients in the postop treatment group were found to be unrelated to age. Lymphatic tumor extension in the primary tumor as well as a positive lymph node, status, were less frequent in the preop treatment group compared with the postop treatment group. The OS and DFS were nearly identical in both treatment groups, being 69% and 55% and 70% and 53% in the preop and postop treatment groups, respectively, at 9 years. A fibrous stromal response to lymph node metastases was found to be significant for DFS but not OS. ECE was similar in both groups (55% vs. 48%; P = 0.12). Only 1% of ECE was found to be related to axillary failure in both treatment arms combined. There was no significant difference with regard to the parameters of survival for patients in the postop treatment group whose lymph nodes contained micrometastases (< 2.0 mm) or mini micrometastases (< 1.0 mm) (the latter detected immunohistochemically with anticytokeratin), and a true-negative lymph node status (not immunohistochemically converted to positive). Conversely, there was no apparent difference with regard to OS in preop treated patients with lymph node micrometastases, mini micrometastases, and macrometastases (P = 0.19). Those with mini micrometastases had a significantly worse OS compared with those with a true-negative lymph node status (P = 0.0007). DFS remained worse for patients in that treatment group with micrometastases and mini micrometastases compared with those with negative lymph nodes, although it was better than that for patients with macrometastases (P = 0.02). CONCLUSIONS. Poor nuclear grade of tumor cells in the preentry FNA or TC specimens in the preop group was predictive of a pCR. AC-induced meganuclear giant cells and apocrine changes and nuclear and histologic grades of the primary tumors also were found to be prognostically significant in patients in the preop treatment group, and the latter two variables were found to be significant for those patients in the postop treatment group. No evidence was found to support the need for axillary lymph node radiation for ECE of lymph node metastases. Extended pathologic or immunohistochemical procedures also appear to be unnecessary for the detection of lymph node mini micro metastases, at least when traditional postop chemotherapy is used. The adverse relation between such small metastases and OS and DFS after preop AC appears to be related to the timing of the chemotherapy administration rather than any pathobiologic reasons. (C) 2002 American Cancer Society. C1 NSABP, Pathol Ctr, Pittsburgh, PA USA. NSABP, Ctr Stat, Pittsburgh, PA USA. NSABP, Operat Ctr, Pittsburgh, PA USA. Aultman Canc Ctr, Canton, OH USA. RP Fisher, ER (reprint author), Allegheny Gen Hosp, Continuing Care Ctr, 5th Floor,320 East North Ave, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10-CA12070, U10-CA37377, U10-CA39806] NR 47 TC 191 Z9 229 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2002 VL 95 IS 4 BP 681 EP 695 DI 10.1002/cncr.10740 PG 15 WC Oncology SC Oncology GA 580MP UT WOS:000177238600003 PM 12209710 ER PT J AU Alexander, HR Libutti, SK Bartlett, DL Pingpank, JF Kranda, K Helsabeck, C Beresnev, T AF Alexander, HR Libutti, SK Bartlett, DL Pingpank, JF Kranda, K Helsabeck, C Beresnev, T TI Hepatic vascular isolation and perfusion for patients with progressive unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy SO CANCER LA English DT Article DE colorectal carcinoma; liver metastases; regional chemotherapy; hyperthermia; isolation perfusion ID TUMOR-NECROSIS-FACTOR; RANDOMIZED TRIAL; INTRAARTERIAL FLOXURIDINE; ARTERIAL INFUSION; CANCER; FLUOROURACIL; LEUCOVORIN; MELPHALAN; FLUORODEOXYURIDINE AB BACKGROUND. Many patients with colorectal carcinoma develop unresectable metastases confined to the liver that remain the life-limiting component of disease despite best available systemic or regional chemotherapy. In the current study, the authors present their results using vascular isolation and perfusion of the liver for individuals with progressive, unresectable liver metastases from colorectal carcinoma that were refractory to both previous systemic and regional chemotherapy. METHODS. Seven patients with refractory, progressive, unresectable colorectal. carcinoma metastases confined to the liver underwent a 60-minute hyperthermic (39-40 degreesC) isolated hepatic perfusion (IHP) and were followed for toxicity, response, and survival. RESULTS, There was no surgical- or treatment- related mortality; all patients experienced transient Grade 3-4 (according to National Cancer Institute common toxicity criteria) hepatic toxicity. At a median potential follow-up of 16 months, the overall objective radiographic response rate (all partial responses) was 71% (5 of 7 assessable patients). It is interesting to note that two patients who were treated with tumor necrosis factor (TNF) alone demonstrated no response to therapy compared with all five patients who were treated with melphalan and TNF (three patients) or melphalan alone (two patients). For the 5 patients who responded to treatment, the median duration of response was 10 months (range, 10-13 months) and in all 7 patients the mean overall survival was 19.7 months (range, 2-33 months), including 5 months and 7.5 months, respectively, for the 2 patients treated with TNF alone. CONCLUSIONS. The results of the current study demonstrate that IHP using melphalan with or without TNF has significant antitumor activity in this patient population. IHP deserves continued clinical evaluation as a therapeutic modality for patients with unresectable colorectal carcinoma metastases to the liver. Cancer Published 2002 by the American Cancer Society.(dagger). C1 NCI, Surg Metab Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Surg Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. NR 27 TC 26 Z9 27 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2002 VL 95 IS 4 BP 730 EP 736 DI 10.1002/cncr.10686 PG 7 WC Oncology SC Oncology GA 580MP UT WOS:000177238600008 PM 12209715 ER PT J AU Feuer, EJ Mariotto, A Merrill, R AF Feuer, EJ Mariotto, A Merrill, R TI Modeling the impact of the decline in distant stage disease on prostate carcinoma mortality rates SO CANCER LA English DT Article DE computer models; prostate carcinoma; mortality rates; prostate specific antigen ID CANCER SURVEILLANCE SERIES; INTERPRETING TRENDS; RADICAL PROSTATECTOMY; SURVIVAL RATES; ANTIGEN; MEN; PSA AB BACKGROUND. The incidence of distant stage prostate carcinoma was relatively flat until 1991 and then started declining rapidly. This decline probably was caused by the shift to earlier stage disease associated with the rapid dissemination of prostate specific antigen (PSA) screening. Prostate carcinoma mortality rates started falling at approximately the same time. In this article, the authors model the potential impact of this stage shift on prostate carcinoma mortality rates given various assumptions concerning the survival of patients with screen-detected local-regional disease. METHODS. The authors used the CAN*TROL 2 computer model to shift each deficit in the number of patients with distant stage disease to local-regional stage disease and modeled the implications on mortality using a set of base, optimistic, and pessimistic survival assumptions. A base survival assumes that a patient with screen-detected local-regional disease of a certain histologic grade has the same prognosis as a patient with clinically detected local-regional disease of same grade (i.e., an assumption of no length bias for patients with screen-detected disease), whereas the optimistic and pessimistic scenarios assume that survival is better or worse, respectively, than the base survival (i.e., complete cure for patients with favorable grade for the optimistic scenario and no improvements in survival for patients with unfavorable grade for the pessimistic scenario). RESULTS. Model results were compared with observed mortality trends. Rising age-adjusted mortality rates peaked in 1991 for white males and in 1993 for black males and then fell 21% and 13% for white males and black males, respectively, from 1990 through 1999. Under the modeled stage-shift intervention, mortality rates would fall 18%, 8%, and 19% for both white males and black males under the base, pessimistic, and optimistic assumptions, respectively. CONCLUSIONS. It is impossible to know what the mortality trends would have been in the absence of the introduction of PSA screening. However, under the base assumption, it appears that the decline in distant stage disease can have a fairly sizable and rapid impact on population mortality. The optimistic scenario is not much improved over the base scenario, which is indicative of the facts that the survival of patients diagnosed with clinical local-regional prostate carcinoma is quite good and that further survival improvements can have only a marginal impact. Under the pessimistic scenario, it appears that something else must be responsible for much of the decline in mortality. Screening trial results from the United States and Europe may verify and isolate the size of any mortality benefit associated with PSA screening. Trial results eventually can be put back into these population models to help quantify the impact of screening, treatment, and other factors on population trends. Published 2002 by the American Cancer Society. C1 NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Brigham Young Univ, Dept Hlth Sci, Provo, UT 84602 USA. RP Feuer, EJ (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504 MSC 8317, Bethesda, MD 20892 USA. NR 20 TC 25 Z9 25 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2002 VL 95 IS 4 BP 870 EP 880 DI 10.1002/cncr.10726 PG 11 WC Oncology SC Oncology GA 580MP UT WOS:000177238600025 PM 12209732 ER PT J AU Dorman, SE Guide, SV Conville, PS DeCarlo, ES Malech, HL Gallin, JI Witebsky, FG Holland, SM AF Dorman, SE Guide, SV Conville, PS DeCarlo, ES Malech, HL Gallin, JI Witebsky, FG Holland, SM TI Nocardia infection in chronic granulomatous disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RESTRICTION-ENDONUCLEASE ANALYSIS; TRANSPLANT RECIPIENTS; DNA AMPLIFICATION; PNEUMONIA; ASTEROIDES; IDENTIFICATION; FARCINICA; PATIENT; CHILD; TAXA AB To determine the clinical characteristics and outcome of Nocardia infection in patients with chronic granulomatous disease (CGD), we reviewed data on 28 episodes of Nocardia infection in 23 patients with CGD. All episodes involved pulmonary infection. The frequency of disseminated nocardiosis was 25% for the case series overall, but it was 56% among episodes in patients receiving neither interferon-gamma (IFN-gamma) nor sulfonamide prophylaxis. Patients receiving prophylaxis with IFN-gamma and/or a sulfonamide were significantly less likely to have disseminated nocardiosis than were patients not receiving these medications, and no patient receiving both medications developed disseminated nocardiosis. One-third of the patients had concomitant fungal infections, and 2 patients had concomitant Legionella infections. The majority of patients were successfully treated with a sulfonamide-containing regimen, even though some patients had developed Nocardia infection while receiving sulfonamide prophylaxis. Nocardia infections in patients with CGD are not usually fatal if treated properly, and prophylaxis with IFN-gamma and a sulfonamide may protect against dissemination. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N103,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. NR 34 TC 40 Z9 44 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2002 VL 35 IS 4 BP 390 EP 394 AR UNSP 1058-4838/2002/3504-0007 DI 10.1086/341416 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 578HQ UT WOS:000177111700007 PM 12145721 ER PT J AU Lawson, ND Weinstein, BM AF Lawson, ND Weinstein, BM TI In vivo imaging of embryonic vascular development using transgenic zebrafish SO DEVELOPMENTAL BIOLOGY LA English DT Article DE angiogenesis; transgenics; vascular development; zebrafish ID CARDIOVASCULAR DEVELOPMENT; ENDOTHELIAL-CELLS; VASCULOGENESIS; ANGIOGENESIS; GENE; MORPHOGENESIS; LIGANDS; GROWTH; EMBRYOGENESIS; HEMATOPOIESIS AB in this study we describe a model system that allows continuous in vivo observation of the vertebrate embryonic vasculature. We find that the zebrafish fli1 promoter is able to drive expression of enhanced green fluorescent protein (EGFP) in all blood vessels throughout embryogenesis. We demonstrate the utility of vascular-specific transgenic zebrafish in conjunction with time-lapse multiphoton laser scanning microscopy by directly observing angiogenesis within the brain of developing embryos. Our images reveal that blood vessels undergoing active angiogenic growth display extensive filopodial activity and pathfinding behavior similar to that of neuronal growth cones. We further show, using the zebrafish mindbomb mutant as an example, that the expression of EGFP within developing blood vessels permits detailed analysis of vascular defects associated with genetic mutations. Thus, these transgenic lines allow detailed analysis of both wild type and mutant embryonic vasculature and, together with the ability to perform large scale forward-genetic screens in zebrafish, will facilitate identification of new mutants affecting vascular development. (C) 2002 Elsevier Science (USA). C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 41 TC 946 Z9 962 U1 15 U2 100 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2002 VL 248 IS 2 BP 307 EP 318 DI 10.1006/dbio.2002.0711 PG 12 WC Developmental Biology SC Developmental Biology GA 585HF UT WOS:000177518800008 PM 12167406 ER PT J AU Miki, K Willis, WD Brown, PR Goulding, EH Fulcher, KD Eddy, EM AF Miki, K Willis, WD Brown, PR Goulding, EH Fulcher, KD Eddy, EM TI Targeted disruption of the Akap4 gene causes defects in sperm flagellum and motility SO DEVELOPMENTAL BIOLOGY LA English DT Article ID PROTEIN-KINASE-A; MOUSE SPERMATOGENIC CELLS; FIBROUS SHEATH FORMATION; OUTER DENSE FIBERS; TYROSINE PHOSPHORYLATION; ANCHORING PROTEINS; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; REGULATORY SUBUNITS; BINDING-PROTEIN; BETA SUBUNIT AB A-kinase anchoring proteins (AKAPs) tether cyclic AMP-dependent protein kinases and thereby localize phosphorylation of target proteins and initiation of signal-transduction processes triggered by cyclic AMP. AKAPs can also be scaffolds for kinases and phosphatases and form macromolecular complexes with other proteins involved in signal transduction. Akap4 is transcribed only in the postmeiotic phase of spermatogenesis and encodes the most abundant protein in the fibrous sheath, a novel cytoskeletal structure present in the principal piece of the sperm flagellum. Previous studies indicated that cyclic AMP-dependent signaling processes are important in the regulation of sperm motility, and gene targeting was used here to test the hypothesis that AKAP4 is a scaffold for protein complexes involved in regulating flagellar function. Sperm numbers were not reduced in male mice lacking AKAP4, but sperm failed to show progressive motility and male mice were infertile. The fibrous sheath anlagen formed, but the definitive fibrous sheath did not develop, the flagellum was shortened, and proteins usually associated with the fibrous sheath were absent or substantially reduced in amount. However, the other cytoskeletal components of the flagellum were present and appeared fully developed. We conclude that AKAP4 is a scaffold protein required for the organization and integrity of the fibrous sheath and that effective sperm motility is lost in the absence of AKAP4 because signal transduction and glycolytic enzymes fail to become associated with the fibrous sheath. (C) 2002 Elsevier Science (USA). C1 NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Point Loma Nazarene Univ, San Diego, CA 92106 USA. RP Eddy, EM (reprint author), NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 59 TC 178 Z9 186 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2002 VL 248 IS 2 BP 331 EP 342 DI 10.1006/dbio.2002.0728 PG 12 WC Developmental Biology SC Developmental Biology GA 585HF UT WOS:000177518800010 PM 12167408 ER PT J AU Semsey, S Geanacopoulos, M Lewis, DEA Adhya, S AF Semsey, S Geanacopoulos, M Lewis, DEA Adhya, S TI Operator-bound GalR dimers close DNA loops by direct interaction: tetramerization and inducer binding SO EMBO JOURNAL LA English DT Article DE gal regulation; protein-protein interface; transcription repression ID INTEGRATION HOST FACTOR; RNA-POLYMERASE; LAC REPRESSOR; TRANSCRIPTION REGULATION; ESCHERICHIA-COLI; PROMOTER; COMPLEX; OPERON; HU; ASSOCIATION AB The assembly of the Gal repressosome, a higher order nucleoprotein complex that represses transcription of the gal operon in Escherichia coli, involves the formation of a DNA loop encompassing the promoter segment. GalR dimers bound to two spatially separated operators, O-E and O-I, specifically interact with the histone-like protein HU and close the loop in supercoiled DNA. We isolated and characterized a GalR mutant containing an amino acid substitution (R282L) that can repress transcription in the absence of HU and supercoiled DNA both in vivo and in vitro. Repression involves the same DNA looping; deletion of either O-E or O-I makes the mutant GalR ineffective in repression. This and other results suggest that the R282L substitution increases the normal affinity between two DNA-bound GalR dimers, allowing looping. We conclude that GalR dimers interact directly and do not use HU as an adaptor in loop closure; HU and DNA supercoiling act in concert to stabilize the GalR tetramer. The stronger GalR-GalR interaction also made the gal transcription non-inducible, suggesting that the inducer binding acts by modulating tetramerization. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Semsey, Szabolcs/L-6329-2013; OI Semsey, Szabolcs/0000-0002-4522-5495 NR 39 TC 41 Z9 42 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 15 PY 2002 VL 21 IS 16 BP 4349 EP 4356 DI 10.1093/emboj/cdf431 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 582MP UT WOS:000177355300015 PM 12169637 ER PT J AU Lieberman, AP Harmison, G Strand, AD Olson, JM Fischbeck, KH AF Lieberman, AP Harmison, G Strand, AD Olson, JM Fischbeck, KH TI Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor SO HUMAN MOLECULAR GENETICS LA English DT Article ID BULBAR MUSCULAR-ATROPHY; CREB-BINDING PROTEIN; HUNTINGTONS-DISEASE; NEURODEGENERATIVE DISEASES; INTRANUCLEAR INCLUSIONS; NUCLEAR-LOCALIZATION; GLUTAMINE REPEATS; DEPENDENT TRANSCRIPTION; MEDIATED TRANSCRIPTION; GENE-EXPRESSION AB Kennedy's disease is a degenerative disease of motor neurons in which the causative mutation is expansion of a CAG/polyglutamine tract near the 5' end of the androgen receptor gene. The mutant protein misfolds, aggregates, and interacts abnormally with other proteins, leading to a novel, toxic gain of function and an alteration of normal function. We used a cell culture model to explore the mechanisms underlying the alterations in androgen receptor function conferred by the mutation. Here we show that cells expressing the wild-type androgen receptor with 24 CAG repeats respond to ligand by showing trophic effects including prolonged survival in low serum, whereas cells expressing the mutant receptor with 65 CAG repeats do not show a robust trophic response. This partial loss of function correlates with decreased levels of the mutant protein due to its preferential degradation by the ubiquitin-proteasome pathway. Expression analysis using oligonucleotide arrays confirms that the mutant receptor has undergone a partial loss of function, and fails to regulate a subset of genes whose expression is normally affected by ligand activation of the wild-type receptor. The mutant receptor has also undergone several functionally important post-translational modifications in the absence of ligand that the wild-type receptor undergoes in the presence of ligand, including acetylation and phosphorylation. These modifications correlate with a ligand-independent gain of function exhibited by the mutant receptor in expression analysis. Our findings suggest that polyglutamine expansion alters androgen receptor function by promoting its degradation and by modifying its activity as a transcription factor. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. RP Lieberman, AP (reprint author), Univ Michigan, Sch Med, Dept Pathol, 1301 Catherine,4233 Med Sci I, Ann Arbor, MI 48109 USA. NR 76 TC 85 Z9 87 U1 0 U2 1 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 AUG 15 PY 2002 VL 11 IS 17 BP 1967 EP 1976 DI 10.1093/hmg/11.17.1967 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 582MX UT WOS:000177356600006 PM 12165558 ER PT J AU Kirby, J Menzies, FM Cookson, MR Bushby, K Shaw, PJ AF Kirby, J Menzies, FM Cookson, MR Bushby, K Shaw, PJ TI Differential gene expression in a cell culture model of SOD1-related familial motor neurone disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU/ZN-SUPEROXIDE-DISMUTASE; GLIAL-CELLS; SPINAL-CORD; TYROSINE KINASE; ORGANELLE TRANSPORT; ICAM-1 EXPRESSION; ENDOTHELIAL-CELLS; TRANSGENIC MICE; NERVOUS-SYSTEM AB Motor neurone disease is caused by mutations in Cu/Zn superoxide dismutase (SOD1) in 15-20% of familial cases, due to a toxic gain of function by the mutant enzyme. However, the underlying mechanism of SOD1-mediated neurodegeneration remains uncertain. By investigating alterations in gene expression in the presence of mutant Cu/Zn SOD, we aimed to identify pathways that contribute to motor neurone injury and cell death. Using a cellular model of familial motor neurone disease, the motor neuronal cell line NSC34 was stably transfected with either normal or mutant (G37R, G93A, I113T) SOD1 cDNAs, and the effect of the presence of these proteins on gene expression was analysed. This model allowed gene expression changes to be studied specifically in cells with a motor neurone phenotype, without interference from genes expressed by glia, astrocytes and other cell types located in the central nervous system. Using a commercially available cDNA membrane array, we investigated the expression levels of 588 genes from key biological pathways. Gene expression was studied in the cells under both basal culture conditions and following oxidative stress induced by serum withdrawal. Twenty-nine differentially expressed genes were identified, 7 of which were specifically downregulated in the presence of the mutant Cu/Zn SOD protein, and whose expression was further studied by real-time PCR. Presence of the mutant Cu/Zn SOD was confirmed to lead to a decrease in expression of KIF3B, a kinesin-like protein, which forms part of the KIF3 molecular motor. c-Fes, thought to be involved in intracellular vesicle transport was also decreased, further implicating the involvement of vesicular trafficking as a mode of action for mutant Cu/Zn SOD. In addition, a decrease was confirmed in ICAM1, a response in part due to the increased expression of SOD1, and decreased Bag1 expression was confirmed in two of the three mutant cell lines, providing further support for the involvement of apoptosis in SOD1-associated motor neurone death. C1 Univ Sheffield, Sch Med & Biomed Sci, Acad Neurol Unit, Sheffield S10 2RX, S Yorkshire, England. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Int Ctr Life, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. RP Kirby, J (reprint author), Univ Sheffield, Sch Med & Biomed Sci, Acad Neurol Unit, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England. RI Shaw, Pamela/A-5215-2009; Kirby, Janine/B-3980-2009; Shaw, Pamela/A-7620-2010; Shaw, Pamela/E-6193-2010; OI Kirby, Janine/0000-0002-7468-5917 NR 86 TC 25 Z9 26 U1 0 U2 1 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 AUG 15 PY 2002 VL 11 IS 17 BP 2061 EP 2075 DI 10.1093/hmg/11.17.2061 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 582MX UT WOS:000177356600015 PM 12165567 ER PT J AU Dores, GM Metayer, C Curtis, RE Lynch, CF Clarke, EA Glimelius, B Storm, H Pukkala, E van Leeuwen, FE Holowaty, EJ Andersson, M Wiklund, T Joensuu, T van't Veer, MB Stovall, M Gospodarowicz, M Travis, LB AF Dores, GM Metayer, C Curtis, RE Lynch, CF Clarke, EA Glimelius, B Storm, H Pukkala, E van Leeuwen, FE Holowaty, EJ Andersson, M Wiklund, T Joensuu, T van't Veer, MB Stovall, M Gospodarowicz, M Travis, LB TI Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID 2ND CANCERS; LUNG-CANCER; BREAST-CANCER; COMBINATION CHEMOTHERAPY; BARRETTS-ESOPHAGUS; RADIATION-THERAPY; TESTICULAR CANCER; SOLID TUMORS; RISK; CHILDHOOD AB Purpose: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin's disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. Patients and Methods: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. Results: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377, O/E = 2.9), digestive tract (Obs 376; O/E = 1.7), and female breast (Obs = 234; O/E 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 5 1 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. Conclusion: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested. (C) 2002 by American Society of Clinical Oncology. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA 52242 USA. Univ Toronto, Canc Care Ontario, Toronto, ON, Canada. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Univ Uppsala Hosp, Dept Oncol, S-75185 Uppsala, Sweden. Danish Canc Soc, Copenhagen, Denmark. Univ Helsinki Hosp, Dept Oncol, Helsinki, Finland. Netherlands Canc Inst, Amsterdam, Netherlands. Dr Daniel Den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. RP Dores, GM (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Suite 7039, Bethesda, MD 20892 USA. NR 59 TC 307 Z9 316 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 15 PY 2002 VL 20 IS 16 BP 3484 EP 3494 DI 10.1200/JCO.2002.090038 PG 11 WC Oncology SC Oncology GA 584NM UT WOS:000177473800017 PM 12177110 ER PT J AU Grem, JL Wilson, R Lehky, T Thomas, R Quinn, M Floeter, MK AF Grem, JL Wilson, R Lehky, T Thomas, R Quinn, M Floeter, MK TI Acute oxaliplatin-induced peripheral-nerve hyperexcitability - In reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Grem, JL (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 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 AUG 15 PY 2002 VL 20 IS 16 BP 3562 EP 3562 PG 1 WC Oncology SC Oncology GA 584NM UT WOS:000177473800029 ER PT J AU McVicar, DW Winkler-Pickett, R Taylor, LS Makrigiannis, A Bennett, M Anderson, SK Ortaldo, JR AF McVicar, DW Winkler-Pickett, R Taylor, LS Makrigiannis, A Bennett, M Anderson, SK Ortaldo, JR TI Aberrant DAP12 signaling in the 129 strain of mice: Implications for the analysis of gene-targeted mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; PROTEIN-TYROSINE KINASE; NK CELLS; T-CELLS; B-CELLS; CLASS-I; RECEPTOR; CYTOMEGALOVIRUS; INFECTION; SYK AB NK cells are implicated in antiviral responses, bone marrow transplantation and tumor immunosurveillance. Their function is controlled, in part, through the Ly49 family of class I binding receptors. Inhibitory Ly49s suppress signaling, while activating Ly49s (i.e., Ly49D) activate NK cells via the DAP12 signaling chain. Activating Ly49 signaling has been studied primarily in C57BL/6 mice, however, 129 substrains are commonly used in gene-targeting experiments. In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production. Consistent with poor-activating Ly49 function, 129/J mice reject bone marrow less efficiently than C57BL/6 mice. Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system. Most importantly, reconstitution of Ly49D in 129/J NK cells demonstrated that the signaling deficit is within the NK cells themselves. These unexpected findings bring into question any NK analysis of 129/J, 129Sv, or gene-targeted mice derived from these strains before complete backcrossing, and provide a possible explanation for the differences observed in the immune response of 129 mice in a variety of models. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Frederick, MD 21702 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. RP McVicar, DW (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Bldg 560,Room 31-93, Frederick, MD 21702 USA. RI Anderson, Stephen/B-1727-2012; McVicar, Daniel/G-1970-2015 OI Anderson, Stephen/0000-0002-7856-4266; FU PHS HHS [N01-C0-56000] NR 53 TC 37 Z9 39 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2002 VL 169 IS 4 BP 1721 EP 1728 PG 8 WC Immunology SC Immunology GA 582RW UT WOS:000177365800009 PM 12165492 ER PT J AU Fowlkes, BJ Robey, EA AF Fowlkes, BJ Robey, EA TI A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; THYMOCYTE DEVELOPMENT; LINEAGE DECISION; EXPRESSION; MATURATION; MICE; INACTIVATION; APOPTOSIS; PATHWAYS; DISTINCT AB The Notch signaling pathway plays an important role in the early steps of T cell development and in the generation of T cell tumors, but its role in the CD4 vs CD8 lineage decision is controversial. Notch1 is not essential for CD4 or CD8 T cell development; however, there are suggestions that multiple Notch family members may act in a redundant fashion during thymic development. In theory, expressing a constitutively activated form of Notch in CD4(+)CD8(+), thymocytes could provide clues about the normal role of Notch in developing CD4 and CD8 T cells. Unfortunately, two different studies of transgenic mice expressing activated forms of Notch1 (Notch1IC) led to conflicting conclusions. In this study, we re-examine the effect of the two Notch1IC transgenes on thymocyte development. We find that both Notch1IC transgenic lines display a decrease in CD4 single positive (SP) thymocytes and a corresponding increase in CD8 SP thymocytes. The enhanced development of CD8 SP thymocytes is dependent on either class I or 11 MHC. Thus, data from two different Notch1IC transgenic lines indicate that Notch activity promotes CD8 and inhibits CD4 SP development. We suggest that the discrepancies in previous reports of Notch1IC transgenic mice are due to differences in the propensity of the two different transgenic lines to develop tumors. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Fowlkes, BJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI42033, AI32985] NR 30 TC 90 Z9 92 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2002 VL 169 IS 4 BP 1817 EP 1821 PG 5 WC Immunology SC Immunology GA 582RW UT WOS:000177365800021 PM 12165504 ER PT J AU Kabat, J Borrego, F Brooks, A Coligan, JE AF Kabat, J Borrego, F Brooks, A Coligan, JE TI Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; TANDEM SH2 DOMAINS; I MOLECULE QA-1(B); NK CELL; ACTIVATING RECEPTORS; PHOSPHATASE SH-PTP2; HLA-E; PROTEIN; SHP-1; COMPLEX AB The human NKG2A chain of the CD94/NKG2A receptor contains two immunoreceptor Tyr-based inhibitory motifs (ITIMs) in its cytoplasmic tail. To determine the relative importance of membrane-distal (residues 6-11) and membrane-proximal (residues 38-43) ITIMs in mediating the inhibitory signal, we made site-directed mutants of NKG2A at the Y (Y8F, Y40F, Y8F/Y40F) and the residues two positions N-terminal (Y-2) of Y (V6A, 138A, V6A/138A) in each motif. Wild-type (wt) and mutated NKG2A were then cotransfected with CD94 into rat basophilic leukemia 2113 cells. Immunochemical analyses after pervanadate treatment showed that each of the mutant molecules could be phosphorylated to expected levels relative to wt NKG2A and that all the mutations significantly reduced the avidity of SH2 domain-bearing tyrosine phosphatase-1 for NKG2A. Confocal microscopy was used to determine whether SH2 domain-bearing tyrosine phosphatase-1 and CD94/NKG2A colocalized intracellularly after receptor ligation. Only the Y8F/Y40F and Y8F mutant NKG2A molecules failed to show a dramatic colocalization. In agreement with this result, the Y8F/Y40F mutant was unable to inhibit FcepsilonRI-mediated serotonin release and the Y8F mutant was relatively ineffective compared with wt NKG2A. In contrast, the Y40F mutant was 70% as effective as wt in mediating inhibition, and the Y-2 mutations did not remarkably affect inhibitory function. These results show that, like KIR, both NKG2A ITIMs are required for mediating the maximal inhibitory signal, but opposite to KIR, the membrane-distal ITIM is of primary importance rather than the membrane-proximal ITIM. This probably reflects the opposite orientation of the ITIMs in type H vs type I proteins. C1 NIAID, Lab Allerg Dis, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, Lab Allerg Dis, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 53 TC 38 Z9 38 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2002 VL 169 IS 4 BP 1948 EP 1958 PG 11 WC Immunology SC Immunology GA 582RW UT WOS:000177365800037 PM 12165520 ER PT J AU Maconi, A Pastorin, G Da Ros, T Spalluto, G Gao, ZG Jacobson, KA Baraldi, PG Cacciari, B Varani, K Moro, S Borea, PA AF Maconi, A Pastorin, G Da Ros, T Spalluto, G Gao, ZG Jacobson, KA Baraldi, PG Cacciari, B Varani, K Moro, S Borea, PA TI Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A(3) adenosine receptor antagonist SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Letter ID PYRAZOLO<4,3-E>1,2,4-TRIAZOLO<1,5-C>PYRIMIDINE DERIVATIVES; HIGHLY POTENT; ACTIVATION; RADIOLIGAND; AGONISTS; LIGANDS AB A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo- [4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (K-i = 0.01 nM) and selectivity for the hA(3) versus A(1), A(2A), and A(2B) receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA(3) receptor indicated a K-B value of 0.20 nM. C1 Univ Trieste, Dipartimento Sci Farmaceut, I-34127 Trieste, Italy. NIDDKD, NIH, Mol Recognit Sect, LBC, Bethesda, MD 20892 USA. Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Univ Ferrara, Dipartimento Med Clin & Sperimentale, Sez Farmacol, I-44100 Ferrara, Italy. Univ Padua, Dipartimento Sci Farmaceut, Mol Modeling Sect, I-35131 Padua, Italy. RP Spalluto, G (reprint author), Univ Trieste, Dipartimento Sci Farmaceut, Piazzale Europa 1, I-34127 Trieste, Italy. RI Moro, Stefano/A-2979-2012; Jacobson, Kenneth/A-1530-2009; Pastorin, Giorgia/B-5907-2015; Baraldi, Pier Giovanni/B-7933-2017 OI Moro, Stefano/0000-0002-7514-3802; Jacobson, Kenneth/0000-0001-8104-1493; NR 26 TC 61 Z9 61 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 AUG 15 PY 2002 VL 45 IS 17 BP 3579 EP 3582 AR UNSP JM020974X DI 10.1021/jm020974x PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 582JE UT WOS:000177346400004 PM 12166930 ER PT J AU Yu, QS Zhu, XX Holloway, HW Whittaker, NF Brossi, A Greig, NH AF Yu, QS Zhu, XX Holloway, HW Whittaker, NF Brossi, A Greig, NH TI Anticholinesterase activity of compounds related to geneserine tautomers. N-oxides and 1,2-oxazines SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ALZHEIMER DRUG PHENSERINE; AMYLOID PRECURSOR PROTEIN; CHOLINESTERASE-INHIBITORS; SELECTIVE INHIBITORS; SENILE DEMENTIA; BUTYRYLCHOLINESTERASE; DISEASE; PLAQUES; ACETYLCHOLINESTERASE; PHYSOSTIGMINE AB A series of phenylcarbamate analogues of geneserine (8, 10, 12, 14) were synthesized from their counterparts, the phenylcarbamate analogues of physostigmine (2-5), by oxidation. The geneserine analogues can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- and time-dependent manner. Assessment by H-1 NMR indicated that the N-oxide structure is adopted at neutral pH and that the compound exists in an equilibrium between several epimers. Evaluation of their biological action to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), ex vivo, demonstrated that the N-oxide (7, 9, 11, 13, 15) and 1,2-oxazine (6, 8, 10, 12, 14) structures possessed similar potencies against AChE, but the latter structures were more potent against BChE. With the exception of the BChE selective inhibitor, 12, none of the geneserine analogues were as potent or enzyme subtype selective as their physostigmine analogue counterparts. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr 4E02, Baltimore, MD 21224 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr 4E02, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 37 Z9 39 U1 0 U2 6 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 AUG 15 PY 2002 VL 45 IS 17 BP 3684 EP 3691 DI 10.1021/jm010491d PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 582JE UT WOS:000177346400015 PM 12166941 ER PT J AU Sherer, TB Betarbet, R Stout, AK Lund, S Baptista, M Panov, AV Cookson, MR Greenamyre, JT AF Sherer, TB Betarbet, R Stout, AK Lund, S Baptista, M Panov, AV Cookson, MR Greenamyre, JT TI An in vitro model of Parkinson's disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; cytochrome c; glutathione; caspase-3; carbonyls; ubiquitin ID HUMAN SUBSTANTIA-NIGRA; LEWY-BODY-DISEASE; COMPLEX-I; CELL-DEATH; DOPAMINERGIC-NEURONS; LIPID-PEROXIDATION; HYDROGEN-PEROXIDE; INDUCED APOPTOSIS; BASAL GANGLIA; PC12 CELLS AB Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nM rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, similar to5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis. C1 Emory Univ, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Greenamyre, JT (reprint author), Emory Univ, Ctr Neurodegenerat Dis, Whitehead Biomed Res Bldg,Room 505M,615 Michael S, Atlanta, GA 30322 USA. RI Greenamyre, J. Timothy/B-4049-2011 FU NINDS NIH HHS [F32NS11132, NS38399] NR 62 TC 367 Z9 387 U1 4 U2 39 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 AUG 15 PY 2002 VL 22 IS 16 BP 7006 EP 7015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 583RB UT WOS:000177421000019 PM 12177198 ER PT J AU Zangen, A Ikemoto, S Zadina, JE Wise, RA AF Zangen, A Ikemoto, S Zadina, JE Wise, RA TI Rewarding and psychomotor stimulant effects of endomorphin-1: Anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens SO JOURNAL OF NEUROSCIENCE LA English DT Article DE endomorphin-1; reward; locomotion; ventral tegmental area; nucleus accumbens; intracranial self administration ID CONDITIONED PLACE PREFERENCE; OPIOID RECEPTOR; BEHAVIORAL-RESPONSES; OPIATE-RECEPTOR; RATS; DOPAMINE; MORPHINE; ANTAGONISTS; SITES; FOOD AB Endomorphin-1 (EM-1) is a recently isolated endogenous peptide having potent analgesic activity and high affinity and selectivity for the mu-opioid receptor. The present study was designed to investigate the rewarding and psychomotor stimulant effects of EM-1 in specific brain regions. We found that rats would learn without priming or response shaping to lever-press for microinjections of EM-1 into the ventral tegmental area (VTA); responding was most vigorous for high-dose injections into the posterior VTA. Rats did not learn to lever-press for microinjections of EM-1 into the nucleus accumbens (NAS) or regions just dorsal to the VTA. Lever-pressing for EM-1 in the VTA was extinguished when vehicle was substituted for the peptide and was reinstated when EM-1 reinforcement was re-established. Conditioned place preference was established by EM-1 injections into the posterior but not the anterior VTA or the NAS. Injection of EM-1 (0.1-1.0 nmol) into the posterior VTA induced robust increases in locomotor activity, whereas injections into the anterior VTA had very weak locomotor-stimulating effects. When injected into the NAS, EM-1 (0.1-10.0 nmol) did not affect locomotor activity. The present findings implicate the posterior VTA as a highly specific and sensitive site for opioid reward and suggest a role for EM-1-containing projections to the posterior VTA in the rewarding effects of other reinforcers. C1 Natl Inst Drug Abuse, NIH, Baltimore, MD 21224 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Neurosci Program, New Orleans, LA 70112 USA. Vet Affairs Med Ctr, New Orleans, LA 70112 USA. RP Zangen, A (reprint author), Natl Inst Drug Abuse, NIH, 5500 Nathan Shock Dr,, Baltimore, MD 21224 USA. RI Wise, Roy/A-6465-2012; OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 47 TC 83 Z9 85 U1 0 U2 4 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 AUG 15 PY 2002 VL 22 IS 16 BP 7225 EP 7233 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 583RB UT WOS:000177421000038 PM 12177217 ER PT J AU Fang, J McCutchan, TF AF Fang, J McCutchan, TF TI Malaria: Thermoregulation in a parasite's life cycle SO NATURE LA English DT Article ID SUBUNIT RIBOSOMAL-RNA; PLASMODIUM-FALCIPARUM; DISTINCT; GENES C1 NIAID, Growth & Dev Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Fang, J (reprint author), NIAID, Growth & Dev Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NR 9 TC 27 Z9 29 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 15 PY 2002 VL 418 IS 6899 BP 742 EP 742 DI 10.1038/418742a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 583UF UT WOS:000177428000029 PM 12181557 ER PT J AU Le, SY Zhang, KZ Maizel, JV AF Le, SY Zhang, KZ Maizel, JV TI RNA molecules with structure dependent functions are uniquely folded SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RIBOSOMAL-RNA; SECONDARY STRUCTURES; SEQUENCE-ANALYSIS; ARCHITECTURE; TRANSLATION; MOTIFS; VIRUS AB Cis-acting elements in post-transcriptional regulation of gene expression are often correlated with distinct local RNA secondary structure. These structures are expected to be significantly more ordered than those anticipated at random because of evolutionary constraints and intrinsic structural properties. In this study, we introduce a computing method to calculate two quantitative measures, NRd and Stscr, for estimating the uniqueness of an RNA secondary structure. NRd is a normalized score based on evaluating how different a natural RNA structure is from those predicted for its randomly shuffled variants. The lower the score NRd the more well ordered is the natural RNA structure. The statistical significance of NRd compared with that computed from structural comparisons among large numbers of randomly permuted sequences is represented by a standardized score, Stscr. We tested the method on the trans-activation response element and Rev response element of HIV-1 mRNA, internal ribosome entry sequence of hepatitis C virus, Tetrahymena thermophila rRNA intron, 100 tRNAs and 14 RNase P RNAs. Our data indicate that functional RNA structures have high Stscr, while other structures have low Stscr. We conclude that RNA functional molecules and/or cis-acting elements with structure dependent functions possess well ordered conformations and they are uniquely folded as measured by this technique. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Frederick, MD 21702 USA. Univ Western Ontario, Dept Comp Sci, London, ON N6A 5B7, Canada. RP Le, SY (reprint author), NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bldg 469,Room 151, Frederick, MD 21702 USA. NR 29 TC 23 Z9 23 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 15 PY 2002 VL 30 IS 16 BP 3574 EP 3582 DI 10.1093/nar/gkf473 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585CN UT WOS:000177505600007 PM 12177299 ER PT J AU Karmakar, P Snowden, CM Ramsden, DA Bohr, VA AF Karmakar, P Snowden, CM Ramsden, DA Bohr, VA TI Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-REPAIR; HELICASE ACTIVITY; SYNDROME CELLS; SYNDROME GENE; WRN PROTEIN; COMPLEX; KINASE; TELOMERE AB The human Werner syndrome protein, WRN, is a member of the RecQ helicase family and contains 3'-->5' helicase and 3'-->5' exonuclease activities. Recently, we showed that the exonuclease activity of WRN is greatly stimulated by the human Ku heterodimer protein. We have now mapped this interaction physically and functionally. The Ku70 subunit specifically interacts with the N-terminus (amino acids 1-368) of WRN, while the Ku80 subunit interacts with its C-terminus (amino acids 940- 1432). Binding between Ku70 and the N-terminus of WRN (amino acids 1-368) is sufficient for stimulation of WRN exonuclease activity. A mutant Ku heterodimer of full-length Ku80 and truncated Ku70 (amino acids 430-542) interacts with C-WRN but not with N-WRN and cannot stimulate WRN exonuclease activity. This emphasizes the functional significance of the interaction between the N-terminus of WRN and Ku70. The interaction between Ku80 and the C-terminus of WRN may modulate some other, as yet unknown, function. The strong interaction between Ku and WRN suggests that these two proteins function together in one or more pathways of DNA metabolism. C1 NIA, Lab Mol Gerontol, IRP, NIH, Baltimore, MD 21224 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, IRP, NIH, Box 1,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCI NIH HHS [CA 84442-01, R01 CA084442] NR 36 TC 77 Z9 77 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 AUG 15 PY 2002 VL 30 IS 16 BP 3583 EP 3591 DI 10.1093/nar/gkf482 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585CN UT WOS:000177505600008 PM 12177300 ER PT J AU Khan, SG Muniz-Medina, V Shahlavi, T Baker, CC Inui, H Ueda, T Emmert, S Schneider, TD Kraemer, KH AF Khan, SG Muniz-Medina, V Shahlavi, T Baker, CC Inui, H Ueda, T Emmert, S Schneider, TD Kraemer, KH TI The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PIGMENTOSUM GROUP-C; POLYMERASE CHAIN-REACTION; XERODERMA-PIGMENTOSUM; RNA SURVEILLANCE; EXCISION-REPAIR; HUMAN GENOME; SKIN-CANCER; IN-VIVO; EXPRESSION; SEQUENCES AB XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in similar to0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in similar to0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (similar to2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. RP Kraemer, KH (reprint author), NCI, Basic Res Lab, Bldg Room 3E24, Bethesda, MD 20892 USA. OI Schneider, Thomas/0000-0002-9841-1531 FU Intramural NIH HHS [Z01 BC004517-31] NR 40 TC 111 Z9 116 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 15 PY 2002 VL 30 IS 16 BP 3624 EP 3631 DI 10.1093/nar/gkf469 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 585CN UT WOS:000177505600012 PM 12177305 ER PT J AU Miyoshi, K Rosner, A Nozawa, M Byrd, C Morgan, F Landesman-Bollag, E Xu, X Seldin, DC Schmidt, EV Taketo, MM Robinson, GW Cardiff, RD Hennighausen, L AF Miyoshi, K Rosner, A Nozawa, M Byrd, C Morgan, F Landesman-Bollag, E Xu, X Seldin, DC Schmidt, EV Taketo, MM Robinson, GW Cardiff, RD Hennighausen, L TI Activation of different Wnt/beta-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors SO ONCOGENE LA English DT Article DE Wnt signaling; beta-catenin activation; Int2/Fgf3; cytokeratin expression; pilar tumor; transdifferentiation ID PROTEIN-KINASE CK2; BETA-CATENIN; TRANSGENIC MICE; CYCLIN D1; FUNCTIONAL INTERACTION; HAIR FOLLICLE; FEMALE MICE; GENE; GLAND; EXPRESSION AB The Wnt/beta-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized beta-catenin (DeltaE3 beta-catenin) in mammary epithelium leads to the transdifferentiation into epidermis- and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from P-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated mammary epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2alpha, DeltaE3 beta-catenin, Cyclin D1, and dominant negative (dn) GSK3beta. Cytokeratin 5 (CK5), which is expressed in both mammary myoepithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in DeltaE3 beta-catenin transgenic mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt I Ob transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2alpha dnGSK3beta and Cyclin D1 transgenic mammary tissues was similar to that in DeltaE3 beta-catenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in mammary epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal mammary epithelium. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Univ Tokushima, Sch Dent, Dept Biochem, Tokushima 7708504, Japan. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. Boston Univ, Med Ctr, Boston, MA 02118 USA. McLaughlin Res Inst, Great Falls, MT USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Kyoto Univ, Grad Sch Med, Kyoto, Japan. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101,8 Ctr Dr, Bethesda, MD 20892 USA. RI Robinson, Gertraud/I-2136-2012 FU NCRR NIH HHS [U42 RR14905]; NIEHS NIH HHS [P01 ES11624] NR 46 TC 85 Z9 90 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 15 PY 2002 VL 21 IS 36 BP 5548 EP 5556 DI 10.1038/sj.onc.1205686 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 583ZM UT WOS:000177442000004 PM 12165853 ER PT J AU Srivatsan, ES Chakrabarti, R Zainabadi, K Pack, SD Benyamini, P Mendonca, MS Yang, PK Kang, K Motamedi, D Sawicki, MP Zhuang, ZP Jesudasan, RA Bengtsson, U Sun, C Roe, BA Stanbridge, EJ Wilczynski, SP Redpath, JL AF Srivatsan, ES Chakrabarti, R Zainabadi, K Pack, SD Benyamini, P Mendonca, MS Yang, PK Kang, K Motamedi, D Sawicki, MP Zhuang, ZP Jesudasan, RA Bengtsson, U Sun, C Roe, BA Stanbridge, EJ Wilczynski, SP Redpath, JL TI Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer SO ONCOGENE LA English DT Article DE cervical cancer; tumor suppressor gene; chromosome 11q13; loss of heterozygosity; fluorescence in situ hybridization; homozygous deletion ID TUMOR-SUPPRESSOR GENE; CARCINOMA CELL-LINES; HELA-CELLS; FRAGILE SITE; HOMOZYGOUS DELETIONS; ENDOCRINE TUMORS; UTERINE CERVIX; BAND 11Q13; FHIT GENE; MEN1 AB Previous molecular genetic studies on HeLa cell (a cervical cancer cell line) derived non-tumorigenic and tumorigenic hybrids have localized a tumor suppressor gene to the long arm of chromosome 11. Analysis of cervical cancer cell lines using chromosome 11 specific probes showed deletion and translocation of 11q13 sequences in five out of eight cell lines. Fluorescence in situ hybridization (FISH), using 11q13 specific probes, has shown interstitial deletion of 11q13 sequences in the HeLa cells. In order to determine whether 11q13 deletions occur in primary cervical tumors, we analysed 36 tumors using 20 different microsatellite and RFLP markers. Semi automated fluorescein based allelotyping was performed to identify loss of heterozygosity (LOH) in tumors. The results showed allelic loss in 17 (47%) tumors. Three different regions of loss, one near MEN1, the second near D11S913, and the third near INT2 locus were observed. The smallest region of deletion overlap at the D11S913 locus was localized to a 300 Kb distance between D11S4908 and D11S5023. Fluorescence in situ hybridization (FISH), using 11q13 specific cosmid and BAC (bacterial artificial chromosome) probes, confirmed allelic deletion in the tumors. PCR analysis further identified homozygous deletion of 11q13 sequences in a primary tumor, in HeLa cells and in two HeLa cell derived tumorigenic hybrid cell lines. The homozygous deletion in the cell lines was mapped to a 5.7 kb sequence of 11q13. We hypothesize therefore that a putative cervical cancer tumor suppressor gene exists within the 300 kb of chromosome 11q13. C1 Univ Calif Los Angeles, Sch Med, VAGLAHS, Dept Surg, Los Angeles, CA 90073 USA. Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Radiat Oncol, Indianapolis, IN 46202 USA. Univ Calif Irvine, Calif Coll Med, Dept Radiat Oncol, Irvine, CA 92697 USA. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. Univ Calif Irvine, Calif Coll Med, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. City Hope Natl Med Ctr, Dept Anat Pathol, Duarte, CA 91010 USA. RP Srivatsan, ES (reprint author), Univ Calif Los Angeles, Sch Med, VAGLAHS, Dept Surg, 10H2,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Pack, Svetlana/C-2020-2014 FU NCI NIH HHS [CA39312, CA19401] NR 55 TC 24 Z9 25 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 15 PY 2002 VL 21 IS 36 BP 5631 EP 5642 DI 10.1038/sj.onc.1205698 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 583ZM UT WOS:000177442000013 PM 12165862 ER PT J AU Zhuang, SM Wiseman, RW Soderkvist, P AF Zhuang, SM Wiseman, RW Soderkvist, P TI Frequent mutations of the Trp53, Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice SO ONCOGENE LA English DT Article DE Trp53; Hras1; Catnb; 1,3-butadiene; mammary adenocarcinomas ID TUMOR-SUPPRESSOR GENE; BREAST-CANCER; HEPATOCELLULAR CARCINOMAS; SOMATIC MUTATIONS; COLON-CARCINOMA; CYCLIN D1; RAS GENES; K-RAS; EXPRESSION; MOUSE AB DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including beta-catenin (Catnb), Ape and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wildtype Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Nras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G-C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Ape mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras] and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers. C1 Linkoping Univ, Fac Hlth Sci, Dept Biomed & Surg, Div Cell Biol, SE-58185 Linkoping, Sweden. NIEHS, Lab Womens Hlth, Res Triangle Pk, NC 27709 USA. RP Zhuang, SM (reprint author), Linkoping Univ, Fac Hlth Sci, Dept Biomed & Surg, Div Cell Biol, SE-58185 Linkoping, Sweden. NR 41 TC 13 Z9 15 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 15 PY 2002 VL 21 IS 36 BP 5643 EP 5648 DI 10.1038/sj.ocn.1205649 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 583ZM UT WOS:000177442000014 PM 12165863 ER PT J AU Weiss, GH AF Weiss, GH TI Some applications of persistent random walks and the telegrapher's equation SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE diffusive transport; ballistic transport; optical imaging ID PHOTON MIGRATION; TRANSPORT-EQUATIONS; MESOSCOPIC DIFFUSION; CRYSTALLINE SOLIDS; LANDAUER EQUATION; 3 DIMENSIONS; HEAT WAVES; TIME; MODEL; FLUORESCENCE AB A persistent random walk can be regarded as a multidimensional Markov process. The bias-free telegraphers equation is partial derivative(2)p/partial derivativet(2) + 1/T partial derivativep/partial derivativet = v(2)del(2)p. It can be regarded as interpolating between the wave equation (T --> infinity) and the diffusion equation (T --> 0). Previously, it has found application in thermodynamics (cf. the review in Rev. Mod. Phys. 61 (1989) 41; 62 (1990) 375). More recent applications are reviewed in the present article. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIH, Div Comp Res & Technol, Math & Stat Computat Lab, Bethesda, MD 20892 USA. RP Weiss, GH (reprint author), NIH, Div Comp Res & Technol, Math & Stat Computat Lab, Bldg 12 A,Room 2007, Bethesda, MD 20892 USA. NR 83 TC 83 Z9 83 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD AUG 15 PY 2002 VL 311 IS 3-4 BP 381 EP 410 AR PII S0378-4371(02)00805-1 DI 10.1016/S0378-4371(02)00805-1 PG 30 WC Physics, Multidisciplinary SC Physics GA 581BK UT WOS:000177271100009 ER PT J AU Marchler-Bauer, A Panchenko, AR Ariel, N Bryant, SH AF Marchler-Bauer, A Panchenko, AR Ariel, N Bryant, SH TI Comparison of sequence and structure alignments for protein domains SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE protein domain identification; sequence alignment; structure alignment; conserved domain database ID SECONDARY STRUCTURE; FOLD RECOGNITION; DATABASE; FAMILIES; CLASSIFICATION; IDENTIFICATION; SIMILARITIES; GENOMICS; PROFILES; CORES AB Profile search methods based on protein domain alignments have proven to be useful tools in comparative sequence analysis. Domain alignments used by currently available search methods have been computed by sequence comparison. With the growth of the protein structure database, however, alignments of many domain pairs have also been computed by structure comparison. Here, we examine the extent to which information from these two sources agrees. We measure agreement with respect to identification of homologous regions in each protein, that is, with respect to the location of domain boundaries. We also measure agreement with respect to identification of homologous residue sites by comparing alignments and assessing the accuracy of the molecular models they predict. We find that domain alignments in publicly available collections based on sequence and structure comparison are largely consistent. However, the homologous regions identified by sequence comparison are often shorter than those identified by 3D structure comparison. In addition, when overall sequence similarity is low alignments from sequence comparison produce less accurate molecular models, suggesting that they less accurately identify homologous sites. These observations suggest that structure comparison results might be used to improve the overall accuracy of domain alignment collections and the performance of profile search methods based on them. C1 NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Bryant, SH (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bldg 38A,Room 8N805, Bethesda, MD 20894 USA. RI Marchler-Bauer, Aron/A-9681-2009; OI Marchler-Bauer, Aron/0000-0003-1516-0712 NR 47 TC 27 Z9 27 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 0887-3585 J9 PROTEINS JI Proteins PD AUG 15 PY 2002 VL 48 IS 3 BP 439 EP 446 DI 10.1002/prot.10163 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 577NP UT WOS:000177068000001 PM 12112669 ER PT J AU Blaney, JE Johnson, DH Manipon, GG Firestone, CY Hanson, CT Murphy, BR Whitehead, SS AF Blaney, JE Johnson, DH Manipon, GG Firestone, CY Hanson, CT Murphy, BR Whitehead, SS TI Genetic basis of attenuation of Dengue virus type 4 small plaque mutants with restricted replication in suckling mice and in SCID mice transplanted with human liver cells SO VIROLOGY LA English DT Article DE Dengue virus; vaccine; mutagenesis; small-plaque; temperature-sensitive; attenuation ID BORNE ENCEPHALITIS-VIRUS; 5' NONCODING REGION; YELLOW-FEVER VIRUS; VACCINE CANDIDATE; 3'-UNTRANSLATED REGION; CHEMICAL MUTAGENESIS; 3'-NONCODING REGION; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; HUMAN VOLUNTEERS AB Mutations that restrict replication of dengue virus have been sought for the generation of recombinant live-attenuated dengue virus vaccines. Dengue virus type 4 (DEN4) was previously grown in Vero cells in the presence of 5-fluorouracil, and the characterization of 1248 mutagenized, Vero cell passaged clones identified 20 temperature-sensitive (ts) mutant viruses that were attenuated (att) in suckling mouse brain (J. E. Blaney, Jr., D. H. Johnson, C. Y Firestone, C. T Hanson, B. R. Murphy, and S. S. Whitehead, 2001, J. Virol. 75(20), 9731-9740). The present investigation has extended these studies by identifying an additional 22 DEN4 mutant viruses which have a small plaque size (sp) phenotype in Vero cells and/or the liver cell line, HuH-7. Five mutant viruses have a so phenotype in both Vero and HuH-7 cells, three of which are also ts. Seventeen mutant viruses have a sp phenotype in only HuH-7 cells, 13 of which are also ts. Each of the sp viruses was growth restricted in the suckling mouse brain, exhibiting a wide range of reduction in replication (9- to 100,000-fold). Complete nucleotide sequence was determined for the 22 DEN4 sp mutant viruses, and nucleotide substitutions were found in the 3'-untranslated region (UTR) as well as in all coding regions except NS4A. Identical mutations have been identified in multiple virus clones, suggesting that they may be involved in the adaptation of DEN4 virus to efficient growth in Vero cells. Six of the 22 sp 5-FU mutant viruses lacked coding mutations in the structural genes, and 17 recombinant DEN4 viruses were generated which separately encoded each of the mutations observed in these six sp viruses. Analysis of the recombinant DEN4 viruses defined the genetic basis of the sp, ts, and att phenotypes observed in the six sp viruses. Mutations in NS1, NS3, and the 3'-UTR were found to confer a greater than 100-fold, 10,000-fold, and 1000-fold reduction in replication of rDEN4 virus in SCID mice transplanted with HuH-7 cells, respectively, which serves as a novel small animal model for DEN4 infection. C1 NIAID, NIH, LID, Bethesda, MD 20892 USA. RP Blaney, JE (reprint author), NIAID, NIH, LID, Bldg 50,Room 6515,50 S Dr,MSC 8007, Bethesda, MD 20892 USA. NR 66 TC 78 Z9 81 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2002 VL 300 IS 1 BP 125 EP 139 DI 10.1006/viro.2002.1528 PG 15 WC Virology SC Virology GA 589UL UT WOS:000177778700014 PM 12202213 ER PT J AU Huestis, MA Choo, RE AF Huestis, MA Choo, RE TI Drug abuse's smallest victims: in utero drug exposure SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article; Proceedings Paper CT 39th Annual International Meeting of the International-Association-of-Forensic-Toxicologists CY AUG 26-30, 2001 CL PRAGUE, CZECH REPUBLIC SP Int Assoc Forens Toxicologists DE drug abused; in utero drug exposure; fetal drug exposure; maternal drug use ID NEONATAL NARCOTIC WITHDRAWAL; PRENATAL MARIJUANA EXPOSURE; HUMAN AMNIOTIC-FLUID; COCAINE EXPOSURE; MECONIUM ANALYSIS; PREGNANT-WOMEN; DEPENDENT MOTHERS; BIRTH-WEIGHT; FETAL HAIR; GC-MS AB The social and economic impact of drug use on our global population continues to increase leaving no geographical, social or cultural group untouched. The National Institute on Drug Abuse (NIDA), in one of the few large surveys of maternal abuse, found that 5.5% of mothers reported taking an illicit substance during gestation. These figures certainly are underestimates due to the stigma of drug use during pregnancy and the accompanying legal, ethical and economic issues. Although drugs of choice and routes of administration vary by country, exposure of our most valuable resource, our children, to the developmental effects of drugs is an enormous problem. In utero drug exposure can have a severe impact not only on the development of the fetus, but also on the child during later stages of life. More than 75% of infants exposed to drugs have major medical problems as compared to 27% of unexposed infants. The cost of treating drug-affected infants was twice the cost of non-affected infants. Obstetrical complications including placental insufficiency, miscarriage, intrauterine death, and increased incidence of infectious and sexually-transmitted diseases are higher in the drug-abusing mother. Treatment for pregnant addicts should be a high priority for our governments. Increased awareness and improvement in our understanding of drug abuse in the medical, legal and social realms will enable us to reduce the barriers to treatment for this important population. Accurate identification of in utero drug exposure has important implications for the care of the mother and child, but can raise difficult legal issues. Society discourages prenatal care with the infliction of harsh criminal penalties. Maternal drug use during pregnancy can be monitored with urine, sweat, oral fluid and/or hair testing. Detection of in utero drug exposure has traditionally been accomplished through urine testing; however, the window of detection is short, reflecting drug use for only a few days before delivery. Monitoring exposure through testing of alternative matrices, such as neonatal meconium and hair, offers advantages including non-invasive collection and detection earlier in gestation. There are many unresolved issues in monitoring in utero drug exposure that urgently require research. These can be divided into research to definitively differentiate drug exposed and non-drug-exposed fetuses, determine the most efficient methods to routinely monitor women's drug use, and determine how these drug test results relate to neonatal and maternal outcomes. Research in this area is difficult and expensive to perform, but necessary to assess accurately drug effects on the fetus. By increasing our understanding of the physiological, biochemical and behavioral effects of gestational drug exposure, we may ultimately provide solutions for better drug prevention, treatment and a reduction in the number of drug-exposed children. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, IRP, CDM Sect, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, IRP, CDM Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 103 TC 74 Z9 77 U1 1 U2 12 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD AUG 14 PY 2002 VL 128 IS 1-2 BP 20 EP 30 AR PII S0379-0738(02)00160-3 DI 10.1016/S0379-0738(02)00160-3 PG 11 WC Medicine, Legal SC Legal Medicine GA 594CF UT WOS:000178030600003 PM 12208017 ER PT J AU Altarescu, G Sun, M Moore, DF Smith, JA Wiggs, EA Solomon, BI Patronas, NJ Frei, KP Gupta, S Kaneski, CR Quarrell, OW Slaugenhaupt, SA Goldin, E Schiffmann, R AF Altarescu, G Sun, M Moore, DF Smith, JA Wiggs, EA Solomon, BI Patronas, NJ Frei, KP Gupta, S Kaneski, CR Quarrell, OW Slaugenhaupt, SA Goldin, E Schiffmann, R TI The neurogenetics of mucolipidosis type IV SO NEUROLOGY LA English DT Review ID NATURAL-HISTORY; CORPUS-CALLOSUM; MUTATIONS; MRI; IDENTIFICATION; MORPHOLOGY; DISEASE; CHANNEL; PATIENT AB Background: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. Objective: To comprehensively characterize the clinical and genetic abnormalities of MLIV. Methods: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every I to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. Results: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. Conclusions: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis. C1 NIH, Warren G Magnuson Clin Ctr, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Speech Language Pathol Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Inst Human Genet, Boston, MA USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA USA. Sheffield Childrens Hosp, N Trent Genet Serv, Sheffield, S Yorkshire, England. RP Schiffmann, R (reprint author), NIH, Warren G Magnuson Clin Ctr, Dev & Metab Neurol Branch, 9000 Rockville Pike,Bldg 10,Rm 3D03, Bethesda, MD 20892 USA. OI Kaneski, Christine/0000-0003-1453-2502 FU NINDS NIH HHS [NS 39995] NR 38 TC 88 Z9 90 U1 1 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 AUG 13 PY 2002 VL 59 IS 3 BP 306 EP 313 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 582EB UT WOS:000177335800004 PM 12182165 ER PT J AU Weaver, JD Huang, MH Albert, M Harris, T Rowe, JW Seeman, TE AF Weaver, JD Huang, MH Albert, M Harris, T Rowe, JW Seeman, TE TI Interleukin-6 and risk of cognitive decline - MacArthur studies of successful aging SO NEUROLOGY LA English DT Article ID LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; TRANSGENIC MICE; CEREBRAL OVEREXPRESSION; DENTATE GYRUS; COMMUNITY; BRAIN; PERFORMANCE; CYTOKINES AB Objective: To investigate whether plasma interleukin-6 (IL-6) is cross-sectionally related to poorer cognitive function and whether a baseline plasma IL-6 measurement can predict risk for decline in cognitive function in longitudinal follow-up of a population-based sample of nondisabled elderly people. Methods: A prospective cohort study of 779 high-functioning men and women aged 70 to 79 from the MacArthur Study of Successful Aging was conducted. Regression modeling was used to investigate whether baseline IL-6 levels (classified by tertiles) were associated with initial cognitive function and whether IL-6 levels predicted subsequent declines in cognitive function from 1988 to 1991 (2.5-year follow-up) and from 1988 to 1995 (7-year follow-up). Results: Subjects in the highest tertile for plasma IL-6 were marginally more likely to exhibit poorer baseline cognitive function (i.e., scores below the median), independent of demographic status, social status, health and health behaviors, and other physiologic variables (odds ratio [OR] = 1.46; 95% CI: 0.97, 2.20). At 2.5 years, those in both the second tertile of IL-6 (OR = 2.21; 95% CI: 1.44, 3.42) and the third tertile (OR = 2.03; 95% Cl: 1.30, 3.19) were at increased risk of cognitive decline even after adjusting for all confounders. At 7 years of follow-up, only those in the highest IL-6 tertile were significantly more likely to exhibit declines in cognition (OR = 1.90; 95% CI: 1.14, 3.18) after adjustment for all confounders. Conclusions: The results suggest a relationship between elevated baseline plasma IL-6 and risk for subsequent decline in cognitive function. These findings are consistent with the hypothesized relationship between brain inflammation, as measured here by elevated plasma IL-6, and neuropathologic disorders. C1 Univ Calif Los Angeles, Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat Gerontol, Boston, MA USA. NIA, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. RP Seeman, TE (reprint author), Univ Calif Los Angeles, Sch Med, Div Geriatr, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. FU NIA NIH HHS [AG-17056, AG-17265] NR 26 TC 267 Z9 276 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 13 PY 2002 VL 59 IS 3 BP 371 EP 378 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 582EB UT WOS:000177335800013 PM 12177370 ER PT J AU Molloy, FM Dalakas, MC Floeter, MK AF Molloy, FM Dalakas, MC Floeter, MK TI Increased brainstem excitability in stiff-person syndrome SO NEUROLOGY LA English DT Article ID REFLEX AB The recovery cycle of the R2 component of the blink reflex was studied in five patients with stiff-person syndrome (SPS) and in seven healthy control subjects. R2 recovery was enhanced in patients with SPS. This result is suggestive of hyperexcitability of brainstem interneuronal. circuits in SPS. Hyperexcitability may result from abnormal input from supra-segmental structures or loss of inhibition by interneurons and is compatible with the proposal that there is a widespread dysfunction of central inhibitory mechanisms in SPS. C1 NINDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), NINDS, Electromyog Sect, NIH, Bldg 10,Rm 5C101,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 10 TC 20 Z9 21 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 AUG 13 PY 2002 VL 59 IS 3 BP 449 EP 451 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 582EB UT WOS:000177335800028 PM 12177385 ER PT J AU Miller, FG Shorr, AF AF Miller, FG Shorr, AF TI Unnecessary use of placebo controls - The case of asthma clinical trials SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID ACTIVE-CONTROL TRIALS; TO-MODERATE ASTHMA; DOUBLE-BLIND; ZAFIRLUKAST; ORTHODOXY; EFFICACY; MYTHS C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. RI Roncada, Cristian/O-2772-2013 NR 24 TC 13 Z9 15 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 12 PY 2002 VL 162 IS 15 BP 1673 EP 1677 DI 10.1001/archinte.162.15.1673 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 581GT UT WOS:000177283900002 PM 12153369 ER PT J AU Kuruppu, JC Corretti, M Mackowiak, P Roghmann, MC AF Kuruppu, JC Corretti, M Mackowiak, P Roghmann, MC TI Overuse of transthoracic echocardiography in the diagnosis of native valve endocarditis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ACTIVE INFECTIVE ENDOCARDITIS; PREDICTING EMBOLIC EVENTS; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; DUKE CRITERIA; SUSPECTED ENDOCARDITIS; COST-EFFECTIVENESS; BACTEREMIA; CHILDREN; THERAPY AB Background: Infective endocarditis (IE) is a diagnostic challenge due to its variable presentation and nonspecific clinical findings. The use of transthoracic echocariography (TTE) has greatly improved the ability to diagnose IE early, and therefore reduce high mortality and morbidity rates. However, reliance on TTE to exclude IE may lead to overuse of this technology in patients with a low pretest probability of IE. Methods: Prospective observational study of all patients referred for TTE to diagnose IE. Clinical factors were used to determine likelihood of IE based on the Von Reyn criteria, and the resulting diagnostic probabilities were correlated with abnormal TTE findings as well as duration of antibiotic therapy. Results: One hundred eleven TTEs performed on 98 patients were included in the analysis. Over 70% of TTEs were obtained in patients in whom the diagnosis of IE was rejected by Von Reyn criteria. Therapeutic management (prolonged antibiotic administration) was associated significantly with Von Reyn categorization, and not significantly affected by TTE results. Conclusions: Most TTEs are obtained in patients with a low pretest probability of IE and do not contribute to therapeutic decision making. We propose a diagnostic algorithm to direct the use of TTE to patients with intermediate or high pretest probability of IE. C1 Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ Maryland, Vet Adm Maryland Hlth Care Syst, Med Care Clin Ctr, Baltimore, MD 21201 USA. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Kuruppu, JC (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 3612B, Bethesda, MD 20892 USA. OI Roghmann, Mary-Claire/0000-0003-1063-9257 NR 29 TC 18 Z9 20 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 12 PY 2002 VL 162 IS 15 BP 1715 EP 1720 DI 10.1001/archinte.162.15.1715 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 581GT UT WOS:000177283900007 PM 12153374 ER PT J AU Emanuel, EJ Ash, A Yu, W Gazelle, G Levinsky, NG Saynina, O McClellan, M Moskowitz, M AF Emanuel, EJ Ash, A Yu, W Gazelle, G Levinsky, NG Saynina, O McClellan, M Moskowitz, M TI Managed care, hospice use, site of death, and medical expenditures in the last year of life SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID POTENTIALLY INEFFECTIVE CARE; COST SAVINGS; DATA SHOW; REIMBURSEMENT; SYSTEM; END AB Background: We examined deaths of Medicare beneficiaries in Massachusetts and California to evaluate the effect of managed care on the use of hospice and site of death and to determine how hospice affects the expenditures for the last year of life. Methods: Medicare data for beneficiaries in Massachusetts (n=37933) and California (n=27685) who died in 1996 were merged with each state's death certificate files to determine site and cause of death. Expenditure data were Health Care Financing Administration payments and were divided into 30-day periods from the date of death back 12 months. Results: In Massachusetts, only 7% of decedents were enrolled in managed care organizations (MCOs); in California, 28%. More than 60% of hospice users had cancer. Hospice use was much lower in Massachusetts than in California (12% vs 18%). In both states, decedents enrolled in MCOs used hospice care much more than those enrolled in fee-for-service plans (17% vs 11% in Massachusetts and 25% vs 15% in California). This pattern persisted for those with cancer and younger (aged 65-74 years) decedents. Decedents receiving hospice care were significantly (P<.001 for both) less likely to die in the hospital (11% vs 43% in Massachusetts and 5% vs 43% in California). Enrollment in MCOs did not affect the proportion of in-hospital deaths (those enrolled in fee-for-service plans vs MCOs: 40% vs 39% in Massachusetts; and 37% vs 34% in California). Expenditures in the last year of life were $28 588 in Massachusetts and $27 814 in California; about one third of the expenditures occurred in the last month before death. Hospital services accounted for more than 50% of all expenditures in both states, despite 77% of decedents being hospitalized in Massachusetts and just 55% being hospitalized in California. Among patients with cancer, expenditures were 13% to 20% lower for those in hospice. Conclusions: Medicare-insured decedents in California were more than 4 times more likely to be enrolled in MCOs, were 50% more likely to use a hospice, and had a 30% lower hospitalization rate than decedents in Massachusetts, yet there are few differences in out-of-hospital deaths or expenditures in the last year of life. However, patients with cancer using hospice did have significant savings. C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Natl Bur Econ Res, Palo Alto, CA USA. Harvard Vanguard Med Associates, Palliat & Support Med Program, Boston, MA USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Hlth Care Res Unit, Boston, MA 02118 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bldg 10,9000 Rockville Pike,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 24 TC 91 Z9 91 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 12 PY 2002 VL 162 IS 15 BP 1722 EP 1728 DI 10.1001/archinte.162.15.1722 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 581GT UT WOS:000177283900008 PM 12153375 ER PT J AU Robertson, KD AF Robertson, KD TI DNA methylation and chromatin - unraveling the tangled web SO ONCOGENE LA English DT Review DE DNA methyltransferase; chromatin; DNA methylation; histone deacetylase; histone methylase; transcriptional repression ID MESSENGER-RNA EXPRESSION; RECOMBINANT HUMAN DNA; EMBRYONIC STEM-CELLS; ICF SYNDROME; DE-NOVO; CYTOSINE-5 METHYLTRANSFERASE; HISTONE DEACETYLASE; MAMMALIAN DEVELOPMENT; REPLICATION FOCI; SATELLITE DNA AB Methylation of cytosines within the CpG dinucleotide by DNA methyltransferases is involved in regulating transcription and chromatin structure, controlling the spread of parasitic elements, maintaining genome stability in the face of vast amounts of repetitive DNA, and X chromosome inactivation. Cellular DNA methylation is highly compartmentalized over the mammalian genome and this compartmentalization is essential for embryonic development. When the complicated mechanisms that control which DNA sequences become methylated go awry, a number of inherited genetic diseases and cancer may result. Much new information has recently come to light regarding how cellular DNA methylation patterns may be established during development and maintained in somatic cells. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Additionally, various regulatory factors interacting with the DNA methyltransferases may direct them to specific DNA sequences, regulate their enzymatic activity, and allow their use as transcriptional repressors. Continued studies of the connections between DNA methylation and chromatin structure and the DNA methyltransferase-associated proteins, will likely reveal that many, if not all, epigenetic modifications of the genome are directly connected. Such studies should also yield new insights into treating diseases involving aberrant DNA methylation. C1 NCI, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. RP Robertson, KD (reprint author), NCI, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. EM robertk@mail.nih.gov OI Robertson, Keith/0000-0002-7508-3328 FU NCI NIH HHS [CA84535-01] NR 135 TC 267 Z9 292 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 12 PY 2002 VL 21 IS 35 BP 5361 EP 5379 DI 10.1038/sj.onc.1205609 PG 19 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 579VC UT WOS:000177197700003 PM 12154399 ER PT J AU Braga, E Senchenko, V Bazov, I Loginov, W Liu, J Ermilova, V Kazubskaya, T Garkavtseva, R Mazurenko, N Kisseljov, F Lerman, MI Klein, G Kisselev, L Zabarovsky, ER AF Braga, E Senchenko, V Bazov, I Loginov, W Liu, J Ermilova, V Kazubskaya, T Garkavtseva, R Mazurenko, N Kisseljov, F Lerman, MI Klein, G Kisselev, L Zabarovsky, ER TI Critical tumor-suppressor gene regions on chromosome 3p in major human epithelial malignancies: Allelotyping and quantitative real-time PCR SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE chromosome 3p; tumor-suppressor gene; loss of heterozygosity; allelotyping; renal cell carcinoma ID RENAL-CELL CARCINOMA; HUMAN LUNG-CANCER; HOMOZYGOUS DELETION; SHORT ARM; NASOPHARYNGEAL CARCINOMA; EPIGENETIC INACTIVATION; FREQUENT BREAKPOINTS; BRONCHIAL EPITHELIUM; MICROCELL HYBRIDS; T(3-8) BREAKPOINT AB To ascertain the involvement of human chromosome 3p and its established critical TSG regions in various epithelial malignancies, 21 polymorphic and 2 nonpolymorphic 3p markers were allelotyped in nonpapillary RCC, NSCLC, CC and BC from a total of 184 patients. LOH was observed with high frequency in all types of cancer studied: RCC (52/57, 91%), BC (41/51, 80%), NSCLC (30/40, 75%) and CC (27/36, 75%). Interstitial deletions, believed to signal TSG inactivation, were verified using the "L-allele rule" and real-time quantitative PCR. Significant correlation was observed between DNA copy numbers for 2 nonpolymorphic STS markers and LOH data for adjacent polymorphic loci. Interstitial deletions in 3p were demonstrated for all cancer types studied. However, the distribution of different types of deletion was characteristic for tumors from various locations. Large terminal deletions were predominantly seen in RCC and NSCLC (51% and 40%, respectively), correlating with clear cell RCC and squamous cell carcinomas of the lung. In addition to the LUCA region at 3p21.3 (centromeric), we found that the AP20 region (3p21.3, telomeric) was frequently affected in all 4 cancers, suggesting that this newly defined critical region contains multiple TSGs. Moreover, at least 3 candidate cancer-specific loci were identified. The telomeric 3p26.1-p2S.3 region was predominantly deleted in RCC and NSCLC. The D3S1286 and D3S3047 markers (3p25.2-p24.3) were deleted nonrandomly in NSCLC. High-frequency LOH was detected in a segment mapped closely distal to the LUCA site (3p21.3), around the D3S2409 and D3S2456 markers. (C) 2002 Wiley-Liss, Inc. C1 Karolinska Inst, MTC, Ctr Genom Res, Microbiol & Tumor Biol Ctr, S-17177 Stockholm, Sweden. Russian State Genet Ctr, Moscow, Russia. Russian Acad Sci, Ctr Bioengn, Moscow, Russia. Russian Acad Med Sci, Blokhir Canc Res Ctr, Moscow, Russia. NCI, Immunobiol Lab, Frederick, MD 21701 USA. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow, Russia. RP Zabarovsky, ER (reprint author), Karolinska Inst, MTC, Ctr Genom Res, Microbiol & Tumor Biol Ctr, Box 280, S-17177 Stockholm, Sweden. RI Zabarovsky, Eugene/A-6645-2010; Senchenko, Vera/C-8992-2014; Braga, Eleonora/P-5574-2016 OI Senchenko, Vera/0000-0002-3119-515X; FU NCI NIH HHS [N01-CO-56000] NR 52 TC 46 Z9 54 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 AUG 10 PY 2002 VL 100 IS 5 BP 534 EP 541 DI 10.1002/ijc.10511 PG 8 WC Oncology SC Oncology GA 577WY UT WOS:000177086700006 PM 12124802 ER PT J AU White, RE Abnet, CC Mungatana, CK Dawsey, SM AF White, RE Abnet, CC Mungatana, CK Dawsey, SM TI Oesophageal cancer: a common malignancy in young people of Bomet District, Kenya SO LANCET LA English DT Article AB Oesophageal cancer is a common cancer with uneven geographical distribution. We reviewed all malignancies diagnosed at Tenwek Hospital (Bomet District, Kenya) between 1989 and 1998. Oesophageal cancer was the most common malignancy; 274 cases accounted for 19% of 1459 malignancies diagnosed, and for a steady rise in total cancer cases during this period. A striking feature of our study was the presence of a subset of very young patients. 26 (11%) patients were aged 30 years or less at diagnosis, and the youngest patient was 14 years old. This area of West Kenya seems to be a high-risk region for oesophageal cancer. C1 Tenwek Hosp, Bomet, Kenya. NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP White, RE (reprint author), Tenwek Hosp, POB 39, Bomet, Kenya. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 5 TC 12 Z9 12 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 10 PY 2002 VL 360 IS 9331 BP 462 EP 463 DI 10.1016/S0140-6736(02)09639-3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 582GZ UT WOS:000177342900016 PM 12241722 ER PT J AU Schmidt, B Wright, LL Davis, P Solimano, A Roberts, RS AF Schmidt, B Wright, LL Davis, P Solimano, A Roberts, RS CA Trial Indomethacin Prophylaxis Pre TI Ibuprofen prophylaxis in preterm neonates SO LANCET LA English DT Letter ID PERSISTENT PULMONARY-HYPERTENSION; INDOMETHACIN; NEWBORN C1 McMaster Univ, Dept Pediat, Hamilton, ON L8N 3Z5, Canada. McMaster Univ, Dept Clin Epidemiol, Hamilton, ON L8N 3Z5, Canada. NICHHD, Neonatl Res Network, Bethesda, MD 20892 USA. Royal Womens Hosp, Melbourne, Vic, Australia. Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada. RP Schmidt, B (reprint author), McMaster Univ, Dept Pediat, Hamilton, ON L8N 3Z5, Canada. NR 5 TC 4 Z9 4 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 10 PY 2002 VL 360 IS 9331 BP 492 EP 492 DI 10.1016/S0140-6736(02)09658-7 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 582GZ UT WOS:000177342900047 PM 12241754 ER PT J AU Symer, DE Connelly, C Szak, ST Caputo, EM Cost, GJ Parmigiani, G Boeke, JD AF Symer, DE Connelly, C Szak, ST Caputo, EM Cost, GJ Parmigiani, G Boeke, JD TI Human L1 retrotransposition is associated with genetic instability in vivo SO CELL LA English DT Article ID HUMAN TRANSPOSABLE ELEMENT; LINE-1 RETROTRANSPOSITION; MAMMALIAN-CELLS; DNA; ENDONUCLEASE; REARRANGEMENTS; RECOMBINATION; INTEGRATION; MECHANISM; EVOLUTION AB Retrotransposons have shaped eukaryotic genomes for millions of years. To analyze the consequences of human Ll retrotransposition, we developed a genetic system to recover many new L1 insertions in somatic cells. Forty-two de novo integrants were recovered that faithfully mimic many aspects of L1s that accumulated since the primate radiation. Their structures experimentally demonstrate an association between Ll retrotransposition and various forms of genetic instability. Numerous L1 element inversions, extra nucleotide insertions, exon deletions, a chromosomal inversion, and flanking sequence comobilization (called 5' transduction) were identified. In a striking number of integrants, short identical sequences were shared between the donor and the target site's 3' end, suggesting a mechanistic model that helps explain the structure of Ll insertions. C1 Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hoipkins, Sidney Kimmel Comprehens Canc Ctr, Dept Med Oncol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Boeke, JD (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, 725 N Wolfe St, Baltimore, MD 21205 USA. EM jboeke@jhmi.edu RI Symer, David/E-4173-2011 FU NCI NIH HHS [CA16519] NR 35 TC 260 Z9 268 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 9 PY 2002 VL 110 IS 3 BP 327 EP 338 DI 10.1016/S0092-8674(02)00839-5 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 583MN UT WOS:000177411800009 PM 12176320 ER PT J AU Boheler, KR Czyz, J Tweedie, D Yang, HT Anisimov, SV Wobus, AM AF Boheler, KR Czyz, J Tweedie, D Yang, HT Anisimov, SV Wobus, AM TI Differentiation of pluripotent embryonic stem cells into cardiomyocytes SO CIRCULATION RESEARCH LA English DT Review DE embryonic stem; embryonic carcinoma; embryonic germ; in vitro differentiation; cardiornyocytes ID LEUKEMIA INHIBITORY FACTOR; IN-VITRO PRESELECTION; HEART TUBE FORMATION; GENE TRAP APPROACH; TRANSCRIPTION FACTOR; CARDIAC MYOCYTES; MOUSE EMBRYOS; HUMAN BLASTOCYSTS; VENTRAL MORPHOGENESIS; FUNCTIONAL-PROPERTIES AB Embryonic stem (ES) cells have been established as permanent lines of undifferentiated pluripotent cells from early mouse embryos. ES cells provide a unique system for the genetic manipulation and the creation of knockout strains of mice through gene targeting. By cultivation in vitro as 3D aggregates called embryoid bodies, ES cells can differentiate into derivatives of all 3 primary germ layers, including cardiomyocytes. Protocols for the in vitro differentiation of ES cells into cardiomyocytes representing all specialized cell types of the heart, such as atrial-like, ventricular-like, sinus nodal-like, and Purkinje-like cells, have been established. During differentiation, cardiac-specific genes as well as proteins, receptors, and ion channels are expressed in a developmental continuum, which closely recapitulates the developmental pattern of early cardiogenesis. Exploitation of ES cell-derived cardiomyocytes has facilitated the analysis of early cardiac development and has permitted in vitro "gain-of-function" or "loss-of-function" genetic studies. Recently, human ES cell lines have been established that can be used to investigate cardiac development and the function of human heart cells and to determine the basic strategies of regenerative cell therapy. This review summarizes the current state of ES cell-derived cardiogenesis and provides an overview of how genomic strategies coupled with this in vitro differentiation system can be applied to cardiac research. C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Inst Plant Genet, Gatersleben, Germany. RP Boheler, KR (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 89 TC 434 Z9 490 U1 3 U2 55 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 9 PY 2002 VL 91 IS 3 BP 189 EP 201 DI 10.1161/01.RES.0000027865.61704.32 PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 585NJ UT WOS:000177530600004 PM 12169644 ER PT J AU Lin, HM Zhao, L Cheng, SY AF Lin, HM Zhao, L Cheng, SY TI Cyclin D1 is a ligand-independent co-repressor for thyroid hormone receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE DEACETYLASE; NUCLEAR RECEPTOR; N-COR; ESTROGEN-RECEPTOR; TRANSCRIPTIONAL REPRESSION; CELL-PROLIFERATION; CLASS-I; ACTIVATION; SMRT; ACETYLTRANSFERASE AB Thyroid hormone receptors (TRs) are critical regulators of growth, differentiation, and homeostasis. TRs function by regulating the expression of thyroid hormone (T3) target genes in both ligand-dependent and -independent pathways. Distinct classes of co-regulatory proteins modulate these two pathways. We show here a novel role of cyclin D1 as a T3-independent corepressor for TRs. Cyclin D1 interacted with TR in vitro and in cells in a ligand-independent manner. Cyclin D1 acted to repress both the silencing activity of the unliganded TR and the transcriptional activity of the liganded TR. The repression was not due to the inhibition of the binding of TR to the thyroid hormone response element but by serving as a ligand-independent bridging factor to selectively recruit HDAC3 to form ternary complexes. The repression was augmented by increasing expression of HDAC3 but not by HDAC1 and was alleviated by trichostatin A. Thus, cyclin D1 is a novel ligand-independent co-repressor that opens a new paradigm to understand the molecular basis of the silencing action of TR. C1 NCI, Mol Biol Lab, NIH, Canc Res Ctr,Gene Regulat Sect, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, Canc Res Ctr,Gene Regulat Sect, 37 Convent Dr,Rm 5128A2,MSC 4264, Bethesda, MD 20892 USA. NR 37 TC 68 Z9 70 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2002 VL 277 IS 32 BP 28733 EP 28741 DI 10.1074/jbc.M203380200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582GX UT WOS:000177342600051 PM 12048199 ER PT J AU Bayle, JH Randazzo, F Johnen, G Kaufman, S Nagy, A Rossant, J Crabtree, GR AF Bayle, JH Randazzo, F Johnen, G Kaufman, S Nagy, A Rossant, J Crabtree, GR TI Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEPATOCYTE NUCLEAR FACTOR-1; TRANSCRIPTION FACTOR HNF1; PTERIN-4-ALPHA-CARBINOLAMINE DEHYDRATASE; 4A-CARBINOLAMINE DEHYDRATASE; PHENYLALANINE-HYDROXYLASE; CRYSTAL-STRUCTURE; PROTEIN; COFACTOR; RAT; DIMERIZATION AB The bifunctional protein DCoH (Dimerizing Cofactor for HNF1) acts as an enzyme in intermediary metabolism and as a binding partner of the HNF1 family of transcriptional activators. HNF1 proteins direct the expression of a variety of genes in the liver, kidney, pancreas, and gut and are critical to the regulation of glucose homeostasis. Mutations of the HNF1 a gene underlie maturity onset diabetes of the young (MODY3) in humans. DCoH acts as a cofactor for HNF1 that stabilizes the dimeric HNF1 complex. DCoH also catalyzes the recycling of tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases. To examine the roles of DCoH, a targeted deletion allele of the murine DCoH gene was created. Mice lacking DCoH are viable and fertile but display hyperphenylalaninemia and a predisposition to cataract formation. Surprisingly, HNF1 function in DCoH null mice is only slightly impaired, and mice are mildly glucose-intolerant in contrast to HNF1alpha null mice, which are diabetic. DCoH function as it pertains to HNF1 activity appears to be partially complemented by a newly identified homolog, DCoH2. C1 Stanford Univ, Beckman Ctr Mol & Genet Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. Stanford Univ, Beckman Ctr Mol & Genet Med, Dept Dev Biol, Stanford, CA 94305 USA. Stanford Univ, Beckman Ctr Mol & Genet Med, Dept Pathol, Stanford, CA 94305 USA. NIMH, Neurochem Lab, Bethesda, MD 20892 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Crabtree, GR (reprint author), Stanford Univ, Sch Med, Dept Dev Biol & Pathol, HHMI, B211,279 Campus Dr, Stanford, CA 94305 USA. RI Nagy, Andras/G-6465-2013 NR 44 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2002 VL 277 IS 32 BP 28884 EP 28891 DI 10.1074/jbc.M201983200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582GX UT WOS:000177342600072 PM 12011081 ER PT J AU Britto, PJ Knipling, L Wolff, J AF Britto, PJ Knipling, L Wolff, J TI The local electrostatic environment determines cysteine reactivity of tubulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-TUBULIN; SULFHYDRYL-GROUPS; VINCA ALKALOIDS; BINDING-SITE; IN-VITRO; PROTEINS; DISULFIDE; PEPTIDES; SULFUR; PALMITOYLATION AB Of the 20 cysteines of rat brain tubulin, some react rapidly with sulfhydryl reagents, and some react slowly. The fast reacting cysteines cannot be distinguished with [C-14]iodoacetamide, N-[C-14]ethylmaleimide, or IAE-DANS ([5-((((2-iodoacetyl)amino)ethyl) amino) naphthalene-l-sulfonic acid]), since modification to mole ratios much less than 1 cysteine/dimer always leads to labeling of 6-7 cysteine residues. These have been identified as Cys-305alpha, Cys-315alpha, Cys-316alpha, Cys-347alpha, Cys-376alpha, Cys-241beta, and Cys-356beta by mass spectroscopy and sequencing. This lack of specificity can be ascribed to reagents that are too reactive; only with the relatively inactive chloroacetamide could we identify Cys-347alpha as the most reactive cysteine of tubulin. Using the 3.5-Angstrom electron diffraction structure, it could be shown that the reactive cysteines were within 6.5 Angstrom of positively charged arginines and lysines or the positive edges of aromatic rings, presumably promoting dissociation of the thiol to the thiolate anion. By the same reasoning the inactivity of a number of less reactive cysteines could be ascribed to inhibition of modification by negatively charged local environments, even with some surface-exposed cysteines. We conclude that the local electrostatic environment of cysteine is an important, although not necessarily the only, determinant of its reactivity. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wolff, J (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 46 TC 68 Z9 69 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 9 PY 2002 VL 277 IS 32 BP 29018 EP 29027 DI 10.1074/jbc.M204263200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582GX UT WOS:000177342600088 PM 12023292 ER PT J AU Weisz, A Mazzola, EP Murphy, CM Ito, Y AF Weisz, A Mazzola, EP Murphy, CM Ito, Y TI Preparative separation of isomeric sulfophthalic acids by conventional and pH-zone-refining counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 22nd ACS National Meeting CY AUG 26-30, 2001 CL CHICAGO, ILLINOIS SP ACS DE counter-current chromatography; preparative chromatography; sulfophthalic acids; organosulfur compounds; phthalic acids; D&C Yellow No. 10; dyes ID COIL PLANET CENTRIFUGE; LIQUID-CHROMATOGRAPHY; PURIFICATION; DERIVATIVES; PHASE AB Two modes of high-speed counter-current chromatography (HSCCC) were applied to separate 3- and 4-sulfophthalic acid from a mixture. Conventional HSCCC was useful for the separation of up to several hundred milligram quantities of these positional isomers, while pH-zone-refining CCC was implemented successfully to separations at the multigram level. The conventional HSCCC separations were performed with a standard J-type HSCCC system that has a superior resolution but a lower level of retention of the stationary phase of the biphasic solvent system used (acidified n-butanol-water). The pH-zone-refining CCC separations were performed with an X-type HSCCC system (a cross-axis system) that has a higher capability for retention of the stationary phase. The purified positional isomers (over 99% pure as determined by HPLC) were characterized by H-1 NMR and negative ion electrospray ionization mass spectrometry. Published by Elsevier Science B.V. C1 US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. US FDA, Off Sci Anal & Support, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, 200 C St SW, Washington, DC 20204 USA. NR 21 TC 28 Z9 32 U1 3 U2 21 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 AUG 9 PY 2002 VL 966 IS 1-2 BP 111 EP 118 AR PII S0021-9673(02)00695-7 DI 10.1016/S0021-9673(02)00695-7 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 582DJ UT WOS:000177334200011 PM 12214685 ER PT J AU Gopich, IV Berezhkovskii, AM Szabo, A AF Gopich, IV Berezhkovskii, AM Szabo, A TI Concentration dependence of the diffusion controlled steady-state rate constant SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID STATIONARY SINKS C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Gopich, IV (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 10 TC 16 Z9 16 U1 1 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 8 PY 2002 VL 117 IS 6 BP 2987 EP 2988 DI 10.1063/1.1490585 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 577BX UT WOS:000177042800062 ER PT J AU Cumming, BG AF Cumming, BG TI An unexpected specialization for horizontal disparity in primate primary visual cortex SO NATURE LA English DT Article ID CORTICAL AREA V1; BINOCULAR DISPARITY; DEPTH DISCRIMINATION; STRIATE CORTEX; COMPLEX CELLS; NEURONS; MACAQUE; MECHANISMS; PERCEPTION; RESPONSES AB The horizontal separation of the eyes means that objects nearer or farther than the fixation point project to different locations on the two retinae, differing principally in their horizontal coordinates (horizontal binocular disparity). Disparity-selective neurons have generally been studied with disparities applied in only one direction 1 (often horizontal), which cannot determine whether the encoding is specialized for processing disparities along the horizontal axis. It is therefore unclear if disparity selectivity represents a specialization for naturally occurring disparities. I used random dot stereograms to study disparity-selective neurons from the primary visual cortex (V1) of awake fixating monkeys. Many combinations of vertical and horizontal disparity were used, characterizing the surface of responses as a function of two-dimensional disparity. Here I report that the response surface usually showed elongation along the horizontal disparity axis, despite the isotropic stimulus. Thus these neurons modulated their firing rate over a wider range of horizontal disparity than vertical disparity. This demonstrates that disparity-selective cells are specialized for processing horizontal disparity, and that existing models(2,3) of disparity selectivity require substantial revision. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Cumming, BG (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. NR 20 TC 70 Z9 72 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 8 PY 2002 VL 418 IS 6898 BP 633 EP 636 DI 10.1038/nature00909 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 581RA UT WOS:000177305600041 PM 12167860 ER PT J AU Little, SJ Holte, S Routy, JP Daar, ES Markowitz, M Collier, AC Koup, RA Mellors, JW Connick, E Conway, B Kilby, M Wang, L Whitcomb, JM Hellmann, NS Richman, DD AF Little, SJ Holte, S Routy, JP Daar, ES Markowitz, M Collier, AC Koup, RA Mellors, JW Connick, E Conway, B Kilby, M Wang, L Whitcomb, JM Hellmann, NS Richman, DD TI Antiretroviral-drug resistance among patients recently infected with HIV SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SOCIETY-USA PANEL; ZIDOVUDINE-RESISTANCE; REVERSE-TRANSCRIPTASE; VERTICAL TRANSMISSION; GENOTYPIC RESISTANCE; THERAPY; MUTATIONS; AIDS; SUSCEPTIBILITY AB Background Among persons in North America who are newly infected With the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent. Methods We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects. Results Over the five-year period, the frequency of transmitted drug resistance increased significantly. The frequency of high-level resistance to one or more drugs (indicated by a value of more than 10 for the ratio of the 50 percent inhibitory concentration [IC50] for the subject's virus to the IC50 for a drug-sensitive reference virus) increased from 3.4 percent during the period from 1995 to 1998 to 12.4 percent during the period from 1999 to 2000 (P = 0.002), and the frequency of multidrug resistance increased from 1.1 percent to 6.2 percent (P = 0.01). The frequency of resistance mutations detected by sequence analysis increased from 8.0 percent to 22.7 percent (P < 0.001), and the frequency of multidrug resistance detected by sequence analysis increased from 3.8 percent to 10.2 percent (P = 0.05). Among subjects infected with drug-resistant virus, the time to viral suppression after the initiation of antiretroviral therapy was longer (P = 0.05), and the time to virologic failure was shorter (P = 0.05). Conclusions The proportion of new HIV infections that involve drug-resistant virus is increasing in North America. Initial antiretroviral therapy is more likely to fail in patients who are infected with drug-resistant virus. Testing for resistance to drugs before therapy begins is now indicated even for recently infected patients. C1 Univ Calif San Diego, Antiviral Res Ctr, Dept Med, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. Univ Washington, Dept Med, Seattle, WA USA. McGill Univ, Dept Med, Ctr Hlth, Montreal, PQ, Canada. Univ Calif Los Angeles, Harbor Med Ctr, Dept Med, Torrance, CA 90509 USA. Aaron Diamond AIDS Res Ctr, New York, NY USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ British Columbia, Dept Pharmacol & Med Therapeut, Vancouver, BC V5Z 1M9, Canada. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Virologic, San Francisco, CA USA. Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. RP Little, SJ (reprint author), Univ Calif San Diego, Antiviral Res Ctr, Dept Med, 150 W Washington St,Ste 100, San Diego, CA 92103 USA. FU NCRR NIH HHS [M01-RR0002, M01-RR00102, M01-RR00425]; NIAID NIH HHS [AI 467376-03, AI 27670, AI 29164, AI 36214, AI 38858, AI 41532, AI 41535, AI 41536, AI 43271-01, AI 43638, AI 47033] NR 50 TC 831 Z9 880 U1 4 U2 38 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 AUG 8 PY 2002 VL 347 IS 6 BP 385 EP 394 DI 10.1056/NEJMoa013552 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 587YR UT WOS:000177672400002 PM 12167680 ER PT J AU Herbrecht, R Denning, DW Patterson, TF Bennett, JE Greene, RE Oestmann, JW Kern, WV Marr, KA Ribaud, P Lortholary, O Sylvester, R Rubin, RH Wingard, JR Stark, P Durand, C Caillot, D Thiel, E Chandrasekar, PH Hodges, MR Schlamm, HT Troke, PF de Pauw, B AF Herbrecht, R Denning, DW Patterson, TF Bennett, JE Greene, RE Oestmann, JW Kern, WV Marr, KA Ribaud, P Lortholary, O Sylvester, R Rubin, RH Wingard, JR Stark, P Durand, C Caillot, D Thiel, E Chandrasekar, PH Hodges, MR Schlamm, HT Troke, PF de Pauw, B CA Invasive Fungal Infect Grp Europea TI Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TRIAL AB Background Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. Methods In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. Results A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients). Conclusions In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B. C1 Hop Hautepierre, Dept Hematol & Oncol, F-67098 Strasbourg, France. Univ Manchester, Manchester, Lancs, England. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. NIAID, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Campus Virchow Klinikum, Charite, Berlin, Germany. Univ Freiberg, Med Klin, Freiburg, Germany. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Inst Pasteur, Paris, France. European Org Res Treatment Canc, Brussels, Belgium. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Florida, Coll Med, Gainesville, FL USA. Univ Calif San Diego, San Diego, CA 92103 USA. Hop Bocage, Dijon, France. Univ Hosp Benjamin Franklin, Berlin, Germany. Wayne State Univ, Sch Med, Detroit, MI USA. Pfizer, Global Res & Dev, New York, NY USA. Pfizer, Global Res & Dev, Sandwich, Kent, England. Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. Hop St Louis, Paris, France. RP Herbrecht, R (reprint author), Hop Hautepierre, Dept Hematol & Oncol, Ave Moliere, F-67098 Strasbourg, France. RI Herbrecht, Raoul/D-3471-2013; OI Herbrecht, Raoul/0000-0002-9381-4876; Denning, David/0000-0001-5626-2251 NR 13 TC 1775 Z9 1901 U1 7 U2 43 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 8 PY 2002 VL 347 IS 6 BP 408 EP 415 DI 10.1056/NEJMoa020191 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 587YR UT WOS:000177672400005 PM 12167683 ER PT J AU Bleesing, JJH Fleisher, RA AF Bleesing, JJH Fleisher, RA TI Immune thrombocytopenic purpura SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; MUTATIONS; APOPTOSIS C1 Arkansas Childrens Hosp, Little Rock, AR 72202 USA. NIH, Bethesda, MD 20892 USA. RP Bleesing, JJH (reprint author), Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA. NR 3 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 AUG 8 PY 2002 VL 347 IS 6 BP 449 EP 450 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 587YR UT WOS:000177672400026 PM 12168644 ER PT J AU Tang, Y Katuri, V Iqbal, S Narayan, T Wang, ZL Lu, RS Mishra, L Mishra, B AF Tang, Y Katuri, V Iqbal, S Narayan, T Wang, ZL Lu, RS Mishra, L Mishra, B TI ELF a beta-spectrin is a neuronal precursor cell marker in developing mammalian brain; structure and organization of the elf/beta-G spectrin gene SO ONCOGENE LA English DT Article DE spectrin; ankyrin; cytoskeleton; neuronal stem cells; gene structure ID CENTRAL-NERVOUS-SYSTEM; MEMBRANE SKELETON; EPITHELIAL-CELLS; MESSENGER-RNA; ERYTHROCYTE SPECTRIN; MOLECULAR-CLONING; LIVER DEVELOPMENT; NEURAL CELLS; IN-VITRO; IDENTIFICATION AB Spectrins play a pivotal role in axonal transport, neurite extension, the organization of synaptic vesicles, as well as for protein sorting in the Golgi apparatus and cell membrane. Among spectrins there is great variability in sequence composition, tissue distribution, and function, with two known genes encoding the alpha-chain, and at least five encoding the beta-chain. It remains unclear as to whether novel beta-spectrins such as elf1-4 are distinct genes or alpha-G-spectrin isoforms. The role for ELF in the developing nervous system has not been identified to date. In this study we demonstrate the genomic structure of elf-3, as well as the expression of ELF in the developing mouse brain using a peptide specific antibody against its distinctive amino-terminal end. Full genomic structural analyses reveal that elf-3 is composed of 31 exons spanning similar to67 kb, and confirm that elf and mouse brain beta-G-spectrin share multiple exons, with a complex form of exon/intron usage. In embryonic stages, E9-12, anti-ELF localized to the primary brain vesicular cells that also labeled strongly with anti-nestin but not anti-vimentin. At E12-14, anti-ELF localized to axonal sprouts in the developing neuroblasts of cortex and purkinje cell layer of the cerebellum, as well as in cell bodies in the diencephalon and metencephalon. Double labeling identified significant co-localization of anti-ELF, nestin and dystrophin in sub ventricular zone cells and in stellate-like cells of the developing forebrain. These studies define clearly the expression of ELF, a new isoform of beta-G-spectrin in the developing brain. Based on its expression pattern, ELF may have a role in neural stem cell development and is a marker of axonal sprouting in mid stages of embryonic development. C1 Temple Univ, Lab Neural GI Dev, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. DVAMC, Lab Dev Mol Biol, Washington, DC 20422 USA. Temple Univ, Sch Med, Philadelphia, PA 19122 USA. Childrens Hosp, Philadelphia, PA 19104 USA. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC USA. RP Temple Univ, Lab Neural GI Dev, Fels Inst Canc Res & Mol Biol, 3307 N Broad St, Philadelphia, PA 19140 USA. EM lopamishra@yahoo.com FU NIDDK NIH HHS [1R01 DK 58637, 1R01 DK56111, 1R03 DK53861] NR 85 TC 15 Z9 16 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD AUG 8 PY 2002 VL 21 IS 34 BP 5255 EP 5267 DI 10.1038/sj.onc.1205548 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 579TL UT WOS:000177193900007 PM 12149647 ER PT J AU Choi, Y Zhang, J Murga, C Yu, H Koller, E Monia, BP Gutkind, JS Li, WQ AF Choi, Y Zhang, J Murga, C Yu, H Koller, E Monia, BP Gutkind, JS Li, WQ TI PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells SO ONCOGENE LA English DT Article DE myeloma; PTEN; SHIP; signal transduction ID PROTEIN-KINASE-B; INOSITOL PHOSPHATASE SHIP; POLYPHOSPHATE 5-PHOSPHATASE SHIP; FORKHEAD TRANSCRIPTION FACTOR; MULTIPLE-MYELOMA; PHOSPHOINOSITIDE 3-KINASE; TUMOR SUPPRESSION; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE; NEGATIVE REGULATION; GLIOBLASTOMA CELLS AB Expression of PTEN tumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3' kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and Delta47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5' phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. RP Li, WQ (reprint author), Georgetown Univ, Med Ctr, Lombardi Canc Ctr, E407,3970 Reservoir Rd NW,New Res Bldg, Washington, DC 20007 USA. RI Gutkind, J. Silvio/A-1053-2009; Murga, Cristina/E-1965-2014 OI Murga, Cristina/0000-0002-8964-4077 NR 68 TC 69 Z9 73 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 8 PY 2002 VL 21 IS 34 BP 5289 EP 5300 DI 10.1038/sj.onc.1205650 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 579TL UT WOS:000177193900010 PM 12149650 ER PT J AU Borio, L AF Borio, L TI Modes of transmission of hemorrhagic fever - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Ctr Civilian Biodef Strategies, Baltimore, MD 21218 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Johns Hopkins Ctr Civilian Biodef Strategies, Baltimore, MD 21218 USA. RP Borio, L (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Ctr Civilian Biodef Strategies, Baltimore, MD 21218 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 AUG 7 PY 2002 VL 288 IS 5 BP 571 EP 571 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 581FJ UT WOS:000177280200007 ER PT J AU Gardin, JM Brunner, D Schreiner, PJ Xie, XY Reid, CL Ruth, K Bild, DE Gidding, SS AF Gardin, JM Brunner, D Schreiner, PJ Xie, XY Reid, CL Ruth, K Bild, DE Gidding, SS TI Demographics and correlates of five-year change in echocardiographic left ventricular mass in young black and white adult men and women: The Coronary Artery Risk Development in Young Adults (CARDIA) study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; SERIAL CHANGES; HEART-DISEASE; BODY-MASS; HYPERTROPHY; CHILDREN; GEOMETRY; REGRESSION; TWIN AB OBJECTIVES The goal of this study was to determine the presence and correlates of change (A) in left ventricular (LV) mass by echocardiography in young adults. BACKGROUND Left ventricular mass is known to be a powerful independent predictor for cardiovascular disease events in adults. However, little is known about A in LV mass over time in young adults. METHODS Coronary Artery Risk Development in Young Adults (CARDIA) is a multicenter, longitudinal, population-based study of black and white men and women who were ages 23 to 35 at the time of their initial two-dimensionally directed M-mode echocardiography exam (year 5); half the cohort had a repeat echocardiography exam five years later (year 10). Data were analyzed from 1,189 participants who had paired echocardiography studies. To minimize reader variability, blinded measurements on initial and repeat echocardiography were performed nearly contemporaneously by the same reader. RESULTS In multilinear regression analyses, significant (p < 0.05) predictors of year 10 two-dimensional guided M-mode LV mass included initial LV mass, initial body mass index (BMI) and change in BMI for all race/gender subgroups. Initial systolic blood pressure (SBP) was a significant predictor of year 10 LV mass in white men and black women; change in SBP was significant in black women with a trend towards significance in white women. Left ventricular mass remained constant in all race/gender subgroups, except black women, where it increased (by 5.9 g [mean]). Black women also had the largest increases in BMI and SBP. In black women, a five-year weight gain of 20 pounds and a 15-mm Hg increase in SBP would be expected to be associated with a 9% to 12% increase in LV mass. CONCLUSIONS Particularly in black women, weight and blood pressure control may be important community health and treatment goals to prevent LV hypertrophy. (C) 2002 by the American College of Cardiology Foundation. C1 Univ Calif Irvine, Dept Med, Div Cardiol, Irvine, CA 92717 USA. Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92717 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. AI PuPont Hosp Children, Nemours Cardiac Ctr, Wilmington, DE USA. RP Gardin, JM (reprint author), St John Hosp & Med Ctr, Div Cardiol, PBII, 22201 Moross Rd,Suite 470, Detroit, MI 48236 USA. FU NHLBI NIH HHS [N01-HC 48047, N01-HC 48050, N01-HC 48049, N01-HC 95095, N01-HC 95100, N01-HC 48048] NR 35 TC 39 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 7 PY 2002 VL 40 IS 3 BP 529 EP 535 AR PII S0735-1097(02)01973-3 DI 10.1016/S0735-1097(02)01973-3 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 579XY UT WOS:000177205200022 PM 12142122 ER PT J AU Liotta, LA AF Liotta, LA TI Stromal therapy: The next step in ovarian cancer treatment SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ANGIOGENESIS; CARCINOMA C1 NCI, Canc Res Ctr, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, Canc Res Ctr, Pathol Lab, NIH, Bldg 10,Rm 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 23 Z9 24 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 7 PY 2002 VL 94 IS 15 BP 1113 EP 1114 PG 2 WC Oncology SC Oncology GA 580JH UT WOS:000177231100001 PM 12165628 ER PT J AU Anderson, WF Guyton, KZ Hiatt, RA Vernon, SW Levin, B Hawk, E AF Anderson, WF Guyton, KZ Hiatt, RA Vernon, SW Levin, B Hawk, E TI Colorectal cancer screening for persons at average risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID FECAL-OCCULT-BLOOD; CONTROLLED TRIAL; VIRTUAL COLONOSCOPY; GASTROINTESTINAL ENDOSCOPY; OBJECTIVE EVALUATION; ASYMPTOMATIC ADULTS; LARGE BOWEL; FOLLOW-UP; MORTALITY; SIGMOIDOSCOPY C1 NCI, Div Canc Prevent, Gastrointestinal & Other Canc Res Grp, EPN, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. CCS Associates, Mt View, CA USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Anderson, WF (reprint author), NCI, Div Canc Prevent, Gastrointestinal & Other Canc Res Grp, EPN, Room 2144,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 92 TC 52 Z9 56 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 7 PY 2002 VL 94 IS 15 BP 1126 EP 1133 PG 8 WC Oncology SC Oncology GA 580JH UT WOS:000177231100009 PM 12165637 ER PT J AU Barlow, WE Lehman, CD Zheng, YY Ballard-Barbash, R Yankaskas, BC Cutter, GR Carney, PA Geller, BM Rosenberg, R Kerlikowske, K Weaver, DL Taplin, SH AF Barlow, WE Lehman, CD Zheng, YY Ballard-Barbash, R Yankaskas, BC Cutter, GR Carney, PA Geller, BM Rosenberg, R Kerlikowske, K Weaver, DL Taplin, SH TI Performance of diagnostic mammography for women with signs or symptoms of breast cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; SCREEN-DETECTED CANCERS; NEW-MEXICO; SENSITIVITY; DENSITY; SPECIFICITY; OUTCOMES; AGE; US; METHODOLOGY AB Background: The performance of diagnostic mammography for women with signs or symptoms of breast cancer has not been well studied. We evaluated whether age, breast density, self-reported breast lump, and previous mammography influence the performance of diagnostic mammography. Methods: From January 1996 through March 1998, prospective diagnostic mammography data from women aged 25-89 years with no previous breast cancer were linked to cancer outcomes data in six mammography registries participating in the Breast Cancer Surveillance Consortium. We used the final mammographic assessment at the end of the imaging work-up to determine abnormal mammographic examination rate, positive predictive value (PPV), sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve. We used age, breast density, prior mammogram, and self-reported breast lump jointly as predictors of performance. All statistical tests were two-sided. Results: Of 41427 diagnostic mammograms, 6279 (15.2%) were judged abnormal. The overall PPV was 21.8%, sensitivity was 85.8%, and specificity was 87.7%. Multivariate analysis showed that sensitivity and specificity generally declined as breast density increased (P = .007 and P < .001, respectively), that previous mammography decreased sensitivity (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.36 to 0.74; P < .001) but increased specificity (OR = 1.43, 95%, CI = 1.31 to 1.57; P < .001), and that a self-reported breast lump increased sensitivity (OR = 1.64, 95% CI = 1.13 to 2.38; P = .013) but decreased specificity (OR = 0.54,95% CI = 0.49 to 0.59; P < .001). ROC analysis showed that higher breast density and previous mammography were negatively related to accuracy (P < .001 for both). Conclusions: Diagnostic mammography in women with signs or symptoms of breast cancer shows higher sensitivity and lower specificity than screening mammography does. Higher breast density and previous mammographic examination appear to impair performance. [J Natl Cancer Inst 2002;94:1151-9]. C1 Univ Washington, Ctr Hlth Studies, Dept Biostat, Grp Hlth Cooperat, Seattle, WA 98101 USA. Univ Washington, Seattle Canc Care Alliance, Dept Radiol, Seattle, WA 98101 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Univ Nevada, Ctr Res Design & Stat Methods, Reno, NV 89557 USA. Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Dept Community & Family Med, Dartmouth Med Sch, Lebanon, NH 03766 USA. Univ Vermont, Coll Med, Burlington, VT USA. Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Washington, Dept Family Med, Seattle, WA 98195 USA. RP Barlow, WE (reprint author), Univ Washington, Ctr Hlth Studies, Dept Biostat, Grp Hlth Cooperat, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. FU NCI NIH HHS [UO1CA86076, UO1CA63731, UO1CA63740, UO1CA86082, UO1CA63736, UO1CA69976, UO1CA70013, UO1CA70040] NR 34 TC 73 Z9 76 U1 3 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 7 PY 2002 VL 94 IS 15 BP 1151 EP 1159 PG 9 WC Oncology SC Oncology GA 580JH UT WOS:000177231100012 PM 12165640 ER PT J AU Wright, AC Ahmed, H Gauthier, JD Silva, AM Vasta, GR AF Wright, AC Ahmed, H Gauthier, JD Silva, AM Vasta, GR TI CDNA cloning and characterization of two iron superoxide dismutases from the oyster parasite Perkinsus marinus SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE superoxide dismutase; cDNA cloning; Perkinsus marinas ID CRASSOSTREA-VIRGINICA HEMOCYTES; TOXOPLASMA-GONDII; ESCHERICHIA-COLI; HYDROGEN-PEROXIDE; LEISHMANIA; CELLS; SUSCEPTIBILITY; MACROPHAGES; SURVIVAL; ENZYME C1 Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, Baltimore, MD 21202 USA. NCI, Struct Biochem Program, SAIC, Frederick, MD 21702 USA. RP Vasta, GR (reprint author), Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, 701 E Pratt St, Baltimore, MD 21202 USA. NR 35 TC 32 Z9 32 U1 0 U2 4 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 AUG 7 PY 2002 VL 123 IS 1 BP 73 EP 77 AR PII S0166-6851(02)00090-7 DI 10.1016/S0166-6851(02)00090-7 PG 5 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 592HG UT WOS:000177930700008 PM 12165391 ER PT J AU Molldrem, JJ Leifer, E Bahceci, E Saunthararajah, Y Rivera, M Dunbar, C Liu, J Nakamura, R Young, NS Barrett, AJ AF Molldrem, JJ Leifer, E Bahceci, E Saunthararajah, Y Rivera, M Dunbar, C Liu, J Nakamura, R Young, NS Barrett, AJ TI Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MEDIATED INHIBITION; APLASTIC-ANEMIA; PATHOPHYSIOLOGY; THERAPY AB Background: Almost half of the deaths that result from myelodysplastic syndromes are due to cytopenia associated with bone marrow failure. Treatment is mostly supportive care. Objective: To determine whether treatment with antithymocyte globulin improves cytopenia and reverses dependence on red blood cell transfusions in patients with myelodysplastic syndromes. Design: Single-treatment, prospective study. Setting: Tertiary referral center. Patients: 61 patients with myelodysplastic syndromes. Intervention: Antithymocyte globulin, 40 mg/kg of body weight, given daily for 4 days. Measurements: Evaluation of bone marrow, blood counts, transfusions, progression, and survival for a median of 30 months (range, 1 to 88 months). Results: Within 8 months of treatment, 21 of 61 patients (34%) no longer required red blood cell transfusions. This independence from transfusions was maintained in 17 responders (81%) for a median of 36 months (range, 3 to 72 months). Ten of 21 patients (47.5%) with severe thrombocytopenia had sustained platelet count increases, and 6 of 11 patients (55%) with severe neutropenia had sustained neutrophil counts of greater than 1 x 109 cells/L. Characteristics favorable for response were younger patient age (P = 0.005) and lower platelet counts (P = 0.038). One of the 21 responders (5%) and 22 of the 40 nonresponders (55%) died before the end of the study (P = 0.008). One of the 21 responders (5%) and 13 of the 40 nonresponders (33%) had disease progression (P = 0.086). Conclusions: Although this study was a nonrandomized, single-treatment study, 34% of patients treated with antithymocyte globulin became transfusion independent. Response was associated with a statistically significant longer survival and an almost significant decreased time to disease progression, Treatment with antithymocyte globulin did not seem to be detrimental because historical overall median survival times were similar to those of nonresponders. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Molldrem, JJ (reprint author), Univ Texas, MD Anderson Canc Ctr, Transplantat Immunol Sect, Dept Blood & Marrow Transplantat, 1515 Holcombe Blvd,Box 448, Houston, TX 77030 USA. FU NCI NIH HHS [CA85843] NR 19 TC 143 Z9 148 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 6 PY 2002 VL 137 IS 3 BP 156 EP 163 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 580XP UT WOS:000177262300002 PM 12160363 ER PT J AU Muller, M Yong, M Peng, XH Petre, B Arora, S Ambudkar, SV AF Muller, M Yong, M Peng, XH Petre, B Arora, S Ambudkar, SV TI Evidence for the role of glycosylation in accessibility of the extracellular domains of human MRP1 (ABCC1) SO BIOCHEMISTRY LA English DT Article ID HUMAN P-GLYCOPROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; RESISTANCE-ASSOCIATED PROTEIN; MULTIDRUG-RESISTANCE; FUNCTIONAL EXPRESSION; MEMBRANE TOPOLOGY; CYSTIC-FIBROSIS; DIFFERENTIAL IMMUNOREACTIVITY; TRANSPORTER SUPERFAMILY; MONOCLONAL-ANTIBODIES AB To enable cell surface localization of the human multidrug resistance protein (MRP1, ABCC1) and to assess the role of the extracellular domains of this transporter, the FLAG epitope tag was introduced into different extracellular loops of the three membrane-spanning domains (MSDs) of the transporter. We constructed and expressed various partially and fully glycosylation-deficient, FLAG-tagged MRPI proteins in a Vaccinia virus-based transient expression system, and the cell surface expression level of MRPI on intact cells was followed by flow cytometry, using the FLAG tag specific monoclonal antibody M2. We also expressed the wild-type MRP1 protein and some of the FLAG-tagged mutants in stably transfected HEK293 cells, and followed the cell surface expression and the transport function of MRPI both by monitoring the efflux of fluorescent substrate and by their ability to confer resistance to HEK293 transfectants to anticancer agents such as daunorubicin and etoposide. When we inserted the FLAG epitope in extracellular loops of the MSD1 or MSD3, the tag was accessible upon removal of N-glycosylation sites (N --> Q at positions 17, 23, and 1006, respectively), whereas the FLAG epitope placed in the MSD2 was not accessible even after removal of all three N-glycosylation sites, indicating that MSD2 region is deeply buried in the plasma membrane. However, all FLAG tagged MRP1 mutants were expressed at the cell surface to the same extent as the wild-type protein and also exhibited normal transport function. Our results demonstrate that the accessibility of the external FLAG epitope is strongly dependent on the position of the tag and the glycosylation state of the different FLAG-tagged MRP1s, and the conformation of extracellular loops in MSD1 and MDS3 does not appear to contribute to the functional status of MRP1. C1 NCI, Cell Biol Lab, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Cell Biol Lab, NIH, Bldg 37,Room 1B-22,37 Convent Dr MSC 4254, Bethesda, MD 20892 USA. RI Ambudkar, Suresh/B-5964-2008 NR 38 TC 42 Z9 42 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 6 PY 2002 VL 41 IS 31 BP 10123 EP 10132 DI 10.1021/bi026075s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 580GZ UT WOS:000177228000040 PM 12146977 ER PT J AU Halcox, JPJ Schenke, WH Zalos, G Mincemoyer, R Prasad, A Waclawiw, MA Nour, KRA Quyyumi, AA AF Halcox, JPJ Schenke, WH Zalos, G Mincemoyer, R Prasad, A Waclawiw, MA Nour, KRA Quyyumi, AA TI Prognostic value of coronary vascular endothelial dysfunction SO CIRCULATION LA English DT Article DE atherosclerosis; coronary disease; endothelium; prognosis; infarction ID PLASMINOGEN-ACTIVATOR RELEASE; NITRIC-OXIDE ACTIVITY; MATRIX METALLOPROTEINASES; ATHEROSCLEROSIS; CIRCULATION; EXPRESSION; DISEASES; HUMANS; IMPACT AB Background-Whether patients at increased risk can be identified from a relatively low-risk population by coronary vascular function testing remains unknown. We investigated the relationship between coronary endothelial function and the occurrence of acute unpredictable cardiovascular events (cardiovascular death, myocardial infarction, stroke, and unstable angina) in patients with and without coronary atherosclerosis (CAD). Methods and Results-We measured the change in coronary vascular resistance (DeltaCVR) and epicardial diameter with intracoronary acetylcholine (ACh, 15 mug/min) to test endothelium-dependent function and sodium nitroprusside (20 mug/min) and adenosine (2.2 mg/min) to test endothelium-independent vascular function in 308 patients undergoing cardiac catheterization (132 with and 176 without CAD). Patients underwent clinical follow-up for a mean of 46 +/- 3 months. Acute vascular events occurred in 35 patients. After multivariate analysis that included CAD and conventional risk factors for atherosclerosis, DeltaCVR with ACh (P=0.02) and epicardial constriction with ACh (P=0.003), together with increasing age, CAD, and body mass index, were independent predictors of adverse events. Thus, patients in the tertile with the best microvascular responses with ACh and those with epicardial dilation with ACh had improved survival by Kaplan-Meier analyses in the total population, as did those in the subset without CAD. Similar improvement in survival was also observed when all adverse events, including revascularization, were considered. Endothelium-independent responses were not predictive of outcome. Conclusions-Epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without CAD, providing both functional and prognostic information that complements angiographic and risk factor assessment. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), Emory Univ Hosp, Suite F606,1364 Clifton Rd NE, Atlanta, GA 30322 USA. OI Halcox, Julian/0000-0001-6926-2947 NR 22 TC 817 Z9 860 U1 4 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 6 PY 2002 VL 106 IS 6 BP 653 EP 658 DI 10.1161/01.CIR.0000025404.78001.D8 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 583HP UT WOS:000177401700006 PM 12163423 ER PT J AU Roux, AVD Chambless, L Markin, SS Arnett, D Eigenbrodt, M Nieto, FJ Szklo, M Sorlie, P AF Roux, AVD Chambless, L Markin, SS Arnett, D Eigenbrodt, M Nieto, FJ Szklo, M Sorlie, P TI Socioeconomic disadvantage associated and change in blood pressure with aging SO CIRCULATION LA English DT Article DE blood pressure; hypertension; aging; risk factors ID CORONARY HEART-DISEASE; RISK-FACTORS; HYPERTENSION; EDUCATION; COHORT; POPULATION; INTERSALT; ADULTS; AGE; MEN AB Background-Few studies have examined how the longitudinal change in blood pressure associated with aging differs across social groups within industrialized countries. Methods and Results-Data from the Atherosclerosis Risk In Communities Study were used to investigate differences in the incidence of hypertension and in aging-related changes in blood pressure by neighborhood and individual socioeconomic factors over a 9-year follow-up. Disadvantage in multiple socioeconomic dimensions was associated with the greatest risk of developing hypertension (age- and sex-adjusted hazard ratio [HR] and 95% CI: HR 1.95, 95% CI 1.38 to 2.75 in whites and HR 1.43, 95% CI 0.96 to 2.13 in blacks). Aging-related increases in systolic blood pressure were inversely associated with socioeconomic position in whites (mean [SEM] 5-year increase in systolic blood pressure 7 [0.7] mm Hg in the most disadvantaged category and 5.4 [0:4] mm Hg in the most advantaged category). In whites, low socioeconomic position was also associated with more rapid declines in diastolic blood pressure after 50 years of age. Socioeconomic differences in hypertension incidence and changes in systolic blood pressure were reduced after adjustment for baseline blood pressure. Conclusion-The change in blood pressure associated with aging varies by social groups within the United States. C1 Columbia Univ Coll Phys & Surg, Div Gen Med, New York, NY 10032 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Roux, AVD (reprint author), Columbia Univ Coll Phys & Surg, Div Gen Med, 622 W 168th St,PH9 E,Rm 105, New York, NY 10032 USA. NR 27 TC 36 Z9 36 U1 1 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 AUG 6 PY 2002 VL 106 IS 6 BP 703 EP 710 DI 10.1161/01.CIR.0000025402.84600.CD PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 583HP UT WOS:000177401700014 ER PT J AU Gustafsson, AB Sayen, MR Williams, SD Crow, MT Gottlieb, RA AF Gustafsson, AB Sayen, MR Williams, SD Crow, MT Gottlieb, RA TI TAT protein transduction into isolated perfused hearts - TAT-apoptosis repressor with caspase recruitment domain is cardioprotective SO CIRCULATION LA English DT Article DE proteins; oxidative stress; apoptosis; ischemia ID HUMAN IMMUNODEFICIENCY VIRUS; MAMMALIAN-CELLS; ARC; DELIVERY AB Background-Linkage of the 11-amino-acid transduction domain of HIV TAT to a heterologous protein allows the protein to be transduced readily into cells. Methods and Results-In this study, we inserted the apoptosis repressor with caspase recruitment domain (ARC) or beta-galactosidase (beta-gal) cDNA into the pTAT-hemagglutinin bacterial expression vector to produce genetic in-frame TAT-ARC or TAT-beta-gal fusion proteins for use in cell culture and in Langendorff perfusion of adult rat hearts. TAT-beta-gal and TAT-ARC were conjugated with Texas Red and could be detected in >95% of cells. TAT-ARC was able to protect H9c2 cells against cell death mediated by hydrogen peroxide, as measured by protection against the loss of mitochondrial membrane potential and preservation of nuclear morphology. Isolated adult hearts were perfused with recombinant TAT-beta-gal or TAT-ARC (20 nmol/L) for 15 minutes and then subjected to 30 minutes of global no-flow ischemia, followed by 2 hours of reperfusion. Protein transduction was assessed by Western blotting of cell lysates and cytosolic and mitochondrial fractions and by fluorescence microscopy of Texas Red-conjugated TAT proteins. TAT-beta-gal and TAT-ARC readily transduced into perfused hearts and were homogeneously distributed. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining, and creatine kinase release was measured. Transduction of TAT-ARC was cardioprotective when administered before global ischemia and reperfusion. Conclusions-Our results demonstrate that TAT-linked fusion protein transduction into the myocardium is feasible and that transduction of TAT-ARC is protective in cell culture and in the perfused heart. C1 Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Scripps Res Inst, Dept Mol & Expt Med, MEM 220,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM robbieg@scripps.edu FU NHLBI NIH HHS [HL-60590]; NIA NIH HHS [AG-13501]; NIDDK NIH HHS [DK-07022] NR 15 TC 93 Z9 97 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 6 PY 2002 VL 106 IS 6 BP 735 EP 739 DI 10.1161/01.CIR.0000023943.50821.F7 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 583HP UT WOS:000177401700019 PM 12163436 ER PT J AU Kamakaka, RT AF Kamakaka, RT TI Chromatin: A connection between loops and barriers? SO CURRENT BIOLOGY LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; YEAST TELOMERES; COMPLEXES AB A genetic screen for proteins that can block the spread of silenced heterochromatin has identified components of the nuclear pores with potential barrier activity. These results suggest that formation of loops of chromatin anchored to the pore could be one mechanism of barrier function. C1 NICHD, NIH, Unit Chromatin & Transcript, Bethesda, MD 20892 USA. RP Kamakaka, RT (reprint author), NICHD, NIH, Unit Chromatin & Transcript, 18T,Rm 106,18 Lib Dr, Bethesda, MD 20892 USA. NR 20 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 6 PY 2002 VL 12 IS 15 BP R535 EP R537 AR PII S0960-9822(02)01032-1 DI 10.1016/S0960-9822(02)01032-1 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 582NM UT WOS:000177358100012 PM 12176379 ER PT J AU van Beek, JD Hess, S Vollrath, F Meier, BH AF van Beek, JD Hess, S Vollrath, F Meier, BH TI The molecular structure of spider dragline silk: Folding and orientation of the protein backbone SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; LOCAL-STRUCTURE; NMR; FIBERS; FIBROIN; MODEL; DISTRIBUTIONS; CORRELATE; SEQUENCE; CRYSTALS AB The design principles of spider dragline silk, nature's high-performance fiber, are still largely unknown, in particular for the noncrystalline glycine-rich domains, which form the bulk of the material. Here we apply two-dimensional solid-state NMR to determine the distribution of the backbone torsion angles (phi,psi) as well as the orientation of the polypeptide backbone toward the fiber at both the glycine and alanine residues. Instead of an "amorphous matrix," suggested earlier for the glycine-rich domains, these new data indicate that all domains in dragline silk have a preferred secondary structure and are strongly oriented, with the chains predominantly parallel to the fiber. As proposed previously, the alanine residues are predominantly found in a 0 sheet conformation. The glycine residues are partly incorporated into the p sheets and otherwise form helical structures with an approximate 3-fold symmetry. C1 Swiss Fed Inst Technol, CH-8093 Zurich, Switzerland. Aarhus Univ, Dept Zool, DK-8000 Aarhus C, Denmark. NIDDK, Struct Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. RP Meier, BH (reprint author), Swiss Fed Inst Technol, CH-8093 Zurich, Switzerland. RI Hess, Sonja/K-4842-2013; Meier, Beat/K-4066-2016 OI Hess, Sonja/0000-0002-5904-9816; Meier, Beat/0000-0002-9107-4464 NR 49 TC 281 Z9 287 U1 9 U2 77 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 AUG 6 PY 2002 VL 99 IS 16 BP 10266 EP 10271 DI 10.1073/pnas.152162299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200011 PM 12149440 ER PT J AU Szabo, I Chen, XH Xin, L Adler, MW Howard, OMZ Oppenheim, JJ Rogers, TJ AF Szabo, I Chen, XH Xin, L Adler, MW Howard, OMZ Oppenheim, JJ Rogers, TJ TI Heterologous desensitization of opioid receptors by chernokines inhibits chemotaxis and enhances the perception of pain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CXC-CHEMOKINE RECEPTOR-4; BLOOD MONONUCLEAR-CELLS; TUMOR-NECROSIS-FACTOR; LEUKOCYTE RECRUITMENT; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; GENE-EXPRESSION; HUMAN-MONOCYTES; RAT AB The chemokines use G protein-coupled receptors to regulate the migratory and proadhesive responses of leukocytes. Based on observations that G protein-coupled receptors undergo heterologous desensitization, we have examined the ability of chemokines to also influence the perception of pain by cross-desensitizing oploid G protein-coupled receptors function in vitro and in vivo. We find that the chemotactic activities of both mu- and delta-oploid receptors are desensitized following activation of the chemokine receptors CCR5, CCR2, CCR7, and CXCR4 but not of the CXCR1 or CXCR2 receptors. Furthermore, we also find that pretreatment with RAN-TES/CCL5, the ligand for CCR1, and CCR5 or SDF-1alpha/CXCL12, the ligand for CXCR4, followed by oploid administration into the periaqueductal gray matter of the brain results in an increased rat tail flick response to a painful stimulus. Because chemokine administration into the periaqueductal gray matter inhibits opioid-induced analgesia, we propose that the activation of proinflammatory chemokine receptors down-regulates the analgesic functions of oploid receptors, and this enhances the perception of pain at inflammatory sites. C1 Temple Univ, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Rogers, TJ (reprint author), Temple Univ, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NCI NIH HHS [R24 CA-88261, R24 CA088261]; NIDA NIH HHS [P30 DA-13429, DA-00376, DA-06650, DA-11130, DA-14230, P30 DA013429, R01 DA006650, R01 DA014230] NR 60 TC 131 Z9 135 U1 2 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10276 EP 10281 DI 10.1073/pnas.102327699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200013 PM 12130663 ER PT J AU Campos-Olivas, R Louis, JM Clerot, D Gronenborn, B Gronenborn, AM AF Campos-Olivas, R Louis, JM Clerot, D Gronenborn, B Gronenborn, AM TI The structure of a replication initiator unites diverse aspects of nucleic acid metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ROLLING-CIRCLE TRANSPOSONS; DNA-BINDING DOMAIN; GENE-A PROTEIN; REP PROTEIN; GEMINIVIRUS REPLICATION; CLEAVAGE; VIRUS; RNA; PLASMID; ORIGIN AB Rolling circle replication is a mechanism for copying single-stranded genomes by means of double-stranded intermediates. A multifunctional replication inititiator protein (Rep) is indispensable for the precise initiation and termination of this process. Despite the ubiquitous presence and fundamental importance of rolling circle replication elements, structural information on their respective replication initiators is still missing. Here we present the solution NMR structure of the catalytic domain of Rep, the initiator protein of tomato yellow leaf curl virus. It is composed of a central five-stranded anti-parallel beta-sheet, flanked by a small two-stranded beta-sheet, a beta-hairpin and two alpha-helices. Surprisingly, the structure reveals that the catalytic Rep domain is related to a large group of proteins that bind RNA or DNA. Identification of Rep as resembling the family of ribonucleoprotein/RNA-recognition motif fold proteins establishes a structure-based evolutionary link between RNA binding proteins, splicing factors, and replication initiators of prokaryotic and eukaryotic single-stranded DNA elements and mammalian DNA tumor viruses. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Ctr Nacl Invest Oncol, Struct & Computat Biol Program, Madrid 28029, Spain. CNRS, Inst Sci Vegetales, F-91198 Gif Sur Yvette, France. RP Gronenborn, AM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Campos-Olivas, Ramon/L-9173-2014; OI Campos-Olivas, Ramon/0000-0002-5743-2221; Gronenborn, Angela M/0000-0001-9072-3525 NR 44 TC 71 Z9 78 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10310 EP 10315 DI 10.1073/pnas.152342699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200019 PM 12130667 ER PT J AU Chattopadhyay, MK Tabor, CW Tabor, H AF Chattopadhyay, MK Tabor, CW Tabor, H TI Absolute requirement of spermidine for growth and cell cycle progression of fission yeast (Schizosaccharomyces pombe) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CASEIN KINASE-II; SACCHAROMYCES-CEREVISIAE; S-PHASE; DNA; POLYAMINES; DECARBOXYLASE; CYTOKINESIS; GENES AB Schizosaccharomyces pombe cells that cannot synthesize spermidine or spermine because of a deletion-insertion in the gene coding for S-adenosylmethionine decarboxylase (Deltaspe2) have an absolute requirement for spermidine for growth. Flow cytometry studies show that in the absence of spermidine an overall delay of the cell cycle progression occurs with some accumulation of cells in the G, phase; as little as 10(-6) M spermidine is sufficient to maintain normal cell cycle distribution and normal growth. Morphologically some of the spermidine-deprived cells become spherical at an early stage with little evidence of cell division. On further incubation in the spermidine-deprived medium, growth occurs in most of the cells, not by cell division but rather by cell elongation, with an abnormal distribution of the actin cytoskeleton, DNA (4', 6-diamidino-2-phenylindole staining), and calcofluor-staining moieties. More prolonged incubation in the spermidine-deficient medium leads to profound morphological changes including nuclear degeneration. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 223, Bethesda, MD 20892 USA. NR 28 TC 30 Z9 31 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 AUG 6 PY 2002 VL 99 IS 16 BP 10330 EP 10334 DI 10.1073/pnas.162362899 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200023 PM 12149471 ER PT J AU Brower, CS Sato, S Tomomori-Sato, C Kamura, T Pause, A Stearman, R Klausner, RD Malik, S Lane, WS Sorokina, I Roeder, RG Conaway, JW Conaway, RC AF Brower, CS Sato, S Tomomori-Sato, C Kamura, T Pause, A Stearman, R Klausner, RD Malik, S Lane, WS Sorokina, I Roeder, RG Conaway, JW Conaway, RC TI Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; RNA-POLYMERASE-II; HIPPEL-LINDAU PROTEIN; SOCS-BOX MOTIF; TRANSCRIPTIONAL REGULATION; METAZOAN CELLS; COMPLEX; ACTIVATION; BINDING; YEAST AB The heterodimeric Elongin BC complex has been shown to interact in vitro and in cells with a conserved BC-box motif found in an increasing number of proteins including RNA polymerase II elongation factor Elongin A, suppressor of cytokine signaling (SOCS)box proteins, and the von Hippel-Lindau tumor suppressor protein. Recently, the Elongin BC complex was found to function as an adaptor that links these BC-box proteins to a module composed of Cullin family members Cul2 or Cul5 and RING-H2 finger protein Rbx1 to reconstitute a family of E3 ubiquitin ligases that activate ubiquitylation by the E2 ubiquitin-conjugating enzyme Ubc5. As part of our effort to understand the functions of Elongin BC-based ubiquitin ligases, we exploited a modified yeast two-hybrid screen to identify a mammalian BC-box protein similar in sequence to Saccharomyces cerevisiae Mediator subunit Med8p. In this report we demonstrate (i) that mammalian MED8 is a subunit of the mammalian Mediator complex and (it) that MED8 can assemble with Elongins B and C, Cul2, and Rbx1 to reconstitute a ubiquitin ligase. Taken together, our findings are consistent with the model that MED8 could function to recruit ubiquitin ligase activity directly to the RNA polymerase II transcriptional machinery. C1 Stowers Inst Med Res, Kansas City, MO 64110 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cell Biol, Fukuoka 812, Japan. Biomega Boehringer Ingelheim Res Inc, Laval, PQ H7S 2G5, Canada. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA. Harvard Univ, Harvard Microchem & Proteom Anal Facil, Cambridge, MA 02138 USA. Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA. RP Conaway, RC (reprint author), Stowers Inst Med Res, Kansas City, MO 64110 USA. OI Conaway, Joan/0000-0002-2786-0663 FU NIGMS NIH HHS [R37 GM41628, R37 GM041628] NR 36 TC 67 Z9 76 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10353 EP 10358 DI 10.1073/pnas.162424199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200027 PM 12149480 ER PT J AU Takeda, H Takami, M Oguni, T Tsuji, T Yoneda, K Sato, H Ihara, N Itoh, T Kata, SR Mishina, Y Womack, JE Moritomo, Y Sugimoto, Y Kunieda, T AF Takeda, H Takami, M Oguni, T Tsuji, T Yoneda, K Sato, H Ihara, N Itoh, T Kata, SR Mishina, Y Womack, JE Moritomo, Y Sugimoto, Y Kunieda, T TI Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; AUTOSOMAL SEX REVERSAL; SRY-RELATED GENE; METAPHYSEAL CHONDRODYSPLASIA; CAMPOMELIC DYSPLASIA; INDIAN HEDGEHOG; BONE-GROWTH; MUTATIONS; PROTEIN; MATRIX AB Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs. Previously, we mapped the locus responsible for the disease on the distal end of bovine chromosome 6. Here, we narrowed the critical region to approximate to2 cM by using linkage analysis, constructed a BAC and YAC contig covering this region, and identified a gene, LIMBIN (LBN), that possessed disease-specific mutations in the affected calves. One mutation was a single nucleotide substitution leading to an activation of a cryptic splicing donor site and the other was a one-base deletion resulting in a frameshift mutation. Strong expression of the Lbn gene was observed in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. These findings indicate that LBN is responsible for bovine chondrodysplastic dwarfism and has a critical role in a skeletal development. C1 Shirakawa Inst Anim Genet, Shirakawa, Fukushima 9618061, Japan. Okayama Univ, Grad Sch Nat Sci & Technol, Okayama 7008530, Japan. Kumamoto Prefectural Agr Res Ctr, Anim Husb Res Inst, Kumamoto 8611113, Japan. Okayama Univ, Grad Sch Med & Dent, Dept Oral Morphol, Okayama 7008525, Japan. Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Kyusyu Tokai Univ, Sch Agr, Kumamoto 8691404, Japan. RP Sugimoto, Y (reprint author), Shirakawa Inst Anim Genet, Shirakawa, Fukushima 9618061, Japan. NR 39 TC 42 Z9 47 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10549 EP 10554 DI 10.1073/pnas.152337899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200061 PM 12136126 ER PT J AU Fan, JS Yang, XL Wang, WG Wood, WH Becker, KG Gorospe, M AF Fan, JS Yang, XL Wang, WG Wood, WH Becker, KG Gorospe, M TI Global analysis of stress-regulated mRNA turnover by using cDNA arrays SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transcription; stress response; gene expression ID MESSENGER-RNA DEGRADATION; MAMMALIAN-CELLS; EXPRESSION; STABILITY; PROTEIN; HUR AB cDNA array technology has proven to be a powerful way to monitor global changes in gene expression patterns. Here, we present an approach that extends the current utility of cDNA arrays to allow the evaluation of the relative roles of transcription and mRNA turnover in governing gene expression on a global basis, compared with current individual gene-by-gene analyses. This method, which involves comparison of large-scale hybridization patterns generated with steady-state mRNA versus newly transcribed (nuclear run-on) RNA, was used to demonstrate the importance of mRNA turnover in regulating gene expression following several conditions of stress. C1 NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIA, DNA Array Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr,Box 12, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 19 TC 162 Z9 167 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10611 EP 10616 DI 10.1073/pnas.162212399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200072 PM 12149460 ER PT J AU Guo, LY Hu-Li, J Zhu, JF Watson, CJ Difilippantonio, MJ Pannetier, C Paul, WE AF Guo, LY Hu-Li, J Zhu, JF Watson, CJ Difilippantonio, MJ Pannetier, C Paul, WE TI In TH2 cells the Il4 gene has a series of accessibility states associated with distinctive probabilities of IL-4 production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELLS; COORDINATE REGULATOR; EXPRESSION; DIFFERENTIATION; ALLELES; INTERLEUKIN-4; ENHANCER; RECEPTOR AB TH2 clones may produce very variable amounts of IL-4. Among six TH2 clones prepared from homozygous or heterozygous mice in which Gfp replaced the first exon of ll4, a range of patterns of CpG methylation in the ll4/ll3 locus was observed correlating with the degree of expression of IL-4 or green fluorescence protein. Patterns of histone acetylation also showed differences between "high" and "low" TH2 clones. These results indicate that in TH2 cells the ll4 locus may display variable patterns of chromatin accessibility associated with distinct degrees of IL-4 expression. This finding suggests a regulation of IL-4 expression keyed to the function of this cytokine in cell/cell interactions and in the regulation of threshold responses. C1 NIA, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIA, Immunol Lab, NIH, Bethesda, MD 20892 USA. RI Zhu, Jinfang/B-7574-2012 FU Intramural NIH HHS [Z99 CA999999] NR 18 TC 60 Z9 62 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 AUG 6 PY 2002 VL 99 IS 16 BP 10623 EP 10628 DI 10.1073/pnas.162360199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200074 PM 12149469 ER PT J AU Peters, J Fowler, E Gatton, M Chen, NH Saul, A Cheng, Q AF Peters, J Fowler, E Gatton, M Chen, NH Saul, A Cheng, Q TI High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHONDROITIN SULFATE-A; RATES IN-VIVO; ANTIGENIC VARIATION; MALARIA; ERYTHROCYTES; ADHESION; SURFACE; CYTOADHERENCE; TRANSCRIPTION; PHENOTYPES AB Plasmodium falciparum, erythrocyte membrane protein 1 (PfEMP1) proteins expressed on the surface of A falciparum-infected erythrocytes undergo antigenic variation by switching the gene expressed within a repertoire of approximately 50 var genes per haploid genome. The switching of PfEMP1 plays an important role in the survival and pathogenesis of the parasite. To understand how a parasite switches its var gene expression in human infections, we investigated the composition and change of var gene transcripts during the acute phase of well-defined laboratory-induced A falciparum infections in naive human hosts. Multiple var transcripts, with the same dominant transcript, were identified in samples collected after three to four asexual-parasite cycles in two volunteers infected with cloned 3D7 P. falciparum via mosquito bites. A major change in composition and frequency of var gene transcripts was observed between the culture used to infect the mosquitoes and the parasites recovered from the infected volunteers. A further change was seen when infected blood from a mosquito-infected volunteer was either passaged to other volunteers or cultured in vitro. The diversity of var transcripts did not increase with time. The results suggest that the switch of var gene expression is reinitiated after mosquito transmission and that var genes may rapidly switch from the first gene expressed after liver stage, but subsequent switching occurs at a much lower rate. C1 Australia Army, Dept Parasitol, Malaria Inst, Enoggera, Qld 4051, Australia. Queensland Inst Med Res, Malaria Lab, Infect Dis Unit, Brisbane, Qld 4029, Australia. NIH, Malaria Vaccine Dev Unit, Rockville, MD 20852 USA. RP Cheng, Q (reprint author), Australia Army, Dept Parasitol, Malaria Inst, Gallipoli Barracks, Enoggera, Qld 4051, Australia. RI Saul, Allan/I-6968-2013; OI Saul, Allan/0000-0003-0665-4091; Gatton, Michelle/0000-0003-1188-609X FU NIAID NIH HHS [AI47500-02, R01 AI047500] NR 27 TC 72 Z9 73 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 AUG 6 PY 2002 VL 99 IS 16 BP 10689 EP 10694 DI 10.1073/pnas.162349899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200085 PM 12142467 ER PT J AU McClain, DA Lubas, WA Cooksey, RC Hazel, M Parker, GJ Love, DC Hanover, JA AF McClain, DA Lubas, WA Cooksey, RC Hazel, M Parker, GJ Love, DC Hanover, JA TI Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID O-LINKED GLCNAC; SKELETAL-MUSCLE CELLS; N-ACETYLGLUCOSAMINE; TRANSGENIC MICE; GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; CYTOSOLIC PROTEINS; IN-VIVO; TETRATRICOPEPTIDE REPEATS; DIABETES-MELLITUS; GLUCOSE-TRANSPORT AB Insulin resistance and beta cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDP-hexosamine biosynthetic pathway leading to "glucose toxicity." How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production. C1 Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. Vet Affairs Med Ctr, Salt Lake City, UT 84112 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. FU NIDDK NIH HHS [DK42356, Z01DK60200-01] NR 48 TC 201 Z9 210 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 AUG 6 PY 2002 VL 99 IS 16 BP 10695 EP 10699 DI 10.1073/pnas.152346899 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200086 PM 12136128 ER PT J AU Natarajan, V Lempicki, RA Sereti, I Badralmaa, Y Adelsberger, JW Metcalf, JA Prieto, DA Stevens, R Baseler, MW Kovacs, JA Lane, HC AF Natarajan, V Lempicki, RA Sereti, I Badralmaa, Y Adelsberger, JW Metcalf, JA Prieto, DA Stevens, R Baseler, MW Kovacs, JA Lane, HC TI Increased peripheral expansion of naive CD4+T cells in vivo after IL-2 treatment of patients with HIV infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RECENT THYMIC EMIGRANTS; T-CELLS; INDEPENDENT ACTIVATION; IMMUNE RECONSTITUTION; TELOMERE LENGTH; INTERLEUKIN-2; CD4(+); LYMPHOCYTES AB Intermittent interleukin-2 (IL-2) therapy has been shown to increase the number of CD4+ T cells, preferentially cells with a naive phenotype, in patients with HIV infection. For this report we investigated the mechanism underlying this expansion by studying the relative roles of peripheral expansion and thymic output. In a cohort of six patients receiving IL-2 over a period of 1 year, the mean number of naive CD4+ T cells increased from 139 to 387 cells per mul while levels of T cell receptor rearrangement excision circles (TRECs) declined from 47,946 to 26,510 copies per 106 naive T cells, thus making it unlikely that the CD4+ T cell count increases were secondary to increase in thymic output. To examine directly the impact of IL-2 on peripheral expansion, peripheral blood mature, naive CD4+ T cells were labeled ex vivo with 5-bromodeoxyuridine as well as stained directly for Ki67. These studies revealed a Mold increase in the percentage of 5-bromodeoxyuridine-positive cells and a 20-40-fold increase in Ki67 staining in the naive CD4+ T cell pool in the setting of IL-2 administration. This degree of increase in mature CD4+ T cell turnover induced by IL-2 does not compromise the future replicative potential of these cells, because longitudinal measurements of telomere length went from 6,981 to 7,153 bp after 1 year of IL-2 therapy. These data strongly suggest that much of the increase in CD4+ cells associated with IL-2 treatment is caused by peripheral expansion of existing naive CD4+ T cells rather than increased thymic output and that these increases occur without compromising the potential of these cells for further cell division. C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick Inc, Ft Detrick, MD 21702 USA. RP Lane, HC (reprint author), NIAID, Immunoregulat Lab, Bldg 10,Room 11S231,10 Ctr Dr,MSC 1894, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU NCI NIH HHS [N01-CO-56000] NR 30 TC 56 Z9 56 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10712 EP 10717 DI 10.1073/pnas.162352399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200089 PM 12149467 ER PT J AU Li, JF Protopopov, A Wang, FL Senchenko, V Petushkov, V Vorontsova, O Petrenko, L Zabarovska, V Muravenko, O Braga, E Kisselev, L Lerman, MI Kashuba, V Klein, G Ernberg, I Wahlestedt, C Zabarovsky, ER AF Li, JF Protopopov, A Wang, FL Senchenko, V Petushkov, V Vorontsova, O Petrenko, L Zabarovska, V Muravenko, O Braga, E Kisselev, L Lerman, MI Kashuba, V Klein, G Ernberg, I Wahlestedt, C Zabarovsky, ER TI Notl subtraction and Notl-specific microarrays to detect copy number and methylation changes in whole genomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPIGENETIC ALTERATIONS; LINKING CLONES; CLONING; CANCER; HYBRIDIZATION; LIBRARIES; MARKERS; PCR AB Methylation, deletions, and amplifications of cancer genes constitute important mechanisms in carcinogenesis. For genome-wide analysis of these changes, we propose the use of Nod clone microarrays and genomic subtraction, because Not! recognition sites are closely associated with CpG islands and genes. We show here that the CODE (Cloning Of DEleted sequences) genomic subtraction procedure can be adapted to Nod flanking sequences and to CpG islands. Because the sequence complexity of this procedure is greatly reduced, only two cycles of subtraction are required. A Nod-CODE procedure can be used to prepare Nod representations (NRs) containing 0.1-0.5% of the total DNA. The NRs contain, on average, 10-fold less repetitive sequences than the whole human genome and can be used as probes for hybridization to Nod microarrays. These microarrays, when probed with NRs, can simultaneously detect copy number changes and methylation. Nod microarrays offer a powerful tool with which to study carcinogenesis. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Karolinska Inst, Ctr Genomics & Bioinformat, S-17177 Stockholm, Sweden. NCI, Immunobiol Lab, Frederick, MD 21702 USA. State Res Ctr VNII Genet, Moscow 113545, Russia. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. Russian Acad Sci, Ctr Bioengn, Moscow 117984, Russia. RP Zabarovsky, ER (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. RI Wahlestedt, Claes/A-7039-2009; Zabarovsky, Eugene/A-6645-2010; Senchenko, Vera/C-8992-2014; Braga, Eleonora/P-5574-2016 OI Senchenko, Vera/0000-0002-3119-515X; NR 24 TC 39 Z9 52 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 AUG 6 PY 2002 VL 99 IS 16 BP 10724 EP 10729 DI 10.1073/pnas.132271699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200091 PM 12149436 ER PT J AU Yue, Y Chen, ZY Gale, NW Blair-Flynn, J Hu, TJ Yue, X Cooper, M Crockett, DP Yancopoulos, GD Tessarollo, L Zhou, RP AF Yue, Y Chen, ZY Gale, NW Blair-Flynn, J Hu, TJ Yue, X Cooper, M Crockett, DP Yancopoulos, GD Tessarollo, L Zhou, RP TI Mistargeting hippocampal axons by expression of a truncated Eph receptor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GANGLION-CELL AXONS; GROWTH-FACTOR RECEPTOR; NEURITE OUTGROWTH; TRANSGENIC MICE; RETINAL AXONS; RETINOTECTAL PROJECTION; EPHRINS STIMULATE; TYROSINE KINASES; TOPOGRAPHIC MAPS; GENETIC-ANALYSIS AB Topographic mapping of axon terminals is a general principle of neural architecture that underlies the interconnections among many neural structures. The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been implicated in the formation of topographic projection maps. We show that multiple Eph receptors and ligands are expressed in the hippocampus and its major subcortical projection target, the lateral septum, and that expression of a truncated Eph receptor in the mouse brain results in a pronounced alteration of the hippocamposeptal topographic map. Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections. C1 Rutgers State Univ, Coll Pharm, Dept Biol Chem, Piscataway, NJ 08854 USA. NCI, Frederick Canc Res & Dev Ctr, Neural Dev Grp, Mouse Canc Genet Program, Frederick, MD 21701 USA. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. RP Zhou, RP (reprint author), Rutgers State Univ, Coll Pharm, Dept Biol Chem, Piscataway, NJ 08854 USA. NR 50 TC 53 Z9 54 U1 2 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10777 EP 10782 DI 10.1073/pnas.162354599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200100 PM 12124402 ER PT J AU Giannakakou, P Nakano, M Nicolaou, KC O'Brate, A Yu, I Blagosklonny, MV Greber, UF Fojo, T AF Giannakakou, P Nakano, M Nicolaou, KC O'Brate, A Yu, I Blagosklonny, MV Greber, UF Fojo, T TI Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CANCER-CELLS; INDIVIDUAL MICROTUBULES; TUBULIN MUTATIONS; TAXOL; ADENOVIRUS; RESISTANCE; GROWTH; VINBLASTINE; INSTABILITY; MECHANISM AB The tumor suppressor protein p53 localizes to microtubules (MT) and, in response to DNA damage, is transported to the nucleus via the MT minus-end-directed motor protein dynein. Dynein is also responsible for MT-mediated nuclear targeting of adenovirus type 2 (Ad2). Here we show that treatment with low concentrations of MT-targeting compounds (MTCs) that do not disrupt the MT network but are known to suppress MT dynamics enhanced p53 nuclear accumulation, and the activation of the p53-downstream target genes. p53 nuclear accumulation required binding of MTCs to MTs and enhanced the induction of p53-up-regulated modulator of apoptosis (PUMA) mRNA and apoptosis on challenging cells with the DNA-damaging drug adriamycin. Low concentrations of MTCs enhanced the rate of movement of fluorescent Ad2 to the nucleus and increased the nuclear targeting efficiency of Ad2. We propose that suppression of MT dynamics by low concentrations of MTCs enhances MT-dependent trafficking toward the minus ends of MTs and facilitates nuclear targeting. C1 Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. Univ Zurich, Inst Zool, CH-8057 Zurich, Switzerland. Scripps Res Inst, Res Inst, Dept Chem, La Jolla, CA 92037 USA. Scripps Res Inst, Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. Johns Hopkins Med Inst, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. New York Med Coll, Brander Canc Res Inst, Hawthorne, NY 10532 USA. New York Med Coll, Dept Med, Hawthorne, NY 10532 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Giannakakou, P (reprint author), Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. RI Greber, Urs/G-9458-2015 OI Greber, Urs/0000-0003-2278-120X NR 39 TC 132 Z9 135 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 6 PY 2002 VL 99 IS 16 BP 10855 EP 10860 DI 10.1073/pnas.132275599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 582HC UT WOS:000177343200113 PM 12145320 ER PT J AU Smith, AB Corbett, RM Pettit, GR Chapuis, JC Schmidt, JM Hamel, E Jung, MK AF Smith, AB Corbett, RM Pettit, GR Chapuis, JC Schmidt, JM Hamel, E Jung, MK TI Synthesis and biological evaluation of a spongistatin AB-spiroketal analogue SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID MARINE NATURAL PRODUCT; ALTOHYRTIN-C SPONGISTATIN-2; SPONGE HYRTIOS-ALTUM; IN-VITRO; PART 2; TUBULIN; PHARMACOPHORE; HALISTATIN-1; INHIBITORS; SEPARATION AB The synthesis of a simplified analogue of the potent, cytotoxic tubulin-depolymerizing agent spongistatin 1, based on the AB spiroketal framework, is presented. The new structural analogue is an extension of a recently described spongistatin congener reported to disrupt microtubules in breast cancer cells in vitro and to alter the microtubule assembly reaction. Cytotoxicity data on the new structural analogue, as well as the parent congener, are reported. We found no significant cytotoxic or antitubulin activity with either compound. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp Frederick, NIH, Frederick, MD 21702 USA. RP Smith, AB (reprint author), Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA-70329, N01-CO-56000, CA-81337] NR 26 TC 19 Z9 19 U1 1 U2 4 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 AUG 5 PY 2002 VL 12 IS 15 BP 2039 EP 2042 AR PII S0960-894X(02)00305-0 DI 10.1016/S0960-894X(02)00305-0 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 580FW UT WOS:000177225400036 PM 12113837 ER PT J AU Segura-Totten, M Kowalski, AK Craigie, R Wilson, KL AF Segura-Totten, M Kowalski, AK Craigie, R Wilson, KL TI Barrier-to-autointegration factor: major roles in chromatin decondensation and nuclear assembly SO JOURNAL OF CELL BIOLOGY LA English DT Article DE HIV; retroviral preintegration complex; nucleus; emerin; nuclear envelope ID LAMINA-ASSOCIATED POLYPEPTIDE-2; HIV TYPE-1 INTEGRATION; LEM-DOMAIN; STRUCTURE DYNAMICS; ENVELOPE FORMATION; FORMATION INVITRO; MEMBRANE PROTEIN; RETROVIRAL DNA; XENOPUS-LAEVIS; EMERIN AB Barrier-to-autointegration factor (BAF) is a DNA-bridging protein, highly conserved in metazoans. BAF binds directly to LEM (LAP2, emerin, MAN1) domain nuclear membrane proteins, including LAP2 and emerin. We used site-directed mutagenesis and biochemical analysis to map functionally important residues in human BAF, including those required for direct binding to DNA or emerin. We also tested wild-type BAF and 25 point mutants for their effects on nuclear assembly in Xenopus egg extracts, which contain similar to12 muM endogenous BAF dimers. Exogenous BAF caused two distinct effects: at low added concentrations, wild-type BAF enhanced chromatin decondensation and nuclear growth; at higher added concentrations, wild-type BAF completely blocked chromatin decondensation and nuclear growth. Mutants fell into four classes, including one that defines a novel functional surface on the BAF dimer. Our results suggest that BAF, unregulated, potently compresses chromatin structure, and that BAF interactions with both DNA and LEM proteins are critical for membrane recruitment and chromatin decondensation during nuclear assembly. C1 Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Wilson, KL (reprint author), Johns Hopkins Univ, Sch Med, Dept Cell Biol, 725 N Wolfe St, Baltimore, MD 21205 USA. FU NIGMS NIH HHS [GM48646, R01 GM048646] NR 34 TC 117 Z9 122 U1 0 U2 0 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 AUG 5 PY 2002 VL 158 IS 3 BP 475 EP 485 DI 10.1083/jcb.200202019 PG 11 WC Cell Biology SC Cell Biology GA 582BM UT WOS:000177329900013 PM 12163470 ER PT J AU Nikonov, AV Snapp, E Lippincott-Schwartz, J Kreibich, G AF Nikonov, AV Snapp, E Lippincott-Schwartz, J Kreibich, G TI Active translocon complexes labeled with GFP-Dad1 diffuse slowly as large polysome arrays in the endoplasmic reticulum SO JOURNAL OF CELL BIOLOGY LA English DT Article DE translocon complex; oligosaccharyltransferase; lateral mobility; FRAP; endoplasmic reticulum ID GOLGI INTERMEDIATE COMPARTMENT; APOPTOTIC CELL-DEATH; FLUID MOSAIC MODEL; OLIGOSACCHARYLTRANSFERASE COMPLEX; MEMBRANE-PROTEINS; LIVING CELLS; ER MEMBRANE; BHK-CELLS; DAD1; RIBOSOMES AB In the ER, the translocon complex (TG) functions in the translocation and cotranslational modification of proteins made on membrane-bound ribosomes. The oligosaccharyltransferase (OST) complex is associated with the TC, and performs the cotranslational N-glycosylation of nascent polypeptide chains. Here we use a GFP-tagged subunit of the OST complex (GFP-Dad1) that rescues the temperature-sensitive (ts) phenotype of tsBN7 cells, where Dad1 is degraded and N-glycosylation is inhibited, to study the lateral mobility of the TC by FRAP. GFP-Dad1 that is functionally incorporated into TCs diffuses extremely slow, exhibiting an effective diffusion constant (Deft) about seven times lower than that of GFP-tagged ER membrane proteins unhindered in their lateral mobility. Termination of protein synthesis significantly increases the lateral mobility of GFP-Dad1 in the ER membranes, but to a level that is still lower than that of free GFP-Dad1. This suggests that GFP-Dad1 as part of the OST remains associated with inactive TCs. Our findings that TCs assembled into membrane-bound polysomes diffuse slowly within the ER have mechanistic implications for the segregation of the ER into smooth and rough domains. C1 NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. NICHHD, Unit Organelle Biol, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Kreibich, G (reprint author), NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. FU NIAMS NIH HHS [5T32 ARO 7190, T32 AR007190] NR 43 TC 51 Z9 51 U1 0 U2 0 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 AUG 5 PY 2002 VL 158 IS 3 BP 497 EP 506 DI 10.1083/jcb.200201116 PG 10 WC Cell Biology SC Cell Biology GA 582BM UT WOS:000177329900015 PM 12163472 ER PT J AU Berezhkovskii, A Hummer, G AF Berezhkovskii, A Hummer, G TI Single-file transport of water molecules through a carbon nanotube SO PHYSICAL REVIEW LETTERS LA English DT Article ID CHANNEL; PERMEABILITY; PORES AB Recent molecular dynamics simulations of water transport through the interior channel of a carbon nanotube in contact with an aqueous reservoir showed that conduction occurred in bursts with collective water motion. A continuous-time random-walk model is used to describe concerted transport through channels densely filled with molecules in a single-file arrangement, as also found in zeolites, as well as ion channels and aquaporins in biological membranes. Theoretical predictions for different collective properties of the single-file transport agree with the simulation results. C1 NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Berezhkovskii, A (reprint author), NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@speck.niddk.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 10 TC 248 Z9 252 U1 10 U2 88 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD AUG 5 PY 2002 VL 89 IS 6 AR 064503 DI 10.1103/PhysRevLett.89.064503 PG 4 WC Physics, Multidisciplinary SC Physics GA 576MT UT WOS:000177009600022 PM 12190588 ER PT J AU Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G Schluchter, MD Colan, SD AF Lipshultz, SE Easley, KA Orav, EJ Kaplan, S Starc, TJ Bricker, JT Lai, WW Moodie, DS Sopko, G Schluchter, MD Colan, SD CA Pediat Pulm Cardiovasc Complicatio TI Cardiovascular status of infants and children of women infected with HIV-1 ((PC2)-C-2 HIV): a cohort study SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROSPECTIVE (PCHIV)-C-2-H-2 MULTICENTER; DOXORUBICIN THERAPY; CARDIAC STRUCTURE; MORTALITY; ZIDOVUDINE; CHILDHOOD AB Background Data from cross-sectional and short-term longitudinal studies have suggested that children infected with HIV-1 might have cardiovascular abnormalities. We aimed to investigate this hypothesis in a long-term cohort study. Methods We measured cardiovascular function every 4-6 months for up to 5 years in a birth cohort of 600 infants born to women infected with HIV-1. We included 93 infants infected with HIV-1 and 463 uninfected infants (internal controls) from the same cohort. We also included a cross-sectionally measured comparison group of 195 healthy children born to mothers who were not infected with HIV-1 (external controls). Findings Children infected with HIV-1 had a significantly higher heart rate at all ages (mean difference 10 bpm, 95% Cl 8-13) than internal controls. At birth, both cohort groups of children had similar low left ventricular (LV) fractional shortening. At 8 months, fractional shortening was similar in internal and external controls, whereas in children infected with HIV-1, fractional shortening remained significantly lower than in controls for the first 20 months of life (mean difference from internal controls at 8 months 3.7%, 2.3-5.1). LV mass was similar at birth in both cohort groups, but became significantly higher in children with HIV-1 from 4-30 months (mean difference 2.4 g at 8 months, 0.9-3.9). Conclusions Vertically-transmitted HIV-1 infection is associated with persistent cardiovascular abnormalities identifiable shortly after birth. Irrespective of their HIV-1 status, infants born to women infected with HIV-1 have significantly worse cardiac function than other infants, suggesting that the uterine environment has an important role in postnatal cardiovascular abnormalities. C1 Univ Rochester, Med Ctr, Sch Med & Dent, Dept Pediat,Div Pediat Cardiol, Rochester, NY 14642 USA. Strong Childrens Hosp, Div Pediat Cardiol, Rochester, NY USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. Boston Med Ctr, Dept Pediat, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Pediat, Div Pediat Cardiol, Cleveland, OH 44195 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Univ Calif Los Angeles, Med Ctr, Dept Pediat, Div Pediat Cardiol, Los Angeles, CA 90024 USA. Mt Sinai Sch Med, Dept Pediat, Div Pediat Cardiol, New York, NY USA. Columbia Univ Coll Phys & Surg, Presbyterian Hosp, Div Pediat Cardiol, Dept Pediat, New York, NY 10032 USA. Baylor Coll Med, Dept Pediat, Div Pediat Cardiol, Houston, TX 77030 USA. NHLBI, Bethesda, MD 20892 USA. Sch Med, Los Angeles, CA USA. RP Lipshultz, SE (reprint author), Univ Rochester, Med Ctr, Sch Med & Dent, Dept Pediat,Div Pediat Cardiol, 601 Elmwood Ave,Box 631, Rochester, NY 14642 USA. RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NCRR NIH HHS [RR-00645, M01 RR000645, M01 RR002172, RR-02172, M01 RR000865, M01 RR000043, RR-00043, RR-00865, RR-00685, M01 RR000188, M01 RR000071, RR-00533, RR-00188, RR-00071, M01 RR000533, K01 RR000188]; NHLBI NIH HHS [N01-HR-96040, N01-HR-96038, N01-HR-96041, N01-HR-96042, N01-HR-96039, N01 HR096043, N01 HR096037] NR 21 TC 45 Z9 46 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 AUG 3 PY 2002 VL 360 IS 9330 BP 368 EP 373 DI 10.1016/S0140-6736(02)09607-1 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 580UY UT WOS:000177255600009 PM 12241776 ER PT J AU Chen, B Athanasiou, M Gu, QP Blair, DG AF Chen, B Athanasiou, M Gu, QP Blair, DG TI Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Drm/Gremlin; ecdysone-inducible; tumorigenesis; p21(Cip1); MAP kinase ID CELL-CYCLE; GENE; EXPRESSION; PROTEIN; GREMLIN; P53; GROWTH; P21; P21(WAF1/CIP1); OVEREXPRESSION AB Drm/Gremlin, a member of the Dan family of BMP antagonists, is known to function in early embryonic development, but is also expressed in a tissue-specific fashion in adults and is significantly downregulated in transformed cells. In this report, we demonstrate that overexpression of Drm in the tumor-derived cell lines Daoy (primitive neuroectodermal) and Saos-2 (osteoblastic), either under ecdysone-inducible or constitutive promoters, significantly inhibits tumorigenesis. Furthermore, Drm overexpression in these cells increases the level of p21(Cip1) protein and reduces the level of phosphorylated p42/44 MAP kinase. Finally, our data indicate that Drm can induce P21(Cip1) transcriptionally via a novel pathway that is independent of p53 and the p38 and p42/44 MAP kinases. These results provide evidence that Drm, can function as a novel transformation suppressor and suggest that this may occur through its affect on the levels of p21(Cip1) and phosphorylated p42/44 MAPK. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Intramural Res Support Program, Frederick, MD 21702 USA. RP Blair, DG (reprint author), NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Bldg 469,Rm 102, Frederick, MD 21702 USA. FU NCI NIH HHS [N01 CO 12400] NR 34 TC 43 Z9 46 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 2 PY 2002 VL 295 IS 5 BP 1135 EP 1141 AR PII S0006-291X(02)00828-8 DI 10.1016/S0006-291X(02)00828-8 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 581TQ UT WOS:000177309700016 PM 12135612 ER PT J AU Hall, D AF Hall, D TI On the role of the macromolecular phase transitions in biology in response to change in solution volume or macromolecular composition: action as an entropy buffer SO BIOPHYSICAL CHEMISTRY LA English DT Article DE cell volume; entropy buffer; non-ideality; cytoskeleton ID SEDIMENTATION EQUILIBRIUM EXPERIMENTS; THERMODYNAMIC NONIDEALITY; CELL-VOLUME; REGULATORY MECHANISMS; PROTEINS; POLYMERIZATION; DEHYDROGENASE; CYTOSKELETON; CYTOPLASM; MODEL AB We have used numerical simulation to demonstrate the potential for macromolecular precipitate solution phase transitions existing within the cell, to play a role in the minimization of changes in location or quaternary state of other macromolecular components, predicted to accompany changes in cell volume. For our modeling we have employed thermodynamic relations that take into account the large effects upon the thermodynamic activity coefficient produced by a solution environment that is highly volume occupied due to the presence of high concentrations of soluble macromolecule. The theoretical approach adopted, along with the simulated results, provide a framework for the interpretation of certain proteins' behavior (e.g. cytoskeletal elements such as tubulin and actin and possibly some prion structures) in response to cell volume change. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Sect Phys Biochem, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Hall, D (reprint author), NIDDKD, Sect Phys Biochem, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RI Hall, Damien/D-9927-2012 OI Hall, Damien/0000-0003-1538-7618 NR 37 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD AUG 2 PY 2002 VL 98 IS 3 BP 233 EP 248 AR PII S0301-4622(02)00072-8 DI 10.1016/S0301-4622(02)00072-8 PG 16 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 581CX UT WOS:000177274500001 PM 12128177 ER PT J AU Lee, D Kim, HZ Jeong, KW Shim, YS Horikawa, I Barrett, JC Choe, J AF Lee, D Kim, HZ Jeong, KW Shim, YS Horikawa, I Barrett, JC Choe, J TI Human papillomavirus E2 down-regulates the human telomerase reverse transcriptase promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NORMAL HUMAN-CELLS; BOVINE PAPILLOMAVIRUS; CATALYTIC SUBUNIT; DNA-REPLICATION; GENE-PRODUCT; TUMOR-CELLS; HTERT GENE; TYPE-16 E6; C-MYC; PROTEIN AB The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a critical step in transformation and differentiation. Human papillomavirus E2 protein inhibits cell growth in HPV-infected cells and triggers apoptosis in HeLa cells. Because E2 induces cell growth suppression and senescence, we hypothesize that the protein may modulate cellular gene expression related to these processes. In this report, we demonstrate that E2 inhibits the hTERT promoter. The mapping of the E2-responsive region of hTERT reveals that Sp1 is important for E2-mediated repression of this promoter in 293T cells. Site-directed mutagenesis data on the hTERT promoter show that E2 does not abolish E-Box-mediated transcription and represses promoter activity via the Sp1 binding site. Furthermore, chromatin immunoprecipitation assays indicate that E2 is actively recruited to the hTERT promoter region. Our findings provide novel insights into the biological function of human papillomavirus E2. C1 Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Choe, J (reprint author), Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. RI Choe, Joonho/F-3066-2011; Lee, Daeyoup/C-1653-2011; OI Lee, Daeyoup/0000-0003-2006-1823 NR 49 TC 43 Z9 46 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2002 VL 277 IS 31 BP 27748 EP 27756 DI 10.1074/jbc.M203706200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 579QR UT WOS:000177189800023 PM 12019268 ER PT J AU Gladwin, MT Wang, XD Reiter, CD Yang, BK Vivas, EX Bonaventura, C Schechter, AN AF Gladwin, MT Wang, XD Reiter, CD Yang, BK Vivas, EX Bonaventura, C Schechter, AN TI S-nitrosohemoglobin is unstable in the reductive erythrocyte environment and lacks O-2/NO-linked allosteric function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SICKLE-CELL HEMOGLOBIN; HIGH OXYGEN-AFFINITY; REGIONAL BLOOD-FLOW; NITRIC-OXIDE; BIOCHEMICAL-CHARACTERIZATION; BIOLOGICAL-ACTIVITY; RELAXING FACTOR; REDOX STATE; NITROSOTHIOLS; BINDING AB Our previous results run counter to the hypothesis that S-nitrosohemoglobin (SNO-Hb) serves as an in vivo reservoir for NO from which NO release is allosterically linked to oxygen release. We show here that SNO-Hb undergoes reductive decomposition in erythrocytes, whereas it is stable in purified solutions and in erythrocyte lysates treated with an oxidant such as ferricyanide. Using an extensively validated methodology that eliminates background nitrite and stabilizes erythrocyte S-nitrosothiols, we find the levels of SNO-Hb in the basal human circulation, including red cell membrane fractions, were 46 +/- 17 nM in human arterial erythrocytes and 69 +/- 11 nM in venous erythrocytes, incompatible with the postulated reservoir function of SNO-Hb. Moreover, we performed experiments on human red blood cells in which we elevated the levels of SNO-Hb to 10,000 times the normal in vivo levels. The elevated levels of intra-erythrocytic SNO-Hb fell rapidly, independent of oxygen tension and hemoglobin saturation. Most of the NO released during this process was oxidized to nitrate. A fraction (25%) was exported as S-nitrosothiol, but this fraction was not increased at low oxygen tensions that favor the deoxy (T-state) conformation of Hb. Results of these studies show that, within the redox-active erythrocyte environment, the beta-globin cysteine 93 is maintained in a reduced state, necessary for normal oxygen affinity, and incapable of oxygen-linked NO storage and delivery. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Marine Freshwater Biomed Ctr, Beaufort, NC 28516 USA. RP Gladwin, MT (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bldg 10,Rm 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 44 TC 123 Z9 125 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2002 VL 277 IS 31 BP 27818 EP 27828 DI 10.1074/jbc.M203236200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 579QR UT WOS:000177189800031 PM 12023289 ER PT J AU Volpi, S Rabadan-Diehl, C Cawley, N Aguilera, G AF Volpi, S Rabadan-Diehl, C Cawley, N Aguilera, G TI Transcriptional regulation of the pituitary vasopressin V1b receptor involves a GAGA-binding protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC STRESS; MESSENGER-RNA; DNA-BINDING; GENE; RAT; PROMOTER; BOX; INVOLVEMENT; ACTIVATION; SECRETION AB The role of CT repeats (inverted GAGA box) in the rat vasopressin V1b receptor (V1bR) promoter in the transcriptional regulation of this gene was studied in H32 hypothalamic cells, which express endogenous V1bR. Transfection of a 2.5-kb V1bR fragment (2161 by upstream and 377 by downstream of the proximal transcriptional start point) into a luciferase vector (V1bRp2.5-Luc) results in promoter activity in these cells. The 670-by proximal promoter fragment containing the GAGA box showed maximal promoter activity, whereas deletion of the GAGA box abolished transcription. Drosophila GAGA-binding protein increased V1bR promoter activity by 11-fold when cotransfected with V1bRp2.5-Luc and increased endogenous V1bR expression. Electrophoretic mobility shift assay showed specific binding of pituitary nuclear extracts to radiolabeled GAGA oligonucleotides, which increased following restraint stress in rats, a condition associated with V1bR up-regulation. DNA-binding activity involved a protein complex because it was abolished by deoxycholate. Size-exclusion column chromatography showed a complex of 127 kDa, which dissociated into similar to70-kDa components after deoxycholate/Nonidet P-40 treatment. This study demonstrates that interactions of GAGA-binding proteins with the GAGA box of the V1bR promoter activate V1bR gene expression and provides a potential mechanism for physiological regulation of V1bR transcription. C1 NICHD, Sect Endocrine Physiol, DEB, NIH, Bethesda, MD 20892 USA. NICHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Volpi, S (reprint author), NICHD, Sect Endocrine Physiol, DEB, NIH, Bldg 10,Rm 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. NR 27 TC 16 Z9 17 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2002 VL 277 IS 31 BP 27829 EP 27838 DI 10.1074/jbc.M201508200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 579QR UT WOS:000177189800032 PM 12023277 ER PT J AU Keeton, EK Fletcher, TM Baumann, CT Hager, GL Smith, CL AF Keeton, EK Fletcher, TM Baumann, CT Hager, GL Smith, CL TI Glucocorticoid receptor domain requirements for chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter in different nucleoprotein contexts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG TERMINAL REPEAT; DNA-BINDING DOMAIN; TRANSACTIVATION DOMAIN; STEROID-RECEPTORS; NUCLEAR RECEPTORS; MMTV PROMOTER; IN-VITRO; PROGESTERONE-RECEPTOR; HORMONE RECEPTORS; GENE-EXPRESSION AB The glucocorticoid receptor (GR) contains several activation domains, tau1 (AF-1), tau2, and AF-2, which were initially defined using transiently transfected reporter constructs. Using domain mutations in the context of full-length GR, this study defines those domains required for activation of the mouse mammary tumor virus (MMTV) promoter in two distinct nucleoprotein configurations. A transiently transfected MMTV template with a disorganized, accessible chromatin structure was largely dependent on the AF-2 domain for activation. In contrast, activation of an MMTV template in organized, replicated chromatin requires both domains but has a relatively larger dependence on the tau1 domain. Domain requirements for GR-induced chromatin remodeling of the latter template were also investigated. Mutation of the AF-2 helix 12 domain partially inhibits the induction of nuclease hypersensitivity, but the inhibition was relieved in the absence of tau1, suggesting the occurrence of an important interaction between the two domains. Further mutational analysis indicates that GR-induced chromatin remodeling requires the ligand-binding domain in the region of helix 3. Our study shows that the GR activation surfaces required for transcriptional modulation of a target promoter were determined in part by its chromatin structure. Within a particular cellular environment the GR appears to possess a significant degree of versatility in the mechanism by which it activates a target promoter. C1 NCI, Lab Receptor Biol& Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Genet, Washington, DC USA. RP Smith, CL (reprint author), NCI, Lab Receptor Biol& Gene Express, Ctr Canc Res, NIH, Bldg 41,Rm B608,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 57 TC 22 Z9 22 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2002 VL 277 IS 31 BP 28247 EP 28255 DI 10.1074/jbc.M203898200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 579QR UT WOS:000177189800083 PM 12029095 ER PT J AU Zingone, A Seidel, J Aloj, L Caraco, C Vaquero, JJ Jagoda, EM Chou, JY Green, MV Eckelman, WC AF Zingone, A Seidel, J Aloj, L Caraco, C Vaquero, JJ Jagoda, EM Chou, JY Green, MV Eckelman, WC TI Monitoring the correction of glycogen storage disease type 1a in a mouse model using [F-18]FDG and a dedicated animal scanner SO LIFE SCIENCES LA English DT Article DE glycogen storage disease type 1a; mouse; [F-18]FDG; G6Pase ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; GLUCOSE-6-PHOSPHATASE SYSTEM; MURINE GLUCOSE-6-PHOSPHATASE; PET; ENZYME; GENE; TRANSPORTER; THERAPY; HUMANS AB Monitoring gene therapy of glycogen storage disease type I a in a mouse model was achieved using [F-18]FDG and a dedicated animal scanner. The G6Pase knockout (KO) mice were compared to the same mice after infusion with a recombinant adenovirus containing the murine G6Pase gene (Ad-mG6Pase). Serial images of the same mouse before and after therapy were obtained and compared with wild-type (WT) mice of the same strain to determine the uptake and retention of [F-18]FDG in the liver. Image data were acquired from heart, blood pool and liver for twenty minutes after injection of [F-18]FDG. The retention of [F-18]FDG was lower for the WT mice compared to the KO mice. The mice treated with adenovirus-mediated gene therapy had retention similar to that found in age-matched WT mice. These studies show that FDG can be used to monitor the G6Pase concentration in liver of WT mice as compared to G6Pase KO mice. In these mice, gene therapy returned the liver function to that found in age matched WT controls as measured by the FDG kinetics in the liver compared to that found in age matched wild type controls. Published by Elsevier Science Inc. C1 NIH, PET Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NICHD, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, PET Dept, Warren Grant Magnuson Clin Ctr, Bld 10 Rm 1C495,10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 32 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD AUG 2 PY 2002 VL 71 IS 11 BP 1293 EP 1301 AR PII S0024-3205(02)01831-3 DI 10.1016/S0024-3205(02)01831-3 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 578HY UT WOS:000177112400007 PM 12106594 ER PT J AU Roth, GS Lane, MA Ingram, DK Mattison, JA Elahi, D Tobin, JD Muller, D Metter, EJ AF Roth, GS Lane, MA Ingram, DK Mattison, JA Elahi, D Tobin, JD Muller, D Metter, EJ TI Biomarkers of caloric restriction may predict longevity in humans SO SCIENCE LA English DT Article ID RHESUS-MONKEYS C1 NIA, Baltimore, MD 21224 USA. RP Roth, GS (reprint author), NIA, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 7 TC 239 Z9 244 U1 1 U2 14 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 AUG 2 PY 2002 VL 297 IS 5582 BP 811 EP 811 DI 10.1126/science.1071851 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 579RZ UT WOS:000177192800042 PM 12161648 ER PT J AU Bulte, JWM Douglas, T Witwer, B Zhang, SC Lewis, BK van Gelderen, P Zywicke, H Duncan, ID Frank, JA AF Bulte, JWM Douglas, T Witwer, B Zhang, SC Lewis, BK van Gelderen, P Zywicke, H Duncan, ID Frank, JA TI Monitoring stem cell therapy in vivo using magnetodendrimers as a new class of cellular MR contrast agents SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT Contrast Media Research Conference CY OCT 14-18, 2001 CL CAPRI, ITALY SP Bracco Imaging, Bracco Res, DuPont Pharmaceut, Nycomed Amersham Imaging, Schering, Guerbet, Berlex, Bracco Byk Gulden, Bracco Res, Switzerland, Daiichi Pharmaceut, Epix Med, Mallinckrodt, MetalProbe, Nihon Medi Phys, Nihon Schering ID POLYAMIDOAMINE DENDRIMERS; NANOCOMPOSITES; NANOPARTICLES; NANOCLUSTERS; PROGENITORS; MYELINATION; TRACKING C1 NINDS, Lab Diagnost Radiol Res, NIH, Bethesda, MD USA. Temple Univ, Dept Chem, Philadelphia, PA 19122 USA. Univ Wisconsin, Sch Vet Med, Dept Med Sci, Madison, WI 53706 USA. RP Bulte, JWM (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, 217 Taylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Bulte, Jeff/A-3240-2008; Douglas, Trevor/F-2748-2011 OI Bulte, Jeff/0000-0003-1202-1610; NR 14 TC 42 Z9 44 U1 0 U2 4 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 AUG PY 2002 VL 9 SU 2 BP S332 EP S335 DI 10.1016/S1076-6332(03)80221-0 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 583QZ UT WOS:000177420700021 PM 12188266 ER PT J AU Frank, JA Zywicke, H Jordan, EK Mitchell, J Lewis, BK Miller, B Bryant, LH Bulte, JWM AF Frank, JA Zywicke, H Jordan, EK Mitchell, J Lewis, BK Miller, B Bryant, LH Bulte, JWM TI Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT Contrast Media Research Conference CY OCT 14-18, 2001 CL CAPRI, ITALY SP Bracco Imaging, Bracco Res, DuPont Pharmaceut, Nycomed Amersham Imaging, Schering, Guerbet, Berlex, Bracco Byk Gulden, Bracco Res, Switzerland, Daiichi Pharmaceut, Epix Med, Mallinckrodt, MetalProbe, Nihon Medi Phys, Nihon Schering ID MESENCHYMAL STEM-CELLS; DELIVERY; NANOPARTICLES; DENDRIMERS; TRACKING C1 NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bldg 10,Rm B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008; Miller, Bradley/G-7426-2014 OI Bulte, Jeff/0000-0003-1202-1610; NR 16 TC 123 Z9 133 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2002 VL 9 SU 2 BP S484 EP S487 DI 10.1016/S1076-6332(03)80271-4 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 583QZ UT WOS:000177420700071 PM 12188316 ER PT J AU Kobayashi, H Saga, T Kawamoto, S Sato, N Hiraga, A Ishimori, T Konishi, J Togashi, K Brechbiel, MW AF Kobayashi, H Saga, T Kawamoto, S Sato, N Hiraga, A Ishimori, T Konishi, J Togashi, K Brechbiel, MW TI Dynamic micro-MRI of liver micrometastasis with a novel liver macromolecular MR contrast agent DAB-Am64-(1B4M-Gd)(64) SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT Contrast Media Research Conference CY OCT 14-18, 2001 CL CAPRI, ITALY SP Bracco Imaging, Bracco Res, DuPont Pharmaceut, Nycomed Amersham Imaging, Schering, Guerbet, Berlex, Bracco Byk Gulden, Bracco Res, Switzerland, Daiichi Pharmaceut, Epix Med, Mallinckrodt, MetalProbe, Nihon Medi Phys, Nihon Schering C1 Hitachi Med Corp, Dept Diagnos & Intervent Imagiol, Tokyo, Japan. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Otsu Municipal Hosp, Dept Radiol, Otsu, Shiga, Japan. Kyoto Univ, Dept Radiol, Kyoto, Japan. Kyoto Univ, Dept Nucl Med & Diagnost Imaging, Kyoto, Japan. RP Kobayashi, H (reprint author), Hitachi Med Corp, Dept Diagnos & Intervent Imagiol, Tokyo, Japan. NR 0 TC 4 Z9 4 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 AUG PY 2002 VL 9 SU 2 BP S452 EP S454 DI 10.1016/S1076-6332(03)80260-X PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 583QZ UT WOS:000177420700060 PM 12188305 ER PT J AU Wiener, EC Konda, SD Wang, S Brechbiel, M AF Wiener, EC Konda, SD Wang, S Brechbiel, M TI Imaging folate binding protein expression with MRI SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT Contrast Media Research Conference CY OCT 14-18, 2001 CL CAPRI, ITALY SP Bracco Imaging, Bracco Res, DuPont Pharmaceut, Nycomed Amersham Imaging, Schering, Guerbet, Berlex, Bracco Byk Gulden, Bracco Res, Switzerland, Daiichi Pharmaceut, Epix Med, Mallinckrodt, MetalProbe, Nihon Medi Phys, Nihon Schering ID RECEPTOR; XENOGRAFTS; TISSUES; I-125; OVARY; DRUG C1 Univ Illinois, Beckman Inst, Urbana, IL 61801 USA. Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. Univ Illinois, Dept Nucl Plasma & Radiol Engn, Urbana, IL 61801 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wiener, EC (reprint author), Univ Illinois, Beckman Inst, 405 N Mathews, Urbana, IL 61801 USA. FU NCI NIH HHS [1-R29-CA61918]; NCRR NIH HHS [5-P41-RR05964]; NIGMS NIH HHS [T32 GM07143] NR 14 TC 11 Z9 11 U1 0 U2 1 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 AUG PY 2002 VL 9 SU 2 BP S316 EP S319 DI 10.1016/S1076-6332(03)80215-5 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 583QZ UT WOS:000177420700015 PM 12188260 ER PT J AU Sevcik, J Lamzin, VS Dauter, Z Wilson, KS AF Sevcik, J Lamzin, VS Dauter, Z Wilson, KS TI Atomic resolution data reveal flexibility in the structure of RNase Sa SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID RIBONUCLEASE SA; STREPTOMYCES-AUREOFACIENS; REFINEMENT; COMPLEX; MOLSCRIPT; PROTEINS AB Ribonuclease from Streptomyces aureofaciens, the bacterial source for the industrial production of chlorotetracycline, is a guanylate endoribonuclease (RNase Sa; EC 3.1.27.3) which hydrolyses the phosphodiester bonds of single-stranded RNA at the 3'-side of guanosine nucleotides with high specificity. The structure of the enzyme was previously refined at atomic resolution (1.2 Angstrom) using room-temperature data. Here, the RNase Sa structure refined against 1.0 Angstrom data collected at cryogenic temperature is reported. There are two surface loops in molecule A and one in molecule B for which two main-chain conformations are modelled: these loops contain active-site residues. The separation for most of the corresponding main-chain atoms in the two conformations is about 0.8 Angstrom, with a maximum of 2.5 Angstrom. The two regions of dual conformation represent the most important differences in comparison with the structure determined at room temperature, where the corresponding loops have one conformation only but the largest degree of anisotropy. The flexibility of the loops observed in the structure of RNase Sa is directly linked to the need for the active site to interact productively with substrates and/or inhibitors. C1 Slovak Acad Sci, Inst Mol Biol, Bratislava 84251, Slovakia. European Mol Biol Lab, Hamburg Outstn, D-22603 Hamburg, Germany. Brookhaven Natl Lab, NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Univ York, Struct Biol Lab, York YO10 5DD, N Yorkshire, England. RP Sevcik, J (reprint author), Slovak Acad Sci, Inst Mol Biol, Dubravska Cesta 21, Bratislava 84251, Slovakia. OI Lamzin, Victor/0000-0002-6058-7793 NR 30 TC 18 Z9 18 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2002 VL 58 BP 1307 EP 1313 DI 10.1107/S0907444902010090 PN 8 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 583QG UT WOS:000177418800008 PM 12136142 ER PT J AU Flippen-Anderson, JL Deschamps, JR Brossi, A Greig, NH AF Flippen-Anderson, JL Deschamps, JR Brossi, A Greig, NH TI 2-hydroxybenzoic acid salt of physostigmine SO ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE LA English DT Article ID ALZHEIMER DRUG PHENSERINE; DISEASE; BUTYRYLCHOLINESTERASE; MEMORY AB Physostigmine, C15H22N3O2, is the major alkaloid found in the seeds of Calabar beans. It was the first anticholinesterase used in the treatment of Alzheimer's disease and is still used in the treatment of glaucoma. The structure of its 2-hydroxybenzoate salt, viz. 5-carbamoyloxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-1-ium benzoate, C15H22N3O2+.C7H5O3-, is reported. C1 USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr 4E02,NIH, Baltimore, MD 21224 USA. RP Flippen-Anderson, JL (reprint author), USN, Res Lab, Struct Matter Lab, Code 6030, Washington, DC 20375 USA. NR 19 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-5368 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Struct Rep. Online PD AUG PY 2002 VL 58 BP o853 EP o855 DI 10.1107/S1600536802012278 PN 8 PG 3 WC Crystallography SC Crystallography GA 578XX UT WOS:000177147300055 ER PT J AU Parry, CDH Bhana, A Pluddemann, A Myers, B Siegfried, N Morojele, NK Flisher, AJ Kozel, NJ AF Parry, CDH Bhana, A Pluddemann, A Myers, B Siegfried, N Morojele, NK Flisher, AJ Kozel, NJ TI The South African Community Epidemiology Network on Drug Use (SACENDU): Description, findings (1997-99) and policy implications SO ADDICTION LA English DT Article DE AOD use; consequences; epidemiology; South Africa; surveillance ID SUBSTANCE-ABUSE AB Aims To (1) describe the South African Community Epidemiology Network on Drug Use (SACENDU), (2) describe trends and associated consequences of alcohol and other drug (AOD) use in South Africa for January 1997 to December 1999 and (3) outline selected policy implications identified by SACENDU participants. Methods A descriptive epidemiological study of ACID indicators based on data gathered from multiple sources, including specialist treatment centres, trauma units and quantitative studies of target groups such as school students and arrestees. Networks were established in five sentinel sites to facilitate the collection, interpretation and dissemination of data. Results Over time alcohol has been the most frequently reported primary substance of abuse across sites. Trauma and psychiatric data highlight the burden associated with alcohol abuse. Cannabis and Mandrax (methaqualone), alone or in combination, are the most frequently reported illicit drugs of abuse, generally comprising the largest proportions of drug-related arrests, drug-related psychiatric diagnoses and drug-positive trauma patients. From 19 9 7 to 19 9 9, a significant increase in indicators for cocaine/crack and heroin occurred in two sites. Ecstasy (MDMA) use, alone or in combination with other substances, is reported among young people. Conclusions A broad range of globally abused substances is present in South Africa and the use and burden of illicit substances appears to be increasing. This points to the importance of ongoing monitoring of ACID trends. Through regular, systematic data collection the SACENDU project has made available more evidence-based information to direct ACID abuse policy and practice and has had an impact on research agendas. C1 MRC S Africa, ADARG, ZA-7505 Tygerberg, South Africa. Univ Durban Westville, Sch Psychol, ZA-4000 Durban, South Africa. MRC, S African Cochrane Ctr, Cape Town, South Africa. Univ Cape Town, Dept Psychiat, ZA-7925 Cape Town, South Africa. NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Parry, CDH (reprint author), MRC S Africa, ADARG, POB 19070, ZA-7505 Tygerberg, South Africa. RI Bhana, Arvin/D-5835-2015; Parry, Charles/A-2906-2009; OI Bhana, Arvin/0000-0003-4235-0108; Parry, Charles/0000-0001-9787-2785; Myers, Bronwyn/0000-0003-0235-6716; Morojele, Neo/0000-0003-2891-2557 NR 16 TC 44 Z9 44 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2002 VL 97 IS 8 BP 969 EP 976 DI 10.1046/j.1360-0443.2002.00145.x PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 583FL UT WOS:000177396000011 PM 12144599 ER PT J AU Wang, TJ Larson, MG Levy, D Leip, EP Benjamin, EJ Wilson, PWF Sutherland, P Omland, T Vasan, RS AF Wang, TJ Larson, MG Levy, D Leip, EP Benjamin, EJ Wilson, PWF Sutherland, P Omland, T Vasan, RS TI Impact of age and sex on plasma natriuretic peptide levels in healthy adults SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; ESSENTIAL-HYPERTENSION; GENE-EXPRESSION; ECHOCARDIOGRAPHY; HYPERTROPHY; POPULATION; RECEPTOR; DISEASE; HUMANS; MARKER AB Assays for natriuretic peptides have received considerable attention as potential screening tests for congestive heart failure and left ventricular dysfunction. However, information regarding the impact of age, sex, and other physiologic characteristics on natriuretic peptide levels is limited. We examined a healthy reference sample of 911 subjects (mean age 55 years, 62% women) from the Framingham Heart Study who were free of hypertension, valvular disease, diabetes, atrial fibrillation, obesity, coronary heart disease, congestive heart failure, and renal failure, and who had normal left ventricular systolic function. Plasma brain natriuretic peptide and N-terminal atrial natriuretic peptide levels were measured, and multivariable regression used to assess correlates of natriuretic peptide levels. The strongest predictors of higher natriuretic peptide levels were older age and female sex. Other multivariable predictors included lower diastolic blood pressure (higher pulse pressure), lower body mass index, and higher left atrial size. Reference limits were then formulated based on the empirical distribution of natriuretic peptide levels by gender both across all ages and partitioned by age. Age-pooled reference limits compared with age-specific limits classified a higher proportion of healthy elderly subjects (17% vs 2.5%), but a lower proportion of healthy young subjects (1% vs 2.5%) as "abnormal." We conclude that interpretation of natriuretic peptide levels should take into consideration gender and possibly age. The reference limits derived from this large, healthy community-based sample will aid in the identification of elevated natriuretic peptide levels in clinical practice. (C) 2002 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiol Div,Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Cardiol Sect, Div Endocrinol, Dept Med,Sch Med, Boston, MA 02215 USA. Natl Hosp Norway, Dept Cardiol, Oslo, Norway. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayne Ave, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01HL67288-01, K24 HL 04334-01A1, N01-HC-25195, R01 HL64753]; NINDS NIH HHS [R01-NS-17950] NR 29 TC 273 Z9 288 U1 0 U2 4 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2002 VL 90 IS 3 BP 254 EP 258 AR PII S0002-9149(02)02464-5 DI 10.1016/S0002-9149(02)02464-5 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 580QZ UT WOS:000177246400010 PM 12127613 ER PT J AU McKeown, NM Meigs, JB Liu, SM Wilson, PWF Jacques, PF AF McKeown, NM Meigs, JB Liu, SM Wilson, PWF Jacques, PF TI Whole-grain intake is favorably associated with metabolic risk factors for type 2 diabetes and cardiovascular disease in the Framingham Offspring Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE whole grains; refined grains; risk factors; survey; Framingham Offspring Study; food-frequency questionnaire; type 2 diabetes; cardiovascular disease ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE; FOOD FREQUENCY QUESTIONNAIRE; IOWA WOMENS HEALTH; HIGH-FIBER DIETS; YOUNG-ADULTS; HIGH-CARBOHYDRATE; FASTING INSULIN; IMPROVE GLUCOSE; BLOOD-PRESSURE AB Background: The influence of whole grains on cardiovascular disease risk may be mediated through multiple pathways, eg, a reduction in blood lipids and blood pressure, an enhancement of insulin sensitivity, and an improvement in blood glucose control. Objective: The objective was to examine the association between diets rich in whole- or refined-grain foods and several metabolic markers of disease risk in the Framingham Offspring Study cohort. Design: Whole-grain intake and metabolic risk markers were assessed in a cross-sectional study of 2941 subjects. Results: After adjustment for potential confounding factors, whole-grain intake was inversely associated with body mass index ((x) over bar: 26.9 in the lowest and 26.4 in the highest quintile of intake; P for trend = 0.06), waist-to-hip ratio (0.92 and 0.91, respectively; P for trend = 0.005), total cholesterol (5.20 and 5.09 mmol/L, respectively; P for trend = 0.06), LDL cholesterol (3.16 and 3.04 mmol/L, respectively; P for trend = 0.02), and fasting insulin (205 and 199 pmol/L, respectively; P for trend = 0.03). There were no significant trends in metabolic risk factor concentrations across quintile categories of refined-grain intake. The inverse association between whole-grain intake and fasting insulin was most striking among overweight participants. The association between wholegrain intake and fasting insulin was attenuated after adjustment for dietary fiber and magnesium. Conclusion: Increased intakes of whole grains may reduce disease risk by means of favorable effects on metabolic risk factors. C1 Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Program Epidemiol, Boston, MA 02111 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Gen Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Prevent Med, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. RP Jacques, PF (reprint author), Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Program Epidemiol, 711 Washington St, Boston, MA 02111 USA. RI Liu, Simin/I-3689-2014 OI Liu, Simin/0000-0003-2098-3844 FU NHLBI NIH HHS [N01-HC-38038]; NIDDK NIH HHS [T32 DK 07651] NR 69 TC 287 Z9 298 U1 2 U2 20 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 AUG PY 2002 VL 76 IS 2 BP 390 EP 398 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 577CV UT WOS:000177044900016 PM 12145012 ER PT J AU Akin, C Jaffe, ES Raffeld, M Kirshenbaum, AS Daley, T Noel, P Metcalfe, DD AF Akin, C Jaffe, ES Raffeld, M Kirshenbaum, AS Daley, T Noel, P Metcalfe, DD TI An immunohistochemical study of the bone marrow lesions of systemic mastocytosis - Expression of stem cell factor by lesional mast cells SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE mastocytosis; mast cells; stem cell factor; B lymphocytes; T lymphocytes; Benign lymphoid aggregates; bone marrow ID C-KIT LIGAND; URTICARIA PIGMENTOSA; ACTIVATING MUTATION; PERIPHERAL-BLOOD; PROGENITOR CELLS; CATALYTIC DOMAIN; LYMPHOID NODULES; DISEASE; DIFFERENTIATION; LEUKEMIA AB The bone marrow biopsy in mastocytosis often reveals characteristic mast cell collections associated with lymphoid cell aggregates. There is limited information on the composition of these aggregates and whether they, contain cytokines important to mast cell growth and development. We thus performed an immunohistochemical characterization of bone marrow lesions in 7 patients with systemic indolent mastocytosis. In nodular lesions, the collections of mast cells were surrounded by lymphoid aggregates; these aggregates consisted of a mixture of B and T cells. Immunohistochemical staining for stem cell factor (SCF) revealed the presence of this cytokine in the lesional mast cells with a granular staining pattern. These results show that the characteristic nodular lesions observed in bone marrow biopsy specimens of patients with mastocytosis bear features of benign lymphoid aggregates and that SCF is present in these lesions, creating a potential autocrine or paracrine growth and differentiation loop for mast cells and lymphoid progenitors. C1 NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. NIH, Hematol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Akin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr,MSC-1881, Bethesda, MD 20892 USA. RI Jaffe, Elaine/G-8984-2014 OI Jaffe, Elaine/0000-0003-4632-0301 NR 38 TC 16 Z9 19 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2002 VL 118 IS 2 BP 242 EP 247 DI 10.1309/71KH-4JE4-E0J1-7THH PG 6 WC Pathology SC Pathology GA 577KQ UT WOS:000177060400015 PM 12162685 ER PT J AU Ioannidis, JPA Rosenberg, PS Goedert, JJ O'Brien, TR AF Ioannidis, JPA Rosenberg, PS Goedert, JJ O'Brien, TR CA Int Meta-Anal HIV Host Genetics TI Commentary: Meta-analysis of individual participants' data in genetic epidemiology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE bias, epidemiology; genetics; meta-analysis ID SINGLE NUCLEOTIDE POLYMORPHISMS; HIV-1 DISEASE PROGRESSION; CHEMOKINE RECEPTOR GENE; PATIENT DATA; INFECTION; CCR5; AIDS; TRIALS; RISK; PUBLICATION AB The authors summarize their experience in the conduct of meta-analysis of individual participants' data (MIPD) with time-to-event analyses in the field of genetic epidemiology. The MIPD offers many advantages compared with a meta-analysis of the published literature. These include standardization of case definitions, outcomes, and covariates; inclusion of updated information; the ability to fully test the assumptions of time-to-event models; better control of confounding; standardization of analyses of genetic loci that are in linkage disequilibrium; evaluation of alternative genetic models and multiple genes; consistent treatment of subpopulations; assessment of sampling bias; and the establishment of an international collaboration with the capability to prospectively update the meta-analyses and synthesize new information on multiple genetic loci and outcomes. The disadvantages of a MIPD compared with a meta-analysis of the published literature are that a much greater commitment of time and resources is required to collect primary data and to coordinate a large collaborative project. An MIPD may collect additional, unpublished data, but it is possible that not all published data may be contributed at the individual level. For questions that justify the required intensive effort, the MIPD method is a useful tool to help clarify the role of candidate genes in complex human diseases. C1 Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, GR-45110 Ioannina, Greece. Fdn Res & Technol Hellas, Ioannina Biomed Res Inst, Ioannina, Greece. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Ioannidis, JPA (reprint author), Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, GR-45110 Ioannina, Greece. EM jioannid@cc.uoi.gr RI Ioannidis, John/G-9836-2011 NR 48 TC 74 Z9 75 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2002 VL 156 IS 3 BP 204 EP 210 DI 10.1093/aje/kwf031 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 577HL UT WOS:000177055400002 PM 12142254 ER PT J AU Astuto, LM Bork, JM Weston, MD Askew, JW Fields, RR Orten, DJ Ohliger, SJ Riazuddin, S Morell, RJ Khan, S Riazuddin, S Kremer, H van Hauwe, P Moller, CG Cremers, CWRJ Ayuso, C Heckenlively, JR Rohrschneider, K Spandau, U Greenberg, J Ramesar, R Reardon, W Bitoun, P Millan, J Legge, R Friedman, TB Kimberling, WJ AF Astuto, LM Bork, JM Weston, MD Askew, JW Fields, RR Orten, DJ Ohliger, SJ Riazuddin, S Morell, RJ Khan, S Riazuddin, S Kremer, H van Hauwe, P Moller, CG Cremers, CWRJ Ayuso, C Heckenlively, JR Rohrschneider, K Spandau, U Greenberg, J Ramesar, R Reardon, W Bitoun, P Millan, J Legge, R Friedman, TB Kimberling, WJ TI CDH23 mutation and phenotype heterogeneity: A profile of 107 diverse families with Usher syndrome and nonsyndromic deafness SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AUTOSOMAL RECESSIVE DEAFNESS; MYOSIN-VIIA GENE; SYNDROME TYPE 1F; RETINITIS-PIGMENTOSA; PREVALENCE; DFNB12; 1C; 1D AB Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. C1 Boys Town Natl Res Hosp, Ctr Study & Treatment Usher Syndrome, Omaha, NE 68131 USA. Univ Nebraska, Med Ctr, Dept Ophthalmol, Omaha, NE USA. Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. Univ Med Ctr Nijmegen, Dept Otorhinolaryngol, Nijmegen, Netherlands. Univ Med Ctr Nijmegen, Dept Human Genet& Otorhinolaryngol, Nijmegen, Netherlands. Sahlgrens Univ Hosp, Dept Audiol, S-41345 Gothenburg, Sweden. Fdn Jimenez Diaz, Madrid, Spain. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Univ Heidelberg, Dept Ophthalmol, Heidelberg, Germany. Univ Cape Town, Sch Med, Dept Human Genet, ZA-7925 Cape Town, South Africa. Univ London, Inst Child Hlth, London WC1N 1EH, England. CHU, Paris, France. Hosp Univ La Fe, Genet Unit, Valencia, Spain. RP Kimberling, WJ (reprint author), Boys Town Natl Res Hosp, Ctr Study & Treatment Usher Syndrome, Omaha, NE 68131 USA. RI Kremer, Hannie/F-5126-2010; Ramesar, Raj/I-6941-2015; Cremers, C.W.R.J./L-4254-2015; OI Kremer, Hannie/0000-0002-0841-8693; Ramesar, Raj/0000-0001-5688-1634; Morell, Robert/0000-0003-1537-7356; Ayuso, Carmen/0000-0002-9242-7065 FU NIDCD NIH HHS [1Z01 DC 00035-05, 1Z01 DC 00039-05, P01 DC 01813, P60 DC 00982, R01 DC 00677-07, T32 DC000035, Z01 DC000039] NR 25 TC 101 Z9 107 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2002 VL 71 IS 2 BP 262 EP 275 DI 10.1086/341558 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 575ZE UT WOS:000176977700005 PM 12075507 ER PT J AU Straub, RE Jiang, YX MacLean, CJ Ma, YL Webb, BT Myakishev, MV Harris-Kerr, C Wormley, B Sadek, H Kadambi, B Cesare, AJ Gibberman, A Wang, X O'Neill, FA Walsh, D Kendler, KS AF Straub, RE Jiang, YX MacLean, CJ Ma, YL Webb, BT Myakishev, MV Harris-Kerr, C Wormley, B Sadek, H Kadambi, B Cesare, AJ Gibberman, A Wang, X O'Neill, FA Walsh, D Kendler, KS TI Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; SINGLE-NUCLEOTIDE POLYMORPHISMS; TYPE-2 DIABETES-MELLITUS; CHROMOSOME 6P; SUSCEPTIBILITY LOCUS; ROSCOMMON FAMILY; LINKAGE ANALYSIS; TRANSMISSION/DISEQUILIBRIUM TEST; COGNITIVE IMPAIRMENT; BRAIN DYSTROPHIN AB Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by (7similar to) Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 ((d) under bar ys (t) under bar robrevi (n) under bar -binding (p) under bar rotein (1) under bar, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008-.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted. C1 Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. Queens Univ Belfast, Dept Psychiat, Belfast, Antrim, North Ireland. Hlth Res Board, Dublin, Ireland. RP Straub, RE (reprint author), NIMH, Clin Brain Disorders Branch, IRP, NIH, Bldg 10,Room 4N-311,MSC 1385, Bethesda, MD 20892 USA. RI O'Neill, Francis/C-5582-2008; Webb, Bradley/B-1459-2009; Cesare, Anthony/F-4691-2010; OI Webb, Bradley/0000-0002-0576-5366; Cesare, Anthony/0000-0002-0864-1254; O'Neill, Francis Anthony/0000-0002-7531-7657 FU NIMH NIH HHS [MH 41953, MH 45390, MH 52537, R01 MH041953] NR 92 TC 574 Z9 602 U1 5 U2 32 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2002 VL 71 IS 2 BP 337 EP 348 DI 10.1086/341750 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 575ZE UT WOS:000176977700012 PM 12098102 ER PT J AU Anikster, Y Huizing, M Anderson, PD Fitzpatrick, DL Klar, A Gross-Kieselstein, E Berkun, Y Shazberg, G Gahl, WA Hurvitz, H AF Anikster, Y Huizing, M Anderson, PD Fitzpatrick, DL Klar, A Gross-Kieselstein, E Berkun, Y Shazberg, G Gahl, WA Hurvitz, H TI Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CHEDIAK-HIGASHI-SYNDROME; MYOSIN-VA GENE; MELANOSOME TRANSPORT; VESICLE TRANSPORT; PALESTINIAN ARABS; ELEJALDE-SYNDROME; PARTIAL ALBINISM; PROTEINS; IDENTIFICATION; CLONING AB Griscelli syndrome (GS), a rare autosomal recessive disorder, is characterized by partial albinism, along with immunologic abnormalities or severe neurological impairment or both. Mutations in one of two different genes on chromosome 15q can cause the different subtypes of GS. Most patients with GS display the hemophagocytic syndrome and have mutations in RAB27A, which codes for a small GTPase. Two patients with neurological involvement have mutations in MYO5A, which codes for an actin-based molecular motor. The RAB27A and MYO5A gene products interact with each other and function in vesicle trafficking. We report the molecular basis of GS in a Muslim Arab kindred whose members have extremely variable neurological involvement, along with the hemophagocytic syndrome and immunologic abnormalities. The patients have normal MYO5A genes but exhibit a homozygous 67.5-kb deletion that eliminates RAB27A mRNA and immunocytofluorescence-detectable protein. We also describe the molecular organization of RAB27A and a multiplex polymerase chain reaction assay for the founder deletion in this kindred. Finally, we propose that all patients with GS have RAB27A mutations and immunologic abnormalities that sometimes result in secondary neurological involvement. The two patients described elsewhere who have MYO5A mutations and neurological complications but no immunologic defects may not have GS but instead may have Elejalde syndrome, a condition characterized by mild hypopigmentation and severe, primary neurological abnormalities. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Bikur Cholim Gen Hosp, Dept Pediat, Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. RP Huizing, M (reprint author), NICHD, NIH, 10 Ctr Dr,MSC 1830,Bldg 10,Rom 9S-241, Bethesda, MD 20892 USA. NR 41 TC 38 Z9 40 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2002 VL 71 IS 2 BP 407 EP 414 DI 10.1086/341606 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 575ZE UT WOS:000176977700019 PM 12058346 ER PT J AU Vahteristo, P Bartkova, J Eerola, H Syrjakoski, K Ojala, S Kilpivaara, O Tamminen, A Kononen, J Aittomaki, K Heikkila, P Holli, K Blomqvist, C Bartek, J Kallioniemi, OP Nevanlinna, H AF Vahteristo, P Bartkova, J Eerola, H Syrjakoski, K Ojala, S Kilpivaara, O Tamminen, A Kononen, J Aittomaki, K Heikkila, P Holli, K Blomqvist, C Bartek, J Kallioniemi, OP Nevanlinna, H TI A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LI-FRAUMENI-SYNDROME; DNA-DAMAGE CHECKPOINT; BRCA2 MUTATIONS; SUSCEPTIBILITY GENES; IN-VIVO; CHK2; KINASE; P53; PROTEIN; FINLAND AB CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63;, P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0001), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women. C1 Univ Helsinki, Cent Hosp, Biomedicum Helsinki B406B, Dept Obstet & Gynecol, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Oncol, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Clin Genet, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Pathol, FIN-00029 Helsinki, Finland. Danish Canc Soc, Inst Canc Biol, Copenhagen, Denmark. Tampere Univ, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ, Dept Oncol, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. Univ Uppsala Hosp, Dept Oncol, S-75185 Uppsala, Sweden. RP Nevanlinna, H (reprint author), Univ Helsinki, Cent Hosp, Biomedicum Helsinki B406B, Dept Obstet & Gynecol, Haartmaninkatu 8,POB 700, FIN-00029 Helsinki, Finland. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; Bartek, Jiri/G-5870-2014 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; NR 28 TC 271 Z9 280 U1 1 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2002 VL 71 IS 2 BP 432 EP 438 DI 10.1086/341943 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 575ZE UT WOS:000176977700023 PM 12094328 ER PT J AU t Mannetje, A Steenland, K Checkoway, H Koskela, RS Koponen, M Attfield, M Chen, JQ Hnizdo, E DeKlerk, N Dosemeci, M AF t Mannetje, A Steenland, K Checkoway, H Koskela, RS Koponen, M Attfield, M Chen, JQ Hnizdo, E DeKlerk, N Dosemeci, M TI Development of quantitative exposure data for a pooled exposure-response analysis of 10 silica cohorts SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE crystalline silica; quantitative exposure estimates; cohorts; diatomaceous earth; granite; industrial sand; pottery; metal mines ID DIATOMACEOUS-EARTH INDUSTRY; AFRICAN GOLD MINERS; VERMONT GRANITE WORKERS; LUNG-CANCER MORTALITY; POTTERY WORKERS; RISK ASSESSMENT; HISTORICAL EXPOSURE; CRYSTALLINE SILICA; DUST EXPOSURES; CHINA AB Background Comprehensive quantitative silica exposure estimates over time, measured in the same units across a number of cohorts, would make possible a pooled exposure-response analysis for lung cancer Such an analysis would help clarify the continuing controversy regarding whether silica causes lung cancer. Methods Existing quantitative exposure datafor 10 silica-exposed cohorts were retrieved from the original investigators. Occupation- and time-specific exposure estimates were either adopted/adapted or developed for each cohort, and converted to milligram per cubic meter (mg/m(3)) respirable crystalline silica. Results Quantitative exposure assignments were typically based on a large number (thousands) of raw measurements, or otherwise consisted of exposure estimates by experts (for two cohorts). Median exposure level of the cohorts ranged between 0.04 and 0.59 mg/m(3) respirable crystalline silica. Exposure estimates were partially validated via their successful prediction of silicosis in these cohorts. Conclusions Existing data were successfully adopted or modified to create comparable quantitative exposure estimates over time for 10 silica-exposed cohorts, permitting a pooled exposure-response analysis. The difficulties encountered in deriving common exposure estimates across cohorts are discussed. (C) 2002 Wiley-Liss, Inc. C1 Int Agcy Res Canc, Unit Environm Canc Epidemiol, F-69372 Lyon, France. Univ Utrecht, IRAS, Environm & Occupat Hlth Div, Utrecht, Netherlands. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Finnish Inst Occupat Hlth, Dept Epidemiol & Biostat, Helsinki, Finland. Outokumpu OVJ, Corp Environm Affairs, Espoo, Finland. NIOSH, Div Resp Dis Studies, Morgantown, WV USA. Tongji Med Univ, Wuhan, Peoples R China. Univ Western Australia, Dept Publ Hlth, Perth, WA 6009, Australia. NCI, Occupat Epdiemiol Branch, Washington, DC USA. RP Steenland, K (reprint author), NIOSH R13, Dept Hlth & Human Serv, Robert A Taft Labs, 4676 Columbia Pkwy, Cincinnati, OH 45226 USA. RI de Klerk, Nicholas/D-8388-2016 OI de Klerk, Nicholas/0000-0001-9223-0767 NR 43 TC 6 Z9 6 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD AUG PY 2002 VL 42 IS 2 BP 73 EP 86 DI 10.1002/ajim.10097 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 577KC UT WOS:000177059200001 ER PT J AU Jones, CA Agodoa, LY Coresh, J Eberhardt, M Chavers, B AF Jones, CA Agodoa, LY Coresh, J Eberhardt, M Chavers, B TI How to measure the prevalence of microalbuminuria in relation to age and gender? Reply SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter ID ALBUMIN; RATIO C1 Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Epidemiol, Hyattsville, MD 20782 USA. Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. RP Jones, CA (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2002 VL 40 IS 2 BP 437 EP 438 DI 10.1053/ajkd.2002.35150 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 578QN UT WOS:000177129800033 ER PT J AU Yoon, DS Wersto, RP Zhou, WB Chrest, FJ Garrett, ES Kwon, TK Gabrielson, E AF Yoon, DS Wersto, RP Zhou, WB Chrest, FJ Garrett, ES Kwon, TK Gabrielson, E TI Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GENETIC INSTABILITY; P53; FEATURES; CELLS; TUMORIGENESIS; ANEUPLOIDY; CARCINOMAS; EXPRESSION; MUTATIONS; PHENOTYPE AB Cytogenetic analyses have revealed that many aneuploid breast cancers have cell-to-cell variations of chromosome copy numbers, suggesting that these neoplasms have instability of chromosome numbers. To directly test for possible chromosomal instability in this disease, we used fluorescent in situ hybridization to monitor copy numbers of multiple chromosomes in cultures of replicating breast cancer-derived cell lines and nonmalignant breast epithelial cells. While most (7 of 9) breast cancer cell fines tested are highly unstable with regard to chromosome copy numbers, others (2 of 9 cell fines) have a moderate level of instability that is higher than the "background" level of normal mammary epithelial cells and MCF-10A cells, but significantly less than that seen in the highly unstable breast cancer cell fines. To evaluate the potential role of a defective mitotic spindle checkpoint as a cause of this chromosomal instability, we used flow cytometry to monitor the response of cells to nocodazole-induced mitotic spindle damage. All cell fines with high levels of chromosomal instability have defective mitotic spindle checkpoints, whereas the cell lines with moderate levels of chromosomal instability (and the stable normal mammary cells and MCF10A cells) arrest in G(2) when challenged with nocodazole. Notably, the extent of mitotic spindle checkpoint deficiency and chromosome numerical instability in these cells is unrelated to the presence or absence of p53 mutations. Our results provide direct evidence for chromosomal instability in breast cancer and show that this instability occurs at variable levels among cells from different cancers, perhaps reflecting different functional classes of chromosomal instability. High levels of chromosomal instability are likely related to defective mitotic checkpoints but not to p53 mutations. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Keimyung Univ, Sch Med, Dept Immunol, Taegu, South Korea. RP Gabrielson, E (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Johns Hopkins Oncol Ctr, 418 N Bond St, Baltimore, MD 21231 USA. FU NCI NIH HHS [5P50CA088843, P50 CA088843] NR 29 TC 69 Z9 75 U1 0 U2 1 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 AUG PY 2002 VL 161 IS 2 BP 391 EP 397 DI 10.1016/S0002-9440(10)64194-6 PG 7 WC Pathology SC Pathology GA 582DQ UT WOS:000177334800007 PM 12163363 ER PT J AU Waki, T Tamura, G Tsuchiya, T Sato, K Nishizuka, S Motoyama, T AF Waki, T Tamura, G Tsuchiya, T Sato, K Nishizuka, S Motoyama, T TI Promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic gastric epithelia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CPG-ISLAND METHYLATION; DNA METHYLATION; MICROSATELLITE INSTABILITY; HYPERMETHYLATION; CANCER; CARCINOMA; STOMACH AB Silencing of tumor suppressor and tumor-related genes by hypermethylation at promoter CpG islands is one of the major events in human tumorigenesis. Promoter methylation is also present in nonneoplastic cells as an age-related tissue-specific phenomenon that precedes the development of neoplasia. To clarify the significance of promoter methylation in nonneoplastic gastric epithelia as a precancerous signal, we investigated promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic cells of various organs obtained at autopsy, and compared the results with those of nonneoplastic epithelia of a cancerous stomach. Methylation of these genes was not seen in nonneoplastic cells of organs from people who were 22 years and younger (0%, 0 of 6). In contrast, E-cadherin and p16 were methylated in nonneoplastic gastric epithelia of persons who were 45 years or older. The numbers were 86% (12 of 14) and 29% (4 of 14), respectively. E-cadherin methylation occurred preferentially in the intestines, whereas p16 methylation was almost restricted to the stomach. For samples obtained from patients with stomach cancer, methylation was frequently observed in both neoplastic and corresponding nonneoplastic gastric epithelia: 47% (44 of 94) and 67% (63 of 94) for E-cadherin, 32% (30 of 94) and 24% (23 of 94) for hMLH1, and 22% (21 of 94) and 44% (41 of 94) for p16, respectively. hMLH1 methylation was not seen in nonneoplastic gastric epithelia from autopsy samples but occurred significantly in samples from nonneoplastic tissues of individuals with stomach cancer. Therefore, detection of hMLH1 methylation in nonneoplastic gastric epithelia may be useful for screening patients who may be at risk of developing gastric cancer. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 9909585, Japan. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), Yamagata Univ, Sch Med, Dept Pathol, Iida Nishi 2-2-2, Yamagata 9909585, Japan. NR 19 TC 109 Z9 118 U1 1 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 AUG PY 2002 VL 161 IS 2 BP 399 EP 403 DI 10.1016/S0002-9440(10)64195-8 PG 5 WC Pathology SC Pathology GA 582DQ UT WOS:000177334800008 PM 12163364 ER PT J AU Bonner, JC Rice, AB Ingram, JL Moomaw, CR Nyska, A Bradbury, A Sessoms, AR Chulada, PC Morgan, DL Zeldin, DC Langenbach, R AF Bonner, JC Rice, AB Ingram, JL Moomaw, CR Nyska, A Bradbury, A Sessoms, AR Chulada, PC Morgan, DL Zeldin, DC Langenbach, R TI Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PROSTAGLANDIN E-2 PRODUCTION; FIBROTIC LUNG FIBROBLASTS; SYNTHASE-DEFICIENT MICE; GROWTH-FACTOR; FACTOR-ALPHA; ARACHIDONIC-ACID; TNF-ALPHA; VANADIUM PENTOXIDE; GENE DISRUPTION AB The cyclooxygenase (COX)-2 enzyme has been implicated as an important mediator of pulmonary fibrosis. in this study, the lung fibrotic responses were investigated in COX-1 or COX-2-deficient (-/-) mice following vanadium pentoxide (V2O5) exposure. Lung histology was normal in saline-instilled wild-type and COX-deficient mice. COX-2(-/-), but not COX-1(-/-) or wild-type mice, exhibited severe inflammatory responses by 3 days following V2O5 exposure and developed pulmonary fibrosis 2 weeks post-V2O5 exposure. Western blot analysis and immunohistochemistry showed that COX-1 protein was present in type 2 epithelial cells, bronchial epithelial cells, and airway smooth muscle cells of saline or V2O5-exposed wild-type and COX-2(-/-) mice. COX-2 protein was present in Clara cells of wildtype and COX-1(-/-) terminal bronchioles and was strongly induced 24 hours after V2O5 exposure. Prostaglandin (PG) E-2 levels in the bronchoalveolar lavage (BAL) fluid from wild-type and COX-1(-/-) mice were significantly up-regulated by V2O5 exposure within 24 hours, whereas PGE(2) was not up-regulated in COX-2(-/-) BAL fluid. Tumor necrosis factor-alpha was elevated in the BAL fluid from all genotypes after V2O5 exposure, but was significantly and chronically elevated in the BAL fluid from COX-2(-/-) mice above wild-type or COX-1(-/-) mice. These findings indicate that the COX-2 enzyme is protective against pulmonary fibrogenesis, and we suggest that COX-2 generation of PGE(2) is an important factor in resolving inflammation. C1 NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Bonner, JC (reprint author), NIEHS, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 31 TC 83 Z9 87 U1 1 U2 1 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 AUG PY 2002 VL 161 IS 2 BP 459 EP 470 DI 10.1016/S0002-9440(10)64202-2 PG 12 WC Pathology SC Pathology GA 582DQ UT WOS:000177334800015 PM 12163371 ER PT J AU Williams, K Schwartz, A Corey, S Orandle, M Kennedy, W Thompson, B Alvarez, X Brown, C Gartner, S Lackner, A AF Williams, K Schwartz, A Corey, S Orandle, M Kennedy, W Thompson, B Alvarez, X Brown, C Gartner, S Lackner, A TI Proliferating cellular nuclear antigen expression as a marker of perivascular macrophages in simian immunodeficiency virus encephalitis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; HUMAN MONONUCLEAR PHAGOCYTES; PERIPHERAL-BLOOD MONOCYTES; IN-SITU HYBRIDIZATION; BONE-MARROW; HIV-1 INFECTION; RHESUS MACAQUES; CEREBROSPINAL-FLUID; RESIDENT MICROGLIA; DNA-REPLICATION AB Brain perivascular macrophages are a major target of simian immunodeficiency virus (SIV) infection in rhesus macaques and HIV infection in humans. Perivascular macrophages are distinct from parenchymal microglia in their location, morphology, expression of myeloid markers, and turnover in the CNS. In contrast to parenchymal microglia, perivascular macrophages are continuously repopulated by blood monocytes, which undergo maturation to macrophages on entering the central nervous system (CNS). We studied differences in monocyte/macrophages in vivo that might account for preferential infection of perivascular macrophages by SIV. In situ hybridization for SIV and proliferating cellular nuclear antigen (PCNA) immunohistochemistry demonstrated that SIV-infected and PCNA-positive cells were predominantly found in perivascular cuffs of viremic animals and in histopathological lesions that characterize SIV encephalitis (SIVE) in animals with AIDS. Multilabel techniques including double-label immunohistochemistry and combined in situ hybridization and immunofluorescence confocal microscopy revealed numerous infected perivascular macrophages that were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing macrophage subpopulations were found in the small intestine and lung of animals with AIDS. While PCNA is used as a marker of cell proliferation it is also strongly expressed in nondividing cells undergoing DNA synthesis and repair. Therefore, more specific markers for cell proliferation including Ki-67, topoisomerase IIalpha, and bromodeoxyuridine (BrdU) incorporation were used which indicated that PCNA-positive cells within SIVE lesions were not proliferating. These observations are consistent with perivascular macrophages; as terminally differentiated, non-dividing cells and underscores biological differences that could potentially define mechanisms of preferential, productive infection of perivascular macrophages in the rhesus macaque model of neuroAIDS. These studies suggest that within CNS and non-CNS tissues there exist subpopulations of macrophages that are SIV-infected and express PCNA. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Med, Div Viral Pathogenesis, Boston, MA 02215 USA. Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Southborough, MA USA. NIH, Rockville, MD USA. Johns Hopkins Med Sch, Dept Neurol, Baltimore, MD USA. RP Williams, K (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Med, Div Viral Pathogenesis, RE-113,330 Brookline Ave, Boston, MA 02215 USA. FU NCRR NIH HHS [RR00168, P51 RR000168, RR07000, T32 RR007000, K26 RR000168]; NINDS NIH HHS [NS37654, R01 NS040237, R01 NS037654, NS40237, NS35732] NR 53 TC 56 Z9 56 U1 1 U2 1 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 AUG PY 2002 VL 161 IS 2 BP 575 EP 585 DI 10.1016/S0002-9440(10)64213-7 PG 11 WC Pathology SC Pathology GA 582DQ UT WOS:000177334800026 PM 12163382 ER PT J AU Roy, TA Blackman, MR Harman, SM Tobin, JD Schrager, M Metter, EJ AF Roy, TA Blackman, MR Harman, SM Tobin, JD Schrager, M Metter, EJ TI Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE aging; skeletal muscle mass ID SKELETAL-MUSCLE MASS; MIDDLE-AGED MEN; RANDOMIZED CONTROLLED TRIAL; CLINICAL RESEARCH-CENTER; HYPOGONADAL MEN; BODY-COMPOSITION; RISK-FACTORS; LUTEINIZING-HORMONE; ELDERLY MEN; HEALTHY-MEN AB Muscle mass and strength losses during aging may be associated with declining levels of serum testosterone (T) in men. Few studies have shown a direct relationship between T and muscle mass and strength. Subjects were 262 men, aged 24-90 yr, from the Baltimore Longitudinal Study of Aging, who had T and sex hormone-binding globulin sex hormone-binding globulin (SHBG) measurements, from which the free T index (FTI) was calculated (T/SHBG) from serum samples collected longitudinally since 1963, total body fat mass and arm and leg fat-free mass (FFM) by dual-energy X-ray absorptiometry and arm and leg strength by dynanomometry. Mixed-effects models estimated T and FTI at the time of mass and strength measurements. Age, total body fat, arm and leg FFM, T, and FTI were significantly associated with concentric and eccentric strength. FTI, not T, was modestly, but directly, related to arm and leg strength after fat, arm and leg FFM, height, and age were accounted for and indirectly through body mass. FTI is a better predictor of arm and leg strength than T in aging men. C1 NIA, Clin Invest Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIH, Clin Invest Lab, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Kronos Lonev Res Inst, Phoenix, AZ 85018 USA. RP Metter, EJ (reprint author), Gerontol Res Ctr, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 50 TC 104 Z9 107 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2002 VL 283 IS 2 BP E284 EP E294 DI 10.1152/ajpendo.00334.2001 PG 11 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 571GL UT WOS:000176709600012 PM 12110533 ER PT J AU Cross, HR Murphy, E Steenbergen, C AF Cross, HR Murphy, E Steenbergen, C TI Ca2+ loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE energetics; gender; nitric oxide synthase; nuclear magnetic resonance spectroscopy ID NITRIC-OXIDE SYNTHASE; ESTROGEN REPLACEMENT THERAPY; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; TRANSGENIC MICE; NO SYNTHASE; IN-VITRO; EXPRESSION; MYOCARDIUM; RAT AB To compare ischemia-reperfusion injury in males versus females under hypercontractile conditions, perfused hearts from 129J mice pretreated with 3 mmol/l Ca2+ or 10(-8) mol/l isoproterenol +/- 10(-6) mol/l N-omega-nitro-L-arginine methyl ester (L-NAME) were subjected to 20 min of ischemia and 40 min of reperfusion while P-31 NMR spectra were acquired. Basal contractility increased equivalently in female versus male hearts with isoproterenol- or Ca2+ treatment. Injury was equivalent in untreated male versus female hearts but was greater in isoproterenol or Ca2+-treated male than female hearts, as indicated by lower postischemic contractile function, ATP, and PCr. Endothelial nitric oxide (NO) synthase (eNOS) expression was higher in female than male hearts, neuronal NOS (nNOS) did not differ, and inducible NOS (iNOS) was undetectable. Ischemic NO production was higher in female than male hearts, and L-NAME increased injury in female isoproterenol- treated hearts. In summary, isoproterenol or high Ca2+ pretreatment increased ischemia-reperfusion injury in males more than females. eNOS expression and NO production were higher in female than male hearts, and L-NAME blocked female protection. Females were therefore protected from the detrimental effects of adrenergic stimulation and Ca2+ loading via a NOS-mediated mechanism. C1 Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Cross, HR (reprint author), Duke Univ, Med Ctr, Dept Pathol, Box 3712, Durham, NC 27710 USA. FU NHLBI NIH HHS [R01 HL039752] NR 23 TC 56 Z9 56 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2002 VL 283 IS 2 BP H481 EP H489 DI 10.1152/ajpheart.00790.2001 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 574GM UT WOS:000176880500004 PM 12124192 ER PT J AU Schultz, CJ Torres, E Londos, C Torday, JS AF Schultz, CJ Torres, E Londos, C Torday, JS TI Role of adipocyte differentiation-related protein in surfactant phospholipid synthesis by type II cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE lipid storage droplets; neutral lipids; fetal lung development ID LIPID INTERSTITIAL CELL; RAT LUNG FIBROBLAST; DROPLETS; PERILIPIN; EXPRESSION; RECEPTOR; ADRP AB Adipocyte differentiation-related protein (ADrP) is an intrinsic lipid storage droplet protein that is highly expressed in lung. ADrP localizes to lipid storage droplets within lipofibroblasts, pulmonary cells characterized by high triacylglycerol, which is a precursor for surfactant phospholipid synthesis by alveolar type II epithelial (EPII) cells. The developmental pattern of ADrP mRNA and protein expression in lung tissue parallels triacylglycerol accumulation in rat lung. ADrP mRNA levels are relatively high in isolated lipofibroblasts, accounting for the high ADrP expression in lung. Isolated EPII cells, which do not store neutral lipids but derive them from lipofibroblasts, have low levels of ADrP mRNA expression. ADrP is found around lipid droplets in cultured lipofibroblasts, but not in EPII cells isolated from developing rat lung. After coculture with lipofibroblasts, EPII cells acquired ADrP, which associates with lipid droplets. Furthermore, H-3-labeled triolein in isolated ADrP-coated lipid droplets is a tenfold better substrate for surfactant phospholipid synthesis by cultured EPII cells than H-3-labeled synthetic triolein alone. Antibodies to ADrP block transfer of neutral lipid. These data suggest a role for ADrP in this novel mechanism for the transfer of lipid between lipofibroblasts and EPII cells. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Harbor UCLA Med Ctr Res & Educ Inst, Dept Pediat, Torrance, CA 90502 USA. Univ Calif Los Angeles, Harbor UCLA Med Ctr Res & Educ Inst, Dept Obstet & Gynecol, Torrance, CA 90502 USA. RP Londos, C (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bldg 50,Room 3133, Bethesda, MD 20892 USA. OI Torday, John/0000-0001-9071-3052 FU NHLBI NIH HHS [HL-55268] NR 37 TC 59 Z9 63 U1 0 U2 3 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 AUG PY 2002 VL 283 IS 2 BP L288 EP L296 DI 10.1152/ajplung.00204.2001 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 571ZD UT WOS:000176748300008 PM 12114189 ER PT J AU Zhang, Z Cai, Q Michea, L Dmitrieva, NI Andrews, P Burg, MB AF Zhang, Z Cai, Q Michea, L Dmitrieva, NI Andrews, P Burg, MB TI Proliferation and osmotic tolerance of renal inner medullary epithelial cells in vivo and in cell culture SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE sodium cloride; urea; renal papilla ID HIGH UREA CONCENTRATIONS; HYPERTONIC STRESS; APOPTOSIS AB Renal inner medullary (IM) cells survive interstitial osmolality that ranges from 600 to 1,700 mosmol/kgH(2)O or more. In contrast, much smaller acute changes killed the cells previously studied in tissue culture, such as mouse IM collecting duct 3 (mIMCD3) cells, that are immortalized with SV40 and proliferate rapidly. Proliferation and DNA replication sensitize mIMCD3 cells to hypertonicity. In the present studies, we observed that proliferating cells were scarce in rat IM. Then, we prepared passage 2 mouse IM epithelial (p2mIME) cells. They have a much lower incidence of DNA replication than do mIMCD3 cells. p2mIME cells survive much greater acute increases in NaCl than do mIMCD3 cells and also tolerate significantly greater acute increases of urea and of NaCl plus urea, but still not to levels as high as occur in vivo. We conclude that immortalization and continued DNA replication account for part of the previously observed difference in osmotic tolerance between IM cells in vivo and in cell culture but that other factors must also be involved. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Los Andes, Fac Med, Lab Cellular & Mol Physiol, Santiago, Chile. Georgetown Univ, Med Ctr, Dept Cell Biol, Washington, DC 20002 USA. RP Zhang, Z (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Rm 6N315,Bldg 10, Bethesda, MD 20892 USA. EM Zhangz@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 12 TC 29 Z9 29 U1 0 U2 1 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 AUG PY 2002 VL 283 IS 2 BP F302 EP F308 DI 10.1152/ajprenal.00038.2002 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 571GK UT WOS:000176709500012 PM 12110514 ER PT J AU Masse, LC Dassa, C Gauvin, L Giles-Corti, B Motl, R AF Masse, LC Dassa, C Gauvin, L Giles-Corti, B Motl, R TI Emerging measurement and statistical methods in physical activity research SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE factor analysis; focus groups; health promotion; interviews; investigative techniques; psychometrics; physical fitness; statistics ID ITEM RESPONSE THEORY; HEALTH-RELATED BEHAVIOR; MULTILEVEL ANALYSIS; EXERCISE ADHERENCE; LATENT-VARIABLES; PERSPECTIVES; ENVIRONMENTS; EDUCATION; PROMOTION; SMOKING AB Although many studies have attempted to identify mediators and moderators of changes in physical activity involvement, the literature is inconclusive regarding which variable(s) relate to physical activity behavior change. The Cooper 2001 Conference series dedicated a session to discussing measurement and statistical methods that could contribute to advancing this research agenda. This article focuses on four such methodologic approaches: qualitative; psychometric; latent-variable, structural equation modeling; and multilevel modeling. The article presents a brief overview of these methods and discusses potential advantages and limitations of using them. C1 NCI, DCCP, BRP, HPRB, Bethesda, MD 20892 USA. Univ Montreal, Dept Social & Prevent Med, Montreal, PQ, Canada. Univ Western Australia, Dept Publ Hlth, Crawley, WA, Australia. Univ Georgia, Dept Exercise Sci, Athens, GA 30602 USA. RP Masse, LC (reprint author), NCI, DCCP, BRP, HPRB, 6130 Execut Blvd,EPN 4076 MSC 7335, Bethesda, MD 20892 USA. NR 92 TC 49 Z9 50 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2002 VL 23 IS 2 SU S BP 44 EP 55 AR PII S0749-3797(02)00473-7 DI 10.1016/S0749-3797(02)00473-7 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 579MJ UT WOS:000177181500008 PM 12133737 ER PT J AU Berrigan, D Troiano, RP AF Berrigan, D Troiano, RP TI The association between urban form and physical activity in US adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE behavior; environment; exercise; health promotion; health surveys; NHANES; physical fitness; walking ID LAND-USE; TRAVEL BEHAVIOR; INTERVENTIONS; DISEASE AB Background: Physical inactivity is associated with multiple adverse health outcomes. Results from the transportation literature suggest that aspects of the urban environment may influence walking for transportation. In this paper we examine the association between a proxy measure of the urban environment and walking behavior. Methods: We analyzed the association between home age and walking behavior in U.S. adults using data from the Third National Health and Nutrition Examination Survey. Logistic regression was used to estimate odds ratios and 95% confidence intervals and to control for the effects of gender, race/ethnicity, age, education level, household income, and activity limitations. Results: Adults who lived in homes built before 1946 and from 1946 to 1973 were significantly more likely to walk 1+ miles greater than or equal to20 times per month than those who lived in homes built after 1973. This association was present among people living in urban and suburban counties, but absent among those living in rural counties. The association was also found in models that controlled for gender, race/ethnicity, age, education, income, and any health-related activity limitation. Other forms of leisure-time physical activity were nor independently associated with home age. Conclusions: These results support the hypothesis that environmental variables influence walking frequency and suggest that home age may be a useful proxy for features of the urban environment that influence physical activity in the form of walking. Such proxy measures could facilitate testing ecologic models of health behavior using survey data. C1 NIH, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Berrigan, D (reprint author), NIH, Div Canc Control & Populat Sci, Execut Plaza N MSC 7344,Room 4005,6130 Execut Blv, Bethesda, MD 20892 USA. OI Troiano, Richard/0000-0002-6807-989X NR 27 TC 116 Z9 118 U1 0 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2002 VL 23 IS 2 SU S BP 74 EP 79 AR PII S0749-3797(02)00476-2 DI 10.1016/S0749-3797(02)00476-2 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 579MJ UT WOS:000177181500011 PM 12133740 ER PT J AU Fee, E Brown, TM Lazarus, J Theerman, P AF Fee, E Brown, TM Lazarus, J Theerman, P TI Young men of 50 and 60 years behave like kids after having read the new work by M. Flourens SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2002 VL 92 IS 8 BP 1222 EP 1222 DI 10.2105/AJPH.92.8.1222 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 578GV UT WOS:000177109800009 PM 12144971 ER PT J AU Brown, TM Fee, E AF Brown, TM Fee, E TI Isaac Max Rubinow - Advocate for social insurance SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. NR 9 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 AUG PY 2002 VL 92 IS 8 BP 1224 EP 1226 DI 10.2105/AJPH.92.8.1224 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 578GV UT WOS:000177109800011 PM 12144973 ER PT J AU Guralnik, JM Alecxih, L Branch, LG Wiener, JM AF Guralnik, JM Alecxih, L Branch, LG Wiener, JM TI Medical and long-term care costs when older persons become more dependent SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID DISABILITY; TRENDS C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Lewin Grp, Falls Church, VA USA. Duke Univ, Ctr Aging & Human Dev, Durham, NC 27706 USA. Urban Inst, Washington, DC 20037 USA. RP Guralnik, JM (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Room 3C-309, Bethesda, MD 20892 USA. NR 7 TC 61 Z9 63 U1 1 U2 3 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 AUG PY 2002 VL 92 IS 8 BP 1244 EP 1245 DI 10.2105/AJPH.92.8.1244 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 578GV UT WOS:000177109800014 PM 12144976 ER PT J AU Foley, DJ Heimovitz, HK Guralnik, JM Brock, DB AF Foley, DJ Heimovitz, HK Guralnik, JM Brock, DB TI Driving life expectancy of persons aged 70 years and older in the United States SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID VEHICLE CRASHES; HEALTH-STATUS; DRIVERS; CESSATION; POPULATION; COMMUNITY; PEOPLE; ADULTS; US AB Objectives. We estimated total life expectancy and driving life expectancy of US drivers aged 70 years and older. Methods. Life table methods were applied to 4699 elderly persons who were driving in 1993 and reassessed in a 1995 survey. Results. Drivers aged 70 to 74 years had a driving life expectancy of approximately 11 years. A higher risk of mortality among men as a cause of driving cessation offset a higher risk of driving cessation not related to mortality among women that resulted in similar driving life expectancies. Conclusions. Nationwide. many elderly drivers quit driving each year and must seek alternative sources of transportation. Because of differences in life expectancy, women require more years of support for transportation. on average, than men after age 70. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Sytel Inc, Rockville, MD USA. RP Foley, DJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. FU NIA NIH HHS [U01 AG-09740, U01 AG009740] NR 37 TC 85 Z9 85 U1 1 U2 4 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 AUG PY 2002 VL 92 IS 8 BP 1284 EP 1289 DI 10.2105/AJPH.92.8.1284 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 578GV UT WOS:000177109800023 PM 12144985 ER PT J AU Masur, H AF Masur, H TI Acquired immunodeficiency syndrome in the intensive care unit - Will human immunodeficiency virus-related admissions continue to decline? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID PNEUMOCYSTIS-CARINII PNEUMONIA; DIAGNOSIS C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. RI Andrade, Hugo/M-6631-2013 OI Andrade, Hugo/0000-0001-6781-6125 NR 10 TC 6 Z9 6 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 AUG 1 PY 2002 VL 166 IS 3 BP 258 EP 259 DI 10.1164/rccm.2205019 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 580QV UT WOS:000177246000002 PM 12153952 ER PT J AU Coorssen, JR Blank, PS Albertorio, F Bezrukov, L Kolosova, I Backlund, PS Zimmerberg, J AF Coorssen, JR Blank, PS Albertorio, F Bezrukov, L Kolosova, I Backlund, PS Zimmerberg, J TI Quantitative femto- to attomole immunodetection of regulated secretory vesicle proteins critical to exocytosis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE quantitative immunodetection; Western blotting; secretory vesicles; SNARE proteins; protein purity ID POLYACRYLAMIDE GEL-ELECTROPHORESIS; MEMBRANE-FUSION; SNARE PROTEINS; NITROCELLULOSE; COMPLEX; NSF; AGGREGATION; SUFFICIENT; ANTIBODY; GRANULES AB Although immunoblotting (Western blotting) is widely used for the detection of specific proteins, it is often thought to be an inadequate technique for accurate and precise measurements of protein concentration. However, an accurate and precise technique is essential for quantitative testing of hypotheses, and thus for the analysis and understanding of proposed molecular mechanisms. The analysis of Ca2+-triggered exocytosis, the ubiquitous eukaryotic process by which vesicles fuse to the plasma membrane and release their contents, requires such an unambiguous identification and a quantitative assessment of the membrane surface density of specific molecules. Newly refined immunoblotting and analysis approaches permit a quantitative analysis of the SNARE protein complement (VAMP, SNAP-25, and syntaxin) of functional secretory vesicles. The method illustrates the feasibility of the routine quantification of femtomole to attomole amounts of known proteins by immunoblotting. The results indicate that sea urchin egg secretory vesicles and synaptic vesicles have markedly similar SNARE densities. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Univ Calgary, Fac Med, Neurosci Res Grp, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada. RP Coorssen, JR (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 36 TC 27 Z9 27 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 2002 VL 307 IS 1 BP 54 EP 62 AR PII S0003-2697(02)00015-5 DI 10.1016/S0003-2697(02)00015-5 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 584ZE UT WOS:000177498000008 PM 12137779 ER PT J AU Freedman, DM Tarone, RE Doody, MM Mohan, A Alexander, BH Boice, JD Linet, MS AF Freedman, DM Tarone, RE Doody, MM Mohan, A Alexander, BH Boice, JD Linet, MS TI Trends in reproductive, smoking, and other chronic disease risk factors by birth cohort and race in a large occupational study population SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE chronic disease; neoplasms; risk factors; trends; menarche; body height; smoking; oral contraceptives; reproduction; parity ID BREAST-CANCER RISK; UNITED-STATES; OVARIAN-CANCER; CARDIOVASCULAR-DISEASE; ORAL-CONTRACEPTIVES; SECULAR TREND; SHORT STATURE; HEIGHT; WOMEN; WEIGHT AB PURPOSE: To illustrate the value of cohort studies to assess trends in chronic disease risk factors. METHODS: In collaboration with the American Registry of Radiologic Technologists and the University of Minnesota, the National Cancer Institute initiated a cohort study of cancer among radiologic technologists. More than 90,000 technologists who responded to a mailed questionnaire were grouped into ten birth cohorts from before 1920 through 1960 and later, and stratified by self-reported racial/ethnic groups. Trends in height, smoking, and reproductive factors were analyzed. RESULTS: Among the trends observed were that the proportion of young men (< 18 years) smoking generally fell in each birth cohort after 1925, whereas the proportion of young women smoking rose for those born after 1950. Among women born since 1940, the mean age at menarche for white women has remained at 12.5 years, but has declined among black and Asian/Pacific Islander women. Recent birth cohorts (since 1955) show among the highest mean ages at birth of first child (> 26 years), highest rates of nulliparity at age 25 (greater than or equal to 63 %), and lowest mean parity levels (less than or equal to 1.7) compared with earlier cohorts. CONCLUSION: Analyses of large cohorts can clarify birth cohort trends in chronic disease risk factors. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, EPS Room 7087,6120 Execut Blvd, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-51016, N02-CP-81005, N01-CP-15673, N02-CP-81121] NR 31 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2002 VL 12 IS 6 BP 363 EP 369 AR PII S1047-2797(01)00295-2 DI 10.1016/S1047-2797(01)00295-2 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 580XH UT WOS:000177261700001 PM 12160594 ER PT J AU Abbott, KC Hypolite, IO Viola, R Poropatich, RK Hshieh, P Cruess, D Hawkes, CA Agodoa, LY AF Abbott, KC Hypolite, IO Viola, R Poropatich, RK Hshieh, P Cruess, D Hawkes, CA Agodoa, LY TI Hospitalizations for cytomegalovirus disease after renal transplantation in the United States SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE cytomegalovirus; viral; hospitalization; renal transplant; complications; dialysis; rejection; antibody induction; mycophenolate mofetil; USRDS ID MYCOPHENOLATE-MOFETIL; INDUCTION IMMUNOSUPPRESSION; ANTILYMPHOCYTE GLOBULIN; RECIPIENTS; INFECTION; PROPHYLAXIS; RISK; REJECTION; GRAFT; OKT3 AB PURPOSE: Risk factors, sites, and mortality of hospitalized cytomegalovirus (CMV) disease in renal transplant recipients have not been studied in a national population, METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System from 1 July 1, 1994 to June 30, 1997 were analyzed in an historical cohort study of patients with a primary discharge diagnosis of CMV disease (ICD9 Code 078.5x). RESULTS: Renal transplant recipients had an incidence density of hospitalized CMV disease of 1.26/100 person years. and 79% of hospitalizations for CMV disease occurred in the first six months post trans plant. The leading manifestation of hospitalized infection was pneumonia In logistic regression analysis controlling for transplant era, pre-transplant dialysis greater than or equal to 6 months, maintenance mycophenolate mofetil (MMF) therapy, and allograft rejection, but not induction antibody therapy, were significantly associated with hospitalized CMV disease. Compared with recipient, with negative CMV serology (R.) who had donor kidneys with negative CMV serology (D-), D+/R- had the highest risk of hospitalization for CMV disease [adjusted odds ratio (AOR) 5,19, 95% confidence interval (CI) 3.89-6.93] followed by D+/R+ recipients, whereas D-/R+ were not at significantly increased risk. In Cox Regression analysis the relative risk of death associated with hospitalized CMV disease was 132 (95% CI 1.02-1.71), CONCLUSIONS: Ever, in modern era, renal transplant recipients were at high risk for hospitalizations for CMV disease, which were associated with decreased patient survival. Current prophylactic measures have apparently not reduced the high risk of D+/R- recipient,. prolonged pre-transplant dialysis and maintenance MMF should also be considered risk factors for hospitalized CMV infection, and prospective trials of prophylactic antiviral therapy should he performed in these subgroups. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDK, Bethesda, MD USA. Walter Reed Army Med Ctr, Serv Pharm, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Pulm Crit Care Serv, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Infect Dis Serv, Washington, DC 20307 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 38 TC 47 Z9 58 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2002 VL 12 IS 6 BP 402 EP 409 AR PII S1047-2797(01)00283-6 DI 10.1016/S1047-2797(01)00283-6 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 580XH UT WOS:000177261700006 PM 12160599 ER PT J AU Schmidt, R Schmidt, H Curb, JD Masaki, K White, LR Launer, LJ AF Schmidt, R Schmidt, H Curb, JD Masaki, K White, LR Launer, LJ TI Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia aging study SO ANNALS OF NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; CORONARY HEART-DISEASE; ALZHEIMERS-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; PLASMA-CONCENTRATION; CEREBROSPINAL-FLUID; APOLIPOPROTEIN-E; JAPANESE MEN; STROKE AB Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease. We evaluated the long-term prospective association between dementia and high-sensitivity C-reactive protein, a nonspecific marker of inflammation. Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program (1968-1970) and subsequently were reexamined 25 years later for dementia in the Honolulu-Asia Aging Study (1991-1996). In a random subsample of 1,050 Honolulu-Asia Aging Study cases and noncases, high-sensitivity C-reactive protein concentrations were measured from serum taken at the second examination; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria. Compared with men in the lowest quartile (< 0.34mg/L) of high-sensitivity C-reactive protein, men in the upper three quartiles had a 3-fold significantly increased risk for all dementias combined, Alzheimer's disease, and vascular dementia. For vascular dementia, the risk increased with increasing quartile. These relations were independent of cardiovascular risk factors and disease. These data support the view that inflammatory markers may reflect not only peripheral disease, but also cerebral disease mechanisms related to dementia, and that these processes are measurable long before clinical symptoms appear. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Karl Franzens Univ Graz, Dept Neurol, A-8010 Graz, Austria. Karl Franzens Univ Graz, Inst Med Biochem & Med Mol Biol, A-8010 Graz, Austria. Pacific Hlth Res Inst, Honolulu, HI USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Gateway Bldg 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [N01-AG-4-2149] NR 50 TC 334 Z9 350 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2002 VL 52 IS 2 BP 168 EP 174 DI 10.1002/ana.10265 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 578UX UT WOS:000177140000006 PM 12210786 ER PT J AU Li, ST Dendi, R Holmes, C Goldstein, DS AF Li, ST Dendi, R Holmes, C Goldstein, DS TI Progressive loss of cardiac sympathetic innervation in Parkinson's disease SO ANNALS OF NEUROLOGY LA English DT Article ID MULTIPLE-SYSTEM ATROPHY; METAIODOBENZYLGUANIDINE MYOCARDIAL SCINTIGRAPHY; I-123 MIBG UPTAKE; AUTONOMIC FAILURE; DIFFERENTIATION; DENERVATION; DYSFUNCTION; HEART AB This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson's disease. In 9 patients without orthostatic hypotension, 6-[F-18]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[F-18]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson's disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying-back mechanism. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Li, ST (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 15 TC 52 Z9 55 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2002 VL 52 IS 2 BP 220 EP 223 DI 10.1002/ana.10236 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 578UX UT WOS:000177140000013 PM 12210793 ER PT J AU Ende, K Mah, L Kass, ES AF Ende, K Mah, L Kass, ES TI Progression of late-stage chronic maxillary atelectasis SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article ID SILENT SINUS C1 NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Kass, ES (reprint author), NIH, Bldg 10,Room 5C400,10 Ctr Dr,MSC 1750, Bethesda, MD 20892 USA. NR 9 TC 4 Z9 5 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD AUG PY 2002 VL 111 IS 8 BP 759 EP 762 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 583LQ UT WOS:000177409700019 PM 12184602 ER PT J AU Kawakami, K Kawakami, M Puri, RK AF Kawakami, K Kawakami, M Puri, RK TI Cytokine receptor as a sensitizer for targeted cancer therapy SO ANTI-CANCER DRUGS LA English DT Review DE cytotoxin therapy; Fas/CD95; gene transfer; immunotherapy; interleukin-13 receptor; sensitization ID TUMOR-NECROSIS-FACTOR; CARCINOMA CELL-LINES; PERMUTED INTERLEUKIN 4-TOXIN; FAS-MEDIATED CYTOTOXICITY; HUMAN-MALIGNANT GLIOMA; INDUCED APOPTOSIS; GENE-TRANSFER; PSEUDOMONAS EXOTOXIN; ALPHA-CHAIN; SIGNAL-TRANSDUCTION AB Introducing a cytokine receptor as a sensitizer into cancer cells offers a unique opportunity for receptor-targeted cancer therapy. It has been shown that transfection of the tumor necrosis factor (TNF) receptor gene in cancer cells or exposing cancer cells to certain reagents which increase expression of TNF receptors results in enhancement of the cytotoxic effect of TNF. In addition, the literature suggests that Fas/CD95-mediated apoptotic tumor cell killing is augmented by gene transfer of Fas Into cancer cells or treatment of cells with agents like cisplatin and interferon (IFN)-gamma. In contrast to these approaches, we have discovered a new approach to cancer therapy; wherein introduction of a cytokine receptor chain into cancer cells sensitizes them to receptor-directed cytotoxins. We have demonstrated that when interieukin (IL)-13 receptor (IL-13R) alpha2 chain, one of the two known IL-13 binding proteins, is introduced into cancer cells that do not express this chain the cells acquire extreme sensitivity to a chimeric fusion cytotoxin composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE). Cells that do not express this chain or express low levels show limited sensitivity to IL13-PE. Acquisition of sensitivity to IL13-PE was observed both in vitro and in vivo when IL-13Ralpha2-transtected human tumor cells were implanted in immunodeficient animals followed by systemic or regional IL13-PE therapy. Our third generation experiments suggest that this approach is feasible for clinical situations as intratumor administration of plasmid carrying the IL-13Ralpha2 chain gene sensitized these tumors to systemic or regional IL13-PE therapy. This unique approach comprising gene transfer of cytokine receptor chain and receptor-targeted cytotoxin administration represents a novel strategy for cancer therapy. [(C) 2002 Lippincott Williams Wilkins.]. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 77 TC 8 Z9 10 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD AUG PY 2002 VL 13 IS 7 BP 693 EP 699 DI 10.1097/00001813-200208000-00003 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 585FV UT WOS:000177515500003 PM 12187325 ER PT J AU Peters, JM Chen, NH Gatton, M Korsinczky, M Fowler, EV Manzetti, S Saul, A Cheng, Q AF Peters, JM Chen, NH Gatton, M Korsinczky, M Fowler, EV Manzetti, S Saul, A Cheng, Q TI Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MOLECULAR-DYNAMICS; PYRIMETHAMINE RESISTANCE; MALARIA PARASITES; BC(1) COMPLEX; IN-VIVO; CHLOROQUINE; DRUG; INFECTIONS; DIVERSITY; ADVANTAGE AB Drug resistance in malarial parasites has become a major obstacle in the control of the disease. Strategies are urgently needed to control the development of resistance and to possibly reverse existing resistance. One key element required to reverse malaria drug resistance is for the parasites to "pay" a biological "cost" or suffer a loss of fitness when acquiring resistance to antimalarial drugs. Such a situation would be a disadvantage to the resistant parasites in the absence of drug pressure. We compared here the relative fitness of atovaquone-resistant Plasmodium falciparum K1 clones with single and double base mutations in their cytochrome b genes to their parent clones during erythrocytic stages in the absence of drug pressure. We found that the double amino acid mutation (M133I and G280D) is associated with a 5 to 9% loss of fitness and that the single amino acid change of M133I did not result in any detectable loss of fitness. Molecular modeling of the interaction of P. falciparum cytochrome b with ubiquinone led to the prediction that a loss of fitness of the malaria parasites would result from the G280D mutation due to its close proximity to the putative ubiquinone-binding site. This appears to have resulted in a weakening of the cytochrome b-ubiquinone complex, thereby causing the electron transport chain to become less efficient. Our results suggest that the prevalence of resistant parasites may decrease after the drug usage is discontinued. C1 Queensland Inst Med Res, Malaria Lab, Infect Dis Unit, Brisbane, Qld 4006, Australia. Australian Army Malaria Inst, Dept Parasitol, Brisbane, Qld, Australia. Queensland Univ Technol, Ctr Mol Biotechnol, Brisbane, Qld, Australia. Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. NIH, Malaria Vaccine Dev Unit, Bethesda, MD 20892 USA. RP Cheng, Q (reprint author), Australian Army Malaria Inst, Dept Parasitol, Gallipoli Barracks, Enoggera, Qld 4051, Australia. RI Manzetti, Sergio/K-8622-2012; Saul, Allan/I-6968-2013; OI Manzetti, Sergio/0000-0003-4240-513X; Saul, Allan/0000-0003-0665-4091; Gatton, Michelle/0000-0003-1188-609X FU NIAID NIH HHS [AI 47500-02, R01 AI047500] NR 38 TC 41 Z9 41 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2002 VL 46 IS 8 BP 2435 EP 2441 DI 10.1128/AAC.46.8.2435-2441.2002 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 575VG UT WOS:000176968700018 PM 12121915 ER PT J AU Groll, AH Wood, L Roden, M Mickiene, D Chiou, CC Townley, E Dad, L Piscitelli, SC Walsh, TJ AF Groll, AH Wood, L Roden, M Mickiene, D Chiou, CC Townley, E Dad, L Piscitelli, SC Walsh, TJ TI Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MULTIPLE-DOSE PHARMACOKINETICS; HIV-INFECTED PATIENTS; ORAL SOLUTION; IN-VITRO; RESISTANT OROPHARYNGEAL; ANTIFUNGAL PROPHYLAXIS; CLINICAL-RESPONSE; FLUCONAZOLE; CHILDREN; CANDIDOSIS AB The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4(+)-cell count, 128/mul) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (C-max), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC(0-24)) the concentration in plasma at the end of the dosing interval (predose) (C-min), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 +/- 0.53 mug/ml, 6.80 +/- 7.4 mug . h/ml, 0.192 +/- 0.06 mug/ml, and 56.48 +/- 44 h, respectively, for the QD regimen and 1.340 +/- 0.75 mug/ml, 23.04 +/- 14.5 mug . h/ml, 0.782 +/- 0.19 mug/ml, and 104.22 +/- 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 +/- 0.9 and 3.53 +/- 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxy-itraconazole/AUC of ITRA) at day 15 were 1.96 +/- 0.1 for the QD regimen and 1.29 +/- 0.2 for the BID regimen, respectively (P < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 +/- 0.8 at baseline to 2.8 +/- 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among C-max, C-min, AUC(0-12), C-max/MIC, C-min/MIC, AUC(0-12)/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients; greater than or equal to5 years old. C1 Natl Canc Inst, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, HIV & AIDS Related Malignancy Branch, NIH, Bethesda, MD 20892 USA. NIH, Pharmacokinet Res Lab, Dept Pharm, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), Natl Canc Inst, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 36 TC 59 Z9 64 U1 0 U2 6 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 AUG PY 2002 VL 46 IS 8 BP 2554 EP 2563 DI 10.1128/AAC.46.8.2554-2563.2002 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 575VG UT WOS:000176968700035 PM 12121932 ER PT J AU Trouba, KJ Hamadeh, HK Amin, RP Germolec, DR AF Trouba, KJ Hamadeh, HK Amin, RP Germolec, DR TI Oxidative stress and its role in skin disease SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID ULTRAVIOLET-B RADIATION; CYCLOBUTANE PYRIMIDINE DIMERS; CONTACT HYPERSENSITIVITY; TUMOR PROMOTION; DNA-DAMAGE; VITAMIN-E; INCREASED SENSITIVITY; FREE-RADICALS; IN-VITRO; POLYMORPHONUCLEAR LEUKOCYTES AB Skin is a major target of oxidative stress due to reactive oxygen species (ROS) that originate in the environment and in the skin itself. ROS are generated during normal metabolism, are an integral part of normal cellular function, and are usually of little harm because of intracellular mechanisms that reduce their damaging effects. Antioxidants attenuate the damaging effects of ROS and can impair and/or reverse many of the events that contribute to epidermal toxicity and disease. However, increased or prolonged free radical action can overwhelm ROS defense mechanisms, contributing to the development of cutaneous diseases and disorders. Although ROS play a role in diseases such as skin cancer, their biological targets and pathogenic mode of action are still not fully understood. In addition, strategies useful in the therapeutic management of ROS action in human skin are still lacking. This review is intended to give investigators an introduction to ROS, antioxidants, two skin disorders influenced by ROS action (skin cancer and psoriasis), and relevant model systems used to study ROS action. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP 111 TW Alexander Dr,Bldg 101,Rm C-140,MD C1-04,PO, Res Triangle Pk, NC 27709 USA. EM germolec@niehs.nih.gov NR 86 TC 125 Z9 132 U1 0 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD AUG PY 2002 VL 4 IS 4 BP 665 EP 673 DI 10.1089/15230860260220175 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 588XN UT WOS:000177727700014 PM 12230879 ER PT J AU Park, GH McNeil, MR Doyle, PJ AF Park, GH McNeil, MR Doyle, PJ TI Lexical access rate of closed-class elements during auditory sentence comprehension in adults with aphasia SO APHASIOLOGY LA English DT Article ID CLASS WORDS; TIME; COMPLEXITY; LANGUAGE; CONTEXT; MODEL AB Background: One hypothesis regarding the underlying impairment in agrammatic comprehension suggests that individuals with this disorder suffer from a reduction in lexical activation of closed-class words and therefore cannot appropriately construct a syntactic frame on which lexical semantic information can be applied (Friederici, 1988). Aims: Given the temporally based hypothesis, this investigation examined the effects of increased inter-word intervals (IWI) following closed-class words on auditory comprehension of various sentence types by individuals with agrammatic comprehension. It was hypothesised that providing a longer temporal window for access and processing of closed-class words would improve sentence structure comprehension. Methods & Procedures: Twelve adults with aphasia participated in an agent identification task given varying auditory sentence stimuli. Six sentence types and six IWI durations served as independent variable while accuracy and response times were measured. Outcomes & Results: Results indicated that auditory sentence comprehension performance improves when IWIs are increased. However, differences exist among individuals in response to specific IWI durations. Conclusions: Implications of delayed access rates of closed-class words in agrammatic comprehension are discussed. C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Va Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. Univ Pittsburgh, Passavant Hosp, Pittsburgh, PA 15260 USA. RP Park, GH (reprint author), NIDCD, NIH, Language Sect, Bldg 10,Room 3C-716, Bethesda, MD 20892 USA. NR 40 TC 3 Z9 3 U1 1 U2 2 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0268-7038 J9 APHASIOLOGY JI Aphasiology PD AUG PY 2002 VL 16 IS 8 BP 801 EP 814 DI 10.1080/02687030244000158 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA 581LQ UT WOS:000177294200003 ER PT J AU Kojima, C Sakurai, T Ochiai, M Kumata, H Qu, W Waalkes, MP Fujiwara, K AF Kojima, C Sakurai, T Ochiai, M Kumata, H Qu, W Waalkes, MP Fujiwara, K TI Cytotoxicological aspects of the organic arsenic compound arsenobetaine in marine animals SO APPLIED ORGANOMETALLIC CHEMISTRY LA English DT Article; Proceedings Paper CT 10th International Symposium on Natural and Industrial Arsenic of the Japanese-Arsenic-Scientists-Society CY NOV 29-30, 2001 CL NIHON UNIV, TOKYO, JAPAN SP Japanese Arsen Scientists Soc HO NIHON UNIV DE arsenobetaine; arsenical; arsenic compound; cytotoxicity; macrophages; liver; skin; marine animal; seafood ID MACROPHAGE ACTIVATION; CELLS AB In this study, we investigated the in vitro cytotoxicity of arsenobetaine [AsBe; trimethyl (carboxymethyl) arsonium zwitterion], which is a major organic arsenic compound in marine animals, to various mammalian cells, such as mouse macrophage RAW264.7 cells, rat liver TRL1215 cells and human skin TIG-112 cells, using a synthetic pure material. As a result, we demonstrated that the cytotoxicity of AsBe is very weak even at concentrations over 20 mmol dm(-3) in all these cells. Also, AsBe did not affect various functions of the murine macrophage RAW264.7 cells, viz interleukin-1alpha production, cellular lysosomal enzyme (acid phosphatase) activity and nitric oxide (NO2-) secretion. AsBe showed a weak effect on the reduced glutathione (GSH) levels in these cells, and it slightly reduced the cellular GSH levels for a while. These data suggest that AsBe shows no cytotoxicity but has some effects on mammalian cells. Copyright (C) 2002 John Wiley Sons, Ltd. C1 Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, Hachioji, Tokyo 1920392, Japan. NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect,NIH, Res Triangle Pk, NC 27709 USA. RP Sakurai, T (reprint author), Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. RI Kumata, Hidetoshi/A-6396-2011 NR 14 TC 7 Z9 7 U1 0 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0268-2605 J9 APPL ORGANOMET CHEM JI Appl. Organomet. Chem. PD AUG PY 2002 VL 16 IS 8 BP 421 EP 426 DI 10.1002/aoc.328 PG 6 WC Chemistry, Applied; Chemistry, Inorganic & Nuclear SC Chemistry GA 582FY UT WOS:000177340200005 ER PT J AU Huffman, SW Bhargava, R Levin, IW AF Huffman, SW Bhargava, R Levin, IW TI Generalized implementation of rapid-scan Fourier transform infrared spectroscopic imaging SO APPLIED SPECTROSCOPY LA English DT Article DE rapid-scan; FT-IR; spectral imaging ID COLLAGEN; PROTEOGLYCAN; SPECTROMETER; CARTILAGE AB We describe a novel, generalized data acquisition sequence to allow rapid-scan Fourier transform infrared (FT-IR) spectroscopic imaging using focal plane array (FPA) detectors. This technique derives its applicability from the reproducible performance of modern FT-IR instrumentation and the availability of FPAs with simultaneous, full array acquisition, or snapshot electronics. Instead of sampling the entire interferogram in one mirror sweep over a predetermined retardation, as in traditional continuous-scanning techniques, the modulated light from the interferometer is recorded over several mirror sweeps. The FPA detector is synchronized for data acquisition after a specified delay with respect to the initiation of the mirror motion to provide a highly under-sampled interferogram. By incorporating appropriate delays in subsequent interferometer mirror scans, the entire interferogram is sampled and reconstructed. The signal-to-noise ratios (SNR) of the resulting interferograms are analyzed and are compared with step-scan spectroscopic imaging data. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. OI Bhargava, Rohit/0000-0001-7360-994X NR 17 TC 25 Z9 25 U1 2 U2 7 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 201B BROADWAY ST, FREDERICK, MD 21701 USA SN 0003-7028 J9 APPL SPECTROSC JI Appl. Spectrosc. PD AUG PY 2002 VL 56 IS 8 BP 965 EP 969 DI 10.1366/000370202760249684 PG 5 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 588JP UT WOS:000177698600003 ER PT J AU Gogtay, N Giedd, J Rapoport, JL AF Gogtay, N Giedd, J Rapoport, JL TI Brain development in healthy, hyperactive, and psychotic children SO ARCHIVES OF NEUROLOGY LA English DT Article ID ONSET SCHIZOPHRENIA; DISORDER; MRI; ADOLESCENCE; CHILDHOOD AB Serious and chronic childhood psychiatric disorders have long been assumed to reflect relatively subtle abnormalities of brain development. Although diagnostic brain imaging is well established in pediatric neurology, it has not yet permitted quantitative assessment of brain abnormalities in children with psychiatric illnesses. Recent advances in brain magnetic resonance imaging (MRI) allow reliable, automated, quantitative measurement of multiple brain regions.(1) The noninvasive nature of MRI also allows periodic rescanning for research purposes, making prospective longitudinal study of brain development feasible in large numbers of healthy children and those with psychiatric illness.(2,3) Longitudinal MRI of the brain also makes possible the mapping of region-specific changes in brain volume over time.(4) C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 3N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008; Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 17 TC 40 Z9 41 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2002 VL 59 IS 8 BP 1244 EP 1248 DI 10.1001/archneur.59.8.1244 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 583DQ UT WOS:000177391000003 PM 12164719 ER PT J AU Buerger, K Zinkowski, R Teipel, SJ Tapiola, T Arai, H Blennow, K Andreasen, N Hofmann-Kiefer, K DeBernardis, J Kerkman, D McCulloch, C Kohnken, R Padberg, F Pirttila, T Schapiro, MB Rapoport, SI Moller, HJ Davies, P Hampel, H AF Buerger, K Zinkowski, R Teipel, SJ Tapiola, T Arai, H Blennow, K Andreasen, N Hofmann-Kiefer, K DeBernardis, J Kerkman, D McCulloch, C Kohnken, R Padberg, F Pirttila, T Schapiro, MB Rapoport, SI Moller, HJ Davies, P Hampel, H TI Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 SO ARCHIVES OF NEUROLOGY LA English DT Article ID LEWY BODIES; INTERNATIONAL WORKSHOP; DEMENTIA; MARKER; CSF; CONSORTIUM AB Background: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). Objectives: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. Design and Setting: Cross-sectional, multicenter, memory clinic-based studies. Participants: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia Lewy body dementia, or other neurological disorder and healthy controls. Main Outcome Measures: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. Results: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels Of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P=.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. Conclusion: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD. C1 Univ Munich, Dementia Res Sect, D-80336 Munich, Germany. Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, Alzheimer Mem Ctr,Memory Clin, D-80336 Munich, Germany. Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Med Ctr, Div Pediat Neurol, Cincinnati, OH 45229 USA. Pitea River Valley Hosp, Dept Rehabil, Pitea, Sweden. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Neurosci, Unit Neurochem, Molndal, Sweden. Tohoku Univ, Sch Med, Dept Geriatr Med, Sendai, Miyagi 980, Japan. Univ Kuopio, Univ Hosp, Dept Neurol & Neurosci, FIN-70211 Kuopio, Finland. Mol Geriatr Corp, Vernon Hills, IL USA. Univ Munich, Dept Anesthesiol, D-80336 Munich, Germany. RP Zinkowski, R (reprint author), Univ Munich, Dementia Res Sect, Nussbaumstr 7, D-80336 Munich, Germany. NR 28 TC 171 Z9 176 U1 3 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2002 VL 59 IS 8 BP 1267 EP 1272 DI 10.1001/archneur.59.8.1267 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 583DQ UT WOS:000177391000006 PM 12164722 ER PT J AU Muellbacher, W Richards, C Ziemann, U Wittenberg, G Weltz, D Boroojerdi, B Cohen, L Hallett, M AF Muellbacher, W Richards, C Ziemann, U Wittenberg, G Weltz, D Boroojerdi, B Cohen, L Hallett, M TI Improving hand function in chronic stroke SO ARCHIVES OF NEUROLOGY LA English DT Article ID HUMAN MOTOR CORTEX; UPPER-LIMB AMPUTATION; ISCHEMIC NERVE BLOCK; DEPENDENT PLASTICITY; MAGNETIC STIMULATION; RAPID REORGANIZATION; CORTICAL AREAS; ADULT MONKEYS; BLOOD-FLOW; MAPS AB Background: Recovery of function following stroke plateaus in about I year, typically leaving upper arm function better than that in the hand. Since there is competition among body parts for territory in the sensorimotor cortex, even limited activity of the upper arm might prevent the hand from gaining more control, particularly when the territory is reduced in size because of the stroke. Deafferentation of a body part in a healthy brain enhances cortical representations of adjacent body parts, and this effect is markedly increased by voluntary activity of the adjacent part. Objective: To explore whether deafferentation of the upper arm, produced by a new technique of regional anesthesia during hand motor practice, helps recovery of hand function in patients with long-term stable weakness of their hand following stroke. Methods and Results: Deafferentation, produced by a new technique of regional anesthesia of the upper arm during hand motor practice, dramatically improved hand motor function including some activities of daily living. The improvement was associated with an increase in transcranial magnetic stimulation-evoked motor output to the practice hand muscles. Conclusion: This is a novel therapeutic strategy that may help improve hand function in patients with long-term weakness after stroke. C1 NINDS, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Sect, Bethesda, MD 20892 USA. NIH, Dept Anesthesia, Bethesda, MD 20892 USA. Univ Frankfurt, Neurol Clin, D-6000 Frankfurt, Germany. Neurol Hosp Vienna, Ludwig Boltzmann Inst, Dept Neurol, Vienna, Austria. RP Hallett, M (reprint author), NINDS, NIH, Human Motor Control Sect, 10 Ctr Dr,Bldg 10,Room 5N226, Bethesda, MD 20892 USA. NR 28 TC 123 Z9 126 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2002 VL 59 IS 8 BP 1278 EP 1282 DI 10.1001/archneur.59.8.1278 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 583DQ UT WOS:000177391000008 PM 12164724 ER PT J AU Pickett, W Schmid, H Boyce, WF Simpson, K Scheidt, PC Mazur, J Molcho, M King, MA Godeau, E Overpeck, M Aszmann, A Szabo, M Harel, Y AF Pickett, W Schmid, H Boyce, WF Simpson, K Scheidt, PC Mazur, J Molcho, M King, MA Godeau, E Overpeck, M Aszmann, A Szabo, M Harel, Y TI Multiple risk behavior and injury - An international analysis of young people SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID CIGARETTE-SMOKING; TAKING BEHAVIOR; HIV-INFECTION; SUBSTANCE USE; DRUG-USE; ADOLESCENTS; CHILDREN; ALCOHOL; YOUTH AB Background: Multiple risk behavior plays an important role in the social etiology of youth injury, yet the consistency of this observation has not been examined multinationally. Objective: To examine reports from young people in 12 countries, by country, age group, sex, and injury type, to quantify the strength and consistency of this association. Setting: World Health Organization collaborative cross-national survey of health behavior in school-aged children. Participants: A multinational representative sample of 49461 students aged 11, 13, and 15 years. Main Exposure Measures: Additive score consisting of counts of self-reported health risk behaviors: smoking, drinking, nonuse of seat belts, bullying, excess time with friends, alienation at school and from parents, truancy, and an unusually poor diet. Main Outcome Measure: Self-report of a medically treated injury. Results: Strong gradients in risk for injury were observed according to the numbers of risk behaviors reported. Overall, youth reporting the largest number (greater than or equal to5 health risk behaviors) experienced injury rates that were 2.46 times higher (95% confidence interval, 2.27-2.67) than those reporting no risk behaviors (adjusted odds ratios for 0 to greater than or equal to5 reported behaviors: 1.00, 1.22, 1.48, 1.73, 1.98, and 2.46, respectively; P<.001 for trend). Similar gradients in risk for injury were observed among youth in all 12 countries and within all demographic subgroups. Risk gradients were especially pronounced for nonsports, fighting-related, and severe injuries. Conclusions: Gradients in risk for youth injury increased in association with numbers of risk behaviors reported in every country examined. This cross-cultural finding indicates that the issue of multiple risk behavior, as assessed via an additive score, merits attention as an etiological construct. This concept may be useful in future injury control research and prevention efforts conducted among populations of young people. C1 Queens Univ, Dept Epidemiol & Community Hlth, Kingston, ON, Canada. Queens Univ, Social Program Evaluat Grp, Kingston, ON, Canada. Canadian Adolescents Risk Res Network, Kingston, ON, Canada. Swiss Inst Prevent Alcohol & Drug Problems, Lausanne, Switzerland. NICHHD, Bethesda, MD 20892 USA. Natl Res Inst Mother & Child, Warsaw, Poland. Bar Ilan Univ, Dept Sociol & Anthropol, Ramat Gan, Israel. Serv Med Rectorat Toulouse, Toulouse, France. Maternal & Child Hlth Bur, Rockville, MD USA. Natl Publ Hlth Ctr, Budapest, Hungary. RP Pickett, W (reprint author), Kingston Gen Hosp, Queens Univ, Dept Epidemiol & Community Hlth, Angada 3,76 Stuart St, Kingston, ON K7L 2V7, Canada. RI Molcho, Michal/A-9260-2013 NR 47 TC 71 Z9 71 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD AUG PY 2002 VL 156 IS 8 BP 786 EP 793 PG 8 WC Pediatrics SC Pediatrics GA 581GV UT WOS:000177284100011 PM 12144369 ER PT J AU Balow, JE AF Balow, JE TI Choosing treatment for proliferative lupus nephritis SO ARTHRITIS AND RHEUMATISM LA English DT Editorial Material ID CONTROLLED TRIAL; PULSE METHYLPREDNISOLONE; COMBINATION THERAPY; RENAL INVOLVEMENT; CYCLOPHOSPHAMIDE; GLOMERULONEPHRITIS; ERYTHEMATOSUS; PREDNISONE; AMERICANS; REGIMENS C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Balow, JE (reprint author), NIDDK, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 31 TC 7 Z9 10 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 1981 EP 1983 DI 10.1002/art.10466 PG 3 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800001 PM 12209498 ER PT J AU Hansen, A Odendahl, M Reiter, K Jacobi, AM Feist, E Scholze, J Burmester, GR Lipsky, PE Dorner, T AF Hansen, A Odendahl, M Reiter, K Jacobi, AM Feist, E Scholze, J Burmester, GR Lipsky, PE Dorner, T TI Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren's syndrome SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; POLYMERASE-CHAIN-REACTION; HELPER T-CELLS; RHEUMATOID-ARTHRITIS; GERMINAL CENTER; PLASMA-CELLS; CD27/CD70 INTERACTION; SYNOVIAL-MEMBRANE; EXPRESSING CD5; LYMPHOCYTE AB Objective. To delineate the mechanism of the abnormalities in B cell biology found in patients with primary Sjogren's syndrome (SS). Methods. The distribution of peripheral B cell subpopulations in 21 patients with primary SS was analyzed by immunofluorescence labeling and flow cytometry. Immunoglobulin rearrangements were analyzed in single B cells isolated from the peripheral blood and parotid glands by fluorescence-activated cell sorting. Results. A significant reduction in the number of peripheral CD27+ memory B cells was found in SS patients, including a significantly reduced number of CD27+/IgD+/IgM+/CD5+ memory B cells. Remarkably, SS patients with secondary lymphoma uniquely exhibited an increase in CD27-expressing peripheral B cells, including CD27(high) plasmablasts. Molecular analysis for mutated Ig gene rearrangements confirmed that CD27 expression distinguished naive and memory cells in SS. In contrast to the peripheral blood, the majority of parotid B cells from I patient examined exhibited both the mutational status and phenotype of memory B cells. Accordingly, the mutational frequencies of V-H rearrangements were significantly greater in parotid B cells than in peripheral blood B cells, whereas the VH gene repertoire appeared to be very similar between the compartments. Conclusion. These data indicate that there is an accumulation/retention of memory B cells in the inflamed salivary glands of SS patients. It is possible that preferential accumulation of CD27+ memory B cells in the inflamed parotid gland explains their reduction in the peripheral blood. C1 Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, D-10098 Berlin, Germany. NIAMSD, NIH, Bethesda, MD 20892 USA. Deutsch Rheumaforschungszentrum Berlin, Berlin, Germany. RP Dorner, T (reprint author), Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, Schumannstr 20-21, D-10098 Berlin, Germany. NR 58 TC 147 Z9 152 U1 0 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 2160 EP 2171 DI 10.1002/art.10445 PG 12 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800024 PM 12209521 ER PT J AU Hull, KM Wong, KD Wood, GM Chu, WS Kastner, DL AF Hull, KM Wong, KD Wood, GM Chu, WS Kastner, DL TI Monocytic fasciitis - A newly recognized clinical feature of tumor necrosis factor receptor dysfunction SO ARTHRITIS AND RHEUMATISM LA English DT Article ID FAMILIAL MEDITERRANEAN FEVER; PROTRACTED FEBRILE MYALGIA; PERIODIC SYNDROME; AUTOINFLAMMATORY SYNDROMES; MUTATION; TNFRSF1A; GENE; AMYLOIDOSIS AB Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that results from mutations in TNFRSF1A, the gene that encodes the 55-kd tumor necrosis factor receptor. Clinically, patients present with recurrent episodes of fever in conjunction with localized inflammation at various sites. Myalgia is one of the most characteristic features of this syndrome and is frequently associated with an overlying erythematous, macular rash that, together with the myalgia, displays centrifugal migration. This has previously been believed to occur as a result of myositis. We describe herein the case of a 60-year-old man with TRAPS, in whom magnetic resonance imaging of the left thigh demonstrated edematous changes in the muscle compartments and surrounding soft tissues. A full-thickness wedge biopsy was performed, and hematoxylin and eosin staining and immunohistochemistry analysis of the specimen demonstrated normal myofibrils but a severely destructive monocytic fasciitis. These results suggest that the myalgia experienced by individuals with TRAPS is due to a monocytic fasciitis and not to myositis. C1 Armed Forces Inst Pathol, Washington, DC 20306 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hull, KM (reprint author), NIAMS, NIH, Bldg 10,Room 9S205,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 15 TC 49 Z9 49 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 2189 EP 2194 DI 10.1002/art.10448 PG 6 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800027 PM 12209524 ER PT J AU Zeuner, RA Ishii, KJ Lizak, MJ Gursel, I Yamada, H Klinman, DM Verthelyi, D AF Zeuner, RA Ishii, KJ Lizak, MJ Gursel, I Yamada, H Klinman, DM Verthelyi, D TI Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides SO ARTHRITIS AND RHEUMATISM LA English DT Article ID 4TH INTERNATIONAL-WORKSHOP; BACTERIAL-DNA; REACTIVE ARTHRITIS; ACTIVATION; MOTIFS; CELLS AB Objective. Bacterial DNA contains immunostimulatory CpG motifs that cause inflammation when injected into the knee joints of normal mice. We examined whether synthetic oligodeoxynucleotides (ODN) that suppress CpG-induced immune responses prevent CpG-induced arthritis. Methods. CpG, suppressive, and/or control ODN were injected into the knees of BALB/c mice. joint swelling and inflammation were evaluated by physical measurement, by histologic analysis of joint tissue, and by magnetic resonance imaging. Results. Immunostimulatory CpG DNA induced local arthritis, characterized by swelling of the knee joints, the presence of inflammatory cell infiltrates, the perivascular accumulation of mononuclear cells, and hyperplasia of the synovial lining. Administering suppressive (but not control) ODN reduced the manifestations and severity of arthritis up to 80%. Conclusion. Suppressive ODN may be useful for the prevention or treatment of arthritis induced by bacterial DNA. C1 US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Kiel, D-24098 Kiel, Germany. RP Klinman, DM (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 8800 Rockville Pike,Bldg 29A,Room 3D10, Bethesda, MD 20014 USA. RI Ishii, Ken/B-1685-2012; OI Ishii, Ken/0000-0002-6728-3872; Gursel, Ihsan/0000-0003-3761-1166 NR 15 TC 67 Z9 73 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 2219 EP 2224 DI 10.1002/art.10423 PG 6 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800031 PM 12209528 ER PT J AU Remmers, EF Joe, B Griffiths, MM Dobbins, DE Dracheva, SV Hashiramoto, A Furuya, T Salstrom, JL Wang, JP Gulko, PS Cannon, GW Wilder, RL AF Remmers, EF Joe, B Griffiths, MM Dobbins, DE Dracheva, SV Hashiramoto, A Furuya, T Salstrom, JL Wang, JP Gulko, PS Cannon, GW Wilder, RL TI Modulation of multiple experimental arthritis models by collagen-induced arthritis quantitative trait loci isolated in congenic rat lines - Different effects of non-major histocompatibility complex quantitative trait loci in males and females SO ARTHRITIS AND RHEUMATISM LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; SUSCEPTIBILITY LOCUS; GENETIC DISSECTION; IMMUNE-RESPONSE; DA RATS; IDENTIFICATION; ADJUVANT; SEVERITY AB Objective. Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F-2 offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs. Methods. CIA-regulatory regions were transferred from the F344 genome to the DA background or vice versa by repeated backcrossing. The arthritis-modulating effects of the transferred alleles were determined by comparing the severity of experimentally induced arthritis in congenic rats with that in DA rats. Results. Congenic lines with either the F344 major histocompatibility complex (MHC) on the DA background or the DA MHC on the F344 background were resistant to CIA, confirming both MHC and non-MHC contributions to the genetic regulation of CIA. F344 alleles at the Cia3 and Cia5 regions of chromosomes 4 and 10 reduced CIA severity relative to that observed in DA rats. F344 Cia4 and Cia6 regions of chromosomes 7 and 8 failed to significantly alter CIA severity. Arthritis-modifying effects of Cia4 and Cia6 were, however, detected in pristane-induced and/or Freund's incomplete adjuvant oil-induced arthritis. The arthritis-modifying effects of the non-MHC CIA-regulatory loci differed in males and females. Conclusion. These congenic lines confirmed the existence and location of genes that regulate the severity of experimental arthritis in rats. Mechanisms responsible for the sex-specificity of individual arthritis-regulatory loci may explain some of the sex differences observed in RA and other autoimmune diseases in humans. C1 NIAMSD, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Univ Utah, Salt Lake City, UT USA. Vet Affairs Salt Lake City Hlth Care Syst, Res Serv, Salt Lake City, UT USA. RP Remmers, EF (reprint author), NIAMSD, 10 Ctr Dr,MSC 1820,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [P01-AR-46213, R01-AR-47423-01] NR 37 TC 49 Z9 50 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 2225 EP 2234 DI 10.1002/art.10439 PG 10 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800032 PM 12209529 ER PT J AU Langford, CA AF Langford, CA TI Rituximab for the treatment of type II mixedcryoglobulinemia - Reply SO ARTHRITIS AND RHEUMATISM LA English DT Letter ID HEPATITIS-C VIRUS; CRYOGLOBULINEMIA; INTERFERON-ALPHA-2B; COMBINATION; INFECTION; RIBAVIRIN; THERAPY C1 NIAID, NIH, Bethesda, MD 20205 USA. RP Langford, CA (reprint author), NIAID, NIH, Bethesda, MD 20205 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2002 VL 46 IS 8 BP 2254 EP 2255 DI 10.1002/art.10351 PG 2 WC Rheumatology SC Rheumatology GA 583WB UT WOS:000177432800039 ER PT J AU Palmore, T Folkers, G Heilman, C La Montagne, JR Fauci, AS AF Palmore, T Folkers, G Heilman, C La Montagne, JR Fauci, AS TI The MAID research agenda on biodefense - The National Institute of Allergy and Infectious Diseases faces new challenges in fighting the war on bioterrorism SO ASM NEWS LA English DT Article ID ANTHRAX; TOXIN C1 NIAID, Dept Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD AUG PY 2002 VL 68 IS 8 BP 375 EP 382 PG 8 WC Microbiology SC Microbiology GA 585FR UT WOS:000177515200009 ER PT J AU Rapoport, JL Castellanos, FX Gogate, N Janson, K Kohler, S Nelson, P AF Rapoport, JL Castellanos, FX Gogate, N Janson, K Kohler, S Nelson, P TI The scientific status of attention deficit hyperactivity disorder (ADHD) - Reply SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Letter ID STATEMENT C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Neurobiol Sect, Lab Dev Neurobiol Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 2 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0004-8674 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD AUG PY 2002 VL 36 IS 4 BP 563 EP 563 PG 1 WC Psychiatry SC Psychiatry GA 582PR UT WOS:000177360800029 ER PT J AU Bussey, TJ Wise, SP Murray, EA AF Bussey, TJ Wise, SP Murray, EA TI Interaction of ventral and orbital prefrontal cortex with inferotemporal cortex in conditional visuomotor learning SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID NONMATCHING-TO-SAMPLE; PERIRHINAL CORTEX; RHESUS-MONKEYS; FRONTAL DISCONNECTION; ORBITOFRONTAL CORTEX; UNCINATE FASCICLE; TEMPORAL LESIONS; MEMORY RETRIEVAL; MACAQUE MONKEYS; BASAL GANGLIA AB Five rhesus monkeys (Macaca mulatta) were trained to learn novel conditional visuomotor associations, to perform this task with familiar stimuli, and to perform a visual matching-to-sample task with the same familiar stimuli. Removal of the orbital and ventral prefrontal cortex (PFv+o) in 1 hemisphere and inferotemporal cortex (IT) in the other, thus completing a surgical disconnection of these 2 regions, yielded an impairment on all 3 tasks. Addition of a premotor cortex lesion to the hemisphere containing the PFv+o lesion did not worsen the impairments. The results indicate that PFv+o interacts with IT in both the learning and retention of conditional visuomotor associations. In addition to those associations, which might be considered lower order rules for choosing a response, frontotemporal interaction also appears to be important for higher order rules, such as those involved in the matching task. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Bussey, TJ (reprint author), Univ Cambridge, Dept Expt Psychol, Downing St, Cambridge CB2 3EB, England. RI Bussey, Timothy/M-2758-2016; OI Bussey, Timothy/0000-0001-7518-4041; Murray, Elisabeth/0000-0003-1450-1642 NR 50 TC 66 Z9 68 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 2002 VL 116 IS 4 BP 703 EP 715 DI 10.1037//0735-7044.116.4.703 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 574VH UT WOS:000176909900019 PM 12148937 ER PT J AU Monk, CS Zhuang, JC Curtis, WJ Ofenloch, IT Tottenham, N Nelson, CA Hu, XP AF Monk, CS Zhuang, JC Curtis, WJ Ofenloch, IT Tottenham, N Nelson, CA Hu, XP TI Human hippocampal activation in the delayed matching- and nonmatching-to-sample memory tasks: An event-related functional MRI approach SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID MEDIAL TEMPORAL-LOBE; RECOGNITION MEMORY; HEMODYNAMIC-RESPONSE; EPISODIC MEMORY; MONKEYS; DAMAGE; IMPAIRMENT; LESIONS; REGION; FMRI AB The delayed matching-to-sample (DMS) and delayed nonmatching-to-sample (DNMS) memory tasks are standard tools used to probe visual recognition memory in human and nonhuman primates. Previous research indicates that structures within the medial temporal lobe, including the hippocampus, make up a crucial memory circuit for successful performance on these tasks. In the present investigation, event-related functional magnetic resonance imaging was used to examine activation in the hippocampus proper during these memory tasks relative to a perceptuomotor task involving the same stimuli. The results indicate that both memory tasks elicited greater activation in the right hippocampus during the encoding phase. These findings are consistent with the work from human patients and animal studies, indicating hippocampal involvement in the DMS and DNMS tasks. C1 Univ Minnesota, Inst Child Dev, Minneapolis, MN USA. Univ Minnesota, Ctr Cognit Sci, Minneapolis, MN USA. Univ Minnesota, Ctr Magnet Resonance Res, Minneapolis, MN USA. Univ Konstanz, Dept Psychol, D-7750 Constance, Germany. Univ Minnesota, Dept Pediat, Minneapolis, MN USA. RP Monk, CS (reprint author), NIMH, Sect Dev & Affect Neurosci, Bldg 15K,Room 204, Bethesda, MD 20892 USA. EM christopher.monk@nih.gov FU NCRR NIH HHS [P41RR08079]; NICHD NIH HHS [5T32HD0715]; NIMH NIH HHS [MH55346, R01 MH091864]; NINDS NIH HHS [NS34458, NS32976] NR 40 TC 21 Z9 21 U1 0 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 2002 VL 116 IS 4 BP 716 EP 721 DI 10.1037//0735-7044.116.4.716 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 574VH UT WOS:000176909900020 PM 12148938 ER PT J AU Niu, JX Scheschonka, A Druey, KM Davis, A Reed, E Kolenko, V Bodnar, R Voyno-Yasenetskaya, T Du, XP Kehrl, J Dulin, NO AF Niu, JX Scheschonka, A Druey, KM Davis, A Reed, E Kolenko, V Bodnar, R Voyno-Yasenetskaya, T Du, XP Kehrl, J Dulin, NO TI RGS3 interacts with 14-3-3 via the N-terminal region distinct from the RGS (regulator of G-protein signalling) domain SO BIOCHEMICAL JOURNAL LA English DT Article DE G-protein; phosphorylation; regulation; RGS protein; signalling ID HETEROTRIMERIC G-PROTEINS; GTPASE-ACTIVATING PROTEINS; SIGNALING PROTEINS; MAP KINASE; PHOSPHORYLATION; 14-3-3-PROTEINS; BINDING; FAMILY; ALPHA; FORM AB RGS3 belongs to a family of the regulators of G-protein signalling (RGS), which bind and inhibit the Galpha subunits of heterotrimeric G-proteins via a homologous RGS domain. Increasing evidence suggests that RGS proteins can also interact with targets other than G-proteins. Employing yeast two-hybrid screening of a cDNA library, we identified an interaction between RGS3 and the phosphoserine-binding protein 14-3-3. This interaction was confirmed by in vitro binding and co-immunoprecipitation experiments. RGS3-deletion analysis revealed the presence of a single 14-3-3-binding site located outside of the RGS domain. Ser(264) was then identified as the 14-3-3-binding site of RGS3. The S(264)A mutation resulted in the loss of RGS3 binding to 14-3-3, without affecting its ability to bind Ga,. Signalling studies showed that the S(264)A mutant was more potent than the wild-type RGS3 in inhibition of G-protein-mediated signalling. Binding experiments revealed that RGS3 exists in two separate pools, either 14-3-3-bound or G-protein-bound, and that the 14-3-3-bound RGS3 is unable to interact with G-proteins. These data are consistent with the model wherein 14-3-3 serves as a scavenger of RGS3, regulating the amounts of RGS3 available for binding G-proteins. This study describes a new level in the regulation of G-protein signalling, in which the inhibitors of G-proteins, RGS proteins, can themselves be regulated by phosphorylation and binding 14-3-3. C1 Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA. Boston Biomed Res Inst, Watertown, MA 02472 USA. RP Dulin, NO (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. OI Kehrl, John/0000-0002-6526-159X NR 43 TC 39 Z9 40 U1 1 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 2002 VL 365 BP 677 EP 684 DI 10.1042/BJ20020390 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582RR UT WOS:000177365400011 PM 11985497 ER PT J AU Horvath, B Spies, C Horvath, G Kox, WJ Miyamoto, S Barry, S Warden, CH Bechmann, I Diano, S Heemskerk, J Horvath, TL AF Horvath, B Spies, C Horvath, G Kox, WJ Miyamoto, S Barry, S Warden, CH Bechmann, I Diano, S Heemskerk, J Horvath, TL TI Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE uncoupling proteins; ethanol tolerance; nociception; transgenic animals; knockout animals; central nervous system ID RAT-BRAIN; MICE; TOLERANCE; OBESITY; GENE; DYSFUNCTION; METABOLISM; EXPOSURE; ETHANOL; HISTORY AB Abuse of ethanol is a major risk factor in medicine, in part because of its widespread effect on the activity of the central nervous system, including behavior, pain, and temperature sensation. Uncoupling protein 2 (UCP2) is a mitochondrial protonophore that regulates cellular energy homeostasis. Its expression in mitochondria of axons and axon terminals of basal forebrain areas suggests that UCP2 may be involved in the regulation of complex neuronal responses to ethanol. We employed a paradigm in which acute exposure to ethanol induces tolerance and altered pain and temperature sensation. In UCP2 overexpressing mice, sensitivity to ethanol was decreased compared to that of wild-type animals, while UCP2 knockouts had increased ethanol sensitivity. In addition, UCP2 expression was inversely correlated with the impairment of pain and temperature sensation induced by ethanol. Taken together, these results indicate that UCP2, a mitochondrial uncoupling protein previously associated with peripheral energy expenditure, is involved in the mediation of acute ethanol exposure on the central nervous system. Enhancement of UCP2 activation after acute alcohol consumption might decrease the time of recovery from intoxication, whereas UCP2 inhibition might decrease the tolerance to ethanol. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06520 USA. Humboldt Univ, Charite, Dept Anesthesiol & Operat Intens Med, Berlin, Germany. Univ Szeged, Fac Med, Dept Physiol, Szeged, Hungary. Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. Humboldt Univ, Charite, Dept Anat & Cell Biol, Berlin, Germany. NINDS, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA. RP Horvath, TL (reprint author), Yale Univ, Sch Med, Dept Obstet & Gynecol, 333 Cedar St,FMB 339, New Haven, CT 06520 USA. FU NIMH NIH HHS [MH-59847]; NINDS NIH HHS [NS-41725] NR 24 TC 23 Z9 25 U1 0 U2 3 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 AUG 1 PY 2002 VL 64 IS 3 BP 369 EP 374 AR PII S0006-2952(02)01167-X DI 10.1016/S0006-2952(02)01167-X PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 586UC UT WOS:000177602900003 PM 12147287 ER PT J AU Klein, DC Ganguly, S Coon, S Weller, JL Obsil, T Hickman, A Dyda, F AF Klein, DC Ganguly, S Coon, S Weller, JL Obsil, T Hickman, A Dyda, F TI 14-3-3 Proteins and photoneuroendocrine transduction: role in controlling the daily rhythm in melatonin SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on 14-3-3 Proteins in Cell Regualation CY APR 08-10, 2002 CL UNIV HERIOT WATT, EDINBURGH, SCOTLAND SP Univ Edinburgh, Div Biomed & Clin Lab Sci HO UNIV HERIOT WATT DE cAMP-dependent protein kinase; N-acetyltransferase; pineal ID SEROTONIN N-ACETYLTRANSFERASE; MULTIPLE SIGNALING PATHWAYS; PROTEASOMAL PROTEOLYSIS; PINEAL-GLAND; CRYSTAL-STRUCTURE; ZETA-ISOFORM; ENZYME; 14-3-3-PROTEINS; EC-2.3.1.87; CLONING AB This paper describes the role 14-3-3 proteins play in vertebrate photoneuroendocrine transduction. 14-3-3 proteins form a complex with arylalkyl-amine N-acetyltransferase (AANAT), the enzyme which turns melatonin production on during the day and off at night. Complex formation is triggered at night by cAMP-dependent phosphorylation of the enzyme, and results in activation and protection against proteolysis. This enhances melatonin production > 10-fold. Light exposure results in dephosphorylation of the enzyme and disassociation from 14-3-3, leading to destruction and a rapid drop in melatonin production and release and circulating levels. C1 NICHHD, Dev Neurobiol Lab, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHHD, Dev Neurobiol Lab, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RI Obsil, Tomas/B-7142-2012 OI Obsil, Tomas/0000-0003-4602-1272 NR 36 TC 27 Z9 27 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2002 VL 30 BP 365 EP 373 PN 4 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593KZ UT WOS:000177991600004 PM 12196096 ER PT J AU Caughey, B Baron, GS AF Caughey, B Baron, GS TI Factors affecting interactions between prion protein isoforms SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Amyloidogenic Proteins Involved in Neurodegeneration and Therapeutic Implications CY APR 08-10, 2002 CL HERIOT-WATT UNIV, EDINBURGH, SCOTLAND SP Mecrk Sharp, Dohme, Ciphergen HO HERIOT-WATT UNIV DE glycosaminoglycan; prion protein conversion; transmissible spongifonm encephalopathy ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE-ASSOCIATED FORM; CELL-FREE FORMATION; CULTURED-CELLS; SULFATED GLYCOSAMINOGLYCANS; RESISTANT STATE; DEXTRAN SULFATE; PRP; INHIBITION; INFECTION AB Interactions between normal, protease-sensitive prion protein (PrP-sen or PrPC) and its protease-resistant isoform (PrP-res or PrPSc) are critical in transmissible spongiform encephalopathy (TSE) diseases. To investigate the propagation of PrP-res between cells we tested whether PrP-res in scrapie brain microsomes can induce the conversion of PrP-sen to PrP-res if the PrP-sen is bound to uninfected raft membranes. Surprisingly, no conversion was observed unless the microsomal and raft membranes were fused or PrP-sen was released from raft membranes. These results suggest that the propagation of infection between cells requires transfer of PrP-res into the membranes of the recipient cell. To assess potential cofactors in PrP conversion, we used cell-free PrP conversion assays to show that heparan sulphate can stimulate PrP-res formation, supporting the idea that endogenous sulphated glycosaminoglycans can act as important cofactors or modulators of PrP-res formation in vivo. In an effort to develop therapeutics, the antimalarial drug quinacrine. was identified as an inhibitor of PrP-res formation in scrapie-infected cell cultures. Confirmation of the latter result by others has led to the initiation of human clinical trials as a treatment for Creutzfeldt-Jakob disease. PrP-res formation can also be inhibited using a variety of other types of small molecule, specific synthetic PrP peptides, and an antiserum directed at the C-terminus of PrP-sen. The latter results help to localize the sites of interaction between PrP-sen and PrP-res. Disruption of those interactions with antibodies or peptidomimetic drugs may be an attractive therapeutic strategy. The likelihood that PrP-res inhibitors can rid TSE-infected tissues of PrP-res would presumably be enhanced if PrP-res formation were reversible. However, our attempts to measure dissociation of PrP-sen from PrP-res have failed under non-denaturing conditions. Finally, we have attempted to induce the spontaneous conversion of PrP-sen into PrP-res using low concentrations of detergents. A conformational conversion from alpha-helical monomers into high-beta-sheet aggregates and fibrils was induced by low concentrations of the detergent sarkosyl; however, the aggregates had neither infectivity nor the characteristic protease-resistance of PrP-res. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NR 46 TC 9 Z9 9 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2002 VL 30 BP 565 EP 569 PN 4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593KZ UT WOS:000177991600046 PM 12196138 ER PT J AU Philpott, CC Protchenko, O Kim, YW Boretsky, Y Shakoury-Elizeh, M AF Philpott, CC Protchenko, O Kim, YW Boretsky, Y Shakoury-Elizeh, M TI The response to iron deprivation in Saccharomyces cerevisiae: expression of siderophore-based systems of iron uptake SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 3rd International Biometals Symposium (BIOMETALS 2002) CY APR 11-13, 2002 CL KINGS COLL LONDON, LONDON, ENGLAND SP Wellcome Trust, British Technol Grp, Apotex, Italfarmaco, Inorgan Biochem Discuss Grp HO KINGS COLL LONDON DE cell wall; transport; yeast ID MAJOR FACILITATOR SUPERFAMILY; TRANSCRIPTIONAL CONTROL; FERRIC REDUCTASE; COPPER UPTAKE; YEAST; TRANSPORT; IDENTIFICATION; GENE; PROTEINS; ENCODES AB The budding yeast Saccharomyces cerevisiae responds to growth in limiting amounts of iron by activating the transcription factor Aft1p and expressing a set of genes that ameliorate the effects of iron deprivation. Analysis of iron-regulated gene expression using cDNA microarrays has revealed the set of genes controlled by iron and Aft1p. Many of these genes are involved in the uptake of siderophore-bound iron from the environment. One family of genes, FIT1, FIT2 and FIT3, codes for mannoproteins that are incorporated into the cell wall via glycosylphosphatidylinositol anchors. These genes are involved in the retention of siderophore-iron in the cell wall. Siderophore-bound iron can be taken up into the cell via two genetically separable systems. One system requires the reduction and release of the iron from the siderophore prior to uptake by members of the Fre family of plasma-membrane metalloreductases. Following reduction and release from the siderophore, the iron is then taken up via the high-affinity ferrous transport system. A set of transporters that specifically recognizes siderophore-iron chelates is also expressed under conditions of iron deprivation. These transporters, encoded by ARN1, ARN2/TAF1, ARN3/SIT1 and ARN4/ENB1, facilitate the uptake of both hydroxamate- and catecholate-type siderophores. The Arn transporters are expressed in intracellular vesicles that correspond to the endosomal compartment, which suggests that intracellular trafficking of the siderophore and/or its transporter may be important for uptake. C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), NIDDKD, Liver Dis Sect, NIH, Bldg 10,Room 9B-16,10 Ctr Dr, Bethesda, MD 20892 USA. OI Boretsky, Yuriy/0000-0001-7892-8915 NR 30 TC 46 Z9 47 U1 1 U2 8 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2002 VL 30 BP 698 EP 702 PN 4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593KZ UT WOS:000177991600076 PM 12196168 ER PT J AU van der Helm, D Chakraborty, R Ferguson, AD Smith, BS Esser, L Deisenhofer, J AF van der Helm, D Chakraborty, R Ferguson, AD Smith, BS Esser, L Deisenhofer, J TI Bipartite gating in the outer membrane protein FecA SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 3rd International Biometals Symposium (BIOMETALS 2002) CY APR 11-13, 2002 CL KINGS COLL LONDON, LONDON, ENGLAND SP Wellcome Trust, British Technol Grp, Apotex, Italfarmaco, Inorgan Biochem Discuss Grp HO KINGS COLL LONDON DE binding; closure; transport ID CRYSTAL-STRUCTURE; FHUA AB The recent structure determination of FecA, with and without ligand, shows the existence of two gates. These are the extracellular loops closing over the binding site and the plug located inside the barrel. It indicates a process which is described as bipartite gating and allows for a rational distinction between the binding event and the transport process. C1 Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. E Tennessee State Univ, Coll Publ & Allied Hlth, Dept Hlth Sci, Johnson City, TN 37614 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP van der Helm, D (reprint author), Univ Oklahoma, Dept Chem & Biochem, 620 Parrington Oval, Norman, OK 73019 USA. NR 8 TC 10 Z9 10 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2002 VL 30 BP 708 EP 710 PN 4 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593KZ UT WOS:000177991600079 PM 12196171 ER PT J AU Planalp, RP Przyborowska, AM Park, G Ye, N Lu, FH Rogers, RD Broker, GA Torti, SV Brechbiel, MW AF Planalp, RP Przyborowska, AM Park, G Ye, N Lu, FH Rogers, RD Broker, GA Torti, SV Brechbiel, MW TI Novel cytotoxic chelators that bind iron(II) selectively over zinc(II) under aqueous aerobic conditions SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 3rd International Biometals Symposium (BIOMETALS 2002) CY APR 11-13, 2002 CL KINGS COLL LONDON, LONDON, ENGLAND SP Wellcome Trust, British Technol Grp, Apotex, Italfarmaco, Inorgan Biochem Discuss Grp HO KINGS COLL LONDON DE antitumour agents; metal-ion complexation; triaminocyclohexane ID COMPLEXES AB To achieve cellular iron deprivation by chelation, it is important to develop chelators with selective metal-binding properties. Selectivity for iron has long been the province of certain oxygen-donor chelators such as desferrioxamine, which target Fe(III) and exploit the strength of a relatively ionic Fe(III)-O interaction. We have been studying novel chelators that possess mechanisms to selectively chelate +2 biometals, particularly tachpyr [N,N',N"-tris(2-pyridylmethyl)-1,3,5-cis,cis-triaminocyclohexane] and derivatives from N,N',N"-trialkylation and pyridine ring alkylation. Metal-exchange and metal-binding competition reactions have been conducted at pH 7.4, 37 degreesC and time periods until no further change was observed (generally 24-48 h). Under anaerobic conditions, tachpyr is strongly selective for iron, binding 95+/-5%,, Fe(II) versus 5+/-5 % Zn(II) in the forms [Fe(tachpyr)](2+) and [Zn(tachpyr)](2+) respectively. Under aerobic conditions, tachpyr complexes Fe(II) more effectively than Fe(III), forming iminopyridyl complexes [Fe(tachpyrox-n](2+) (n = 2,4) by O-2-induced and iron-mediated oxidative dehydrogenation. Complexes [Fe(tachpyr-ox-n)(2+) are also strongly bound forms of iron that are unaffected by an excess of Zn(II) (75 mol zinc: 1 mol iron complex). The preference of tachpyr for iron over zinc under aerobic conditions appears to be hindered by oxidation of Fe(II) to Fe(III), such that the proportions bound are 44+/-10% Fe(II) versus 56+/-10% Zn(II), in the respective forms [Fe(tachpyr-ox-n)](2+) and [Zn(tachpyr)](2+). However, upon addition of the reducing agent Na2S2O4 that converts Fe(III) to Fe(II), the binding proportions shift to 76+/-10 % Fe(II) versus 24+/-10% Zn(II), demonstrating a clear preference of tachpyr for Fe(II) over Zn(II). Iron(II) is in the low-spin state in [Fe(tachpyr)](2+) and [Fe(tachpyrox-n)](2+) (n = 2,4), which is a likely cause of the observed selectivity. N-methylation of tachpyr [giving (N-methyl)(3)tachpyr] results in the loss of selectivity for Fe(II), which is attributed to the steric effect of the methyl groups and a resulting high-spin state of Fe(II) in [Fe(N-methyl)(3)tachpyr)](2+). The relationship of chelator selectivity to cytotoxicity in the tach family will be discussed. C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. RP Planalp, RP (reprint author), Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. OI Rogers, Robin D./0000-0001-9843-7494 FU NIDDK NIH HHS [R01-DK57781] NR 13 TC 11 Z9 12 U1 1 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2002 VL 30 BP 758 EP 762 PN 4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 593KZ UT WOS:000177991600096 PM 12196188 ER PT J AU Lingappa, VR Rutkowski, DT Hegde, RS Andersen, OS AF Lingappa, VR Rutkowski, DT Hegde, RS Andersen, OS TI Conformational control through translocational regulation: a new view of secretory and membrane protein folding SO BIOESSAYS LA English DT Article ID ENDOPLASMIC-RETICULUM MEMBRANE; HUMAN P-GLYCOPROTEIN; PRION PROTEIN; SIGNAL SEQUENCE; CONDUCTING CHANNEL; APOLIPOPROTEIN-B; LIPID BILAYER; BIOGENESIS; TRANSLOCON; RIBOSOME AB We suggest a new view of secretory and membrane protein folding that emphasizes the role of pathways of biogenesis in generating functional and conformational heterogeneity. In this view, heterogeneity results from action of accessory factors either directly binding specific sequences of the nascent chain, or indirectly, changing the environment in which a particular domain is synthesized. Entrained by signaling pathways, these variables create a combinatorial set of necessary-but-not-sufficient conditions that enhance synthesis and folding of particular alternate, functional, conformational forms. We therefore propose that protein conformation is productively regulated by the cell during translocation across the endoplasmic reticulum (ER), a concept that may account for currently poorly understood aspects of physiological function, natural selection, and disease pathogenesis. (C) 2002 Wiley Periodicals, Inc. C1 Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, Ithaca, NY 14853 USA. RP Lingappa, VR (reprint author), Univ Calif San Francisco, Dept Physiol, 513 Pamassus ave, San Francisco, CA 94143 USA. OI Hegde, Ramanujan/0000-0001-8338-852X NR 58 TC 7 Z9 7 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD AUG PY 2002 VL 24 IS 8 BP 741 EP 748 DI 10.1002/bies.10130 PG 8 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 577ZG UT WOS:000177092500010 PM 12210535 ER PT J AU Tanabe, L Wilbur, WJ AF Tanabe, L Wilbur, WJ TI Tagging gene and protein names in biomedical text SO BIOINFORMATICS LA English DT Article ID RESOURCES AB Motivation: The MEDLINE database of biomedical abstracts contains scientific knowledge about thousands of interacting genes and proteins. Automated text processing can aid in the comprehension and synthesis of this valuable information. The fundamental task of identifying gene and protein names is a necessary first step towards making full use of the information encoded in biomedical text. This remains a challenging task due to the irregularities and ambiguities in gene and protein nomenclature. We propose to approach the detection of gene and protein names in scientific abstracts as part-of-speech tagging, the most basic form of linguistic corpus annotation. Results: We present a method for tagging gene and protein names in biomedical text using a combination of statistical and knowledge-based strategies. This method incorporates automatically generated rules from a transformation-based part-of-speech tagger, and manually generated rules from morphological clues, low frequency trigrams, indicator terms, suffixes and part-of-speech information. Results of an experiment on a test corpus of 56K MEDLINE documents demonstrate that our method to extract gene and protein names can be applied to large sets of MEDLINE abstracts, without the need for special conditions or human experts to predetermine relevant subsets. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Tanabe, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 19 TC 147 Z9 156 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG PY 2002 VL 18 IS 8 BP 1124 EP 1132 DI 10.1093/bioinformatics/18.8.1124 PG 9 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 585BZ UT WOS:000177504400012 PM 12176836 ER PT J AU Reynolds, CF Charney, DS AF Reynolds, CF Charney, DS TI Unmet needs in the diagnosis and treatment of mood disorders in later life SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. NIMH, Bethesda, MD 20892 USA. RP Reynolds, CF (reprint author), Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, 3811 O Hara St, Pittsburgh, PA 15213 USA. NR 15 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2002 VL 52 IS 3 BP 145 EP 147 AR PII S0006-3223(02)01464-6 DI 10.1016/S0006-3223(02)01464-6 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 584TG UT WOS:000177484400001 ER PT J AU Alexopoulos, GS Borson, S Cuthbert, BN Devanand, DP Mulsant, BH Olin, JT Oslin, DW AF Alexopoulos, GS Borson, S Cuthbert, BN Devanand, DP Mulsant, BH Olin, JT Oslin, DW TI Assessment of late life depression SO BIOLOGICAL PSYCHIATRY LA English DT Review DE assessment; late life; depression ID PRIMARY-CARE PATIENTS; ALZHEIMERS-DISEASE; MAJOR DEPRESSION; GERIATRIC DEPRESSION; COGNITIVE DECLINE; PHYSICAL ILLNESS; MINOR DEPRESSION; ELDERLY PATIENTS; OLDER ADULTS; VASCULAR DEPRESSION AB This article focuses on diagnostic and nosologic challenges intrinsic to geriatric depression, including characteristics interfering with symptom and syndrome ascertainment, the impact of in medical and cognitive disorders, the usefulness of screening instruments, and barriers imposed by treatment settings. The article also identifies gaps in existing knowledge and outlines a research agenda. Nosologic characterization of depressives syndromes contributed by specific medical disorders may lead to effective strategies for prevention and treatment 4 depression. Studies need to examine whether treatment of depression can improve the outcome of medical illnesses requiring active patient involvement in treatment. Considering disability a distinct aspect of health status may add an important dimension to the assessment of depression and result in complementary, interventions aimed at depression and disability concurrently. The provisional criteria for depression of Alzheimer's disease, if validated, may facilitate treatment research. Studies need to characterize cognitive dysfunctions associated with later development of dementia or poor treatment response in patients with depression. Care managers working together with primary care physicians can improve the recognition and treatment of depressed elderly patients by obtaining the training in using validated instruments and treatment algorithms. (C) 2002 Society of Biological Psychiatry. C1 Cornell Univ, Weil Med Sch, Cornell Inst Geriatr Psychiat, Weil Med Coll, White Plains, NY 10605 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. NIMH, Adult Psychopathol & Prevent Res Branch, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. NIMH, Geriatr Psychopharmacol Program, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Alexopoulos, GS (reprint author), Cornell Univ, Weil Med Sch, Cornell Inst Geriatr Psychiat, Weil Med Coll, 21 Bloomingdale Rd, White Plains, NY 10605 USA. FU NIMH NIH HHS [P30 MH49762, K01 MH01613, K08 MH01599, MH50513, R01 MH42819, R01 MH51842, R01 MH52247, R01 MH59381] NR 126 TC 75 Z9 76 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2002 VL 52 IS 3 BP 164 EP 174 AR PII S0006-3223(02)01381-1 DI 10.1016/S0006-3223(02)01381-1 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 584TG UT WOS:000177484400005 PM 12182923 ER PT J AU Lyketsos, CG Olin, J AF Lyketsos, CG Olin, J TI Depression in Alzheimer's disease: Overview and treatment SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; dementia; depression; epidemiology; treatment ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND TRIAL; PSYCHIATRIC PHENOMENA; MAJOR DEPRESSION; PRIMARY DEMENTIA; BEHAVIORAL DISTURBANCES; CLINICAL-TRIAL; DISORDERS; SYMPTOMS; PSYCHOSIS AB Psychiatric disturbances affect as many as 90% of patients with Alzheimer's disease (AD) and tire a major focus of treatment. Depression is one of the most frequent psychiatric complications of AD, acting as many as 50% of patients. In this context, depression is a significant public health problem that has a series of serious adverse consequences for patients and their caregivers. There has been little research into the course or treatment Of depression associated with AD. This is in part due to the absence of validated operational criteria for defining depression in AD. Recently, the National Institute of Mental Health (NIMH) convened an expert consensus panel to develop draft criteria for depression of Alzheimer's disease (NIMH-dAD) and to establish research priorities in this area. This article provides on overview of recent knowledge with regard to depression in AD with a special emphasis on its treatment. We conclude with recommendations for further research in this area, (C) 2002 Society of Biological Psychiatry. C1 Johns Hopkins Sch Med, Neuropsychiat Serv, Baltimore, MD USA. Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. NIMH, Adult & Geriatr Treatment & Prevent Intervent Res, Bethesda, MD 20892 USA. RP Lyketsos, CG (reprint author), Johns Hopkins Univ Hosp, Osler 320, Baltimore, MD 21287 USA. FU NIMH NIH HHS [1R01-MH56511] NR 65 TC 147 Z9 153 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2002 VL 52 IS 3 BP 243 EP 252 AR PII S0006-3223(02)01348-3 DI 10.1016/S0006-3223(02)01348-3 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 584TG UT WOS:000177484400012 PM 12182930 ER PT J AU Hernandez, S Ford, H Marquez, VE AF Hernandez, S Ford, H Marquez, VE TI Is the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID RECEPTOR AGONISTS; INHIBITORS; SUBSTRATE; CONFORMATION; DESIGN; POTENT AB The aglycone of (North)-methanocarbadeoxyadenosine [(N)-MCdA, (5)], a relatively weak Substrate for adenosme deaminase (ADA)-relative rate of deamination ca. 100 times lower than adenosine-was modified with substitutions at positions 6 (6-fluoro, compound 6) and 8 (8-aza, compound 7) with the intent to improve the level of hydration and hence hydrolysis by ADA. In these substrates the fused cyclopropane moiety constrains the cyclopentane ring to mimic the conformation of a furanose sugar in the North hemisphere of the pseudorotational cycle, which matches the conformation of the ribose ring of adenosine in complex with ADA. The order of susceptibility to ADA hydrolysis was adenosine > > (N)-MCdA (5)approximate to(N)-6F-MCdP (6) > (N)-8-aza-MCdA (7). Despite the known fact that 8-azaadenosine is hydrolyzed twice as fast as adenosine, the corresponding carbocyclic analogue 7 was hydrolyzed at approximately half the rate of the parent 5. These results argue in favor of the critical role of the O(4) oxygen atom and its associated anomeric effect in assisting hydrolysis by ADA. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21701 USA. RP Marquez, VE (reprint author), NCI, Ctr Canc Res, Med Chem Lab, 376 Boyles St, Frederick, MD 21701 USA. NR 26 TC 18 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG PY 2002 VL 10 IS 8 BP 2723 EP 2730 AR PII S0968-0896(02)00099-8 DI 10.1016/S0968-0896(02)00099-8 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 564BQ UT WOS:000176294500030 PM 12057661 ER PT J AU Xu, GZ Kannan, A Hartman, TL Wargo, H Watson, K Turpin, JA Buckheit, RW Johnson, AA Pommier, Y Cushman, M AF Xu, GZ Kannan, A Hartman, TL Wargo, H Watson, K Turpin, JA Buckheit, RW Johnson, AA Pommier, Y Cushman, M TI Synthesis of substituted diarylmethylenepiperidines (DAMPs), a novel class of anti-HIV agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITORS; ALKENYLDIARYLMETHANE ADAM SERIES; COSALANE ANALOGS; ANTIRETROVIRAL THERAPY; BIOLOGICAL EVALUATION; ENHANCED POTENCIES; PHARMACOPHORE; INFECTION; MECHANISM AB Substituted diarymethylenepiperidines (DAMPs) were synthesized as conformationally restricted analogues of the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although, like the ADAMs, the DAMPs were found to inhibit the cytopathic effect of HIV-1(RF) in CEM-SS cells, they were completely inactive as inhibitors of HIV-1 reverse transcriptase. The DAMPs were assessed for inhibition of HIV attachment and fusion. DAMP 14 was active in both assays with IC50 values of 26.5 muM (TI 3.8) and 12.1 muM (TI: > 8), respectively. DAMP 15 also inhibited HIV fusion with all IC50 12.8 muM (TI: > 6), but not virus attachment. However, attempts to verity inhibition of virus attachment and fusion as antiviral targets using time-of-addition experiments failed to confirm these observations, and instead identified all antiviral target Occurring after completion of reverse transcription. DAMPs 11, 12, 14, and 15 were found to inhibit virus replication if added 8 h post virus exposure, and DAMP 11 was equipotent at inhibition of virus replication if added 24 It after Virus addition. DAMPs 11, 12, and 15 did not inhibit virus replication in TNF-alpha induced latently infected U1 cells, a model for post-integrative antiviral targets. When tested in both 3' end-processing and strand-transfer assays in the presence of HIV-1 integrase. none of the DAMPs showed any inhibitory activity, indicating that HIV-1 integrase is not involved in the mechanism of the antiviral action. Thus, the DAMPs are novel conformationally restricted analogues of the previously published ADAM series with all unidentified antiviral target bounded by the completion of reverse transcription and virus integration. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. So Res Inst, Infect Dis Res Dept, Frederick, MD 21701 USA. NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. FU NIAID NIH HHS [R01 AI 43637] NR 25 TC 14 Z9 14 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG PY 2002 VL 10 IS 8 BP 2807 EP 2816 AR PII S0968-0896(02)00095-0 DI 10.1016/S0968-0896(02)00095-0 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 564BQ UT WOS:000176294500040 PM 12057671 ER PT J AU Keskin, O Durell, SR Bahar, I Jernigan, RL Covell, DG AF Keskin, O Durell, SR Bahar, I Jernigan, RL Covell, DG TI Relating molecular flexibility to function: A case study of tubulin SO BIOPHYSICAL JOURNAL LA English DT Article ID NORMAL-MODE ANALYSIS; DOMAIN MOTIONS; BETA-TUBULIN; MICROTUBULE STRUCTURE; VIBRATIONAL DYNAMICS; SINGLE-PARAMETER; PROTEIN DYNAMICS; TAXOL; POLYMERIZATION; SITE AB Microtubules (MT), along with a variety of associated motor proteins, are involved in a range of cellular functions including vesicle movement, chromosome segregation, and cell motility. MTs are assemblies of heterodimeric proteins, alphabeta-tubulins, the structure of which has been determined by electron crystallography of zinc-induced, pacilitaxel-stabilized tubulin sheets. These data provide a basis for examining relationships between structural features and protein function. Here, we study the fluctuation dynamics of the tubulin dinner with the aim of elucidating its functional motions relevant to substrate binding, polymerization/depolymerization and MT assembly. A coarse-grained model, harmonically constrained according to the crystal structure, is used to explore the global dynamics of the dimer. Our results identify six regions of collective motion, comprised of structurally close but discontinuous sequence fragments, observed only in the dimeric form, dimerization being a prerequisite for domain identification. Boundaries between regions of collective motions appear to act as linkages, found primarily within secondary-structure elements that lack sequence conservation, but are located at minima in the fluctuation curve, at positions of hydrophobic residues. Residue fluctuations within these domains identify the most mobile regions as loops involved in recognition of the adjacent regions. The least mobile regions are associated with nucleotide binding sites where lethal mutations occur. The functional coupling of motions between and within regions identifies three global motions: torsional and wobbling movements, en bloc, between the alpha- and beta-tubulin monomers, and stretching longitudinally. Further analysis finds the antitumor drug pacilitaxel (TaxotereR) to reduce flexibility in the M loop of the beta-tubulin monomer; an effect that may contribute to tightening lateral interactions between protofilaments assembled into MTs. Our analysis provides insights into relationships between intramolecular tubulin movements of MT organization and function. C1 Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. NCI, Mol Struct Sect, Lab Expt & Computat Biol, Div Basic Sci,NIH, Bethesda, MD 20892 USA. Koc Univ, Dept Chem, Coll Arts & Sci, TR-80910 Istanbul, Turkey. NCI, Computat Technol Lab, Screening Technol Branch, Dev Therapeut Program,NIH, Frederick, MD 21702 USA. RP Keskin, O (reprint author), Ft Detrick Bldg 430,Room 215, Frederick, MD 21702 USA. RI Jernigan, Robert/A-5421-2012 FU NCI NIH HHS [N01-CO-56000] NR 55 TC 94 Z9 100 U1 1 U2 9 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2002 VL 83 IS 2 BP 663 EP 680 PG 18 WC Biophysics SC Biophysics GA 579VE UT WOS:000177197900006 PM 12124255 ER PT J AU Balbach, JJ Petkova, AT Oyler, NA Antzutkin, ON Gordon, DJ Meredith, SC Tycko, R AF Balbach, JJ Petkova, AT Oyler, NA Antzutkin, ON Gordon, DJ Meredith, SC Tycko, R TI Supramolecular structure in full-length Alzheimer's beta-amyloid fibrils: Evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance SO BIOPHYSICAL JOURNAL LA English DT Article ID ATOMIC-FORCE MICROSCOPY; ANGLE SPINNING NMR; SYNCHROTRON X-RAY; IN-VITRO; SECONDARY-STRUCTURE; VIRULENCE FACTOR; ROTATING SOLIDS; CORE STRUCTURE; PEPTIDE; DISEASE AB We report constraints on the supramolecular structure of amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)) obtained from solid-state nuclear magnetic resonance (NMR) measurements of intermolecular dipole-dipole couplings between C-13 labels at 11 carbon sites in residues 2 through 39. The measurements are carried out under magic-angle spinning conditions, using the constant-time finite-pulse radiofrequency-driven recoupling (fpRFDR-CT) technique. We also present one-dimensional C-13 magic-angle spinning NMR spectra of the labeled Abeta(1-40). samples. The fpRFDR-CT data reveal nearest-neighbor intermolecular distances of 4.8 +/- 0.5 Angstrom for carbon sites from residues 12 through 39, indicating a parallel alignment of neighboring peptide chains in the predominantly beta-sheet structure of the amyloid fibrils. The one-dimensional NMR spectra indicate structural order at these sites. The fpRFDR-CT data and NMR spectra also indicate structural disorder in the N-terminal segment of Abeta(1-40), including the first nine residues. These results place strong constraints on any molecular-level structural model for full-length beta-amyloid fibrils. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Lulea Univ Technol, Div Inorgan Chem, S-95187 Lulea, Sweden. Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. NR 58 TC 238 Z9 240 U1 4 U2 38 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2002 VL 83 IS 2 BP 1205 EP 1216 PG 12 WC Biophysics SC Biophysics GA 579VE UT WOS:000177197900051 PM 12124300 ER PT J AU Carninci, P Nakamura, M Sato, K Hayashizaki, Y Brownstein, MJ AF Carninci, P Nakamura, M Sato, K Hayashizaki, Y Brownstein, MJ TI Cytoplasmic RNA extraction from fresh and frozen mammalian tissues SO BIOTECHNIQUES LA English DT Article ID LENGTH-CDNA LIBRARIES; FULL-LENGTH; CAP-TRAPPER; COLLECTION; DISCOVERY; CLONING AB The quality of collections of expressed sequence tags and full-length cDNAs is adversely affected by the presence of "junk" clones derived from unspliced or partially spliced RNAs present in conventional total RNA preparations. One can overcome this problem by using intact cytoplasmic RNA to create cDNA libraries, but the methods in the literature that describe the preparation of RNA only work well for extracting cultured cells. Cell lines are not as diverse as one would like, and to clone comprehensive sets of human and model organism full-length cDNAs, libraries have to be prepared from tissue samples. Thus, we have developed a robust and inexpensive method that allows intact cytoplasmic RNA to be extracted from both fresh and frozen. mammalian tissues. A mouse full-length, cap-trapped cDNA library prepared with RNA using this new procedure had excellent characteristics. C1 RIKEN, Genome Sci Lab, Wako, Saitama 3510198, Japan. NHGRI, Genet Lab, NIMH, NIH, Bethesda, MD 20892 USA. RIKEN, Yokohama Inst, Yokohama, Kanagawa, Japan. RP Carninci, P (reprint author), RIKEN, Genome Sci Lab, Wako Main Campus,2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM rgscerg@gsc.riken.go.jp RI Brownstein, Michael/B-8609-2009; Carninci, Piero/K-1568-2014 OI Carninci, Piero/0000-0001-7202-7243 NR 11 TC 9 Z9 9 U1 0 U2 2 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2002 VL 33 IS 2 BP 306 EP 309 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 583PQ UT WOS:000177416600011 PM 12188181 ER PT J AU Chung, EJ Hwang, SG Nguyen, P Lee, S Kim, JS Kim, JW Henkart, PA Bottaro, DP Soon, L Bonvini, P Lee, SJ Karp, JE Oh, HJ Rubin, JS Trepel, JB AF Chung, EJ Hwang, SG Nguyen, P Lee, S Kim, JS Kim, JW Henkart, PA Bottaro, DP Soon, L Bonvini, P Lee, SJ Karp, JE Oh, HJ Rubin, JS Trepel, JB TI Regulation of leukemic cell adhesion, proliferation, and survival by beta-catenin SO BLOOD LA English DT Article ID UBIQUITIN-PROTEASOME PATHWAY; WNT SIGNAL-TRANSDUCTION; CYCLIN D1; MEDIATED REGULATION; CALPAIN PROTEASE; CARCINOMA-CELLS; ALPHA-CATENIN; C-MYC; APOPTOSIS; EXPRESSION AB In epithelial cells beta-catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of beta-catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for beta-catenin in hematologic malignancies has not been reported. beta-Catenin is not detectable in normal peripheral blood T cells but is expressed in T-acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. beta-Catenin function was examined in Jurkat T-acute lymphoblastic leukemia cells. Overexpression of dominant-negative beta-catenin or dominant-negative TCF reduced beta-catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of beta-catenin expression with beta-catenin antisense down-regulated adhesion of Jurkat cells in response to phytolhemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspase-dependent limited proteolysis of beta-catenin N- and C-terminal regions and rapid redistribution of beta-catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear beta-catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of beta-catenin nuclear signaling. The data suggest that R-catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival. (C) 2002 by The American Society of Hematology. C1 NCI, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Trepel, JB (reprint author), NCI, Med Oncol Clin Res Unit, NIH, Bldg 10,room 12N230, Bethesda, MD 20892 USA. RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 62 TC 91 Z9 100 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2002 VL 100 IS 3 BP 982 EP 990 DI 10.1182/blood.V100.3.982 PG 9 WC Hematology SC Hematology GA 578LA UT WOS:000177118000032 PM 12130512 ER PT J AU Nagakura, S Ishihara, S Dunn, DE Nishimura, J Kawaguchi, T Horikawa, K Hidaka, M Kagimoto, T Eto, N Mitsuya, H Kinoshita, T Young, NS Nakakuma, H AF Nagakura, S Ishihara, S Dunn, DE Nishimura, J Kawaguchi, T Horikawa, K Hidaka, M Kagimoto, T Eto, N Mitsuya, H Kinoshita, T Young, NS Nakakuma, H TI Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro SO BLOOD LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; APLASTIC-ANEMIA; NK CELLS; BONE-MARROW; MYELODYSPLASTIC SYNDROMES; HEMATOPOIETIC-CELLS; ANCHORED PROTEINS; MOLECULAR-BASIS; NKG2D RECEPTOR; MEDIATED LYSIS AB The cloning of the PIG-A gene has facilitated the unraveling of the complex pathophysiology of paroxysmal nocturnal hemoglobinuria (PNH). Of current major concern is the mechanism by which a PNH clone expands. Many reports have suggested that an immune mechanism operates to cause bone marrow failure in some patients with PNH, aplastic anemia, and myelodysplastic syndromes. Because blood cells of PNH phenotype are often found in patients with these marrow diseases, one hypothesis is that the PNH clone escapes immune attack, producing a survival advantage by immunoselection. To test this hypothesis, we examined the sensitivity of blood cells, with or without PIG-A mutations, to killing by natural killer (NK) cells, using Cr-51-release assay in vitro. To both peripheral blood and cultured NK cells, PIG-A mutant cells prepared from myeloid and lymphoid leukemic cell lines were less susceptible than their control counterparts (reverted from the mutant cells by transfection with a PIG-A cDNA). NK activity was completely abolished with concanamycin A and by calcium chelation, indicating that killing was perforin-dependent. There were no differences in major histo-compatibility (MHC) class I expression or sensitivity to either purified perforin or to interleukin-2-activated NK cells between PIG-A mutant and control cells. From these results, we infer that PIG-A mutant cells lack molecules needed for NK activation or to trigger perforin-mediated killing. Our experiments suggest that PIG-A mutations confer a relative survival advantage to a PNH clone, contributing to selective expansion of these cells in the setting of marrow injury by cytotoxic lymphocytes. (C) 2002 by The American Society of Hematology. C1 Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8608556, Japan. NHLBI, Hematol Branch, NIH, Bethesda, MD USA. Osaka Univ, Microbial Dis Res Inst, Dept Immunoregulat, Osaka, Japan. Miyazaki Univ, Dept Biochem & Appl Biosci, Miyazaki, Japan. RP Nakakuma, H (reprint author), Kumamoto Univ, Sch Med, Dept Internal Med 2, Honjo 1-1-1, Kumamoto 8608556, Japan. RI Kinoshita, Taroh/C-7353-2009 NR 76 TC 27 Z9 29 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2002 VL 100 IS 3 BP 1031 EP 1037 DI 10.1182/blood.V100.3.1031 PG 7 WC Hematology SC Hematology GA 578LA UT WOS:000177118000039 PM 12130519 ER PT J AU Magnusson, MK Meade, KE Nakamura, R Barrett, J Dunbar, CE AF Magnusson, MK Meade, KE Nakamura, R Barrett, J Dunbar, CE TI Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene SO BLOOD LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; BCR-ABL; PROTEIN; MECHANISM; GENE; TEL AB Platelet-derived growth factor p receptor (PDGFOR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor ST1571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFOR fusion oncogene family, rabaptin-5PDGFbetaR. A patient with CMML carrying the rabaptin-5-PDGFbetaR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptasepolymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by ST1571, the patient was started on ST1571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that ST1571 may be an effective targeted therapy in patients with CMML related to PDGFOR fusion oncogenes. (C) 2002 by The American Society of Hematology. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Magnusson, MK (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,MSC1652,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 14 TC 95 Z9 99 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2002 VL 100 IS 3 BP 1088 EP 1091 DI 10.1182/blood-2002-01-0165 PG 4 WC Hematology SC Hematology GA 578LA UT WOS:000177118000052 PM 12130532 ER PT J AU Ishibe, N Albitar, M Jilani, IB Goldin, LR Marti, GE Caporaso, NE AF Ishibe, N Albitar, M Jilani, IB Goldin, LR Marti, GE Caporaso, NE TI CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not SO BLOOD LA English DT Letter ID V-H GENES; PROGNOSTIC FACTOR; B-CLL; MUTATION C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Ishibe, N (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. NR 15 TC 31 Z9 31 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 AUG 1 PY 2002 VL 100 IS 3 BP 1100 EP 1101 DI 10.1182/blood-2002-03-0938 PG 2 WC Hematology SC Hematology GA 578LA UT WOS:000177118000060 PM 12150154 ER PT J AU Nakamura, R Cortez, K Solomon, S Battiwalla, M Gill, VJ Hensel, N Childs, R Barrett, AJ AF Nakamura, R Cortez, K Solomon, S Battiwalla, M Gill, VJ Hensel, N Childs, R Barrett, AJ TI High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Article DE cytomegalovirus; high-dose acyclovir; pp65 antigenemia; T cell-depleted stem cell transplantation; non-myeloablative stem cell transplantation ID BONE-MARROW TRANSPLANTATION; HEMATOLOGICAL MALIGNANCIES; PP65 ANTIGENEMIA; VIRUS INFECTION; RISK-FACTORS; ADD-BACK; RECIPIENTS; PROPHYLAXIS; SURVIVAL; ENGRAFTMENT AB We evaluated high-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. One hundred and seventy-four consecutive patients who were at risk for CMV infection (either recipient or donor seropositive) and received either intensive chemoradiotherapy and a T cell-depleted stem cell transplant followed by delayed add-back of donor T cells (TCDT: n = 98), or a non-myeloablative preparative regimen followed by an unmanipulated peripheral blood stem cell transplant (NMT: n = 76) from an HLA-identical sibling donor were studied. All received high-dose acyclovir (HDACV) from day - 7 for 3 months post-transplant in conjunction with weekly CMV pp65 antigenemia monitoring and pre-emptive treatment with intravenous immunoglobulin (not CMV-specific) and ganciclovir. The actuarial probabilities of developing pp65 antigenemia were 83 +/- 4% after TCDT and 41 +/- 6% after NMT (P < 0.00001) with reactivation occurring earlier in the TCDT group (the median 36 days vs 55 days). We observed no reactivation of CMV in seronegative recipients with a seropositive donor (n = 23). A total of 11 patients (5 in TCDT, 6 in NMT) developed CMV disease within 400 days after transplantation, and one death was clearly attributable to CMV interstitial pneumonitis (IP). This strategy was associated with effective control of CMV antigenemia in the majority of patients and near-complete eradication of fatal CMV IP. C1 NHLBI, Stem Cell Allogen Transplantat Unit, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD USA. RP Barrett, AJ (reprint author), NHLBI, Stem Cell Allogen Transplantat Unit, NIH, Bldg 10,9000 Rockville Pike,Room 7C103, Bethesda, MD 20892 USA. NR 40 TC 18 Z9 18 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2002 VL 30 IS 4 BP 235 EP 242 DI 10.1038/sj.bmt.1703648 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 592XY UT WOS:000177963200006 PM 12203140 ER PT J AU Miller, DH Barkhof, F Frank, JA Parker, GJM Thompson, AJ AF Miller, David H. Barkhof, Frederik Frank, Joseph A. Parker, Geoffrey J. M. Thompson, Alan J. TI Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance SO BRAIN LA English DT Review DE multiple sclerosis; MRI; atrophy ID SPINAL-CORD ATROPHY; RELAPSING-REMITTING MS; QUANTITATIVE VOLUMETRIC-ANALYSIS; PROGRESSIVE CEREBRAL ATROPHY; BRAIN PARENCHYMAL FRACTION; MAGNETIC-RESONANCE IMAGES; FOLLOW-UP; WHITE-MATTER; MR-IMAGES; GLATIRAMER ACETATE AB MRI methods are widely used to follow the pathological evolution of multiple sclerosis in life and its modification by treatment. To date, measures of the number and volume of macroscopically visible lesions have been studied most often. These MRI outcomes have demonstrated clear treatment effects but without a commensurate clinical benefit, suggesting that there are other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis pathology, whether it arises in macroscopic lesions or in the normal appearing tissues. An International Workshop recently considered the measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss of these structures, especially axons, although variable effects on tissue volumes may also arise from glial cell proliferation or loss, gliosis, inflammation and oedema. Significant correlations found between brain volume and other putative MR neuronal markers also indicate that atrophy reflects axonal loss. Numerous methods are available for the measurement of global and regional brain volumes and upper cervical cord cross-sectional area that are highly reproducible and sensitive to changes within 6-12 months. In general, 3D-T-1-weighted acquisitions and largely automated segmentation approaches are optimal. Whereas normalized volumes are desirable for cross-sectional studies, absolute volume measures are adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis, developing gradually following the appearance of inflammatory lesions. This probably reflects both inflammation-induced axonal loss followed by Wallerian degeneration and post-inflammatory neurodegeneration that may be partly due to failure of remyelination. One component of atrophy appears to be independent of focal lesions. Existing immunomodulatory therapies have had limited effects on progressive atrophy, concordant with their modest effects on progressive disability. Atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti-inflammatory, remyelinating or neuroprotective therapies. C1 UCL Inst Neurol, NMR Res Unit, Dept Neuroinflammat, London WC1N 3BG, England. Univ Manchester, Dept Imaging Sci & Biomed Engn, Manchester, Lancs, England. Free Univ Amsterdam Hosp, Dept Radiol, Amsterdam, Netherlands. Natl Inst Hlth, Lab Diagnost Radiol, Expt Neuroimaging Sect, Washington, DC USA. RP Miller, DH (reprint author), UCL Inst Neurol, NMR Res Unit, Dept Neuroinflammat, Queen Sq, London WC1N 3BG, England. EM d.miller@ion.ucl.ac.uk RI Thompson, Alan/C-2654-2008 OI Thompson, Alan/0000-0002-4333-8496 FU Multiple Sclerosis Society [491] NR 105 TC 360 Z9 368 U1 0 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2002 VL 125 BP 1676 EP 1695 DI 10.1093/brain/awf177 PN 8 PG 20 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V42NS UT WOS:000202874800002 PM 12135961 ER PT J AU Chu, KC Anderson, WF AF Chu, KC Anderson, WF TI Rates for breast cancer characteristics by estrogen and progesterone receptor status in the major racial/ethnic groups SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; estrogen receptor; progesterone receptor; racial/ethnic groups ID PROLIFERATION; EXPRESSION; WOMEN; ALPHA; RISK AB It has been reported that age-specific breast cancer rates vary by estrogen receptor and progesterone receptor status. We report breast cancer rates for age-at-diagnosis, stage-at-diagnosis, histological grade and type by estrogen (ER) and progesterone (PgR) receptor status in six major racial/ethnic groups. The average annual age-adjusted rates for breast cancers with estrogen receptor positive (ER+), ER-, progesterone receptor positive (PgR(+)), PgR(-), ER(+)PgR(+), ER(+)PgR(-), ER(-)PgR(+) and ER(-)PgR(-) are determined from 123,732 breast cancers with known ER status, diagnosed from 1992 to 1998 from 11 Surveillance, Epidemiology, and End Results (SEER) cancer registries. For each racial/ethnic group, their ER+ (ER(+)PgR(+) and ER(+)PgR(-)) age-specific rates increased with age (but at a slower pace after ages 50-54) while their ER- (ER- PgR(+) and ER(-)PgR(-)) age-specific rates did not increase after ages 50-54. The rank orders of the rates among the racial/ethnic groups varied by ER/PgR status. The stage I rates were greater than the stage II rates for the ER/PgR groups except for ER- and ER(-)PgR(-) cancers. The grade 2 (moderately differentiated) rates were greater than the grades 3 and 4 (poorly differentiated and undifferentiated cancers) rates for ER+ cancers, but not for ER- cancers. These results suggest that although breast cancer is a disease with enormous heterogeneity, the multiple types of breast cancer can be separated into distinct subgroups by their ER status, and perhaps by their ER/PgR status, and their cancer characteristics may be important in understanding the multiple nature of breast cancer. C1 NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. NCI, Chemoprevent Branch, Div Canc Prevent, Bethesda, MD 20892 USA. RP Chu, KC (reprint author), NCI, Ctr Reduce Canc Hlth Dispar, Bldg I,6116 Execut Blvd,Room 6029,9000 Rockville, Bethesda, MD 20892 USA. NR 28 TC 68 Z9 70 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2002 VL 74 IS 3 BP 199 EP 211 DI 10.1023/A:1016361932220 PG 13 WC Oncology SC Oncology GA 573CE UT WOS:000176811100001 PM 12206512 ER PT J AU Gammon, MD Neugut, AI Santella, RM Teitelbaum, SL Britton, JA Terry, MB Eng, SM Wolff, MS Stellman, SD Kabat, GC Levin, B Bradlow, HL Hatch, M Beyea, J Camann, D Trent, M Senie, RT Garbowski, GC Maffeo, C Montalvan, P Berkowitz, GS Kemeny, M Citron, M Schnabel, F Schuss, A Hajdu, S Vincguerra, V Collman, GW Obrams, GI AF Gammon, MD Neugut, AI Santella, RM Teitelbaum, SL Britton, JA Terry, MB Eng, SM Wolff, MS Stellman, SD Kabat, GC Levin, B Bradlow, HL Hatch, M Beyea, J Camann, D Trent, M Senie, RT Garbowski, GC Maffeo, C Montalvan, P Berkowitz, GS Kemeny, M Citron, M Schnabel, F Schuss, A Hajdu, S Vincguerra, V Collman, GW Obrams, GI TI The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; environment; case-control study; DDT; epidemiologic methods; hormones; Long Island; organochlorines; PAH; PCBs ID CIGARETTE-SMOKING; ORGANOCHLORINE COMPOUNDS; CHLORINATED HYDROCARBONS; EPIDEMIOLOGIC EVIDENCE; GENETIC POLYMORPHISMS; AROMATIC-HYDROCARBONS; ALCOHOL-CONSUMPTION; WOMEN; DIET; HYPOTHESIS AB The Long Island Breast Cancer Study Project is a federally mandated, population-based case-control study to determine whether breast cancer risk among women in the counties of Nassau and Suffolk, NY, is associated with selected environmental exposures, assessed by blood samples, self-reports, and environmental home samples. This report describes the collaborative project's background, rationale, methods, participation rates, and distributions of known risk factors for breast cancer by case-control status, by blood donation, and by availability of environmental home samples. Interview response rates among eligible cases and controls were 82.1% (n, = 1,508) and 62.8% (n = 1,556), respectively. Among case and control respondents who completed the interviewer-administered questionnaire, 98.2 and 97.6% self-completed the food frequency questionnaire; 73.0 and 73.3% donated a blood sample; and 93.0 and 83.3% donated a urine sample. Among a random sample of case and control respondents who are long-term residents, samples of dust (83.6 and 83.0%); soil (93.5 and 89.7%); and water (94.3 and 93.9%) were collected. Established risk factors for breast cancer that were found to increase risk among Long Island women include lower parity, late age at first birth, little or no breast feeding, and family history of breast cancer. Factors that were found to be associated with a decreased likelihood that a respondent would donate blood include increasing age and past smoking; factors associated with an increased probability include white or other race, alcohol use, ever breastfed, ever use of hormone replacement therapy, ever use of oral contraceptives, and ever had a mammogram. Long-term residents (defined as 15+ years in the interview home) with environmental home samples did not differ from other long-term residents, although there were a number of differences in risk factor distributions between long-term residents and other participants, as anticipated. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10027 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Environm Hlth Sci, New York, NY 10027 USA. Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. Amer Hlth Fdn, New York, NY 10017 USA. SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. Columbia Univ, Joseph L Mailman Publ Hlth, Div Biostat, New York, NY 10032 USA. Cornell Med Ctr, Strang Res Lab, New York, NY USA. Consulting Publ Interest, Lambertville, NJ USA. SW Res Inst, San Antonio, TX USA. Suffolk Cty Dept Hlth Serv, Hauppauge, NY USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Sociomed Sci, New York, NY USA. Westat Corp, Rockville, MD USA. SUNY Stony Brook, Dept Surg, Stony Brook, NY 11794 USA. Long Isl Jewish Med Ctr, Dept Med, Queens, NY USA. Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA. S Nassau Communities Hosp, Dept Surg, Oceanside, NY USA. Winthrop Univ Hosp, Dept Pathol, Mineola, NY 11501 USA. N Shore Univ Hosp, Dept Pathol, Manhasset, NY 11030 USA. N Shore Univ Hosp, Don Monti Div Oncol, Manhasset, NY 11030 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NCI, Bethesda, MD 20892 USA. RP Gammon, MD (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, CB 7400,Mc Gavran Greenberg Hall, Chapel Hill, NC 27599 USA. OI Beyea, Jan/0000-0002-0547-880X; Bradlow, H Leon/0000-0002-2397-3679 FU NCI NIH HHS [UO1CA/ES66572] NR 51 TC 141 Z9 141 U1 4 U2 15 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2002 VL 74 IS 3 BP 235 EP 254 DI 10.1023/A:1016387020854 PG 20 WC Oncology SC Oncology GA 573CE UT WOS:000176811100004 PM 12206514 ER PT J AU Zhu, Y Spitz, MR Zheng, YL Hong, WK Wu, XF AF Zhu, Y Spitz, MR Zheng, YL Hong, WK Wu, XF TI BPDE-induced lymphocytic 3p21.3 aberrations may predict head and neck carcinoma risk SO CANCER LA English DT Article DE BPDE; chromosomal aberration; FISH; HNSCC ID SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENES; LUNG-CANCER; HOMOZYGOUS DELETION; FRAGILE SITES; SHORT ARM; 3P; PREDISPOSITION; CHROMOSOME-3; HETEROZYGOSITY AB BACKGROUND. Tobacco exposure is an established risk factor for head and neck squamous cell carcinoma (HNSCC). Benzo [alpha] pyrene diol expoxide (BPDE), a main metabolic product of the tobacco smoke constituent benzo[alpha]pyrene, induces chromosomal aberrations at specific loci. Chromosomal aberrations in peripheral blood lymphocytes (PBLs) induced by BPDE may reflect individuals' genetic susceptibility to tobacco carcinogens. METHODS. This study was designed to detect BPDE-induced aberrations in PBLs at locus 3p21.3 in cultured lymphocytic cells. Our hypothesis is that the presence of BPDE-induced 3p21.3 aberrations is a biomarker of an individual's genetic susceptibility and that individuals with these aberrations are at an increased risk for HNSCC. PBL cultures from 52 cases and 54 controls were treated with 2 muM BPDE for 24 hours before the 3p21.3 aberrations were assessed by flourescence in situ hybridization. One thousand lymphocyte interphases were scored for each sample. RESULTS. We found that BPDE-induced chromosome 3p21.3 aberrations occurred more frequently in cases (mean: 31.4 per 1000 cells) than in controls (mean: 22.1 per 1000 cells; P < 0.001). However, when 6q27 was selected as a control locus, no such difference was observed (P = 0.545). When the 75th percentile value of induced aberrations in the controls was used as a cutoff point to classify 3p21.3 BPDE-induced sensitivity, 30 of the 52 cases (57.69%) and only 14 of the 54 controls (25.93%) were sensitive to BPDE exposure. This approach resulted in an odds ratio of 4.8 (95% confidence interval: 1.87-12.28) for HNSCC risk associated with BPDE-induced 3p21.3 aberrations. There was also a dose-response relationship between the number of BPDE-induced aberrations at 3p21.3 and risk for HNSCC. CONCLUSIONS. The results from this study demonstrated that 3p21.3 may be a specific molecular target of tobacco carcinogens and that BPDE sensitivity at this locus may reflect an individual's genetic susceptibility to HNSCC. C1 Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Div Canc Med, Houston, TX USA. RP Wu, XF (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, 1515 Holcombe Blvd,Box 189, Houston, TX 77030 USA. FU NCI NIH HHS [CA 86390, P01 CA 52051]; PHS HHS [R01 74880] NR 28 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2002 VL 95 IS 3 BP 563 EP 568 DI 10.1002/cncr.10689 PG 6 WC Oncology SC Oncology GA 578FW UT WOS:000177107600013 PM 12209748 ER PT J AU Thompson, FE Patterson, BH Weinstein, SJ McAdams, M Spate, VL Hamman, RF Levine, RS Mallin, K Stolley, PD Brinton, LA Morris, JS Ziegler, RG AF Thompson, FE Patterson, BH Weinstein, SJ McAdams, M Spate, VL Hamman, RF Levine, RS Mallin, K Stolley, PD Brinton, LA Morris, JS Ziegler, RG TI Serum selenium and the risk of cervical cancer among women in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE cervical neoplasms; in-situ; selenium; smoking ID TOTAL PARENTERAL-NUTRITION; SUBSEQUENT RISK; HUMAN PAPILLOMAVIRUS; CHEMOPREVENTIVE AGENTS; INTERVENTION TRIALS; PROSTATE-CANCER; WHITE WOMEN; US WOMEN; SUPPLEMENTATION; PREVENTION AB Objective: To explore the relationship between serum selenium and cervical cancer. Methods: We conducted a case-control study of cervical cancer in five areas around Birmingham, AL; Chicago, IL; Denver, CO; Miami, FL; and Philadelphia, PA. Community controls were selected by random-digit dialing and were matched to invasive cervical cancer cases by age, race/ethnicity, and telephone exchange. Serum selenium was determined by neutron activation analysis. Logistic regression analysis controlling for known risk factors of cervical cancer, including human papillomavirus (HPV) type-16 measured serologically, was performed on 227 invasive cases, 127 in-situ cases, and 526 controls. Results: Values of serum selenium ranged from 67.5 to 185.0 ng/ml. Adjusted odds ratios for invasive cervical cancer by quintile were: 1.0 (highest selenium), 1.1, 1.0, 0.8, and 1.0 (lowest selenium), p for trend = 0.82. Similar patterns were observed for Stage I invasive, and Stages II-IV invasive cases, suggesting severity of disease did not influence the null results. Although no associations were seen among current or never smokers, a protective effect of selenium was suggested among former smokers. Effect modification was not evident for other variables examined. Conclusions: This study does not support a relationship between serum selenium and invasive cervical cancer at typical serum selenium levels in the US. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. Univ Missouri, Res Reactor Ctr, Columbia, MO USA. Univ Colorado, Sch Med, Dept Prevent Med & Biostat, Denver, CO USA. Meharry Med Coll, Dept Occupat & Prevent Med, Nashville, TN 37208 USA. Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Thompson, FE (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, EPN 4016,6130 Execut Blvd MSC 7344, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 49 TC 9 Z9 10 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2002 VL 13 IS 6 BP 517 EP 526 DI 10.1023/A:1016328407610 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 573AU UT WOS:000176807800005 PM 12195641 ER PT J AU McDonald, PAG Williams, R Dawkins, F Adams-Campbell, LL AF McDonald, PAG Williams, R Dawkins, F Adams-Campbell, LL TI Breast cancer survival in African American women: Is alcohol consumption a prognostic indicator? SO CANCER CAUSES & CONTROL LA English DT Article DE African American women; alcohol consumption; breast cancer; postmenopausal; survival ID POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; RACIAL-DIFFERENCES; UNITED-STATES; WHITE WOMEN; RISK; MORTALITY; BLACK; RACE; POPULATION AB Objective: Compromised breast cancer survival in African American women is well established. Factors associated with poorer survival in this group are not fully elucidated. This analysis examined the influence of alcohol consumption on breast cancer survival in African American women accrued to a hospital-based study. Methods: One hundred twenty-five postmenopausal women (mean age = 64.2 +/- 12.2 years) diagnosed with invasive breast carcinoma between August 1989 and December 1994, and accrued to a hospital-based study of the disease, were followed for survival through December 1998. Cox proportional hazards regression models, adjusted for cigarette smoking, summary stage of disease, and treatment explored the association between alcohol use and breast cancer survival. Results: Premorbid alcohol consumption of at least one drink per week was associated with 2.7-fold increase in risk of death (95% CI 1.3-5.8). Conclusions: This study suggests compromised breast cancer survival among postmenopausal women who reported drinking at least one alcoholic beverage per week, a preliminary finding that warrants further investigation. C1 Howard Univ, Ctr Canc, Div Canc Prevent Control & Populat Sci, Washington, DC 20059 USA. Howard Univ, Coll Med, Dept Med, Washington, DC 20059 USA. Howard Univ, Hosp Tumor Registry, Washington, DC 20059 USA. RP McDonald, PAG (reprint author), NIH, 6130 Execut Blvd,EPN 4065, Bethesda, MD 20892 USA. OI Green, Paige/0000-0001-7886-8924 FU NCI NIH HHS [CA55772]; NIA NIH HHS [K01AG00817] NR 48 TC 33 Z9 33 U1 1 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2002 VL 13 IS 6 BP 543 EP 549 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 573AU UT WOS:000176807800008 PM 12195644 ER PT J AU Flood, A Caprario, L Chaterjee, N Lacey, JV Schairer, C Schatzkin, A AF Flood, A Caprario, L Chaterjee, N Lacey, JV Schairer, C Schatzkin, A TI Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE alcohol; colorectal cancer; DNA methylation; folate; methionine ID NESTED CASE-CONTROL; ADENOMA-CARCINOMA SEQUENCE; COLON-CANCER; CIGARETTE-SMOKING; RISK-FACTORS; DNA METHYLATION; JAPANESE MEN; LIFE-STYLE; METHYLENETETRAHYDROFOLATE REDUCTASE; PLASMA FOLATE AB Objective: We investigated the associations of folate, methionine, and alcohol intake, as well as combinations of these factors, with risk of colorectal cancer (CRC). Methods: We assessed diet using a 62-item food-frequency questionnaire among 45,264 women in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-up Study. After an average of 8.5 years of follow-up, 490 cases of CRC were identified. Results: Dietary folate showed only a slight inverse association with the risk of CRC (RR = 0.86, 95% CI 0.65-1.13 for high vs. low quintile, p for trend = 0.14), and the association for total folate was null. Consuming more than two servings of alcohol per day was only slightly associated with CRC in this cohort (RR = 1.16, 95% CI 0.63-2.14). Combinations of high alcohol and low total folate did not result in a higher risk of CRC. There was no association between methionine and colorectal cancer. Conclusions: This study shows limited association between alcohol intake and CRC. The non-association of total folate and methionine with CRC, and the null results from the combined folate and alcohol analyses, suggest that what effect alcohol may have on CRC is unrelated to the methyl-group metabolism pathway. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Flood, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7232, Bethesda, MD 20892 USA. NR 49 TC 42 Z9 44 U1 1 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2002 VL 13 IS 6 BP 551 EP 561 DI 10.1023/A:1016330609603 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 573AU UT WOS:000176807800009 PM 12195645 ER PT J AU Nickerson, ML Warren, MB Toro, JR Matrosova, V Glenn, G Turner, ML Duray, P Merino, M Choyke, P Pavlovich, CP Sharma, N Walther, M Munroe, D Hill, R Maher, E Greenberg, C Lerman, MI Linehan, WM Zbar, B Schmidt, LS AF Nickerson, ML Warren, MB Toro, JR Matrosova, V Glenn, G Turner, ML Duray, P Merino, M Choyke, P Pavlovich, CP Sharma, N Walther, M Munroe, D Hill, R Maher, E Greenberg, C Lerman, MI Linehan, WM Zbar, B Schmidt, LS TI Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome SO CANCER CELL LA English DT Article ID PAPILLARY RENAL CARCINOMAS; SPONTANEOUS PNEUMOTHORAX; MET PROTOONCOGENE; SUPPRESSOR GENE; CELL CARCINOMA; NEOPLASIA; CANCER; GERMLINE; FAMILIES; MAPS AB Birt-Hogg-Dube (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C-8 tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development. C1 NCI, Intramural Res Support Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Mol Technol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Ctr Canc Res, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20894 USA. NCI, Dermatol Branch, Canc Res Ctr, NIH, Bethesda, MD 20894 USA. NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20894 USA. NCI, Urol Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20894 USA. NIH, Ctr Clin, Bethesda, MD 20894 USA. Univ Birmingham, Sch Med, Dept Pediat & Child Hlth, Sect Med & Mol Genet, Birmingham, W Midlands, England. Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3T 2N2, Canada. RP Schmidt, LS (reprint author), NCI, Intramural Res Support Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RI MAHER, EAMONN/A-9507-2008 OI MAHER, EAMONN/0000-0002-6226-6918 FU PHS HHS [N01-C0-12400] NR 30 TC 422 Z9 432 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2002 VL 2 IS 2 BP 157 EP 164 DI 10.1016/S1535-6108(02)00104-6 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599UB UT WOS:000178352600011 PM 12204536 ER PT J AU Vail, DM Kurzman, ID Glawe, PC O'Brien, MG Chun, R Garrett, LD Obradovich, JE Fred, RM Khanna, C Colbern, GT Working, PK AF Vail, DM Kurzman, ID Glawe, PC O'Brien, MG Chun, R Garrett, LD Obradovich, JE Fred, RM Khanna, C Colbern, GT Working, PK TI STEALTH liposome-encapsulated cisplatin (SPI-77) versus carboplatin as adjuvant therapy for spontaneously arising osteosarcoma (OSA) in the dog: a randomized multicenter clinical trial SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE stealth liposome; cisplatin; carboplatin; osteosarcoma; canine ID ALKALINE-PHOSPHATASE ACTIVITY; APPENDICULAR OSTEOSARCOMA; PEGYLATED LIPOSOMES; MURAMYL TRIPEPTIDE; PHASE-I; AMPUTATION; PHARMACOKINETICS; TUMORS; MODELS; TISSUE AB Purpose: This trial was designed to compare the efficacy of adjuvant STEALH liposome-encapsulated cisplatin (SPI-77) to "standard-of-care" carboplatin therapy in dogs with osteosarcoma (OSA) in the context of a randomized study design. Methods: The study included 40 pet dogs with spontaneously arising OSA which were randomized to receive SPI-77 (350 mg/m(2) i.v. every 3 weeks for four treatments) or carboplatin (300 mg/m(2) i.v. every 3 weeks for four treatments) along with amputation of the affected limb. Median disease-free (DFS) and overall survival (OS) were compared using standard life-table analysis. Results: The median follow-up was 693 days (range 321-730 days). Of 38 dogs eligible for follow-up, 25 were dead of their disease, 9 were alive and disease-free (8 receiving SPI-77, 1 receiving carboplatin; P=0.02), 2 were free of disease when they were lost to follow-up at 321 and 395 days, and 2 had died of an unrelated disease. The median DFS times for dogs treated with SPI-77 and carboplatin were 156 and 123 days, respectively (P=0.19). The median OS times for dogs treated with SPI-77 and carboplatin were 333 and 207 days, respectively (P=0.18). Conclusions: While STEALTH liposome encapsulation of cisplatin allowed the safe administration of five times the maximally tolerated dose of free cisplatin to dogs without concurrent hydration protocols, this did not translate into significantly prolonged DFS or OS. However, a larger proportion of dogs receiving SPI-77 enjoyed long-term DFS when compared with dogs receiving carboplatin. C1 Univ Wisconsin, Sch Vet Med, Dept Med Sci, Madison, WI 53706 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI 53706 USA. Sonora Vet Specialists, Phoenix, AZ 85032 USA. VCA W Los Angeles Anim Hosp, Los Angeles, CA 90025 USA. Kansas State Univ, Sch Vet Med, Manhattan, KS 66506 USA. Oakland Vet Referral Serv, Bloomfield Hills, MI 48302 USA. Red Bank Vet Referral Ctr, Red Bank, NJ 07701 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. ALZA Corp, Mt View, CA 94043 USA. RP Vail, DM (reprint author), Univ Wisconsin, Sch Vet Med, Dept Med Sci, 2015 Linden Dr W, Madison, WI 53706 USA. NR 28 TC 49 Z9 49 U1 2 U2 11 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2002 VL 50 IS 2 BP 131 EP 136 DI 10.1007/s00280-002-0469-8 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 591FN UT WOS:000177869200008 PM 12172978 ER PT J AU Chang, S Wu, XF Yu, H Spitz, MR AF Chang, S Wu, XF Yu, H Spitz, MR TI Plasma concentrations of insulin-like growth factors among healthy adult men and postmenopausal women: Associations with body composition, lifestyle, and reproductive factors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COLORECTAL-CANCER RISK; FACTOR-BINDING PROTEINS; FACTOR-I; PROSTATE-CANCER; PHYSICAL-ACTIVITY; BREAST-CANCER; IGF-I; COLLEGE ALUMNI; FACTOR (IGF)-I; UNITED-STATES AB As evidence builds for cancer risk associated with insulin-like growth factors (IGFs) and their binding proteins (BPs), capitalizing on such associations for cancer prevention requires identifying the determinants of IGF levels. We measured plasma IGF-I, IGF-II, and IGF BP-3 in a cross-section of 210 men and 171 postmenopausal women enrolled in research as healthy controls. Using linear regression adjusted for age and ethnicity, we evaluated associations between IGF and IGF BP levels and gender, height, body mass index (BMI), smoking, caloric intake, physical activity, and reproductive factors. As expected, women using hormone replacement therapy (HRT) recently had significantly lower IGF-I levels than nonusers. Overall, IGF-I and IGF BP-3 levels did not differ by gender, although men had significantly higher molar ratios of IGF-I to IGF BP-3 and lower plasma IGF-II than women without recent HRT use. For men, BMI was a better predictor of IGF-I levels than height, whereas for women, height was more important. Lower IGF-II levels for both genders were associated with higher BMI and lower physical activity. Lower physical activity was associated with lower IGF BP-3 levels among men. Miscarriage number and menopausal age were positively associated with IGF BP-3 levels. HRT use strongly depressed IGF-I levels among smokers, and additional analysis revealed no remarkable associations. Caloric intake was negatively associated with IGF-I levels among men. Results for ratios of IGF-I and IGF-II to IGF BP-3 generally reflected those for IGF-I and IGF-II levels, respectively. In conclusion, whereas some traditional cancer risk factors were associated with IGF levels, altogether, they accounted for <15% of the total variability in plasma levels for each IGF, suggesting that other factors influence IGF levels. C1 Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. RP Chang, S (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Prevent, 6120 Execut Blvd EPS,Suite T-41,MSC 7105, Bethesda, MD 20892 USA. NR 47 TC 56 Z9 56 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2002 VL 11 IS 8 BP 758 EP 766 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 581UK UT WOS:000177311700012 PM 12163330 ER PT J AU Fears, TR Ziegler, RG Donaldson, JL Falk, RT Hoover, RN Stanczyk, FZ Vaught, JB Gail, MH AF Fears, TR Ziegler, RG Donaldson, JL Falk, RT Hoover, RN Stanczyk, FZ Vaught, JB Gail, MH TI Reproducibility studies and interlaboratory concordance for androgen assays of male plasma hormone levels SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article AB To help us identify appropriate techniques and laboratories for measuring hormones, we studied the variability and reproducibility of assay measurements of androstanediol glucuronide, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, dihydrotestosterone, testosterone, androstanediol, androsterone glucuronide, and androsterone sulfate for five men. Four sets of two aliquots from each sample were sent to participating laboratories, and one set was used for analyses monthly for four consecutive months. For each assay, estimates of components of variance were then used to estimate the coefficient of variation, the intraclass correlation between measurements on different days from a given individual, and the minimum detectable relative difference for a standard design. These data indicate that for at least one of the laboratories a single sample with two laboratory replicates per sample of androstanediol glucuronide, androstenedrone, DHEA, DHEA sulfate, and dihydrotestosterone yields an intraclass correlation coefficient exceeding 0.80 and can be used to discriminate reliably among men. The results for testosterone, androstanediol, androsterone, glucuronide, and androsterone sulfate do not meet this test. These data do not allow us to estimate the component of variation that corresponds to repeated blood samples taken over time from the same man. This reliability study design is, however, entirely appropriate for the typical case-control study which utilizes only one sample per subject. C1 NCI, Biostat Branch, Bethesda, MD 20892 USA. NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Fears, TR (reprint author), NCI, Biostat Branch, 6120 Execut Blvd,EPS-8040, Bethesda, MD 20892 USA. NR 2 TC 7 Z9 7 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2002 VL 11 IS 8 BP 785 EP 789 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 581UK UT WOS:000177311700017 PM 12163335 ER PT J AU Lo, HS Hu, N Gere, S Lu, N Su, H Goldstein, AM Taylor, PR Lee, MP AF Lo, HS Hu, N Gere, S Lu, N Su, H Goldstein, AM Taylor, PR Lee, MP TI Identification of somatic mutations of the RNF6 gene in human esophageal squamous cell carcinoma SO CANCER RESEARCH LA English DT Article ID ALLELIC LOSS; INACTIVATION; POPULATION AB We mapped a tumor suppressor gene locus to an 800-kb interval on human chromosome 13q12.11 for esophageal squamous cell carcinoma (ESCC). Two genes, ML-1 and RNF6, are located within this 800-kb interval. We analyzed both genes for the presence of mutations in 24 ESCC primary tumors and 16 tumor cell lines by directly sequencing the PCR products that were amplified from each exon. No mutation was detected in ML-1. In contrast, three somatic mutations in the RNF6 gene were detected in the ESCC primary tumors, and one mutation was also found in a tumor cell line. Identification of multiple somatic mutations in RNF6 suggests that RNF6 is a potential tumor suppressor gene involved in the pathogenesis of ESCC. C1 NCI, Lab Populat Genet, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. Chinese Acad Med Sci, Hosp, Beijing 100021, Peoples R China. RP Taylor, PR (reprint author), NCI, Lab Populat Genet, Bethesda, MD 20892 USA. NR 11 TC 13 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 AUG 1 PY 2002 VL 62 IS 15 BP 4191 EP 4193 PG 3 WC Oncology SC Oncology GA 578EZ UT WOS:000177105600005 PM 12154016 ER PT J AU Gunning, WT Kramer, PM Steele, VE Pereira, MA AF Gunning, WT Kramer, PM Steele, VE Pereira, MA TI Chemoprevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-induced lung tumors in mice SO CANCER RESEARCH LA English DT Article ID CANCER CHEMOPREVENTION; GROWTH; STRAIN AB 5-Leukotriene pathway inhibitors, Accolate, MK-886, and Zileuton, were evaluated as chemopreventive agents in female strain A mice. The mice were administered by injection vinyl carbamate (2 X 16 m g) to induce lung tumors. Two weeks later, they received in their diet Accolate (270 and 540 mg/kg), MK-886 (30 mg/kg), Zileuton (600 and 1200 mg/kg), or combinations containing the lower concentration of two agents. Thirteen weeks later, Accolate, Zileuton (only the high concentration), and combinations of Zileuton with either Accolate or MK-886 reduced lung tumor multiplicity. At week 43, MK-886, Accolate, and Zileuton reduced lung tumor multiplicity by 37.8, 29.5, and 28.1%, respectively. They also decreased the size of the tumors and the yield of carcinomas. These results demonstrate that leukotriene inhibitors prevent lung tumors and slow the growth and progression of adenomas to carcinoma; leukotriene inhibitors warrant further consideration for potential use in humans. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Gunning, WT (reprint author), Med Coll Ohio, Dept Pathol, Block Hlth Sci Bldg,3035 Arlington Ave, Toledo, OH 43614 USA. RI Gunning, William/E-4681-2010 FU NCI NIH HHS [N01-CN-85146] NR 16 TC 48 Z9 53 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2002 VL 62 IS 15 BP 4199 EP 4201 PG 3 WC Oncology SC Oncology GA 578EZ UT WOS:000177105600007 PM 12154018 ER PT J AU Rapisarda, A Uranchimeg, B Scudiero, DA Selby, M Sausville, EA Shoemaker, RH Melillo, G AF Rapisarda, A Uranchimeg, B Scudiero, DA Selby, M Sausville, EA Shoemaker, RH Melillo, G TI Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; OXIDE SYNTHASE PROMOTER; DOUBLE-STRAND BREAKS; DNA TOPOISOMERASE-I; NF-KAPPA-B; FACTOR 1-ALPHA; TUMOR ANGIOGENESIS; RESPONSIVE ELEMENT; GENE-EXPRESSION; HIF-ALPHA AB Hypoxia-inducible factor I (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation. HIF-1 has been implicated in the regulation of genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase] and anaerobic metabolism (e.g., glycolytic enzymes). HIF-1 is essential for angiogenesis and is associated with tumor progression. In addition, overexpression of HIF-1alpha has been demonstrated in many common human cancers. Therefore, HIF-1 is an attractive molecular target for development of novel cancer therapeutics. We have developed a cell-based high-throughput screen for the identification of small molecule inhibitors of the HIF-1 pathway. We have genetically engineered U251 human glioma cells to stably express a recombinant vector in which the luciferase reporter gene is under control of three copies of a canonical hypoxia-responsive element (U251-HRE). U251-HRE cells consistently expressed luciferase in a hypoxia- and HIF-1-dependent fashion. We now report the results of a pilot screen of the National Cancer Institute "Diversity Set," a collection of approximately 2000 compounds selected to represent the greater chemical diversity of the National Cancer Institute chemical repository. We found four compounds that specifically inhibited HIF-1-dependent induction of luciferase but not luciferase expression driven by a constitutive promoter. In addition, these compounds inhibited hypoxic induction of VEGF mRNA and protein expression in U251 cells. Interestingly, three compounds are closely related camptothecin analogues and topoisomerase (Topo)-I inhibitors. We show that concomitant with HIF-1 and VEGF inhibition, the activity of the Topo-I inhibitors tested is associated with induction of cyclooxygenase 2 mRNA expression. The luciferase-based high-throughput screen is a feasible tool for the identification of small molecule inhibitors of HIF-1 transcriptional activation. In addition, our results suggest that altered Topo-I function may be associated with repression of HIF-1-dependent induction of gene expression. C1 NCI, DTP, Tumor Hypoxia Lab, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Melillo, G (reprint author), NCI, DTP, Tumor Hypoxia Lab, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillo@dtpax2.neiferf.gov FU NCI NIH HHS [N01-CO-56000] NR 41 TC 374 Z9 390 U1 0 U2 21 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2002 VL 62 IS 15 BP 4316 EP 4324 PG 9 WC Oncology SC Oncology GA 578EZ UT WOS:000177105600024 PM 12154035 ER PT J AU Kaluz, S Kaluzova, M Chrastina, A Olive, PL Pastorekova, S Pastorek, J Lerman, MI Stanbridge, EJ AF Kaluz, S Kaluzova, M Chrastina, A Olive, PL Pastorekova, S Pastorek, J Lerman, MI Stanbridge, EJ TI Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: A role for phosphatidylinositol 3 '-kinase SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TRANSMEMBRANE CARBONIC-ANHYDRASES; SMOOTH-MUSCLE CELLS; TRANSCRIPTIONAL REGULATION; SIGNALING PATHWAY; CARCINOMA-CELLS; PROSTATE-CANCER; GENE-EXPRESSION; NITRIC-OXIDE; PROTEIN AB Transcription of the gene coding for the tumor-associated antigen MN/carbonic anhydrase IX (CAIX) is regulated by hypoxia-inducible factor 1 (HIF-1). Previous studies identified CAIX expression in areas adjacent to hypoxic regions in solid tumors and suggested supplementary/alternative modes of regulation. To better understand the mechanisms activating CAIX expression, we characterized the cell density-dependent induction of CAIX in HeLa cells. This process is anchorage and serum independent and is not mediated by a soluble factor, decreased pH, or lowered glucose concentration. Stabilization of HIF-1alpha was not observed in dense cultures. In contrast to sparse cell culture conditions, phosphatidylinositol 3'-kinase (PI3K) activity was significantly increased in dense HeLa cultures. The PI3K inhibitors LY294002 and wortmannin inhibited CAIX expression in dense cultures in a dose-dependent manner, specifically targeting the CA9 promoter (-173/+31 region) that was transactivated by constitutively active p110 PI3K subunit. The mechanism controlling CAIX expression in dense cultures is, however, dependent on lowered O-2 tension because stirring abrogates induction of CAIX expression. Hypoxia- and cell density-induced CAIX expressions were mediated by two seemingly independent mechanisms, as documented by the additive effect of increased cell density and treatment with the hypoxia-mimic CoCl2 on levels of CAIX expression. The minimal cell density-dependent region within the CA9 promoter consists of the juxtaposed protected region 1 and hypoxia-response elements. However cell density-dependent CAIX expression was abrogated in the HIF-1alpha-deficient Ka13.5 cells, suggesting an important role of HIF-1 in the corresponding mechanism. Thus, induction of CAIX in high-density cultures requires separate but interdependent pathways of PI3K activation and a minimal level of HIF-1alpha. These interdependent pathways function at a lowered O-2 concentration that is, however, above that necessary for HIF-1a stabilization. C1 Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. Slovak Acad Sci, Inst Virol, Bratislava, Slovakia. British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 1L3, Canada. NCI, Immunobiol Lab, NIH, Bethesda, MD 20889 USA. RP Stanbridge, EJ (reprint author), Univ Calif Irvine, Dept Microbiol & Mol Genet, Med Sci 1 B210, Irvine, CA 92697 USA. FU NCI NIH HHS [CA 19401] NR 49 TC 111 Z9 113 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2002 VL 62 IS 15 BP 4469 EP 4477 PG 9 WC Oncology SC Oncology GA 578EZ UT WOS:000177105600046 PM 12154057 ER PT J AU Li, HZ Velasco-Miguel, S Vass, WC Parada, LF DeClue, JE AF Li, HZ Velasco-Miguel, S Vass, WC Parada, LF DeClue, JE TI Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1 : p53 mouse tumor model SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE ARREST; SCHWANN-CELLS; NEUROFIBROMATOSIS TYPE-1; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; BENIGN NEUROFIBROMAS; TYROSINE KINASES; SUPPRESSOR GENE; NF1 GENE; RAS; MUTATION AB The human disease neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene, and is characterized by the formation of benign and malignant tumors of the peripheral nervous system. We have shown previously that aberrant expression of the epidermal growth factor receptor (EGFR) is a common feature of human NF1-related tumor development in humans and in NF1 animal models. One recent approach taken to investigate the changes associated with NF1 tumor formation is the development of the Nf1:p53 mouse tumor model. Here, we examined a series of tumor cell lines derived from Nf1:p53 mice for their expression of EGFR family members. Immunoblotting analyses revealed that 23 of the 24 cell lines examined express the EGFR, and 24 of 24 express the related tyrosine kinase erbB2, whereas erbB3 was detected in only 6 of 24. All of the cell lines expressing EGFR responded to epidermal growth factor (EGF) by activation of the downstream signaling pathways, mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase/MAP kinase, and phosphatidylinositol 3'-kinase (PI3k)/AKT. Growth of the cell lines was greatly stimulated by EGF in vitro and could be blocked by an antagonist of the EGFR. In addition, inhibition of the PI3k pathway potently inhibited the EGF-dependent growth of these cell lines, whereas inhibition of the MAP/extracellular signal-regulated kinase kinase/MAP kinase pathway had more limited effects. We conclude that EGFR expression is a common feature of the Nf1:p53 tumor cell lines and that inhibition of this molecule or its downstream target PI3k, may be useful in the treatment of NF1-related malignancies. C1 NCI, Cellular Oncol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Ctr Dev Biol, Dallas, TX 75235 USA. RP DeClue, JE (reprint author), NCI, Cellular Oncol Lab, Canc Res Ctr, NIH, Bldg 36,Room 1D-32,MSC 4040,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Parada, luis/B-9400-2014 FU NINDS NIH HHS [R01 NS034296-06] NR 55 TC 61 Z9 62 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2002 VL 62 IS 15 BP 4507 EP 4513 PG 7 WC Oncology SC Oncology GA 578EZ UT WOS:000177105600051 PM 12154062 ER PT J AU Benhamou, S Lee, WJ Alexandrie, AK Boffetta, P Bouchardy, C Butkiewicz, D Brockmoller, J Clapper, ML Daly, A Dolzan, V Ford, J Gaspari, L Haugen, A Hirvonen, A Husgafvel-Pursiainen, K Ingelman-Sundberg, M Kalina, I Kihara, M Kremers, P Le Marchand, L London, SJ Nazar-Stewart, V Onon-Kihara, M Rannug, A Romkes, M Ryberg, D Seidegard, J Shields, P Strange, RC Stucker, I To-Figueras, J Brennan, P Taioli, E AF Benhamou, S Lee, WJ Alexandrie, AK Boffetta, P Bouchardy, C Butkiewicz, D Brockmoller, J Clapper, ML Daly, A Dolzan, V Ford, J Gaspari, L Haugen, A Hirvonen, A Husgafvel-Pursiainen, K Ingelman-Sundberg, M Kalina, I Kihara, M Kremers, P Le Marchand, L London, SJ Nazar-Stewart, V Onon-Kihara, M Rannug, A Romkes, M Ryberg, D Seidegard, J Shields, P Strange, RC Stucker, I To-Figueras, J Brennan, P Taioli, E TI Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk SO CARCINOGENESIS LA English DT Article ID DNA ADDUCT LEVELS; GENETIC-POLYMORPHISM; GSTT1 GENOTYPES; METABOLIZING-ENZYMES; AFRICAN-AMERICANS; GSTM1 GENOTYPES; MU POLYMORPHISM; UNITED-STATES; SUSCEPTIBILITY; SMOKERS AB Susceptibility to lung cancer may in part be attributable to inter-individual variability in metabolic activation or detoxification of tobacco carcinogens. The glutathione S-transferase M1 (GSTM1) genetic polymorphism has been extensively studied in this context; two recent meta-analyses of case-control studies suggested an association between GSTM1 deletion and lung cancer. At least 15 studies have been published after these overviews. We undertook a new meta-analysis to summarize the results of 43 published case-control studies including >18 000 individuals. A slight excess of risk of lung cancer for individuals with the GSTM1 null genotype was found (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.07-1.27). No evidence of publication bias was found (P = 0.4), however, it is not easy to estimate the extent of such bias and we cannot rule out some degree of publication bias in our results. A pooled analysis of the original data of about 9500 subjects involved in 21 case-control studies from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC) data set was performed to assess the role of GSTM1 genotype as a modifier of the effect of smoking on lung cancer risk with adequate power. Analyses revealed no evidence of increased risk of lung cancer among carriers of the GSTM1 null genotype (age-, gender- and center-adjusted OR = 1.08, 95% CI 0.98-1.18) and no evidence of interaction between GSTM1 genotype and either smoking status or cumulative tobacco consumption. C1 INSERM, U521, EMI 00 06, Evry, France. Int Agcy Res Canc, F-69372 Lyon, France. Karolinska Inst, Stockholm, Sweden. Natl Inst Working Life, Stockholm, Sweden. Geneva Canc Registry, Geneva, Switzerland. Ctr Oncol, Gliwice, Poland. Univ Gottingen, D-3400 Gottingen, Germany. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Ljubljana, Ljubljana 61000, Slovenia. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Osped Maggiore, IRCCS, Milan, Italy. Natl Inst Occupat Hlth, Oslo, Norway. Finnish Inst Occupat Hlth, Helsinki, Finland. Safarik Univ, Kosice, Slovakia. Kyoto Univ, Sch Publ Hlth, Kyoto, Japan. Inst Pathol, Liege, Belgium. Univ Hawaii, Honolulu, HI 96822 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Nagasaki Univ, Grad Sch Med, Nagasaki 852, Japan. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Lund Univ, Lund, Sweden. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Keele Univ, Keele, Staffs, England. INSERM, U170, Villejuif, France. Hosp Clin Barcelona, Barcelona, Spain. RP Benhamou, S (reprint author), INSERM, U521, EMI 00 06, Evry, France. EM benhamou@evry.inserm.fr RI Daly, Ann/H-3144-2011; Shields, Peter/I-1644-2012; Benhamou, Simone/K-6554-2015; OI Daly, Ann/0000-0002-7321-0629; London, Stephanie/0000-0003-4911-5290 NR 54 TC 186 Z9 192 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2002 VL 23 IS 8 BP 1343 EP 1350 DI 10.1093/carcin/23.8.1343 PG 8 WC Oncology SC Oncology GA 580JG UT WOS:000177231000012 PM 12151353 ER PT J AU Vanderwinden, JM Gillard, K De Laet, MH Messam, CA Schiffmann, SN AF Vanderwinden, JM Gillard, K De Laet, MH Messam, CA Schiffmann, SN TI Distribution of the intermediate filament nestin in the muscularis propria of the human gastrointestinal tract SO CELL AND TISSUE RESEARCH LA English DT Article DE confocal microscopy; enteric nervous system; glial cells; immunohistochemistry; interstitial cells of Cajal; human ID INTERSTITIAL-CELLS; PROTEIN NESTIN; REACTIVE ASTROCYTES; SKELETAL-MUSCLE; EXPRESSION; CAJAL; MOUSE; CNS; RAT; INTESTINE AB The intermediate filament nestin is expressed in neural stem cells, neuroectodermal tumors and various adult tissues. In the gastrointestinal (GI) tract, nestin has been reported in glial cells. Recently, nestin has been reported in interstitial cells of Cajal (ICC) and in gastrointestinal stromal tumors, thought to derive from ICC. Here we investigated nestin immunoreactivity (-ir) in the normal human GI tract, with emphasis on Kit-ir ICC. Two different antibodies specific for human nestin and multicolor high-resolution confocal microscopy were used on material from our human GI tissue collection. The staining pattern of both nestin antibodies was similar. In labeled cells, nestin-ir appeared filamentous. Most intramuscular ICC in antrum and all myenteric ICC (ICC-MP) in small intestine were nestin-ir, while nestin-ir was not detected in deep muscular plexus ICC. In the colon, some - but not all - ICC-MP and most ICC in the circular musculature were nestin-ir while nestin-ir was not detected in ICC in the longitudinal musculature and in the submuscular plexus. In addition, many Kit-negative cells were nestin-ir in all regions. Neurons and smooth muscle cells were consistently nestin negative, while most S100-ir glial cells were nestin-ir. In addition, nestin-ir was also present in some CD34-ir fibroblast-like cells, in endothelium and in other cell types in the mucosa and serosa. In conclusion, nestin-ir is abundantly present in the normal human GI tract. Among a number of cell types, several, but not all, subpopulations of Kit-ir ICC were nestin-ir. The functional significance of nestin in the GI tract remains obscure. C1 Free Univ Brussels, Neurophysiol Lab, Fac Med, B-1070 Brussels, Belgium. Hop Univ Enfants Reine Fabiola, Dept Chirurg Pediat, Brussels, Belgium. NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Vanderwinden, JM (reprint author), Free Univ Brussels, Neurophysiol Lab, Fac Med, 808 Route Lennik,Campus Erasme,CP 601, B-1070 Brussels, Belgium. NR 31 TC 34 Z9 34 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD AUG PY 2002 VL 309 IS 2 BP 261 EP 268 DI 10.1007/s00441-002-0590-3 PG 8 WC Cell Biology SC Cell Biology GA 584HQ UT WOS:000177461500007 PM 12172785 ER PT J AU Sapozhnikov, AM Gusarova, GA Ponomarev, ED Telford, WG AF Sapozhnikov, AM Gusarova, GA Ponomarev, ED Telford, WG TI Translocation of cytoplasmic HSP70 onto the surface of EL-4 cells during apoptosis SO CELL PROLIFERATION LA English DT Article ID HEAT-SHOCK PROTEINS; MOLECULAR CHAPERONES; HYDROGEN-PEROXIDE; LYMPHOMA-CELLS; TUMOR-CELLS; EXPRESSION; BCL-2; MEMBRANE; PATHWAY; CASPASES AB Heat shock proteins (HSPs) are involved in a variety of intracellular processes and can have both pro- and anti-apoptotic action. However, little is known about the role of HSPs in the progression of apoptosis. Translocation of HSPs to the surface of apoptotic cells is a previously observed phenomenon demonstrating participation of these proteins in execution of the terminal stages of apoptosis. In a previous study we showed that development of EL-4 lymphoma cell apoptosis in vitro is accompanied by elevation of surface HSP expression. In this study we used this model to analyse the relationship of HSP70 expression and its translocation to the cell surface during apoptosis with some key intracellular events. Our data demonstrate a synchronization of surface and intracellular HSP70 expression with bcl-2 expression, intracellular reactive oxygen species (ROS) concentration and caspase-3 activity. A maximum level of surface and intracellular HSP70 expression was observed at an irreversible phase of EL-4 cell apoptosis after mitochondrial potential depolarization. In addition, an enhancement of the relative level of cytoplasmic HSP70 translocation to the cell surface was concomitant with EL-4 cell apoptosis. However, the size of surface and intracellular pools of HSP70, increasing for initial and intermediate stages of cell death, decreased at the terminal phase of apoptosis. Western blot analysis of HSP70 in conditioned supernatant obtained from EL-4 cell tissue showed that the observed decrease of HSP70 cell content might be due to surface HSP70 shedding into the intercellular space. C1 Shemyakin & Ovchinnikov Inst Bioorgan Chem, Div Immunol, Moscow 117997, Russia. NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sapozhnikov, AM (reprint author), Shemyakin & Ovchinnikov Inst Bioorgan Chem, Div Immunol, 16-10 Miklukho Maklaya Str,V-437, Moscow 117997, Russia. NR 38 TC 18 Z9 20 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7722 J9 CELL PROLIFERAT JI Cell Prolif. PD AUG PY 2002 VL 35 IS 4 BP 193 EP 206 AR UNSP CPR_239.fm DI 10.1046/j.1365-2184.2002.00239.x PG 14 WC Cell Biology SC Cell Biology GA 579WA UT WOS:000177199700001 PM 12153612 ER PT J AU Ivanova, AV Ivanov, SV AF Ivanova, AV Ivanov, SV TI Differential display analysis of gene expression in yeast SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE RNA differential display; clr4; yeast; differential expression ID POLYMERASE-CHAIN-REACTION; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; BUDDING YEAST; PCR; IDENTIFICATION; ACTIVATION; MEIOSIS AB RNA differential display (DD) is a powerful and straightforward method that employs random reverse-transcription polymerase chain reaction amplification of mRNA species with electrophoresis for comparative analysis of two or more transcriptomes. The small yeast genome represents a convenient model for studying basic functions of the eukaryotic genome and simultaneously provides valuable information towards further refinement of this technique. Several examples discussed below illustrate how DD coupled with classical yeast genetic approaches may be used for studying transcriptionally regulated genetic systems. C1 NCI, Canc Res Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Canc Res Ctr, IRSP, SAIC Frederick, Frederick, MD 21702 USA. RP Ivanova, AV (reprint author), NCI, Canc Res Ctr, Immunobiol Lab, Bldg 560,Room 12-71,POB B, Frederick, MD 21702 USA. NR 23 TC 5 Z9 5 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD AUG PY 2002 VL 59 IS 8 BP 1241 EP 1245 DI 10.1007/s00018-002-8502-y PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 596PC UT WOS:000178172400002 PM 12363027 ER PT J AU Goodwin, RD Pine, DS AF Goodwin, RD Pine, DS TI Respiratory disease and panic attacks among adults in the United States SO CHEST LA English DT Article DE asthma; panic attacks; respiratory disease ID ANXIETY DISORDERS; MAJOR DEPRESSION; ASTHMA; PREVALENCE; ASSOCIATION; IMPAIRMENT; DISABILITY; QUALITY; COPD; LIFE AB Objective: To determine the association between respiratory disease and panic attacks among adults in the US population. Method: Data were drawn from the Midlife Development in the United States Survey (n = 3,032), a representative sample of adults aged 25 to 74 years. Multivariate logistic regression analyses were used to determine the relationship between self-reported respiratory, and other lung disease and panic attacks, major depression, generalized anxiety disorder, and alcohol/substance use disorders. Results: After adjusting for demographic characteristics, comorbid mental disorders, and comorbid physical disorders, self-reported respiratory disease (ie, asthma, chronic bronchitis, or emphysema) was associated with a significantly increased likelihood of panic attacks (odds ratio, 1.7; confidence interval, 1.2 to 2.4). Other self-reported lung disease was also associated with a significantly increased odds of panic attacks (odds ratio, 2.3; confidence interval, 1.2 to 4.2), and having both self-reported respiratory disease and another lung disease was associated with increased likelihood of panic attacks (odds ratio, 4.1; confidence interval, 1.7, 9.9). These associations also persisted after adjusting for demographic characteristics, comorbid mental disorders, and physical comorbidity. Conclusion: These findings are consistent with and extend previous clinical and epidemiologic data by showing a specific association between self-reported respiratory disease and panic attacks among adults. Future studies that investigate the relationship between respiratory disease and panic attacks, and other mental disorders, using prospectively collected data on respiratory functioning, may help to improve our understanding of the mechanism of this association. C1 Columbia Univ Coll Phys & Surg, Dept Psychiat, Div Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. NIMH, Bethesda, MD 20892 USA. RP Goodwin, RD (reprint author), 1051 Riverside Dr,Unit 43, New York, NY 10032 USA. NR 28 TC 60 Z9 61 U1 4 U2 5 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2002 VL 122 IS 2 BP 645 EP 650 DI 10.1378/chest.122.2.645 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 584CJ UT WOS:000177449400044 PM 12171845 ER PT J AU Lozanoff, S Uyehara, CFT Ma, WB Himenes, M AF Lozanoff, S Uyehara, CFT Ma, WB Himenes, M TI Heritable pathologic hypertension and chronic renal failure in the Br mutant mouse. SO CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY LA English DT Meeting Abstract DE hypertension; kidney; Br C1 Univ Hawaii, Sch Med, Dept Anat & Reprod Biol, Honolulu, HI 96822 USA. Tripler Army Med Hosp, Pharmacol Res Lab, Honolulu, HI USA. NCI, Immunol Lab, Frederick, MD USA. Univ Hawaii, Lab Anim Serv, Honolulu, HI 96822 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0305-1870 J9 CLIN EXP PHARMACOL P JI Clin. Exp. Pharmacol. Physiol. PD AUG PY 2002 VL 29 IS 8 BP A98 EP A98 PG 1 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 570CB UT WOS:000176639600099 ER PT J AU Voltchikhina, SA Yacono, BC Cheng, L Heller, P Lakatta, EG Talan, MI AF Voltchikhina, SA Yacono, BC Cheng, L Heller, P Lakatta, EG Talan, MI TI Non-dilated phenotype of chronic heart failure (HF) following experimental myocardial infarction (MI) in mice. SO CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY LA English DT Meeting Abstract DE chronic heart failure; left ventricular elastance; mouse C1 NIA, Cardiovasc Sci Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0305-1870 J9 CLIN EXP PHARMACOL P JI Clin. Exp. Pharmacol. Physiol. PD AUG PY 2002 VL 29 IS 8 BP A82 EP A83 PG 2 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 570CB UT WOS:000176639600058 ER PT J AU Goldstein, DS Holmes, C Dendi, R Li, ST Brentzel, S Vernino, S AF Goldstein, DS Holmes, C Dendi, R Li, ST Brentzel, S Vernino, S TI Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE pandysantonica; autoimmune autonomic neuropathy ID ORTHOSTATIC HYPOTENSION; AUTONOMIC NEUROPATHY; FAILURE; 6-FLUORODOPAMINE; CATECHOLS AB We report the case of a patient with chronic autonomic failure who had evidence of decreased postganglionic traffic to intact sympathetic nerve terminals. The patient complained mainly of decreased salivation, constipation, dry skin, and orthostatic intolerance. There was no evidence of central neurodegeneration. Autonomic function testing showed orthostatic hypotension without tachycardia and abnormal blood pressure and pulse rate responses to the Valsalva maneuver, indicating combined sympathetic and parasympathetic neurocirculatory failure. In contrast to patients with pure autonomic failure, the patient had normal left ventricular myocardial concentrations of 6-[(18) F]fluorodopamine-derived radioactivity, establishing intact postganglionic sympathetic innervation; and in contrast to patients with multiple system atrophy or baroreflex failure, the patient had a low plasma norepinephrine concentration and brisk norepinephrine response to orthostasis. These findings indicated an impediment to ganglionic neurotransmission. Serologic testing demonstrated a circulating antibody to the ganglionic nicotinic acetylcholine receptor. The findings in this case support the concept that circulating antibodies to this receptor can interfere with ganglionic neurotransmission and produce autoimmune autonomic neuropathy. C1 NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. Mayo Clin, Dept Neurol, Rochester, MN USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Bldg 10,Room 6N252, Bethesda, MD 20892 USA. NR 16 TC 33 Z9 34 U1 1 U2 1 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD AUG PY 2002 VL 12 IS 4 BP 281 EP 285 DI 10.1007/s10286-002-0020-3 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 605DX UT WOS:000178661100012 PM 12357282 ER PT J AU Hildesheim, J Fornace, AJ AF Hildesheim, J Fornace, AJ TI Gadd45a: An elusive yet attractive candidate gene in pancreatic cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID P53-REGULATED PROTEIN GADD45; CELL NUCLEAR ANTIGEN; DNA-DAMAGE; GROWTH-ARREST; STRESS-RESPONSE; A431 CELLS; CHECKPOINT; ACTIVATION; KINASE; EXPRESSION C1 NCI, Gene Response Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hildesheim, J (reprint author), NCI, Gene Response Sect, Canc Res Ctr, NIH, Bldg 37,Room 6144,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 34 TC 33 Z9 36 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2002 VL 8 IS 8 BP 2475 EP 2479 PG 5 WC Oncology SC Oncology GA 585JB UT WOS:000177520700002 PM 12171872 ER PT J AU Pourquier, P Gioffre, C Kohlhagen, G Urasaki, Y Goldwasser, F Hertel, LW Yu, SY Pon, RT Gmeiner, WH Pommier, Y AF Pourquier, P Gioffre, C Kohlhagen, G Urasaki, Y Goldwasser, F Hertel, LW Yu, SY Pon, RT Gmeiner, WH Pommier, Y TI Gemcitabine (2 ',2 '-difluoro-2 '-deoxycytidine), an antimetabolite that poisons topoisomerase I SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; CLEAVABLE COMPLEXES; DNA-SYNTHESIS; PHASE-III; ARA-C; CAMPTOTHECIN; 2',2'-DIFLUORODEOXYCYTIDINE; TOPOTECAN; VITRO; 1-BETA-D-ARABINOFURANOSYLCYTOSINE AB Purpose: Gemcitabine-containing regimens are among standard therapies for the treatment of advanced non-small cell lung, pancreatic, or bladder cancers. Gemcitabine is a nucleoside analogue and its cytotoxicity is correlated with incorporation into genomic DNA and concomitant inhibition of DNA synthesis. However, it is still unclear by which mechanism(s) gemcitabine incorporation leads to cell death. Experimental Design: We used purified oligode-oxynucleotides to study the effects of gemeitabine incorporation on topoisornerase I (top1) activity and tested the role of top1 poisoning in gemcitabine-induced cytotoxicity in cancer cells. Results: We found that top1-mediated DNA cleavage was enhanced when gemcitabine was incorporated immediately 3' from a top1 cleavage site on the nonscissile strand. This position-specific enhancement was attributable to an increased DNA cleavage by top1 and was likely to have resulted from a combination of gemcitabine-induced conformational and electrostatic effects. Gemcitabine also enhanced camptothecin-induced cleavage complexes. We also detected top1 cleavage complexes in human leukemia CEM cells treated with gemcitabine and a 5-fold resistance of P388/CPT45 top1-deficient cells to gemcitabine, indicating that poisoning of top1 can contribute to the antitumor activity of gemcitabine. Conclusions: The present results extend our recent finding that incorporation Of 1-beta-D-arabinofuranosylcytosine into DNA can induce top1 cleavage complexes [P. Pourquier et al. Proc. Natl. Acad. Sci. USA, 97. 1885-1890, 2000]. The enhancement of camptothecin-induced top1 cleavage complexes may, at least in part, contribute to the synergistic or additive effects of gemcitabine in combination with topotecan and irinotecan in human breast or lung cancer cells. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Hop Cochin, Unite Oncol Med, F-75674 Paris, France. Eli Lilly & Co, Lilly Res Labs, Canc Res Div, Indianapolis, IN 46285 USA. Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27109 USA. Univ Calgary, Core DNA Synth Facil, Calgary, AB, Canada. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01 CA060612] NR 38 TC 56 Z9 58 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2002 VL 8 IS 8 BP 2499 EP 2504 PG 6 WC Oncology SC Oncology GA 585JB UT WOS:000177520700005 PM 12171875 ER PT J AU Tolcher, AW Reyno, L Venner, PM Ernst, SD Moore, M Geary, RS Chi, K Hall, S Walsh, W Dorr, A Eisenhauer, E AF Tolcher, AW Reyno, L Venner, PM Ernst, SD Moore, M Geary, RS Chi, K Hall, S Walsh, W Dorr, A Eisenhauer, E TI A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; STANDARD CHEMOTHERAPEUTIC-AGENTS; ISIS-5132 CGP 69846A; ANTITUMOR-ACTIVITY; RAF KINASE; SIGNAL-TRANSDUCTION; ALPHA EXPRESSION; PHORBOL ESTER; PKC-ALPHA; NUDE-MICE AB Purpose: Protein kinase C (PKC)-alpha and Raf-1 are important elements of proliferative signal transduction pathways in both normal and malignant cells. Abrogation of either Raf-1 or PKC-alpha function can both inhibit cellular proliferation and induce apoptosis in several experimental cancer models including prostate cancer cell lines. ISIS 3521 and ISIS 5132 are antisense phosphorothioate oligonucleotides that inhibit PKC-alpha and Raf-1 expression, respectively, and induce a broad spectrum of antiproliferative and antitumor effects in several human tumor cell lines. In Phase I evaluation both ISIS 3521 and ISIS 5132 could be safely administered on 21-day i.v. infusion schedules and demonstrated preliminary evidence of antitumor activity. On the basis of these findings, a randomized Phase H study of ISIS 3521 and ISIS 5132 was performed in two comparable cohorts of patients who had chemotherapy-naive, hormone-refractory prostate cancer (HRPC). Patients and Methods: Patients with documented evidence of metastatic HRPC and a prostate-specific antigen (PSA) value greater than or equal to20 ng/ml were randomized to receive treatment with either ISIS 3521 or ISIS 5132 as a continuous i.v. infusion for 21 days repeated every 4 weeks. Patients were stratified according to the presence or absence of bidimensionally measurable disease at the time of randomization. The principal endpoints included PSA response, objective response in patients with bidimensionally measurable disease, and treatment failure defined as new or worsening symptoms; a fall in performance status of 2 levels; new or objective progression of disease; or a rise in PSA for 12 weeks without symptom improvement. Plasma samples were collected to assess individual steady-state concentrations and to relate this pharmacokinetic parameter to observed toxicities and responses. Results: Thirty-one patients were randomized in this study; 15 patients received 43 courses of ISIS 3521 and 16 patients received 48 courses of ISIS 5132. The most common toxicities observed were mild to moderate (grade I or 2) fatigue and lethargy in 21% and 56% of patients treated with ISIS 3521 and ISIS 5132, respectively. Although no objective or PSA responses were observed in any patient treated with ISIS 3521 or ISIS 5132, persistent stable disease was observed in 3 patients for 5 or more months, and in 5 patients the PSA values did not rise >25% for 120 days or longer. Conclusions: The antisense oligonucleotides ISIS 3521 and ISIS 5132, at these doses and on this schedule, do not possess clinically significant single-agent antitumor activity in HRPC. Protracted stable disease in some patients may indicate a cytostatic effect. Additional work is required to define the optimal role of PKC-alpha or Raf-1 inhibition in the treatment of HRPC. C1 British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Hamilton Reg Canc Ctr, Hamilton, ON L8V 1C3, Canada. Tom Baker Canc Clin, Calgary, AB T2N 4N2, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. ISIS Pharmaceut Inc, Carlsbad, CA USA. NCI, Kingston, ON K7L 3N6, Canada. RP Tolcher, AW (reprint author), Inst Drug Res, Canc Therapy & Res Ctr, 8122 Datapoint Dr,Suite 250, San Antonio, TX 78229 USA. NR 37 TC 103 Z9 109 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2002 VL 8 IS 8 BP 2530 EP 2535 PG 6 WC Oncology SC Oncology GA 585JB UT WOS:000177520700010 PM 12171880 ER PT J AU Salcedo, R Martins-Green, M Gertz, B Oppenheim, JJ Murphy, WJ AF Salcedo, R Martins-Green, M Gertz, B Oppenheim, JJ Murphy, WJ TI Combined administration of antibodies to human interleukin 8 and epidermal growth factor receptor results in increased antimetastatic effects on human breast carcinoma xenografts SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN OVARIAN-CANCER; HUMAN-MELANOMA CELLS; EGF-RECEPTOR; FACTOR-ALPHA; CHEMOKINE RECEPTORS; ENDOTHELIAL-CELLS; TUMOR-GROWTH; HUMAN LUNG; EXPRESSION; ANGIOGENESIS AB Purpose: Current antibody-based immunotherapeutic approaches under evaluation for breast carcinoma are limited in target scope. For example, administration of the human epidermal growth factor receptor (EGFR) antibody, alone or in combination with a chemotherapeutic drug, is thought to primarily inhibit tumor cell proliferation. The aim of this study was to assess the effects of a combined blockade designed to inhibit tumor growth by inhibition of proliferation rate and the proinflammatory effects of interleukin (IL) 8. Experimental Design: A human breast carcinoma cell line that produces high levels of IL-8 was injected s.c. into severe combined immunodeficient mice. IL-8 has been reported to augment the progression of some human tumors; thus, we used a human IL-8 antibody, ABXIL8, in combination with anti-EGFR, ABXEGFR, to inhibit the metastasis of MDA231 tumors. Results: Whereas anti-IL-8 alone had no appreciable antimetastatic effect, the combination of ABXIL8 significantly enhanced the antitumor effects of ABXEGFR, resulting in greater survival of SCID tumor-bearing mice. This effect on survival was correlated with decreased metastatic spread and decreased tumor size in mice receiving both antibodies. Intriguingly, in vitro studies indicate that this antibody combination markedly inhibited matrix metallo-proteinase activity associated with MDA-231 cells to a greater degree than either antibody alone. Conclusion: Combined administration of these two human antibodies using growth factor blockade in conjunction with chemokine blockade may thus provide a more effective approach for treatment of metastatic human breast carcinoma. C1 NCI, SAIC Frederick, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Lab Mol Immunoregulat, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Calif Riverside, Dept Biol, Riverside, CA 92521 USA. RP Murphy, WJ (reprint author), NCI, SAIC Frederick, Intramural Res Support Program, Sci Applicat Int Corp, Bldg 567,Room 209, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 50 TC 33 Z9 37 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2002 VL 8 IS 8 BP 2655 EP 2665 PG 11 WC Oncology SC Oncology GA 585JB UT WOS:000177520700028 PM 12171898 ER PT J AU Srinivas, PR Verma, M Zhao, YM Srivastava, S AF Srinivas, PR Verma, M Zhao, YM Srivastava, S TI Proteomics for cancer biomarker discovery SO CLINICAL CHEMISTRY LA English DT Review ID TANDEM-MASS-SPECTROMETRY; LASER CAPTURE MICRODISSECTION; COMPLEX PROTEIN MIXTURES; MEMBRANE ANTIGEN; PROSTATE-CANCER; 2-DIMENSIONAL ELECTROPHORESIS; SEQUENCE DATABASES; DIFFERENTIAL DISPLAY; GEL ELECTROPHORESIS; SAMPLE PREPARATION AB The emergence of novel technologies allows researchers to facilitate the comprehensive analyses of genomes, transcriptomes, and proteomes in health and disease. The information that is expected from such technologies may soon exert a dramatic change in the pace of cancer research and impact dramatically on the care of cancer patients. These approaches have already demonstrated the power of molecular medicine in discriminating among disease subtypes that are not recognizable by traditional pathologic criteria and in identifying specific genetic events involved in cancer progression. This review covers a selection of advances in the realm of proteomics and its promise for cancer biomarker discovery. It also addresses issues regarding sample preparation and specificity and discusses current challenges that need to be overcome. Finally, the review touches on the efforts of the Early Detection Research Network at the National Cancer Institute in promoting biomarker discovery for translation at the clinical level. (C) 2002 American Association for Clinical Chemistry. C1 NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RP Srivastava, S (reprint author), NCI, Div Canc Prevent, Canc Biomarkers Res Grp, 6130 Execut Blvd,Room EPN 330F, Rockville, MD 20852 USA. EM ss1a@nih.gov NR 72 TC 161 Z9 186 U1 3 U2 31 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2002 VL 48 IS 8 BP 1160 EP 1169 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 576GZ UT WOS:000176996500004 PM 12142368 ER PT J AU Peters, KF Kong, F Hanslo, M Biesecker, BB AF Peters, KF Kong, F Hanslo, M Biesecker, BB TI Living with Marfan syndrome III. Quality of life and reproductive planning SO CLINICAL GENETICS LA English DT Article DE family; gender; genetic counseling; Marfan syndrome; prenatal diagnosis; quality of life; reproduction; sex drive ID PREIMPLANTATION GENETIC DIAGNOSIS; PRENATAL-DIAGNOSIS; DECISION-MAKING; FBN1 MUTATIONS; YOUNG-ADULTS; OF-LIFE; DISORDERS; ATTITUDES; PREGNANCY; ABORTION AB As individuals with Marfan syndrome are increasingly diagnosed earlier in life and prior to life-threatening cardiovascular events, there is opportunity to study factors that influence their reproductive planning and quality of life. In this study of 174 affected adults, the overall quality of life was reported to be adequate, although it was significantly decreased within the spiritual/psychological domain. Approximately 62% agreed that having Marfan syndrome significantly affected their reproductive decision-making. This view was correlated with age of diagnosis, mitral valve prolapse, and the view that Marfan syndrome has adverse consequences on life. Sixty-nine percent reported personal interest in prenatal testing for Marfan syndrome. Respondents most commonly cited increased worries about personal health and the recurrence risk as ways that Marfan syndrome affects their reproductive decisions. Age, striae, back pain, and low quality of life were each independently correlated with lack of sex drive. These results affirm the importance of both clinical and psychosocial issues on affected adults' reproductive decision-making and sexual well-being. Genetic professionals are ideally positioned to discuss concerns about quality of life and reproduction with patients with Marfan syndrome and refer those with significant concerns for further evaluation and management. C1 Penn State Univ, Ctr Dev & Hlth Genet, Dept Med, University Pk, PA 16802 USA. Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. Univ Cape Town, Dept Stat, ZA-7925 Cape Town, South Africa. RP Peters, KF (reprint author), Penn State Univ, Ctr Dev & Hlth Genet, Dept Med, 101 Amy Gardner House, University Pk, PA 16802 USA. NR 66 TC 28 Z9 29 U1 1 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD AUG PY 2002 VL 62 IS 2 BP 110 EP 120 DI 10.1034/j.1399-0004.2002.620203.x PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 585KV UT WOS:000177524700009 PM 12220448 ER PT J AU Gandhi, M Bacchetti, P Miotti, P Quinn, TC Veronese, F Greenblatt, RM AF Gandhi, M Bacchetti, P Miotti, P Quinn, TC Veronese, F Greenblatt, RM TI Does patient sex affect human immunodeficiency virus levels? SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID HIV-1 RNA LEVELS; HEPATITIS-C-VIRUS; PLASMA VIRAL LOAD; CHLAMYDIA-TRACHOMATIS INFECTION; MONONUCLEAR CELL COCULTURES; FEMALE REPRODUCTIVE-TRACT; INHIBIN-B LEVELS; TYPE-1 RNA; GENDER DIFFERENCES; PERIPHERAL-BLOOD AB We undertook a critical epidemiological review of the available evidence concerning whether women have lower levels of human immunodeficiency virus (HIV) RNA than do men at similar stages of HIV infection. The 13 studies included in this analysis reported viral load measurements in HIV-infected men and women at a single point in time (cross-sectional studies) or over time (longitudinal studies). Seven of the 9 cross-sectional studies demonstrated that women had 0.13-0.35 log(10) (similar to2-fold) lower levels of HIV RNA than do men, despite controlling for CD4(+) cell count. Four longitudinal studies revealed that women had 0.33-0.78 log(10) (2- to 6-fold) lower levels of HIV RNA than do men, even when controlling for time since seroconversion. Adjustment for possible confounders of the relationship between sex and viral load, including age, race, mode of virus transmission, and antiretroviral therapy use, did not change this outcome. This finding is significant, because viral loads are frequently used to guide the initiation and modification of antiretroviral therapy. C1 Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. NIH, Off AIDS Res, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Gandhi, M (reprint author), Univ Calif San Francisco, Dept Med, Div Infect Dis, Box 1352, San Francisco, CA 94143 USA. NR 97 TC 83 Z9 85 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2002 VL 35 IS 3 BP 313 EP 322 DI 10.1086/341249 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 573QA UT WOS:000176841300015 PM 12115098 ER EF